Breast Cancer

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.

Adam M. Brufsky, MD, PhD
University of Pittsburgh School of Medicine, Pittsburgh, PA

Estrogen receptor (ER) signaling plays a critical role in many breast cancers. As a result, endocrine therapy is a mainstay in the treatment plan for patients with hormone receptor-positive breast cancer. Although patients with metastatic breast cancer (MBC) are often given several lines of endocrine therapy throughout the course of their disease, the optimal sequence of and exact mechanisms of resistance to endocrine therapy remain unclear. Endocrine therapies include aromatase inhibitors, selective ER modulators, and selective ER downregulators. These agents interfere with ER signaling and inhibit breast cancer growth, but their mechanisms of action (MOAs) are distinct and potential mechanisms of resistance vary. Patient-specific factors (eg, tumor characteristics, burden of disease, patient preferences, and treatment history) and the MOAs of the available agents are important considerations. This review discusses the latest understanding of ER biology, the mechanistic differences between endocrine therapies, and future directions in endocrine therapy for MBC.

Although many different agents have been used in the clinic to treat these patients, aromatase inhibitors (AIs) and antiestrogens form the two major categories of endocrine therapy in current use. These two types of agents have distinct mechanisms of action (MOAs).1 AIs reduce circulating estrogen levels by preventing the conversion of androstenedione into estrogen in peripheral tissues. 1 Antiestrogens, also referred to as ER antagonists, can be further classified into two subgroups based on their MOA: the selective ER modulators (SERMs), typified by tamoxifen, and the selective ER downregulators (SERDs), exemplified by fulvestrant (Faslodex).1

A number of randomized clinical studies have demonstrated the efficacy of tamoxifen and the AIs (anastrozole, letrozole, and exemestane) in the adjuvant2–5 and metastatic6–8 settings. Fulvestrant has demonstrated effectiveness in the metastatic setting.9–13

For a PDF of the complete article, click on the link to the left of this article.

Adam M. Brufsky, MD, PhD
University of Pittsburgh School of Medicine, Pittsburgh, PA

Estrogen receptor (ER) signaling plays a critical role in many breast cancers. As a result, endocrine therapy is a mainstay in the treatment plan for patients with hormone receptor-positive breast cancer. Although patients with metastatic breast cancer (MBC) are often given several lines of endocrine therapy throughout the course of their disease, the optimal sequence of and exact mechanisms of resistance to endocrine therapy remain unclear. Endocrine therapies include aromatase inhibitors, selective ER modulators, and selective ER downregulators. These agents interfere with ER signaling and inhibit breast cancer growth, but their mechanisms of action (MOAs) are distinct and potential mechanisms of resistance vary. Patient-specific factors (eg, tumor characteristics, burden of disease, patient preferences, and treatment history) and the MOAs of the available agents are important considerations. This review discusses the latest understanding of ER biology, the mechanistic differences between endocrine therapies, and future directions in endocrine therapy for MBC.

Although many different agents have been used in the clinic to treat these patients, aromatase inhibitors (AIs) and antiestrogens form the two major categories of endocrine therapy in current use. These two types of agents have distinct mechanisms of action (MOAs).1 AIs reduce circulating estrogen levels by preventing the conversion of androstenedione into estrogen in peripheral tissues. 1 Antiestrogens, also referred to as ER antagonists, can be further classified into two subgroups based on their MOA: the selective ER modulators (SERMs), typified by tamoxifen, and the selective ER downregulators (SERDs), exemplified by fulvestrant (Faslodex).1

A number of randomized clinical studies have demonstrated the efficacy of tamoxifen and the AIs (anastrozole, letrozole, and exemestane) in the adjuvant2–5 and metastatic6–8 settings. Fulvestrant has demonstrated effectiveness in the metastatic setting.9–13

For a PDF of the complete article, click on the link to the left of this article.

Adam M. Brufsky, MD, PhD
University of Pittsburgh School of Medicine, Pittsburgh, PA

Estrogen receptor (ER) signaling plays a critical role in many breast cancers. As a result, endocrine therapy is a mainstay in the treatment plan for patients with hormone receptor-positive breast cancer. Although patients with metastatic breast cancer (MBC) are often given several lines of endocrine therapy throughout the course of their disease, the optimal sequence of and exact mechanisms of resistance to endocrine therapy remain unclear. Endocrine therapies include aromatase inhibitors, selective ER modulators, and selective ER downregulators. These agents interfere with ER signaling and inhibit breast cancer growth, but their mechanisms of action (MOAs) are distinct and potential mechanisms of resistance vary. Patient-specific factors (eg, tumor characteristics, burden of disease, patient preferences, and treatment history) and the MOAs of the available agents are important considerations. This review discusses the latest understanding of ER biology, the mechanistic differences between endocrine therapies, and future directions in endocrine therapy for MBC.

Although many different agents have been used in the clinic to treat these patients, aromatase inhibitors (AIs) and antiestrogens form the two major categories of endocrine therapy in current use. These two types of agents have distinct mechanisms of action (MOAs).1 AIs reduce circulating estrogen levels by preventing the conversion of androstenedione into estrogen in peripheral tissues. 1 Antiestrogens, also referred to as ER antagonists, can be further classified into two subgroups based on their MOA: the selective ER modulators (SERMs), typified by tamoxifen, and the selective ER downregulators (SERDs), exemplified by fulvestrant (Faslodex).1

A number of randomized clinical studies have demonstrated the efficacy of tamoxifen and the AIs (anastrozole, letrozole, and exemestane) in the adjuvant2–5 and metastatic6–8 settings. Fulvestrant has demonstrated effectiveness in the metastatic setting.9–13

For a PDF of the complete article, click on the link to the left of this article.

Dr. David H Henry summarizes key articles in the July issue of the journal Community Oncology. Topics include Exemestane for postmenopausal women at increased risk of breast cancer and a summary of key research from the 2011 ASCO meeting, including crizotinib for ALK+ non-small cell lung cancer and vemurafenib and ipilimumab for metastatic melanoma.

Dr. David H Henry summarizes key articles in the July issue of the journal Community Oncology. Topics include Exemestane for postmenopausal women at increased risk of breast cancer and a summary of key research from the 2011 ASCO meeting, including crizotinib for ALK+ non-small cell lung cancer and vemurafenib and ipilimumab for metastatic melanoma.

Dr. David H Henry summarizes key articles in the July issue of the journal Community Oncology. Topics include Exemestane for postmenopausal women at increased risk of breast cancer and a summary of key research from the 2011 ASCO meeting, including crizotinib for ALK+ non-small cell lung cancer and vemurafenib and ipilimumab for metastatic melanoma.

Yes – It Is Time to Consider a Paradigm Shift.

By Dr. Seema Khan

In stage IV breast cancer, local therapy is not considered important except for controlling symptoms. But recent large-scale retrospective studies tell us that, if you follow enough women long enough, you see a difference in survival related to control of local disease. These emerging data tell us it’s time to consider a paradigm shift in the treatment of stage IV breast cancer.

Researchers are finding that primary site treatment regimens are important because an intact primary tumor can serve as a continued source of new metastatic lesions. There is reason, therefore, to believe that treating these can prolong life.

First explored by Dr. Larry Norton and Joan Massagué, Ph.D., (Nature Med. 2006;12:875-8), the concept of cancer self-seeding holds that cells from the primary tumor not only travel unidirectionally to seed metastases but also return to the primary tumor, self-seeding it and helping it to grow even more.

This view incorporates the microenvironment of the primary tumor. Here, fibroblasts and other cells – particularly mesenchymal stem cells derived from bone marrow – may play a very important role, creating a reactive stroma that seems to release growth-promoting substances that increase the metastatic efficiency of the circulating cells.

Robert A. Weinberg, Ph.D., published data showing that these mesenchymal stem cells are pluripotent progenitor cells. When weakly metastatic human breast cancer cells were mixed with these stem cells, the cancer cells’ metastatic potential greatly increased. The breast cancer cells then stimulated the stem cells to secrete a chemokine which – in turn – enhanced the cancer cells’ motility and their ability to invade and metastasize (Nature 2007;449:557-63). In effect, the primary tumor acts like a filling station, giving these tumor cells more energy to go out and metastasize in different sites.

Although such studies remain animal models, I think we can say there is a basis for primary tumor therapy in the metastatic setting. A dozen or more retrospective studies of large institutional series, cancer databases, and population-based studies have examined outcomes in women treated with and without surgical resection. Data on about 30,000 women have been published, with about 50% receiving some form of primary tumor therapy. The survival benefit across them is quite consistent, with the hazard ratio of death over a given time period reduced from 30% to 50%.

These studies do demonstrate selection bias: Women treated with surgical removal were more likely to be young, white, married, with smaller tumors and a lower burden of disease, and it is possible that they would have done better anyway. Studies have also shown that better survival, even in stage IV cancer, occurs in women who have a therapeutic target (that is, hormone receptors or HER2). But there was still a significant survival benefit for surgery.

Surgical resection may also confer benefit by preventing the primary tumor in the breast from becoming a quality of-life problem. At Northwestern Memorial Hospital, Chicago, we conducted a study that showed the odds of symptomatic chest wall disease were far lower in the surgical group, compared with the nonsurgical group. In this 2008 study, we found that women with good local control– surgical or systemic - did better. Time to first progression was prolonged by 50% in the surgical group, while chest wall control was associated with a 60% improvement in overall survival, regardless of whether surgical resection was performed (Cancer 2008;113:2011-9).

So the question is, do we need a randomized trial? My unbiased answer is that we do – and I am the principal investigator of such a trial open to all U.S. and Canadian institutions (NCT01242800). The end points are survival, local control, and quality of life. In addition, the trial will provide an opportunity to answer biological questions regarding the relationship between the primary tumor and metastatic site. Only when we have samples of primary and metastatic tumors can we settle this continuing debate.

