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. 2024 May 1;42(13):1520-1530.
doi: 10.1200/JCO.23.01080. Epub 2024 Feb 5.

Machine Learning Predicts Oxaliplatin Benefit in Early Colon Cancer

Lujia Chen  1 , Ying Wang  2 , Chunhui Cai  1 , Ying Ding  3   4 , Rim S Kim  2   5 , Corey Lipchik  2 , Patrick G Gavin  2   6 , Greg Yothers  3   4 , Carmen J Allegra  7 , Nicholas J Petrelli  8 , Jennifer Marie Suga  9 , Judith O Hopkins  10 , Naoyuki G Saito  11 , Terry Evans  12 , Srinivas Jujjavarapu  13 , Norman Wolmark  2   12   14 , Peter C Lucas  2   12   14 , Soonmyung Paik  2   15 , Min Sun  12   14   16 , Katherine L Pogue-Geile  2 , Xinghua Lu  1   16
Affiliations

Machine Learning Predicts Oxaliplatin Benefit in Early Colon Cancer

Lujia Chen et al. J Clin Oncol. .

Erratum in

  • Erratum: Machine Learning Predicts Oxaliplatin Benefit in Early Colon Cancer.
    Chen L, Wang Y, Cai C, Ding Y, Kim RS, Lipchik C, Gavin PG, Yothers G, Allegra CJ, Petrelli NJ, Suga JM, Hopkins JO, Saito NG, Evans T, Jujjavarapu S, Wolmark N, Lucas PC, Paik S, Sun M, Pogue-Geile KL, Lu X. Chen L, et al. J Clin Oncol. 2025 Oct 2:JCO2502281. doi: 10.1200/JCO-25-02281. Online ahead of print. J Clin Oncol. 2025. PMID: 41037767 No abstract available.

Abstract

Purpose: A combination of fluorouracil, leucovorin, and oxaliplatin (FOLFOX) is the standard for adjuvant therapy of resected early-stage colon cancer (CC). Oxaliplatin leads to lasting and disabling neurotoxicity. Reserving the regimen for patients who benefit from oxaliplatin would maximize efficacy and minimize unnecessary adverse side effects.

Methods: We trained a new machine learning model, referred to as the colon oxaliplatin signature (COLOXIS) model, for predicting response to oxaliplatin-containing regimens. We examined whether COLOXIS was predictive of oxaliplatin benefits in the CC adjuvant setting among 1,065 patients treated with 5-fluorouracil plus leucovorin (FULV; n = 421) or FULV + oxaliplatin (FOLFOX; n = 644) from NSABP C-07 and C-08 phase III trials. The COLOXIS model dichotomizes patients into COLOXIS+ (oxaliplatin responder) and COLOXIS- (nonresponder) groups. Eight-year recurrence-free survival was used to evaluate oxaliplatin benefits within each of the groups, and the predictive value of the COLOXIS model was assessed using the P value associated with the interaction term (int P) between the model prediction and the treatment effect.

Results: Among 1,065 patients, 526 were predicted as COLOXIS+ and 539 as COLOXIS-. The COLOXIS+ prediction was associated with prognosis for FULV-treated patients (hazard ratio [HR], 1.52 [95% CI, 1.07 to 2.15]; P = .017). The model was predictive of oxaliplatin benefits: COLOXIS+ patients benefited from oxaliplatin (HR, 0.65 [95% CI, 0.48 to 0.89]; P = .0065; int P = .03), but COLOXIS- patients did not (COLOXIS- HR, 1.08 [95% CI, 0.77 to 1.52]; P = .65).

Conclusion: The COLOXIS model is predictive of oxaliplatin benefits in the CC adjuvant setting. The results provide evidence supporting a change in CC adjuvant therapy: reserve oxaliplatin only for COLOXIS+ patients, but further investigation is warranted.

Trial registration: ClinicalTrials.gov NCT00096278 NCT00004931.

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Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Figures

FIG 1.
FIG 1.
Recurrence-free survival of the study cohort of patients receiving different regimens. (A) Kaplan-Meier curves of patients treated with FULV in C-07, FLOX in C-07, and FOLFOX in C-08. (B) Kaplan-Meier curves of FULV versus merged FOLFOX and FLOX. FLOX, fluorouracil (bolus administration) + leucovorin + oxaliplatin; FOLFOX, fluorouracil + leucovorin + oxaliplatin; FULV, fluorouracil + leucovorin.
FIG 2.
FIG 2.
COLOXIS signature as a prognostic marker. (A) Kaplan-Meier curves of COLOXIS+ and COLOXIS– groups of the overall cohort. (B) Kaplan-Meier curves of FULV-treated patients grouped according to COLOXIS+ and COLOXIS– classification. (C) Kaplan-Meier plot of patients treated with FOLFOX grouped according to COLOXIS+ and COLOXIS– classification. COLOXIS, colon oxaliplatin signature; FOLFOX, fluorouracil + leucovorin + oxaliplatin; FULV, fluorouracil + leucovorin.
FIG 3.
FIG 3.
Predicting the benefit of oxaliplatin. (A) Kaplan-Meier plot of RFSs of patients treated with FULV and FOLFOX among the COLOXIS+ subpopulation. The log-rank test and interaction analysis P values are shown. (B) Kaplan-Meier plot of RFSs of patients treated with FULV versus FOLFOX among the COLOXIS– subpopulation. Log-rank test P value is shown. (C) Kaplan-Meier plot of OSs of patients treated with FULV and FOLFOX among the COLOXIS+ subpopulation. Log-rank test P value is shown. (D) Kaplan-Meier plot of OSs of patients treated with FULV versus FOLFOX among the COLOXIS– subpopulation. Log-rank test P value is shown. COLOXIS, colon oxaliplatin signature; FOLFOX, fluorouracil + leucovorin + oxaliplatin; FULV, fluorouracil + leucovorin; OS, overall survival; RFS, recurrence-free survival.
FIG 4.
FIG 4.
Multivariate Cox proportional hazard analyses of clinical variables and treatments. (A) The COLOXIS+ group. (B) The COLOXIS– group. COLOXIS, colon oxaliplatin signature. *P < 0.1, **P < 0.01, ***P < 0.001
FIG 5.
FIG 5.
Treatment effects of oxaliplatin in patients with different disease stages. (A) Kaplan-Meier plots of patients with different stages and treatments in the COLOXIS+ subpopulation. (B) Kaplan-Meier plots of patients with different stages and treatments in the COLOXIS– subpopulation. COLOXIS, colon oxaliplatin signature; FOLFOX, fluorouracil + leucovorin + oxaliplatin; FULV, fluorouracil + leucovorin.
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