Lani
10-19-2005, 09:40 PM
Printable version
Drug halves breast cancer returns
The drug is already used for advanced cancer
The drug Herceptin cuts the risk of tumours returning in women with early stage breast cancer by 50%, a US study has shown.
A second study in the New England Journal of Medicine showed Herceptin can also reduce cancer recurrence when combined with a chemotherapy drug.
A leading cancer expert called the studies' findings "stunning".
But they will increase pressure on regulators to make Herceptin available for early as well as advanced cancers.
These are stunning results for women who have got this particular sort of breast cancer
Dr John Toy, Cancer Research UK
Herceptin, which also has the generic name traztuzumab, targets a protein called HER2, which appears to be over-abundant in some women's breast cancers.
An estimated fifth of breast cancer cases - around 10,000 women in the UK - are HER2 positive.
Roche, which makes Herceptin, has to submit an application to European regulators before the drug can be licensed for use in early-stage disease.
The National Institute for Health and Clinical Excellence then has to give its approval for the drug to be prescribed on the NHS.
The government has said this process should be fast-tracked. But it is likely to be next spring before Herceptin goes through all these regulatory hoops.
Until then, it will be up to primary care trusts (PCTs) to decide if they will fund the treatment for women, which can cost £30,000 a year.
On Tuesday, PCTs in Devon and Cornwall announced they would fund the treatment, and last month Barbara Clark won her battle to persuade Somerset PCT to pay for her to have the drug.
These results are so unprecedented that it requires an unprecedented response
Professor Ian Smith, UK-based researcher
The first study, by the Breast Cancer Group of international researchers and sponsored by Roche, looked at the effect of giving Herceptin to breast cancer patients who had already had surgery and a course of chemotherapy.
Almost 1,700 women received one year's treatment with Herceptin and a group of equal size were simply observed.
After 12 months, 13% (220) of the group under observation had seen a recurrence of their cancer, 34 of whom had died.
In the group taking Herceptin, just 127 women (7.5%) had seen a recurrence of their cancer, with 23 cancer-related deaths.
Women on a two-year course of Herceptin are currently being followed up by the same researchers. Results so far are also promising.
Professor Ian Smith, head of the Royal Marsden Hospital and Institute of Cancer Research, who worked on the study, told the BBC News website: "This is one of the most important developments in breast cancer treatment.
"It is only a minority of women who will benefit from it, but for that minority it makes an enormous difference."
He said women should be given the drug before it has passed through the regulatory process.
"Normally, it's reasonable to wait until the drug is licensed.
"But these results are so unprecedented that it requires an unprecedented response, which is to make it accessible before it is licensed."
'Undoubted benefits'
The second study combined results from two US trials covering 3,350 women given Herceptin either in combination with the drug paclitaxel (Taxol) or alone. Other women were given Taxol alone.
Taking both drugs together reduced the risk a woman's cancer would return by half, and the risk of death by a third.
Dr John Toy, medical director at Cancer Research UK, said: "These are stunning results for women who have got this particular sort of breast cancer.
"Each of the trials shows undoubted benefits."
He added: "These papers are in a top medical journal and the data is robust."
But Dr Toy said it would be important to see longer-term results from the studies, as cancers often recurred in HER2 positive women 18 months to two years after their initial diagnosis.
Dr Toy said he hoped there would be no unnecessary delay in the regulatory process for the drug to be approved for use in women with early-stage breast cancer.
He said that, until that time, PCTs would be faced with a decision over whether to give a drug for an unlicensed use to women who would be asking for it.
Jeremy Hughes, chief executive at Breakthrough Breast Cancer, said the studies showed one of the "biggest breakthroughs in breast cancer treatment."
^^^^^^^^^^^^^^^^^^^^
Trastuzumab May Prompt Change in Practice Recommendations for HER2-Positive Breast Cancer CME
News Author: Laurie Barclay, MD
Oct. 19, 2005 — The findings of two studies with trastuzumab reported in the Oct. 20 issue of The New England Journal of Medicine suggests, according to the editorialist, that it is time to change practice with respect to HER-2 positive breast cancer.