Dr. Seema Khan is the Bluhm Family Professor of Cancer Research at the Lurie Comprehensive Cancer Center, Chicago.

No – Case Selection Bias Is Behind the Survival Advantage.

By Dr. Blake Cady

It’s true that some studies show an increase in stage IV breast cancer survival after primary site resection – but this more likely reflects a bias of case selection than a true benefit of local therapy.

Any findings of positive benefit other than case selection must be biologically plausible. The suggestion that the primary tumor releases some sort of growth-promoting substance that is gone when you remove the tumor, inhibiting metastatic disease has not yet been proven in humans; nor has the proposition that continued cell shedding might further metastasis.

Decreased tumor burden has sometimes been shown to increase the usefulness of systemic therapy, but I think that, all in all, case selection simply promotes breast surgery in patients with a better prognosis.

To show improved survival, we must find causality and not simply coincidence. Findings from large case series or cancer databases are unable to provide the answer. Although registry interpretations can provide basic data, they often break down when you attempt to extract detailed data.

Sometimes a stage IV cancer is registered initially on the basis of a pulmonary or liver shadow on imaging, which later is proven not to have been metastatic disease – and the case is never amended in the registry. There are also registry misinterpretations of the type of surgery that’s been done.

We performed a matched pair analysis of stage IV breast cancer patients with and without resection of the primary tumor. This was based on the Partners Health Care Consortium cancer database, which included information on 19,464 invasive breast cancers treated between 1970 and 2002; 808 of these (4%) were recorded as stage IV. Of these, 622 were analyzed by case matching that considered age, diagnostic date, metastatic disease location, estrogen-receptor status, and systemic therapy (Ann. Surg. Oncol. 2008; 15:3384-95).

It’s absolutely true that there was a statistically significant difference in survival in the overall comparison of surgery vs. no surgery. With bone metastases only, it was still statistically significant, but with a substantially lower difference in survival. In visceral metastases, the difference became nonsignificant.

Looking at therapy sequence in those who had the same type of systemic therapy, but with chemotherapy before or after surgery, you see a suggestion that giving systemic therapy first with a clinical response, which is a favorable prognostic indication, leads to a selection bias in choosing patients for surgery.

I reviewed the 86 cases who survived 5 years with records available. In those records, 22 were actually not stage IV disease, leaving 64 with confirmed stage IV (M1) – an overall 10% 5-year survival rate. Patients who survived were significantly younger than those who did not survive, significantly more likely to have estrogen receptor-positive tumors, and significantly more likely to have bone rather than visceral metastases or oligometastatic disease – all of which are good prognostic factors.

Among the 64 5-year survivors, 25 had therapeutic breast surgery. Of these, 8 had an excellent chemotherapy response followed by breast surgery; 8 had delayed surgery following a failure of systemic therapy; 7 had an initial therapeutic and curative surgery, but staging revealed metastases because of unexpected positive nodes; and 2 had initial surgery with oligometastatic resection.

Thirty-nine patients had no therapeutic breast surgery, and, of these, 16 had an excellent response to systemic therapy; 15 had slowly progressive disease; and 8 had oligometastatic disease – a positive prognostic factor. Thus, favorable prognostic factors led to a selection of primary-site surgery, whereas poor prognostic factors mean that primary-site surgery was avoided, contradicting the assumption of its therapeutic benefit.

There were also surgical discrepancies among the 5-year survivors. The registry listed 11 as having had breast surgery, while a chart review showed that surgery was not therapeutic. Five were listed as having no breast surgery, while they had indeed undergone a therapeutic operation.

Cancer registry data are not reliable for defining stage IV disease, discriminating advanced local disease with bone involvement from true distant, imaging-confirmed metastasis, or assessing surgical procedures. Case selection bias accounts for most, if not all, of the apparent survival advantage.

Dr. Blake Cady is professor of surgery (emeritus) at Harvard Medical School, Boston, and at Brown University, Providence, R.I.

Yes – It Is Time to Consider a Paradigm Shift.

By Dr. Seema Khan

In stage IV breast cancer, local therapy is not considered important except for controlling symptoms. But recent large-scale retrospective studies tell us that, if you follow enough women long enough, you see a difference in survival related to control of local disease. These emerging data tell us it’s time to consider a paradigm shift in the treatment of stage IV breast cancer.

Researchers are finding that primary site treatment regimens are important because an intact primary tumor can serve as a continued source of new metastatic lesions. There is reason, therefore, to believe that treating these can prolong life.

First explored by Dr. Larry Norton and Joan Massagué, Ph.D., (Nature Med. 2006;12:875-8), the concept of cancer self-seeding holds that cells from the primary tumor not only travel unidirectionally to seed metastases but also return to the primary tumor, self-seeding it and helping it to grow even more.

This view incorporates the microenvironment of the primary tumor. Here, fibroblasts and other cells – particularly mesenchymal stem cells derived from bone marrow – may play a very important role, creating a reactive stroma that seems to release growth-promoting substances that increase the metastatic efficiency of the circulating cells.

Robert A. Weinberg, Ph.D., published data showing that these mesenchymal stem cells are pluripotent progenitor cells. When weakly metastatic human breast cancer cells were mixed with these stem cells, the cancer cells’ metastatic potential greatly increased. The breast cancer cells then stimulated the stem cells to secrete a chemokine which – in turn – enhanced the cancer cells’ motility and their ability to invade and metastasize (Nature 2007;449:557-63). In effect, the primary tumor acts like a filling station, giving these tumor cells more energy to go out and metastasize in different sites.

Although such studies remain animal models, I think we can say there is a basis for primary tumor therapy in the metastatic setting. A dozen or more retrospective studies of large institutional series, cancer databases, and population-based studies have examined outcomes in women treated with and without surgical resection. Data on about 30,000 women have been published, with about 50% receiving some form of primary tumor therapy. The survival benefit across them is quite consistent, with the hazard ratio of death over a given time period reduced from 30% to 50%.

These studies do demonstrate selection bias: Women treated with surgical removal were more likely to be young, white, married, with smaller tumors and a lower burden of disease, and it is possible that they would have done better anyway. Studies have also shown that better survival, even in stage IV cancer, occurs in women who have a therapeutic target (that is, hormone receptors or HER2). But there was still a significant survival benefit for surgery.

Surgical resection may also confer benefit by preventing the primary tumor in the breast from becoming a quality of-life problem. At Northwestern Memorial Hospital, Chicago, we conducted a study that showed the odds of symptomatic chest wall disease were far lower in the surgical group, compared with the nonsurgical group. In this 2008 study, we found that women with good local control– surgical or systemic - did better. Time to first progression was prolonged by 50% in the surgical group, while chest wall control was associated with a 60% improvement in overall survival, regardless of whether surgical resection was performed (Cancer 2008;113:2011-9).

So the question is, do we need a randomized trial? My unbiased answer is that we do – and I am the principal investigator of such a trial open to all U.S. and Canadian institutions (NCT01242800). The end points are survival, local control, and quality of life. In addition, the trial will provide an opportunity to answer biological questions regarding the relationship between the primary tumor and metastatic site. Only when we have samples of primary and metastatic tumors can we settle this continuing debate.

Dr. Seema Khan is the Bluhm Family Professor of Cancer Research at the Lurie Comprehensive Cancer Center, Chicago.

No – Case Selection Bias Is Behind the Survival Advantage.

By Dr. Blake Cady

It’s true that some studies show an increase in stage IV breast cancer survival after primary site resection – but this more likely reflects a bias of case selection than a true benefit of local therapy.

Any findings of positive benefit other than case selection must be biologically plausible. The suggestion that the primary tumor releases some sort of growth-promoting substance that is gone when you remove the tumor, inhibiting metastatic disease has not yet been proven in humans; nor has the proposition that continued cell shedding might further metastasis.

Decreased tumor burden has sometimes been shown to increase the usefulness of systemic therapy, but I think that, all in all, case selection simply promotes breast surgery in patients with a better prognosis.

To show improved survival, we must find causality and not simply coincidence. Findings from large case series or cancer databases are unable to provide the answer. Although registry interpretations can provide basic data, they often break down when you attempt to extract detailed data.

Sometimes a stage IV cancer is registered initially on the basis of a pulmonary or liver shadow on imaging, which later is proven not to have been metastatic disease – and the case is never amended in the registry. There are also registry misinterpretations of the type of surgery that’s been done.

We performed a matched pair analysis of stage IV breast cancer patients with and without resection of the primary tumor. This was based on the Partners Health Care Consortium cancer database, which included information on 19,464 invasive breast cancers treated between 1970 and 2002; 808 of these (4%) were recorded as stage IV. Of these, 622 were analyzed by case matching that considered age, diagnostic date, metastatic disease location, estrogen-receptor status, and systemic therapy (Ann. Surg. Oncol. 2008; 15:3384-95).

It’s absolutely true that there was a statistically significant difference in survival in the overall comparison of surgery vs. no surgery. With bone metastases only, it was still statistically significant, but with a substantially lower difference in survival. In visceral metastases, the difference became nonsignificant.

Looking at therapy sequence in those who had the same type of systemic therapy, but with chemotherapy before or after surgery, you see a suggestion that giving systemic therapy first with a clinical response, which is a favorable prognostic indication, leads to a selection bias in choosing patients for surgery.

I reviewed the 86 cases who survived 5 years with records available. In those records, 22 were actually not stage IV disease, leaving 64 with confirmed stage IV (M1) – an overall 10% 5-year survival rate. Patients who survived were significantly younger than those who did not survive, significantly more likely to have estrogen receptor-positive tumors, and significantly more likely to have bone rather than visceral metastases or oligometastatic disease – all of which are good prognostic factors.

