AACR Annual Meeting 2012

CHICAGO – Maintenance immunotherapy with low-dose interleukin-2 and 13-cis-retinoic acid demonstrated an "unexpected" survival benefit in a phase II trial among 500 patients who had derived clinical benefit from chemotherapy for a variety of stage IV cancers, investigators from Italy reported.

The 15-year disease-free survival and overall survival rates reached 32.6% and 36.8%, respectively, in the open, nonrandomized trial, and a breakdown by tumor type showed better outcomes than seen in historic controls, Dr. Francesco Recchia reported at the annual meeting of the American Association for Cancer Research.

©AACR/Phil McCarten

Comparing their data with outcomes for the most commonly treated metastatic cancers in the Surveillance, Epidemiology, and End Results (SEER) database in the United States, the investigators found their 5-year overall survival rates were 42.7% vs. 23.3% for breast cancer, 26.4% vs. 3.6% for lung cancer, 43.6% vs. 11.7% for colorectal cancer, and 23% vs. 11% for renal cancer.

"The good and unexpected results of this immunotherapy regimen were seen in all types of cancer: ovarian cancer and recurrent ovarian cancer, non–small cell lung cancer, cardiac metastases of sarcoma, colorectal cancer, gastric cancer, renal cell carcinoma, melanoma, head and neck cancer, breast cancer, and pancreatic cancer," said Dr. Recchia, director of oncology at the Civilian Hospital in Avezzano (Italy).

"The best merit of our research is the low cost of this therapy," he added.

The impetus for the phase II trial was an observation, in 1995, that a patient, who could not tolerate standard high-dose (18 x 10⁶ IU/m²) IL-2 therapy for metastatic melanoma, experienced a long-lasting response to low-dose subcutaneous IL-2. Dr. Recchia and his colleagues conducted a series of phase I and II randomized studies of low-dose IL-2 with and without retinoic acid, ultimately determining that the combination of the two agents was most effective in increasing natural killer (NK) cell populations and decreasing vascular endothelial growth factor (VEGF) expression.

In the current study, after a median follow-up of 60 months, Dr. Recchia and his colleagues observed a statistically significant increase in the number of NK cells – mediators of lytic activity against cancer cell lines – from a baseline mean of 309/mm³ to a mean of 579/mm³. They also found a statistically significant decrease in VEGF expression, from a baseline mean of 520 pg/mm³ to a mean of 150 pg/mm³ in the study participants.

"Both of these mechanisms are associated with slowing cancer growth," he said in an interview.

All of the patients enrolled in the study were in chemotherapy-induced remission, with good performance status, from stage IV cancer, and all (median age 61 years) were treated for 1 year with self-administered subcutaneous IL-2 (1.8 x 10⁶ IU) and oral 13-cis-retinoic acid (0.5 mg/kg) 5 days per week for two consecutive 3-week cycles, with a 1-week rest. This was followed by continued intermittently scheduled therapy for 5 years or until disease progression, with assessment of NK cells, serum VEGF, tumor response, and toxicity every 4 months, Dr. Recchia said.

The study’s primary end point was NK cell and VEGF response, he added, noting that disease-free survival, overall survival, and toxicity in various tumor types were secondary end points.

The treatment was not associated with any World Health Organization grade 3 or 4 toxicities, Dr. Recchia reported. Grade 2 cutaneous toxicity (20%), fever (13%), mild hypothyroidism (5%), and triglyceride elevation (15%) were observed, he said; one patient discontinued treatment because of grade 2 urticaria.

Prior to using the maintenance regimen in clinical practice, the findings of the current study have to be validated in a blinded, controlled, randomized trial, said Dr. Recchia, noting that a phase III study is underway in patients with advanced breast cancer.

Dr. Recchia reported having no relevant financial conflicts of interest.

CHICAGO – Maintenance immunotherapy with low-dose interleukin-2 and 13-cis-retinoic acid demonstrated an "unexpected" survival benefit in a phase II trial among 500 patients who had derived clinical benefit from chemotherapy for a variety of stage IV cancers, investigators from Italy reported.

The 15-year disease-free survival and overall survival rates reached 32.6% and 36.8%, respectively, in the open, nonrandomized trial, and a breakdown by tumor type showed better outcomes than seen in historic controls, Dr. Francesco Recchia reported at the annual meeting of the American Association for Cancer Research.

©AACR/Phil McCarten

Comparing their data with outcomes for the most commonly treated metastatic cancers in the Surveillance, Epidemiology, and End Results (SEER) database in the United States, the investigators found their 5-year overall survival rates were 42.7% vs. 23.3% for breast cancer, 26.4% vs. 3.6% for lung cancer, 43.6% vs. 11.7% for colorectal cancer, and 23% vs. 11% for renal cancer.

"The good and unexpected results of this immunotherapy regimen were seen in all types of cancer: ovarian cancer and recurrent ovarian cancer, non–small cell lung cancer, cardiac metastases of sarcoma, colorectal cancer, gastric cancer, renal cell carcinoma, melanoma, head and neck cancer, breast cancer, and pancreatic cancer," said Dr. Recchia, director of oncology at the Civilian Hospital in Avezzano (Italy).

"The best merit of our research is the low cost of this therapy," he added.

The impetus for the phase II trial was an observation, in 1995, that a patient, who could not tolerate standard high-dose (18 x 10⁶ IU/m²) IL-2 therapy for metastatic melanoma, experienced a long-lasting response to low-dose subcutaneous IL-2. Dr. Recchia and his colleagues conducted a series of phase I and II randomized studies of low-dose IL-2 with and without retinoic acid, ultimately determining that the combination of the two agents was most effective in increasing natural killer (NK) cell populations and decreasing vascular endothelial growth factor (VEGF) expression.

In the current study, after a median follow-up of 60 months, Dr. Recchia and his colleagues observed a statistically significant increase in the number of NK cells – mediators of lytic activity against cancer cell lines – from a baseline mean of 309/mm³ to a mean of 579/mm³. They also found a statistically significant decrease in VEGF expression, from a baseline mean of 520 pg/mm³ to a mean of 150 pg/mm³ in the study participants.

"Both of these mechanisms are associated with slowing cancer growth," he said in an interview.

All of the patients enrolled in the study were in chemotherapy-induced remission, with good performance status, from stage IV cancer, and all (median age 61 years) were treated for 1 year with self-administered subcutaneous IL-2 (1.8 x 10⁶ IU) and oral 13-cis-retinoic acid (0.5 mg/kg) 5 days per week for two consecutive 3-week cycles, with a 1-week rest. This was followed by continued intermittently scheduled therapy for 5 years or until disease progression, with assessment of NK cells, serum VEGF, tumor response, and toxicity every 4 months, Dr. Recchia said.

The study’s primary end point was NK cell and VEGF response, he added, noting that disease-free survival, overall survival, and toxicity in various tumor types were secondary end points.

The treatment was not associated with any World Health Organization grade 3 or 4 toxicities, Dr. Recchia reported. Grade 2 cutaneous toxicity (20%), fever (13%), mild hypothyroidism (5%), and triglyceride elevation (15%) were observed, he said; one patient discontinued treatment because of grade 2 urticaria.

Prior to using the maintenance regimen in clinical practice, the findings of the current study have to be validated in a blinded, controlled, randomized trial, said Dr. Recchia, noting that a phase III study is underway in patients with advanced breast cancer.

Dr. Recchia reported having no relevant financial conflicts of interest.

CHICAGO – Maintenance immunotherapy with low-dose interleukin-2 and 13-cis-retinoic acid demonstrated an "unexpected" survival benefit in a phase II trial among 500 patients who had derived clinical benefit from chemotherapy for a variety of stage IV cancers, investigators from Italy reported.

The 15-year disease-free survival and overall survival rates reached 32.6% and 36.8%, respectively, in the open, nonrandomized trial, and a breakdown by tumor type showed better outcomes than seen in historic controls, Dr. Francesco Recchia reported at the annual meeting of the American Association for Cancer Research.

©AACR/Phil McCarten

Comparing their data with outcomes for the most commonly treated metastatic cancers in the Surveillance, Epidemiology, and End Results (SEER) database in the United States, the investigators found their 5-year overall survival rates were 42.7% vs. 23.3% for breast cancer, 26.4% vs. 3.6% for lung cancer, 43.6% vs. 11.7% for colorectal cancer, and 23% vs. 11% for renal cancer.

"The good and unexpected results of this immunotherapy regimen were seen in all types of cancer: ovarian cancer and recurrent ovarian cancer, non–small cell lung cancer, cardiac metastases of sarcoma, colorectal cancer, gastric cancer, renal cell carcinoma, melanoma, head and neck cancer, breast cancer, and pancreatic cancer," said Dr. Recchia, director of oncology at the Civilian Hospital in Avezzano (Italy).

"The best merit of our research is the low cost of this therapy," he added.

The impetus for the phase II trial was an observation, in 1995, that a patient, who could not tolerate standard high-dose (18 x 10⁶ IU/m²) IL-2 therapy for metastatic melanoma, experienced a long-lasting response to low-dose subcutaneous IL-2. Dr. Recchia and his colleagues conducted a series of phase I and II randomized studies of low-dose IL-2 with and without retinoic acid, ultimately determining that the combination of the two agents was most effective in increasing natural killer (NK) cell populations and decreasing vascular endothelial growth factor (VEGF) expression.

In the current study, after a median follow-up of 60 months, Dr. Recchia and his colleagues observed a statistically significant increase in the number of NK cells – mediators of lytic activity against cancer cell lines – from a baseline mean of 309/mm³ to a mean of 579/mm³. They also found a statistically significant decrease in VEGF expression, from a baseline mean of 520 pg/mm³ to a mean of 150 pg/mm³ in the study participants.

