Dual HER2 Blockade Strategies Advance in Breast Cancer Trials

Efforts to build on the effectiveness of trastuzumab with a dual blockade of the HER2 pathway continue to suggest such a strategy has the potential to enhance outcomes for HER2-positive breast cancer patients.

Genentech announced this summer that the combination of trastuzumab (Herceptin) and docetaxel (Taxotere) with the investigational agent pertuzumab (Omnitarg) met the primary end point of improved progression-free survival in the randomized, double-blind, placebo-controlled phase III CLEOPATRA trial.

A monoclonal antibody, pertuzumab prevents the HER2 receptor from pairing with other HER receptors, including HER1/EGFR, HER3, and HER4, according to Genentech. The Roche-owned company released no data, but said it expects to submit the trial results for "global regulatory approval" this year. A spokesperson said the results will be submitted at "an upcoming medical meeting,"

Trastuzumab emtansine (formerly known as trastuzumab-DM1) is also in ongoing trials, assessing it in various combinations involving trastuzumab, pertuzumab, and lapatinib (Tykerb), the last of which is a dual inhibitor of HER2 and the epidermal growth factor receptor (EGFR). Genentech is developing this experimental antibody-drug conjugate, with Immunogen. It sought accelerated approval based on a positive phase II study last summer but was rebuffed by the Food and Drug Administration on grounds that patients in the trial had not exhausted other therapies.

Since then, the combination of trastuzumab and lapatinib – both approved for HER2-positive breast cancer – was shown to boost complete response rates to 74% when combined with preoperative chemotherapy in a phase II trial reported in June at the annual meeting of the American Society of Clinical Oncology (ASCO).

The study was one of a trio of neoadjuvant trials that evaluated whether complete responses rates could be bettered by adding lapatinib to chemotherapy plus trastuzumab or by combining lapatinib and trastuzumab without chemotherapy, but with the option of endocrine therapy.

Trastuzumab, Lapatinib, and Chemotherapy

Investigators in the phase II CHER-LOB study defined pathological complete response (pCR) as the complete disappearance of invasive residual disease in the breast and axillary nodes. Among 115 evaluable women, the pCR rate increased from 25.7% with chemotherapy plus trastuzumab (arm A) and 27.8% with chemotherapy plus lapatinib (arm B) to 43.1% with the addition of lapatinib to chemotherapy plus trastuzumab (arm C).

The cardiac safety data were reassuring, with no reports of heart failure or significant loss of left ventricular function. Diarrhea, however, was a significant toxicity that caused dose reductions and treatment interruptions in the majority of patients receiving chemotherapy plus lapatinib, acknowledged Dr. Valentina Guarneri of the Modena (Italy) University Hospital. Grade 3 or higher diarrhea was reported in 36% of 39 patients in arm B and 33% of 46 patients in arm C. Permanent lapatinib discontinuation occurred in 25.6% and 13%, respectively.

Because of the high incidence of diarrhea, the protocol was amended to reduce continuous daily dosing of lapatinib from 1,500 mg to 1,250 mg in arm B and from 1,000 mg to 750 mg in arm C. After the amendment, dose reductions fell from 80% to 54% in arm B and from 55% to 34% in arm C, she said.

Chemotherapy consisted of weekly paclitaxel 80 mg/m² for 12 weeks followed by four cycles of fluorouracil 600 mg/m² plus epirubicin 75 mg/m² plus cyclophosphamide 600 mg/m² every 3 weeks (FE₇₅C). Trastuzumab 4 mg/m² was given as a loading dose, followed by 2 mg/m² every week.

A Similar Protocol but With Modifications

The second trial extended the 24-week preoperative FE₇₅C chemotherapy sequence to 26 weeks after a 2-week run-in period of anti-HER2 therapy and used weekly paclitaxel after, rather than before, FE₇₅C. Also, the daily lapatinib dose was set at 1,250 mg in arm B and increased from 750 mg-1,000 mg in arm C. Trastuzumab dosing was the same as above.