Among the 64 5-year survivors, 25 had therapeutic breast surgery. Of these, 8 had an excellent chemotherapy response followed by breast surgery; 8 had delayed surgery following a failure of systemic therapy; 7 had an initial therapeutic and curative surgery, but staging revealed metastases because of unexpected positive nodes; and 2 had initial surgery with oligometastatic resection.

Thirty-nine patients had no therapeutic breast surgery, and, of these, 16 had an excellent response to systemic therapy; 15 had slowly progressive disease; and 8 had oligometastatic disease – a positive prognostic factor. Thus, favorable prognostic factors led to a selection of primary-site surgery, whereas poor prognostic factors mean that primary-site surgery was avoided, contradicting the assumption of its therapeutic benefit.

There were also surgical discrepancies among the 5-year survivors. The registry listed 11 as having had breast surgery, while a chart review showed that surgery was not therapeutic. Five were listed as having no breast surgery, while they had indeed undergone a therapeutic operation.

Cancer registry data are not reliable for defining stage IV disease, discriminating advanced local disease with bone involvement from true distant, imaging-confirmed metastasis, or assessing surgical procedures. Case selection bias accounts for most, if not all, of the apparent survival advantage.

Dr. Blake Cady is professor of surgery (emeritus) at Harvard Medical School, Boston, and at Brown University, Providence, R.I.

Yes – It Is Time to Consider a Paradigm Shift.

By Dr. Seema Khan

In stage IV breast cancer, local therapy is not considered important except for controlling symptoms. But recent large-scale retrospective studies tell us that, if you follow enough women long enough, you see a difference in survival related to control of local disease. These emerging data tell us it’s time to consider a paradigm shift in the treatment of stage IV breast cancer.

Researchers are finding that primary site treatment regimens are important because an intact primary tumor can serve as a continued source of new metastatic lesions. There is reason, therefore, to believe that treating these can prolong life.

First explored by Dr. Larry Norton and Joan Massagué, Ph.D., (Nature Med. 2006;12:875-8), the concept of cancer self-seeding holds that cells from the primary tumor not only travel unidirectionally to seed metastases but also return to the primary tumor, self-seeding it and helping it to grow even more.

This view incorporates the microenvironment of the primary tumor. Here, fibroblasts and other cells – particularly mesenchymal stem cells derived from bone marrow – may play a very important role, creating a reactive stroma that seems to release growth-promoting substances that increase the metastatic efficiency of the circulating cells.

Robert A. Weinberg, Ph.D., published data showing that these mesenchymal stem cells are pluripotent progenitor cells. When weakly metastatic human breast cancer cells were mixed with these stem cells, the cancer cells’ metastatic potential greatly increased. The breast cancer cells then stimulated the stem cells to secrete a chemokine which – in turn – enhanced the cancer cells’ motility and their ability to invade and metastasize (Nature 2007;449:557-63). In effect, the primary tumor acts like a filling station, giving these tumor cells more energy to go out and metastasize in different sites.

Although such studies remain animal models, I think we can say there is a basis for primary tumor therapy in the metastatic setting. A dozen or more retrospective studies of large institutional series, cancer databases, and population-based studies have examined outcomes in women treated with and without surgical resection. Data on about 30,000 women have been published, with about 50% receiving some form of primary tumor therapy. The survival benefit across them is quite consistent, with the hazard ratio of death over a given time period reduced from 30% to 50%.

These studies do demonstrate selection bias: Women treated with surgical removal were more likely to be young, white, married, with smaller tumors and a lower burden of disease, and it is possible that they would have done better anyway. Studies have also shown that better survival, even in stage IV cancer, occurs in women who have a therapeutic target (that is, hormone receptors or HER2). But there was still a significant survival benefit for surgery.

Surgical resection may also confer benefit by preventing the primary tumor in the breast from becoming a quality of-life problem. At Northwestern Memorial Hospital, Chicago, we conducted a study that showed the odds of symptomatic chest wall disease were far lower in the surgical group, compared with the nonsurgical group. In this 2008 study, we found that women with good local control– surgical or systemic - did better. Time to first progression was prolonged by 50% in the surgical group, while chest wall control was associated with a 60% improvement in overall survival, regardless of whether surgical resection was performed (Cancer 2008;113:2011-9).

So the question is, do we need a randomized trial? My unbiased answer is that we do – and I am the principal investigator of such a trial open to all U.S. and Canadian institutions (NCT01242800). The end points are survival, local control, and quality of life. In addition, the trial will provide an opportunity to answer biological questions regarding the relationship between the primary tumor and metastatic site. Only when we have samples of primary and metastatic tumors can we settle this continuing debate.

Dr. Seema Khan is the Bluhm Family Professor of Cancer Research at the Lurie Comprehensive Cancer Center, Chicago.

No – Case Selection Bias Is Behind the Survival Advantage.

By Dr. Blake Cady

It’s true that some studies show an increase in stage IV breast cancer survival after primary site resection – but this more likely reflects a bias of case selection than a true benefit of local therapy.

Any findings of positive benefit other than case selection must be biologically plausible. The suggestion that the primary tumor releases some sort of growth-promoting substance that is gone when you remove the tumor, inhibiting metastatic disease has not yet been proven in humans; nor has the proposition that continued cell shedding might further metastasis.

Decreased tumor burden has sometimes been shown to increase the usefulness of systemic therapy, but I think that, all in all, case selection simply promotes breast surgery in patients with a better prognosis.

To show improved survival, we must find causality and not simply coincidence. Findings from large case series or cancer databases are unable to provide the answer. Although registry interpretations can provide basic data, they often break down when you attempt to extract detailed data.

Sometimes a stage IV cancer is registered initially on the basis of a pulmonary or liver shadow on imaging, which later is proven not to have been metastatic disease – and the case is never amended in the registry. There are also registry misinterpretations of the type of surgery that’s been done.

We performed a matched pair analysis of stage IV breast cancer patients with and without resection of the primary tumor. This was based on the Partners Health Care Consortium cancer database, which included information on 19,464 invasive breast cancers treated between 1970 and 2002; 808 of these (4%) were recorded as stage IV. Of these, 622 were analyzed by case matching that considered age, diagnostic date, metastatic disease location, estrogen-receptor status, and systemic therapy (Ann. Surg. Oncol. 2008; 15:3384-95).

It’s absolutely true that there was a statistically significant difference in survival in the overall comparison of surgery vs. no surgery. With bone metastases only, it was still statistically significant, but with a substantially lower difference in survival. In visceral metastases, the difference became nonsignificant.

Looking at therapy sequence in those who had the same type of systemic therapy, but with chemotherapy before or after surgery, you see a suggestion that giving systemic therapy first with a clinical response, which is a favorable prognostic indication, leads to a selection bias in choosing patients for surgery.

I reviewed the 86 cases who survived 5 years with records available. In those records, 22 were actually not stage IV disease, leaving 64 with confirmed stage IV (M1) – an overall 10% 5-year survival rate. Patients who survived were significantly younger than those who did not survive, significantly more likely to have estrogen receptor-positive tumors, and significantly more likely to have bone rather than visceral metastases or oligometastatic disease – all of which are good prognostic factors.

Among the 64 5-year survivors, 25 had therapeutic breast surgery. Of these, 8 had an excellent chemotherapy response followed by breast surgery; 8 had delayed surgery following a failure of systemic therapy; 7 had an initial therapeutic and curative surgery, but staging revealed metastases because of unexpected positive nodes; and 2 had initial surgery with oligometastatic resection.

Thirty-nine patients had no therapeutic breast surgery, and, of these, 16 had an excellent response to systemic therapy; 15 had slowly progressive disease; and 8 had oligometastatic disease – a positive prognostic factor. Thus, favorable prognostic factors led to a selection of primary-site surgery, whereas poor prognostic factors mean that primary-site surgery was avoided, contradicting the assumption of its therapeutic benefit.

There were also surgical discrepancies among the 5-year survivors. The registry listed 11 as having had breast surgery, while a chart review showed that surgery was not therapeutic. Five were listed as having no breast surgery, while they had indeed undergone a therapeutic operation.

Cancer registry data are not reliable for defining stage IV disease, discriminating advanced local disease with bone involvement from true distant, imaging-confirmed metastasis, or assessing surgical procedures. Case selection bias accounts for most, if not all, of the apparent survival advantage.

Dr. Blake Cady is professor of surgery (emeritus) at Harvard Medical School, Boston, and at Brown University, Providence, R.I.

The recent bevacizumab (Avastin) hearing yielded a result that was not surprising, as the jury, or ODAC [Oncologic Drugs Advisory Committee], members were largely the reviewers who participated in last year's discussion and negative vote. Furthermore, in this era of attempting to have impartial experts by eliminating those with scientific or financial conflicts, it was unfortunate that the panel consisted of so few breast cancer specialists.

Seemingly lost in the emotion of the debate was the simple fact that the addition of bevacizumab to standard therapy reached statistically positive end points in each of the randomized, well-controlled, first-line metastatic breast cancer studies.

The results are complicated by the use of different chemotherapy combinations with Avastin. It is not logical to expect the same outcomes with each regimen. While the "magnitude of benefit" and the lack of an overall survival advantage would certainly have an effect on the prescribing patterns of medical oncologists, those factors do not seem sufficient to withdraw the labeled indication.

The safety and toxicity issues also appear overstated for an agent still approved and widely used in colon, lung, kidney, and brain cancer. The 2 days of hearings were filled with passion and emotion.

It will be interesting to see whether FDA Commissioner Dr. Margaret Hamburg is able to hear through the noise and reach a compromise that will be the best for our patients. For example, the treatment of subsets of women with limited options, such as those with triple-negative breast cancer, could still be part of a more restricted label, as could the treatment of those women already receiving the agent.

