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Clinical Trial
. 2025 Sep 2;31(17):3715-3724.
doi: 10.1158/1078-0432.CCR-25-0338.

FOXC1 Expression Predicts Capecitabine Efficacy in Patients with Triple-Negative Breast Cancer from the GEICAM_CIBOMA Trial

Federico Rojo  1   2 , Clive R Taylor  3 , Carlos Barrios  4   5 , Laura Torrecillas  4   6 , Manuel Ruiz-Borrego  1   7 , Sandra Perez-Buira  2 , Jose Bines  4   8 , Angel Guerrero-Zotano  1   9 , Jose A Garcia-Saenz  1   10 , Roberto Torres  4   11 , Juan de la Haba-Rodriguez  1   12   13 , Francisco Ayala  1   14   15 , Henry Gomez  4   16   17 , Antonio Llombart  1   18 , Maria Rodriguez de la Borbolla  1   19 , Jose Manuel Baena-Cañada  1   20 , Agusti Barnadas  1   21 , Lourdes Calvo  1   22 , Jesus Herranz  1 , Raul Rincon  1 , Rosalia Caballero  1 , Begoña Bermejo  1   13   23 , Partha S Ray  3 , Miguel Martin  1   13   15   24 ; GEICAM_CIBOMA Clinical Trial Group
Affiliations
Clinical Trial

FOXC1 Expression Predicts Capecitabine Efficacy in Patients with Triple-Negative Breast Cancer from the GEICAM_CIBOMA Trial

Federico Rojo et al. Clin Cancer Res. .

Abstract

Purpose: In a prespecified GEICAM_CIBOMA trial (NCT00130533) correlative analysis, PAM50 non-basal-like breast cancer (non-BLBC) status distinguished patients with triple-negative breast cancer (TNBC) who are most likely to benefit from adjuvant capecitabine. The standardized forkhead box C1 (FOXC1) IHC test has demonstrated strong reliability in classifying the BLBC subtype throughout TNBC cohorts. This translational analysis aimed to evaluate the prognostic/predictive significance of BLBC classification by FOXC1 IHC in the phase III GEICAM_CIBOMA clinical trial.

Experimental design: Tumor tissues from patients with TNBC randomized to standard (neo)adjuvant chemotherapy followed by capecitabine versus observation were analyzed using the standardized FOXC1 IHC test to assess its BLBC/non-BLBC TNBC subtyping capacity as a distant relapse-free survival clinical outcome predictor of capecitabine benefit (exploratory endpoints: disease-free survival, overall survival, and recurrence-free survival).

Results: A total of 705 (80.5%) patients from the GEICAM_CIBOMA trial were evaluable for FOXC1 expression analysis, with balanced distribution between the trial's treatments. FOXC1 proportion/intensity (VFOXC1) score-based subtyping demonstrated a strong association [AUC = 0.87; 95% confidence interval (CI), 0.84-0.91] and agreement (κ index = 0.43; P < 0.0001) with PAM50 molecular subtyping. VFOXC1 non-BLBC TNBC subtype was a significant independent predictor of clinical benefit with capecitabine for distant relapse-free survival (HR, 0.44; 95% CI, 0.25-0.76; P = 0.003). This predictive effect of VFOXC1 non-BLBC on capecitabine efficacy was further confirmed at disease-free survival (HR, 0.47; 95% CI, 0.28-0.78; P = 0.003), overall survival (HR, 0.48; 95% CI, 0.24-0.96; P = 0.038), and recurrence-free survival (HR, 0.39; 95% CI, 0.22-0.72; P = 0.002).

Conclusions: This ambispective GEICAM_CIBOMA translational analysis validated FOXC1-based basal-like/non-basal-like subtyping as a pragmatic alternative to PAM50 subtyping and independently predicted the benefit of adding capecitabine to standard (neo)adjuvant chemotherapy in TNBC.

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Conflict of interest statement

