BACKGROUND Older women with breast cancer are underrepresented in clinical trials, and data on the effects of adjuvant chemotherapy in such patients are scant. We tested for the noninferiority of capecitabine as compared with standard chemotherapy in women with breast cancer who were 65 years of age or older. METHODS We randomly assigned patients with stage I, II, IIIA, or IIIB breast cancer to standard chemotherapy (either cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide plus doxorubicin) or capecitabine. Endocrine therapy was recommended after chemotherapy in patients with hormone-receptor–positive tumors. A Bayesian statistical design was used with a range in sample size from 600 to 1800 patients. The primary end point was relapse-free survival. RESULTS When the 600th patient was enrolled, the probability that, with longer follow-up, capecitabine therapy was highly likely to be inferior to standard chemotherapy met a prescribed level, and enrollment was discontinued. After an additional year of follow-up, the hazard ratio for disease recurrence or death in the capecitabine group was 2.09 (95% confidence interval, 1.38 to 3.17; P<0.001). Patients who were randomly assigned to capecitabine were twice as likely to have a relapse and almost twice as likely to die as patients who were randomly assigned to standard chemotherapy (P = 0.02). At 3 years, the rate of relapse-free survival was 68% in the capecitabine group versus 85% in the standard-chemotherapy group, and the overall survival rate was 86% versus 91%. Two patients in the capecitabine group died of treatment-related complications; as compared with patients receiving capecitabine, twice as many patients receiving standard chemotherapy had moderate-to-severe toxic effects (64% vs. 33%). CONCLUSIONS Standard adjuvant chemotherapy is superior to capecitabine in patients with early-stage breast cancer who are 65 years of age or older. (ClinicalTrials.gov number, NCT00024102.)

Aims A prospectively enrolled patient cohort was used to assess whether the prediction of CYP2D6 phenotype activity from genotype data could be improved by reclassification of diplotypes or alleles. Methods Three hundred and fifty‐five patients receiving tamoxifen 20 mg were genotyped for CYP2D6 and tamoxifen metabolite concentrations were measured. The endoxifen : N‐desmethly‐tamoxifen metabolic ratio, as a surrogate of CYP2D6 activity, was compared across four diplotypes (EM/IM, EM/PM, IM/IM, IM/PM) that are typically collapsed into an intermediate metabolizer (IM) phenotype. The relative metabolic activity of each allele type (UM, EM, IM, and PM) and each EM and IM allele was estimated for comparison with the activity scores typically assigned, 2, 1, 0.5 and 0, respectively. Results Each of the four IM diplotypes have distinct CYP2D6 activity from each other and from the EM and PM phenotype groups (each P < 0.05). Setting the activity of an EM allele at 1.0, the relative activities of a UM, IM and PM allele were 0.85, 0.67 and 0.52, respectively. The activity of the EM alleles were statistically different (P < 0.0001), with the CYP2D6*2 allele (scaled activity = 0.63) closer in activity to an IM than an EM allele. The activity of the IM alleles were also statistically different (P = 0.014). Conclusion The current systems for translating CYP2D6 genotype into phenotype are not optimally calibrated, particularly in regards to IM diplotypes and the *2 allele. Additional research is needed to improve the prediction of CYP2D6 activity from genetic data for individualized dosing of CYP2D6 dependent drugs.

PURPOSE Older women with breast cancer remain under-represented in clinical trials. The Cancer and Leukemia Group B 49907 trial focused on women age 65 years and older. We previously reported the primary analysis after a median follow-up of 2.4 years. Standard adjuvant chemotherapy showed significant improvements in recurrence-free survival (RFS) and overall survival compared with capecitabine. We now update results at a median follow-up of 11.4 years. PATIENTS AND METHODS Patients age 65 years or older with early breast cancer were randomly assigned to either standard adjuvant chemotherapy (physician’s choice of either cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide and doxorubicin) or capecitabine. An adaptive Bayesian design was used to determine sample size and test noninferiority of capecitabine. The primary end point was RFS. RESULTS The design stopped accrual with 633 patients at its first sample size assessment. RFS remains significantly longer for patients treated with standard chemotherapy. At 10 years, in patients treated with standard chemotherapy versus capecitabine, the RFS rates were 56% and 50%, respectively (hazard ratio [HR], 0.80; P = .03); breast cancer–specific survival rates were 88% and 82%, respectively (HR, 0.62; P = .03); and overall survival rates were 62% and 56%, respectively (HR, 0.84; P = .16). With longer follow-up, standard chemotherapy remains superior to capecitabine among hormone receptor–negative patients (HR, 0.66; P = .02), but not among hormone receptor–positive patients (HR, 0.89; P = .43). Overall, 43.9% of patients have died (13.1% from breast cancer, 16.4% from causes other than breast cancer, and 14.1% from unknown causes). Second nonbreast cancers occurred in 14.1% of patients. CONCLUSION With longer follow-up, RFS remains superior for standard adjuvant chemotherapy versus capecitabine, especially in patients with hormone receptor–negative disease. Competing risks in this older population dilute overall survival benefits.

Background. Polymorphic CYP2D6 is primarily responsible for metabolic activation of tamoxifen to endoxifen. We previously reported that by increasingthe daily tamoxifen dose to 40 mg/day in CYP2D6 intermediate metabolizer (IM), but not poor metabolizer (PM), patients achieve endoxifen concentrations similar to those of extensive metabolizer patients on 20 mg/day. We expanded enrollment to assess the safety of CYP2D6 genotypeguided dose escalation and investigate concentration differences between races. Methods. PM and IM breast cancer patients currently receiving tamoxifen at 20 mg/day were enrolled for genotype-guided escalation to 40 mg/day. Endoxifen was measured at baseline and after 4 months. Quality-of-life data were collected using the Functional Assessment of Cancer Therapy-Breast (FACT-B) and Breast Cancer Prevention Trial Menopausal Symptom Scale at baseline and after 4 months.

Functional decline was common in older women receiving adjuvant chemotherapy for breast cancer in a clinical trial. Although half recovered their physical function, one-third had a clinically meaningful decline at 12 months. Strategies are needed to prevent functional decline in older adults receiving chemotherapy.