Requiring further clinical research, including the investigation of predictive biomarkers, as the sponsor has proposed, is also a reasonable course of action while maintaining the current accelerated approval with paclitaxel. Strategies for oncology drug development, the use of the accelerated approval process, and the design of clinical trials will be greatly affected by this very important decision.

-Howard A. Burris III, M.D.

-William J. Gradishar, M.D.

-Hope S. Rugo, M.D.

Dr. Burris, editor of The Oncology Report, is chief medical officer and director of drug development at the Sarah Cannon Research Institute in Nashville. Dr. Gradishar and Dr. Rugo are associate editors of The Oncology Report. Dr. Gradishar is the Betsy Bramsen Professor of Breast Oncology and director of the Maggie Daley Center For Women's Cancer Care at the Robert H. Lurie Comprehensive Cancer Center and Northwestern University Feinberg School of Medicine in Chicago. Dr. Rugo is clinical professor of medicine and director, Breast Oncology and Clinical Trials Education at the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco.

The recent bevacizumab (Avastin) hearing yielded a result that was not surprising, as the jury, or ODAC [Oncologic Drugs Advisory Committee], members were largely the reviewers who participated in last year's discussion and negative vote. Furthermore, in this era of attempting to have impartial experts by eliminating those with scientific or financial conflicts, it was unfortunate that the panel consisted of so few breast cancer specialists.

Seemingly lost in the emotion of the debate was the simple fact that the addition of bevacizumab to standard therapy reached statistically positive end points in each of the randomized, well-controlled, first-line metastatic breast cancer studies.

The results are complicated by the use of different chemotherapy combinations with Avastin. It is not logical to expect the same outcomes with each regimen. While the "magnitude of benefit" and the lack of an overall survival advantage would certainly have an effect on the prescribing patterns of medical oncologists, those factors do not seem sufficient to withdraw the labeled indication.

The safety and toxicity issues also appear overstated for an agent still approved and widely used in colon, lung, kidney, and brain cancer. The 2 days of hearings were filled with passion and emotion.

It will be interesting to see whether FDA Commissioner Dr. Margaret Hamburg is able to hear through the noise and reach a compromise that will be the best for our patients. For example, the treatment of subsets of women with limited options, such as those with triple-negative breast cancer, could still be part of a more restricted label, as could the treatment of those women already receiving the agent.

Requiring further clinical research, including the investigation of predictive biomarkers, as the sponsor has proposed, is also a reasonable course of action while maintaining the current accelerated approval with paclitaxel. Strategies for oncology drug development, the use of the accelerated approval process, and the design of clinical trials will be greatly affected by this very important decision.

-Howard A. Burris III, M.D.

-William J. Gradishar, M.D.

-Hope S. Rugo, M.D.

Dr. Burris, editor of The Oncology Report, is chief medical officer and director of drug development at the Sarah Cannon Research Institute in Nashville. Dr. Gradishar and Dr. Rugo are associate editors of The Oncology Report. Dr. Gradishar is the Betsy Bramsen Professor of Breast Oncology and director of the Maggie Daley Center For Women's Cancer Care at the Robert H. Lurie Comprehensive Cancer Center and Northwestern University Feinberg School of Medicine in Chicago. Dr. Rugo is clinical professor of medicine and director, Breast Oncology and Clinical Trials Education at the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco.

The recent bevacizumab (Avastin) hearing yielded a result that was not surprising, as the jury, or ODAC [Oncologic Drugs Advisory Committee], members were largely the reviewers who participated in last year's discussion and negative vote. Furthermore, in this era of attempting to have impartial experts by eliminating those with scientific or financial conflicts, it was unfortunate that the panel consisted of so few breast cancer specialists.

Seemingly lost in the emotion of the debate was the simple fact that the addition of bevacizumab to standard therapy reached statistically positive end points in each of the randomized, well-controlled, first-line metastatic breast cancer studies.

The results are complicated by the use of different chemotherapy combinations with Avastin. It is not logical to expect the same outcomes with each regimen. While the "magnitude of benefit" and the lack of an overall survival advantage would certainly have an effect on the prescribing patterns of medical oncologists, those factors do not seem sufficient to withdraw the labeled indication.

The safety and toxicity issues also appear overstated for an agent still approved and widely used in colon, lung, kidney, and brain cancer. The 2 days of hearings were filled with passion and emotion.

It will be interesting to see whether FDA Commissioner Dr. Margaret Hamburg is able to hear through the noise and reach a compromise that will be the best for our patients. For example, the treatment of subsets of women with limited options, such as those with triple-negative breast cancer, could still be part of a more restricted label, as could the treatment of those women already receiving the agent.

Requiring further clinical research, including the investigation of predictive biomarkers, as the sponsor has proposed, is also a reasonable course of action while maintaining the current accelerated approval with paclitaxel. Strategies for oncology drug development, the use of the accelerated approval process, and the design of clinical trials will be greatly affected by this very important decision.

-Howard A. Burris III, M.D.

-William J. Gradishar, M.D.

-Hope S. Rugo, M.D.

Dr. Burris, editor of The Oncology Report, is chief medical officer and director of drug development at the Sarah Cannon Research Institute in Nashville. Dr. Gradishar and Dr. Rugo are associate editors of The Oncology Report. Dr. Gradishar is the Betsy Bramsen Professor of Breast Oncology and director of the Maggie Daley Center For Women's Cancer Care at the Robert H. Lurie Comprehensive Cancer Center and Northwestern University Feinberg School of Medicine in Chicago. Dr. Rugo is clinical professor of medicine and director, Breast Oncology and Clinical Trials Education at the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco.

In a move that should surprise no one, the National Comprehensive Cancer Network’s panel of breast cancer experts has voted 24-0-1 to stand by its endorsement of bevacizumab (Avastin) for metastatic breast cancer.

Photo credit: Flickr user Earls37a (CC)

The unanimous vote echoes the position taken by the panel at the NCCN’s annual conference earlier this year. “The data observed in the [E2100 trial] really had not changed from its approval previously, and we thought that if the data were compelling 2 years ago, why isn’t it compelling enough today?” panel chair Dr. Robert W. Carlson of Stanford (Calif.) University said at that time.

The new endorsement is not the strongest, with an evidence designation of 2A, but the expert panel called bevacizumab in combination with paclitaxel “an appropriate therapeutic option for metastatic breast cancer.”

The panel conveyed its thinking in the following footnote:

“Randomized clinical trials in metastatic breast cancer document that the addition of bevacizumab to some first- or second-line chemotherapy agents modestly improves time to progression and response rates but does not improve overall survival. The time to progression impact may vary among cytotoxic agents and appears greatest with bevacizumab in combination with weekly paclitaxel.”

The unanimity of NCCN panel’s stance – in direct opposition to the unanimity of the Food and Drug Administration’s Oncologic Drugs Advisory Committee’s 6-0 vote in favor of withdrawing Avastin’s indication for metastatic breast cancer does raise the question of how the proposed withdrawal is viewed by breast cancer experts.

But breast specialists were in short supply on the pared-down advisory committee — a reality noted in a joint comment by Dr. Howard A. Burris III, editor of The Oncology Report, and associate editors Dr. Hope S. Rugo and Dr. William J. Gradishar. In the comment, posted online in advance of print publication, the three oncologists wonder whether “FDA Commissioner [Dr. Margaret] Hamburg is able to hear through the noise and reach a compromise that will be the best for our patients.”

The Pink Sheet, a sister publication of The Oncology Report, tallied 34 speakers in the public portion of last month’s sturm-und-drang hearing — 4 favoring withdrawal, 22 against, 1 defending the pivotal Eastern Cooperative Oncology Group E2100 study, 1 calling for better collaboration on breast biomarker research, and 6 “who generally opposed withdrawing the [metastatic breast cancer] claim but spoke primarily to express concerns about FDA approval standards and the potential impact a withdrawal decision could have on development and approval of oncology treatments in settings beyond breast cancer.”

Public comments on the proposed withdrawal were due to close today, July 28. It will be interesting to see how comments stack up after the mishmash that came in on Medicare’s deliberations over coverage for the prostate cancer drug Provenge.

Meanwhile, the dueling parties — Genentech, Inc. and the FDA’s Center for Drug Evaluation and Research — have been granted an extra week until Aug. 4 for their post-hearing submissions. Considering the current stalemate in Congress, one can only wonder whether there will be anyone at the FDA to read them.

– Jane Salodof MacNeil

In a move that should surprise no one, the National Comprehensive Cancer Network’s panel of breast cancer experts has voted 24-0-1 to stand by its endorsement of bevacizumab (Avastin) for metastatic breast cancer.

Photo credit: Flickr user Earls37a (CC)

The unanimous vote echoes the position taken by the panel at the NCCN’s annual conference earlier this year. “The data observed in the [E2100 trial] really had not changed from its approval previously, and we thought that if the data were compelling 2 years ago, why isn’t it compelling enough today?” panel chair Dr. Robert W. Carlson of Stanford (Calif.) University said at that time.

The new endorsement is not the strongest, with an evidence designation of 2A, but the expert panel called bevacizumab in combination with paclitaxel “an appropriate therapeutic option for metastatic breast cancer.”

The panel conveyed its thinking in the following footnote:

“Randomized clinical trials in metastatic breast cancer document that the addition of bevacizumab to some first- or second-line chemotherapy agents modestly improves time to progression and response rates but does not improve overall survival. The time to progression impact may vary among cytotoxic agents and appears greatest with bevacizumab in combination with weekly paclitaxel.”

The unanimity of NCCN panel’s stance – in direct opposition to the unanimity of the Food and Drug Administration’s Oncologic Drugs Advisory Committee’s 6-0 vote in favor of withdrawing Avastin’s indication for metastatic breast cancer does raise the question of how the proposed withdrawal is viewed by breast cancer experts.