Using this protocol, pCR rates among 78 evaluable women reached 54% with chemotherapy plus trastuzumab (arm A), 45% with chemotherapy plus lapatinib (arm B), and 74% with double HER2 blockade plus chemotherapy (arm C), reported Dr. Frankie Ann Holmes with Texas Oncology in Houston.

Patients had stage II-III biopsy proven invasive HER2-positive breast cancer, whereas CHER-LOB limited enrollment to stage II-IIIA disease.

Headed in the Right Direction

Invited discussant Dr. Gunther von Minckwitz, with the German Breast Group, said that despite the small patient numbers, the pCR rates were quite impressive, especially for the study presented by Dr. Holmes, and are in range with previous trials using longer chemotherapy regimens.

The difference in pCR rates between the two studies could be explained by the small sample sizes and differences in patient characteristics. "Still the tendency is going in the same direction," he observed.

Dr. von Minckwitz urged caution in using pCR as an end point, however, particularly among patients with HER2-positive and estrogen receptor (ER)-positive disease. His own meta-analysis presented at ASCO of seven German neoadjuvant breast trials using anthracycline/taxane regimens with or without trastuzumab, showed that pCR strongly correlates with disease-free survival in higher risk groups such as ductal, HER2-positive, and ER-negative disease, but not in luminal A-like and ER-positive/HER2-positive tumors (Abstract 1028).

Lapatinib vs. Trastuzumab Sans Chemo

The third study used neoadjuvant lapatinib 1,000 mg daily plus trastuzumab at a loading dose of 4 mg/kg followed by 2 mg/kg weekly, without chemotherapy, in women with large HER2-positive tumors (median 6 cm; range 1.5-30 cm). In an effort to overcome estrogen receptor crosstalk, ER-positive patients also received letrozole (Femara), plus goserelin, if premenopausal.

A pCR, defined as no invasive cancer in the breast only, was achieved by 28% of the 64 evaluable patients – 21% of ER-positive and 40% of ER-negative patients, Dr. Jenny C. Chang reported on behalf of the Translational Breast Cancer Research Consortium (TBCRC) 006 investigators. No patient progressed during the 12 weeks of targeted therapy alone.

The secondary end point of residual disease of less than 1 cm (near pCR) was seen in 56% of ER-positive and 48% of ER-negative patients, suggesting that these patients may benefit from longer therapy, she said. In all, 62% of patients were ER positive, 62% had a tumor size greater than 5 cm, and 54% were premenopausal.

The regimen in the phase II TBCRC 006 study was very well tolerated, with only five patients discontinuing therapy and 3 reports of grade 3/4 abnormal liver function tests that completely resolved.

Further study is needed before suggesting that select patients with HER2-positive tumors may not need neoadjuvant chemotherapy, said Dr. Chang, director of the Methodist Cancer Center in Houston.

The data compare favorably with those reported at the 2010 San Antonio Breast Cancer Symposium from the phase II NEOSPHERE trial, in which 17% of patients overall, 6% of ER-positive and 29% of ER-negative patients experienced a pCR after 12 weeks of neoadjuvant trastuzumab plus the monoclonal antibody, pertuzumab, Dr. von Minckwitz observed.

New insights are expected from three upcoming neoadjuvant chemotherapy trials in HER2-positive breast cancer: Cancer and Leukemia Group B 40601, European Organization for Research and Treatment of Cancer 10054 and a National Surgical Adjuvant Breast and Bowel Project B-41.

Molecular Profiles Begin to Emerge

Dr. Holmes and her colleagues conducted a variety of molecular analyses in tumor samples from 49 patients before and after anti-HER2 therapy. She reported that their findings indicate the following:

• Baseline phosphorylated EGFR tyrosine1068 is a marker of nonresponse to lapatinib.

• Baseline activation of autophagy correlates with no pCR to all therapies.

• Baseline ratios of phosphorylated Forkhead box O to PTEN and PI3K correlate with response.

• Phosphorylated STAT5 after trastuzumab correlates with pCR.