"Trastuzumab, a recombinant monoclonal antibody against HER2, has clinical activity in advanced breast cancer that overexpresses HER2," write Martine J. Piccart-Gebhart, MD, PhD, from the Université Libre de Bruxelles in Brussels, Belgium, and colleagues from the Herceptin Adjuvant (HERA) Trial Study Team. "Trastuzumab is not associated with the adverse events that typically occur with chemotherapy, such as alopecia, myelosuppression, and severe nausea and vomiting. With the exception of hypersensitivity, which has been seen mainly and occasionally with the first infusion, cardiotoxicity (principally congestive heart failure [CHF]) is the most important adverse effect of trastuzumab."
In this international, multicenter trial, patients with HER2-positive and either node-negative or node-positive breast cancer who had completed locoregional therapy and at least four cycles of neoadjuvant or adjuvant chemotherapy were randomized to two years of treatment with trastuzumab given every three weeks (n = 1,694), one year of trastuzumab (n = 1,694), or observation (n = 1,693).
This interim report compares patients who received trastuzumab for one year with those who received only observation. At median follow-up of one year, there were 347 events, defined as recurrence of breast cancer, contralateral breast cancer, second nonbreast malignant disease, or death. Of these 347 events, 127 (36.6%) events were in the trastuzumab group and 220 (63.4%) in the observation group. Compared with the observation group, the trastuzumab group had an unadjusted hazard ratio (HR) for an event of 0.54 (95% confidence interval, 0.43 - 0.67; P < .0001) or an absolute benefit in terms of disease-free survival at two years of 8.4 percentage points.
There were 29 deaths in the trastuzumab group and 37 in the observation group; overall survival was not significantly different. In the trastuzumab group, 0.5% developed severe cardiotoxicity.
"One year of treatment with trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among women with HER2-positive breast cancer," the authors write. "This degree of benefit in early breast cancer is the largest to be reported since the introduction of tamoxifen in hormone-receptor–positive disease."
Study limitations include short follow-up period, incomplete picture of the risks associated with trastuzumab, possible lack of generalizability to women treated outside clinical trials, and lack of information on the question of trastuzumab timing.
"The results of this trial indicate that one year of adjuvant trastuzumab should be considered a standard option on completion of locoregional therapy and neoadjuvant or adjuvant chemotherapy for women who fulfill the study eligibility criteria used in the HERA trial," the authors conclude.
F. Hoffmann-La Roche supported this study and employs three of its authors. Some of the other authors have disclosed various financial arrangements with the Breast International Group [BIG]; Roche; Genentech, the maker of trastuzumab; GlaxoSmithKline; AstraZeneca; and/or Chugai.
The second report, from Edward H. Romond, MD, from the National Surgical Adjuvant Breast and Bowel Project in Pittsburgh, Pennsylvania, and colleagues, describes the combined results of two trials that compared adjuvant chemotherapy with or without concurrent trastuzumab in women with surgically removed HER2-positive breast cancer.
The National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide followed by paclitaxel every three weeks (group 1) vs the same regimen plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel (group 2). The North Central Cancer Treatment Group trial N9831 compared three regimens: doxorubicin and cyclophosphamide followed by weekly paclitaxel (group A), the same regimen followed by 52 weeks of trastuzumab after paclitaxel (group B), and the same regimen plus 52 weeks of trastuzumab started simultaneously with paclitaxel (group C).
In a combined interim analysis after the occurrence of 355 events (recurrent, second primary cancer, or death before recurrence), groups 1 and A (the control group) were compared with groups 2 and C (the trastuzumab group), and group B was excluded because trastuzumab was not given at the same time as paclitaxel.
By March 15, 2005, 394 events had been reported, triggering the first scheduled interim analysis. At that time, 2,043 patients (of a planned total of 2,700) were enrolled in trial B-31, and 1,633 patients (of a total of 2,000 for the comparison of group A with group C) were enrolled in trial N9831. Of the 394 events, 133 (33.8%) were in the trastuzumab group and 261 (66.2%) were in the control group (HR, 0.48; P < .0001), leading to early trial termination.
At three years, the absolute difference in disease-free survival between the trastuzumab group and the control group was 12%. Trastuzumab was associated with a 33% reduction in the risk of death (P = .015). In the trastuzumab group, the three-year cumulative incidence of class III or IV CHF or death from cardiac causes was 4.1% in trial B-31 and 2.9% in trial N9831.