But breast specialists were in short supply on the pared-down advisory committee — a reality noted in a joint comment by Dr. Howard A. Burris III, editor of The Oncology Report, and associate editors Dr. Hope S. Rugo and Dr. William J. Gradishar. In the comment, posted online in advance of print publication, the three oncologists wonder whether “FDA Commissioner [Dr. Margaret] Hamburg is able to hear through the noise and reach a compromise that will be the best for our patients.”

The Pink Sheet, a sister publication of The Oncology Report, tallied 34 speakers in the public portion of last month’s sturm-und-drang hearing — 4 favoring withdrawal, 22 against, 1 defending the pivotal Eastern Cooperative Oncology Group E2100 study, 1 calling for better collaboration on breast biomarker research, and 6 “who generally opposed withdrawing the [metastatic breast cancer] claim but spoke primarily to express concerns about FDA approval standards and the potential impact a withdrawal decision could have on development and approval of oncology treatments in settings beyond breast cancer.”

Public comments on the proposed withdrawal were due to close today, July 28. It will be interesting to see how comments stack up after the mishmash that came in on Medicare’s deliberations over coverage for the prostate cancer drug Provenge.

Meanwhile, the dueling parties — Genentech, Inc. and the FDA’s Center for Drug Evaluation and Research — have been granted an extra week until Aug. 4 for their post-hearing submissions. Considering the current stalemate in Congress, one can only wonder whether there will be anyone at the FDA to read them.

– Jane Salodof MacNeil

In a move that should surprise no one, the National Comprehensive Cancer Network’s panel of breast cancer experts has voted 24-0-1 to stand by its endorsement of bevacizumab (Avastin) for metastatic breast cancer.

Photo credit: Flickr user Earls37a (CC)

The unanimous vote echoes the position taken by the panel at the NCCN’s annual conference earlier this year. “The data observed in the [E2100 trial] really had not changed from its approval previously, and we thought that if the data were compelling 2 years ago, why isn’t it compelling enough today?” panel chair Dr. Robert W. Carlson of Stanford (Calif.) University said at that time.

The new endorsement is not the strongest, with an evidence designation of 2A, but the expert panel called bevacizumab in combination with paclitaxel “an appropriate therapeutic option for metastatic breast cancer.”

The panel conveyed its thinking in the following footnote:

“Randomized clinical trials in metastatic breast cancer document that the addition of bevacizumab to some first- or second-line chemotherapy agents modestly improves time to progression and response rates but does not improve overall survival. The time to progression impact may vary among cytotoxic agents and appears greatest with bevacizumab in combination with weekly paclitaxel.”

The unanimity of NCCN panel’s stance – in direct opposition to the unanimity of the Food and Drug Administration’s Oncologic Drugs Advisory Committee’s 6-0 vote in favor of withdrawing Avastin’s indication for metastatic breast cancer does raise the question of how the proposed withdrawal is viewed by breast cancer experts.

But breast specialists were in short supply on the pared-down advisory committee — a reality noted in a joint comment by Dr. Howard A. Burris III, editor of The Oncology Report, and associate editors Dr. Hope S. Rugo and Dr. William J. Gradishar. In the comment, posted online in advance of print publication, the three oncologists wonder whether “FDA Commissioner [Dr. Margaret] Hamburg is able to hear through the noise and reach a compromise that will be the best for our patients.”

The Pink Sheet, a sister publication of The Oncology Report, tallied 34 speakers in the public portion of last month’s sturm-und-drang hearing — 4 favoring withdrawal, 22 against, 1 defending the pivotal Eastern Cooperative Oncology Group E2100 study, 1 calling for better collaboration on breast biomarker research, and 6 “who generally opposed withdrawing the [metastatic breast cancer] claim but spoke primarily to express concerns about FDA approval standards and the potential impact a withdrawal decision could have on development and approval of oncology treatments in settings beyond breast cancer.”

Public comments on the proposed withdrawal were due to close today, July 28. It will be interesting to see how comments stack up after the mishmash that came in on Medicare’s deliberations over coverage for the prostate cancer drug Provenge.

Meanwhile, the dueling parties — Genentech, Inc. and the FDA’s Center for Drug Evaluation and Research — have been granted an extra week until Aug. 4 for their post-hearing submissions. Considering the current stalemate in Congress, one can only wonder whether there will be anyone at the FDA to read them.

– Jane Salodof MacNeil

Computer-aided detection software does not help clinicians analyze and interpret film-screen screening mammograms, results from a large multicenter study demonstrated.

The findings "raise concerns that CAD, as currently implemented in clinical practice, may have little or no impact on breast cancer mortality, which may depend on earlier detection of invasive breast cancer," researchers led by Dr. Joshua J. Fenton reported online July 27 in the Journal of the National Cancer Institute.

Dr. Fenton of the department of family and community medicine at the center for health care policy and research of the University of California, Davis, and his associates analyzed records from 684,956 women who underwent more than 1.6 million film-screen screening mammograms in 1998-2006 at 90 facilities that are members of the Breast Cancer Surveillance Consortium (BCSC), a federally supported effort that links mammography data to cancer outcomes in seven states (California, Colorado, North Carolina, New Hampshire, New Mexico, Washington, and Vermont).

The researchers used random effects logistic regression to estimate the associations between CAD and specificity, sensitivity, and positive predictive value while adjusting for factors that might influence mammography findings, including patient age, breast density, and use of hormone therapy (J. Natl. Cancer Inst. 2011 July 27 [doi:10.1093/jnci/djr298]).

More than half of the women studied (61%) were aged 40-59 years. Of the 90 BCSC facilities, 25 (28%) implemented CAD and used it for an average of 28 months during the study period. All told, 793 radiologists interpreted the results, including 154 (19%) at facilities with CAD.

After adjusting for BCSC registry, patient characteristics, hormone therapy use, and year of mammography interpretation, the researchers found that CAD use was associated with a statistically significant lower specificity (odds ratio, 0.87) and positive predictive value (OR, 0.89), and an increase in sensitivity (OR, 1.06) that was not statistically significant.

When the sensitivity analysis was limited to invasive cancers only, CAD use was no longer associated with increased sensitivity (OR, 0.96). When the analysis was limited to ductal carcinoma in situ, CAD use was associated with greater sensitivity (OR, 1.55), yet this did not reach statistical significance.

There were also no statistically significant differences between CAD use and no-CAD in the odds of overall breast cancer detection (OR, 1.01), the diagnosis of stage I invasive cancer compared with later-stage invasive cancer (OR, 0.97), or the diagnosis of invasive tumors of 15 mm or less in size, compared with those greater than 15 mm (OR, 0.92).

Dr. Fenton and his associates acknowledged certain limitations of the study, including the absence of digital mammography data. "Whereas CAD algorithms perform a similar alerting function in the film-screen and digital environments, film-screen mammograms must be digitized before CAD analysis, and digitization may introduce noise and adversely affect performance," they wrote.

"However, small retrospective studies suggest that the performance impacts of CAD are similar when used in digital and film-screen environments. Because prior research suggests that facilities apply CAD on nearly all mammograms after implementation, these analyses assumed that all mammograms were interpreted with CAD after implementation – another limitation of this study."

The study was supported by grants from the National Cancer Institute and the American Cancer Society. A study coauthor disclosed holding stock options and serving as a medical consultant for Hologic Inc., a manufacturer of CAD equipment that had "no role in data collection, analysis, or interpretation."

Computer-aided detection software does not help clinicians analyze and interpret film-screen screening mammograms, results from a large multicenter study demonstrated.

The findings "raise concerns that CAD, as currently implemented in clinical practice, may have little or no impact on breast cancer mortality, which may depend on earlier detection of invasive breast cancer," researchers led by Dr. Joshua J. Fenton reported online July 27 in the Journal of the National Cancer Institute.

Dr. Fenton of the department of family and community medicine at the center for health care policy and research of the University of California, Davis, and his associates analyzed records from 684,956 women who underwent more than 1.6 million film-screen screening mammograms in 1998-2006 at 90 facilities that are members of the Breast Cancer Surveillance Consortium (BCSC), a federally supported effort that links mammography data to cancer outcomes in seven states (California, Colorado, North Carolina, New Hampshire, New Mexico, Washington, and Vermont).

The researchers used random effects logistic regression to estimate the associations between CAD and specificity, sensitivity, and positive predictive value while adjusting for factors that might influence mammography findings, including patient age, breast density, and use of hormone therapy (J. Natl. Cancer Inst. 2011 July 27 [doi:10.1093/jnci/djr298]).

More than half of the women studied (61%) were aged 40-59 years. Of the 90 BCSC facilities, 25 (28%) implemented CAD and used it for an average of 28 months during the study period. All told, 793 radiologists interpreted the results, including 154 (19%) at facilities with CAD.

After adjusting for BCSC registry, patient characteristics, hormone therapy use, and year of mammography interpretation, the researchers found that CAD use was associated with a statistically significant lower specificity (odds ratio, 0.87) and positive predictive value (OR, 0.89), and an increase in sensitivity (OR, 1.06) that was not statistically significant.

When the sensitivity analysis was limited to invasive cancers only, CAD use was no longer associated with increased sensitivity (OR, 0.96). When the analysis was limited to ductal carcinoma in situ, CAD use was associated with greater sensitivity (OR, 1.55), yet this did not reach statistical significance.

There were also no statistically significant differences between CAD use and no-CAD in the odds of overall breast cancer detection (OR, 1.01), the diagnosis of stage I invasive cancer compared with later-stage invasive cancer (OR, 0.97), or the diagnosis of invasive tumors of 15 mm or less in size, compared with those greater than 15 mm (OR, 0.92).

