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In addition to these targeted approaches, adjuvant chemotherapy that includes alkylating agents, antimetabolites, anthracyclines, and taxanes in various combinations has contributed to the overall improvement in outcomes among women with operable breast cancer. As compared with women with estrogen-receptor–positive disease, women with estrogen-receptor–negative breast cancer benefit more from chemotherapy. A recent retrospective analysis of three trials by the Cancer and Leukemia Group B (CALGB) suggests very little overall benefit of adjuvant chemotherapy for women with estrogen-receptor–positive breast cancer who received tamoxifen for 5 years after receiving chemotherapy.4
Is it possible to define an optimal adjuvant chemotherapy program for individual patients with either estrogen-receptor–positive or estrogen-receptor–negative breast cancer to maximize the benefit and minimize toxic effects? The article by Hayes et al.5 in this issue of the Journal addresses this question.
Hayes et al. report their retrospective analysis of an adjuvant-chemotherapy trial, CALGB 9344/INT0148 (referred to below as CALGB 9344), for women with lymph node–positive breast cancer.6 The trial began in 1994 to test the benefit of adding four cycles of the taxane paclitaxel after four cycles of doxorubicin plus cyclophosphamide. The trial also investigated whether doxorubicin at higher than standard doses was beneficial, and the answer was that escalating the dose of doxorubicin did not benefit any subgroup of patients. Women with estrogen-receptor–positive breast cancer received tamoxifen for 5 years after chemotherapy. When the results of the trial were first presented at the American Society of Clinical Oncology meeting in May 1998, a small but statistically significant benefit from the addition of four cycles of paclitaxel every 3 weeks after doxorubicin plus cyclophosphamide was reported.7 This result changed clinical practice, and the use of adjuvant paclitaxel rose dramatically well before the publication of the results in 2003.
The study by Hayes et al.5 was designed to determine whether paclitaxel administered after doxorubicin plus cyclophosphamide was equally beneficial to all subgroups of women enrolled in the CALGB 9344 trial. New information was added by testing the tissue blocks from the original tumors for HER2 positivity with the use of assays for overexpression and gene amplification. The results are noteworthy. There was a significant clinical benefit from the addition of paclitaxel to the treatment of women with HER2-positive breast cancer. Most of these women had HER2-positive, estrogen-receptor–negative breast cancer, a profile associated with a relatively poor prognosis, but the small subgroup of women with HER2-positive, estrogen-receptor–positive disease also benefited from paclitaxel. However, women with HER2-negative, estrogen-receptor–positive breast cancer, the most common category of the disease, did not benefit from the addition of paclitaxel to doxorubicin plus cyclophosphamide.
Why should we spare our patients from paclitaxel? The toxicity profile of this drug is unique. Hypersensitivity reactions (including, rarely, anaphylaxis) occur during the infusion of paclitaxel, despite premedication with corticosteroids. Such reactions were reported in 6% of patients in the CALGB 9344 trial. A transient symptom complex of myalgia, arthralgia, and neuralgia is common within 2 to 3 days after the infusion. Neurotoxicity, the predominant side effect, was reported in 18% of patients in the CALGB 9344 trial. For some patients, numbness and tingling in the hands and feet last for months or even years after treatment is completed.8
Thirteen years have passed since the first patient was enrolled in the CALGB 9344 trial. During this time, important changes in practice may have diminished the value of adding paclitaxel to chemotherapy for women with HER2-negative, estrogen-receptor–positive breast cancer. For instance, advances in adjuvant endocrine therapy reduce the proportional benefit of adjuvant chemotherapy for women with estrogen-receptor–positive breast cancer. In postmenopausal women, the incorporation of an aromatase inhibitor (anastrozole, exemestane, or letrozole) into adjuvant therapy prolongs disease-free survival more than does treatment with tamoxifen for 5 years.9
Hayes and his coauthors caution us not to change clinical practice on the basis of their retrospective analysis, but oncologists have a responsibility to their patients to be aware of this report. A similar trial of doxorubicin plus cyclophosphamide followed by paclitaxel involving 3100 patients was published by the National Surgical Adjuvant Breast and Bowel Project in 2005. The results showed a small benefit in 5-year disease-free survival but no difference in overall survival as a result of the addition of paclitaxel in women with estrogen-receptor–negative or estrogen-receptor–positive disease. There was no analysis of outcome according to HER2 status.10
In the analysis by Hayes et al., women with HER2-positive breast cancer benefited from receiving four cycles of paclitaxel every 3 weeks after receiving doxorubicin plus cyclophosphamide, regardless of the estrogen-receptor status of the tumor. How does this treatment fit into contemporary adjuvant-chemotherapy programs that incorporate trastuzumab into the treatment of HER2-positive breast cancer? Most such programs include a taxane. However, in a pivotal trial that showed clinically significant improvement in disease-free survival from administration of trastuzumab after adjuvant chemotherapy, 74% of the patients were treated without a taxane and still benefited from trastuzumab.3
More difficult to define is the effect of the report by Hayes and colleagues on the treatment of women with HER2-negative, estrogen-receptor–positive breast cancer. According to this report, the addition of four cycles of paclitaxel every 3 weeks after treatment with doxorubicin plus cyclophosphamide is unlikely to benefit these patients. However, this is not a call to abandon taxanes for this group of patients. The 3-week schedule of treatment with paclitaxel is not the only way to include a taxane in adjuvant therapy. In more recent trials, "dose-dense" therapy using the same doses of doxorubicin plus cyclophosphamide and paclitaxel every 2 weeks has been shown to be more effective than the same regimen every 3 weeks.11 Adjuvant trials that use paclitaxel weekly instead of every 3 weeks and the adoption of the alternative taxane, docetaxel, for adjuvant therapy point to more choices.12,13 It would be of great value if the investigators in charge of these more recent trials analyzed their results retrospectively with respect to HER2 and estrogen-receptor status.
Leaders of clinical trials should continue to look backward, when appropriate, for data such as those presented by Hayes et al. In looking to the future, correlative science must be incorporated into modern clinical trials in breast cancer. The days of "one size fits all" therapy for patients with breast cancer are coming to an end.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Division of Hematology–Oncology, Weill Cornell Medical College, Cornell University Medical Center, New York.
References
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Related Letters:
HER2 and Response to Paclitaxel in Node-Positive Breast Cancer
Roukos D. H., Ferretti G., Felici A., Cognetti F., Mehta R., Nash I., Hayes D. F., Berry D., Moore A.
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N Engl J Med 2008;
358:197-199, Jan 10, 2008.
Correspondence
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