Clinical Outcomes in Patients With Colon Cancer With Microsatellite Instability of Sporadic or Familial Origin Treated With Adjuvant FOLFOX With or Without Cetuximab: A Pooled Analysis of the PETACC8 and N0147 Trials

Aziz Zaanan; Qian Shi; Julien Taieb; Steven R Alberts; Jeffrey P Meyers; Thomas C Smyrk; Catherine Julie; Ayman Zawadi; Josep Tabernero; Enrico Mini; Richard M Goldberg; Gunnar Folprecht; Jean Luc Van Laethem; Karine Le Malicot; Daniel J Sargent; Pierre Laurent-Puig; Frank A Sinicrope

doi:10.1200/PO.19.00237

Clinical Outcomes in Patients With Colon Cancer With Microsatellite Instability of Sporadic or Familial Origin Treated With Adjuvant FOLFOX With or Without Cetuximab: A Pooled Analysis of the PETACC8 and N0147 Trials

JCO Precis Oncol. 2020 Feb 26:4:PO.19.00237. doi: 10.1200/PO.19.00237. eCollection 2020.

Authors

Aziz Zaanan^{1

2}, Qian Shi³, Julien Taieb^{4

2}, Steven R Alberts⁵, Jeffrey P Meyers³, Thomas C Smyrk⁶, Catherine Julie^{7

8}, Ayman Zawadi⁹, Josep Tabernero^{10

11}, Enrico Mini^{12

13}, Richard M Goldberg¹⁴, Gunnar Folprecht¹⁵, Jean Luc Van Laethem¹⁶, Karine Le Malicot¹⁷, Daniel J Sargent³, Pierre Laurent-Puig^{4

18}, Frank A Sinicrope^{1

19}

Affiliations

¹ Department of Medicine, Mayo Clinic, Rochester, MN.
² Department of Gastroenterology and Digestive Oncology, European Georges Pompidou Hospital, Assistance Publique Hôpitaux de Paris (APHP), Paris, France.
³ Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN.
⁴ Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Descartes, Université Paris Diderot, Université Sorbonne Paris Cité, Paris, France.
⁵ Department of Oncology, Mayo Clinic, Rochester, MN.
⁶ Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.
⁷ Department of Pathology, Ambroise Paré Hospital, APHP, Boulogne-Billancourt, France.
⁸ Versailles Saint-Quentin-en-Yvelines University, Boulogne-Billancourt, France.
⁹ Radiotherapy Unit, Departmental Hospital Center, La Roche-Sur-Yon, France.
¹⁰ Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain.
¹¹ Vall d'Hebron Institute of Oncology, University of Vic, IOB-Quiron, Barcelona, Spain.
¹² Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy.
¹³ DENOTHE Excellence Center, University of Florence, Florence, Italy.
¹⁴ West Virginia University Cancer Institute, Morgantown, WV.
¹⁵ First Medical Department, University Hospital Carl Gustav Carus, Dresden, Germany.
¹⁶ Department of Gastroenterology, Erasme Hospital University, Brussels, Belgium.
¹⁷ Department of Statistics, Fédération Francophone de Cancérologie Digestive, Dijon, France.
¹⁸ Department of Biology, European Georges Pompidou Hospital, APHP, Paris, France.
¹⁹ Mayo Comprehensive Cancer Center, Rochester, MN.

Abstract

Purpose: The microsatellite instability (MSI) or deficient mismatch repair (dMMR) phenotype is usually regarded as a single biologic entity, given the absence of comparative analyses regarding prognosis and response to chemotherapy between sporadic and familial dMMR cancers.

Patients and methods: Patients with stage III colon cancers were randomly assigned to FOLFOX (leucovorin, fluorouracil, and oxaliplatin) with or without cetuximab in 2 large adjuvant phase III trials (N = 5,577). Among patients with MSI and KRAS exon 2 wild-type (WT) tumors, the prognostic and predictive impacts of sporadic versus familial dMMR cancers and BRAF V600E mutational status were determined. Multivariable Cox proportional hazards models were used to assess disease-free survival (DFS) by treatment arm, adjusting for age, sex, tumor grade, Eastern Cooperative Oncology Group performance status, pT/pN stage, and primary tumor location.

Results: Among patients with MSI status with complete data for dMMR mechanism analysis (n = 354), 255 (72%) had sporadic (BRAF mutation and/or MLH1 methylation) and 99 (28%) had familial tumors (BRAF WT and unmethylated MLH1 or loss of MSH2/MSH6/PMS2 protein expression). A large proportion of dMMR sporadic tumors were mutated for BRAF (n = 200). In patients treated with FOLFOX, DFS did not differ statistically by dMMR mechanism, whereas in patients treated with FOLFOX plus cetuximab, those with sporadic tumors had worse DFS than those with familial cancers (multivariable hazard ratio, 2.69; 95% CI, 1.02 to 7.08; P = .04). Considering the predictive utility, the interaction between treatment and dMMR mechanism was significant (P = .03). Furthermore, a nonsignificant trend toward a deleterious effect of adding cetuximab to FOLFOX was observed in patients with BRAF-mutant but not BRAF WT tumors.

Conclusion: The addition of cetuximab to adjuvant FOLFOX was associated with shorter DFS in patients with sporadic dMMR colon cancer. Additional studies are needed to validate these results in metastatic disease.

Abstract

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