The molecular profiles suggest that pCR tumors rely on a truncated, rudimentary social network, while resistant tumors use a far more extensive network of autophagy and stem cell–regulated pathways to evade therapy and are thus harder to kill, Dr. Holmes said.

"Despite the limitations, this exploratory analysis shows that the pathway to accelerating the cure of breast cancer is available in every oncologist’s office if she or he can network to tissue-based research trials," she said.

The CHER-LOB investigators tested tumor samples for p95HER2, which is expressed in approximately 30% of HER2-positive breast cancer patients and thought to confer resistance to trastuzumab. No significant differences were observed in all treatment arms in pCR rates based on p95HER2 expression, Dr. Guarneri said.

The p95HER2 results contradict earlier research, observed Dr. von Minckwitz. "We really have to design these biomarker studies very cautiously and the first [issue] we have to address is that we have to have sufficient numbers to study," he added.

CHER-LOB was supported by GlaxoSmithKline. Dr. Guarneri reports no conflicts. Dr. Holmes reports a consultant-advisory role with Phillips Home Monitoring and honoraria from Genentech and Novartis. Dr. Chang reports no relevant conflicts. Dr. Von Minckwitz reports honoraria from Amgen, Roche, and Sanofi-Aventis and research funding from Abraxis BioScience, Amgen, Bayer, GSK, Novartis, Pfizer, Roche, Sanofi-Aventis, and bioMérieux.

Efforts to build on the effectiveness of trastuzumab with a dual blockade of the HER2 pathway continue to suggest such a strategy has the potential to enhance outcomes for HER2-positive breast cancer patients.

Genentech announced this summer that the combination of trastuzumab (Herceptin) and docetaxel (Taxotere) with the investigational agent pertuzumab (Omnitarg) met the primary end point of improved progression-free survival in the randomized, double-blind, placebo-controlled phase III CLEOPATRA trial.

A monoclonal antibody, pertuzumab prevents the HER2 receptor from pairing with other HER receptors, including HER1/EGFR, HER3, and HER4, according to Genentech. The Roche-owned company released no data, but said it expects to submit the trial results for "global regulatory approval" this year. A spokesperson said the results will be submitted at "an upcoming medical meeting,"

Trastuzumab emtansine (formerly known as trastuzumab-DM1) is also in ongoing trials, assessing it in various combinations involving trastuzumab, pertuzumab, and lapatinib (Tykerb), the last of which is a dual inhibitor of HER2 and the epidermal growth factor receptor (EGFR). Genentech is developing this experimental antibody-drug conjugate, with Immunogen. It sought accelerated approval based on a positive phase II study last summer but was rebuffed by the Food and Drug Administration on grounds that patients in the trial had not exhausted other therapies.

Since then, the combination of trastuzumab and lapatinib – both approved for HER2-positive breast cancer – was shown to boost complete response rates to 74% when combined with preoperative chemotherapy in a phase II trial reported in June at the annual meeting of the American Society of Clinical Oncology (ASCO).

The study was one of a trio of neoadjuvant trials that evaluated whether complete responses rates could be bettered by adding lapatinib to chemotherapy plus trastuzumab or by combining lapatinib and trastuzumab without chemotherapy, but with the option of endocrine therapy.

Trastuzumab, Lapatinib, and Chemotherapy

Investigators in the phase II CHER-LOB study defined pathological complete response (pCR) as the complete disappearance of invasive residual disease in the breast and axillary nodes. Among 115 evaluable women, the pCR rate increased from 25.7% with chemotherapy plus trastuzumab (arm A) and 27.8% with chemotherapy plus lapatinib (arm B) to 43.1% with the addition of lapatinib to chemotherapy plus trastuzumab (arm C).

The cardiac safety data were reassuring, with no reports of heart failure or significant loss of left ventricular function. Diarrhea, however, was a significant toxicity that caused dose reductions and treatment interruptions in the majority of patients receiving chemotherapy plus lapatinib, acknowledged Dr. Valentina Guarneri of the Modena (Italy) University Hospital. Grade 3 or higher diarrhea was reported in 36% of 39 patients in arm B and 33% of 46 patients in arm C. Permanent lapatinib discontinuation occurred in 25.6% and 13%, respectively.