"Trastuzumab combined with paclitaxel after doxorubicin and cyclophosphamide improves outcomes among women with surgically removed HER2-positive breast cancer," the authors write. "The reduction was similar among women with hormone-receptor–negative tumors and women with hormone-receptor–positive tumors. No subgroups that did not appear to benefit from trastuzumab therapy were identified."
Study limitations include insufficient data to comment on the effect of trastuzumab in women with node-negative breast cancer, relatively little follow-up information beyond three years, and insufficient follow-up to adequately evaluate the efficacy of concurrent as compared with sequential administration of trastuzumab.
The Public Health Service supported this study. Genentech provided trastuzumab and partial funding for both trials. Some of the authors have disclosed various financial arrangements with the Breast Cancer Research Foundation and/or Genentech.
In an accompanying editorial, Gabriel N. Hortobagyi, MD, from the University of Texas M.D. Anderson Cancer Center in Houston, calls the results from these trials "simply stunning," but notes that longer follow-up is needed regarding cardiotoxicity.
"On the basis of these results, our care of patients with HER2-positive breast cancer must change today," Dr. Hortobagyi writes. "Certainly, patients with lymph-node–positive, HER2-positive breast cancer should receive trastuzumab as part of optimal adjuvant systemic therapy, unless the antibody is clearly contraindicated. Patients with negative lymph nodes, whose estimated risk of recurrence after optimal chemotherapy and endocrine therapy comfortably exceeds the risk of the cardiac toxic effects of trastuzumab, should also be offered the antibody."
N Engl J Med. 2005;353:1659-1684, 1734-1736
Learning Objectives for This Educational Activity
Upon completion of this activity, participants will be able to:
Describe the benefits of trastuzumab as adjuvant therapy for operable high-risk breast cancer.
Identify the adverse effects associated with use of trastuzumab as an adjuvant in chemotherapy for breast cancer.
Clinical Context
Trastuzumab is a monoclonal antibody approved by the U.S. Food and Drug Administration in 1998 as first-line treatment with paclitaxel for HER2-positive metastatic breast cancer. The benefits of trastuzumab resulted in two sponsored studies of adjuvant trastuzumab with standard chemotherapy by the National Cancer Institute. These trials include trial B-31 that compares four cycles of doxorubicin and cyclophosphamide followed by weekly paclitaxel for 12 weeks (group 1) vs the same chemotherapy plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel (group 2) and trial N9831 that compares four cycles of doxorubicin and cyclophosphamide followed by weekly paclitaxel for 12 weeks (group A) vs the same regimen plus 52 weeks of trastuzumab given concurrently with paclitaxel (group C).
The current study is a report of the combined analysis of the two trials (group 1 and A [controls] vs groups 2 and C [the trastuzumab group]). The trials were terminated after the first interim analysis because of the demonstrated superiority of the trastuzumab regimen.
Study Highlights
Inclusion criteria were women with HER2-positive gene, node-positive disease (except after 2003 when high-risk node-negative disease was included); adequate hematopoietic, renal, and hepatic function; and left ventricular ejection fraction (LVEF) within normal limits.
Complete resection of the primary tumor and axillary node dissection were required.
Exclusion criteria were metastatic disease, angina, severe conduction abnormalities, left ventricular hypertrophy, uncontrolled hypertension, pericardial effusion or a history of myocardial infarction, CHF, or cardiomyopathy.
In the B-31 trial, treatment consisted of 60 mg per m2 of doxorubicin and 600 mg per m2 of cyclophosphamide every 21 days for 4 cycles, followed by 175 mg per m2 of paclitaxel every 3 weeks for 4 cycles (group 1) or the same regimen with the addition of trastuzumab, beginning with a loading dose of 4 mg per kg body weight followed by weekly doses of 2 mg per kg for 51 weeks (group 2).
In the N9831 trial, groups A and C used the same regimen as in the B-31 trial, except that the paclitaxel dose was 80 mg per m2.
In both trials, patients treated with lumpectomy underwent radiotherapy that was continued during treatment with trastuzumab.
Women with estrogen- or progesterone-positive tumors received 20 mg of tamoxifen daily for 5 years.