Dr. Fenton and his associates acknowledged certain limitations of the study, including the absence of digital mammography data. "Whereas CAD algorithms perform a similar alerting function in the film-screen and digital environments, film-screen mammograms must be digitized before CAD analysis, and digitization may introduce noise and adversely affect performance," they wrote.

"However, small retrospective studies suggest that the performance impacts of CAD are similar when used in digital and film-screen environments. Because prior research suggests that facilities apply CAD on nearly all mammograms after implementation, these analyses assumed that all mammograms were interpreted with CAD after implementation – another limitation of this study."

The study was supported by grants from the National Cancer Institute and the American Cancer Society. A study coauthor disclosed holding stock options and serving as a medical consultant for Hologic Inc., a manufacturer of CAD equipment that had "no role in data collection, analysis, or interpretation."

Computer-aided detection software does not help clinicians analyze and interpret film-screen screening mammograms, results from a large multicenter study demonstrated.

The findings "raise concerns that CAD, as currently implemented in clinical practice, may have little or no impact on breast cancer mortality, which may depend on earlier detection of invasive breast cancer," researchers led by Dr. Joshua J. Fenton reported online July 27 in the Journal of the National Cancer Institute.

Dr. Fenton of the department of family and community medicine at the center for health care policy and research of the University of California, Davis, and his associates analyzed records from 684,956 women who underwent more than 1.6 million film-screen screening mammograms in 1998-2006 at 90 facilities that are members of the Breast Cancer Surveillance Consortium (BCSC), a federally supported effort that links mammography data to cancer outcomes in seven states (California, Colorado, North Carolina, New Hampshire, New Mexico, Washington, and Vermont).

The researchers used random effects logistic regression to estimate the associations between CAD and specificity, sensitivity, and positive predictive value while adjusting for factors that might influence mammography findings, including patient age, breast density, and use of hormone therapy (J. Natl. Cancer Inst. 2011 July 27 [doi:10.1093/jnci/djr298]).

More than half of the women studied (61%) were aged 40-59 years. Of the 90 BCSC facilities, 25 (28%) implemented CAD and used it for an average of 28 months during the study period. All told, 793 radiologists interpreted the results, including 154 (19%) at facilities with CAD.

After adjusting for BCSC registry, patient characteristics, hormone therapy use, and year of mammography interpretation, the researchers found that CAD use was associated with a statistically significant lower specificity (odds ratio, 0.87) and positive predictive value (OR, 0.89), and an increase in sensitivity (OR, 1.06) that was not statistically significant.

When the sensitivity analysis was limited to invasive cancers only, CAD use was no longer associated with increased sensitivity (OR, 0.96). When the analysis was limited to ductal carcinoma in situ, CAD use was associated with greater sensitivity (OR, 1.55), yet this did not reach statistical significance.

There were also no statistically significant differences between CAD use and no-CAD in the odds of overall breast cancer detection (OR, 1.01), the diagnosis of stage I invasive cancer compared with later-stage invasive cancer (OR, 0.97), or the diagnosis of invasive tumors of 15 mm or less in size, compared with those greater than 15 mm (OR, 0.92).

Dr. Fenton and his associates acknowledged certain limitations of the study, including the absence of digital mammography data. "Whereas CAD algorithms perform a similar alerting function in the film-screen and digital environments, film-screen mammograms must be digitized before CAD analysis, and digitization may introduce noise and adversely affect performance," they wrote.

"However, small retrospective studies suggest that the performance impacts of CAD are similar when used in digital and film-screen environments. Because prior research suggests that facilities apply CAD on nearly all mammograms after implementation, these analyses assumed that all mammograms were interpreted with CAD after implementation – another limitation of this study."

The study was supported by grants from the National Cancer Institute and the American Cancer Society. A study coauthor disclosed holding stock options and serving as a medical consultant for Hologic Inc., a manufacturer of CAD equipment that had "no role in data collection, analysis, or interpretation."

Among patients with early-stage breast cancer whose sentinel nodes were negative for metastases on hematoxylin-eosin testing, a later finding of occult metastases using immunohistochemical staining did not impact survival, according to a report in the July 27 issue of JAMA.

Such occult sentinel node metastases were found in approximately 10% of more than 3,900 patients who participated in the Z0010 trial and whose sentinel node specimens had been tumor-negative on hematoxylin-eosin staining. Yet 5-year rates of overall survival were nearly identical – at just over 95% – between women who were found to have occult metastases and those who were not, said Dr. Armando E. Giuliano of the division of surgical oncology, John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica, Calif., and his associates.

Occult metastases identified on immunohistochemical examination of bone marrow yielded conflicting results, so it wasn’t clear whether those metastases may impact survival.

Taken together, these findings show that routine immunohistochemical examination of both bone marrow and sentinel nodes that tested negative with hematoxylin-eosin staining are not clinically warranted for early-stage breast cancer, the investigators said.

The American College of Surgeons Oncology Group (ACOSOG) began the prospective, observational Z0010 trial in 1999 at 126 medical centers to examine the significance of occult metastases in lymph nodes and bone marrow among women undergoing breast-conserving surgery, sentinel lymph node dissection, and whole breast irradiation for T1 or T2 node-negative breast cancer. A total of 3,904 study subjects whose lymph nodes were hematoxylin-eosin negative were included in this analysis of Z0010 data.

Of these, 349 specimens (10.5%) were found to have occult metastases on immunohistochemical examination. Five-year overall survival was 95.7% for patients who had occult nodal metastases, which was not significantly different from the 95.1% rate for patients who did not.

Similarly, 5-year disease-free survival was 92.2% for patients who had occult nodal metastases, which was not significantly different from the 90.4% rate for patients who did not, Dr. Giuliano and his colleagues said (JAMA 2011;306:385-93).

The presence or absence of occult nodal metastases also had no impact on survival when the women were categorized according to adjuvant systemic therapy. Five-year overall survival was 96.3% without adjuvant systemic therapy and 95.7% with adjuvant systemic therapy for women who had occult metastases. Similarly, 5-year disease-free survival was 91.4% and 91%, respectively.

Bone marrow biopsy specimens were obtained in 3,413 patients, and immunocytochemistry revealed occult bone metastases in 104 women (3%). In the initial, univariable analysis, the presence of bone metastases appeared to reduce survival, but this association did not persist in multivariable analyses. Most likely, the small number of positive specimens in this study made it impossible to determine whether bone metastases truly impacted survival, the researchers said.

In the future, "improved techniques for isolating and detecting occult tumor cells may make their assessment in the bone marrow more efficient and feasible," they added.

The Z10010 study was supported by the National Institutes of Health and the American College of Surgeons Oncology Group (ACOSOG). Dr. Giuliano and his associates reported support from ACOSOG; three coauthors reported support from industry sources.

Among patients with early-stage breast cancer whose sentinel nodes were negative for metastases on hematoxylin-eosin testing, a later finding of occult metastases using immunohistochemical staining did not impact survival, according to a report in the July 27 issue of JAMA.

Such occult sentinel node metastases were found in approximately 10% of more than 3,900 patients who participated in the Z0010 trial and whose sentinel node specimens had been tumor-negative on hematoxylin-eosin staining. Yet 5-year rates of overall survival were nearly identical – at just over 95% – between women who were found to have occult metastases and those who were not, said Dr. Armando E. Giuliano of the division of surgical oncology, John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica, Calif., and his associates.

Occult metastases identified on immunohistochemical examination of bone marrow yielded conflicting results, so it wasn’t clear whether those metastases may impact survival.

Taken together, these findings show that routine immunohistochemical examination of both bone marrow and sentinel nodes that tested negative with hematoxylin-eosin staining are not clinically warranted for early-stage breast cancer, the investigators said.

The American College of Surgeons Oncology Group (ACOSOG) began the prospective, observational Z0010 trial in 1999 at 126 medical centers to examine the significance of occult metastases in lymph nodes and bone marrow among women undergoing breast-conserving surgery, sentinel lymph node dissection, and whole breast irradiation for T1 or T2 node-negative breast cancer. A total of 3,904 study subjects whose lymph nodes were hematoxylin-eosin negative were included in this analysis of Z0010 data.

Of these, 349 specimens (10.5%) were found to have occult metastases on immunohistochemical examination. Five-year overall survival was 95.7% for patients who had occult nodal metastases, which was not significantly different from the 95.1% rate for patients who did not.

Similarly, 5-year disease-free survival was 92.2% for patients who had occult nodal metastases, which was not significantly different from the 90.4% rate for patients who did not, Dr. Giuliano and his colleagues said (JAMA 2011;306:385-93).

The presence or absence of occult nodal metastases also had no impact on survival when the women were categorized according to adjuvant systemic therapy. Five-year overall survival was 96.3% without adjuvant systemic therapy and 95.7% with adjuvant systemic therapy for women who had occult metastases. Similarly, 5-year disease-free survival was 91.4% and 91%, respectively.

Bone marrow biopsy specimens were obtained in 3,413 patients, and immunocytochemistry revealed occult bone metastases in 104 women (3%). In the initial, univariable analysis, the presence of bone metastases appeared to reduce survival, but this association did not persist in multivariable analyses. Most likely, the small number of positive specimens in this study made it impossible to determine whether bone metastases truly impacted survival, the researchers said.

In the future, "improved techniques for isolating and detecting occult tumor cells may make their assessment in the bone marrow more efficient and feasible," they added.

The Z10010 study was supported by the National Institutes of Health and the American College of Surgeons Oncology Group (ACOSOG). Dr. Giuliano and his associates reported support from ACOSOG; three coauthors reported support from industry sources.