Because of the high incidence of diarrhea, the protocol was amended to reduce continuous daily dosing of lapatinib from 1,500 mg to 1,250 mg in arm B and from 1,000 mg to 750 mg in arm C. After the amendment, dose reductions fell from 80% to 54% in arm B and from 55% to 34% in arm C, she said.

Chemotherapy consisted of weekly paclitaxel 80 mg/m² for 12 weeks followed by four cycles of fluorouracil 600 mg/m² plus epirubicin 75 mg/m² plus cyclophosphamide 600 mg/m² every 3 weeks (FE₇₅C). Trastuzumab 4 mg/m² was given as a loading dose, followed by 2 mg/m² every week.

A Similar Protocol but With Modifications

The second trial extended the 24-week preoperative FE₇₅C chemotherapy sequence to 26 weeks after a 2-week run-in period of anti-HER2 therapy and used weekly paclitaxel after, rather than before, FE₇₅C. Also, the daily lapatinib dose was set at 1,250 mg in arm B and increased from 750 mg-1,000 mg in arm C. Trastuzumab dosing was the same as above.

Using this protocol, pCR rates among 78 evaluable women reached 54% with chemotherapy plus trastuzumab (arm A), 45% with chemotherapy plus lapatinib (arm B), and 74% with double HER2 blockade plus chemotherapy (arm C), reported Dr. Frankie Ann Holmes with Texas Oncology in Houston.

Patients had stage II-III biopsy proven invasive HER2-positive breast cancer, whereas CHER-LOB limited enrollment to stage II-IIIA disease.

Headed in the Right Direction

Invited discussant Dr. Gunther von Minckwitz, with the German Breast Group, said that despite the small patient numbers, the pCR rates were quite impressive, especially for the study presented by Dr. Holmes, and are in range with previous trials using longer chemotherapy regimens.

The difference in pCR rates between the two studies could be explained by the small sample sizes and differences in patient characteristics. "Still the tendency is going in the same direction," he observed.

Dr. von Minckwitz urged caution in using pCR as an end point, however, particularly among patients with HER2-positive and estrogen receptor (ER)-positive disease. His own meta-analysis presented at ASCO of seven German neoadjuvant breast trials using anthracycline/taxane regimens with or without trastuzumab, showed that pCR strongly correlates with disease-free survival in higher risk groups such as ductal, HER2-positive, and ER-negative disease, but not in luminal A-like and ER-positive/HER2-positive tumors (Abstract 1028).

Lapatinib vs. Trastuzumab Sans Chemo

The third study used neoadjuvant lapatinib 1,000 mg daily plus trastuzumab at a loading dose of 4 mg/kg followed by 2 mg/kg weekly, without chemotherapy, in women with large HER2-positive tumors (median 6 cm; range 1.5-30 cm). In an effort to overcome estrogen receptor crosstalk, ER-positive patients also received letrozole (Femara), plus goserelin, if premenopausal.

A pCR, defined as no invasive cancer in the breast only, was achieved by 28% of the 64 evaluable patients – 21% of ER-positive and 40% of ER-negative patients, Dr. Jenny C. Chang reported on behalf of the Translational Breast Cancer Research Consortium (TBCRC) 006 investigators. No patient progressed during the 12 weeks of targeted therapy alone.

The secondary end point of residual disease of less than 1 cm (near pCR) was seen in 56% of ER-positive and 48% of ER-negative patients, suggesting that these patients may benefit from longer therapy, she said. In all, 62% of patients were ER positive, 62% had a tumor size greater than 5 cm, and 54% were premenopausal.

The regimen in the phase II TBCRC 006 study was very well tolerated, with only five patients discontinuing therapy and 3 reports of grade 3/4 abnormal liver function tests that completely resolved.

