136MO - Differential benefit of low-dose cyclophosphamide and methotrexate maintenance chemotherapy among TNBC subtypes in the context of the IBCSG 22-00 study

Background

Triple-negative breast cancer (TNBC) is a heterogeneous disease with at least five molecular subtypes characterized by distinct gene expression, genomic and tumor microenvironment (TME) profiles. The phase III adjuvant IBCSG 22-00 trial evaluating low-dose cyclophosphamide and methotrexate (CM) chemotherapy did not show a clinical benefit in unselected TNBC patients. Here, we aimed to explore whether specific TNBC molecular subtypes and TME features could predict benefit to low-dose CM maintenance chemotherapy in the IBCSG 22-00 study.

Methods

RNA sequencing was performed on a selection of 347 TNBC FFPE tumor samples matched in a 1:3 relapse cases and non-relapse controls ratio. TNBC subtypes were computed applying the methodology described by Bareche et al. and Burstein et al. GDSC database was used to analyze the resistance of methotrexate across TNBC cell lines.

Results

Immunomodulatory (IM) and basal-like/immune activated (BLIA) molecular subtypes showed a significant survival benefit when treated with low-dose CM compared to those who were not (DFS: HR = 0.5; 95% CI, 0.28 to 0.89; p interaction = 0.018 and HR = 0.49; 95% CI, 0.27 to 0.9; p interaction = 0.021). Of interest, high expression of regulatory T-cell immune signature was also associated with better prognosis in the CM arm highlighting the potential antitumor T-cell response of cyclophosphamide. In contrast, we observed worse outcome in mesenchymal (M) subtype when treated with low-dose CM (DFS: HR = 1.9; 95% CI, 1.2 to 3; p interaction = 0.0044) suggesting potential intrinsic resistance of M tumors with embryonic stem cell characteristics to methotrexate. These results were further substantiated in TNBC cell lines experiments where tumor cells with a mesenchymal phenotype showed resistance to methotrexate (t value = 2.22; p = 0.037).

Conclusions

Our results showed a differential benefit of low-dose CM maintenance therapy among TNBC subtypes highlighting a substantial TNBC heterogeneity regarding treatment response. Low-dose CM maintenance therapy could be considered as a potential immunomodulatory strategy for TNBC tumors with IM phenotype in the adjuvant setting. Further validation of these findings is warranted.

Clinical trial identification

NIH: NCT00022516 Release date: January 27, 2003.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Breast Cancer Research Foundation (BCRF).

Disclosure

M.A. Colleoni: Financial Interests, Personal, Research Grant: Roche; Financial Interests, Personal, Other, Co-Chair Scientific Committee IBCSG: IBCSG. S. Loi: Financial Interests, Institutional, Funding, Research: Novartis, BMS, Merck, Puma Biotechnology, Eli Lilly, Nektar Therapeutics, AstraZeneca, Roche-Genentech, Seattle Genetics; Non-Financial Interests, Other, Consultant: Seattle Genetics, Novartis, BMS, Merck, AstraZeneca, Eli Lilly, Pfizer, Gilead Therapeutics, Roche-Genentech; Financial Interests, Institutional, Other, Consultant: Aduro Biotech, Novartis, GlaxoSmithKline, Roche-Genentech, AstraZeneca, Silverback Therapeutics, G1 Therapeutics, Puma Biotechnology, Pfizer, Gilead Therapeutics, Daiichi Sankyo, Merck, Amunix, Tallac Therapeutics, Eli Lilly, BMS; Financial Interests, Personal, Other, Consultant: Seattle Genetics. G. Viale: Financial Interests, Personal, Other, Honoraria: MSD Oncology, Pfizer, Daiichi Sankyo Europe GmbH; Financial Interests, Personal, Advisory Role: Dako, Roche/Genentech, Novartis, Bayer, Daiichi Sankyo, MSD Oncology, Menarini; Financial Interests, Personal, Speaker’s Bureau: Roche/Genentech; Financial Interests, Personal, Funding: Roche/Genentech; Financial Interests, Institutional, Funding: Ventana Medical Systems, Dako/Agilent Technologies, Cepheid; Financial Interests, Personal, Other, Travel, Accomodations, Expenses: Roche. M.M. Regan: Financial Interests, Personal, Advisory Board, Also invited speaker: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board, Includes consulting.: Tolmar Pharmaceuticals; Financial Interests, Personal, Invited Speaker: WebMD; Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb, Bayer; Financial Interests, Institutional, Other, Director of IBCSG Statistical and Data Management Center for IBCSG investigator-initiated clinical trial supported by company: Novartis; Financial Interests, Institutional, Other, Director of IBCSG Statistical and Data Management Center for IBCSG investigator-initiated clinical trials supported by company: Pfizer, Ipsen, TerSera; Financial Interests, Institutional, Other, Director of IBCSG Statistical and Data Management Center for IBCSG investigator-initiated clinical trial drug supply from company: Roche; Financial Interests, Institutional, Other, Director of IBCSG Statistical and Data Management Center for IBCSG investigator-initiated clinical trials supported or drug supply from company: AstraZeneca; Financial Interests, Institutional, Other, Director of IBCSG Statistical and Data Management Center for IBCSG investigator-initiated clinical trials with funding from company: Debiopharm; Non-Financial Interests, Advisory Role: Bristol-Myers Squibb. C. Sotiriou: Financial Interests, Institutional, Advisory Board: Astellas, Vertex, Seattle Genetics, AMGEN, INC, Merck & Co; Financial Interests, Personal, Advisory Board: Cepheid, Puma; Financial Interests, Personal, Invited Speaker: Eisai, Prime oncology, Teva; Financial Interests, Institutional, Other, Travel: Roche; Financial Interests, Institutional, Other, Internal speaker: Genentech; Financial Interests, Personal, Other, Regional speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: Exact Sciences. All other authors have declared no conflicts of interest.