LVEF was assessed at baseline, 6, 9, and 18 months.
The primary outcome was disease-free survival.
Secondary outcomes included overall survival, time to recurrence, death from breast cancer, contralateral breast cancer, other primary cancers, and adverse effects.
85% of patients were younger than 60 years, nearly 90% had 1 to 9 positive nodes, 53% had estrogen- or progesterone-receptor–positive status, more than 80% had tumor size of 2 to more than 4 cm, and tumor grade was intermediate to poor in 95%.
Completion rate for the first part of chemotherapy was more than 90%. Completion rate for trastuzumab was 69% with dropouts before 51 weeks due to adverse effects or recurrence.
Median follow-up was 2 years.
There were 261 events in the control and 133 events in the trastuzumab group.
The HR for a first event in the trastuzumab group was 0.48.
The % of patients alive at 3 years was 87.1% in the trastuzumab and 75.4% in the control group, with an absolute difference of 11.8% points.
At 4 years, the respective percentages of those alive were 85.3% and 67.1%.
There were 62 deaths in the trastuzumab and 92 deaths in the control group, with an absolute survival rate of 94.3% in the trastuzumab and 91.7% in the control group (difference, 2.5% points).
At 4 years, the respective % of deaths were 86.6% and 91.4%.
Distant metastases were reported in 96 patients in the trastuzumab and 193 patients in the control group.
The HR for a first distant recurrence was 0.47 in the trastuzumab group.
At 3 years, 90.4% of women in the trastuzumab group were free of distant recurrence vs 81.5% of women in the control group.
The respective rates of distant recurrence at 4 years were 89.7% and 73.7%.
There was a reduction in nonbreast second primary tumors in the B-31 but not in the N9831 trial.
The benefits of trastuzumab applied to local, regional, and distant sites.
The number of positive nodes, pathologic tumor size, hormone-receptor status, and tumor grade were significant predictors of disease-free survival.
The cumulative incidence of New York Heart Association (NYHA) grade III or IV CHF was 4.1% in the trastuzumab and 0.8% in the control group.
Incidence of death from cardiac causes was 2.9% in the trastuzumab and 0% in the control group.
Drug halves breast cancer returns
The drug is already used for advanced cancer
The drug Herceptin cuts the risk of tumours returning in women with early stage breast cancer by 50%, a US study has shown.
A second study in the New England Journal of Medicine showed Herceptin can also reduce cancer recurrence when combined with a chemotherapy drug.
A leading cancer expert called the studies' findings "stunning".
But they will increase pressure on regulators to make Herceptin available for early as well as advanced cancers.
These are stunning results for women who have got this particular sort of breast cancer
Dr John Toy, Cancer Research UK
Herceptin, which also has the generic name traztuzumab, targets a protein called HER2, which appears to be over-abundant in some women's breast cancers.
An estimated fifth of breast cancer cases - around 10,000 women in the UK - are HER2 positive.
Roche, which makes Herceptin, has to submit an application to European regulators before the drug can be licensed for use in early-stage disease.
The National Institute for Health and Clinical Excellence then has to give its approval for the drug to be prescribed on the NHS.
The government has said this process should be fast-tracked. But it is likely to be next spring before Herceptin goes through all these regulatory hoops.
Until then, it will be up to primary care trusts (PCTs) to decide if they will fund the treatment for women, which can cost £30,000 a year.
On Tuesday, PCTs in Devon and Cornwall announced they would fund the treatment, and last month Barbara Clark won her battle to persuade Somerset PCT to pay for her to have the drug.
These results are so unprecedented that it requires an unprecedented response
Professor Ian Smith, UK-based researcher
The first study, by the Breast Cancer Group of international researchers and sponsored by Roche, looked at the effect of giving Herceptin to breast cancer patients who had already had surgery and a course of chemotherapy.
Almost 1,700 women received one year's treatment with Herceptin and a group of equal size were simply observed.
After 12 months, 13% (220) of the group under observation had seen a recurrence of their cancer, 34 of whom had died.
In the group taking Herceptin, just 127 women (7.5%) had seen a recurrence of their cancer, with 23 cancer-related deaths.
Women on a two-year course of Herceptin are currently being followed up by the same researchers. Results so far are also promising.
