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. 2024 Jun 29;27(8):110425.
doi: 10.1016/j.isci.2024.110425. eCollection 2024 Aug 16.

Predictive gene expression profile for adjuvant taxane benefit in breast cancer in the MATADOR trial

Mark Opdam  1 , Annelot G J van Rossum  1 , Marlous Hoogstraat  2   3 , Gergana Bounova  2   3 , Hugo M Horlings  4 , Erik van Werkhoven  5 , Ingrid A M Mandjes  6 , A Elise van Leeuwen-Stok  7 , Sander Canisius  1   2 , Harm van Tinteren  5 , Alex L T Imholz  8 , Johanneke E A Portielje  9   10 , Monique E M M Bos  11 , Sandra Bakker  12 , Jelle Wesseling  1   4   13 , Lennart Kester  1   3 , Jacco van Rheenen  1   3 , Emiel J Rutgers  14 , Renee X de Menezes  15   16 , Lodewyk F A Wessels  2   3   17 , Marleen Kok  18   19 , Hendrika M Oosterkamp  20 , Sabine C Linn  1   19   21 ; MATADOR trialists’ group for the Dutch Breast Cancer Research Group (BOOG)
Collaborators, Affiliations

Predictive gene expression profile for adjuvant taxane benefit in breast cancer in the MATADOR trial

Mark Opdam et al. iScience. .

Abstract

The primary objective of the prospective, randomized, multicenter, phase 3 biomarker Microarray Analysis in breast cancer to Taylor Adjuvant Drugs Or Regimens trial (MATADOR: ISRCTN61893718) is to generate a gene expression profile that can predict benefit from either docetaxel, doxorubicin, and cyclophosphamide (TAC) or dose-dense scheduled doxorubicin and cyclophosphamide (ddAC). Patients with a pT1-3, pN0-3 tumor were randomized 1:1 between ddAC and TAC. The primary endpoint was a gene profile-treatment interaction for recurrence-free survival (RFS). We observed 117 RFS events in 664 patients with a median follow-up of 7 years. Hallmark gene set analyses showed significant association between enrichment in immune-related gene expression and favorable outcome after TAC in hormone receptor-negative, human epidermal growth factor receptor 2 (HER2)-negative breast cancer (BC) (triple-negative breast cancer [TNBC]). We validated this association in TNBC patients treated with TAC on H&E slides; stromal tumor-infiltrating lymphocytes (sTILs) ≥20% was associated with longer RFS (hazard ratio 0.18, p = 0.01), while in patients treated with ddAC no difference in RFS was seen (hazard ratio 0.92, p = 0.86, p interaction = 0.02).

Keywords: Cancer; Clinical genetics; Oncology.

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Conflict of interest statement

S.C.L. and H.M.O. received an institutional unrestricted research grant from Sanofi and Amgen to conduct the MATADOR study (ISRCTN61893718); H.M.O. received institutional research support funding from Roche; M.K. received institutional research support funding from Roche, BMS, and AZ; S.C.L. received institutional research support funding from Agendia, Amgen, AstraZeneca, Eurocept, Genentech, Immunomedics (now Gilead), Roche, Sanofi, and TESARO (now GSK). S.C.L. is an advisory board member for AstraZeneca for which the institute receives compensation, and for Cergentis (pro bono). S.C.L. receives funding for educational activities from Daiichi Sankyo, paid to the institute. H.M.O. is an advisory board member for Roche, Pfizer, and Novartis. M.K. is an advisory board member for AZ, BMS, Roche, MSD, and Daiichi for which the institute receives compensation.

Figures

None
Graphical abstract
Figure 1
Figure 1
Association between validation profile index score and recurrence-free survival (A–C) Profile obtained using a model with LASSO penalty on 496 patients with high quality of RNA reads (A). Low-profiled index score stratified for treatment (B). High-profile index score stratified for treatment (C). p value of the log rank test is shown.
Figure 2
Figure 2
Strength of associations of Hallmark gene sets with recurrence-free survival (A and B) Shown for all patients and split by treatment arm (A), and in triple-negative breast cancer only (B). The gene sets are ordered according to Goeman’s globaltest statistic, and p values are represented by the size of the black dot. Immune-related processes are depicted by a red dot. A, doxorubicin; C, cyclophosphamide; T, docetaxel; dd, dose-dense.
Figure 3
Figure 3
Recurrence-free survival stratified by treatment, shown for patients with low and high number of stromal tumor-infiltrating lymphocytes (sTILs) (A–D) Kaplan-Meier curve for clinical high-risk patients. Triple-negative breast cancer and sTILs abundance labeled as low (<20%; A) and high (≥20%; B). Test for interaction (p 0.02) is calculated in Table 3. Patients with hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative (HR+HER2−)tumors, low sTILs <10%: C), and high sTILs (≥10%; D). Test for interaction (p 0.16) is calculated in Table 4. Unadjusted cox proportional hazard ratio with a 95% confidence interval (CI) and corresponding p value is shown. A, doxorubicin; C, cyclophosphamide; T, docetaxel; dd, dose-dense.
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