Susan London

SAN FRANCISCO – Serial administration of two vaccines that stimulate the immune response to pancreatic cancer antigens prolonged survival of metastatic disease by about 2 months, according to Dr. Dung T. Le.

A team led by Dr. Le of the Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center in Baltimore tested the vaccines – GVAX Pancreas and CRS-207 – in 90 patients.

The interim results of the phase II trial showed that overall survival was about 4 months with GVAX alone but was 6 months with GVAX followed by CRS-207, Dr. Le reported in a press briefing held before the annual Gastrointestinal Cancers Symposium. The symposium was sponsored by the American Society of Clinical Oncology.

In fact, the efficacy data met the criteria for an early halt to the trial, and patients in the single-vaccine arm are now receiving both vaccines.

"This is the first randomized study of immunotherapy in metastatic pancreatic cancer demonstrating an improvement in survival," commented press briefing moderator Dr. Smitha Krishnamurthi of Case Western Reserve University in Cleveland. "Patients who received at least one dose of the CRS-207 vaccine had a doubling of 1-year survival, and this was accomplished without the side effects of chemotherapy."

Safety results suggested that the vaccines were well tolerated. Local reactions of erythema, warmth, and swelling after intradermal administration of GVAX, as well as transient fevers and chills after infusion of CRS-207, were generally mild and transient.

"Additional clinical study of the combination treatment is underway in a three-arm study testing the combination, CRS-207 alone, and chemotherapy alone," Dr. Le noted.

GVAX is an allogeneic whole-cell vaccine. Its genetically modified pancreatic cancer cells secrete granulocyte macrophage colony-stimulating factor, which attracts dendritic cells to the vaccine site, Dr. Le explained. It is given after low-dose cyclophosphamide to inhibit a regulatory T-cell response.

CRS-207 consists of live-attenuated Listeria monocytogenes virus vaccine that expresses mesothelin. The vaccine stimulates innate and adaptive immunity to mesothelin, which is highly expressed in pancreatic cancer cells.

The investigators tested the vaccines serially in part because GVAX induces a response to a wide variety of tumor-associated antigens, and CRS-207 then boosts the response to mesothelin.

Patients in the trial, sponsored by Aduro BioTech, had declined or had experienced a failure of prior chemotherapy.

They were randomized 2:1 to receive either two doses of GVAX followed by four doses of CRS-207 or to receive six doses of GVAX therapy alone, with all doses spaced 3 weeks apart. Repeated courses were allowed as long as patients were medically stable.

With a median follow-up of 7.8 months, median overall survival among all patients who received at least one dose of vaccine was longer by nearly 2 months with dual-vaccine therapy compared with single-vaccine therapy (6.1 vs. 3.9 months; hazard ratio 0.59; P = .03).

The 1-year probability of survival was doubled with dual versus single therapy (24% vs. 12%), according to Dr. Le.

In a per-protocol analysis restricted to patients who received at least three doses of vaccine, dual therapy had a greater 5-month overall survival benefit (9.7 vs. 4.6 months; hazard ratio 0.53; P = .03).

Dr. Le disclosed no relevant financial conflicts.

SAN FRANCISCO – Serial administration of two vaccines that stimulate the immune response to pancreatic cancer antigens prolonged survival of metastatic disease by about 2 months, according to Dr. Dung T. Le.

A team led by Dr. Le of the Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center in Baltimore tested the vaccines – GVAX Pancreas and CRS-207 – in 90 patients.

The interim results of the phase II trial showed that overall survival was about 4 months with GVAX alone but was 6 months with GVAX followed by CRS-207, Dr. Le reported in a press briefing held before the annual Gastrointestinal Cancers Symposium. The symposium was sponsored by the American Society of Clinical Oncology.

In fact, the efficacy data met the criteria for an early halt to the trial, and patients in the single-vaccine arm are now receiving both vaccines.

"This is the first randomized study of immunotherapy in metastatic pancreatic cancer demonstrating an improvement in survival," commented press briefing moderator Dr. Smitha Krishnamurthi of Case Western Reserve University in Cleveland. "Patients who received at least one dose of the CRS-207 vaccine had a doubling of 1-year survival, and this was accomplished without the side effects of chemotherapy."

Safety results suggested that the vaccines were well tolerated. Local reactions of erythema, warmth, and swelling after intradermal administration of GVAX, as well as transient fevers and chills after infusion of CRS-207, were generally mild and transient.

"Additional clinical study of the combination treatment is underway in a three-arm study testing the combination, CRS-207 alone, and chemotherapy alone," Dr. Le noted.

GVAX is an allogeneic whole-cell vaccine. Its genetically modified pancreatic cancer cells secrete granulocyte macrophage colony-stimulating factor, which attracts dendritic cells to the vaccine site, Dr. Le explained. It is given after low-dose cyclophosphamide to inhibit a regulatory T-cell response.

CRS-207 consists of live-attenuated Listeria monocytogenes virus vaccine that expresses mesothelin. The vaccine stimulates innate and adaptive immunity to mesothelin, which is highly expressed in pancreatic cancer cells.

The investigators tested the vaccines serially in part because GVAX induces a response to a wide variety of tumor-associated antigens, and CRS-207 then boosts the response to mesothelin.

Patients in the trial, sponsored by Aduro BioTech, had declined or had experienced a failure of prior chemotherapy.

They were randomized 2:1 to receive either two doses of GVAX followed by four doses of CRS-207 or to receive six doses of GVAX therapy alone, with all doses spaced 3 weeks apart. Repeated courses were allowed as long as patients were medically stable.

With a median follow-up of 7.8 months, median overall survival among all patients who received at least one dose of vaccine was longer by nearly 2 months with dual-vaccine therapy compared with single-vaccine therapy (6.1 vs. 3.9 months; hazard ratio 0.59; P = .03).

The 1-year probability of survival was doubled with dual versus single therapy (24% vs. 12%), according to Dr. Le.

In a per-protocol analysis restricted to patients who received at least three doses of vaccine, dual therapy had a greater 5-month overall survival benefit (9.7 vs. 4.6 months; hazard ratio 0.53; P = .03).

Dr. Le disclosed no relevant financial conflicts.

SAN FRANCISCO – Serial administration of two vaccines that stimulate the immune response to pancreatic cancer antigens prolonged survival of metastatic disease by about 2 months, according to Dr. Dung T. Le.

A team led by Dr. Le of the Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center in Baltimore tested the vaccines – GVAX Pancreas and CRS-207 – in 90 patients.

The interim results of the phase II trial showed that overall survival was about 4 months with GVAX alone but was 6 months with GVAX followed by CRS-207, Dr. Le reported in a press briefing held before the annual Gastrointestinal Cancers Symposium. The symposium was sponsored by the American Society of Clinical Oncology.

In fact, the efficacy data met the criteria for an early halt to the trial, and patients in the single-vaccine arm are now receiving both vaccines.

"This is the first randomized study of immunotherapy in metastatic pancreatic cancer demonstrating an improvement in survival," commented press briefing moderator Dr. Smitha Krishnamurthi of Case Western Reserve University in Cleveland. "Patients who received at least one dose of the CRS-207 vaccine had a doubling of 1-year survival, and this was accomplished without the side effects of chemotherapy."

Safety results suggested that the vaccines were well tolerated. Local reactions of erythema, warmth, and swelling after intradermal administration of GVAX, as well as transient fevers and chills after infusion of CRS-207, were generally mild and transient.

"Additional clinical study of the combination treatment is underway in a three-arm study testing the combination, CRS-207 alone, and chemotherapy alone," Dr. Le noted.

GVAX is an allogeneic whole-cell vaccine. Its genetically modified pancreatic cancer cells secrete granulocyte macrophage colony-stimulating factor, which attracts dendritic cells to the vaccine site, Dr. Le explained. It is given after low-dose cyclophosphamide to inhibit a regulatory T-cell response.

CRS-207 consists of live-attenuated Listeria monocytogenes virus vaccine that expresses mesothelin. The vaccine stimulates innate and adaptive immunity to mesothelin, which is highly expressed in pancreatic cancer cells.

The investigators tested the vaccines serially in part because GVAX induces a response to a wide variety of tumor-associated antigens, and CRS-207 then boosts the response to mesothelin.

Patients in the trial, sponsored by Aduro BioTech, had declined or had experienced a failure of prior chemotherapy.

They were randomized 2:1 to receive either two doses of GVAX followed by four doses of CRS-207 or to receive six doses of GVAX therapy alone, with all doses spaced 3 weeks apart. Repeated courses were allowed as long as patients were medically stable.

With a median follow-up of 7.8 months, median overall survival among all patients who received at least one dose of vaccine was longer by nearly 2 months with dual-vaccine therapy compared with single-vaccine therapy (6.1 vs. 3.9 months; hazard ratio 0.59; P = .03).

The 1-year probability of survival was doubled with dual versus single therapy (24% vs. 12%), according to Dr. Le.

In a per-protocol analysis restricted to patients who received at least three doses of vaccine, dual therapy had a greater 5-month overall survival benefit (9.7 vs. 4.6 months; hazard ratio 0.53; P = .03).

Dr. Le disclosed no relevant financial conflicts.

SAN FRANCISCO – Patients with metastatic colorectal cancer should be broadly tested for RAS mutations before being treated with panitumumab, according to new data from a phase III trial.

"Patients with tumors mutated in the RAS genes are unlikely to benefit from the addition of panitumumab to FOLFIRI, similar to what was seen in the patients with only a KRAS exon 2 mutation," study investigator Dr. Marc Peeters said in a press briefing.

The investigators performed genetic testing of 597 patients who had participated in an Amgen-sponsored second-line trial and whose tumors were wild type (negative) for KRAS exon 2 mutations – about 55% of the entire trial population, he reported at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

Almost one-fifth of the patients were found to have tumor mutations in other KRAS exons or in NRAS exons, noted Dr. Peeters, professor of oncology at Antwerp University Hospital in Edegem, Belgium.

<pamong>

The trial randomized patients to FOLFIRI alone or in combination with panitumumab (Vectibix). Vectibix is manufactured by Amgen and approved by the Food and Drug Administration for the treatment of progressive EGFR-expressing metastatic colorectal cancer.

The investigators tested the banked tumor samples for other RAS mutations – specifically mutations in KRAS exons 3 and 4 and NRAS exons 2, 3, and 4.

Results showed that adding panitumumab improved the response rate among all patients whose tumors were wild type at KRAS exon 2, compared with FOLFIRI therapy alone (35% vs. 10%, respectively). Adding panitumumab to FOLFIRI therapy in patients whose tumors were also wild type for all of the RAS mutations, compared with FOLFIRI therapy alone, garnered an even higher response rate (41% vs. 10%), Dr. Peeters reported.

Also, the previously reported lack of panitumumab efficacy on response among patients whose tumors harbored KRAS exon 2 mutations, compared with those who did not harbor the mutation (13% vs. 14%), was also evident in those whose tumors harbored mutations in any of the other RAS mutations assessed, compared those who did nor harbor the mutation (15% vs. 13%), he said.

Panitumumab had a progression-free survival benefit among all patients whose tumors were wild type for KRAS exon 2 (median, 5.9 vs. 3.9 months; hazard ratio, 0.73; P = .004), but benefit was greater among those whose tumors were also wild type for all of the RAS mutations (median, 6.4 vs. 4.4 months; HR, 0.69; P = .006).

The addition of panitumumab did not significantly improve overall survival among patients whose tumors were wild type for KRAS exon 2, but there was a trend toward improvement among patients whose tumors were also wild type for all of the other RAS mutations (median, 16.2 vs. 13.9 months; HR, 0.80; P = .077).

"These results clearly support the fact that we need RAS testing when we want to treat our patients with panitumumab in the setting of metastatic colorectal cancer," said Dr. Peeters.

The trial’s findings were similar to those of PRIME (Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy), noted press briefing moderator Dr. Smitha Krishnamurthi, associate professor at Case Western Reserve University in Cleveland.

PRIME tested the addition of panitumumab to FOLFOX in the first-line setting, and recent analyses showed that RAS mutations were a negative predictor of panitumumab benefit (N. Engl. J. Med. 2013;369:1023-34).

"These results [presented by Dr. Peeters], as well as those from the PRIME and FIRE trials ... indicate that expanded RAS testing should become the standard of care in order to best identify patients who will benefit from anti-EGFR therapy," Dr. Krishnamurthi noted.

The current trial was sponsored by Amgen. Dr. Peeters disclosed that he is a consultant/advisor to and receives honoraria and research funding from Amgen. Dr. Krishnamurthi did not report having any conflicts of interest.

This article was updated 1/27/2014.

</pamong>

SAN FRANCISCO – Patients with metastatic colorectal cancer should be broadly tested for RAS mutations before being treated with panitumumab, according to new data from a phase III trial.

"Patients with tumors mutated in the RAS genes are unlikely to benefit from the addition of panitumumab to FOLFIRI, similar to what was seen in the patients with only a KRAS exon 2 mutation," study investigator Dr. Marc Peeters said in a press briefing.

The investigators performed genetic testing of 597 patients who had participated in an Amgen-sponsored second-line trial and whose tumors were wild type (negative) for KRAS exon 2 mutations – about 55% of the entire trial population, he reported at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

Almost one-fifth of the patients were found to have tumor mutations in other KRAS exons or in NRAS exons, noted Dr. Peeters, professor of oncology at Antwerp University Hospital in Edegem, Belgium.

<pamong>

The trial randomized patients to FOLFIRI alone or in combination with panitumumab (Vectibix). Vectibix is manufactured by Amgen and approved by the Food and Drug Administration for the treatment of progressive EGFR-expressing metastatic colorectal cancer.

The investigators tested the banked tumor samples for other RAS mutations – specifically mutations in KRAS exons 3 and 4 and NRAS exons 2, 3, and 4.

Results showed that adding panitumumab improved the response rate among all patients whose tumors were wild type at KRAS exon 2, compared with FOLFIRI therapy alone (35% vs. 10%, respectively). Adding panitumumab to FOLFIRI therapy in patients whose tumors were also wild type for all of the RAS mutations, compared with FOLFIRI therapy alone, garnered an even higher response rate (41% vs. 10%), Dr. Peeters reported.

Also, the previously reported lack of panitumumab efficacy on response among patients whose tumors harbored KRAS exon 2 mutations, compared with those who did not harbor the mutation (13% vs. 14%), was also evident in those whose tumors harbored mutations in any of the other RAS mutations assessed, compared those who did nor harbor the mutation (15% vs. 13%), he said.

Panitumumab had a progression-free survival benefit among all patients whose tumors were wild type for KRAS exon 2 (median, 5.9 vs. 3.9 months; hazard ratio, 0.73; P = .004), but benefit was greater among those whose tumors were also wild type for all of the RAS mutations (median, 6.4 vs. 4.4 months; HR, 0.69; P = .006).

