Efficacy of Adjuvant Trastuzumab for Patients With Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer and Tumors ≤ 2 cm: A Meta-Analysis of the Randomized Trastuzumab Trials

Abstract

Purpose: We compared efficacy of trastuzumab versus no trastuzumab in patients with small (≤ 2 cm) human epidermal growth factor receptor 2 (HER2) -positive breast cancer treated in randomized trials.

Methods: A meta-analysis was conducted using data from five of the six adjuvant trastuzumab trials. Efficacy end points were disease-free survival (DFS) and overall survival (OS). Separate analyses were prospectively planned for hormone receptor (HR) -positive and HR-negative cohorts. Random effect models and Yusuf-Peto fixed effects models assessed the impact of heterogeneity on baseline hazards and treatment effects across studies. Peto-Pike cumulative incidence estimates were stratified by study and nodal status.

Results: Median follow-up time was 8 years. For 2,263 patients with HR-positive disease, 8-year cumulative incidence rates comparing trastuzumab versus no trastuzumab were 17.3% versus 24.3% (P < .001) for DFS and 7.8% versus 11.6% (P = .005) for OS, respectively; for 1,092 HR-positive patients with zero or one positive lymph nodes, results were 12.7% versus 19.4% (P = .005) for DFS and 5.3% versus 7.4% (P = .12) for OS, respectively. For 1,957 patients with HR-negative disease, 8-year cumulative incidence rates were 24.0% versus 33.4% (P < .001) for DFS and 12.4% versus 21.2% (P < .001) for OS, respectively; for 1,040 HR-negative patients with zero or one positive lymph nodes, results were 20.4% versus 26.3% (P = .05) for DFS and 8.2% versus 12.2% (P = .084) for OS, respectively.

Conclusion: Women with HER2-positive tumors ≤ 2 cm in the randomized trastuzumab trials derived substantial DFS and OS benefit from adjuvant trastuzumab. Trastuzumab-treated patients with HR-positive disease and ≤ one positive lymph node may be candidates for trials assessing less aggressive treatment approaches.

Trial registration: ClinicalTrials.gov NCT00004067 NCT00005970 NCT00045032 NCT00054587.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

© 2015 by American Society of Clinical Oncology.

Figures

Fig 1.

Patient characteristics by hormone receptor (HR) status. (A) HR-positive tumor categories; (B) HR-positive nodal status; (C) HR-negative tumor categories; (D) HR-negative nodal status. FinHER, Finland Herceptin Study; HERA, Herceptin Adjuvant Study; NSABP, National Surgical Adjuvant Breast and Bowel Project; PACS, Programme Adjuvant Cancer Sein.

Fig 2.

Disease-free survival for (A) hormone receptor (HR) –positive and (B) HR-negative disease treated with or without trastuzumab (Tras). FinHER, Finland Herceptin Study; HERA, Herceptin Adjuvant Study; NSABP, National Surgical Adjuvant Breast and Bowel Project; PACS, Programme Adjuvant Cancer Sein.

Fig 2.

Disease-free survival for (A) hormone receptor (HR) –positive and (B) HR-negative disease treated with or without trastuzumab (Tras). FinHER, Finland Herceptin Study; HERA, Herceptin Adjuvant Study; NSABP, National Surgical Adjuvant Breast and Bowel Project; PACS, Programme Adjuvant Cancer Sein.

Fig 3.

Cumulative incidence of a disease-free survival (DFS) event and death for patients with hormone receptor–positive disease and tumors ≤ 2 cm. (A) DFS event among all 2,263 patients; (B) overall survival (OS) event among all 2,263 patients; (C) DFS event among 1,092 patients with ≤ one positive lymph node; (D) OS event among 1,092 patients with ≤ one positive lymph node. Hazard ratios come from fixed effects model stratified by study.

Fig 4.

Cumulative incidence of a disease-free survival (DFS) event and death for patients with hormone receptor–negative disease and tumors ≤ 2 cm. (A) DFS event among all 1,957 patients; (B) overall survival (OS) event among all 1,957 patients; (C) DFS event among 1,040 patients with ≤ one positive lymph node; (D) OS event among 1,040 patients with ≤ one positive lymph node. The hazard ratio in panel A comes from the mixed effects model, which accounts for study-to-study heterogeneity, whereas the hazard ratios in panels B, C, and D come from the fixed effects model stratified by study.