J Taieb1, Q Shi2, L Pederson2, S Alberts3, N Wolmark4, E Van Cutsem5, A de Gramont6, R Kerr7, A Grothey8, S Lonardi9, T Yoshino10, G Yothers11, F A Sinicrope12, A Zaanan13, T André14. 1. Department of Gastroenterology and GI oncology, Sorbonne Paris Cité, Université Paris Descartes, Hopital Européen Georges Pompidou, Paris, France. Electronic address: jtaieb75@gmail.com. 2. Department of Health Science Research, Mayo Clinic, Rochester. 3. Division of Medical Oncology, Mayo Clinic, Rochester. 4. National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, USA. 5. Department of Medical Oncology, University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium. 6. Department of Medical Oncology, Franco British Institute, Levallois Perret, France. 7. MRC Clinical Trials Unit at UCL, London, UK. 8. Department of GI Oncology, West Cancer Center, The University of Tennessee, Memphis, USA. 9. Department of Medical Oncology Unit 1, Veneto Oncology Institute-IRCCS, Padua, Italy. 10. Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan. 11. Department of Biostatistics, University of Pittsburgh, Pittsburgh. 12. Department of Oncology, Mayo Clinic Comprehensive Cancer Center, Rochester, USA. 13. Department of Gastroenterology and GI oncology, Sorbonne Paris Cité, Université Paris Descartes, Hopital Européen Georges Pompidou, Paris, France. 14. Department of Medical Oncology, Sorbonne Universités and Hôpital Saint-Antoine, Assistance Publique - Hôpitaux de Paris and Groupe Coopérateur Multidisciplinaire en Oncologie (GERCOR), Paris, France.
Abstract
BACKGROUND: Microsatellite instable/deficient mismatch repair (MSI/dMMR) metastatic colorectal cancers have been reported to have a poor prognosis. Frequent co-occurrence of MSI/dMMR and BRAFV600E complicates the association. PATIENTS AND METHODS: Patients with resected stage III colon cancer (CC) from seven adjuvant studies with available data for disease recurrence and MMR and BRAFV600E status were analyzed. The primary end point was survival after recurrence (SAR). Associations of markers with SAR were analyzed using Cox proportional hazards models adjusted for age, gender, performance status, T stage, N stage, primary tumor location, grade, KRAS status, and timing of recurrence. RESULTS: Among 2630 patients with cancer recurrence (1491 men [56.7%], mean age, 58.5 [19-85] years), multivariable analysis revealed that patients with MSI/dMMR tumors had significantly longer SAR than did patients with microsatellite stable/proficient MMR tumors (MSS/pMMR) (adjusted hazard ratio [aHR], 0.82; 95% CI [confidence interval], 0.69-0.98; P = 0.029). This finding remained when looking at patients treated with standard oxaliplatin-based adjuvant chemotherapy regimens only (aHR, 0.76; 95% CI, 0.58-1.00; P = 0.048). Same trends for SAR were observed when analyzing MSI/dMMR versus MSS/pMMR tumor subgroups lacking BRAFV600E (aHR, 0.84; P = 0.10) or those harboring BRAFV600E (aHR, 0.88; P = 0.43), without reaching statistical significance. Furthermore, SAR was significantly shorter in tumors with BRAFV600E versus those lacking this mutation (aHR, 2.06; 95% CI, 1.73-2.46; P < 0.0001), even in the subgroup of MSI/dMMR tumors (aHR, 2.65; 95% CI, 1.67-4.21; P < 0.0001). Other factors associated with a shorter SAR were as follows: older age, male gender, T4/N2, proximal primary tumor location, poorly differentiated adenocarcinoma, and early recurrence. CONCLUSIONS: In stage III CC patients recurring after adjuvant chemotherapy, and before the era of immunotherapy, the MSI/dMMR phenotype was associated with a better SAR compared with MSS/pMMR. BRAFV600E mutation was a poor prognostic factor for both MSI/dMMR and MSS/pMMR patients. TRIAL IDENTIFICATION NUMBERS: NCT00079274, NCT00265811, NCT00004931, NCT00004931, NCT00026273, NCT00096278, NCT00112918.
BACKGROUND: Microsatellite instable/deficient mismatch repair (MSI/dMMR) metastatic colorectal cancers have been reported to have a poor prognosis. Frequent co-occurrence of MSI/dMMR and BRAFV600E complicates the association. PATIENTS AND METHODS: Patients with resected stage III colon cancer (CC) from seven adjuvant studies with available data for disease recurrence and MMR and BRAFV600E status were analyzed. The primary end point was survival after recurrence (SAR). Associations of markers with SAR were analyzed using Cox proportional hazards models adjusted for age, gender, performance status, T stage, N stage, primary tumor location, grade, KRAS status, and timing of recurrence. RESULTS: Among 2630 patients with cancer recurrence (1491 men [56.7%], mean age, 58.5 [19-85] years), multivariable analysis revealed that patients with MSI/dMMR tumors had significantly longer SAR than did patients with microsatellite stable/proficient MMR tumors (MSS/pMMR) (adjusted hazard ratio [aHR], 0.82; 95% CI [confidence interval], 0.69-0.98; P = 0.029). This finding remained when looking at patients treated with standard oxaliplatin-based adjuvant chemotherapy regimens only (aHR, 0.76; 95% CI, 0.58-1.00; P = 0.048). Same trends for SAR were observed when analyzing MSI/dMMR versus MSS/pMMR tumor subgroups lacking BRAFV600E (aHR, 0.84; P = 0.10) or those harboring BRAFV600E (aHR, 0.88; P = 0.43), without reaching statistical significance. Furthermore, SAR was significantly shorter in tumors with BRAFV600E versus those lacking this mutation (aHR, 2.06; 95% CI, 1.73-2.46; P < 0.0001), even in the subgroup of MSI/dMMR tumors (aHR, 2.65; 95% CI, 1.67-4.21; P < 0.0001). Other factors associated with a shorter SAR were as follows: older age, male gender, T4/N2, proximal primary tumor location, poorly differentiated adenocarcinoma, and early recurrence. CONCLUSIONS: In stage III CC patients recurring after adjuvant chemotherapy, and before the era of immunotherapy, the MSI/dMMR phenotype was associated with a better SAR compared with MSS/pMMR. BRAFV600E mutation was a poor prognostic factor for both MSI/dMMR and MSS/pMMR patients. TRIAL IDENTIFICATION NUMBERS: NCT00079274, NCT00265811, NCT00004931, NCT00004931, NCT00026273, NCT00096278, NCT00112918.
Authors: Aziz Zaanan; Julie Henriques; Romain Cohen; David Sefrioui; Camille Evrard; Christelle de la Fouchardiere; Thierry Lecomte; Thomas Aparicio; Magali Svrcek; Julien Taieb; Thierry André; Dewi Vernerey; David Tougeron Journal: J Natl Cancer Inst Date: 2021-04-06 Impact factor: 13.506
Authors: Romain Cohen; Julien Taieb; Jack Fiskum; Greg Yothers; Richard Goldberg; Takayuki Yoshino; Steven Alberts; Carmen Allegra; Aimery de Gramont; Jean-Francois Seitz; Michael O'Connell; Daniel Haller; Norman Wolmark; Charles Erlichman; Alberto Zaniboni; Sara Lonardi; Rachel Kerr; Axel Grothey; Frank A Sinicrope; Thierry André; Qian Shi Journal: J Clin Oncol Date: 2020-12-23 Impact factor: 44.544