The addition of panitumumab did not significantly improve overall survival among patients whose tumors were wild type for KRAS exon 2, but there was a trend toward improvement among patients whose tumors were also wild type for all of the other RAS mutations (median, 16.2 vs. 13.9 months; HR, 0.80; P = .077).

"These results clearly support the fact that we need RAS testing when we want to treat our patients with panitumumab in the setting of metastatic colorectal cancer," said Dr. Peeters.

The trial’s findings were similar to those of PRIME (Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy), noted press briefing moderator Dr. Smitha Krishnamurthi, associate professor at Case Western Reserve University in Cleveland.

PRIME tested the addition of panitumumab to FOLFOX in the first-line setting, and recent analyses showed that RAS mutations were a negative predictor of panitumumab benefit (N. Engl. J. Med. 2013;369:1023-34).

"These results [presented by Dr. Peeters], as well as those from the PRIME and FIRE trials ... indicate that expanded RAS testing should become the standard of care in order to best identify patients who will benefit from anti-EGFR therapy," Dr. Krishnamurthi noted.

The current trial was sponsored by Amgen. Dr. Peeters disclosed that he is a consultant/advisor to and receives honoraria and research funding from Amgen. Dr. Krishnamurthi did not report having any conflicts of interest.

This article was updated 1/27/2014.

</pamong>

SAN FRANCISCO – Patients with metastatic colorectal cancer should be broadly tested for RAS mutations before being treated with panitumumab, according to new data from a phase III trial.

"Patients with tumors mutated in the RAS genes are unlikely to benefit from the addition of panitumumab to FOLFIRI, similar to what was seen in the patients with only a KRAS exon 2 mutation," study investigator Dr. Marc Peeters said in a press briefing.

The investigators performed genetic testing of 597 patients who had participated in an Amgen-sponsored second-line trial and whose tumors were wild type (negative) for KRAS exon 2 mutations – about 55% of the entire trial population, he reported at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

Almost one-fifth of the patients were found to have tumor mutations in other KRAS exons or in NRAS exons, noted Dr. Peeters, professor of oncology at Antwerp University Hospital in Edegem, Belgium.

<pamong>

The trial randomized patients to FOLFIRI alone or in combination with panitumumab (Vectibix). Vectibix is manufactured by Amgen and approved by the Food and Drug Administration for the treatment of progressive EGFR-expressing metastatic colorectal cancer.

The investigators tested the banked tumor samples for other RAS mutations – specifically mutations in KRAS exons 3 and 4 and NRAS exons 2, 3, and 4.

Results showed that adding panitumumab improved the response rate among all patients whose tumors were wild type at KRAS exon 2, compared with FOLFIRI therapy alone (35% vs. 10%, respectively). Adding panitumumab to FOLFIRI therapy in patients whose tumors were also wild type for all of the RAS mutations, compared with FOLFIRI therapy alone, garnered an even higher response rate (41% vs. 10%), Dr. Peeters reported.

Also, the previously reported lack of panitumumab efficacy on response among patients whose tumors harbored KRAS exon 2 mutations, compared with those who did not harbor the mutation (13% vs. 14%), was also evident in those whose tumors harbored mutations in any of the other RAS mutations assessed, compared those who did nor harbor the mutation (15% vs. 13%), he said.

Panitumumab had a progression-free survival benefit among all patients whose tumors were wild type for KRAS exon 2 (median, 5.9 vs. 3.9 months; hazard ratio, 0.73; P = .004), but benefit was greater among those whose tumors were also wild type for all of the RAS mutations (median, 6.4 vs. 4.4 months; HR, 0.69; P = .006).

The addition of panitumumab did not significantly improve overall survival among patients whose tumors were wild type for KRAS exon 2, but there was a trend toward improvement among patients whose tumors were also wild type for all of the other RAS mutations (median, 16.2 vs. 13.9 months; HR, 0.80; P = .077).

"These results clearly support the fact that we need RAS testing when we want to treat our patients with panitumumab in the setting of metastatic colorectal cancer," said Dr. Peeters.

The trial’s findings were similar to those of PRIME (Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy), noted press briefing moderator Dr. Smitha Krishnamurthi, associate professor at Case Western Reserve University in Cleveland.

PRIME tested the addition of panitumumab to FOLFOX in the first-line setting, and recent analyses showed that RAS mutations were a negative predictor of panitumumab benefit (N. Engl. J. Med. 2013;369:1023-34).

"These results [presented by Dr. Peeters], as well as those from the PRIME and FIRE trials ... indicate that expanded RAS testing should become the standard of care in order to best identify patients who will benefit from anti-EGFR therapy," Dr. Krishnamurthi noted.

The current trial was sponsored by Amgen. Dr. Peeters disclosed that he is a consultant/advisor to and receives honoraria and research funding from Amgen. Dr. Krishnamurthi did not report having any conflicts of interest.

This article was updated 1/27/2014.

</pamong>

Ramucirumab is likely to expand the treatment options for advanced gastric adenocarcinoma, given new data from a randomized phase III trial being reported at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

The 665 patients in the trial, known as RAINBOW (Ramucirumab in Metastatic Gastric Adenocarcinoma), were treated in the second-line setting with paclitaxel plus either placebo or ramucirumab, an investigational targeted anti-angiogenic agent.

The main results showed that compared with adding placebo, adding ramucirumab prolonged overall survival, the trial’s primary endpoint, by more than 2 months, first author Dr. Hansjochen Wilke, director of the department of oncology, hematology, and center of palliative care at Kliniken Essen-Mitte, Germany, reported during a presscast in advance of the meeting.

Furthermore, the ramucirumab-chemotherapy combination was associated with better response rates and progression-free survival.

Certain grade 3 or worse adverse events, such as hypertension, were more common with ramucirumab, but these events were manageable.

"The results of the RAINBOW trial and the recently published REGARD [Ramucirumab Monotherapy for Previously Treated Advanced Gastric or Gastro-esophageal Junction Adenocarcinoma] trial" (Lancet 2014;383:31-9) – which showed the benefit of this agent when added to best supportive care, also in the second line – "clearly demonstrate that ramucirumab is an effective new drug for the treatment of patients with metastatic or locally advanced unresectable gastric cancer if they have failed prior first-line platinum- and 5-FU-based combination chemotherapy," he commented.

"This largest gastric cancer second-line trial clearly demonstrates that an effective second-line therapy improves survival in patients with metastatic and far-advanced gastric cancer, and we expect that these results and other recently published randomized trial data will lead to a situation in which more patients will now be routinely treated in the second-line treatment situation if they are fit for such treatment," he added.

In fact, the Food and Drug Administration (FDA) last year assigned ramucirumab a priority review designation as a second-line treatment for advanced gastric cancer, and is expected to release its decision sometime in 2014.

Press briefing moderator Dr. Smitha Krishnamurthi, an associate professor at Case Western Reserve University, Cleveland, noted that expanding treatment options for advanced gastric cancer remains important in the United States, even though this cancer’s incidence is low compared with that worldwide.

"We do have patients with gastric cancer here, and it is a poor-prognosis cancer in the United States, as it is throughout the world," she elaborated. "So we are excited to have what appears to be an active drug for the second-line setting that can be used instead of best supportive care, or in addition to chemotherapy for patients who can tolerate chemotherapy. We are anxiously awaiting word from the FDA about approval of ramucirumab, which is expected later this year."

Patients were eligible for the global RAINBOW trial if they had experienced progression of metastatic or unresectable locally advanced gastric or gastroesophageal junction adenocarcinoma on first-line platinum- and fluoropyrimidine-containing combination therapy. They were randomized evenly to double-blind treatment with paclitaxel plus either placebo or ramucirumab (manufactured by Eli Lilly), a monoclonal antibody to vascular endothelial growth factor receptor 2 (VEGFR-2).

Relative to placebo, ramucirumab prolonged median overall survival (9.63 vs. 7.36 months; hazard ratio, 0.81; P = .017), Dr. Wilke reported.

"This difference of 2.3 months is an astonishingly good result in such a challenging patient population. This difference was not only statistically significant but also clinically meaningful," he commented.

Ramucirumab also prolonged progression-free survival (4.40 vs. 2.86 months; HR, 0.64; P < .0001) and nearly doubled the response rate (28% vs. 16%, P = .0001).

Tumor samples are being analyzed to identify biomarkers predicting a great likelihood of benefiting from ramucirumab, according to the investigators.

Relative to placebo, ramucirumab led to higher rates of certain grade 3 or worse adverse events, such as hypertension (15% vs. 3%), bleeding/hemorrhage (4% vs. 2%), proteinuria (1.2% vs. 0%), and gastrointestinal perforation (1.2% vs. 0%). None of the cases of hypertension or proteinuria were of grade 4 or worse.

The rate of neutropenia was also sharply higher with ramucirumab than with placebo (41% vs. 19%), but the rate of febrile neutropenia was similar.

Overall, these adverse events were generally manageable and seldom led to trial discontinuation, according to Dr. Wilke.

Dr. Wilke disclosed that he receives honoraria from Eli Lilly. The trial was sponsored by Eli Lilly.

Ramucirumab is likely to expand the treatment options for advanced gastric adenocarcinoma, given new data from a randomized phase III trial being reported at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

The 665 patients in the trial, known as RAINBOW (Ramucirumab in Metastatic Gastric Adenocarcinoma), were treated in the second-line setting with paclitaxel plus either placebo or ramucirumab, an investigational targeted anti-angiogenic agent.

The main results showed that compared with adding placebo, adding ramucirumab prolonged overall survival, the trial’s primary endpoint, by more than 2 months, first author Dr. Hansjochen Wilke, director of the department of oncology, hematology, and center of palliative care at Kliniken Essen-Mitte, Germany, reported during a presscast in advance of the meeting.

Furthermore, the ramucirumab-chemotherapy combination was associated with better response rates and progression-free survival.

Certain grade 3 or worse adverse events, such as hypertension, were more common with ramucirumab, but these events were manageable.

"The results of the RAINBOW trial and the recently published REGARD [Ramucirumab Monotherapy for Previously Treated Advanced Gastric or Gastro-esophageal Junction Adenocarcinoma] trial" (Lancet 2014;383:31-9) – which showed the benefit of this agent when added to best supportive care, also in the second line – "clearly demonstrate that ramucirumab is an effective new drug for the treatment of patients with metastatic or locally advanced unresectable gastric cancer if they have failed prior first-line platinum- and 5-FU-based combination chemotherapy," he commented.

"This largest gastric cancer second-line trial clearly demonstrates that an effective second-line therapy improves survival in patients with metastatic and far-advanced gastric cancer, and we expect that these results and other recently published randomized trial data will lead to a situation in which more patients will now be routinely treated in the second-line treatment situation if they are fit for such treatment," he added.

In fact, the Food and Drug Administration (FDA) last year assigned ramucirumab a priority review designation as a second-line treatment for advanced gastric cancer, and is expected to release its decision sometime in 2014.

Press briefing moderator Dr. Smitha Krishnamurthi, an associate professor at Case Western Reserve University, Cleveland, noted that expanding treatment options for advanced gastric cancer remains important in the United States, even though this cancer’s incidence is low compared with that worldwide.

"We do have patients with gastric cancer here, and it is a poor-prognosis cancer in the United States, as it is throughout the world," she elaborated. "So we are excited to have what appears to be an active drug for the second-line setting that can be used instead of best supportive care, or in addition to chemotherapy for patients who can tolerate chemotherapy. We are anxiously awaiting word from the FDA about approval of ramucirumab, which is expected later this year."

Patients were eligible for the global RAINBOW trial if they had experienced progression of metastatic or unresectable locally advanced gastric or gastroesophageal junction adenocarcinoma on first-line platinum- and fluoropyrimidine-containing combination therapy. They were randomized evenly to double-blind treatment with paclitaxel plus either placebo or ramucirumab (manufactured by Eli Lilly), a monoclonal antibody to vascular endothelial growth factor receptor 2 (VEGFR-2).

Relative to placebo, ramucirumab prolonged median overall survival (9.63 vs. 7.36 months; hazard ratio, 0.81; P = .017), Dr. Wilke reported.

"This difference of 2.3 months is an astonishingly good result in such a challenging patient population. This difference was not only statistically significant but also clinically meaningful," he commented.

Ramucirumab also prolonged progression-free survival (4.40 vs. 2.86 months; HR, 0.64; P < .0001) and nearly doubled the response rate (28% vs. 16%, P = .0001).

Tumor samples are being analyzed to identify biomarkers predicting a great likelihood of benefiting from ramucirumab, according to the investigators.

Relative to placebo, ramucirumab led to higher rates of certain grade 3 or worse adverse events, such as hypertension (15% vs. 3%), bleeding/hemorrhage (4% vs. 2%), proteinuria (1.2% vs. 0%), and gastrointestinal perforation (1.2% vs. 0%). None of the cases of hypertension or proteinuria were of grade 4 or worse.

The rate of neutropenia was also sharply higher with ramucirumab than with placebo (41% vs. 19%), but the rate of febrile neutropenia was similar.

Overall, these adverse events were generally manageable and seldom led to trial discontinuation, according to Dr. Wilke.

Dr. Wilke disclosed that he receives honoraria from Eli Lilly. The trial was sponsored by Eli Lilly.

Ramucirumab is likely to expand the treatment options for advanced gastric adenocarcinoma, given new data from a randomized phase III trial being reported at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

The 665 patients in the trial, known as RAINBOW (Ramucirumab in Metastatic Gastric Adenocarcinoma), were treated in the second-line setting with paclitaxel plus either placebo or ramucirumab, an investigational targeted anti-angiogenic agent.

The main results showed that compared with adding placebo, adding ramucirumab prolonged overall survival, the trial’s primary endpoint, by more than 2 months, first author Dr. Hansjochen Wilke, director of the department of oncology, hematology, and center of palliative care at Kliniken Essen-Mitte, Germany, reported during a presscast in advance of the meeting.

Furthermore, the ramucirumab-chemotherapy combination was associated with better response rates and progression-free survival.

Certain grade 3 or worse adverse events, such as hypertension, were more common with ramucirumab, but these events were manageable.

"The results of the RAINBOW trial and the recently published REGARD [Ramucirumab Monotherapy for Previously Treated Advanced Gastric or Gastro-esophageal Junction Adenocarcinoma] trial" (Lancet 2014;383:31-9) – which showed the benefit of this agent when added to best supportive care, also in the second line – "clearly demonstrate that ramucirumab is an effective new drug for the treatment of patients with metastatic or locally advanced unresectable gastric cancer if they have failed prior first-line platinum- and 5-FU-based combination chemotherapy," he commented.