"Both of these mechanisms are associated with slowing cancer growth," he said in an interview.

All of the patients enrolled in the study were in chemotherapy-induced remission, with good performance status, from stage IV cancer, and all (median age 61 years) were treated for 1 year with self-administered subcutaneous IL-2 (1.8 x 10⁶ IU) and oral 13-cis-retinoic acid (0.5 mg/kg) 5 days per week for two consecutive 3-week cycles, with a 1-week rest. This was followed by continued intermittently scheduled therapy for 5 years or until disease progression, with assessment of NK cells, serum VEGF, tumor response, and toxicity every 4 months, Dr. Recchia said.

The study’s primary end point was NK cell and VEGF response, he added, noting that disease-free survival, overall survival, and toxicity in various tumor types were secondary end points.

The treatment was not associated with any World Health Organization grade 3 or 4 toxicities, Dr. Recchia reported. Grade 2 cutaneous toxicity (20%), fever (13%), mild hypothyroidism (5%), and triglyceride elevation (15%) were observed, he said; one patient discontinued treatment because of grade 2 urticaria.

Prior to using the maintenance regimen in clinical practice, the findings of the current study have to be validated in a blinded, controlled, randomized trial, said Dr. Recchia, noting that a phase III study is underway in patients with advanced breast cancer.

Dr. Recchia reported having no relevant financial conflicts of interest.

CHICAGO – Two targeted therapies may be better than one for the treatment of refractory Ewing’s sarcoma, according to findings of an early clinical trial reported at the annual meeting of the American Association for Cancer Research.

Combining the investigational agent cixutumumab with temsirolimus (Torisel) resulted in 2 complete responses and 3 partial responses in 17 adolescent and young adult patients with heavily pretreated disease in the phase I clinical trial.

© 2012 AACR/Todd Buchanan

Cixutumumab, a novel monoclonal antibody targeting the insulin-like growth factor 1-receptor (IGF-1R), is under investigation for various cancers. Temsirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is approved for the treatment of advanced renal cell carcinomas.

The two drugs have previously been used as single treatment agents, producing mixed results, according to Dr. Aung Naing of the department of investigational cancer therapeutics at the University of Texas M.D. Anderson Cancer Center in Houston.

Based on data from preclinical studies, "we hypothesized that combining the two could help prevent drug-resistance, which is a common problem in Ewing’s sarcoma," he said in an interview. The two agents target molecular pathways associated with cell proliferation and survival, abnormal blood vessel growth, and resistance to both chemotherapy and radiation therapy, Dr. Naing explained.

To test their hypothesis, the investigators enrolled 20 patients, median age 20 years, with Ewing’s sarcoma (17) or desmoplastic small-round-cell tumors (3) in the trial. The median number of prior therapies per patient was 6. Two patients previously received temsirolimus and six previously received an IGF-1R inhibitor, he said.

All of the patients received 6 mg/kg of intravenous cixutumumab and 25-37.5mg of intravenous temsirolimus weekly for 4-week cycles, with restaging after 8 weeks, Dr. Naing reported.

At a median follow-up of 8.9 months, 7 of the 20 patients (35%) had achieved a complete or partial response or stable disease lasting more than 5 months.

In Ewing’s sarcoma patients specifically, 29% had evidence of tumor regression greater than 20%, Dr. Naing said, noting, "Two patients achieved complete responses, one of which lasted 27 months."

The most frequent, possibly drug-related toxicities included thrombocytopenia (85%), mucositis (80%), hypercholesterolemia (75%), hypertriglyceridemia (70%), and hyperglycemia (65%).

"Most were grade 1-2 [toxicities], but four of the seven best responders developed grade 3 mucositis, myelosuppression, or hyperglycemia, which were managed while maintaining drug dose," Dr. Naing stated.

"Typically, patients who develop these types of grade 3 toxicities would be removed from the study, but we were able to continue with treatment after receiving approval from the sponsor and notification from our institutional review board," he said. Because the toxicities were able to be controlled using supportive measures, "the drug dose did not have to be compromised."

One of the Ewing’s sarcoma patients had achieved a partial response with prior IGF-1R treatment. After initiating the combination therapy, this patient had a mixed response with "remarkable" regression in three lung nodules but progression in a fourth. Morphoproteomic analysis of biopsy samples from this patient demonstrated upregulation of mTOR and ERK/MEK signals, suggesting the possibility that a combination of IGFR/mTOR and MAPK/ERK kinase (MEK) inhibitors might warrant investigation in order to reverse resistance, according to Dr. Naing.

Based on the evidence of activity for the drug combination, the investigators are planning further studies in larger numbers of patients with tumors in the Ewing’s sarcoma family, as well as additional studies into the underlying mechanisms of resistance in individual patients, Dr. Naing said during a press conference.

The results of this study were published simultaneously in Clinical Cancer Research (2012 [doi:10.1158/1078-0432.CCR-12-0061]).

Dr. Naing reported having no relevant financial relationships to disclose.

CHICAGO – Two targeted therapies may be better than one for the treatment of refractory Ewing’s sarcoma, according to findings of an early clinical trial reported at the annual meeting of the American Association for Cancer Research.

Combining the investigational agent cixutumumab with temsirolimus (Torisel) resulted in 2 complete responses and 3 partial responses in 17 adolescent and young adult patients with heavily pretreated disease in the phase I clinical trial.

© 2012 AACR/Todd Buchanan

Cixutumumab, a novel monoclonal antibody targeting the insulin-like growth factor 1-receptor (IGF-1R), is under investigation for various cancers. Temsirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is approved for the treatment of advanced renal cell carcinomas.

The two drugs have previously been used as single treatment agents, producing mixed results, according to Dr. Aung Naing of the department of investigational cancer therapeutics at the University of Texas M.D. Anderson Cancer Center in Houston.

Based on data from preclinical studies, "we hypothesized that combining the two could help prevent drug-resistance, which is a common problem in Ewing’s sarcoma," he said in an interview. The two agents target molecular pathways associated with cell proliferation and survival, abnormal blood vessel growth, and resistance to both chemotherapy and radiation therapy, Dr. Naing explained.

To test their hypothesis, the investigators enrolled 20 patients, median age 20 years, with Ewing’s sarcoma (17) or desmoplastic small-round-cell tumors (3) in the trial. The median number of prior therapies per patient was 6. Two patients previously received temsirolimus and six previously received an IGF-1R inhibitor, he said.

All of the patients received 6 mg/kg of intravenous cixutumumab and 25-37.5mg of intravenous temsirolimus weekly for 4-week cycles, with restaging after 8 weeks, Dr. Naing reported.

At a median follow-up of 8.9 months, 7 of the 20 patients (35%) had achieved a complete or partial response or stable disease lasting more than 5 months.

In Ewing’s sarcoma patients specifically, 29% had evidence of tumor regression greater than 20%, Dr. Naing said, noting, "Two patients achieved complete responses, one of which lasted 27 months."

The most frequent, possibly drug-related toxicities included thrombocytopenia (85%), mucositis (80%), hypercholesterolemia (75%), hypertriglyceridemia (70%), and hyperglycemia (65%).

"Most were grade 1-2 [toxicities], but four of the seven best responders developed grade 3 mucositis, myelosuppression, or hyperglycemia, which were managed while maintaining drug dose," Dr. Naing stated.

"Typically, patients who develop these types of grade 3 toxicities would be removed from the study, but we were able to continue with treatment after receiving approval from the sponsor and notification from our institutional review board," he said. Because the toxicities were able to be controlled using supportive measures, "the drug dose did not have to be compromised."

One of the Ewing’s sarcoma patients had achieved a partial response with prior IGF-1R treatment. After initiating the combination therapy, this patient had a mixed response with "remarkable" regression in three lung nodules but progression in a fourth. Morphoproteomic analysis of biopsy samples from this patient demonstrated upregulation of mTOR and ERK/MEK signals, suggesting the possibility that a combination of IGFR/mTOR and MAPK/ERK kinase (MEK) inhibitors might warrant investigation in order to reverse resistance, according to Dr. Naing.

Based on the evidence of activity for the drug combination, the investigators are planning further studies in larger numbers of patients with tumors in the Ewing’s sarcoma family, as well as additional studies into the underlying mechanisms of resistance in individual patients, Dr. Naing said during a press conference.

The results of this study were published simultaneously in Clinical Cancer Research (2012 [doi:10.1158/1078-0432.CCR-12-0061]).

Dr. Naing reported having no relevant financial relationships to disclose.

CHICAGO – Two targeted therapies may be better than one for the treatment of refractory Ewing’s sarcoma, according to findings of an early clinical trial reported at the annual meeting of the American Association for Cancer Research.

Combining the investigational agent cixutumumab with temsirolimus (Torisel) resulted in 2 complete responses and 3 partial responses in 17 adolescent and young adult patients with heavily pretreated disease in the phase I clinical trial.

© 2012 AACR/Todd Buchanan

Cixutumumab, a novel monoclonal antibody targeting the insulin-like growth factor 1-receptor (IGF-1R), is under investigation for various cancers. Temsirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is approved for the treatment of advanced renal cell carcinomas.

The two drugs have previously been used as single treatment agents, producing mixed results, according to Dr. Aung Naing of the department of investigational cancer therapeutics at the University of Texas M.D. Anderson Cancer Center in Houston.

Based on data from preclinical studies, "we hypothesized that combining the two could help prevent drug-resistance, which is a common problem in Ewing’s sarcoma," he said in an interview. The two agents target molecular pathways associated with cell proliferation and survival, abnormal blood vessel growth, and resistance to both chemotherapy and radiation therapy, Dr. Naing explained.

