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

ABSTRACT

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.

KEYWORDS:

• Breast cancer
• immunomodulation
• comedication
• pCR
• TILs

Author Contributions

Conceptualization, F.R. and L.Z; Experimentation and resources, S.Y., P.O., A.P., E. Marangoni, E.Montlaudon; Formal Analysis, A.-S. H., L. Derosa.; Data acquisition: M.P., J. G., D.d.C., M.L.; Data Curation; C.V., L.-S. T., L. Darrigues; Methodology, B.A., E.L.; Writing – Original Draft, A.-S. H., L. Derosa. F.R., and L.Z; Writing – Review & Editing, F.R., G.K. and L.Z; Supervision, F.R. and L.Z.; Funding Acquisition, F.R., and L.Z.

Acknowledgments

We are thankful to the animal facility team of Gustave Roussy and all the technicians form Center GF Leclerc. LZ and GK were supported by the Ligue contre le Cancer (équipe labelisée); Agence National de la Recherche (ANR) – Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Chancelerie des universités de Paris (Legs Poix), Fondation de France; Fondation pour la Recherche Médicale (FRM); a donation by Elior; the European Commission (ArtForce); the European Research Council (ERC); Fondation Carrefour; Institut National du Cancer (INCa); Inserm (HTE); Institut Universitaire de France; LeDucq Foundation; the LabEx Immuno-Oncology; the RHU Torino Lumière; the Swiss Bridge Foundation; the Seerave and Carrefour Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI).

Disclosure of Interest

LZ and GK are cofounders of EverImmune, a biotech company devoted to the use of commensal bacteria for the treatment of cancers.

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website.