"This largest gastric cancer second-line trial clearly demonstrates that an effective second-line therapy improves survival in patients with metastatic and far-advanced gastric cancer, and we expect that these results and other recently published randomized trial data will lead to a situation in which more patients will now be routinely treated in the second-line treatment situation if they are fit for such treatment," he added.

In fact, the Food and Drug Administration (FDA) last year assigned ramucirumab a priority review designation as a second-line treatment for advanced gastric cancer, and is expected to release its decision sometime in 2014.

Press briefing moderator Dr. Smitha Krishnamurthi, an associate professor at Case Western Reserve University, Cleveland, noted that expanding treatment options for advanced gastric cancer remains important in the United States, even though this cancer’s incidence is low compared with that worldwide.

"We do have patients with gastric cancer here, and it is a poor-prognosis cancer in the United States, as it is throughout the world," she elaborated. "So we are excited to have what appears to be an active drug for the second-line setting that can be used instead of best supportive care, or in addition to chemotherapy for patients who can tolerate chemotherapy. We are anxiously awaiting word from the FDA about approval of ramucirumab, which is expected later this year."

Patients were eligible for the global RAINBOW trial if they had experienced progression of metastatic or unresectable locally advanced gastric or gastroesophageal junction adenocarcinoma on first-line platinum- and fluoropyrimidine-containing combination therapy. They were randomized evenly to double-blind treatment with paclitaxel plus either placebo or ramucirumab (manufactured by Eli Lilly), a monoclonal antibody to vascular endothelial growth factor receptor 2 (VEGFR-2).

Relative to placebo, ramucirumab prolonged median overall survival (9.63 vs. 7.36 months; hazard ratio, 0.81; P = .017), Dr. Wilke reported.

"This difference of 2.3 months is an astonishingly good result in such a challenging patient population. This difference was not only statistically significant but also clinically meaningful," he commented.

Ramucirumab also prolonged progression-free survival (4.40 vs. 2.86 months; HR, 0.64; P < .0001) and nearly doubled the response rate (28% vs. 16%, P = .0001).

Tumor samples are being analyzed to identify biomarkers predicting a great likelihood of benefiting from ramucirumab, according to the investigators.

Relative to placebo, ramucirumab led to higher rates of certain grade 3 or worse adverse events, such as hypertension (15% vs. 3%), bleeding/hemorrhage (4% vs. 2%), proteinuria (1.2% vs. 0%), and gastrointestinal perforation (1.2% vs. 0%). None of the cases of hypertension or proteinuria were of grade 4 or worse.

The rate of neutropenia was also sharply higher with ramucirumab than with placebo (41% vs. 19%), but the rate of febrile neutropenia was similar.

Overall, these adverse events were generally manageable and seldom led to trial discontinuation, according to Dr. Wilke.

Dr. Wilke disclosed that he receives honoraria from Eli Lilly. The trial was sponsored by Eli Lilly.

SAN ANTONIO – Surgical removal of the primary tumor and affected lymph nodes afforded no overall survival benefit in women who had metastatic breast cancer at initial presentation, according to a pair of randomized trials presented at the San Antonio Breast Cancer Symposium.

In a first trial, conducted among 350 women in India who had responded to initial chemotherapy, about 20% of the women were still alive at 5 years regardless of whether they had surgery or just received more systemic therapy, first author Dr. Rajendra Badwe, director of the Tata Memorial Hospital in Mumbai, India, reported in a session and at a press briefing.

Superior locoregional control conferred by surgery was canceled out by a higher risk of progression in distant sites, lending support to more than 20-year-old preclinical data by Dr. Bernard Fisher and his colleagues suggesting that an intact primary suppresses growth of distant metastases (Cancer Res. 1989;49:1996-2001).

"Locoregional treatment of the primary tumor in women presenting with metastatic breast cancer did not result in any overall survival benefit and hence should not be offered as a routine practice," Dr. Badwe commented.

"The biological fallout of this study is that surgical removal of the primary tumor in these women appears to confer a growth advantage on distant metastases. ... This is the first time that we have evidence in human studies that locoregional treatment has a great kinetic effect on distant metastases," he added.

In a second trial, conducted among 293 women in Turkey with untreated de novo metastatic breast cancer, median estimated survival was statistically indistinguishable, at about 3.5 years, regardless of whether women had up-front surgery or simply systemic therapy, first author Dr. Atilla Soran reported in a session on behalf of the Turkish Federation of Societies for Breast Diseases.

Subgroup analyses suggested that surgery conferred a survival advantage among women with solitary bone metastases but a survival disadvantage among women with multiple liver or lung metastases.

The rate of locoregional progression was one-fifth as high with surgery as with systemic therapy.

"There was no statistically significant difference in overall survival at early follow-up, but we need longer follow-up," Dr. Soran commented. "There were potentially important subgroup differences."

The two trials have implications – both for other ongoing trials and for patient care – according to invited discussant Dr. Seema A. Khan, a professor of surgery and Bluhm Family Professor of Cancer Research at Northwestern University, Chicago, and a physician at the university’s Lynn Sage Breast Center.

"A large benefit of primary site local therapy seems unlikely based on the data we saw today," she maintained. "The assumptions we have used in our ongoing trial designs will need to be reassessed. Preplanned pooled analyses may yield sufficient power to detect smaller differences."

As for patient care, "it is pretty clear that at this point in time, we have to make sure that our patients understand that there is really no proven survival advantage to primary site local therapy," Dr. Khan said. "So I don’t think this treatment should be offered to patients with asymptomatic tumors unless they are participating in a clinical trial. There may be a local control advantage; we need to see more data on that."

Indian trial

Participants in the Indian trial, conducted between 2005 and 2013, were women with de novo metastatic breast cancer who had had a complete or partial response to anthracycline chemotherapy alone or with a taxane.

They were randomized evenly to receive locoregional therapy (lumpectomy or mastectomy with axillary lymph node dissection, plus radiation therapy to the chest wall or breast and lymph nodes) or no locoregional therapy as a control. Both groups received hormonal therapy if indicated.

In the control group, about 10% of women underwent a palliative mastectomy because of impending fungation or pain in the breast, as permitted by study protocol, according to Dr. Badwe.

The patients thus received contemporary therapy, he said, except that the 16% with HER2-positive disease did not receive the targeted agent trastuzumab (Herceptin).

Results showed that median overall survival was about 18 months, and the 5-year rate was 19.2% with locoregional therapy and 20.5% without it, a nonsignificant difference. "Uniformly, there was no difference at all in any subsets," Dr. Badwe reported.

The study had a one-sided superiority design, he noted. "We wouldn’t have been able to see a 2.5- or 3-month difference, or a 4% detriment" in overall survival.

The surgery group had a lower risk of local progression-free survival events (hazard ratio, 0.16; P = .00), but a higher risk of distant progression-free survival events (HR, 1.42; P = .01).

Several theories might explain why removal of the primary would accelerate growth of metastases, according to Dr. Badwe.

"The first and the foremost is that the act of surgery itself might elaborate some growth factors which might allow metastatic disease to grow. The second possibility, which was suggested by Dr. Fisher (Cancer Res. 1989;49:1996-2001) is that the primary tumor, which predates the onset of distant metastases, elaborates some inhibitory factors, and they are not there once the primary tumor is removed, bestowing autonomy of growth on the distant metastases," he explained. "And the third possibility is the act of surgery might induce some more metastatic processes by dissemination and create new disease."

Session attendee Dr. Steven Vogl, an oncologist in the Bronx, N.Y., said, "The ascertainment of disease progression requires disease that you can follow. A woman with bone-only metastases with her cancer in place, you can tell when her cancer is getting worse because the primary site or the axillary nodes are getting bigger. It’s much more difficult if you’ve taken those off and irradiated the chest wall. Have you looked at your data to see if that’s what was going on, why you had more distant metastases, because they couldn’t progress locally? This is a medical trial explanation that contradicts Fisher’s biologic hypothesis."

"There was a fixed time duration at which systemic investigations were performed to assess whether the distant metastases progressed," Dr. Badwe replied. If anything, the patients who did not have surgery had more assessments of their distant metastases, he said.

Dr. Tari A. King, a session attendee from the Memorial Sloan-Kettering Cancer Center, New York, noted that a lack of HER2 therapy in the trial may have had a large effect.

"We do have prospective registry data here [abstract 18-09, presented in a poster session] from a trial that we completed in the United States sponsored by the Translational Breast Cancer Research Consortium, and the patients in our study, whether they received surgery or not, their 2-year overall survival is far superior to what you’ve just showed us," she commented. "So I’m not sure that we can really apply your data to the modern targeted therapy regimens that we see in the United States."

Turkish trial

The Turkish trial, known as the MF07-01 trial, was conduced between 2008 and 2012 among treatment-naïve patients.

They were randomized evenly to receive either systemic therapy alone or surgery for the primary tumor (with or without axillary dissection) followed by radiation therapy if indicated, plus systemic therapy.

All patients received hormonal therapy as needed, and those with HER2-positive disease received trastuzumab.

With a median follow-up of 18 months, the median overall survival was 46 months with initial surgery and 42 months with initial systemic therapy, a nonsignificant difference, reported Dr. Soran, who disclosed no relevant conflicts of interest.

In unplanned subgroup analyses, the findings were similar for most subgroups of patients. However, surgery yielded superior survival in patients with solitary bone metastases (not reached vs. 42 months, P = .02) and inferior survival in patients having multiple liver or pulmonary metastases (16 months vs. not reached, P = .02).

The rate of locoregional progression was much lower with initial surgery than with initial systemic therapy (0.7% vs. 3.6%).

Dr. Soran emphasized that the trial’s planned median follow-up is 36 months, so the presented results are only preliminary. Quality of life and morbidity analyses are ongoing.

Dr. Badwe and Dr. Soran disclosed no relevant conflicts of interest.

SAN ANTONIO – Surgical removal of the primary tumor and affected lymph nodes afforded no overall survival benefit in women who had metastatic breast cancer at initial presentation, according to a pair of randomized trials presented at the San Antonio Breast Cancer Symposium.

In a first trial, conducted among 350 women in India who had responded to initial chemotherapy, about 20% of the women were still alive at 5 years regardless of whether they had surgery or just received more systemic therapy, first author Dr. Rajendra Badwe, director of the Tata Memorial Hospital in Mumbai, India, reported in a session and at a press briefing.

Superior locoregional control conferred by surgery was canceled out by a higher risk of progression in distant sites, lending support to more than 20-year-old preclinical data by Dr. Bernard Fisher and his colleagues suggesting that an intact primary suppresses growth of distant metastases (Cancer Res. 1989;49:1996-2001).

"Locoregional treatment of the primary tumor in women presenting with metastatic breast cancer did not result in any overall survival benefit and hence should not be offered as a routine practice," Dr. Badwe commented.

"The biological fallout of this study is that surgical removal of the primary tumor in these women appears to confer a growth advantage on distant metastases. ... This is the first time that we have evidence in human studies that locoregional treatment has a great kinetic effect on distant metastases," he added.

In a second trial, conducted among 293 women in Turkey with untreated de novo metastatic breast cancer, median estimated survival was statistically indistinguishable, at about 3.5 years, regardless of whether women had up-front surgery or simply systemic therapy, first author Dr. Atilla Soran reported in a session on behalf of the Turkish Federation of Societies for Breast Diseases.

Subgroup analyses suggested that surgery conferred a survival advantage among women with solitary bone metastases but a survival disadvantage among women with multiple liver or lung metastases.

The rate of locoregional progression was one-fifth as high with surgery as with systemic therapy.

"There was no statistically significant difference in overall survival at early follow-up, but we need longer follow-up," Dr. Soran commented. "There were potentially important subgroup differences."

The two trials have implications – both for other ongoing trials and for patient care – according to invited discussant Dr. Seema A. Khan, a professor of surgery and Bluhm Family Professor of Cancer Research at Northwestern University, Chicago, and a physician at the university’s Lynn Sage Breast Center.

"A large benefit of primary site local therapy seems unlikely based on the data we saw today," she maintained. "The assumptions we have used in our ongoing trial designs will need to be reassessed. Preplanned pooled analyses may yield sufficient power to detect smaller differences."

As for patient care, "it is pretty clear that at this point in time, we have to make sure that our patients understand that there is really no proven survival advantage to primary site local therapy," Dr. Khan said. "So I don’t think this treatment should be offered to patients with asymptomatic tumors unless they are participating in a clinical trial. There may be a local control advantage; we need to see more data on that."

Indian trial

Participants in the Indian trial, conducted between 2005 and 2013, were women with de novo metastatic breast cancer who had had a complete or partial response to anthracycline chemotherapy alone or with a taxane.

They were randomized evenly to receive locoregional therapy (lumpectomy or mastectomy with axillary lymph node dissection, plus radiation therapy to the chest wall or breast and lymph nodes) or no locoregional therapy as a control. Both groups received hormonal therapy if indicated.

In the control group, about 10% of women underwent a palliative mastectomy because of impending fungation or pain in the breast, as permitted by study protocol, according to Dr. Badwe.

The patients thus received contemporary therapy, he said, except that the 16% with HER2-positive disease did not receive the targeted agent trastuzumab (Herceptin).

Results showed that median overall survival was about 18 months, and the 5-year rate was 19.2% with locoregional therapy and 20.5% without it, a nonsignificant difference. "Uniformly, there was no difference at all in any subsets," Dr. Badwe reported.

The study had a one-sided superiority design, he noted. "We wouldn’t have been able to see a 2.5- or 3-month difference, or a 4% detriment" in overall survival.

The surgery group had a lower risk of local progression-free survival events (hazard ratio, 0.16; P = .00), but a higher risk of distant progression-free survival events (HR, 1.42; P = .01).

Several theories might explain why removal of the primary would accelerate growth of metastases, according to Dr. Badwe.

"The first and the foremost is that the act of surgery itself might elaborate some growth factors which might allow metastatic disease to grow. The second possibility, which was suggested by Dr. Fisher (Cancer Res. 1989;49:1996-2001) is that the primary tumor, which predates the onset of distant metastases, elaborates some inhibitory factors, and they are not there once the primary tumor is removed, bestowing autonomy of growth on the distant metastases," he explained. "And the third possibility is the act of surgery might induce some more metastatic processes by dissemination and create new disease."

Session attendee Dr. Steven Vogl, an oncologist in the Bronx, N.Y., said, "The ascertainment of disease progression requires disease that you can follow. A woman with bone-only metastases with her cancer in place, you can tell when her cancer is getting worse because the primary site or the axillary nodes are getting bigger. It’s much more difficult if you’ve taken those off and irradiated the chest wall. Have you looked at your data to see if that’s what was going on, why you had more distant metastases, because they couldn’t progress locally? This is a medical trial explanation that contradicts Fisher’s biologic hypothesis."