F. Rojo reports grants and personal fees from Roche, AstraZeneca, Astellas Pharma, Agilent Technologies, Menarini-Stemline Therapeutics, Novartis, and Pfizer and personal fees from Bristol Myers Squibb, MSD, Merck, GSK, AbbVie, and BeiGene outside the submitted work. C.R. Taylor reports serving as an occasional consultant for Onconostic Technologies, Inc., with stock options. C. Barrios reports grants/research support (to the institution) from Amgen, AstraZeneca, Aveo Oncology, BioNTech, Bristol Myers Squibb, Daiichi Sankyo, Dizal Pharma, Exelixis, Fortrea, Gilead Sciences, GSK, ICON, IQVIA, Janssen Pharmaceuticals, Labcorp, Eli Lilly and Company, Medpace, MSD, Novartis, Novocure, Nuvisan, OBI Pharma, Parexel, Pfizer, PharmaMar, PPD, PSI, Regeneron Pharmaceuticals, Roche/Genentech, Samsung, Sandoz, Sanofi, Seagen, Servier, Stemline Therapeutics, Syneos Health, Taiho Pharmaceutical, Takeda Pharmaceuticals, Tolmar, TRIO Pharmaceuticals, and The World Wide Pharma and personal fees for being on the advisory boards and consulting, travel, and presentation honoraria from Adium Pharma, Novartis, Pfizer, Roche/Genentech, MSD, AstraZeneca, Eli Lilly and Company, Daiichi Sankyo, and Gilead Sciences during the conduct of the study, as well as grants/research support (to the institution) from Amgen, AstraZeneca, Aveo Oncology, BioNTech, Bristol Myers Squibb, Daiichi Sankyo, Dizal Pharma, Exelixis, Fortrea, Gilead Sciences, GSK, ICON, IQVIA, Janssen Pharmaceuticals, Labcorp, Eli Lilly and Company, Medpace, MSD, Novartis, Novocure, Nuvisan, OBI Pharma, Parexel, Pfizer, PharmaMar, PPD, PSI, Regeneron Pharmaceuticals, Roche/Genentech, Samsung, Sandoz, Sanofi, Seagen, Servier, Stemline Therapeutics, Syneos Health, Taiho Pharmaceutical, Takeda Pharmaceuticals, Tolmar, TRIO Pharmaceuticals, and The World Wide Pharma and personal fees for being on the advisory boards and consulting, travel, presentation honoraria from Adium Pharma, Novartis, Pfizer, Roche/Genentech, MSD, AstraZeneca, Eli Lilly and Company, Daiichi Sankyo, and Gilead Sciences outside the submitted work. J. Bines reports personal fees from Roche outside the submitted work. A. Guerrero-Zotano reports nonfinancial support from Roche and Gilead Sciences, personal fees and nonfinancial support from Novartis, AstraZeneca, Daiichi Sankyo, and Pierre Fabre, and personal fees from Eli Lilly and Company and Palex outside the submitted work. J.A. Garcia-Saenz reports personal fees from AstraZeneca, Daiichi Sankyo, Exact Sciences, Gilead Sciences, Eli Lilly and Company, Pfizer, Novartis, and Roche and grants from Stemline Therapeutics outside the submitted work. F. Ayala reports personal fees from Eli Lilly and Company, Gilead Sciences, Pfizer, Novartis, Seagen, and Adium Pharma, grants from Daiichi Sankyo, nonfinancial support from Novartis, Daiichi Sankyo, Gilead Sciences, and Roche, and grants from Roche outside the submitted work. A. Llombart reports personal fees and nonfinancial support from Eli Lilly and Company, grants and personal fees from Roche/Genentech, Novartis, Gilead Sciences, AstraZeneca, and Daiichi Sankyo, grants, personal fees, and nonfinancial support from Pfizer, grants and nonfinancial support from Menarini-Stemline Therapeutics, personal fees from MSD and Exact Sciences, and grants from Agendia during the conduct of the study. J.M. Baena-Cañada reports grants from GEICAM and personal fees and nonfinancial support from Roche during the conduct of the study. A. Barnadas reports grants from Roche during the conduct of the study, as well as personal fees from Novartis, Roche, Pfizer, Gilead Sciences, Daiichi Sankyo, and Menarini outside the submitted work. B. Bermejo reports personal fees from Novartis, Pfizer, Eli Lilly and Company, Roche, Menarini, Gilead Sciences, and AstraZeneca outside the submitted work. P.S. Ray reports nonfinancial support from Onconostic Technologies Inc. during the conduct of the study, as well as a patent for FOXC1 in Cancer pending and issued. M. Martin reports personal fees from Pfizer, Eli Lilly and Company, GSK, Novartis, AstraZeneca, and MSD and personal fees and nonfinancial support from Roche outside the submitted work. No disclosures were reported by the other authors.

Figures

Figure 1.
Figure 1.
CONSORT flow diagram for cases included in the GEICAM_CIBOMA translational study cohort of TNBC. The analysis of the translational study cohort followed a prospective–retrospective design testing prespecified primary and secondary hypotheses using high-quality clinical trial materials with adherence to REMARK criteria and to the guidelines for the use of archived clinical trial specimens for predictive biomarker evaluation on clinical trials. *IHC basal-like status was defined as TNBC with any staining for CK5/6 or EGFR.
Figure 2.
Figure 2.
Survival analyses showing the primary endpoint of DRFS for patients randomly assigned to the capecitabine or observation arm in the GEICAM_CIBOMA translational study cohort. A, FOXC1 IHC detection by the standardized FOXC1 IHC test, showing positive (right image) and negative (left image) staining in two representative TNBC tumor samples from the GEICAM_CIBOMA trial cohort. The line shows 30 µm. Magnification, ×200. B and C, Kaplan–Meier curves for VFOXC1.
Figure 3.
Figure 3.
Forest plot for the GEICAM_CIBOMA translational study cohort primary endpoint of DRFS at (A) full GEICAM_CIBOMA trial follow-up, (B) 5-year DRFS, and (C) 8-year DRFS on the capecitabine arm versus observation arm for basal-like/nonbasal category variables. HRs, 95% CI, and P values are derived from Cox regression analyses adjusted for age, menopausal status, histologic grade, tumor size, stage, breast surgery, region, nodal status, and CT regimen.
See this image and copyright information in PMC

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