Among patients with early-stage breast cancer whose sentinel nodes were negative for metastases on hematoxylin-eosin testing, a later finding of occult metastases using immunohistochemical staining did not impact survival, according to a report in the July 27 issue of JAMA.

Such occult sentinel node metastases were found in approximately 10% of more than 3,900 patients who participated in the Z0010 trial and whose sentinel node specimens had been tumor-negative on hematoxylin-eosin staining. Yet 5-year rates of overall survival were nearly identical – at just over 95% – between women who were found to have occult metastases and those who were not, said Dr. Armando E. Giuliano of the division of surgical oncology, John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica, Calif., and his associates.

Occult metastases identified on immunohistochemical examination of bone marrow yielded conflicting results, so it wasn’t clear whether those metastases may impact survival.

Taken together, these findings show that routine immunohistochemical examination of both bone marrow and sentinel nodes that tested negative with hematoxylin-eosin staining are not clinically warranted for early-stage breast cancer, the investigators said.

The American College of Surgeons Oncology Group (ACOSOG) began the prospective, observational Z0010 trial in 1999 at 126 medical centers to examine the significance of occult metastases in lymph nodes and bone marrow among women undergoing breast-conserving surgery, sentinel lymph node dissection, and whole breast irradiation for T1 or T2 node-negative breast cancer. A total of 3,904 study subjects whose lymph nodes were hematoxylin-eosin negative were included in this analysis of Z0010 data.

Of these, 349 specimens (10.5%) were found to have occult metastases on immunohistochemical examination. Five-year overall survival was 95.7% for patients who had occult nodal metastases, which was not significantly different from the 95.1% rate for patients who did not.

Similarly, 5-year disease-free survival was 92.2% for patients who had occult nodal metastases, which was not significantly different from the 90.4% rate for patients who did not, Dr. Giuliano and his colleagues said (JAMA 2011;306:385-93).

The presence or absence of occult nodal metastases also had no impact on survival when the women were categorized according to adjuvant systemic therapy. Five-year overall survival was 96.3% without adjuvant systemic therapy and 95.7% with adjuvant systemic therapy for women who had occult metastases. Similarly, 5-year disease-free survival was 91.4% and 91%, respectively.

Bone marrow biopsy specimens were obtained in 3,413 patients, and immunocytochemistry revealed occult bone metastases in 104 women (3%). In the initial, univariable analysis, the presence of bone metastases appeared to reduce survival, but this association did not persist in multivariable analyses. Most likely, the small number of positive specimens in this study made it impossible to determine whether bone metastases truly impacted survival, the researchers said.

In the future, "improved techniques for isolating and detecting occult tumor cells may make their assessment in the bone marrow more efficient and feasible," they added.

The Z10010 study was supported by the National Institutes of Health and the American College of Surgeons Oncology Group (ACOSOG). Dr. Giuliano and his associates reported support from ACOSOG; three coauthors reported support from industry sources.

Taking the GnRH analogue triptorelin during chemotherapy led to a 17% absolute reduction in the occurrence of early menopause in young women with early-stage breast cancer, investigators reported in the July 20 issue of JAMA.

"Our results suggest that temporarily suppressing ovarian function by administering triptorelin reduces the incidence of chemotherapy-induced early menopause. This treatment can therefore be offered to premenopausal patients with breast cancer who wish to decrease the risk of permanent ovarian failure associated with chemotherapy," wrote Dr. Lucia Del Mastro of Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy, and her associates.

In what they described as the largest phase III study to examine this issue, the investigators assessed 281 women aged 18-45 years who were treated for stage I, II, or III breast cancer at 16 Italian medical centers. The patients were randomly assigned to receive adjuvant or neoadjuvant chemotherapy alone or chemotherapy plus IM triptorelin, and were followed for 1 year to compare the incidence of early menopause.

For this open-label trial, early menopause was defined as no resumption of menstrual activity and postmenopausal levels of follicle-stimulating hormone (FSH).

Women with hormone-senstive tumors were also given tamoxifen for 5 years following the end of chemotherapy. Those whose ovarian function returned during the follow-up year also received triptorelin every 4 weeks until ovarian function had been suppressed for at least 2 years, to optimize their chance of eradicating the breast cancer.

The rate of early menopause was 25.9% for chemotherapy alone, compared with 8.9% for the addition of triptorelin, an absolute decrease of 17%. The number of patients who needed to take triptorelin to prevent one case of early menopause was only six, Dr. Del Mastro and her colleagues wrote (JAMA 2011;306:269-76).

Moreover, in a multivariate analysis, the only factor found to significantly reduce the development of premature menopause was the use of triptorelin.

In a secondary analysis of a subgroup of 260 patients, menses resumed in 49.6% of the chemotherapy-only group, compared with 63.3% of the chemotherapy-plus-triptorelin group. The median time to resumption of menses was 6.7 months with the addition of triptorelin, but was not reached in the women who received chemotherapy alone.

"There was no difference in the incidence of selected toxicities that may have been partly related to the use of triptorelin," they added.

Longer follow-up is needed to assess the long-term maintenance of ovarian function and preservation of fertility in these patients. However, "at the time of the last annual follow-up, 1 full-term pregnancy in the chemotherapy-alone group and three pregnancies (one full-term, one premature delivery, and one voluntary abortion) in the chemotherapy plus triptorelin group were reported," Dr. Del Mastro and fellow researchers said.

In addition, longer follow-up is necessary to assess the effectiveness of the breast cancer therapy. So far, it doesn’t appear that adding triptorelin interferes with chemotherapy’s effects. There have been 27 breast cancer recurrences (13 with chemotherapy alone and 14 with the addition of triptorelin) and 11 deaths (3 in the chemotherapy-alone group, 8 in the chemotherapy plus triptorelin group), the researchers said.

The mechanisms by which GnRH analogues may preserve ovarian function "are not fully understood but may include the interruption of FSH secretion, a decrease in utero-ovarian perfusion, the activation of GnRH receptors, the up-regulation of intragonadal antiapoptotic molecules such as sphingosine-1-phosphate, or the protection of undifferentiated germ-line stem cells," they noted.

Taking the GnRH analogue triptorelin during chemotherapy led to a 17% absolute reduction in the occurrence of early menopause in young women with early-stage breast cancer, investigators reported in the July 20 issue of JAMA.

"Our results suggest that temporarily suppressing ovarian function by administering triptorelin reduces the incidence of chemotherapy-induced early menopause. This treatment can therefore be offered to premenopausal patients with breast cancer who wish to decrease the risk of permanent ovarian failure associated with chemotherapy," wrote Dr. Lucia Del Mastro of Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy, and her associates.

In what they described as the largest phase III study to examine this issue, the investigators assessed 281 women aged 18-45 years who were treated for stage I, II, or III breast cancer at 16 Italian medical centers. The patients were randomly assigned to receive adjuvant or neoadjuvant chemotherapy alone or chemotherapy plus IM triptorelin, and were followed for 1 year to compare the incidence of early menopause.

For this open-label trial, early menopause was defined as no resumption of menstrual activity and postmenopausal levels of follicle-stimulating hormone (FSH).

Women with hormone-senstive tumors were also given tamoxifen for 5 years following the end of chemotherapy. Those whose ovarian function returned during the follow-up year also received triptorelin every 4 weeks until ovarian function had been suppressed for at least 2 years, to optimize their chance of eradicating the breast cancer.

The rate of early menopause was 25.9% for chemotherapy alone, compared with 8.9% for the addition of triptorelin, an absolute decrease of 17%. The number of patients who needed to take triptorelin to prevent one case of early menopause was only six, Dr. Del Mastro and her colleagues wrote (JAMA 2011;306:269-76).

Moreover, in a multivariate analysis, the only factor found to significantly reduce the development of premature menopause was the use of triptorelin.

In a secondary analysis of a subgroup of 260 patients, menses resumed in 49.6% of the chemotherapy-only group, compared with 63.3% of the chemotherapy-plus-triptorelin group. The median time to resumption of menses was 6.7 months with the addition of triptorelin, but was not reached in the women who received chemotherapy alone.

"There was no difference in the incidence of selected toxicities that may have been partly related to the use of triptorelin," they added.

Longer follow-up is needed to assess the long-term maintenance of ovarian function and preservation of fertility in these patients. However, "at the time of the last annual follow-up, 1 full-term pregnancy in the chemotherapy-alone group and three pregnancies (one full-term, one premature delivery, and one voluntary abortion) in the chemotherapy plus triptorelin group were reported," Dr. Del Mastro and fellow researchers said.

In addition, longer follow-up is necessary to assess the effectiveness of the breast cancer therapy. So far, it doesn’t appear that adding triptorelin interferes with chemotherapy’s effects. There have been 27 breast cancer recurrences (13 with chemotherapy alone and 14 with the addition of triptorelin) and 11 deaths (3 in the chemotherapy-alone group, 8 in the chemotherapy plus triptorelin group), the researchers said.

The mechanisms by which GnRH analogues may preserve ovarian function "are not fully understood but may include the interruption of FSH secretion, a decrease in utero-ovarian perfusion, the activation of GnRH receptors, the up-regulation of intragonadal antiapoptotic molecules such as sphingosine-1-phosphate, or the protection of undifferentiated germ-line stem cells," they noted.

Taking the GnRH analogue triptorelin during chemotherapy led to a 17% absolute reduction in the occurrence of early menopause in young women with early-stage breast cancer, investigators reported in the July 20 issue of JAMA.

"Our results suggest that temporarily suppressing ovarian function by administering triptorelin reduces the incidence of chemotherapy-induced early menopause. This treatment can therefore be offered to premenopausal patients with breast cancer who wish to decrease the risk of permanent ovarian failure associated with chemotherapy," wrote Dr. Lucia Del Mastro of Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy, and her associates.

