Publikation
Integrated Molecular and Immune Phenotype of HER2-Positive Breast Cancer and Response to Neoadjuvant Therapy: A NeoALTTO Exploratory Analysis
Wissenschaftlicher Artikel/Review - 21.09.2021
Pizzamiglio Sara, Cappelletti Vera, Cinieri Saverio, Piccart Martine, Daidone Maria Grazia, Pruneri Giancarlo, Colombo Mario Paolo, Tagliabue Elda, Verderio Paolo, Huober Jens, Nuciforo Paolo, Izquierdo Miguel, Ciniselli Chiara Maura, Triulzi Tiziana, Gargiuli Chiara, De Cecco Loris, de Azambuja Evandro, Fumagalli Debora, Sotiriou Christos, Harbeck Nadia, Di Cosimo Serena
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PURPOSE
Little is known about the efficacy of HER2-targeted therapy in patients with breast cancer showing different HER2-pathway dependence and immune phenotypes. Herein, we report a NeoALTTO exploratory analysis evaluating the clinical value of 22 types of tumor-infiltrating immune cells by CIBERSORT and 5 immune-related metagenes in the overall patient population, and in subgroups defined by the TRAR classifier as HER2-addicted (TRAR-low) or not (TRAR-high).
PATIENTS AND METHODS
Association of baseline TRAR, immune-related metagenes, and CIBERSORT data with pathologic complete response (pCR) and event-free survival (EFS) were assessed using logistic and Cox regression models. Corrections for multiple testing were performed by the Bonferroni method.
RESULTS
A total of 226 patients were analyzed: 80 (35%) achieved a pCR, and 64 (28%) experienced a relapse with a median follow-up of 6.7 (interquartile range 6.1-6.8) years; 108 cases were classified as TRAR-low, and 118 TRAR-high. Overall, γδ T-cell fraction [OR = 2.69; 95% confidence interval (CI), 1.40-5.18], and no immune-related metagenes were predictive of pCR. Notably, lymphocyte-specific kinase (LCK) predicted pCR to combination (OR = 2.53; 95% CI, 1.12-5.69), but not to single-agent trastuzumab or lapatinib [OR = 0.74; 95% CI, 0.45-1.22 ( = 0.01)]. Integrating LCK with γδ T cells in a multivariate model added to the discriminatory capability of clinical and molecular variables with a shift in AUC from 0.80 (95% CI, 0.74-0.86) to 0.83 (95% CI, 0.78-0.89). In TRAR-low cases, activated mast cells, IFN and MHCII were reduced, and STAT1, HCK1, and γδ T cells were associated with pCR. STAT1 was broadly associated with improved EFS regardless of pCR, and nodal status in overall (HR = 0.68; 95% CI, 0.49-0.94) and in TRAR-low cases (HR = 0.50; 95% CI, 0.30-0.86).
CONCLUSIONS
Immuno-phenotyping holds the promise to complement current predictive models in HER2-positive breast cancer and to assist in new therapeutic development.