Further study is needed before suggesting that select patients with HER2-positive tumors may not need neoadjuvant chemotherapy, said Dr. Chang, director of the Methodist Cancer Center in Houston.

The data compare favorably with those reported at the 2010 San Antonio Breast Cancer Symposium from the phase II NEOSPHERE trial, in which 17% of patients overall, 6% of ER-positive and 29% of ER-negative patients experienced a pCR after 12 weeks of neoadjuvant trastuzumab plus the monoclonal antibody, pertuzumab, Dr. von Minckwitz observed.

New insights are expected from three upcoming neoadjuvant chemotherapy trials in HER2-positive breast cancer: Cancer and Leukemia Group B 40601, European Organization for Research and Treatment of Cancer 10054 and a National Surgical Adjuvant Breast and Bowel Project B-41.

Molecular Profiles Begin to Emerge

Dr. Holmes and her colleagues conducted a variety of molecular analyses in tumor samples from 49 patients before and after anti-HER2 therapy. She reported that their findings indicate the following:

• Baseline phosphorylated EGFR tyrosine1068 is a marker of nonresponse to lapatinib.

• Baseline activation of autophagy correlates with no pCR to all therapies.

• Baseline ratios of phosphorylated Forkhead box O to PTEN and PI3K correlate with response.

• Phosphorylated STAT5 after trastuzumab correlates with pCR.

The molecular profiles suggest that pCR tumors rely on a truncated, rudimentary social network, while resistant tumors use a far more extensive network of autophagy and stem cell–regulated pathways to evade therapy and are thus harder to kill, Dr. Holmes said.

"Despite the limitations, this exploratory analysis shows that the pathway to accelerating the cure of breast cancer is available in every oncologist’s office if she or he can network to tissue-based research trials," she said.

The CHER-LOB investigators tested tumor samples for p95HER2, which is expressed in approximately 30% of HER2-positive breast cancer patients and thought to confer resistance to trastuzumab. No significant differences were observed in all treatment arms in pCR rates based on p95HER2 expression, Dr. Guarneri said.

The p95HER2 results contradict earlier research, observed Dr. von Minckwitz. "We really have to design these biomarker studies very cautiously and the first [issue] we have to address is that we have to have sufficient numbers to study," he added.

CHER-LOB was supported by GlaxoSmithKline. Dr. Guarneri reports no conflicts. Dr. Holmes reports a consultant-advisory role with Phillips Home Monitoring and honoraria from Genentech and Novartis. Dr. Chang reports no relevant conflicts. Dr. Von Minckwitz reports honoraria from Amgen, Roche, and Sanofi-Aventis and research funding from Abraxis BioScience, Amgen, Bayer, GSK, Novartis, Pfizer, Roche, Sanofi-Aventis, and bioMérieux.

Efforts to build on the effectiveness of trastuzumab with a dual blockade of the HER2 pathway continue to suggest such a strategy has the potential to enhance outcomes for HER2-positive breast cancer patients.

Genentech announced this summer that the combination of trastuzumab (Herceptin) and docetaxel (Taxotere) with the investigational agent pertuzumab (Omnitarg) met the primary end point of improved progression-free survival in the randomized, double-blind, placebo-controlled phase III CLEOPATRA trial.

A monoclonal antibody, pertuzumab prevents the HER2 receptor from pairing with other HER receptors, including HER1/EGFR, HER3, and HER4, according to Genentech. The Roche-owned company released no data, but said it expects to submit the trial results for "global regulatory approval" this year. A spokesperson said the results will be submitted at "an upcoming medical meeting,"

Trastuzumab emtansine (formerly known as trastuzumab-DM1) is also in ongoing trials, assessing it in various combinations involving trastuzumab, pertuzumab, and lapatinib (Tykerb), the last of which is a dual inhibitor of HER2 and the epidermal growth factor receptor (EGFR). Genentech is developing this experimental antibody-drug conjugate, with Immunogen. It sought accelerated approval based on a positive phase II study last summer but was rebuffed by the Food and Drug Administration on grounds that patients in the trial had not exhausted other therapies.

