Van Poznak, Catherine

PURPOSE Long-term outcomes of patients with stage I human epidermal growth factor receptor 2 (HER2)–positive breast cancer receiving adjuvant trastuzumab emtansine (T-DM1) remain undefined, and prognostic predictors represent an unmet need. METHODS In the ATEMPT phase II trial, patients with stage I centrally confirmed HER2-positive breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for 1 year or paclitaxel plus trastuzumab (TH). Coprimary objectives were to compare the incidence of clinically relevant toxicities between arms and to evaluate invasive disease-free survival (iDFS) with T-DM1. Correlative analyses included the HER2DX genomic tool, multiomic evaluations of HER2 heterogeneity, and predictors of thrombocytopenia. RESULTS After a median follow-up of 5.8 years, 11 iDFS events were observed in the T-DM1 arm, consistent with a 5-year iDFS of 97.0% (95% CI, 95.2 to 98.7). At 5 years, the recurrence-free interval (RFI) was 98.3% (95% CI, 97.0 to 99.7), the overall survival was 97.8% (95% CI, 96.3 to 99.3), and the breast cancer-specific survival was 99.4% (95% CI, 98.6 to 100). Comparable iDFS was observed with T-DM1 irrespective of tumor size, hormone receptor status, centrally determined HER2 immunohistochemical score, and receipt of T-DM1 for more or less than 6 months. Although ATEMPT was not powered for this end point, the 5-year iDFS in the TH arm was 91.1%. Among patients with sufficient tissue for HER2DX testing (n = 187), 5-year outcomes significantly differed according to HER2DX risk score, with better RFI (98.1% v 81.8%, hazard ratio [HR], 0.10, P = .01) and iDFS (96.3% v 81.8%, HR, 0.20, P = .047) among patients with HER2DX low-risk versus high-risk tumors, respectively. CONCLUSION Adjuvant T-DM1 for 1 year leads to outstanding long-term outcomes for patients with stage I HER2-positive breast cancer. A high HER2DX risk score predicted a higher risk of recurrence in ATEMPT.

Abstract Introduction Prospective data about quality of life (QoL) in men with breast cancer (BC) are lacking. A prospective registry (EORTC10085) of men with all BC stages, including a QoL correlative study, was performed as part of the International Male Breast Cancer Program. Methods Questionnaires at BC diagnosis included the EORTC QLQ-C30 and BR23 (BC specific module), adapted for men. High functioning and global health/QoL scores indicate high functioning levels/high QoL; high symptom-focused measures scores indicate high symptoms/problems levels. EORTC reference data for healthy men and women with BC were used for comparisons. Results Of 422 men consenting to participate, 363 were evaluable. Median age was 67 years, and median time between diagnosis and survey was 1.1 months. A total of 114 men (45%) had node-positive early disease, and 28 (8%) had advanced disease. Baseline mean global health status score was 73 (SD: 21), better than in female BC reference data (62, SD: 25). Common symptoms in male BC were fatigue (22, SD: 24), insomnia (21, SD: 28), and pain (16, SD: 23), for which women’s mean scores indicated more burdensome symptoms at 33 (SD: 26), 30 (SD: 32), and 29 (SD: 29). Men’s mean sexual activity score was 31 (SD: 26), with less sexual activity in older patients or advanced disease. Conclusions QoL and symptom burden in male BC patients appears no worse (and possibly better) than that in female patients. Future analyses on impact of treatment on symptoms and QoL over time, may support tailoring of male BC management.

Abstract Background Hypercalcemia of malignancy (HCM) is the most common metabolic complication of malignancies, but its incidence may be declining due to potent chemotherapeutic agents. The high mortality associated with HCM has declined markedly due to the introduction of increasingly effective chemotherapeutic drugs. Despite the widespread availability of efficacious medications to treat HCM, evidence-based recommendations to manage this debilitating condition are lacking. Objective To develop guidelines for the treatment of adults with HCM. Methods A multidisciplinary panel of clinical experts, together with experts in systematic literature review, identified and prioritized 8 clinical questions related to the treatment of HCM in adult patients. The systematic reviews (SRs) queried electronic databases for studies relevant to the selected questions. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make recommendations. An independent SR was conducted in parallel to assess patients' and physicians' values and preferences, costs, resources needed, acceptability, feasibility, equity, and other domains relevant to the Evidence-to-Decision framework as well as to enable judgements and recommendations. Results The panel recommends (strong recommendation) in adults with HCM treatment with denosumab (Dmab) or an intravenous (IV) bisphosphonate (BP). The following recommendations were based on low certainty of the evidence. The panel suggests (conditional recommendation) (1) in adults with HCM, the use of Dmab rather than an IV BP; (2) in adults with severe HCM, a combination of calcitonin and an IV BP or Dmab therapy as initial treatment; and (3) in adults with refractory/recurrent HCM despite treatment with BP, the use of Dmab. The panel suggests (conditional recommendation) the addition of an IV BP or Dmab in adult patients with hypercalcemia due to tumors associated with high calcitriol levels who are already receiving glucocorticoid therapy but continue to have severe or symptomatic HCM. The panel suggests (conditional recommendation) in adult patients with hypercalcemia due to parathyroid carcinoma, treatment with either a calcimimetic or an antiresorptive (IV BP or Dmab). The panel judges the treatments as probably accessible and feasible for most recommendations but noted variability in costs, resources required, and their impact on equity. Conclusions The panel's recommendations are based on currently available evidence considering the most important outcomes in HCM to patients and key stakeholders. Treatment of the primary malignancy is instrumental for controlling hypercalcemia and preventing its recurrence. The recommendations provide a framework for the medical management of adults with HCM and incorporate important decisional and contextual factors. The guidelines underscore current knowledge gaps that can be used to establish future research agendas.

PURPOSE The ATEMPT trial was designed to determine if treatment with trastuzumab emtansine (T-DM1) caused less toxicity than paclitaxel plus trastuzumab (TH) and yielded clinically acceptable invasive disease-free survival (iDFS) among patients with stage I human epidermal growth factor receptor 2–positive (HER2+) breast cancer (BC). METHODS Patients with stage I centrally confirmed HER2+ BC were randomly assigned 3:1 to T-DM1 or TH and received T-DM1 3.6 mg/kg IV every 3 weeks for 17 cycles or T 80 mg/m 2 IV with H once every week × 12 weeks (4 mg/kg load →2 mg/kg), followed by H × 39 weeks (6 mg/kg once every 3 weeks). The co-primary objectives were to compare the incidence of clinically relevant toxicities (CRTs) in patients treated with T-DM1 versus TH and to evaluate iDFS in patients receiving T-DM1. RESULTS The analysis population includes all 497 patients who initiated protocol therapy (383 T-DM1 and 114 TH). CRTs were experienced by 46% of patients on T-DM1 and 47% of patients on TH ( P = .83). The 3-year iDFS for T-DM1 was 97.8% (95% CI, 96.3 to 99.3), which rejected the null hypothesis ( P < .0001). Serially collected patient-reported outcomes indicated that patients treated with T-DM1 had less neuropathy and alopecia and better work productivity compared with patients on TH. CONCLUSION Among patients with stage I HER2+ BC, one year of adjuvant T-DM1 was associated with excellent 3-year iDFS, but was not associated with fewer CRT compared with TH.