To test their hypothesis, the investigators enrolled 20 patients, median age 20 years, with Ewing’s sarcoma (17) or desmoplastic small-round-cell tumors (3) in the trial. The median number of prior therapies per patient was 6. Two patients previously received temsirolimus and six previously received an IGF-1R inhibitor, he said.

All of the patients received 6 mg/kg of intravenous cixutumumab and 25-37.5mg of intravenous temsirolimus weekly for 4-week cycles, with restaging after 8 weeks, Dr. Naing reported.

At a median follow-up of 8.9 months, 7 of the 20 patients (35%) had achieved a complete or partial response or stable disease lasting more than 5 months.

In Ewing’s sarcoma patients specifically, 29% had evidence of tumor regression greater than 20%, Dr. Naing said, noting, "Two patients achieved complete responses, one of which lasted 27 months."

The most frequent, possibly drug-related toxicities included thrombocytopenia (85%), mucositis (80%), hypercholesterolemia (75%), hypertriglyceridemia (70%), and hyperglycemia (65%).

"Most were grade 1-2 [toxicities], but four of the seven best responders developed grade 3 mucositis, myelosuppression, or hyperglycemia, which were managed while maintaining drug dose," Dr. Naing stated.

"Typically, patients who develop these types of grade 3 toxicities would be removed from the study, but we were able to continue with treatment after receiving approval from the sponsor and notification from our institutional review board," he said. Because the toxicities were able to be controlled using supportive measures, "the drug dose did not have to be compromised."

One of the Ewing’s sarcoma patients had achieved a partial response with prior IGF-1R treatment. After initiating the combination therapy, this patient had a mixed response with "remarkable" regression in three lung nodules but progression in a fourth. Morphoproteomic analysis of biopsy samples from this patient demonstrated upregulation of mTOR and ERK/MEK signals, suggesting the possibility that a combination of IGFR/mTOR and MAPK/ERK kinase (MEK) inhibitors might warrant investigation in order to reverse resistance, according to Dr. Naing.

Based on the evidence of activity for the drug combination, the investigators are planning further studies in larger numbers of patients with tumors in the Ewing’s sarcoma family, as well as additional studies into the underlying mechanisms of resistance in individual patients, Dr. Naing said during a press conference.

The results of this study were published simultaneously in Clinical Cancer Research (2012 [doi:10.1158/1078-0432.CCR-12-0061]).

Dr. Naing reported having no relevant financial relationships to disclose.

CHICAGO – About half of men with castration-resistant prostate cancer demonstrated considerable declines in prostate-specific antigen levels when treated with the investigational agent galeterone in a phase I dose-escalation trial, investigators reported.

Galeterone (TOK-001), an orally available, semisynthetic steroid analogue, mounts a three-pronged attack on prostate cancer, according to Dr. R. Bruce Montgomery of the University of Washington in Seattle. It inhibits CYP17 lyase (a key enzyme in the androgen production pathway in the disease), inhibits androgen-receptor binding, and disrupts internal androgen-receptor production in prostate cancer cells.

This novel triple-target mechanism, which was identified in preclinical studies, "could help prevent drug resistance," Dr. Montgomery said during a press briefing at the annual meeting of the American Association for Cancer Research, where the data were presented.

To evaluate the safety and efficacy of the drug, Dr. Montgomery and his colleagues enrolled 49 men with metastatic and nonmetastatic, chemotherapy-naive, castration-resistant prostate cancer (CRPC) in the ARMOR1 trial sponsored by Tokai Pharmaceuticals.

All of the men, who ranged in age from 48-93 years, had an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1, as well as disease progression during androgen ablation therapy. Exclusion criteria included prior treatment with ketoconazole, MDV3100, abiraterone (Zytiga), sipuleucel-T (Provenge), TAK-700, mitoxantrone (Novantrone), or chemotherapy based on either docetaxel (Taxotere) or cabazitaxel (Jevtana).

The study participants were randomized to eight dose-escalation cohorts that received single or split daily doses of galeterone ranging from 650 mg to 2,600 mg per day for 12 weeks, followed by optional continuation in an extension phase, Dr. Montgomery explained.

Efficacy was a secondary outcome measure, which was assessed based on change in PSA level, changes from baseline in CT/MRI and bone scans, RECIST (Response Evaluation Criteria in Solid Tumors) data, and laboratory measures.

A majority of patients had PSA reductions; among them, 11 patients had PSA reductions of at least 50% and an additional 13 patients had PSA reductions of 30%-49%, reported Dr. Montgomery, noting that the magnitude of the reductions were dose related. In addition, some patients had evidence of a reduction in tumor size on CT scans.

"The improved PSA response indicates that the drug is getting to the target, because PSA expression is controlled by the androgen receptor," he said in an interview. "The fact that so many patients had a PSA reduction of 30% or more is exceptional in a phase I dose-finding trial."

The primary outcome measures were tolerability and safety, as measured by the incidence of adverse events and the change from baseline in clinical laboratory assessments, physical examination, vital signs, and electrocardiograms, he said.

Grade 1 and 2 adverse events were reported in 58% and 30% of the patients, respectively. These included fatigue (36.7%), abnormal AST tests (32.7%), abnormal ALT tests (30.6%), nausea (28.6%), diarrhea (26.5%), and pruritis (24.5%), Dr. Montgomery reported.

In all, "15 patients had transient grade 2/3 liver-enzyme elevations, including 11 who required dose interruptions," he said.

Of the 11 patients with dose interruptions, 7 resumed galeterone treatment, and 6 completed the treatment without recurrent grade 3 elevations in liver enzymes, he added, noting that "the transaminitis was not dose-related and was very transient."

The finding does suggest, however, that regular monitoring of liver function enzymes may be warranted in men taking the drug, he said.

Of nine serious adverse events reported in the study, only one was linked to galeterone. "The single, related grade 4 adverse event was rhabdomyolysis in a patient with renal insufficiency who was on simvastatin therapy," Dr. Montgomery said. "No cases of adrenal mineralocorticoid excess were observed."

The study did not reveal dose proportionality, but "the maximum tolerated dose was identified at the doses evaluated in the trial," Dr. Montgomery said. Therefore, Tokai Pharmaceuticals is currently reformulating the drug "to optimize pharmacokinetics and pharmacodynamics."

The new formulation will be evaluated later this year in a phase II clinical trial, he said.

Tokai Pharmaceuticals sponsored the trial. Dr. Montgomery disclosed no relevant financial conflicts of interest.

CHICAGO – About half of men with castration-resistant prostate cancer demonstrated considerable declines in prostate-specific antigen levels when treated with the investigational agent galeterone in a phase I dose-escalation trial, investigators reported.

Galeterone (TOK-001), an orally available, semisynthetic steroid analogue, mounts a three-pronged attack on prostate cancer, according to Dr. R. Bruce Montgomery of the University of Washington in Seattle. It inhibits CYP17 lyase (a key enzyme in the androgen production pathway in the disease), inhibits androgen-receptor binding, and disrupts internal androgen-receptor production in prostate cancer cells.

This novel triple-target mechanism, which was identified in preclinical studies, "could help prevent drug resistance," Dr. Montgomery said during a press briefing at the annual meeting of the American Association for Cancer Research, where the data were presented.

To evaluate the safety and efficacy of the drug, Dr. Montgomery and his colleagues enrolled 49 men with metastatic and nonmetastatic, chemotherapy-naive, castration-resistant prostate cancer (CRPC) in the ARMOR1 trial sponsored by Tokai Pharmaceuticals.

All of the men, who ranged in age from 48-93 years, had an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1, as well as disease progression during androgen ablation therapy. Exclusion criteria included prior treatment with ketoconazole, MDV3100, abiraterone (Zytiga), sipuleucel-T (Provenge), TAK-700, mitoxantrone (Novantrone), or chemotherapy based on either docetaxel (Taxotere) or cabazitaxel (Jevtana).

The study participants were randomized to eight dose-escalation cohorts that received single or split daily doses of galeterone ranging from 650 mg to 2,600 mg per day for 12 weeks, followed by optional continuation in an extension phase, Dr. Montgomery explained.

Efficacy was a secondary outcome measure, which was assessed based on change in PSA level, changes from baseline in CT/MRI and bone scans, RECIST (Response Evaluation Criteria in Solid Tumors) data, and laboratory measures.

A majority of patients had PSA reductions; among them, 11 patients had PSA reductions of at least 50% and an additional 13 patients had PSA reductions of 30%-49%, reported Dr. Montgomery, noting that the magnitude of the reductions were dose related. In addition, some patients had evidence of a reduction in tumor size on CT scans.

"The improved PSA response indicates that the drug is getting to the target, because PSA expression is controlled by the androgen receptor," he said in an interview. "The fact that so many patients had a PSA reduction of 30% or more is exceptional in a phase I dose-finding trial."

The primary outcome measures were tolerability and safety, as measured by the incidence of adverse events and the change from baseline in clinical laboratory assessments, physical examination, vital signs, and electrocardiograms, he said.

Grade 1 and 2 adverse events were reported in 58% and 30% of the patients, respectively. These included fatigue (36.7%), abnormal AST tests (32.7%), abnormal ALT tests (30.6%), nausea (28.6%), diarrhea (26.5%), and pruritis (24.5%), Dr. Montgomery reported.

In all, "15 patients had transient grade 2/3 liver-enzyme elevations, including 11 who required dose interruptions," he said.

