Background and Method: The overexpression of the human epidermal growth factor receptor 2 (HER2) in breast cancer is correlated with accelerated tumor progression and an unfavorable clinical outcome. Since the introduction of trastuzumab in 2002, the treatment of HER2-positive breast cancer has been revolutionized, leading to significant improvements in survival. This retrospective, multicenter study aimed to describe the characteristics of patients with HER2-positive metastatic breast cancer (MBC) who maintained disease control for a minimum of three years after first-line therapy with trastuzumab and/or pertuzumab combined with chemotherapy. Results: Among 280 eligible patients, 48 (17.5%) were classified as long-term responders. The study population primarily consisted of women with a median age of 56.7 years at diagnosis; de novo metastatic presentation was observed in approximately 70% of cases. An objective response rate of nearly 90% was observed, with a median duration of response of 5.8 years. Median progression-free survival was 11.0 years [95% CI: 6.6—not reached], and median overall survival was not reached [95% CI: 10.9—not reached]. Furthermore, about 15% of patients were able to discontinue systemic therapy without immediate disease progression. Discussion and Conclusions: These findings indicate the potential of achieving prolonged disease control in a subset of patients with HER2-positive MBC, raising questions about therapeutic intensification and potential treatment discontinuation strategies. This study underscores the need for future research to identify predictive factors of durable response and assess the feasibility of adaptive treatment strategies, including planned treatment discontinuation.

Objectives: This study aimed to fill the data gap regarding the prevalence of germline (g) BRCA1/2 mutations in patients with metastatic breast cancer (mBC) in France. Methods: A prospective gBRCA1/BRCA2 mutation analysis was proposed to all patients with mBC treated in seven French centers between 19 February and 30 November 2015. The BRCA TrueTM test (Pathway Genomics^®, San Diego, CA, USA) analyzed the coding and flanking regions of BRCA1 and BRCA2 genes using next-generation sequencing, Sanger sequencing, and multiplex ligation-dependent probe amplification. Results: Among 407 included mBC patients, 11 (2.7%) carried pathogenic gBRCA1/2 mutations. Of these, five (45%) would not have met standard criteria for genetic screening. Compared with non-carriers, gBRCA1/2 carriers were significantly younger at mBC diagnosis (47.5 vs. 60.7 years, p = 0.0006), had higher-grade tumor histology (p = 0.044), and had a higher rate of contralateral recurrence (36.4% vs. 11.6%, p = 0.035), with comparable adjusted survival (median overall survival 74.9 vs. 100.1 months, p = 0.97). Variants of uncertain significance were identified in 17 (4.2%) patients. Conclusions: The 2.7% prevalence of gBRCA1/2 mutations in this prospective French mBC cohort was relatively low. Nearly half of the mutation carriers would not have been routinely referred for oncogenetic counseling, underscoring the potential value of broader genetic screening in this population.