"There was a fixed time duration at which systemic investigations were performed to assess whether the distant metastases progressed," Dr. Badwe replied. If anything, the patients who did not have surgery had more assessments of their distant metastases, he said.

Dr. Tari A. King, a session attendee from the Memorial Sloan-Kettering Cancer Center, New York, noted that a lack of HER2 therapy in the trial may have had a large effect.

"We do have prospective registry data here [abstract 18-09, presented in a poster session] from a trial that we completed in the United States sponsored by the Translational Breast Cancer Research Consortium, and the patients in our study, whether they received surgery or not, their 2-year overall survival is far superior to what you’ve just showed us," she commented. "So I’m not sure that we can really apply your data to the modern targeted therapy regimens that we see in the United States."

Turkish trial

The Turkish trial, known as the MF07-01 trial, was conduced between 2008 and 2012 among treatment-naïve patients.

They were randomized evenly to receive either systemic therapy alone or surgery for the primary tumor (with or without axillary dissection) followed by radiation therapy if indicated, plus systemic therapy.

All patients received hormonal therapy as needed, and those with HER2-positive disease received trastuzumab.

With a median follow-up of 18 months, the median overall survival was 46 months with initial surgery and 42 months with initial systemic therapy, a nonsignificant difference, reported Dr. Soran, who disclosed no relevant conflicts of interest.

In unplanned subgroup analyses, the findings were similar for most subgroups of patients. However, surgery yielded superior survival in patients with solitary bone metastases (not reached vs. 42 months, P = .02) and inferior survival in patients having multiple liver or pulmonary metastases (16 months vs. not reached, P = .02).

The rate of locoregional progression was much lower with initial surgery than with initial systemic therapy (0.7% vs. 3.6%).

Dr. Soran emphasized that the trial’s planned median follow-up is 36 months, so the presented results are only preliminary. Quality of life and morbidity analyses are ongoing.

Dr. Badwe and Dr. Soran disclosed no relevant conflicts of interest.

SAN ANTONIO – Surgical removal of the primary tumor and affected lymph nodes afforded no overall survival benefit in women who had metastatic breast cancer at initial presentation, according to a pair of randomized trials presented at the San Antonio Breast Cancer Symposium.

In a first trial, conducted among 350 women in India who had responded to initial chemotherapy, about 20% of the women were still alive at 5 years regardless of whether they had surgery or just received more systemic therapy, first author Dr. Rajendra Badwe, director of the Tata Memorial Hospital in Mumbai, India, reported in a session and at a press briefing.

Superior locoregional control conferred by surgery was canceled out by a higher risk of progression in distant sites, lending support to more than 20-year-old preclinical data by Dr. Bernard Fisher and his colleagues suggesting that an intact primary suppresses growth of distant metastases (Cancer Res. 1989;49:1996-2001).

"Locoregional treatment of the primary tumor in women presenting with metastatic breast cancer did not result in any overall survival benefit and hence should not be offered as a routine practice," Dr. Badwe commented.

"The biological fallout of this study is that surgical removal of the primary tumor in these women appears to confer a growth advantage on distant metastases. ... This is the first time that we have evidence in human studies that locoregional treatment has a great kinetic effect on distant metastases," he added.

In a second trial, conducted among 293 women in Turkey with untreated de novo metastatic breast cancer, median estimated survival was statistically indistinguishable, at about 3.5 years, regardless of whether women had up-front surgery or simply systemic therapy, first author Dr. Atilla Soran reported in a session on behalf of the Turkish Federation of Societies for Breast Diseases.

Subgroup analyses suggested that surgery conferred a survival advantage among women with solitary bone metastases but a survival disadvantage among women with multiple liver or lung metastases.

The rate of locoregional progression was one-fifth as high with surgery as with systemic therapy.

"There was no statistically significant difference in overall survival at early follow-up, but we need longer follow-up," Dr. Soran commented. "There were potentially important subgroup differences."

The two trials have implications – both for other ongoing trials and for patient care – according to invited discussant Dr. Seema A. Khan, a professor of surgery and Bluhm Family Professor of Cancer Research at Northwestern University, Chicago, and a physician at the university’s Lynn Sage Breast Center.

"A large benefit of primary site local therapy seems unlikely based on the data we saw today," she maintained. "The assumptions we have used in our ongoing trial designs will need to be reassessed. Preplanned pooled analyses may yield sufficient power to detect smaller differences."

As for patient care, "it is pretty clear that at this point in time, we have to make sure that our patients understand that there is really no proven survival advantage to primary site local therapy," Dr. Khan said. "So I don’t think this treatment should be offered to patients with asymptomatic tumors unless they are participating in a clinical trial. There may be a local control advantage; we need to see more data on that."

Indian trial

Participants in the Indian trial, conducted between 2005 and 2013, were women with de novo metastatic breast cancer who had had a complete or partial response to anthracycline chemotherapy alone or with a taxane.

They were randomized evenly to receive locoregional therapy (lumpectomy or mastectomy with axillary lymph node dissection, plus radiation therapy to the chest wall or breast and lymph nodes) or no locoregional therapy as a control. Both groups received hormonal therapy if indicated.

In the control group, about 10% of women underwent a palliative mastectomy because of impending fungation or pain in the breast, as permitted by study protocol, according to Dr. Badwe.

The patients thus received contemporary therapy, he said, except that the 16% with HER2-positive disease did not receive the targeted agent trastuzumab (Herceptin).

Results showed that median overall survival was about 18 months, and the 5-year rate was 19.2% with locoregional therapy and 20.5% without it, a nonsignificant difference. "Uniformly, there was no difference at all in any subsets," Dr. Badwe reported.

The study had a one-sided superiority design, he noted. "We wouldn’t have been able to see a 2.5- or 3-month difference, or a 4% detriment" in overall survival.

The surgery group had a lower risk of local progression-free survival events (hazard ratio, 0.16; P = .00), but a higher risk of distant progression-free survival events (HR, 1.42; P = .01).

Several theories might explain why removal of the primary would accelerate growth of metastases, according to Dr. Badwe.

"The first and the foremost is that the act of surgery itself might elaborate some growth factors which might allow metastatic disease to grow. The second possibility, which was suggested by Dr. Fisher (Cancer Res. 1989;49:1996-2001) is that the primary tumor, which predates the onset of distant metastases, elaborates some inhibitory factors, and they are not there once the primary tumor is removed, bestowing autonomy of growth on the distant metastases," he explained. "And the third possibility is the act of surgery might induce some more metastatic processes by dissemination and create new disease."

Session attendee Dr. Steven Vogl, an oncologist in the Bronx, N.Y., said, "The ascertainment of disease progression requires disease that you can follow. A woman with bone-only metastases with her cancer in place, you can tell when her cancer is getting worse because the primary site or the axillary nodes are getting bigger. It’s much more difficult if you’ve taken those off and irradiated the chest wall. Have you looked at your data to see if that’s what was going on, why you had more distant metastases, because they couldn’t progress locally? This is a medical trial explanation that contradicts Fisher’s biologic hypothesis."

"There was a fixed time duration at which systemic investigations were performed to assess whether the distant metastases progressed," Dr. Badwe replied. If anything, the patients who did not have surgery had more assessments of their distant metastases, he said.

Dr. Tari A. King, a session attendee from the Memorial Sloan-Kettering Cancer Center, New York, noted that a lack of HER2 therapy in the trial may have had a large effect.

"We do have prospective registry data here [abstract 18-09, presented in a poster session] from a trial that we completed in the United States sponsored by the Translational Breast Cancer Research Consortium, and the patients in our study, whether they received surgery or not, their 2-year overall survival is far superior to what you’ve just showed us," she commented. "So I’m not sure that we can really apply your data to the modern targeted therapy regimens that we see in the United States."

Turkish trial

The Turkish trial, known as the MF07-01 trial, was conduced between 2008 and 2012 among treatment-naïve patients.

They were randomized evenly to receive either systemic therapy alone or surgery for the primary tumor (with or without axillary dissection) followed by radiation therapy if indicated, plus systemic therapy.

All patients received hormonal therapy as needed, and those with HER2-positive disease received trastuzumab.

With a median follow-up of 18 months, the median overall survival was 46 months with initial surgery and 42 months with initial systemic therapy, a nonsignificant difference, reported Dr. Soran, who disclosed no relevant conflicts of interest.

In unplanned subgroup analyses, the findings were similar for most subgroups of patients. However, surgery yielded superior survival in patients with solitary bone metastases (not reached vs. 42 months, P = .02) and inferior survival in patients having multiple liver or pulmonary metastases (16 months vs. not reached, P = .02).

The rate of locoregional progression was much lower with initial surgery than with initial systemic therapy (0.7% vs. 3.6%).

Dr. Soran emphasized that the trial’s planned median follow-up is 36 months, so the presented results are only preliminary. Quality of life and morbidity analyses are ongoing.

Dr. Badwe and Dr. Soran disclosed no relevant conflicts of interest.

WOODINVILLE, WASH. – Identifying the culprit in allergic contact dermatitis often requires careful sleuthing and tailored patch testing, according to Dr. James G. Marks Jr.

Dr. Marks reviewed the current options for patch testing trays, described several cases of allergic contact dermatitis, and shared pointers for diagnosis and management at the annual Coastal Dermatology Symposium.

Allergen-screening series

Dermatologists can now choose from a variety of standard screening trays for patch testing, said Dr. Marks, professor and chair of the department of dermatology, Pennsylvania State University, Hershey. The TRUE test (the only one approved by the Food and Drug Administration) contains 35 antigens.

However, dermatologists can supplement and customize these screening trays to create a system specific to their practice and geographic area. Dr. Marks said he uses a customized tray with 100 antigens.

"The important point is there is no universal standard screening tray, so pick what works for you," he said.

"Those of you who use the TRUE test, great; as you know in the last year you have had another panel [added], so you get more screening antigens," he said. "It makes sense intuitively, and it’s proven by publications of the North American [Contact Dermatitis] Group and others that the more antigens you test with, the more positives you get and the more relevant reactions you can get," he explained.

"Then create your own," Dr. Marks advised. "So if you use the TRUE test, maybe supplement ... with a few more allergens."

Alpha-methylene-gamma-butyrolactone

Florists may come in contact with alpha-methylene-gamma-butyrolactone through handling Alstroemeria (also known as Peruvian lily), a flower popular because of its long-lasting blooms.

The compound is found in the sap that leaks out from cut stems; thus, the presentation is typically finger dermatitis, Dr. Marks said at the meeting, which was presented by the Caribbean Dermatology Symposium.

"It is the most common cause of allergic contact dermatitis in florists. So if you see florists, this is the allergen until proven otherwise," he said.

The compound is also found in the white epidermis of tulips, in which case it is known as tuliposide A. About half of tulip bulb sorters are allergic to it.

"You either patch test with parts of the Alstroemeria plant or get the allergen alpha-methylene-gamma-butyrolactone" commercially, Dr. Marks said. "I test everyone to alpha-methylene-gamma-butyrolactone, even though it’s a small subset. That’s one of my 100 [antigens]."

Methylisothiazolinone

"Methylisothiazolinone has become a very important and hot allergen," Dr. Marks commented. This allergen is increasingly used in personal care products and requires a special approach to patch testing. It is found in many wet wipes, use of which can produce, for example, perioral dermatitis.

The standard combination test antigen, applied at 100 parts per million, contains 3 parts methylchloroisothiazolinone (MCI) and 1 part methylisothiazolinone (MI), he noted. Thus, "you are really only patch testing to 25 parts per million of MI."

"The recommended concentration of patch test to MI is a bit in flux," said Dr. Marks; the North American group currently uses 2,000 parts per million but is considering halving that number, he noted.

"You can see how you can miss patients who are allergic to MI if you only patch test to MCI/MI," he commented. "So those of you who are using the TRUE test, you are going to miss patients who are allergic to MI."

"The important point is you’ve got to test both – MCI/MI and MI alone. ... You should supplement what you are patch testing with MI, certainly at least at 1,000 parts per million, if not at 2,000," Dr. Marks advised.

"The Cosmetic Ingredient Review, which sets limits for [MI] in the U.S., is going to be reevaluating, and I’m sure will be having lower limits in leave-on and rinse-off products," he noted.

Rubber accelerators

Surgeons may develop particularly problematic allergic contact dermatitis as a reaction to the rubber accelerators used in the manufacturing of many surgical gloves, Dr. Marks noted.

He described the case of a surgeon who developed severe hand dermatitis and eventually a generalized dermatitis. "In this case, if you used the TRUE test, you would make the diagnosis; he was positive to thiuram and carba mix."

Allergen avoidance entailed finding an alternative, rubber-free surgical glove, the Derma Prene Ultra glove (manufactured by Ansell), which is made of neoprene. Also, the surgeon switched to vinyl exam gloves for outpatient care.

"There may be other surgical gloves ...," Dr. Marks acknowledged. "But be sure and keep this some place because some time in the future when you have your surgeon friend with hand dermatitis, you can recommend that glove after you patch test them and prove that they are rubber-accelerator positive."

Cocamidopropyl betaine contaminants

Patients may develop allergic contact dermatitis after using shampoos and bath gels containing cocamidopropyl betaine, a surfactant.

In fact, they are actually reacting to a contaminant or impurity generated in the manufacturing process, either 3-dimethylaminopropylamine or amidoamine, according to Dr. Marks.

"So if you have pure cocamidopropyl betaine, there will be no allergy," he noted. But if you test for "cocamidopropyl betaine, and what you are patch testing with is from, say, Chemotechnique or Allergeaze, it’s going to have presumably the contaminants or the impurities in it, 3-dimethylaminopropylamine and amidoamine."

Treatment entails careful reading of labels on personal care products and avoidance of those containing cocamidopropyl betaine.

Acrylates

Don’t rule out acrylates – either acrylic or methacrylic acid – monomers that are polymerized with heat or light to form solid plastics that can cause reactions.

"The monomers are both irritants and allergens, so you need the right concentration to patch test to," Dr. Marks noted. "They are found in all sorts of things – adhesives, inks, artificial nails, dental resins, bone cement, and plastics."

Presentations may vary widely, including, for example, finger dermatitis in patients who have sculptured nails, and gum stomatitis in patients who have undergone procedures involving dental resin, said Dr. Marks.

"If you have workers or patients who have exposure to acrylates, you need more extensive screening," Dr. Marks advised, noting that his acrylate patch test series contains six compounds.