Of the 11 patients with dose interruptions, 7 resumed galeterone treatment, and 6 completed the treatment without recurrent grade 3 elevations in liver enzymes, he added, noting that "the transaminitis was not dose-related and was very transient."

The finding does suggest, however, that regular monitoring of liver function enzymes may be warranted in men taking the drug, he said.

Of nine serious adverse events reported in the study, only one was linked to galeterone. "The single, related grade 4 adverse event was rhabdomyolysis in a patient with renal insufficiency who was on simvastatin therapy," Dr. Montgomery said. "No cases of adrenal mineralocorticoid excess were observed."

The study did not reveal dose proportionality, but "the maximum tolerated dose was identified at the doses evaluated in the trial," Dr. Montgomery said. Therefore, Tokai Pharmaceuticals is currently reformulating the drug "to optimize pharmacokinetics and pharmacodynamics."

The new formulation will be evaluated later this year in a phase II clinical trial, he said.

Tokai Pharmaceuticals sponsored the trial. Dr. Montgomery disclosed no relevant financial conflicts of interest.

CHICAGO – About half of men with castration-resistant prostate cancer demonstrated considerable declines in prostate-specific antigen levels when treated with the investigational agent galeterone in a phase I dose-escalation trial, investigators reported.

Galeterone (TOK-001), an orally available, semisynthetic steroid analogue, mounts a three-pronged attack on prostate cancer, according to Dr. R. Bruce Montgomery of the University of Washington in Seattle. It inhibits CYP17 lyase (a key enzyme in the androgen production pathway in the disease), inhibits androgen-receptor binding, and disrupts internal androgen-receptor production in prostate cancer cells.

This novel triple-target mechanism, which was identified in preclinical studies, "could help prevent drug resistance," Dr. Montgomery said during a press briefing at the annual meeting of the American Association for Cancer Research, where the data were presented.

To evaluate the safety and efficacy of the drug, Dr. Montgomery and his colleagues enrolled 49 men with metastatic and nonmetastatic, chemotherapy-naive, castration-resistant prostate cancer (CRPC) in the ARMOR1 trial sponsored by Tokai Pharmaceuticals.

All of the men, who ranged in age from 48-93 years, had an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1, as well as disease progression during androgen ablation therapy. Exclusion criteria included prior treatment with ketoconazole, MDV3100, abiraterone (Zytiga), sipuleucel-T (Provenge), TAK-700, mitoxantrone (Novantrone), or chemotherapy based on either docetaxel (Taxotere) or cabazitaxel (Jevtana).

The study participants were randomized to eight dose-escalation cohorts that received single or split daily doses of galeterone ranging from 650 mg to 2,600 mg per day for 12 weeks, followed by optional continuation in an extension phase, Dr. Montgomery explained.

Efficacy was a secondary outcome measure, which was assessed based on change in PSA level, changes from baseline in CT/MRI and bone scans, RECIST (Response Evaluation Criteria in Solid Tumors) data, and laboratory measures.

A majority of patients had PSA reductions; among them, 11 patients had PSA reductions of at least 50% and an additional 13 patients had PSA reductions of 30%-49%, reported Dr. Montgomery, noting that the magnitude of the reductions were dose related. In addition, some patients had evidence of a reduction in tumor size on CT scans.

"The improved PSA response indicates that the drug is getting to the target, because PSA expression is controlled by the androgen receptor," he said in an interview. "The fact that so many patients had a PSA reduction of 30% or more is exceptional in a phase I dose-finding trial."

The primary outcome measures were tolerability and safety, as measured by the incidence of adverse events and the change from baseline in clinical laboratory assessments, physical examination, vital signs, and electrocardiograms, he said.

Grade 1 and 2 adverse events were reported in 58% and 30% of the patients, respectively. These included fatigue (36.7%), abnormal AST tests (32.7%), abnormal ALT tests (30.6%), nausea (28.6%), diarrhea (26.5%), and pruritis (24.5%), Dr. Montgomery reported.

In all, "15 patients had transient grade 2/3 liver-enzyme elevations, including 11 who required dose interruptions," he said.

Of the 11 patients with dose interruptions, 7 resumed galeterone treatment, and 6 completed the treatment without recurrent grade 3 elevations in liver enzymes, he added, noting that "the transaminitis was not dose-related and was very transient."

The finding does suggest, however, that regular monitoring of liver function enzymes may be warranted in men taking the drug, he said.

Of nine serious adverse events reported in the study, only one was linked to galeterone. "The single, related grade 4 adverse event was rhabdomyolysis in a patient with renal insufficiency who was on simvastatin therapy," Dr. Montgomery said. "No cases of adrenal mineralocorticoid excess were observed."

The study did not reveal dose proportionality, but "the maximum tolerated dose was identified at the doses evaluated in the trial," Dr. Montgomery said. Therefore, Tokai Pharmaceuticals is currently reformulating the drug "to optimize pharmacokinetics and pharmacodynamics."

The new formulation will be evaluated later this year in a phase II clinical trial, he said.

Tokai Pharmaceuticals sponsored the trial. Dr. Montgomery disclosed no relevant financial conflicts of interest.

CHICAGO – Combination therapy with nanoparticle albumin bound–paclitaxel and carboplatin may be an option for the subset of advanced non–small cell lung cancer patients who are ineligible for bevacizumab treatment because of bleeding risk.

The combined treatment produced an objective response rate of more than 40% among non–small cell lung cancer (NSCLC) patients with squamous histology or other hemorrhagic risk factors in a single-arm, single institution, phase II trial presented at the annual meeting of the American Association for Cancer Research.

The preliminary results, which include evidence of "tolerable toxicity," are especially encouraging because of the limited treatment options available to this patient population, according to the senior investigator Dr. Gregory Otterson of the Ohio State University Comprehensive Cancer Center in Columbus.

Much attention has been focused on the addition of bevacizumab (Avastin) to platinum-based chemotherapy in the treatment of advanced NSCLC because the combination has been shown to improve objective response rates, progression-free survival, and overall survival in this population, Dr. Otterson explained. However, bevacizumab’s association with hemorrhagic complications precludes its indication for patients already at increased risk of bleeding, including those with squamous cell carcinoma or a history of hemoptysis, as well as those taking anticoagulant medication,

For these patients, paclitaxel – a compound that stabilizes microtubules to induce cell death – plus the DNA-targeting platinum compound carboplatin is a common therapeutic option, but it is frequently associated with hypersensitivity reactions to the toxic solvent Cremophor through which paclitaxel is delivered. In contrast, nab-paclitaxel (Abraxane) is a solvent-free formulation delivered by a nanoparticle technology that binds to the natural protein albumin.

"It is thought that delivering paclitaxel with this technology causes fewer hypersensitivity reactions and may lead to greater drug uptake in tumors," Dr. Otterson said, noting that "higher doses can be administered over a shorter infusion time without the need for special infusion sets or premedications."

A previous randomized controlled trial comparing the nab-paclitaxel plus carboplatin combination with the conventional paclitaxel plus carboplatin combination in advanced NSCLC patients demonstrated superior overall response rates with the former combination, especially in patients with squamous cell histology, Dr. Otterson said. Based on this finding, the current study is focusing specifically on squamous cell patients and others whose bleeding risk precludes bevacizumab treatment, he said.

The investigators enrolled 63 chemotherapy-naive NSCLC patients (21 female and 42 male) in the trial, including 48 with squamous cell carcinoma, 9 with adenocarcinomas, 4 with NSCLC not otherwise specified, and 2 with adenosquamous carcinoma, Dr. Otterson said. Of the patients with nonsquamous disease, 11 had a history of hemoptysis and 2 had a history of thrombosis, while one patient was undergoing therapeutic anticoagulation. The average tobacco use history for all of the patients, median age 63 years, was 50-pack years, he said.

At baseline, microRNA profiles were generated from blood/serum samples acquired from all of the patients. Treatment was administered every 21 days, initially at 300 mg per m²/AUC=6, then adjusted to 260 mg per m²/AUC=6 because of excess neuropathy, Dr. Otterson said. The study’s primary end point is overall response rate: safety and toxicities as well as overall survival and progression-free survival are secondary end points.

Preliminary findings for 53 patients evaluable to date indicate that 22 patients experienced a partial response to the therapy, while none experienced a complete response, for an ORR of 41.5%. The investigators observed stable disease in 21 patients, and progressive disease in 10 patients, Dr. Otterson said.

With respect to tolerability, "more than 10% of the patients experienced grade 3/4 toxicities," including hematologic toxicity in 36 patients febrile neutropenia in 9, infection in 15, sensory neuropathy in 17, dyspnea in 10, and dehydration in 8. Additionally, there were four deaths, reported as grade 5 toxicities, including sudden death in one patient and respiratory failure in another, he said.

Although median overall survival and progression-free survival, at 9.7 months and 5 months, respectively, "were not as high as we would have liked to see," the apparent durability of the treatment – some of the patients did not require additional treatment for at least 6 months – is "surprising and promising," Dr. Otterson said: "Based on the findings, additional investigation in the squamous cell population, in particular, is warranted."

The study was supported by Abraxis Biosciences. Dr. Otterson reported having no relevant conflicts of interest.

CHICAGO – Combination therapy with nanoparticle albumin bound–paclitaxel and carboplatin may be an option for the subset of advanced non–small cell lung cancer patients who are ineligible for bevacizumab treatment because of bleeding risk.

The combined treatment produced an objective response rate of more than 40% among non–small cell lung cancer (NSCLC) patients with squamous histology or other hemorrhagic risk factors in a single-arm, single institution, phase II trial presented at the annual meeting of the American Association for Cancer Research.