Since then, the combination of trastuzumab and lapatinib – both approved for HER2-positive breast cancer – was shown to boost complete response rates to 74% when combined with preoperative chemotherapy in a phase II trial reported in June at the annual meeting of the American Society of Clinical Oncology (ASCO).

The study was one of a trio of neoadjuvant trials that evaluated whether complete responses rates could be bettered by adding lapatinib to chemotherapy plus trastuzumab or by combining lapatinib and trastuzumab without chemotherapy, but with the option of endocrine therapy.

Trastuzumab, Lapatinib, and Chemotherapy

Investigators in the phase II CHER-LOB study defined pathological complete response (pCR) as the complete disappearance of invasive residual disease in the breast and axillary nodes. Among 115 evaluable women, the pCR rate increased from 25.7% with chemotherapy plus trastuzumab (arm A) and 27.8% with chemotherapy plus lapatinib (arm B) to 43.1% with the addition of lapatinib to chemotherapy plus trastuzumab (arm C).

The cardiac safety data were reassuring, with no reports of heart failure or significant loss of left ventricular function. Diarrhea, however, was a significant toxicity that caused dose reductions and treatment interruptions in the majority of patients receiving chemotherapy plus lapatinib, acknowledged Dr. Valentina Guarneri of the Modena (Italy) University Hospital. Grade 3 or higher diarrhea was reported in 36% of 39 patients in arm B and 33% of 46 patients in arm C. Permanent lapatinib discontinuation occurred in 25.6% and 13%, respectively.

Because of the high incidence of diarrhea, the protocol was amended to reduce continuous daily dosing of lapatinib from 1,500 mg to 1,250 mg in arm B and from 1,000 mg to 750 mg in arm C. After the amendment, dose reductions fell from 80% to 54% in arm B and from 55% to 34% in arm C, she said.

Chemotherapy consisted of weekly paclitaxel 80 mg/m² for 12 weeks followed by four cycles of fluorouracil 600 mg/m² plus epirubicin 75 mg/m² plus cyclophosphamide 600 mg/m² every 3 weeks (FE₇₅C). Trastuzumab 4 mg/m² was given as a loading dose, followed by 2 mg/m² every week.

A Similar Protocol but With Modifications

The second trial extended the 24-week preoperative FE₇₅C chemotherapy sequence to 26 weeks after a 2-week run-in period of anti-HER2 therapy and used weekly paclitaxel after, rather than before, FE₇₅C. Also, the daily lapatinib dose was set at 1,250 mg in arm B and increased from 750 mg-1,000 mg in arm C. Trastuzumab dosing was the same as above.

Using this protocol, pCR rates among 78 evaluable women reached 54% with chemotherapy plus trastuzumab (arm A), 45% with chemotherapy plus lapatinib (arm B), and 74% with double HER2 blockade plus chemotherapy (arm C), reported Dr. Frankie Ann Holmes with Texas Oncology in Houston.

Patients had stage II-III biopsy proven invasive HER2-positive breast cancer, whereas CHER-LOB limited enrollment to stage II-IIIA disease.

Headed in the Right Direction

Invited discussant Dr. Gunther von Minckwitz, with the German Breast Group, said that despite the small patient numbers, the pCR rates were quite impressive, especially for the study presented by Dr. Holmes, and are in range with previous trials using longer chemotherapy regimens.

The difference in pCR rates between the two studies could be explained by the small sample sizes and differences in patient characteristics. "Still the tendency is going in the same direction," he observed.

Dr. von Minckwitz urged caution in using pCR as an end point, however, particularly among patients with HER2-positive and estrogen receptor (ER)-positive disease. His own meta-analysis presented at ASCO of seven German neoadjuvant breast trials using anthracycline/taxane regimens with or without trastuzumab, showed that pCR strongly correlates with disease-free survival in higher risk groups such as ductal, HER2-positive, and ER-negative disease, but not in luminal A-like and ER-positive/HER2-positive tumors (Abstract 1028).