"No one is a screen for all of them," he commented. "Some [experts] feel that ethyl acrylate is the best screen; certainly, for sculptured nails it’s good." Others in his series include methyl methacrylate (found in bone cement) and ethyl cyanoacrylate (found in Super Glue adhesive).

Glyceryl thioglycolate

Allergy to glyceryl thioglycolate, found in acid permanent waves, can manifest as hand dermatitis in hairdressers and as dermatitis of the face, neck, and ears in their clients.

"If you see hairdressers [in your practice], you should consider strongly having this antigen as part of your [patch test] armamentarium," Dr. Marks recommended.

Alkaline perms, by contrast, do not contain glyceryl thioglycolate and thus provide a simple solution. "You can cure that hairdresser, and she or he can continue to do perms just by switching from an acid to an alkaline perm," he explained.

Dr. Marks said he had no relevant financial disclosures.

sknews@frontlinemedcom.com

WOODINVILLE, WASH. – Identifying the culprit in allergic contact dermatitis often requires careful sleuthing and tailored patch testing, according to Dr. James G. Marks Jr.

Dr. Marks reviewed the current options for patch testing trays, described several cases of allergic contact dermatitis, and shared pointers for diagnosis and management at the annual Coastal Dermatology Symposium.

Allergen-screening series

Dermatologists can now choose from a variety of standard screening trays for patch testing, said Dr. Marks, professor and chair of the department of dermatology, Pennsylvania State University, Hershey. The TRUE test (the only one approved by the Food and Drug Administration) contains 35 antigens.

However, dermatologists can supplement and customize these screening trays to create a system specific to their practice and geographic area. Dr. Marks said he uses a customized tray with 100 antigens.

"The important point is there is no universal standard screening tray, so pick what works for you," he said.

"Those of you who use the TRUE test, great; as you know in the last year you have had another panel [added], so you get more screening antigens," he said. "It makes sense intuitively, and it’s proven by publications of the North American [Contact Dermatitis] Group and others that the more antigens you test with, the more positives you get and the more relevant reactions you can get," he explained.

"Then create your own," Dr. Marks advised. "So if you use the TRUE test, maybe supplement ... with a few more allergens."

Alpha-methylene-gamma-butyrolactone

Florists may come in contact with alpha-methylene-gamma-butyrolactone through handling Alstroemeria (also known as Peruvian lily), a flower popular because of its long-lasting blooms.

The compound is found in the sap that leaks out from cut stems; thus, the presentation is typically finger dermatitis, Dr. Marks said at the meeting, which was presented by the Caribbean Dermatology Symposium.

"It is the most common cause of allergic contact dermatitis in florists. So if you see florists, this is the allergen until proven otherwise," he said.

The compound is also found in the white epidermis of tulips, in which case it is known as tuliposide A. About half of tulip bulb sorters are allergic to it.

"You either patch test with parts of the Alstroemeria plant or get the allergen alpha-methylene-gamma-butyrolactone" commercially, Dr. Marks said. "I test everyone to alpha-methylene-gamma-butyrolactone, even though it’s a small subset. That’s one of my 100 [antigens]."

Methylisothiazolinone

"Methylisothiazolinone has become a very important and hot allergen," Dr. Marks commented. This allergen is increasingly used in personal care products and requires a special approach to patch testing. It is found in many wet wipes, use of which can produce, for example, perioral dermatitis.

The standard combination test antigen, applied at 100 parts per million, contains 3 parts methylchloroisothiazolinone (MCI) and 1 part methylisothiazolinone (MI), he noted. Thus, "you are really only patch testing to 25 parts per million of MI."

"The recommended concentration of patch test to MI is a bit in flux," said Dr. Marks; the North American group currently uses 2,000 parts per million but is considering halving that number, he noted.

"You can see how you can miss patients who are allergic to MI if you only patch test to MCI/MI," he commented. "So those of you who are using the TRUE test, you are going to miss patients who are allergic to MI."

"The important point is you’ve got to test both – MCI/MI and MI alone. ... You should supplement what you are patch testing with MI, certainly at least at 1,000 parts per million, if not at 2,000," Dr. Marks advised.

"The Cosmetic Ingredient Review, which sets limits for [MI] in the U.S., is going to be reevaluating, and I’m sure will be having lower limits in leave-on and rinse-off products," he noted.

Rubber accelerators

Surgeons may develop particularly problematic allergic contact dermatitis as a reaction to the rubber accelerators used in the manufacturing of many surgical gloves, Dr. Marks noted.

He described the case of a surgeon who developed severe hand dermatitis and eventually a generalized dermatitis. "In this case, if you used the TRUE test, you would make the diagnosis; he was positive to thiuram and carba mix."

Allergen avoidance entailed finding an alternative, rubber-free surgical glove, the Derma Prene Ultra glove (manufactured by Ansell), which is made of neoprene. Also, the surgeon switched to vinyl exam gloves for outpatient care.

"There may be other surgical gloves ...," Dr. Marks acknowledged. "But be sure and keep this some place because some time in the future when you have your surgeon friend with hand dermatitis, you can recommend that glove after you patch test them and prove that they are rubber-accelerator positive."

Cocamidopropyl betaine contaminants

Patients may develop allergic contact dermatitis after using shampoos and bath gels containing cocamidopropyl betaine, a surfactant.

In fact, they are actually reacting to a contaminant or impurity generated in the manufacturing process, either 3-dimethylaminopropylamine or amidoamine, according to Dr. Marks.

"So if you have pure cocamidopropyl betaine, there will be no allergy," he noted. But if you test for "cocamidopropyl betaine, and what you are patch testing with is from, say, Chemotechnique or Allergeaze, it’s going to have presumably the contaminants or the impurities in it, 3-dimethylaminopropylamine and amidoamine."

Treatment entails careful reading of labels on personal care products and avoidance of those containing cocamidopropyl betaine.

Acrylates

Don’t rule out acrylates – either acrylic or methacrylic acid – monomers that are polymerized with heat or light to form solid plastics that can cause reactions.

"The monomers are both irritants and allergens, so you need the right concentration to patch test to," Dr. Marks noted. "They are found in all sorts of things – adhesives, inks, artificial nails, dental resins, bone cement, and plastics."

Presentations may vary widely, including, for example, finger dermatitis in patients who have sculptured nails, and gum stomatitis in patients who have undergone procedures involving dental resin, said Dr. Marks.

"If you have workers or patients who have exposure to acrylates, you need more extensive screening," Dr. Marks advised, noting that his acrylate patch test series contains six compounds.

"No one is a screen for all of them," he commented. "Some [experts] feel that ethyl acrylate is the best screen; certainly, for sculptured nails it’s good." Others in his series include methyl methacrylate (found in bone cement) and ethyl cyanoacrylate (found in Super Glue adhesive).

Glyceryl thioglycolate

Allergy to glyceryl thioglycolate, found in acid permanent waves, can manifest as hand dermatitis in hairdressers and as dermatitis of the face, neck, and ears in their clients.

"If you see hairdressers [in your practice], you should consider strongly having this antigen as part of your [patch test] armamentarium," Dr. Marks recommended.

Alkaline perms, by contrast, do not contain glyceryl thioglycolate and thus provide a simple solution. "You can cure that hairdresser, and she or he can continue to do perms just by switching from an acid to an alkaline perm," he explained.

Dr. Marks said he had no relevant financial disclosures.

sknews@frontlinemedcom.com

WOODINVILLE, WASH. – Identifying the culprit in allergic contact dermatitis often requires careful sleuthing and tailored patch testing, according to Dr. James G. Marks Jr.

Dr. Marks reviewed the current options for patch testing trays, described several cases of allergic contact dermatitis, and shared pointers for diagnosis and management at the annual Coastal Dermatology Symposium.

Allergen-screening series

Dermatologists can now choose from a variety of standard screening trays for patch testing, said Dr. Marks, professor and chair of the department of dermatology, Pennsylvania State University, Hershey. The TRUE test (the only one approved by the Food and Drug Administration) contains 35 antigens.

However, dermatologists can supplement and customize these screening trays to create a system specific to their practice and geographic area. Dr. Marks said he uses a customized tray with 100 antigens.

"The important point is there is no universal standard screening tray, so pick what works for you," he said.

"Those of you who use the TRUE test, great; as you know in the last year you have had another panel [added], so you get more screening antigens," he said. "It makes sense intuitively, and it’s proven by publications of the North American [Contact Dermatitis] Group and others that the more antigens you test with, the more positives you get and the more relevant reactions you can get," he explained.

"Then create your own," Dr. Marks advised. "So if you use the TRUE test, maybe supplement ... with a few more allergens."

Alpha-methylene-gamma-butyrolactone

Florists may come in contact with alpha-methylene-gamma-butyrolactone through handling Alstroemeria (also known as Peruvian lily), a flower popular because of its long-lasting blooms.

The compound is found in the sap that leaks out from cut stems; thus, the presentation is typically finger dermatitis, Dr. Marks said at the meeting, which was presented by the Caribbean Dermatology Symposium.

"It is the most common cause of allergic contact dermatitis in florists. So if you see florists, this is the allergen until proven otherwise," he said.

The compound is also found in the white epidermis of tulips, in which case it is known as tuliposide A. About half of tulip bulb sorters are allergic to it.

"You either patch test with parts of the Alstroemeria plant or get the allergen alpha-methylene-gamma-butyrolactone" commercially, Dr. Marks said. "I test everyone to alpha-methylene-gamma-butyrolactone, even though it’s a small subset. That’s one of my 100 [antigens]."

Methylisothiazolinone

"Methylisothiazolinone has become a very important and hot allergen," Dr. Marks commented. This allergen is increasingly used in personal care products and requires a special approach to patch testing. It is found in many wet wipes, use of which can produce, for example, perioral dermatitis.

The standard combination test antigen, applied at 100 parts per million, contains 3 parts methylchloroisothiazolinone (MCI) and 1 part methylisothiazolinone (MI), he noted. Thus, "you are really only patch testing to 25 parts per million of MI."

"The recommended concentration of patch test to MI is a bit in flux," said Dr. Marks; the North American group currently uses 2,000 parts per million but is considering halving that number, he noted.

"You can see how you can miss patients who are allergic to MI if you only patch test to MCI/MI," he commented. "So those of you who are using the TRUE test, you are going to miss patients who are allergic to MI."

"The important point is you’ve got to test both – MCI/MI and MI alone. ... You should supplement what you are patch testing with MI, certainly at least at 1,000 parts per million, if not at 2,000," Dr. Marks advised.

"The Cosmetic Ingredient Review, which sets limits for [MI] in the U.S., is going to be reevaluating, and I’m sure will be having lower limits in leave-on and rinse-off products," he noted.

Rubber accelerators

Surgeons may develop particularly problematic allergic contact dermatitis as a reaction to the rubber accelerators used in the manufacturing of many surgical gloves, Dr. Marks noted.

He described the case of a surgeon who developed severe hand dermatitis and eventually a generalized dermatitis. "In this case, if you used the TRUE test, you would make the diagnosis; he was positive to thiuram and carba mix."

Allergen avoidance entailed finding an alternative, rubber-free surgical glove, the Derma Prene Ultra glove (manufactured by Ansell), which is made of neoprene. Also, the surgeon switched to vinyl exam gloves for outpatient care.

"There may be other surgical gloves ...," Dr. Marks acknowledged. "But be sure and keep this some place because some time in the future when you have your surgeon friend with hand dermatitis, you can recommend that glove after you patch test them and prove that they are rubber-accelerator positive."

Cocamidopropyl betaine contaminants

Patients may develop allergic contact dermatitis after using shampoos and bath gels containing cocamidopropyl betaine, a surfactant.

In fact, they are actually reacting to a contaminant or impurity generated in the manufacturing process, either 3-dimethylaminopropylamine or amidoamine, according to Dr. Marks.

"So if you have pure cocamidopropyl betaine, there will be no allergy," he noted. But if you test for "cocamidopropyl betaine, and what you are patch testing with is from, say, Chemotechnique or Allergeaze, it’s going to have presumably the contaminants or the impurities in it, 3-dimethylaminopropylamine and amidoamine."

Treatment entails careful reading of labels on personal care products and avoidance of those containing cocamidopropyl betaine.

Acrylates

Don’t rule out acrylates – either acrylic or methacrylic acid – monomers that are polymerized with heat or light to form solid plastics that can cause reactions.

"The monomers are both irritants and allergens, so you need the right concentration to patch test to," Dr. Marks noted. "They are found in all sorts of things – adhesives, inks, artificial nails, dental resins, bone cement, and plastics."

Presentations may vary widely, including, for example, finger dermatitis in patients who have sculptured nails, and gum stomatitis in patients who have undergone procedures involving dental resin, said Dr. Marks.

"If you have workers or patients who have exposure to acrylates, you need more extensive screening," Dr. Marks advised, noting that his acrylate patch test series contains six compounds.

"No one is a screen for all of them," he commented. "Some [experts] feel that ethyl acrylate is the best screen; certainly, for sculptured nails it’s good." Others in his series include methyl methacrylate (found in bone cement) and ethyl cyanoacrylate (found in Super Glue adhesive).

Glyceryl thioglycolate

Allergy to glyceryl thioglycolate, found in acid permanent waves, can manifest as hand dermatitis in hairdressers and as dermatitis of the face, neck, and ears in their clients.

"If you see hairdressers [in your practice], you should consider strongly having this antigen as part of your [patch test] armamentarium," Dr. Marks recommended.

Alkaline perms, by contrast, do not contain glyceryl thioglycolate and thus provide a simple solution. "You can cure that hairdresser, and she or he can continue to do perms just by switching from an acid to an alkaline perm," he explained.

Dr. Marks said he had no relevant financial disclosures.

sknews@frontlinemedcom.com

WOODINVILLE, WASH. – Identifying the culprit in allergic contact dermatitis often requires careful sleuthing and tailored patch testing, according to Dr. James G. Marks Jr.

Dr. Marks reviewed the current options for patch testing trays, described several cases of allergic contact dermatitis, and shared pointers for diagnosis and management at the annual Coastal Dermatology Symposium.

Allergen-screening series

Dermatologists can now choose from a variety of standard screening trays for patch testing, said Dr. Marks, professor and chair of the department of dermatology, Pennsylvania State University, Hershey. The TRUE test (the only one approved by the Food and Drug Administration) contains 35 antigens.

However, dermatologists can supplement and customize these screening trays to create a system specific to their practice and geographic area. Dr. Marks said he uses a customized tray with 100 antigens.

"The important point is there is no universal standard screening tray, so pick what works for you," he said.

"Those of you who use the TRUE test, great; as you know in the last year you have had another panel [added], so you get more screening antigens," he said. "It makes sense intuitively, and it’s proven by publications of the North American [Contact Dermatitis] Group and others that the more antigens you test with, the more positives you get and the more relevant reactions you can get," he explained.