The preliminary results, which include evidence of "tolerable toxicity," are especially encouraging because of the limited treatment options available to this patient population, according to the senior investigator Dr. Gregory Otterson of the Ohio State University Comprehensive Cancer Center in Columbus.

Much attention has been focused on the addition of bevacizumab (Avastin) to platinum-based chemotherapy in the treatment of advanced NSCLC because the combination has been shown to improve objective response rates, progression-free survival, and overall survival in this population, Dr. Otterson explained. However, bevacizumab’s association with hemorrhagic complications precludes its indication for patients already at increased risk of bleeding, including those with squamous cell carcinoma or a history of hemoptysis, as well as those taking anticoagulant medication,

For these patients, paclitaxel – a compound that stabilizes microtubules to induce cell death – plus the DNA-targeting platinum compound carboplatin is a common therapeutic option, but it is frequently associated with hypersensitivity reactions to the toxic solvent Cremophor through which paclitaxel is delivered. In contrast, nab-paclitaxel (Abraxane) is a solvent-free formulation delivered by a nanoparticle technology that binds to the natural protein albumin.

"It is thought that delivering paclitaxel with this technology causes fewer hypersensitivity reactions and may lead to greater drug uptake in tumors," Dr. Otterson said, noting that "higher doses can be administered over a shorter infusion time without the need for special infusion sets or premedications."

A previous randomized controlled trial comparing the nab-paclitaxel plus carboplatin combination with the conventional paclitaxel plus carboplatin combination in advanced NSCLC patients demonstrated superior overall response rates with the former combination, especially in patients with squamous cell histology, Dr. Otterson said. Based on this finding, the current study is focusing specifically on squamous cell patients and others whose bleeding risk precludes bevacizumab treatment, he said.

The investigators enrolled 63 chemotherapy-naive NSCLC patients (21 female and 42 male) in the trial, including 48 with squamous cell carcinoma, 9 with adenocarcinomas, 4 with NSCLC not otherwise specified, and 2 with adenosquamous carcinoma, Dr. Otterson said. Of the patients with nonsquamous disease, 11 had a history of hemoptysis and 2 had a history of thrombosis, while one patient was undergoing therapeutic anticoagulation. The average tobacco use history for all of the patients, median age 63 years, was 50-pack years, he said.

At baseline, microRNA profiles were generated from blood/serum samples acquired from all of the patients. Treatment was administered every 21 days, initially at 300 mg per m²/AUC=6, then adjusted to 260 mg per m²/AUC=6 because of excess neuropathy, Dr. Otterson said. The study’s primary end point is overall response rate: safety and toxicities as well as overall survival and progression-free survival are secondary end points.

Preliminary findings for 53 patients evaluable to date indicate that 22 patients experienced a partial response to the therapy, while none experienced a complete response, for an ORR of 41.5%. The investigators observed stable disease in 21 patients, and progressive disease in 10 patients, Dr. Otterson said.

With respect to tolerability, "more than 10% of the patients experienced grade 3/4 toxicities," including hematologic toxicity in 36 patients febrile neutropenia in 9, infection in 15, sensory neuropathy in 17, dyspnea in 10, and dehydration in 8. Additionally, there were four deaths, reported as grade 5 toxicities, including sudden death in one patient and respiratory failure in another, he said.

Although median overall survival and progression-free survival, at 9.7 months and 5 months, respectively, "were not as high as we would have liked to see," the apparent durability of the treatment – some of the patients did not require additional treatment for at least 6 months – is "surprising and promising," Dr. Otterson said: "Based on the findings, additional investigation in the squamous cell population, in particular, is warranted."

The study was supported by Abraxis Biosciences. Dr. Otterson reported having no relevant conflicts of interest.

CHICAGO – Combination therapy with nanoparticle albumin bound–paclitaxel and carboplatin may be an option for the subset of advanced non–small cell lung cancer patients who are ineligible for bevacizumab treatment because of bleeding risk.

The combined treatment produced an objective response rate of more than 40% among non–small cell lung cancer (NSCLC) patients with squamous histology or other hemorrhagic risk factors in a single-arm, single institution, phase II trial presented at the annual meeting of the American Association for Cancer Research.

The preliminary results, which include evidence of "tolerable toxicity," are especially encouraging because of the limited treatment options available to this patient population, according to the senior investigator Dr. Gregory Otterson of the Ohio State University Comprehensive Cancer Center in Columbus.

Much attention has been focused on the addition of bevacizumab (Avastin) to platinum-based chemotherapy in the treatment of advanced NSCLC because the combination has been shown to improve objective response rates, progression-free survival, and overall survival in this population, Dr. Otterson explained. However, bevacizumab’s association with hemorrhagic complications precludes its indication for patients already at increased risk of bleeding, including those with squamous cell carcinoma or a history of hemoptysis, as well as those taking anticoagulant medication,

For these patients, paclitaxel – a compound that stabilizes microtubules to induce cell death – plus the DNA-targeting platinum compound carboplatin is a common therapeutic option, but it is frequently associated with hypersensitivity reactions to the toxic solvent Cremophor through which paclitaxel is delivered. In contrast, nab-paclitaxel (Abraxane) is a solvent-free formulation delivered by a nanoparticle technology that binds to the natural protein albumin.

"It is thought that delivering paclitaxel with this technology causes fewer hypersensitivity reactions and may lead to greater drug uptake in tumors," Dr. Otterson said, noting that "higher doses can be administered over a shorter infusion time without the need for special infusion sets or premedications."

A previous randomized controlled trial comparing the nab-paclitaxel plus carboplatin combination with the conventional paclitaxel plus carboplatin combination in advanced NSCLC patients demonstrated superior overall response rates with the former combination, especially in patients with squamous cell histology, Dr. Otterson said. Based on this finding, the current study is focusing specifically on squamous cell patients and others whose bleeding risk precludes bevacizumab treatment, he said.

The investigators enrolled 63 chemotherapy-naive NSCLC patients (21 female and 42 male) in the trial, including 48 with squamous cell carcinoma, 9 with adenocarcinomas, 4 with NSCLC not otherwise specified, and 2 with adenosquamous carcinoma, Dr. Otterson said. Of the patients with nonsquamous disease, 11 had a history of hemoptysis and 2 had a history of thrombosis, while one patient was undergoing therapeutic anticoagulation. The average tobacco use history for all of the patients, median age 63 years, was 50-pack years, he said.

At baseline, microRNA profiles were generated from blood/serum samples acquired from all of the patients. Treatment was administered every 21 days, initially at 300 mg per m²/AUC=6, then adjusted to 260 mg per m²/AUC=6 because of excess neuropathy, Dr. Otterson said. The study’s primary end point is overall response rate: safety and toxicities as well as overall survival and progression-free survival are secondary end points.

Preliminary findings for 53 patients evaluable to date indicate that 22 patients experienced a partial response to the therapy, while none experienced a complete response, for an ORR of 41.5%. The investigators observed stable disease in 21 patients, and progressive disease in 10 patients, Dr. Otterson said.

With respect to tolerability, "more than 10% of the patients experienced grade 3/4 toxicities," including hematologic toxicity in 36 patients febrile neutropenia in 9, infection in 15, sensory neuropathy in 17, dyspnea in 10, and dehydration in 8. Additionally, there were four deaths, reported as grade 5 toxicities, including sudden death in one patient and respiratory failure in another, he said.

Although median overall survival and progression-free survival, at 9.7 months and 5 months, respectively, "were not as high as we would have liked to see," the apparent durability of the treatment – some of the patients did not require additional treatment for at least 6 months – is "surprising and promising," Dr. Otterson said: "Based on the findings, additional investigation in the squamous cell population, in particular, is warranted."

The study was supported by Abraxis Biosciences. Dr. Otterson reported having no relevant conflicts of interest.

CHICAGO – Immunotherapy with peptide vaccines may offer a much-needed therapeutic option for gliomas in children, which carry a poor prognosis despite current treatments.

In a pilot trial of subcutaneous vaccinations with peptides for glioma-associated antigen (GAA) epitopes in children who have been newly diagnosed with brain stem gliomas, cerebral high-grade gliomas, or recurrent gliomas, the immunotherapy was well tolerated and demonstrated immunologic and clinical activity, Dr. Ian F. Pollack reported April 2 at the annual meeting of the American Association for Cancer Research.

© Todd Buchanan/2012 AACR

Based on significant experience with immunotherapy for adult gliomas, "we extended these insights to childhood gliomas – malignant astrocytomas of the brain stem and cerebral hemispheres and recurrent low-grade gliomas – based on our observations of their glioma-associated antigen expression profiles," Dr. Pollack explained during a press conference.

For the pilot study, Dr. Pollack, chief of pediatric neurosurgery at Children’s Hospital of Pittsburgh Brain Care Institute, and his colleagues have enrolled 27 human leukocyte antigen (HLA) A2–positive children to date, including 16 who are newly diagnosed with brain stem gliomas, 5 with newly diagnosed high-grade gliomas, and 6 with recurrent gliomas. The GAAs were EphA2, interleukin-13 receptor alpha 2 (IL-13RA2), and survivin, he said.

All of the children received eight courses of subcutaneous vaccinations with peptides for GAA epitopes emulsified in Montanide-ISA-51 every 3 weeks, along with intramuscular injections of the immunoadjuvant poly-ICLC, which promotes the infiltration of effector T cells into intracranial gliomas.

"Our primary end points were safety and T-cell response against vaccine-targeted [GAAs]," he said, noting that treatment response was assessed clinically and by MRI.

