Postmastectomy radiation therapy in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer: a retrospective exploratory cohort analysis of the adjuvant lapatinib and/or trastuzumab treatment optimization (ALTTO) trial [BIG 2-06/NCCTG N063D (Alliance)].

Background: Postmastectomy radiation therapy (PMRT) improves locoregional control and survival in patients with early breast cancer, but it is unclear whether these benefits extend to human epidermal growth factor receptor 2 (HER2)-positive patients in the anti-HER2 era. Methods: This was a retrospective cohort analysis of prospectively collected data from the phase III ALTTO trial and includes all ALTTO participants who underwent mastectomy regardless of randomisation arm. The phase III ALTTO trial enrolled patients between 2007 and 2011 from 946 centers from 44 countries in four different continents. Eligible patients had histologically confirmed HER2-positive breast cancer with either node-positive disease or node-negative disease with pathologic tumour size ≥1 cm. PMRT was non-randomised and delivered at the investigator's discretion. Primary efficacy analyses were conducted in the intention-to-treat population; safety analyses included all patients who received at least 1 dose of anti-HER2 therapy. Endpoints were locoregional recurrence (LRR), distant recurrence (TTDR), disease-free (DFS), and overall survival (OS). DFS and OS were analysed using Cox models; LRR and TTDR competing risk models. All models included the interaction between number of metastatic nodes, 0 (pN0), 1-3 (pN1) or ≥4 (pN2) and PMRT. Multivariable models accounted for patient and tumour characteristics. Hazard ratios (HR) and their 95% confidence interval (CI) are reported. Findings: Overall, 4154 patients treated with mastectomy were analysed: 1987 (47.8%) with and 2167 (52.2%) without PMRT. Baseline characteristics were worse in the PMRT group, whereas adjuvant endocrine and chemotherapy use/type was similar between groups. At a median follow-up of 9.2 years (IQR, 6.4-10), 129 LRR events occurred: 43 (2.2%) in the PMRT group and 86 (4.0%) in the no-PMRT group. In patients with pN2, PMRT was associated with improved LRR control (HR 0.31; 95% CI 0.16-0.59), TTDR (HR 0.59; 95% CI 0.44-0.79), DFS (HR 0.58; 95% CI 0.45-0.75), and OS (HR 0.61; 95% CI 0.44-0.86). In patients with pN1, PMRT showed marginal benefit in DFS (HR 0.82; 95% CI 0.64-1.05) but not in LRR (HR not calculated), TTDR (HR 0.89; 95% CI 0.65-1.23), nor OS (HR 0.88; 95% CI 0.62-1.24). Only 229 (15%) patients with pN0 received PMRT, with no evidence of benefit in any endpoints. Interpretation: In this large HER2-positive, predominantly node-positive, adjuvant cohort, PMRT improved locoregional control and conferred a clinically meaningful survival benefit in pN2. In the landscape of personalized treatment and growing interest in axillary de-escalation, future prospective studies are warranted to better define which HER2-positive patients with low nodal burden (particularly pN1 disease) derive meaningful benefit from PMRT in the context of modern systemic therapy. Funding: The publication of this analysis was funded by the Italian Ministry of Health through Ricerca Corrente funds.