"Then create your own," Dr. Marks advised. "So if you use the TRUE test, maybe supplement ... with a few more allergens."

Alpha-methylene-gamma-butyrolactone

Florists may come in contact with alpha-methylene-gamma-butyrolactone through handling Alstroemeria (also known as Peruvian lily), a flower popular because of its long-lasting blooms.

The compound is found in the sap that leaks out from cut stems; thus, the presentation is typically finger dermatitis, Dr. Marks said at the meeting, which was presented by the Caribbean Dermatology Symposium.

"It is the most common cause of allergic contact dermatitis in florists. So if you see florists, this is the allergen until proven otherwise," he said.

The compound is also found in the white epidermis of tulips, in which case it is known as tuliposide A. About half of tulip bulb sorters are allergic to it.

"You either patch test with parts of the Alstroemeria plant or get the allergen alpha-methylene-gamma-butyrolactone" commercially, Dr. Marks said. "I test everyone to alpha-methylene-gamma-butyrolactone, even though it’s a small subset. That’s one of my 100 [antigens]."

Methylisothiazolinone

"Methylisothiazolinone has become a very important and hot allergen," Dr. Marks commented. This allergen is increasingly used in personal care products and requires a special approach to patch testing. It is found in many wet wipes, use of which can produce, for example, perioral dermatitis.

The standard combination test antigen, applied at 100 parts per million, contains 3 parts methylchloroisothiazolinone (MCI) and 1 part methylisothiazolinone (MI), he noted. Thus, "you are really only patch testing to 25 parts per million of MI."

"The recommended concentration of patch test to MI is a bit in flux," said Dr. Marks; the North American group currently uses 2,000 parts per million but is considering halving that number, he noted.

"You can see how you can miss patients who are allergic to MI if you only patch test to MCI/MI," he commented. "So those of you who are using the TRUE test, you are going to miss patients who are allergic to MI."

"The important point is you’ve got to test both – MCI/MI and MI alone. ... You should supplement what you are patch testing with MI, certainly at least at 1,000 parts per million, if not at 2,000," Dr. Marks advised.

"The Cosmetic Ingredient Review, which sets limits for [MI] in the U.S., is going to be reevaluating, and I’m sure will be having lower limits in leave-on and rinse-off products," he noted.

Rubber accelerators

Surgeons may develop particularly problematic allergic contact dermatitis as a reaction to the rubber accelerators used in the manufacturing of many surgical gloves, Dr. Marks noted.

He described the case of a surgeon who developed severe hand dermatitis and eventually a generalized dermatitis. "In this case, if you used the TRUE test, you would make the diagnosis; he was positive to thiuram and carba mix."

Allergen avoidance entailed finding an alternative, rubber-free surgical glove, the Derma Prene Ultra glove (manufactured by Ansell), which is made of neoprene. Also, the surgeon switched to vinyl exam gloves for outpatient care.

"There may be other surgical gloves ...," Dr. Marks acknowledged. "But be sure and keep this some place because some time in the future when you have your surgeon friend with hand dermatitis, you can recommend that glove after you patch test them and prove that they are rubber-accelerator positive."

Cocamidopropyl betaine contaminants

Patients may develop allergic contact dermatitis after using shampoos and bath gels containing cocamidopropyl betaine, a surfactant.

In fact, they are actually reacting to a contaminant or impurity generated in the manufacturing process, either 3-dimethylaminopropylamine or amidoamine, according to Dr. Marks.

"So if you have pure cocamidopropyl betaine, there will be no allergy," he noted. But if you test for "cocamidopropyl betaine, and what you are patch testing with is from, say, Chemotechnique or Allergeaze, it’s going to have presumably the contaminants or the impurities in it, 3-dimethylaminopropylamine and amidoamine."

Treatment entails careful reading of labels on personal care products and avoidance of those containing cocamidopropyl betaine.

Acrylates

Don’t rule out acrylates – either acrylic or methacrylic acid – monomers that are polymerized with heat or light to form solid plastics that can cause reactions.

"The monomers are both irritants and allergens, so you need the right concentration to patch test to," Dr. Marks noted. "They are found in all sorts of things – adhesives, inks, artificial nails, dental resins, bone cement, and plastics."

Presentations may vary widely, including, for example, finger dermatitis in patients who have sculptured nails, and gum stomatitis in patients who have undergone procedures involving dental resin, said Dr. Marks.

"If you have workers or patients who have exposure to acrylates, you need more extensive screening," Dr. Marks advised, noting that his acrylate patch test series contains six compounds.

"No one is a screen for all of them," he commented. "Some [experts] feel that ethyl acrylate is the best screen; certainly, for sculptured nails it’s good." Others in his series include methyl methacrylate (found in bone cement) and ethyl cyanoacrylate (found in Super Glue adhesive).

Glyceryl thioglycolate

Allergy to glyceryl thioglycolate, found in acid permanent waves, can manifest as hand dermatitis in hairdressers and as dermatitis of the face, neck, and ears in their clients.

"If you see hairdressers [in your practice], you should consider strongly having this antigen as part of your [patch test] armamentarium," Dr. Marks recommended.

Alkaline perms, by contrast, do not contain glyceryl thioglycolate and thus provide a simple solution. "You can cure that hairdresser, and she or he can continue to do perms just by switching from an acid to an alkaline perm," he explained.

Dr. Marks said he had no relevant financial disclosures.

sknews@frontlinemedcom.com

WOODINVILLE, WASH. – Identifying the culprit in allergic contact dermatitis often requires careful sleuthing and tailored patch testing, according to Dr. James G. Marks Jr.

Dr. Marks reviewed the current options for patch testing trays, described several cases of allergic contact dermatitis, and shared pointers for diagnosis and management at the annual Coastal Dermatology Symposium.

Allergen-screening series

Dermatologists can now choose from a variety of standard screening trays for patch testing, said Dr. Marks, professor and chair of the department of dermatology, Pennsylvania State University, Hershey. The TRUE test (the only one approved by the Food and Drug Administration) contains 35 antigens.

However, dermatologists can supplement and customize these screening trays to create a system specific to their practice and geographic area. Dr. Marks said he uses a customized tray with 100 antigens.

"The important point is there is no universal standard screening tray, so pick what works for you," he said.

"Those of you who use the TRUE test, great; as you know in the last year you have had another panel [added], so you get more screening antigens," he said. "It makes sense intuitively, and it’s proven by publications of the North American [Contact Dermatitis] Group and others that the more antigens you test with, the more positives you get and the more relevant reactions you can get," he explained.

"Then create your own," Dr. Marks advised. "So if you use the TRUE test, maybe supplement ... with a few more allergens."

Alpha-methylene-gamma-butyrolactone

Florists may come in contact with alpha-methylene-gamma-butyrolactone through handling Alstroemeria (also known as Peruvian lily), a flower popular because of its long-lasting blooms.

The compound is found in the sap that leaks out from cut stems; thus, the presentation is typically finger dermatitis, Dr. Marks said at the meeting, which was presented by the Caribbean Dermatology Symposium.

"It is the most common cause of allergic contact dermatitis in florists. So if you see florists, this is the allergen until proven otherwise," he said.

The compound is also found in the white epidermis of tulips, in which case it is known as tuliposide A. About half of tulip bulb sorters are allergic to it.

"You either patch test with parts of the Alstroemeria plant or get the allergen alpha-methylene-gamma-butyrolactone" commercially, Dr. Marks said. "I test everyone to alpha-methylene-gamma-butyrolactone, even though it’s a small subset. That’s one of my 100 [antigens]."

Methylisothiazolinone

"Methylisothiazolinone has become a very important and hot allergen," Dr. Marks commented. This allergen is increasingly used in personal care products and requires a special approach to patch testing. It is found in many wet wipes, use of which can produce, for example, perioral dermatitis.

The standard combination test antigen, applied at 100 parts per million, contains 3 parts methylchloroisothiazolinone (MCI) and 1 part methylisothiazolinone (MI), he noted. Thus, "you are really only patch testing to 25 parts per million of MI."

"The recommended concentration of patch test to MI is a bit in flux," said Dr. Marks; the North American group currently uses 2,000 parts per million but is considering halving that number, he noted.

"You can see how you can miss patients who are allergic to MI if you only patch test to MCI/MI," he commented. "So those of you who are using the TRUE test, you are going to miss patients who are allergic to MI."

"The important point is you’ve got to test both – MCI/MI and MI alone. ... You should supplement what you are patch testing with MI, certainly at least at 1,000 parts per million, if not at 2,000," Dr. Marks advised.

"The Cosmetic Ingredient Review, which sets limits for [MI] in the U.S., is going to be reevaluating, and I’m sure will be having lower limits in leave-on and rinse-off products," he noted.

Rubber accelerators

Surgeons may develop particularly problematic allergic contact dermatitis as a reaction to the rubber accelerators used in the manufacturing of many surgical gloves, Dr. Marks noted.

He described the case of a surgeon who developed severe hand dermatitis and eventually a generalized dermatitis. "In this case, if you used the TRUE test, you would make the diagnosis; he was positive to thiuram and carba mix."

Allergen avoidance entailed finding an alternative, rubber-free surgical glove, the Derma Prene Ultra glove (manufactured by Ansell), which is made of neoprene. Also, the surgeon switched to vinyl exam gloves for outpatient care.

"There may be other surgical gloves ...," Dr. Marks acknowledged. "But be sure and keep this some place because some time in the future when you have your surgeon friend with hand dermatitis, you can recommend that glove after you patch test them and prove that they are rubber-accelerator positive."

Cocamidopropyl betaine contaminants

Patients may develop allergic contact dermatitis after using shampoos and bath gels containing cocamidopropyl betaine, a surfactant.

In fact, they are actually reacting to a contaminant or impurity generated in the manufacturing process, either 3-dimethylaminopropylamine or amidoamine, according to Dr. Marks.

"So if you have pure cocamidopropyl betaine, there will be no allergy," he noted. But if you test for "cocamidopropyl betaine, and what you are patch testing with is from, say, Chemotechnique or Allergeaze, it’s going to have presumably the contaminants or the impurities in it, 3-dimethylaminopropylamine and amidoamine."

Treatment entails careful reading of labels on personal care products and avoidance of those containing cocamidopropyl betaine.

Acrylates

Don’t rule out acrylates – either acrylic or methacrylic acid – monomers that are polymerized with heat or light to form solid plastics that can cause reactions.

"The monomers are both irritants and allergens, so you need the right concentration to patch test to," Dr. Marks noted. "They are found in all sorts of things – adhesives, inks, artificial nails, dental resins, bone cement, and plastics."

Presentations may vary widely, including, for example, finger dermatitis in patients who have sculptured nails, and gum stomatitis in patients who have undergone procedures involving dental resin, said Dr. Marks.

"If you have workers or patients who have exposure to acrylates, you need more extensive screening," Dr. Marks advised, noting that his acrylate patch test series contains six compounds.

"No one is a screen for all of them," he commented. "Some [experts] feel that ethyl acrylate is the best screen; certainly, for sculptured nails it’s good." Others in his series include methyl methacrylate (found in bone cement) and ethyl cyanoacrylate (found in Super Glue adhesive).

Glyceryl thioglycolate

Allergy to glyceryl thioglycolate, found in acid permanent waves, can manifest as hand dermatitis in hairdressers and as dermatitis of the face, neck, and ears in their clients.

"If you see hairdressers [in your practice], you should consider strongly having this antigen as part of your [patch test] armamentarium," Dr. Marks recommended.

Alkaline perms, by contrast, do not contain glyceryl thioglycolate and thus provide a simple solution. "You can cure that hairdresser, and she or he can continue to do perms just by switching from an acid to an alkaline perm," he explained.

Dr. Marks said he had no relevant financial disclosures.

sknews@frontlinemedcom.com

WOODINVILLE, WASH. – Identifying the culprit in allergic contact dermatitis often requires careful sleuthing and tailored patch testing, according to Dr. James G. Marks Jr.

Dr. Marks reviewed the current options for patch testing trays, described several cases of allergic contact dermatitis, and shared pointers for diagnosis and management at the annual Coastal Dermatology Symposium.

Allergen-screening series

Dermatologists can now choose from a variety of standard screening trays for patch testing, said Dr. Marks, professor and chair of the department of dermatology, Pennsylvania State University, Hershey. The TRUE test (the only one approved by the Food and Drug Administration) contains 35 antigens.

However, dermatologists can supplement and customize these screening trays to create a system specific to their practice and geographic area. Dr. Marks said he uses a customized tray with 100 antigens.

"The important point is there is no universal standard screening tray, so pick what works for you," he said.

"Those of you who use the TRUE test, great; as you know in the last year you have had another panel [added], so you get more screening antigens," he said. "It makes sense intuitively, and it’s proven by publications of the North American [Contact Dermatitis] Group and others that the more antigens you test with, the more positives you get and the more relevant reactions you can get," he explained.

"Then create your own," Dr. Marks advised. "So if you use the TRUE test, maybe supplement ... with a few more allergens."

Alpha-methylene-gamma-butyrolactone

Florists may come in contact with alpha-methylene-gamma-butyrolactone through handling Alstroemeria (also known as Peruvian lily), a flower popular because of its long-lasting blooms.

The compound is found in the sap that leaks out from cut stems; thus, the presentation is typically finger dermatitis, Dr. Marks said at the meeting, which was presented by the Caribbean Dermatology Symposium.

"It is the most common cause of allergic contact dermatitis in florists. So if you see florists, this is the allergen until proven otherwise," he said.

The compound is also found in the white epidermis of tulips, in which case it is known as tuliposide A. About half of tulip bulb sorters are allergic to it.

"You either patch test with parts of the Alstroemeria plant or get the allergen alpha-methylene-gamma-butyrolactone" commercially, Dr. Marks said. "I test everyone to alpha-methylene-gamma-butyrolactone, even though it’s a small subset. That’s one of my 100 [antigens]."

Methylisothiazolinone

"Methylisothiazolinone has become a very important and hot allergen," Dr. Marks commented. This allergen is increasingly used in personal care products and requires a special approach to patch testing. It is found in many wet wipes, use of which can produce, for example, perioral dermatitis.

The standard combination test antigen, applied at 100 parts per million, contains 3 parts methylchloroisothiazolinone (MCI) and 1 part methylisothiazolinone (MI), he noted. Thus, "you are really only patch testing to 25 parts per million of MI."

"The recommended concentration of patch test to MI is a bit in flux," said Dr. Marks; the North American group currently uses 2,000 parts per million but is considering halving that number, he noted.

"You can see how you can miss patients who are allergic to MI if you only patch test to MCI/MI," he commented. "So those of you who are using the TRUE test, you are going to miss patients who are allergic to MI."

