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.

中文翻译：

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喜剧药物影响乳腺癌对新辅助化疗的免疫浸润和病理反应。

免疫监测在乳腺癌（BC）的预后和进展中起着重要作用，并且可以通过免疫原性化学疗法进行调节。在队列为1023 BC的新辅助化疗（NAC）患者中，有40％的人接受了大多数与衰老和合并症相关的药物治疗。我们系统地分析了1178例并行治疗（根据解剖治疗化学（ATC）分类系统进行的分类）对肿瘤浸润淋巴细胞（TILs）密度和病理完全反应（pCR）的脱靶效应。在ATC系统的第1级，主要的解剖类药物是针对神经系统的药物（N类，占39.1％），心血管疾病（C类，占26.6％），饮食和代谢（A类，占16.9％）或荷尔蒙制剂（H级，6.5％）。在第2级 最常见的治疗类别是精神抑制药（N05），止痛药（N02）和精神镇痛药（N06）。三阴性BC（TNBC）的NAC前TIL密度受H，N和A类药物的影响，而HER2 + BC中的TIL密度与C类药物的使用有关。肾素-血管紧张素系统（C09）在整个BC或TNBC人群以及HER2阳性BC人群中均与pCR独立相关。重要的是，仅3级催眠药（N05C）就能减少BC小鼠的肿瘤生长，并以T细胞依赖性方式增强环磷酰胺的抗癌活性。这些发现促进了对癌症中药物相互作用的进一步探索，并为改善NAC在卑诗省的疗效提供了前瞻性的药物重新定位策略。