In what they described as the largest phase III study to examine this issue, the investigators assessed 281 women aged 18-45 years who were treated for stage I, II, or III breast cancer at 16 Italian medical centers. The patients were randomly assigned to receive adjuvant or neoadjuvant chemotherapy alone or chemotherapy plus IM triptorelin, and were followed for 1 year to compare the incidence of early menopause.

For this open-label trial, early menopause was defined as no resumption of menstrual activity and postmenopausal levels of follicle-stimulating hormone (FSH).

Women with hormone-senstive tumors were also given tamoxifen for 5 years following the end of chemotherapy. Those whose ovarian function returned during the follow-up year also received triptorelin every 4 weeks until ovarian function had been suppressed for at least 2 years, to optimize their chance of eradicating the breast cancer.

The rate of early menopause was 25.9% for chemotherapy alone, compared with 8.9% for the addition of triptorelin, an absolute decrease of 17%. The number of patients who needed to take triptorelin to prevent one case of early menopause was only six, Dr. Del Mastro and her colleagues wrote (JAMA 2011;306:269-76).

Moreover, in a multivariate analysis, the only factor found to significantly reduce the development of premature menopause was the use of triptorelin.

In a secondary analysis of a subgroup of 260 patients, menses resumed in 49.6% of the chemotherapy-only group, compared with 63.3% of the chemotherapy-plus-triptorelin group. The median time to resumption of menses was 6.7 months with the addition of triptorelin, but was not reached in the women who received chemotherapy alone.

"There was no difference in the incidence of selected toxicities that may have been partly related to the use of triptorelin," they added.

Longer follow-up is needed to assess the long-term maintenance of ovarian function and preservation of fertility in these patients. However, "at the time of the last annual follow-up, 1 full-term pregnancy in the chemotherapy-alone group and three pregnancies (one full-term, one premature delivery, and one voluntary abortion) in the chemotherapy plus triptorelin group were reported," Dr. Del Mastro and fellow researchers said.

In addition, longer follow-up is necessary to assess the effectiveness of the breast cancer therapy. So far, it doesn’t appear that adding triptorelin interferes with chemotherapy’s effects. There have been 27 breast cancer recurrences (13 with chemotherapy alone and 14 with the addition of triptorelin) and 11 deaths (3 in the chemotherapy-alone group, 8 in the chemotherapy plus triptorelin group), the researchers said.

The mechanisms by which GnRH analogues may preserve ovarian function "are not fully understood but may include the interruption of FSH secretion, a decrease in utero-ovarian perfusion, the activation of GnRH receptors, the up-regulation of intragonadal antiapoptotic molecules such as sphingosine-1-phosphate, or the protection of undifferentiated germ-line stem cells," they noted.

BOSTON – Obesity increases the odds of a woman with breast cancer dying from her disease, according to a retrospective data analysis.

Further, this link between obesity and breast cancer death is strongest among those obese women who have estrogen receptor (ER) positive cancer, according to the analysis of data on nearly 4,000 participants in the California Teachers Study.

Photo credit: © Kokhanchikov / fotolia.com

"This is another reason why the public should be aware of the importance of maintaining a healthy body weight, particularly how it pertains to cancer and especially breast cancer," according to Christina M. Dieli-Conwright Ph.D., an assistant research professor at City of Hope National Medical Center, Duarte, Calif. She presented the findings at the annual meeting of The Endocrine Society.

The study looked at a cohort of women who had taken a self-administered baseline questionnaire in 1995-1996 and who were diagnosed with their first primary invasive breast cancer between 1995 and 2006. Of the 3,995 women studied through 2007, 262 died of breast cancer and 321 died of nonbreast cancer causes.

There was a significant association between breast cancer mortality and body mass index (BMI) (P = .03). Women who were obese (defined as BMI greater than or equal to 30 kg/m²) had a 69% increased risk of dying of their breast cancer than women with a BMI less than 25. A similar increased risk in breast cancer mortality was seen in women who were overweight at age 18 (defined as BMI 25-29) compared to those with BMI less than 25. No significant associations were noted between weight and deaths due to nonbreast cancer causes or deaths due to all causes.

When the data were stratified according to estrogen receptor status, weight and breast cancer mortality were significantly related among women who were ER positive (P = 0.04), but not for those who were ER negative (P = .41). Obese women who were ER positive had a 64% increased risk of death due to breast cancer compared to those who had BMI less than 25. No significant associations were seen between weight and death due to all causes according to ER receptor status. Interestingly, there was more than a threefold increase in death from breast cancer in women who were ER negative if they were overweight at age 18 years.

Obesity at baseline almost doubled the breast cancer mortality risk (relative risk 1.91, 95% confidence interval 1.27-2.87) in women diagnosed with regional or distant disease, while there was no such association in obese women with localized disease. Higher risk of death from breast cancer and from all causes were also documented for women who had been overweight at age 18 for both localized and regional/distant disease.

Dr. Dieli-Conwright said that the findings add to a growing body of evidence linking obesity with the risk of developing breast cancer and with the risk of dying from it.

Dr. Dieli-Conwright reported having no conflicts of interest.

BOSTON – Obesity increases the odds of a woman with breast cancer dying from her disease, according to a retrospective data analysis.

Further, this link between obesity and breast cancer death is strongest among those obese women who have estrogen receptor (ER) positive cancer, according to the analysis of data on nearly 4,000 participants in the California Teachers Study.

Photo credit: © Kokhanchikov / fotolia.com

"This is another reason why the public should be aware of the importance of maintaining a healthy body weight, particularly how it pertains to cancer and especially breast cancer," according to Christina M. Dieli-Conwright Ph.D., an assistant research professor at City of Hope National Medical Center, Duarte, Calif. She presented the findings at the annual meeting of The Endocrine Society.

The study looked at a cohort of women who had taken a self-administered baseline questionnaire in 1995-1996 and who were diagnosed with their first primary invasive breast cancer between 1995 and 2006. Of the 3,995 women studied through 2007, 262 died of breast cancer and 321 died of nonbreast cancer causes.

There was a significant association between breast cancer mortality and body mass index (BMI) (P = .03). Women who were obese (defined as BMI greater than or equal to 30 kg/m²) had a 69% increased risk of dying of their breast cancer than women with a BMI less than 25. A similar increased risk in breast cancer mortality was seen in women who were overweight at age 18 (defined as BMI 25-29) compared to those with BMI less than 25. No significant associations were noted between weight and deaths due to nonbreast cancer causes or deaths due to all causes.

When the data were stratified according to estrogen receptor status, weight and breast cancer mortality were significantly related among women who were ER positive (P = 0.04), but not for those who were ER negative (P = .41). Obese women who were ER positive had a 64% increased risk of death due to breast cancer compared to those who had BMI less than 25. No significant associations were seen between weight and death due to all causes according to ER receptor status. Interestingly, there was more than a threefold increase in death from breast cancer in women who were ER negative if they were overweight at age 18 years.

Obesity at baseline almost doubled the breast cancer mortality risk (relative risk 1.91, 95% confidence interval 1.27-2.87) in women diagnosed with regional or distant disease, while there was no such association in obese women with localized disease. Higher risk of death from breast cancer and from all causes were also documented for women who had been overweight at age 18 for both localized and regional/distant disease.

Dr. Dieli-Conwright said that the findings add to a growing body of evidence linking obesity with the risk of developing breast cancer and with the risk of dying from it.

Dr. Dieli-Conwright reported having no conflicts of interest.

BOSTON – Obesity increases the odds of a woman with breast cancer dying from her disease, according to a retrospective data analysis.

Further, this link between obesity and breast cancer death is strongest among those obese women who have estrogen receptor (ER) positive cancer, according to the analysis of data on nearly 4,000 participants in the California Teachers Study.

Photo credit: © Kokhanchikov / fotolia.com

"This is another reason why the public should be aware of the importance of maintaining a healthy body weight, particularly how it pertains to cancer and especially breast cancer," according to Christina M. Dieli-Conwright Ph.D., an assistant research professor at City of Hope National Medical Center, Duarte, Calif. She presented the findings at the annual meeting of The Endocrine Society.

The study looked at a cohort of women who had taken a self-administered baseline questionnaire in 1995-1996 and who were diagnosed with their first primary invasive breast cancer between 1995 and 2006. Of the 3,995 women studied through 2007, 262 died of breast cancer and 321 died of nonbreast cancer causes.

There was a significant association between breast cancer mortality and body mass index (BMI) (P = .03). Women who were obese (defined as BMI greater than or equal to 30 kg/m²) had a 69% increased risk of dying of their breast cancer than women with a BMI less than 25. A similar increased risk in breast cancer mortality was seen in women who were overweight at age 18 (defined as BMI 25-29) compared to those with BMI less than 25. No significant associations were noted between weight and deaths due to nonbreast cancer causes or deaths due to all causes.

When the data were stratified according to estrogen receptor status, weight and breast cancer mortality were significantly related among women who were ER positive (P = 0.04), but not for those who were ER negative (P = .41). Obese women who were ER positive had a 64% increased risk of death due to breast cancer compared to those who had BMI less than 25. No significant associations were seen between weight and death due to all causes according to ER receptor status. Interestingly, there was more than a threefold increase in death from breast cancer in women who were ER negative if they were overweight at age 18 years.

Obesity at baseline almost doubled the breast cancer mortality risk (relative risk 1.91, 95% confidence interval 1.27-2.87) in women diagnosed with regional or distant disease, while there was no such association in obese women with localized disease. Higher risk of death from breast cancer and from all causes were also documented for women who had been overweight at age 18 for both localized and regional/distant disease.

Dr. Dieli-Conwright said that the findings add to a growing body of evidence linking obesity with the risk of developing breast cancer and with the risk of dying from it.

Dr. Dieli-Conwright reported having no conflicts of interest.