The preliminary results reported at the meeting are based on an interim analysis of 22 evaluable patients. To date, no non–central nervous system toxicities have limited the vaccine dosages, Dr. Pollack said. Of the 22 children, 4 showed signs of rapidly progressive disease, 14 had stable disease for more than 3 months, 3 had sustained partial responses, and 1 had prolonged disease-free status after surgery, he reported.

Symptomatic "pseudoprogression" – consisting of transient neurologic deterioration and tumor enlargement, followed by tumor regression and stabilization on decreasing steroid doses with sustained partial response – was observed in four of the children with brain stem glioma, said Dr. Pollack, who is also codirector of the University of Pittsburgh Cancer Institute’s brain tumor program.

Results of the ELISPOT (enzyme-linked immunosorbent spot) assay, which was completed in seven of the children, showed responses in six of them. Specifically, the investigators observed responses to IL-13RA2 in five cases, EphA2 in three cases, and survivin in three cases, Dr. Pollack said.

"Based on what we’ve seen so far, it seems that these kids are able to mount immune responses to the vaccine at high rates, possibly higher than we’ve seen in adult studies," likely because of their robust immune systems, he said in an interview.

The observation of immunologic and clinical response – particularly the evidence of tumor shrinkage in children with very high-risk tumors – "has been extremely encouraging and somewhat surprising," Dr. Pollack reported. "This is the first study of its type that examined peptide vaccine therapy for children with brain tumors like this."

The findings are especially notable because children with these tumors generally do not respond well to standard chemotherapy, he said, stressing that if further study validates the early findings, "immunotherapy may be a promising strategy to control tumor growth."

The study was funded by the National Institutes of Health. Dr. Pollack disclosed having no potential conflicts of interest.

CHICAGO – Immunotherapy with peptide vaccines may offer a much-needed therapeutic option for gliomas in children, which carry a poor prognosis despite current treatments.

In a pilot trial of subcutaneous vaccinations with peptides for glioma-associated antigen (GAA) epitopes in children who have been newly diagnosed with brain stem gliomas, cerebral high-grade gliomas, or recurrent gliomas, the immunotherapy was well tolerated and demonstrated immunologic and clinical activity, Dr. Ian F. Pollack reported April 2 at the annual meeting of the American Association for Cancer Research.

© Todd Buchanan/2012 AACR

Based on significant experience with immunotherapy for adult gliomas, "we extended these insights to childhood gliomas – malignant astrocytomas of the brain stem and cerebral hemispheres and recurrent low-grade gliomas – based on our observations of their glioma-associated antigen expression profiles," Dr. Pollack explained during a press conference.

For the pilot study, Dr. Pollack, chief of pediatric neurosurgery at Children’s Hospital of Pittsburgh Brain Care Institute, and his colleagues have enrolled 27 human leukocyte antigen (HLA) A2–positive children to date, including 16 who are newly diagnosed with brain stem gliomas, 5 with newly diagnosed high-grade gliomas, and 6 with recurrent gliomas. The GAAs were EphA2, interleukin-13 receptor alpha 2 (IL-13RA2), and survivin, he said.

All of the children received eight courses of subcutaneous vaccinations with peptides for GAA epitopes emulsified in Montanide-ISA-51 every 3 weeks, along with intramuscular injections of the immunoadjuvant poly-ICLC, which promotes the infiltration of effector T cells into intracranial gliomas.

"Our primary end points were safety and T-cell response against vaccine-targeted [GAAs]," he said, noting that treatment response was assessed clinically and by MRI.

The preliminary results reported at the meeting are based on an interim analysis of 22 evaluable patients. To date, no non–central nervous system toxicities have limited the vaccine dosages, Dr. Pollack said. Of the 22 children, 4 showed signs of rapidly progressive disease, 14 had stable disease for more than 3 months, 3 had sustained partial responses, and 1 had prolonged disease-free status after surgery, he reported.

Symptomatic "pseudoprogression" – consisting of transient neurologic deterioration and tumor enlargement, followed by tumor regression and stabilization on decreasing steroid doses with sustained partial response – was observed in four of the children with brain stem glioma, said Dr. Pollack, who is also codirector of the University of Pittsburgh Cancer Institute’s brain tumor program.

Results of the ELISPOT (enzyme-linked immunosorbent spot) assay, which was completed in seven of the children, showed responses in six of them. Specifically, the investigators observed responses to IL-13RA2 in five cases, EphA2 in three cases, and survivin in three cases, Dr. Pollack said.

"Based on what we’ve seen so far, it seems that these kids are able to mount immune responses to the vaccine at high rates, possibly higher than we’ve seen in adult studies," likely because of their robust immune systems, he said in an interview.

The observation of immunologic and clinical response – particularly the evidence of tumor shrinkage in children with very high-risk tumors – "has been extremely encouraging and somewhat surprising," Dr. Pollack reported. "This is the first study of its type that examined peptide vaccine therapy for children with brain tumors like this."

The findings are especially notable because children with these tumors generally do not respond well to standard chemotherapy, he said, stressing that if further study validates the early findings, "immunotherapy may be a promising strategy to control tumor growth."

The study was funded by the National Institutes of Health. Dr. Pollack disclosed having no potential conflicts of interest.

CHICAGO – Immunotherapy with peptide vaccines may offer a much-needed therapeutic option for gliomas in children, which carry a poor prognosis despite current treatments.

In a pilot trial of subcutaneous vaccinations with peptides for glioma-associated antigen (GAA) epitopes in children who have been newly diagnosed with brain stem gliomas, cerebral high-grade gliomas, or recurrent gliomas, the immunotherapy was well tolerated and demonstrated immunologic and clinical activity, Dr. Ian F. Pollack reported April 2 at the annual meeting of the American Association for Cancer Research.

© Todd Buchanan/2012 AACR

Based on significant experience with immunotherapy for adult gliomas, "we extended these insights to childhood gliomas – malignant astrocytomas of the brain stem and cerebral hemispheres and recurrent low-grade gliomas – based on our observations of their glioma-associated antigen expression profiles," Dr. Pollack explained during a press conference.

For the pilot study, Dr. Pollack, chief of pediatric neurosurgery at Children’s Hospital of Pittsburgh Brain Care Institute, and his colleagues have enrolled 27 human leukocyte antigen (HLA) A2–positive children to date, including 16 who are newly diagnosed with brain stem gliomas, 5 with newly diagnosed high-grade gliomas, and 6 with recurrent gliomas. The GAAs were EphA2, interleukin-13 receptor alpha 2 (IL-13RA2), and survivin, he said.

All of the children received eight courses of subcutaneous vaccinations with peptides for GAA epitopes emulsified in Montanide-ISA-51 every 3 weeks, along with intramuscular injections of the immunoadjuvant poly-ICLC, which promotes the infiltration of effector T cells into intracranial gliomas.

"Our primary end points were safety and T-cell response against vaccine-targeted [GAAs]," he said, noting that treatment response was assessed clinically and by MRI.

The preliminary results reported at the meeting are based on an interim analysis of 22 evaluable patients. To date, no non–central nervous system toxicities have limited the vaccine dosages, Dr. Pollack said. Of the 22 children, 4 showed signs of rapidly progressive disease, 14 had stable disease for more than 3 months, 3 had sustained partial responses, and 1 had prolonged disease-free status after surgery, he reported.

Symptomatic "pseudoprogression" – consisting of transient neurologic deterioration and tumor enlargement, followed by tumor regression and stabilization on decreasing steroid doses with sustained partial response – was observed in four of the children with brain stem glioma, said Dr. Pollack, who is also codirector of the University of Pittsburgh Cancer Institute’s brain tumor program.

Results of the ELISPOT (enzyme-linked immunosorbent spot) assay, which was completed in seven of the children, showed responses in six of them. Specifically, the investigators observed responses to IL-13RA2 in five cases, EphA2 in three cases, and survivin in three cases, Dr. Pollack said.

"Based on what we’ve seen so far, it seems that these kids are able to mount immune responses to the vaccine at high rates, possibly higher than we’ve seen in adult studies," likely because of their robust immune systems, he said in an interview.

The observation of immunologic and clinical response – particularly the evidence of tumor shrinkage in children with very high-risk tumors – "has been extremely encouraging and somewhat surprising," Dr. Pollack reported. "This is the first study of its type that examined peptide vaccine therapy for children with brain tumors like this."

The findings are especially notable because children with these tumors generally do not respond well to standard chemotherapy, he said, stressing that if further study validates the early findings, "immunotherapy may be a promising strategy to control tumor growth."

The study was funded by the National Institutes of Health. Dr. Pollack disclosed having no potential conflicts of interest.

CHICAGO – Older breast cancer patients with the luminal A tumor subtype may be able to forgo whole breast radiation therapy if they are taking tamoxifen or other breast cancer hormone therapy.

Preliminary results from a randomized clinical trial of tamoxifen with and without radiation therapy showed that radiation therapy had minimal impact on the risk of developing ipsilateral breast tumor recurrence in patients aged 50 years and older with T1 and T2 node-negative breast cancer identified with luminal A disease based on 6-marker immunohistochemistry testing.

Diana Mahoney/IMNG Medical Media

In contrast, radiation therapy appeared to decrease the risk of breast cancer relapse in patients with luminal B, human epidermal growth factor receptor 2 (HER2)–enriched, and basal tumor subtypes, according to radiation oncologist Dr. Fei-Fei Liu of Princess Margaret Hospital, the Ontario Cancer Institute, and the University of Toronto, all in Toronto. She discussed the findings in a press conference April 1 at the annual meeting of the American Association for Cancer Research.

Luminal A tumors – estrogen receptor (ER) or progesterone receptor (PR) positive, HER2-negative, and low Ki-67 (a nuclear marker for cell proliferation) – are associated with a relatively good prognosis compared with the other subtypes, she noted.