Professor Ian Smith, head of the Royal Marsden Hospital and Institute of Cancer Research, who worked on the study, told the BBC News website: "This is one of the most important developments in breast cancer treatment.
"It is only a minority of women who will benefit from it, but for that minority it makes an enormous difference."
He said women should be given the drug before it has passed through the regulatory process.
"Normally, it's reasonable to wait until the drug is licensed.
"But these results are so unprecedented that it requires an unprecedented response, which is to make it accessible before it is licensed."
'Undoubted benefits'
The second study combined results from two US trials covering 3,350 women given Herceptin either in combination with the drug paclitaxel (Taxol) or alone. Other women were given Taxol alone.
Taking both drugs together reduced the risk a woman's cancer would return by half, and the risk of death by a third.
Dr John Toy, medical director at Cancer Research UK, said: "These are stunning results for women who have got this particular sort of breast cancer.
"Each of the trials shows undoubted benefits."
He added: "These papers are in a top medical journal and the data is robust."
But Dr Toy said it would be important to see longer-term results from the studies, as cancers often recurred in HER2 positive women 18 months to two years after their initial diagnosis.
Dr Toy said he hoped there would be no unnecessary delay in the regulatory process for the drug to be approved for use in women with early-stage breast cancer.
He said that, until that time, PCTs would be faced with a decision over whether to give a drug for an unlicensed use to women who would be asking for it.
Jeremy Hughes, chief executive at Breakthrough Breast Cancer, said the studies showed one of the "biggest breakthroughs in breast cancer treatment."
^^^^^^^^^^^^^^^^^^^^
Trastuzumab May Prompt Change in Practice Recommendations for HER2-Positive Breast Cancer CME
News Author: Laurie Barclay, MD
Oct. 19, 2005 — The findings of two studies with trastuzumab reported in the Oct. 20 issue of The New England Journal of Medicine suggests, according to the editorialist, that it is time to change practice with respect to HER-2 positive breast cancer.
"Trastuzumab, a recombinant monoclonal antibody against HER2, has clinical activity in advanced breast cancer that overexpresses HER2," write Martine J. Piccart-Gebhart, MD, PhD, from the Université Libre de Bruxelles in Brussels, Belgium, and colleagues from the Herceptin Adjuvant (HERA) Trial Study Team. "Trastuzumab is not associated with the adverse events that typically occur with chemotherapy, such as alopecia, myelosuppression, and severe nausea and vomiting. With the exception of hypersensitivity, which has been seen mainly and occasionally with the first infusion, cardiotoxicity (principally congestive heart failure [CHF]) is the most important adverse effect of trastuzumab."
In this international, multicenter trial, patients with HER2-positive and either node-negative or node-positive breast cancer who had completed locoregional therapy and at least four cycles of neoadjuvant or adjuvant chemotherapy were randomized to two years of treatment with trastuzumab given every three weeks (n = 1,694), one year of trastuzumab (n = 1,694), or observation (n = 1,693).
This interim report compares patients who received trastuzumab for one year with those who received only observation. At median follow-up of one year, there were 347 events, defined as recurrence of breast cancer, contralateral breast cancer, second nonbreast malignant disease, or death. Of these 347 events, 127 (36.6%) events were in the trastuzumab group and 220 (63.4%) in the observation group. Compared with the observation group, the trastuzumab group had an unadjusted hazard ratio (HR) for an event of 0.54 (95% confidence interval, 0.43 - 0.67; P < .0001) or an absolute benefit in terms of disease-free survival at two years of 8.4 percentage points.
There were 29 deaths in the trastuzumab group and 37 in the observation group; overall survival was not significantly different. In the trastuzumab group, 0.5% developed severe cardiotoxicity.
"One year of treatment with trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among women with HER2-positive breast cancer," the authors write. "This degree of benefit in early breast cancer is the largest to be reported since the introduction of tamoxifen in hormone-receptor–positive disease."
Study limitations include short follow-up period, incomplete picture of the risks associated with trastuzumab, possible lack of generalizability to women treated outside clinical trials, and lack of information on the question of trastuzumab timing.
"The results of this trial indicate that one year of adjuvant trastuzumab should be considered a standard option on completion of locoregional therapy and neoadjuvant or adjuvant chemotherapy for women who fulfill the study eligibility criteria used in the HERA trial," the authors conclude.
