Dose-dense adjuvant chemotherapy in patients with HER2-low early breast cancer: An exploratory analysis of the GIM2 trial.
Authors: Chiara Molinelli, Virginia Delucchi, Eva Blondeaux, Luca Boni, Francesca Poggio, Grazia Arpino, Cecilia Nisticò, Alessandra Fabi, Michelino De Laurentiis, Fabio Puglisi, Guilherme Nader Marta, Alessandra Fozza, Francesca Pitto, Matteo Lambertini, Lucia Del Mastro
Journal: Journal of Clinical Oncology (2024)

532 Background: Dose-dense (DD) adjuvant chemotherapy represents the standard treatment for patients with node-positive early-stage HER2-negative breast cancer, but its role in HER2-low disease is unknown. In this exploratory analysis of the Gruppo Italiano Mammella 2 (GIM2) trial, we investigated efficacy of DD chemotherapy among patients affected by HER2-negative breast cancer according to HER2 immunohistochemistry (IHC) score (low vs. zero). Methods: Patients with node-positive early breast cancer were randomly assigned to receive either DD or standard schedule anthracycline- and taxane-based chemotherapy. HER2 status was assessed locally. Tumours with HER2 score 0 were classified as HER2-zero, while those with a HER2 score 1+ or 2+ without fluorescence in situ hybridization (FISH) amplification were defined as HER2-low. Some tumours were classified as HER2-negative with unknown IHC score. Survival outcomes were compared between patients with HER2-zero vs HER2-low tumours. Results: Among 2003 patients enrolled in the GIM2 trial, 1243 subjects were eligible for this analysis. Median age was 52 years (interquartile range [IQR] 44-59) and 604 patients (48.6%) were pre-menopausal. Hormone receptor status was positive in 87.9% of cancers. 475 tumours were classified as HER2-zero (38.2%), 446 (35.9%) were defined HER2-low and 322 (25.9%) were HER2-negative with unknown IHC score. No significant differences were found in terms of baseline characteristics between these three subgroups. At a median follow-up of 14.9 years (IQR 8.4-16.2), no significant interaction was observed between treatment effect and HER2 status in invasive disease-free survival (iDFS) (p for interaction=0.46) nor in overall survival (OS) (p for interaction=0.43). Comparing patients with HER2-zero breast cancer with those affected by HER2-low tumours, no significant differences in iDFS were observed (15yr iDFS were 61% vs. 54%, respectively, p=0.25), nor OS differences (15yr OS were 75% vs. 72%, respectively, p=0.19). When investigating DD schedule efficacy among patients with HER2-zero tumours, hazard ratio (HR) for iDFS was 0.64 (95% confidence interval [CI] 0.46-0.87) and HR for OS was 0.57 (95%CI 0.38-0.88). Similarly, within patients affected by HER2-low breast cancer, HR was 0.83 (95%CI 0.62-1.11) for iDFS and 0.83 (95%CI 0.57-1.22) for OS. These results were consistent with the findings of efficacy of DD chemotherapy in the overall population included in this analysis (HR for iDFS 0.73 [95%CI 0.61-0.89]; HR for OS 0.69 [95%CI 0.54-0.88]). Conclusions: In this exploratory analysis of a large phase III adjuvant trial, HER2 status (i.e. HER2-zero vs HER2low) did not show prognostic value. In patients with high-risk early breast cancer, the benefit of DD chemotherapy was observed irrespective of HER2 status. Clinical trial information: NCT00433420 .