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This article presents a review of the breast cancer medication trastuzumab, its mechanism of action and clinical value. In general, patients with breast-cancer cells that overexpress human epidermal growth factor receptor type 2 (HER2) have decreased overall survival and may have differential responses to treatment. Trastuzumab works by binding to the domain of HER2 and inhibiting the proliferation and survival of HER2-dependent tumors. Many studies of the drug are outlined. The most pivotal of all showed that the activity of trastuzumab in combination with chemotherapy was more effective than chemotherapy alone.

A reply by Clifford A. Hudis to letters to the editor about his article “Trastuzumab — mechanism of action and use in clinical practice” in the July 5, 2007 issue is presented.

The article reflects on the MINDACT trial which examined whether the 70-gene signature would reduce the use of adjuvant chemotherapy for breast cancer. It states that a high bar or a randomized design for the trial would be required to convince clinicians and patients that chemotherapy is not needed in healthy younger patients. It concludes that a team of well-coordinated and highly collaborative team of investigators can efficiently carry out a potentially practice-changing study.

Building on a foundation of clinical and laboratory observations, translational research, broad collaborations, and global education, adjuvant therapy for early-stage breast cancer has been an effective public health intervention. Standardization and even a one-size-fits-all philosophy were supported by individual trials and the worldwide overviews that showed proportional reductions in risk with chemotherapy in particular. Because higher risk, identified anatomically on the basis of tumor size or the presence of ipsilateral axillary nodal metastases, was associated with greater absolute therapeutic benefit, many clinical groups set risk thresholds, defined as a tumor size of 1 cm in the greatest dimension or any . . . [ABSTRACT FROM AUTHOR]

The article discusses a study which examined the treatment of human epidermal growth factor receptor type 2 (HER2)-positive breast cancer using adjuvant paclitaxel and trastuzumab. Topics discussed include the risk of early cancer recurrence, effectiveness and adverse events associated with the adjuvant therapy, and the rate of survival free from the disease.

Background: The status of human epidermal growth factor receptor type 2 (HER2) in breast-cancer cells predicts clinical outcomes in women who receive adjuvant anthracycline-based chemotherapy. We hypothesized that HER2 positivity predicts a benefit from adjuvant doxorubicin doses above standard levels, from the addition of paclitaxel after adjuvant chemotherapy with doxorubicin plus cyclophosphamide, or from both. Methods: We randomly selected 1500 women from 3121 women with node-positive breast cancer who had been randomly assigned to receive doxorubicin (60, 75, or 90 mg per square meter of body-surface area) plus cyclophosphamide (600 mg per square meter) for four cycles, followed by four cycles of paclitaxel (175 mg per square meter) or observation. Tissue blocks from 1322 of these 1500 women were available. Immunohistochemical analyses of these tissue specimens for HER2 with the CB11 monoclonal antibody against HER2 or with a polyclonal-antibody assay kit and fluorescence in situ hybridization for HER2 amplification were performed. Results: No interaction was observed between HER2 positivity and doxorubicin doses above 60 mg per square meter. HER2 positivity was, however, associated with a significant benefit from paclitaxel. The interaction between HER2 positivity and the addition of paclitaxel to the treatment was associated with a hazard ratio for recurrence of 0.59 (P=0.01). Patients with a HER2-positive breast cancer benefited from paclitaxel, regardless of estrogen-receptor status, but paclitaxel did not benefit patients with HER2-negative, estrogen-receptor–positive cancers. Conclusions: The expression or amplification, or both, of HER2 by a breast cancer is associated with a benefit from the addition of paclitaxel after adjuvant treatment with doxorubicin (<60 mg per square meter) plus cyclophosphamide in node-positive breast cancer, regardless of estrogen-receptor status. Patients with HER2-negative, estrogen-receptor–positive, node-positive breast cancer may gain little benefit from the administration of paclitaxel after adjuvant chemotherapy with doxorubicin plus cyclophosphamide. N Engl J Med 2007;357:1496-506. [ABSTRACT FROM AUTHOR]

Background: In women 70 years of age or older who have early breast cancer, it is unclear whether lumpectomy plus tamoxifen is as effective as lumpectomy followed by tamoxifen plus radiation therapy. Methods: Between July 1994 and February 1999, we randomly assigned 636 women who were 70 years of age or older and who had clinical stage I (T1N0M0 according to the tumor–node–metastasis classification), estrogen-receptor–positive breast carcinoma treated by lumpectomy to receive tamoxifen plus radiation therapy (317 women) or tamoxifen alone (319 women). Primary end points were the time to local or regional recurrence, the frequency of mastectomy for recurrence, breast-cancer–specific survival, the time to distant metastasis, and overall survival. Results: The only significant difference between the two groups was in the rate of local or regional recurrence at five years (1 percent in the group given tamoxifen plus irradiation and 4 percent in the group given tamoxifen alone, P<0.001). There were no significant differences between the two groups with regard to the rates of mastectomy for local recurrence, distant metastases, or five-year rates of overall survival (87 percent in the group given tamoxifen plus irradiation and 86 percent in the tamoxifen group, P=0.94). Assessment by physicians and patients of cosmetic results and adverse events uniformly rated tamoxifen plus irradiation inferior to tamoxifen alone. Conclusions: Lumpectomy plus adjuvant therapy with tamoxifen alone is a realistic choice for the treatment of women 70 years of age or older who have early, estrogen-receptor–positive breast cancer. N Engl J Med 2004;351:971-7. [ABSTRACT FROM AUTHOR]

Background: Risk-reducing salpingo-oophorectomy is often considered by carriers of BRCA mutations who have completed childbearing. However, there are limited data supporting the efficacy of this approach. We prospectively compared the effect of risk-reducing salpingo-oophorectomy with that of surveillance for ovarian cancer on the incidence of subsequent breast cancer and BRCA-related gynecologic cancers in women with BRCA mutations. Methods: All women with BRCA1 or BRCA2 mutations identified during a six-year period were offered enrollment in a prospective follow-up study. A total of 170 women 35 years of age or older who had not undergone bilateral oophorectomy chose to undergo either surveillance for ovarian cancer or risk-reducing salpingo-oophorectomy. Follow-up involved an annual questionnaire, telephone contact, and reviews of medical records. The time to cancer in the two groups was compared by Kaplan–Meier analysis and a Cox proportional-hazards model. Results: During a mean follow-up of 24.2 months, breast cancer was diagnosed in 3 of the 98 women who chose risk-reducing salpingo-oophorectomy and peritoneal cancer was diagnosed in 1 woman in this group. Among the 72 women who chose surveillance, breast cancer was diagnosed in 8, ovarian cancer in 4, and peritoneal cancer in 1. The time to breast cancer or BRCA-related gynecologic cancer was longer in the salpingo-oophorectomy group, with a hazard ratio for subsequent breast cancer or BRCA-related gynecologic cancer of 0.25 (95 percent confidence interval, 0.08 to 0.74). Conclusions: Salpingo-oophorectomy in carriers of BRCA mutations can decrease the risk of breast cancer and BRCA-related gynecologic cancer. (N Engl J Med 2002;346:1609-15.) [ABSTRACT FROM AUTHOR]