F. Hoffmann-La Roche supported this study and employs three of its authors. Some of the other authors have disclosed various financial arrangements with the Breast International Group [BIG]; Roche; Genentech, the maker of trastuzumab; GlaxoSmithKline; AstraZeneca; and/or Chugai.
The second report, from Edward H. Romond, MD, from the National Surgical Adjuvant Breast and Bowel Project in Pittsburgh, Pennsylvania, and colleagues, describes the combined results of two trials that compared adjuvant chemotherapy with or without concurrent trastuzumab in women with surgically removed HER2-positive breast cancer.
The National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide followed by paclitaxel every three weeks (group 1) vs the same regimen plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel (group 2). The North Central Cancer Treatment Group trial N9831 compared three regimens: doxorubicin and cyclophosphamide followed by weekly paclitaxel (group A), the same regimen followed by 52 weeks of trastuzumab after paclitaxel (group B), and the same regimen plus 52 weeks of trastuzumab started simultaneously with paclitaxel (group C).
In a combined interim analysis after the occurrence of 355 events (recurrent, second primary cancer, or death before recurrence), groups 1 and A (the control group) were compared with groups 2 and C (the trastuzumab group), and group B was excluded because trastuzumab was not given at the same time as paclitaxel.
By March 15, 2005, 394 events had been reported, triggering the first scheduled interim analysis. At that time, 2,043 patients (of a planned total of 2,700) were enrolled in trial B-31, and 1,633 patients (of a total of 2,000 for the comparison of group A with group C) were enrolled in trial N9831. Of the 394 events, 133 (33.8%) were in the trastuzumab group and 261 (66.2%) were in the control group (HR, 0.48; P < .0001), leading to early trial termination.
At three years, the absolute difference in disease-free survival between the trastuzumab group and the control group was 12%. Trastuzumab was associated with a 33% reduction in the risk of death (P = .015). In the trastuzumab group, the three-year cumulative incidence of class III or IV CHF or death from cardiac causes was 4.1% in trial B-31 and 2.9% in trial N9831.
"Trastuzumab combined with paclitaxel after doxorubicin and cyclophosphamide improves outcomes among women with surgically removed HER2-positive breast cancer," the authors write. "The reduction was similar among women with hormone-receptor–negative tumors and women with hormone-receptor–positive tumors. No subgroups that did not appear to benefit from trastuzumab therapy were identified."
Study limitations include insufficient data to comment on the effect of trastuzumab in women with node-negative breast cancer, relatively little follow-up information beyond three years, and insufficient follow-up to adequately evaluate the efficacy of concurrent as compared with sequential administration of trastuzumab.
The Public Health Service supported this study. Genentech provided trastuzumab and partial funding for both trials. Some of the authors have disclosed various financial arrangements with the Breast Cancer Research Foundation and/or Genentech.
In an accompanying editorial, Gabriel N. Hortobagyi, MD, from the University of Texas M.D. Anderson Cancer Center in Houston, calls the results from these trials "simply stunning," but notes that longer follow-up is needed regarding cardiotoxicity.
"On the basis of these results, our care of patients with HER2-positive breast cancer must change today," Dr. Hortobagyi writes. "Certainly, patients with lymph-node–positive, HER2-positive breast cancer should receive trastuzumab as part of optimal adjuvant systemic therapy, unless the antibody is clearly contraindicated. Patients with negative lymph nodes, whose estimated risk of recurrence after optimal chemotherapy and endocrine therapy comfortably exceeds the risk of the cardiac toxic effects of trastuzumab, should also be offered the antibody."
N Engl J Med. 2005;353:1659-1684, 1734-1736
Learning Objectives for This Educational Activity
Upon completion of this activity, participants will be able to:
Describe the benefits of trastuzumab as adjuvant therapy for operable high-risk breast cancer.
Identify the adverse effects associated with use of trastuzumab as an adjuvant in chemotherapy for breast cancer.