To determine the predictive value of tumor subtype for ipsilateral recurrence in this population, Dr. Liu and her colleagues performed molecular subtyping for ER, PR, Ki-67, HER2, EGFR, and cytokeratine 5/6 on 304 available tumor specimens from 769 women in a clinical trial. All had been randomized to treatment with tamoxifen and whole breast radiation or tamoxifen alone between December 1992 and June 2000.

Based on the subtyping results, the patients were classified as luminal A, luminal B, luminal HER2, HER2-enriched, basal-like, or triple-negative phenotype–non-basal and followed for a median of 10 years, she said.

In the overall group of 769 women, the recurrence rate at a median of 10 years was 13.8% in the tamoxifen-only group and 5.0% in the combination group, Dr. Liu reported, noting that, in a multivariate analysis, "patient age, tumor size, estrogen-receptor positive status, and combination tamoxifen/whole breast radiation therapy were all significant factors."

Of the 304 tissue microarrays, 145 came from patients treated with tamoxifen only and 159 from patients treated with tamoxifen plus radiotherapy. In this population, the best outcomes were observed in 133 patients with luminal A tumors; their rate of ipsilateral recurrence was statistically similar at 8% among those in the tamoxifen-only group and 4.6% in the tamoxifen plus radiation group, Dr. Liu reported.

The 103 women older than 60 years with luminal A tumors fared particularly well, with rates of 4.3% with tamoxifen alone and 6.0% with tamoxifen and radiotherapy. The respective rates for the 114 women with grade I-II luminal A tumors also were similar at 4.9% and 5.5%, she said.

In contrast, the ipsilateral recurrence rates for the tamoxifen only and tamoxifen plus radiation groups were, respectively, 16.1% and 3.9% in 82 patients with luminal B tumors (differentiated from luminal A tumors by Ki-67 expression greater than 14%), said Dr. Liu.

Further, although the number of HER2 (11), HER2-enriched (11), and basal-like tumors (16) were small, "we saw higher relapse rates in patients who did not undergo radiation therapy," she said.

Luminal A lymph-node negative breast cancer represents approximately 25% of all cases of newly diagnosed breast cancer in North America, according to Dr. Liu. In addition to sparing a large number of women unnecessary radiation exposures, unwanted side effects, and inconvenience, bypassing radiation therapy in early cases would save millions of health care dollars each year.

"We estimated a savings of $20 million annually in Ontario if radiation therapy were avoided in early luminal A [breast cancer]," she said. "Extrapolating the figures to the [United States] resulted in a savings of about $400 million per year."

Dr. Liu stressed that the data presented at the meeting are preliminary but noted that, if the findings are validated through the analysis of a larger number of tumor samples, "we would recommend adding Ki-67 to the current standard immunohistochemistry panel, and discussing the possibility of avoiding radiation with lymph node–negative patients in whom the luminal A subtype is identified, if they are taking tamoxifen or an equivalent medication, especially patients who are 60 years old or older."

Dr. Liu disclosed no conflicts of interest.

CHICAGO – Older breast cancer patients with the luminal A tumor subtype may be able to forgo whole breast radiation therapy if they are taking tamoxifen or other breast cancer hormone therapy.

Preliminary results from a randomized clinical trial of tamoxifen with and without radiation therapy showed that radiation therapy had minimal impact on the risk of developing ipsilateral breast tumor recurrence in patients aged 50 years and older with T1 and T2 node-negative breast cancer identified with luminal A disease based on 6-marker immunohistochemistry testing.

Diana Mahoney/IMNG Medical Media

In contrast, radiation therapy appeared to decrease the risk of breast cancer relapse in patients with luminal B, human epidermal growth factor receptor 2 (HER2)–enriched, and basal tumor subtypes, according to radiation oncologist Dr. Fei-Fei Liu of Princess Margaret Hospital, the Ontario Cancer Institute, and the University of Toronto, all in Toronto. She discussed the findings in a press conference April 1 at the annual meeting of the American Association for Cancer Research.

Luminal A tumors – estrogen receptor (ER) or progesterone receptor (PR) positive, HER2-negative, and low Ki-67 (a nuclear marker for cell proliferation) – are associated with a relatively good prognosis compared with the other subtypes, she noted.

To determine the predictive value of tumor subtype for ipsilateral recurrence in this population, Dr. Liu and her colleagues performed molecular subtyping for ER, PR, Ki-67, HER2, EGFR, and cytokeratine 5/6 on 304 available tumor specimens from 769 women in a clinical trial. All had been randomized to treatment with tamoxifen and whole breast radiation or tamoxifen alone between December 1992 and June 2000.

Based on the subtyping results, the patients were classified as luminal A, luminal B, luminal HER2, HER2-enriched, basal-like, or triple-negative phenotype–non-basal and followed for a median of 10 years, she said.

In the overall group of 769 women, the recurrence rate at a median of 10 years was 13.8% in the tamoxifen-only group and 5.0% in the combination group, Dr. Liu reported, noting that, in a multivariate analysis, "patient age, tumor size, estrogen-receptor positive status, and combination tamoxifen/whole breast radiation therapy were all significant factors."

Of the 304 tissue microarrays, 145 came from patients treated with tamoxifen only and 159 from patients treated with tamoxifen plus radiotherapy. In this population, the best outcomes were observed in 133 patients with luminal A tumors; their rate of ipsilateral recurrence was statistically similar at 8% among those in the tamoxifen-only group and 4.6% in the tamoxifen plus radiation group, Dr. Liu reported.

The 103 women older than 60 years with luminal A tumors fared particularly well, with rates of 4.3% with tamoxifen alone and 6.0% with tamoxifen and radiotherapy. The respective rates for the 114 women with grade I-II luminal A tumors also were similar at 4.9% and 5.5%, she said.

In contrast, the ipsilateral recurrence rates for the tamoxifen only and tamoxifen plus radiation groups were, respectively, 16.1% and 3.9% in 82 patients with luminal B tumors (differentiated from luminal A tumors by Ki-67 expression greater than 14%), said Dr. Liu.

Further, although the number of HER2 (11), HER2-enriched (11), and basal-like tumors (16) were small, "we saw higher relapse rates in patients who did not undergo radiation therapy," she said.

Luminal A lymph-node negative breast cancer represents approximately 25% of all cases of newly diagnosed breast cancer in North America, according to Dr. Liu. In addition to sparing a large number of women unnecessary radiation exposures, unwanted side effects, and inconvenience, bypassing radiation therapy in early cases would save millions of health care dollars each year.

"We estimated a savings of $20 million annually in Ontario if radiation therapy were avoided in early luminal A [breast cancer]," she said. "Extrapolating the figures to the [United States] resulted in a savings of about $400 million per year."

Dr. Liu stressed that the data presented at the meeting are preliminary but noted that, if the findings are validated through the analysis of a larger number of tumor samples, "we would recommend adding Ki-67 to the current standard immunohistochemistry panel, and discussing the possibility of avoiding radiation with lymph node–negative patients in whom the luminal A subtype is identified, if they are taking tamoxifen or an equivalent medication, especially patients who are 60 years old or older."

Dr. Liu disclosed no conflicts of interest.

CHICAGO – Older breast cancer patients with the luminal A tumor subtype may be able to forgo whole breast radiation therapy if they are taking tamoxifen or other breast cancer hormone therapy.

Preliminary results from a randomized clinical trial of tamoxifen with and without radiation therapy showed that radiation therapy had minimal impact on the risk of developing ipsilateral breast tumor recurrence in patients aged 50 years and older with T1 and T2 node-negative breast cancer identified with luminal A disease based on 6-marker immunohistochemistry testing.

Diana Mahoney/IMNG Medical Media

In contrast, radiation therapy appeared to decrease the risk of breast cancer relapse in patients with luminal B, human epidermal growth factor receptor 2 (HER2)–enriched, and basal tumor subtypes, according to radiation oncologist Dr. Fei-Fei Liu of Princess Margaret Hospital, the Ontario Cancer Institute, and the University of Toronto, all in Toronto. She discussed the findings in a press conference April 1 at the annual meeting of the American Association for Cancer Research.

Luminal A tumors – estrogen receptor (ER) or progesterone receptor (PR) positive, HER2-negative, and low Ki-67 (a nuclear marker for cell proliferation) – are associated with a relatively good prognosis compared with the other subtypes, she noted.

To determine the predictive value of tumor subtype for ipsilateral recurrence in this population, Dr. Liu and her colleagues performed molecular subtyping for ER, PR, Ki-67, HER2, EGFR, and cytokeratine 5/6 on 304 available tumor specimens from 769 women in a clinical trial. All had been randomized to treatment with tamoxifen and whole breast radiation or tamoxifen alone between December 1992 and June 2000.

Based on the subtyping results, the patients were classified as luminal A, luminal B, luminal HER2, HER2-enriched, basal-like, or triple-negative phenotype–non-basal and followed for a median of 10 years, she said.

In the overall group of 769 women, the recurrence rate at a median of 10 years was 13.8% in the tamoxifen-only group and 5.0% in the combination group, Dr. Liu reported, noting that, in a multivariate analysis, "patient age, tumor size, estrogen-receptor positive status, and combination tamoxifen/whole breast radiation therapy were all significant factors."

Of the 304 tissue microarrays, 145 came from patients treated with tamoxifen only and 159 from patients treated with tamoxifen plus radiotherapy. In this population, the best outcomes were observed in 133 patients with luminal A tumors; their rate of ipsilateral recurrence was statistically similar at 8% among those in the tamoxifen-only group and 4.6% in the tamoxifen plus radiation group, Dr. Liu reported.

