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Background The mammalian target of rapamycin (mTOR) pathway is a driver of breast tumorigenesis. The mTOR inhibitor everolimus reverses antihormonal therapy resistance and is an approved therapy for metastatic breast cancer. A synergistic effect with fluoropyrimidine has been suggested. The present study evaluated the safety and tolerability of an all-oral combination of everolimus and capecitabine for metastatic breast cancer (MBC). Patients and Methods MBC patients naive to capecitabine and mTOR inhibitors who had received ≤ 3 previous chemotherapy regimens in the metastatic setting were eligible for the present study. The patients were scheduled to receive capecitabine 825 mg/m 2 twice daily for 14 days in a 21-day cycle, combined with everolimus in 5 separate dose cohorts: 2.5 mg every other day, 2.5 mg daily, 5 mg daily, 7.5 mg daily, and 10 mg daily. A 3+3 design was used. The maximum tolerated dose was based on the dose-limiting toxicity of everolimus plus capecitabine. Results A total of 18 patients were enrolled in the present trial. The median age was 58 years. Most had received previous anthracycline (83%) and taxane (94%) therapy. The maximum tolerated dose was everolimus 7.5 mg daily and capecitabine 825 mg/m 2 . The incidence of grade 3 events was low and mainly hematologic in nature. One incident each of grade 4 neutropenia, thrombocytopenia, hyperglycemia, and mucositis occurred. No grade 5 events occurred. The clinical benefit rate was 50%. The median progression-free survival was 196 days, and the median overall survival was 569 days. Conclusion The all-oral regimen of everolimus with capecitabine is active and well tolerated, with encouraging results for progression-free survival, overall survival, and clinical benefit rate in patients with MBC.

The mammalian target of rapamycin (mTOR) pathway is a driver of breast tumorigenesis. The mTOR inhibitor everolimus reverses antihormonal therapy resistance and is an approved therapy for metastatic breast cancer. A synergistic effect with fluoropyrimidine has been suggested. The present study evaluated the safety and tolerability of an all-oral combination of everolimus and capecitabine for metastatic breast cancer (MBC).MBC patients naive to capecitabine and mTOR inhibitors who had received ≤ 3 previous chemotherapy regimens in the metastatic setting were eligible for the present study. The patients were scheduled to receive capecitabine 825 mg/mA total of 18 patients were enrolled in the present trial. The median age was 58 years. Most had received previous anthracycline (83%) and taxane (94%) therapy. The maximum tolerated dose was everolimus 7.5 mg daily and capecitabine 825 mg/mThe all-oral regimen of everolimus with capecitabine is active and well tolerated, with encouraging results for progression-free survival, overall survival, and clinical benefit rate in patients with MBC.

BACKGROUND Although BRCA1 and BRCA2 were identified in 1994 and 1995, respectively, to the authors' knowledge the optimal management of women with BRCA-associated breast carcinoma remains incompletely defined. The current study evaluates the appropriateness of breast-conserving therapy (BCT) in women with BRCA mutations. METHODS Between May 1992 and October 2003, 87 female participants in genetic testing protocols were identified who 1) were found to have deleterious germline BRCA mutations and 2) reported a history of invasive breast carcinoma that was treated with wide local excision and radiation therapy. Clinical records were reviewed and follow-up was updated. RESULTS The 87 subjects underwent BCT for 95 invasive breast tumors (8 women received BCT for metachronous bilateral tumors). In all 95 treated breasts, the 5-year and 10-year probabilities of metachronous ipsilateral breast carcinoma (MIBC) were 11.2% and 13.6%, respectively. Among the 87 subjects, the 5-year and 10-year probabilities of metachronous contralateral breast carcinoma (CBC) after treatment of the index tumor were 11.9% and 37.6%. No clinical factors were identified that were associated with either MIBC or CBC, including the use of tamoxifen or chemotherapy. CONCLUSIONS Women with BRCA-associated breast carcinoma who undergo BCT appear to have risks of MIBC that are similar to those reported for young women without known mutations. The indications for unilateral mastectomy in this group of women should be the same as those for women with nonhereditary carcinoma. However, significant risks of CBC and possibly late MIBC may prompt the serious consideration of bilateral mastectomy as a preventive measure. Cancer 2005. © 2004 American Cancer Society.