Efficacy and Safety of Trastuzumab Emtansine Plus Capecitabine vs Trastuzumab Emtansine Alone in Patients With Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer A Phase 1 and Randomized Phase 2 Trial

Importance: ERBB2 (HER2)-targeted therapy provides benefits in metastatic breast cancer (mBC) and gastric cancer, but additional treatments are needed to maximize efficacy and quality of life. Objective: To determine maximum tolerated doses (MTDs) of trastuzumab emtansine (T-DM1) plus capecitabine in patients with previously treated ERBB2-positive mBC and locally advanced/metastatic gastric cancer (LA/mGC) (phase 1) and the efficacy and safety of this combination vs T-DM1 alone in patients with mBC (phase 2). Design, setting, and participants: The MTD in phase 1 was assessed using a 3 + 3 design with capecitabine dose modification. Phase 2 was an open-label, randomized, international multicenter study of patients with mBC treated with T-DM1 plus capecitabine or T-DM1 alone. Eligible patients had previously treated ERBB2-positive mBC or LA/mGC with no prior chemotherapy treatment for advanced disease. Interventions: Patients in the phase 1 mBC cohort received capecitabine (750 mg/m2, 700 mg/m2, or 650 mg/m2 twice daily, days 1-14 of a 3-week cycle) plus T-DM1 3.6 mg/kg every 3 weeks. Patients with LA/mGC received capecitabine at the mBC phase 1 MTD, de-escalating as needed, plus T-DM1 2.4 mg/kg weekly. In phase 2, patients with mBC were randomized (1:1) to receive capecitabine (at the phase 1 MTD) plus T-DM1 or T-DM1 alone. Main outcomes and measures: The phase 1 primary objective was to identify the MTD of capecitabine plus T-DM1. The phase 2 primary outcome was investigator-assessed overall response rate (ORR). Results: In phase 1, the median (range) age was 54.0 (37-71) and 57.5 (53-70) years for patients with mBC and patients with LA/mGC, respectively. The capecitabine MTD was identified as 700 mg/m2 in 11 patients with mBC and 6 patients with LA/mGC evaluable for dose-limiting toxic effects. In phase 2, between October 2014 and April 2016, patients with mBC (median [range] age, 52.0 [28-80] years) were randomized to receive combination therapy (n = 81) or T-DM1 (n = 80). The ORR was 44% (36 of 81 patients) and 36% (29 of 80 patients) in the combination and T-DM1 groups, respectively (difference, 8.2%; 90% CI, -4.5 to 20.9; P = .34; clinical cutoff, May 31, 2017). Adverse events (AEs) were reported in 78 of 82 patients (95%) in the combination group, with 36 (44%) experiencing grade 3-4 AEs, and 69 of 78 patients (88%) in the T-DM1 group, with 32 (41%) experiencing grade 3-4 AEs. No grade 5 AEs were reported. Conclusions and relevance: Adding capecitabine to T-DM1 did not statistically increase ORR associated with T-DM1 in patients with previously treated ERBB2-positive mBC. The combination group reported more AEs, but with no unexpected toxic effects

Increased mortality risk associated with medial breast tumors may be due to untreated internal mammary node metastases

Recent reports suggest that medial breast tumors are independently associated with decreased disease-free and overall survival compared with lateral breast tumors. Surgical evidence indicates that medial tumors with positive axillary nodes have an increased rate of internal mammary node (IMN) metastases. It is hypothesized that IMN disease that does not receive local therapy (surgery or radiotherapy) may be a reservoir for eventual systemic spread, and may account for the increased recurrence and death rates associated with medial tumors. Although early trials are divided as to the benefit of local IMN therapy, they were conducted largely in the absence of adjuvant systemic therapy. Are there reliable methods to assess IMN status, and does IMN irradiation significantly reduce the excess risk of medial tumors in women who receive today's "standard" adjuvant systemic therapy?SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Do we have good surrogate endpoints for survival in breast cancer studies?

SCOPUS: cp.jinfo:eu-repo/semantics/publishe

Standard medical treatment for early breast cancer

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Classic Chemotherapy Papers in Classic Papers in Breast Disease

Editors :Baum, M. and Henderson, C.info:eu-repo/semantics/published

An overview of HER2

SCOPUS: re.jinfo:eu-repo/semantics/publishe

Classic Chemotherapy Papers in Classic Papers in Breast Disease

Editors :Baum, M. and Henderson, C.info:eu-repo/semantics/published

Landmark adjuvant randomized clinical trials of systemic therapy in early breast cancer

SCOPUS: re.jinfo:eu-repo/semantics/publishe