"The important point is you’ve got to test both – MCI/MI and MI alone. ... You should supplement what you are patch testing with MI, certainly at least at 1,000 parts per million, if not at 2,000," Dr. Marks advised.

"The Cosmetic Ingredient Review, which sets limits for [MI] in the U.S., is going to be reevaluating, and I’m sure will be having lower limits in leave-on and rinse-off products," he noted.

Rubber accelerators

Surgeons may develop particularly problematic allergic contact dermatitis as a reaction to the rubber accelerators used in the manufacturing of many surgical gloves, Dr. Marks noted.

He described the case of a surgeon who developed severe hand dermatitis and eventually a generalized dermatitis. "In this case, if you used the TRUE test, you would make the diagnosis; he was positive to thiuram and carba mix."

Allergen avoidance entailed finding an alternative, rubber-free surgical glove, the Derma Prene Ultra glove (manufactured by Ansell), which is made of neoprene. Also, the surgeon switched to vinyl exam gloves for outpatient care.

"There may be other surgical gloves ...," Dr. Marks acknowledged. "But be sure and keep this some place because some time in the future when you have your surgeon friend with hand dermatitis, you can recommend that glove after you patch test them and prove that they are rubber-accelerator positive."

Cocamidopropyl betaine contaminants

Patients may develop allergic contact dermatitis after using shampoos and bath gels containing cocamidopropyl betaine, a surfactant.

In fact, they are actually reacting to a contaminant or impurity generated in the manufacturing process, either 3-dimethylaminopropylamine or amidoamine, according to Dr. Marks.

"So if you have pure cocamidopropyl betaine, there will be no allergy," he noted. But if you test for "cocamidopropyl betaine, and what you are patch testing with is from, say, Chemotechnique or Allergeaze, it’s going to have presumably the contaminants or the impurities in it, 3-dimethylaminopropylamine and amidoamine."

Treatment entails careful reading of labels on personal care products and avoidance of those containing cocamidopropyl betaine.

Acrylates

Don’t rule out acrylates – either acrylic or methacrylic acid – monomers that are polymerized with heat or light to form solid plastics that can cause reactions.

"The monomers are both irritants and allergens, so you need the right concentration to patch test to," Dr. Marks noted. "They are found in all sorts of things – adhesives, inks, artificial nails, dental resins, bone cement, and plastics."

Presentations may vary widely, including, for example, finger dermatitis in patients who have sculptured nails, and gum stomatitis in patients who have undergone procedures involving dental resin, said Dr. Marks.

"If you have workers or patients who have exposure to acrylates, you need more extensive screening," Dr. Marks advised, noting that his acrylate patch test series contains six compounds.

"No one is a screen for all of them," he commented. "Some [experts] feel that ethyl acrylate is the best screen; certainly, for sculptured nails it’s good." Others in his series include methyl methacrylate (found in bone cement) and ethyl cyanoacrylate (found in Super Glue adhesive).

Glyceryl thioglycolate

Allergy to glyceryl thioglycolate, found in acid permanent waves, can manifest as hand dermatitis in hairdressers and as dermatitis of the face, neck, and ears in their clients.

"If you see hairdressers [in your practice], you should consider strongly having this antigen as part of your [patch test] armamentarium," Dr. Marks recommended.

Alkaline perms, by contrast, do not contain glyceryl thioglycolate and thus provide a simple solution. "You can cure that hairdresser, and she or he can continue to do perms just by switching from an acid to an alkaline perm," he explained.

Dr. Marks said he had no relevant financial disclosures.

sknews@frontlinemedcom.com

SAN ANTONIO – When added to standard neoadjuvant chemotherapy, carboplatin and bevacizumab each improve the odds of eradicating local disease in women with triple-negative breast cancer, but their impact on toxicity differs, based on findings from a randomized phase II trial.

Adding carboplatin to standard chemotherapy improved the odds of pathologic complete response (pCR) by 71%-76% with some increase in toxicity such as neutropenia and thrombocytopenia. Adding the antiangiogenic agent bevacizumab improved the odds of pCR by 58%, but with a considerable increase in toxicity such as hypertension and postoperative complications, based on results of the Cancer and Leukemia Group B (CALGB)/Alliance 40603 trial of 443 women with stage II or III triple-negative breast cancer. Dr. William M. Sikov reported the results in a session and at a press briefing at the San Antonio Breast Cancer Symposium.

Dr. Sikov of Warren Alpert Medical School of Brown University, Providence, R.I., acknowledged that the trial was not powered to assess recurrence-free and overall survivals. While it remains unclear whether pCR predicts improved survival, data from other trials and a meta-analysis suggest that pCR is a good surrogate endpoint and have prompted the Food and Drug Administration to consider this endpoint for new drug approval pending long-term data.

Based on the results from this trial and those of the similar GeparSixto trial reported at the 2013 ASCO annual meeting, he said, "if you have decided a patient with triple-negative breast cancer should receive neoadjuvant chemotherapy based on the size of the tumor, based on the desire to improve the chance of breast conservation, then I think it makes sense to add carboplatin to your neoadjuvant regimen, and that you can comfortably do so with acceptable additional toxicities."

Alternatively, Dr. Sikov said that bevacizumab "increased the pCR rate, but at the cost of significant toxicities, and I don’t think that [bevacizumab] should be routinely added to neoadjuvant chemotherapy."

In the CALGB/Alliance 40603 trial, which was funded in part by Genentech, about three-fourths of the women were white, and roughly two-thirds had clinical stage II disease; 55% had clinically positive nodes.

All of the women were treated with weekly paclitaxel followed by dose-dense AC (doxorubicin and cyclophosphamide).

In a 2-by-2 factorial design, patients were randomized to additionally receive carboplatin or not, and to additionally receive bevacizumab (Avastin) or not.

Adding carboplatin increased the rate of pCR in the breast only (60% vs. 46%; odds ratio, 1.76; P = .002) and pCR in both the breast and axilla (54% vs. 41%; odds ratio, 1.71; P = .003).

Similarly, adding bevacizumab increased the rate of pCR in the breast only (59% vs. 48%; odds ratio, 1.58; P = .009) but conferred only a trend toward an increased rate of pCR in both the breast and axilla (52% vs. 44%; odds ratio, 1.36; P = .057).

There was no significant interaction between the treatment effect of carboplatin and the treatment effect of bevacizumab, according to Dr. Sikov, who disclosed no conflicts of interest related to the trial.

In terms of toxicity, adding carboplatin increased rates of grade 3 or worse neutropenia and thrombocytopenia. Adding bevacizumab increased rates of grade 3 or worse hypertension, bleeding, and thrombosis. And adding both drugs increased rates of both sets of adverse events, with a higher rate of grade 3 or worse febrile neutropenia.

Serious adverse events were more common with added bevacizumab and with added carboplatin-bevacizumab. For example, 15% and 16% of patients in these arms, respectively, developed febrile neutropenia during receipt of the AC part of chemotherapy.

Also, addition of bevacizumab was associated with a higher rate of postsurgical complications (9% vs. 5%), most often hematoma or seroma, and a higher rate of delayed surgical complications (4% vs. 1%), such as wound healing issues.

SAN ANTONIO – When added to standard neoadjuvant chemotherapy, carboplatin and bevacizumab each improve the odds of eradicating local disease in women with triple-negative breast cancer, but their impact on toxicity differs, based on findings from a randomized phase II trial.

Adding carboplatin to standard chemotherapy improved the odds of pathologic complete response (pCR) by 71%-76% with some increase in toxicity such as neutropenia and thrombocytopenia. Adding the antiangiogenic agent bevacizumab improved the odds of pCR by 58%, but with a considerable increase in toxicity such as hypertension and postoperative complications, based on results of the Cancer and Leukemia Group B (CALGB)/Alliance 40603 trial of 443 women with stage II or III triple-negative breast cancer. Dr. William M. Sikov reported the results in a session and at a press briefing at the San Antonio Breast Cancer Symposium.

Dr. Sikov of Warren Alpert Medical School of Brown University, Providence, R.I., acknowledged that the trial was not powered to assess recurrence-free and overall survivals. While it remains unclear whether pCR predicts improved survival, data from other trials and a meta-analysis suggest that pCR is a good surrogate endpoint and have prompted the Food and Drug Administration to consider this endpoint for new drug approval pending long-term data.

Based on the results from this trial and those of the similar GeparSixto trial reported at the 2013 ASCO annual meeting, he said, "if you have decided a patient with triple-negative breast cancer should receive neoadjuvant chemotherapy based on the size of the tumor, based on the desire to improve the chance of breast conservation, then I think it makes sense to add carboplatin to your neoadjuvant regimen, and that you can comfortably do so with acceptable additional toxicities."

Alternatively, Dr. Sikov said that bevacizumab "increased the pCR rate, but at the cost of significant toxicities, and I don’t think that [bevacizumab] should be routinely added to neoadjuvant chemotherapy."

In the CALGB/Alliance 40603 trial, which was funded in part by Genentech, about three-fourths of the women were white, and roughly two-thirds had clinical stage II disease; 55% had clinically positive nodes.

All of the women were treated with weekly paclitaxel followed by dose-dense AC (doxorubicin and cyclophosphamide).

In a 2-by-2 factorial design, patients were randomized to additionally receive carboplatin or not, and to additionally receive bevacizumab (Avastin) or not.

Adding carboplatin increased the rate of pCR in the breast only (60% vs. 46%; odds ratio, 1.76; P = .002) and pCR in both the breast and axilla (54% vs. 41%; odds ratio, 1.71; P = .003).

Similarly, adding bevacizumab increased the rate of pCR in the breast only (59% vs. 48%; odds ratio, 1.58; P = .009) but conferred only a trend toward an increased rate of pCR in both the breast and axilla (52% vs. 44%; odds ratio, 1.36; P = .057).

There was no significant interaction between the treatment effect of carboplatin and the treatment effect of bevacizumab, according to Dr. Sikov, who disclosed no conflicts of interest related to the trial.

In terms of toxicity, adding carboplatin increased rates of grade 3 or worse neutropenia and thrombocytopenia. Adding bevacizumab increased rates of grade 3 or worse hypertension, bleeding, and thrombosis. And adding both drugs increased rates of both sets of adverse events, with a higher rate of grade 3 or worse febrile neutropenia.

Serious adverse events were more common with added bevacizumab and with added carboplatin-bevacizumab. For example, 15% and 16% of patients in these arms, respectively, developed febrile neutropenia during receipt of the AC part of chemotherapy.

Also, addition of bevacizumab was associated with a higher rate of postsurgical complications (9% vs. 5%), most often hematoma or seroma, and a higher rate of delayed surgical complications (4% vs. 1%), such as wound healing issues.

SAN ANTONIO – When added to standard neoadjuvant chemotherapy, carboplatin and bevacizumab each improve the odds of eradicating local disease in women with triple-negative breast cancer, but their impact on toxicity differs, based on findings from a randomized phase II trial.

Adding carboplatin to standard chemotherapy improved the odds of pathologic complete response (pCR) by 71%-76% with some increase in toxicity such as neutropenia and thrombocytopenia. Adding the antiangiogenic agent bevacizumab improved the odds of pCR by 58%, but with a considerable increase in toxicity such as hypertension and postoperative complications, based on results of the Cancer and Leukemia Group B (CALGB)/Alliance 40603 trial of 443 women with stage II or III triple-negative breast cancer. Dr. William M. Sikov reported the results in a session and at a press briefing at the San Antonio Breast Cancer Symposium.

Dr. Sikov of Warren Alpert Medical School of Brown University, Providence, R.I., acknowledged that the trial was not powered to assess recurrence-free and overall survivals. While it remains unclear whether pCR predicts improved survival, data from other trials and a meta-analysis suggest that pCR is a good surrogate endpoint and have prompted the Food and Drug Administration to consider this endpoint for new drug approval pending long-term data.

Based on the results from this trial and those of the similar GeparSixto trial reported at the 2013 ASCO annual meeting, he said, "if you have decided a patient with triple-negative breast cancer should receive neoadjuvant chemotherapy based on the size of the tumor, based on the desire to improve the chance of breast conservation, then I think it makes sense to add carboplatin to your neoadjuvant regimen, and that you can comfortably do so with acceptable additional toxicities."

Alternatively, Dr. Sikov said that bevacizumab "increased the pCR rate, but at the cost of significant toxicities, and I don’t think that [bevacizumab] should be routinely added to neoadjuvant chemotherapy."

In the CALGB/Alliance 40603 trial, which was funded in part by Genentech, about three-fourths of the women were white, and roughly two-thirds had clinical stage II disease; 55% had clinically positive nodes.

All of the women were treated with weekly paclitaxel followed by dose-dense AC (doxorubicin and cyclophosphamide).

In a 2-by-2 factorial design, patients were randomized to additionally receive carboplatin or not, and to additionally receive bevacizumab (Avastin) or not.

Adding carboplatin increased the rate of pCR in the breast only (60% vs. 46%; odds ratio, 1.76; P = .002) and pCR in both the breast and axilla (54% vs. 41%; odds ratio, 1.71; P = .003).

Similarly, adding bevacizumab increased the rate of pCR in the breast only (59% vs. 48%; odds ratio, 1.58; P = .009) but conferred only a trend toward an increased rate of pCR in both the breast and axilla (52% vs. 44%; odds ratio, 1.36; P = .057).

There was no significant interaction between the treatment effect of carboplatin and the treatment effect of bevacizumab, according to Dr. Sikov, who disclosed no conflicts of interest related to the trial.

In terms of toxicity, adding carboplatin increased rates of grade 3 or worse neutropenia and thrombocytopenia. Adding bevacizumab increased rates of grade 3 or worse hypertension, bleeding, and thrombosis. And adding both drugs increased rates of both sets of adverse events, with a higher rate of grade 3 or worse febrile neutropenia.

Serious adverse events were more common with added bevacizumab and with added carboplatin-bevacizumab. For example, 15% and 16% of patients in these arms, respectively, developed febrile neutropenia during receipt of the AC part of chemotherapy.

Also, addition of bevacizumab was associated with a higher rate of postsurgical complications (9% vs. 5%), most often hematoma or seroma, and a higher rate of delayed surgical complications (4% vs. 1%), such as wound healing issues.

SAN ANTONIO – The combination of veliparib and carboplatin is the first "graduate" of the I-SPY 2 trial, investigators reported at the San Antonio Breast Cancer Symposium.

The phase 2 trial uses an adaptive design to screen novel agents and regimens by assessing whether they improve response when added to neoadjuvant chemotherapy, with the aim of matching them to breast cancer biomarker signatures most likely to respond.

