BACKGROUND Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who have disease progression after therapy with multiple HER2-targeted agents have limited treatment options. Tucatinib is an investigational, oral, highly selective inhibitor of the HER2 tyrosine kinase. METHODS We randomly assigned patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine, who had or did not have brain metastases, to receive either tucatinib or placebo, in combination with trastuzumab and capecitabine. The primary end point was progression-free survival among the first 480 patients who underwent randomization. Secondary end points, assessed in the total population (612 patients), included overall survival, progression-free survival among patients with brain metastases, confirmed objective response rate, and safety. RESULTS Progression-free survival at 1 year was 33.1% in the tucatinib-combination group and 12.3% in the placebo-combination group (hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.42 to 0.71; P<0.001), and the median duration of progression-free survival was 7.8 months and 5.6 months, respectively. Overall survival at 2 years was 44.9% in the tucatinib-combination group and 26.6% in the placebocombination group (hazard ratio for death, 0.66; 95% CI, 0.50 to 0.88; P = 0.005), and the median overall survival was 21.9 months and 17.4 months, respectively. Among the patients with brain metastases, progression-free survival at 1 year was 24.9% in the tucatinib-combination group and 0% in the placebo-combination group (hazard ratio, 0.48; 95% CI, 0.34 to 0.69; P<0.001), and the median progression-free survival was 7.6 months and 5.4 months, respectively. Common adverse events in the tucatinib group included diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, fatigue, and vomiting. Diarrhea and elevated aminotransferase levels of grade 3 or higher were more common in the tucatinib-combination group than in the placebo-combination group. CONCLUSIONS In heavily pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, adding tucatinib to trastuzumab and capecitabine resulted in better progression-free survival and overall survival outcomes than adding placebo; the risks of diarrhea and elevated aminotransferase levels were higher with tucatinib.

This large-scale genomic analysis illustrates that breast cancer arising in young women is a unique biologic entity driven by unifying oncogenic signaling pathways, is characterized by less hormone sensitivity and higher HER-2/EGFR expression, and warrants further study to offer this poor-prognosis group of women better preventative and therapeutic options.

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Approximately 7% of women with breast cancer are diagnosed before the age of 40 years, and this disease accounts for more than 40% of all cancer in women in this age group. Survival rates are worse when compared to those in older women, and multivariate analysis has shown younger age to be an independent predictor of adverse outcome. Inherited syndromes, specifically BRCA1 and BRCA2, must be considered when developing treatment algorithms for younger women. Chemotherapy, endocrine, and local therapies have the potential to significantly impact both the physiologic health -including future fertility, premature menopause, and bone health-and the psychological health of young women as they face a diagnosis of breast cancer.Although a diagnosis of breast cancer is distressing at any age, this occurrence in young women is fraught with several unique challenges. This article reviews the distinct epidemiology, etiology, clinicopathologic characteristics, biology, treatment strategies, outcomes, and psychosocial challenges of breast cancer before 40 years of age. Also included in this review are issues of familial breast cancer, fertility, premature menopause, breast cancer during pregnancy, and bone health. The US Surveillance, Epidemiology and End Results (SEER) database was the source of data for the tables and graphs presented here. 1 EpidemiologyThe American Cancer Society (ACS) estimates that 182,460 women in the United States were diagnosed with breast cancer in 2008 and that 40,480 women died of the disease during the year. 2 The incidence of breast cancer appears to have a sigmoid function in women less than 55 years of age (Figure 1, lower panel), with 6.6% of all cases diagnosed before age 40, 2.4% diagnosed before age 35, and 1% diagnosed before age 30 (Figure 2, inset). The individual average risk of a woman developing breast cancer was 1 in 173 by the age of 40 and approximately 1 in 1,500 by the age of 30 (Table 1). Of all cancers diagnosed among women, more than 40% is breast cancer by the age of 40, 20% by the age of 30, and slightly more than 2% by 20 years of age (Figure 1, upper panel).