The 103 women older than 60 years with luminal A tumors fared particularly well, with rates of 4.3% with tamoxifen alone and 6.0% with tamoxifen and radiotherapy. The respective rates for the 114 women with grade I-II luminal A tumors also were similar at 4.9% and 5.5%, she said.

In contrast, the ipsilateral recurrence rates for the tamoxifen only and tamoxifen plus radiation groups were, respectively, 16.1% and 3.9% in 82 patients with luminal B tumors (differentiated from luminal A tumors by Ki-67 expression greater than 14%), said Dr. Liu.

Further, although the number of HER2 (11), HER2-enriched (11), and basal-like tumors (16) were small, "we saw higher relapse rates in patients who did not undergo radiation therapy," she said.

Luminal A lymph-node negative breast cancer represents approximately 25% of all cases of newly diagnosed breast cancer in North America, according to Dr. Liu. In addition to sparing a large number of women unnecessary radiation exposures, unwanted side effects, and inconvenience, bypassing radiation therapy in early cases would save millions of health care dollars each year.

"We estimated a savings of $20 million annually in Ontario if radiation therapy were avoided in early luminal A [breast cancer]," she said. "Extrapolating the figures to the [United States] resulted in a savings of about $400 million per year."

Dr. Liu stressed that the data presented at the meeting are preliminary but noted that, if the findings are validated through the analysis of a larger number of tumor samples, "we would recommend adding Ki-67 to the current standard immunohistochemistry panel, and discussing the possibility of avoiding radiation with lymph node–negative patients in whom the luminal A subtype is identified, if they are taking tamoxifen or an equivalent medication, especially patients who are 60 years old or older."

Dr. Liu disclosed no conflicts of interest.

CHICAGO – Long-term use of estrogen-only therapy increases the risk of postmenopausal women developing breast cancer, according to new data from the Nurses’ Health Study.

The finding, reported April 1 by Dr. Wendy Chen at the annual meeting of the American Association for Cancer Research, suggests that opting for progesterone-free hormone therapy for the treatment of menopause symptoms should not be considered the risk-free alternative to combination progesterone plus estrogen formulations.

Still, the absolute risks were small. During the study’s 1.57 million person-years of follow-up from 1980 through 2008, 5,631 incident invasive breast cancers were diagnosed and 884 of the women died of breast cancer.

To evaluate the breast cancer risk associated with long-term use of both combined and estrogen-only hormone therapy, Dr. Chen of Brigham and Women’s Hospital in Boston and her colleagues evaluated data collected over 28 years through the Nurses’ Health Study. Of the 121,700 study participants who were aged 30-55 years in 1976, women who used estrogen-only therapy for 10.0-14.9 years and for 15.0-19.9 years had, respectively, a 22% and 43% increased risk of developing breast cancer relative to those women not on hormone therapy (HT).

"Our data also confirmed the previously reported increased risk associated with combined hormone therapy," Dr. Chen stated, noting that women in the study who used progesterone plus estrogen for 10-14.9 years had an 88% increased risk of developing breast cancer relative to those not on HT and the risk increased to more than twofold in women using it for up to 20 years. Further, the risk of developing breast cancer does not appear to plateau over time, but rather continues to increase. "The longer women use [HT]. The higher their risk," she said.

In a separate analysis, the investigators restricted the study population to healthy, active postmenopausal women 50-79 years with an intact uterus – the same population observed in the Women’s Health Initiative. "What we saw was a decline in breast cancer risk among women using estrogen-only therapy for less than 10 years, but an increased risk among those women using estrogen for 15-20 years," Dr. Chen said.

Importantly, although breast cancer incidence was increased in the HT groups, "there was no increase in the risk of fatal breast cancer, either with combined or estrogen-only therapy," Dr. Chen stressed. "This is something we are continuing to investigate."

The findings have the potential to increase the confusion regarding HT and to perhaps reignite the hormone therapy debate, Dr. Chen acknowledged in an interview. However, they should be considered in their proper context. "While the relative risk of developing breast cancer in increased, the absolute risk associated with [HT] are low," she said.

The observed effects associated with HT were stronger for estrogen receptor–positive tumors and among thinner women, Dr. Chen noted, adding that the results were similar when limited to women who underwent regular breast cancer screening.

The study was funded by the National Cancer Institute. Dr. Chen disclosed no financial conflicts of interest.

CHICAGO – Long-term use of estrogen-only therapy increases the risk of postmenopausal women developing breast cancer, according to new data from the Nurses’ Health Study.

The finding, reported April 1 by Dr. Wendy Chen at the annual meeting of the American Association for Cancer Research, suggests that opting for progesterone-free hormone therapy for the treatment of menopause symptoms should not be considered the risk-free alternative to combination progesterone plus estrogen formulations.

Still, the absolute risks were small. During the study’s 1.57 million person-years of follow-up from 1980 through 2008, 5,631 incident invasive breast cancers were diagnosed and 884 of the women died of breast cancer.

To evaluate the breast cancer risk associated with long-term use of both combined and estrogen-only hormone therapy, Dr. Chen of Brigham and Women’s Hospital in Boston and her colleagues evaluated data collected over 28 years through the Nurses’ Health Study. Of the 121,700 study participants who were aged 30-55 years in 1976, women who used estrogen-only therapy for 10.0-14.9 years and for 15.0-19.9 years had, respectively, a 22% and 43% increased risk of developing breast cancer relative to those women not on hormone therapy (HT).

"Our data also confirmed the previously reported increased risk associated with combined hormone therapy," Dr. Chen stated, noting that women in the study who used progesterone plus estrogen for 10-14.9 years had an 88% increased risk of developing breast cancer relative to those not on HT and the risk increased to more than twofold in women using it for up to 20 years. Further, the risk of developing breast cancer does not appear to plateau over time, but rather continues to increase. "The longer women use [HT]. The higher their risk," she said.

In a separate analysis, the investigators restricted the study population to healthy, active postmenopausal women 50-79 years with an intact uterus – the same population observed in the Women’s Health Initiative. "What we saw was a decline in breast cancer risk among women using estrogen-only therapy for less than 10 years, but an increased risk among those women using estrogen for 15-20 years," Dr. Chen said.

Importantly, although breast cancer incidence was increased in the HT groups, "there was no increase in the risk of fatal breast cancer, either with combined or estrogen-only therapy," Dr. Chen stressed. "This is something we are continuing to investigate."

The findings have the potential to increase the confusion regarding HT and to perhaps reignite the hormone therapy debate, Dr. Chen acknowledged in an interview. However, they should be considered in their proper context. "While the relative risk of developing breast cancer in increased, the absolute risk associated with [HT] are low," she said.

The observed effects associated with HT were stronger for estrogen receptor–positive tumors and among thinner women, Dr. Chen noted, adding that the results were similar when limited to women who underwent regular breast cancer screening.

The study was funded by the National Cancer Institute. Dr. Chen disclosed no financial conflicts of interest.

CHICAGO – Long-term use of estrogen-only therapy increases the risk of postmenopausal women developing breast cancer, according to new data from the Nurses’ Health Study.

The finding, reported April 1 by Dr. Wendy Chen at the annual meeting of the American Association for Cancer Research, suggests that opting for progesterone-free hormone therapy for the treatment of menopause symptoms should not be considered the risk-free alternative to combination progesterone plus estrogen formulations.

Still, the absolute risks were small. During the study’s 1.57 million person-years of follow-up from 1980 through 2008, 5,631 incident invasive breast cancers were diagnosed and 884 of the women died of breast cancer.

To evaluate the breast cancer risk associated with long-term use of both combined and estrogen-only hormone therapy, Dr. Chen of Brigham and Women’s Hospital in Boston and her colleagues evaluated data collected over 28 years through the Nurses’ Health Study. Of the 121,700 study participants who were aged 30-55 years in 1976, women who used estrogen-only therapy for 10.0-14.9 years and for 15.0-19.9 years had, respectively, a 22% and 43% increased risk of developing breast cancer relative to those women not on hormone therapy (HT).

"Our data also confirmed the previously reported increased risk associated with combined hormone therapy," Dr. Chen stated, noting that women in the study who used progesterone plus estrogen for 10-14.9 years had an 88% increased risk of developing breast cancer relative to those not on HT and the risk increased to more than twofold in women using it for up to 20 years. Further, the risk of developing breast cancer does not appear to plateau over time, but rather continues to increase. "The longer women use [HT]. The higher their risk," she said.

In a separate analysis, the investigators restricted the study population to healthy, active postmenopausal women 50-79 years with an intact uterus – the same population observed in the Women’s Health Initiative. "What we saw was a decline in breast cancer risk among women using estrogen-only therapy for less than 10 years, but an increased risk among those women using estrogen for 15-20 years," Dr. Chen said.

Importantly, although breast cancer incidence was increased in the HT groups, "there was no increase in the risk of fatal breast cancer, either with combined or estrogen-only therapy," Dr. Chen stressed. "This is something we are continuing to investigate."

The findings have the potential to increase the confusion regarding HT and to perhaps reignite the hormone therapy debate, Dr. Chen acknowledged in an interview. However, they should be considered in their proper context. "While the relative risk of developing breast cancer in increased, the absolute risk associated with [HT] are low," she said.

The observed effects associated with HT were stronger for estrogen receptor–positive tumors and among thinner women, Dr. Chen noted, adding that the results were similar when limited to women who underwent regular breast cancer screening.

The study was funded by the National Cancer Institute. Dr. Chen disclosed no financial conflicts of interest.