The novel agents or regimens graduate, or meet the bar for further testing, if there is a 85% probability or better that they will be superior to chemotherapy alone for at least one signature in a modestly sized phase 3 neoadjuvant trial.

First results from 115 patients, reported in a session and press briefing by lead author Dr. Hope S. Rugo, showed that based on the estimated pathologic complete responses (pCRs) seen, there was a 90% probability that the combination of veliparib—an oral investigational inhibitor of poly-ADP-ribose, or PARP—and carboplatin added to chemotherapy would be superior to chemotherapy alone among patients with triple-negative disease.

In contrast, the probability in all patients with HER2-negative disease was only slightly better than a coin toss. And the probability in the subset with hormone receptor–positive, HER2-negative disease was less than one in 10.

"Veliparib and carboplatin has graduated with the triple-negative signature, the subset recommended for this drug’s subsequent development," said Dr. Rugo, who is a professor of medicine and director of breast oncology and clinical trials education at the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco.

"We identified a biomarker signature–drug pair for veliparib and carboplatin on the basis of a modest number of patients...This trial design will accelerate the process of identifying drugs that are effective for specific breast cancer subtypes and thereby reduce the cost, time, and numbers of patients needed to get effective drugs to market," she noted.

The trial was not designed to assess the contribution of each agent—veliparib (ABT-888, manufactured by AbbVie) and carboplatin—individually, Dr. Rugo acknowledged; regardless, their combination had a large effect size.

"I-SPY 2 is a biomarker-rich trial. Additional response predictors are under evaluation," such as BRCA status, she further noted.

"A lot of work has been done with the FDA [Food and Drug Administration] recently evaluating drugs for accelerated approval based on their response in the neoadjuvant setting. How this plays out in the future for other drugs [besides pertuzumab] remains to be seen," Dr. Rugo commented. "Clearly there needs to be a plan for outcome data that can correspond to the pCR rates in order for these drugs to obtain final approval. But there is the hope that this will be a mechanism for accelerated approval."

The trial has six other arms testing investigational regimens. Results for the arm that is testing neratinib (PB272, Puma Biotechnology), a tyrosine kinase inhibitor, are expected shortly.

Women are eligible for I-SPY 2 (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging And moLecular Analysis 2) if they have tumors measuring at least 2.5 cm. Those whose tumors have all of three favorable characteristics (hormone receptor positive, HER2 negative, and Low MammaPrint result) are excluded.

Eight biomarker signatures are created according to hormone receptor status, HER2 status, and MammaPrint result (High or Ultra High).

The trial uses adaptive randomization, whereby each patient’s MRI and pCR data are fed into an algorithm, affecting how the next patient is randomized. "This allows us to learn and adapt from each patient as we go along, and each new patient benefits from information obtained from the prior patient. In addition, this allows us to add and drop agents as we go along based on success of each agent or regimen," explained Dr. Rugo, who disclosed no conflicts of interest related to the trial.

Patients are randomized to receive weekly paclitaxel plus a novel agent/regimen or weekly paclitaxel alone—each followed by standard doxorubicin and cyclophosphamide (AC) chemotherapy and then surgery. The endpoint of pCR is defined as no residual cancer in the breast or lymph nodes at the time of surgery.

The results are used to predict the probability of superiority in a phase 3 neoadjuvant trial having just 300 patients and using pCR as its endpoint.

The findings that Dr. Rugo presented were based on 115 patients with HER2-negative disease: 71 randomized to veliparib-carboplatin plus chemotherapy and 44 randomized to chemotherapy alone.

Among patients with triple-negative disease, the estimated rate of pCR was 52% with veliparib-carboplatin and 26% without it. There was a 90% predictive probability that the combination with chemotherapy would be superior to chemotherapy alone in phase 3 testing in this subset.

In contrast, the difference in estimated pCR rates with addition of veliparib-carboplatin was much smaller among all patients with HER2-negative disease (33% vs. 22%) and in the opposite direction among the subset with hormone receptor–positive, HER2-negative disease (14% vs. 19%). The predictive probabilities that the combination with chemotherapy would be superior in phase 3 testing in these groups were just 55% and 9%, respectively.

"The toxicity was moderately increased as expected, but it was well managed with dose reduction and delay," Dr. Rugo reported.

Dr. Rugo disclosed no relevant conflicts of interest.

SAN ANTONIO – The combination of veliparib and carboplatin is the first "graduate" of the I-SPY 2 trial, investigators reported at the San Antonio Breast Cancer Symposium.

The phase 2 trial uses an adaptive design to screen novel agents and regimens by assessing whether they improve response when added to neoadjuvant chemotherapy, with the aim of matching them to breast cancer biomarker signatures most likely to respond.

The novel agents or regimens graduate, or meet the bar for further testing, if there is a 85% probability or better that they will be superior to chemotherapy alone for at least one signature in a modestly sized phase 3 neoadjuvant trial.

First results from 115 patients, reported in a session and press briefing by lead author Dr. Hope S. Rugo, showed that based on the estimated pathologic complete responses (pCRs) seen, there was a 90% probability that the combination of veliparib—an oral investigational inhibitor of poly-ADP-ribose, or PARP—and carboplatin added to chemotherapy would be superior to chemotherapy alone among patients with triple-negative disease.

In contrast, the probability in all patients with HER2-negative disease was only slightly better than a coin toss. And the probability in the subset with hormone receptor–positive, HER2-negative disease was less than one in 10.

"Veliparib and carboplatin has graduated with the triple-negative signature, the subset recommended for this drug’s subsequent development," said Dr. Rugo, who is a professor of medicine and director of breast oncology and clinical trials education at the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco.

"We identified a biomarker signature–drug pair for veliparib and carboplatin on the basis of a modest number of patients...This trial design will accelerate the process of identifying drugs that are effective for specific breast cancer subtypes and thereby reduce the cost, time, and numbers of patients needed to get effective drugs to market," she noted.

The trial was not designed to assess the contribution of each agent—veliparib (ABT-888, manufactured by AbbVie) and carboplatin—individually, Dr. Rugo acknowledged; regardless, their combination had a large effect size.

"I-SPY 2 is a biomarker-rich trial. Additional response predictors are under evaluation," such as BRCA status, she further noted.

"A lot of work has been done with the FDA [Food and Drug Administration] recently evaluating drugs for accelerated approval based on their response in the neoadjuvant setting. How this plays out in the future for other drugs [besides pertuzumab] remains to be seen," Dr. Rugo commented. "Clearly there needs to be a plan for outcome data that can correspond to the pCR rates in order for these drugs to obtain final approval. But there is the hope that this will be a mechanism for accelerated approval."

The trial has six other arms testing investigational regimens. Results for the arm that is testing neratinib (PB272, Puma Biotechnology), a tyrosine kinase inhibitor, are expected shortly.

Women are eligible for I-SPY 2 (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging And moLecular Analysis 2) if they have tumors measuring at least 2.5 cm. Those whose tumors have all of three favorable characteristics (hormone receptor positive, HER2 negative, and Low MammaPrint result) are excluded.

Eight biomarker signatures are created according to hormone receptor status, HER2 status, and MammaPrint result (High or Ultra High).

The trial uses adaptive randomization, whereby each patient’s MRI and pCR data are fed into an algorithm, affecting how the next patient is randomized. "This allows us to learn and adapt from each patient as we go along, and each new patient benefits from information obtained from the prior patient. In addition, this allows us to add and drop agents as we go along based on success of each agent or regimen," explained Dr. Rugo, who disclosed no conflicts of interest related to the trial.

Patients are randomized to receive weekly paclitaxel plus a novel agent/regimen or weekly paclitaxel alone—each followed by standard doxorubicin and cyclophosphamide (AC) chemotherapy and then surgery. The endpoint of pCR is defined as no residual cancer in the breast or lymph nodes at the time of surgery.

The results are used to predict the probability of superiority in a phase 3 neoadjuvant trial having just 300 patients and using pCR as its endpoint.

The findings that Dr. Rugo presented were based on 115 patients with HER2-negative disease: 71 randomized to veliparib-carboplatin plus chemotherapy and 44 randomized to chemotherapy alone.

Among patients with triple-negative disease, the estimated rate of pCR was 52% with veliparib-carboplatin and 26% without it. There was a 90% predictive probability that the combination with chemotherapy would be superior to chemotherapy alone in phase 3 testing in this subset.

In contrast, the difference in estimated pCR rates with addition of veliparib-carboplatin was much smaller among all patients with HER2-negative disease (33% vs. 22%) and in the opposite direction among the subset with hormone receptor–positive, HER2-negative disease (14% vs. 19%). The predictive probabilities that the combination with chemotherapy would be superior in phase 3 testing in these groups were just 55% and 9%, respectively.

"The toxicity was moderately increased as expected, but it was well managed with dose reduction and delay," Dr. Rugo reported.

Dr. Rugo disclosed no relevant conflicts of interest.

SAN ANTONIO – The combination of veliparib and carboplatin is the first "graduate" of the I-SPY 2 trial, investigators reported at the San Antonio Breast Cancer Symposium.

The phase 2 trial uses an adaptive design to screen novel agents and regimens by assessing whether they improve response when added to neoadjuvant chemotherapy, with the aim of matching them to breast cancer biomarker signatures most likely to respond.

The novel agents or regimens graduate, or meet the bar for further testing, if there is a 85% probability or better that they will be superior to chemotherapy alone for at least one signature in a modestly sized phase 3 neoadjuvant trial.

First results from 115 patients, reported in a session and press briefing by lead author Dr. Hope S. Rugo, showed that based on the estimated pathologic complete responses (pCRs) seen, there was a 90% probability that the combination of veliparib—an oral investigational inhibitor of poly-ADP-ribose, or PARP—and carboplatin added to chemotherapy would be superior to chemotherapy alone among patients with triple-negative disease.

In contrast, the probability in all patients with HER2-negative disease was only slightly better than a coin toss. And the probability in the subset with hormone receptor–positive, HER2-negative disease was less than one in 10.

"Veliparib and carboplatin has graduated with the triple-negative signature, the subset recommended for this drug’s subsequent development," said Dr. Rugo, who is a professor of medicine and director of breast oncology and clinical trials education at the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco.

"We identified a biomarker signature–drug pair for veliparib and carboplatin on the basis of a modest number of patients...This trial design will accelerate the process of identifying drugs that are effective for specific breast cancer subtypes and thereby reduce the cost, time, and numbers of patients needed to get effective drugs to market," she noted.

The trial was not designed to assess the contribution of each agent—veliparib (ABT-888, manufactured by AbbVie) and carboplatin—individually, Dr. Rugo acknowledged; regardless, their combination had a large effect size.

"I-SPY 2 is a biomarker-rich trial. Additional response predictors are under evaluation," such as BRCA status, she further noted.

"A lot of work has been done with the FDA [Food and Drug Administration] recently evaluating drugs for accelerated approval based on their response in the neoadjuvant setting. How this plays out in the future for other drugs [besides pertuzumab] remains to be seen," Dr. Rugo commented. "Clearly there needs to be a plan for outcome data that can correspond to the pCR rates in order for these drugs to obtain final approval. But there is the hope that this will be a mechanism for accelerated approval."

The trial has six other arms testing investigational regimens. Results for the arm that is testing neratinib (PB272, Puma Biotechnology), a tyrosine kinase inhibitor, are expected shortly.

Women are eligible for I-SPY 2 (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging And moLecular Analysis 2) if they have tumors measuring at least 2.5 cm. Those whose tumors have all of three favorable characteristics (hormone receptor positive, HER2 negative, and Low MammaPrint result) are excluded.

Eight biomarker signatures are created according to hormone receptor status, HER2 status, and MammaPrint result (High or Ultra High).

The trial uses adaptive randomization, whereby each patient’s MRI and pCR data are fed into an algorithm, affecting how the next patient is randomized. "This allows us to learn and adapt from each patient as we go along, and each new patient benefits from information obtained from the prior patient. In addition, this allows us to add and drop agents as we go along based on success of each agent or regimen," explained Dr. Rugo, who disclosed no conflicts of interest related to the trial.

Patients are randomized to receive weekly paclitaxel plus a novel agent/regimen or weekly paclitaxel alone—each followed by standard doxorubicin and cyclophosphamide (AC) chemotherapy and then surgery. The endpoint of pCR is defined as no residual cancer in the breast or lymph nodes at the time of surgery.

The results are used to predict the probability of superiority in a phase 3 neoadjuvant trial having just 300 patients and using pCR as its endpoint.

The findings that Dr. Rugo presented were based on 115 patients with HER2-negative disease: 71 randomized to veliparib-carboplatin plus chemotherapy and 44 randomized to chemotherapy alone.

Among patients with triple-negative disease, the estimated rate of pCR was 52% with veliparib-carboplatin and 26% without it. There was a 90% predictive probability that the combination with chemotherapy would be superior to chemotherapy alone in phase 3 testing in this subset.

In contrast, the difference in estimated pCR rates with addition of veliparib-carboplatin was much smaller among all patients with HER2-negative disease (33% vs. 22%) and in the opposite direction among the subset with hormone receptor–positive, HER2-negative disease (14% vs. 19%). The predictive probabilities that the combination with chemotherapy would be superior in phase 3 testing in these groups were just 55% and 9%, respectively.

"The toxicity was moderately increased as expected, but it was well managed with dose reduction and delay," Dr. Rugo reported.

Dr. Rugo disclosed no relevant conflicts of interest.

SAN ANTONIO – In patients with metastatic breast cancer who responded favorably to initial chemotherapy, radiotherapy and surgical removal of primary tumors failed to enhance overall survival, a new study has shown.

In an interview at the San Antonio Breast Cancer Symposium, study investigator Dr. Rajendra Badwe offers his perspectives on loco-regional treatment vs. chemotherapy alone, and he discusses why surgical removal of primary tumors might be linked to later spread of metastatic disease.

SAN ANTONIO – In patients with metastatic breast cancer who responded favorably to initial chemotherapy, radiotherapy and surgical removal of primary tumors failed to enhance overall survival, a new study has shown.

In an interview at the San Antonio Breast Cancer Symposium, study investigator Dr. Rajendra Badwe offers his perspectives on loco-regional treatment vs. chemotherapy alone, and he discusses why surgical removal of primary tumors might be linked to later spread of metastatic disease.

SAN ANTONIO – In patients with metastatic breast cancer who responded favorably to initial chemotherapy, radiotherapy and surgical removal of primary tumors failed to enhance overall survival, a new study has shown.

In an interview at the San Antonio Breast Cancer Symposium, study investigator Dr. Rajendra Badwe offers his perspectives on loco-regional treatment vs. chemotherapy alone, and he discusses why surgical removal of primary tumors might be linked to later spread of metastatic disease.