Lapatinib vs. Trastuzumab Sans Chemo

The third study used neoadjuvant lapatinib 1,000 mg daily plus trastuzumab at a loading dose of 4 mg/kg followed by 2 mg/kg weekly, without chemotherapy, in women with large HER2-positive tumors (median 6 cm; range 1.5-30 cm). In an effort to overcome estrogen receptor crosstalk, ER-positive patients also received letrozole (Femara), plus goserelin, if premenopausal.

A pCR, defined as no invasive cancer in the breast only, was achieved by 28% of the 64 evaluable patients – 21% of ER-positive and 40% of ER-negative patients, Dr. Jenny C. Chang reported on behalf of the Translational Breast Cancer Research Consortium (TBCRC) 006 investigators. No patient progressed during the 12 weeks of targeted therapy alone.

The secondary end point of residual disease of less than 1 cm (near pCR) was seen in 56% of ER-positive and 48% of ER-negative patients, suggesting that these patients may benefit from longer therapy, she said. In all, 62% of patients were ER positive, 62% had a tumor size greater than 5 cm, and 54% were premenopausal.

The regimen in the phase II TBCRC 006 study was very well tolerated, with only five patients discontinuing therapy and 3 reports of grade 3/4 abnormal liver function tests that completely resolved.

Further study is needed before suggesting that select patients with HER2-positive tumors may not need neoadjuvant chemotherapy, said Dr. Chang, director of the Methodist Cancer Center in Houston.

The data compare favorably with those reported at the 2010 San Antonio Breast Cancer Symposium from the phase II NEOSPHERE trial, in which 17% of patients overall, 6% of ER-positive and 29% of ER-negative patients experienced a pCR after 12 weeks of neoadjuvant trastuzumab plus the monoclonal antibody, pertuzumab, Dr. von Minckwitz observed.

New insights are expected from three upcoming neoadjuvant chemotherapy trials in HER2-positive breast cancer: Cancer and Leukemia Group B 40601, European Organization for Research and Treatment of Cancer 10054 and a National Surgical Adjuvant Breast and Bowel Project B-41.

Molecular Profiles Begin to Emerge

Dr. Holmes and her colleagues conducted a variety of molecular analyses in tumor samples from 49 patients before and after anti-HER2 therapy. She reported that their findings indicate the following:

• Baseline phosphorylated EGFR tyrosine1068 is a marker of nonresponse to lapatinib.

• Baseline activation of autophagy correlates with no pCR to all therapies.

• Baseline ratios of phosphorylated Forkhead box O to PTEN and PI3K correlate with response.

• Phosphorylated STAT5 after trastuzumab correlates with pCR.

The molecular profiles suggest that pCR tumors rely on a truncated, rudimentary social network, while resistant tumors use a far more extensive network of autophagy and stem cell–regulated pathways to evade therapy and are thus harder to kill, Dr. Holmes said.

"Despite the limitations, this exploratory analysis shows that the pathway to accelerating the cure of breast cancer is available in every oncologist’s office if she or he can network to tissue-based research trials," she said.

The CHER-LOB investigators tested tumor samples for p95HER2, which is expressed in approximately 30% of HER2-positive breast cancer patients and thought to confer resistance to trastuzumab. No significant differences were observed in all treatment arms in pCR rates based on p95HER2 expression, Dr. Guarneri said.

The p95HER2 results contradict earlier research, observed Dr. von Minckwitz. "We really have to design these biomarker studies very cautiously and the first [issue] we have to address is that we have to have sufficient numbers to study," he added.

CHER-LOB was supported by GlaxoSmithKline. Dr. Guarneri reports no conflicts. Dr. Holmes reports a consultant-advisory role with Phillips Home Monitoring and honoraria from Genentech and Novartis. Dr. Chang reports no relevant conflicts. Dr. Von Minckwitz reports honoraria from Amgen, Roche, and Sanofi-Aventis and research funding from Abraxis BioScience, Amgen, Bayer, GSK, Novartis, Pfizer, Roche, Sanofi-Aventis, and bioMérieux.