Clinical Context
Trastuzumab is a monoclonal antibody approved by the U.S. Food and Drug Administration in 1998 as first-line treatment with paclitaxel for HER2-positive metastatic breast cancer. The benefits of trastuzumab resulted in two sponsored studies of adjuvant trastuzumab with standard chemotherapy by the National Cancer Institute. These trials include trial B-31 that compares four cycles of doxorubicin and cyclophosphamide followed by weekly paclitaxel for 12 weeks (group 1) vs the same chemotherapy plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel (group 2) and trial N9831 that compares four cycles of doxorubicin and cyclophosphamide followed by weekly paclitaxel for 12 weeks (group A) vs the same regimen plus 52 weeks of trastuzumab given concurrently with paclitaxel (group C).
The current study is a report of the combined analysis of the two trials (group 1 and A [controls] vs groups 2 and C [the trastuzumab group]). The trials were terminated after the first interim analysis because of the demonstrated superiority of the trastuzumab regimen.
Study Highlights
Inclusion criteria were women with HER2-positive gene, node-positive disease (except after 2003 when high-risk node-negative disease was included); adequate hematopoietic, renal, and hepatic function; and left ventricular ejection fraction (LVEF) within normal limits.
Complete resection of the primary tumor and axillary node dissection were required.
Exclusion criteria were metastatic disease, angina, severe conduction abnormalities, left ventricular hypertrophy, uncontrolled hypertension, pericardial effusion or a history of myocardial infarction, CHF, or cardiomyopathy.
In the B-31 trial, treatment consisted of 60 mg per m2 of doxorubicin and 600 mg per m2 of cyclophosphamide every 21 days for 4 cycles, followed by 175 mg per m2 of paclitaxel every 3 weeks for 4 cycles (group 1) or the same regimen with the addition of trastuzumab, beginning with a loading dose of 4 mg per kg body weight followed by weekly doses of 2 mg per kg for 51 weeks (group 2).
In the N9831 trial, groups A and C used the same regimen as in the B-31 trial, except that the paclitaxel dose was 80 mg per m2.
In both trials, patients treated with lumpectomy underwent radiotherapy that was continued during treatment with trastuzumab.
Women with estrogen- or progesterone-positive tumors received 20 mg of tamoxifen daily for 5 years.
LVEF was assessed at baseline, 6, 9, and 18 months.
The primary outcome was disease-free survival.
Secondary outcomes included overall survival, time to recurrence, death from breast cancer, contralateral breast cancer, other primary cancers, and adverse effects.
85% of patients were younger than 60 years, nearly 90% had 1 to 9 positive nodes, 53% had estrogen- or progesterone-receptor–positive status, more than 80% had tumor size of 2 to more than 4 cm, and tumor grade was intermediate to poor in 95%.
Completion rate for the first part of chemotherapy was more than 90%. Completion rate for trastuzumab was 69% with dropouts before 51 weeks due to adverse effects or recurrence.
Median follow-up was 2 years.
There were 261 events in the control and 133 events in the trastuzumab group.
The HR for a first event in the trastuzumab group was 0.48.
The % of patients alive at 3 years was 87.1% in the trastuzumab and 75.4% in the control group, with an absolute difference of 11.8% points.
At 4 years, the respective percentages of those alive were 85.3% and 67.1%.
There were 62 deaths in the trastuzumab and 92 deaths in the control group, with an absolute survival rate of 94.3% in the trastuzumab and 91.7% in the control group (difference, 2.5% points).
At 4 years, the respective % of deaths were 86.6% and 91.4%.
Distant metastases were reported in 96 patients in the trastuzumab and 193 patients in the control group.
The HR for a first distant recurrence was 0.47 in the trastuzumab group.
At 3 years, 90.4% of women in the trastuzumab group were free of distant recurrence vs 81.5% of women in the control group.
The respective rates of distant recurrence at 4 years were 89.7% and 73.7%.
There was a reduction in nonbreast second primary tumors in the B-31 but not in the N9831 trial.
The benefits of trastuzumab applied to local, regional, and distant sites.
The number of positive nodes, pathologic tumor size, hormone-receptor status, and tumor grade were significant predictors of disease-free survival.
The cumulative incidence of New York Heart Association (NYHA) grade III or IV CHF was 4.1% in the trastuzumab and 0.8% in the control group.
Incidence of death from cardiac causes was 2.9% in the trastuzumab and 0% in the control group.