Comedications influence immune infiltration and pathological response to neoadjuvant chemotherapy in breast cancer

• Main Authors: Anne-Sophie Hamy, Lisa Derosa, Constance Valdelièvre, Satoru Yonekura, Paule Opolon, Maël Priour, Julien Guerin, Jean-Yves Pierga, Bernard Asselain, Diane De Croze, Alice Pinheiro, Marick Lae, Laure-Sophie Talagrand, Enora Laas, Lauren Darrigues, Beatriz Grandal, Elisabetta Marangoni, Elodie Montaudon, Guido Kroemer, Laurence Zitvogel, Fabien Reyal
• Format: Article
• Language: English
• Published: Taylor & Francis Group 2020-01-01
• Series: OncoImmunology
• Subjects: breast cancer; immunomodulation; comedication; pcr; tils
• Online Access: http://dx.doi.org/10.1080/2162402X.2019.1677427

Immunosurveillance plays an important role in breast cancer (BC) prognosis and progression, and can be geared by immunogenic chemotherapy. In a cohort of 1023 BC patients treated with neoadjuvant chemotherapy (NAC), 40% of the individuals took comedications mostly linked to aging and comorbidities. We systematically analyzed the off-target effects of 1178 concurrent comedications (classified according to the Anatomical Therapeutic Chemical (ATC) Classification System) on the density of tumor-infiltrating lymphocytes (TILs) and pathological complete responses (pCR). At level 1 of the ATC system, the main anatomical classes of drugs were those targeting the nervous system (class N, 39.1%), cardiovascular disorders (class C, 26.6%), alimentary and metabolism (class A, 16.9%), or hormonal preparations (class H, 6.5%). At level 2, the most frequent therapeutic classes were psycholeptics (N05), analgesics (N02), and psychoanaleptics (N06). Pre-NAC TIL density in triple-negative BC (TNBC) was influenced by medications from class H, N, and A, while TIL density in HER2+ BC was associated with the use of class C. Psycholeptics (N05) and agents acting on the renin-angiotensin system (C09) were independently associated with pCR in the whole population of BC or TNBC, and in HER2-positive BC, respectively. Importantly, level 3 hypnotics (N05C) alone were able to reduce tumor growth in BC bearing mice and increased the anti-cancer activity of cyclophosphamide in a T cell-dependent manner. These findings prompt for further exploration of drugs interactions in cancer, and for prospective drug-repositioning strategies to improve the efficacy of NAC in BC.