Annals of Surgical Oncology

, Volume 26, Issue 11, pp 3561–3567 | Cite as

Influence of Molecular Status on Recurrence Site in Patients Treated for a Stage III Colon Cancer: a Post Hoc Analysis of the PETACC-8 Trial

  • M. BruzziEmail author
  • E. Auclin
  • R. Lo Dico
  • T. Voron
  • M. Karoui
  • E. Espin
  • F. Cianchi
  • J. Weitz
  • A. Buggenhout
  • R. Malafosse
  • F. Denimal
  • K. Le Malicot
  • D. Vernerey
  • R. Douard
  • J. F. Emile
  • C. Lepage
  • P. Laurent-Puig
  • J. Taieb
Colorectal Cancer



Recurrence patterns in stage III colon cancer (CC) patients according to molecular markers remain unclear. The objective of the study was to assess recurrence patterns according to microsatellite instability (MSI), RAS and BRAFV600E status in stage III CC patients.


All stage III CC patients from the PETACC-8 randomized trial tested for MSI, RAS and BRAFV600E status were included. The site and characteristics of recurrence were analyzed according to molecular status. Survival after recurrence (SAR) was analyzed.


A total of 1650 patients were included. Recurrence occurred in 434 patients (26.3%). Microsatellite stable (MSS) patients had a significantly higher recurrence rate (27.2% vs. 18.7%, P = 0.02) with a trend to more pulmonary recurrence (28.8% vs. 12.9%, P = 0.06) when compared to MSI patients. MSI patients experienced more regional lymph nodes compared to MSS (12.9% vs. 4%, P = 0.046). In the MSS population, the recurrence rate was significantly higher in RAS (32.2%) or BRAF (32.3%) patients when compared to double wild-type patients (19.9%) (p < 0.001); no preferential site of recurrence was observed according to RAS and BRAFV600E mutations. Finally, decreased SAR was observed in the case of peritoneal recurrence or more than two recurrence sites.


Microsatellite, RAS and BRAFV600E status influences recurrence rates in stage III CC patients. However, only microsatellite status seems to be associated with specific recurrence patterns. More than two recurrence sites and recurrence in the peritoneum were associated with poorer SAR.


Supplementary material

10434_2019_7513_MOESM1_ESM.docx (15 kb)
Supplementary material 1 (DOCX 14 kb)
10434_2019_7513_MOESM2_ESM.docx (15 kb)
Supplementary material 2 (DOCX 14 kb)


  1. 1.
    Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 Countries. CA Cancer J Clin. 2018;68:394–424.CrossRefPubMedGoogle Scholar
  2. 2.
    Lecomte T, Andre T, Fibeau F, et al. Cancer du côlon non métastatique. Chapitre 3. Thésaurus Natl Cancérologie Dig. Accessed 21 Jan 2019.
  3. 3.
    André T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343–51.CrossRefGoogle Scholar
  4. 4.
    Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005;352:2696–704.CrossRefPubMedGoogle Scholar
  5. 5.
    Auclin E, Zaanan A, Vernerey D, et al. Subgroups and prognostication in stage III colon cancer: future perspectives for adjuvant therapy. Ann Oncol. 2017;28:958–68.PubMedGoogle Scholar
  6. 6.
    Sinicrope FA, Shi Q, Smyrk TC, et al. Molecular markers identify subtypes of stage III colon cancer associated with patient outcomes. Gastroenterology. 2015;148:88–99.Google Scholar
  7. 7.
    Zaanan A, Shi Q, Taieb J, et al. Role of deficient DNA mismatch repair status in patients with stage III colon cancer treated with FOLFOX adjuvant chemotherapy a pooled analysis from 2 randomized clinical trials. JAMA Oncol. 2018;4:379–83.CrossRefPubMedGoogle Scholar
  8. 8.
    Taieb J, Zaanan A, Le Malicot K, et al. Prognostic effect of BRAF and KRAS mutations in patients with stage III colon cancer treated with leucovorin, fluorouracil, and oxaliplatin with or without cetuximab. JAMA Oncol. 2016;2:643–53.CrossRefPubMedGoogle Scholar
  9. 9.
    Taieb J, Le Malicot K, Shi Q, et al. Prognostic value of BRAF and KRAS mutations in MSI and MSS stage III colon cancer. J Natl Cancer Inst. 2017;109:1–12.CrossRefGoogle Scholar
  10. 10.
    Blons H, Emile JF, Le Malicot K, et al. Prognostic value of KRAS mutations in stage III colon cancer: post hoc analysis of the PETACC8 phase III trial dataset. Ann Oncol. 2014;25:2378–85.CrossRefPubMedGoogle Scholar
  11. 11.
    Taieb J, Tabernero J, Mini E, et al. Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15:862–73.CrossRefPubMedGoogle Scholar
  12. 12.
    Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016;27:1386–422.CrossRefPubMedGoogle Scholar
  13. 13.
    Prasanna T, Karapetis CS, Roder D, et al. The survival outcome of patients with metastatic colorectal cancer based on the site of metastases and the impact of molecular markers and site of primary cancer on metastatic pattern. Acta Oncol. 2018;57:1438–44.CrossRefPubMedGoogle Scholar
  14. 14.
    Tran B, Kopetz S, Tie J, et al. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer. 2011;117:4623–32.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Fujiyoshi K, Yamamoto G, Takenoya T, et al. Metastatic pattern of stage IV colorectal cancer with high-frequency microsatellite instability as a prognostic factor. Anticancer Res. 2017;37:239–47.CrossRefPubMedGoogle Scholar
  16. 16.
    Sinicrope FA, Shi Q, Allegra CJ, et al. Association of DNA mismatch repair and mutations in BRAF and KRAS with survival after recurrence in stage III colon cancers: a secondary analysis of 2 randomized clinical trials. JAMA Oncol. 2017;3:472–80.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Venderbosch S, Nagtegaal ID, Maughan TS, et al. Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies. Clin Cancer Res. 2014;20:5322–30.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Goldstein J, Tran B, Ensor J, et al. Multicenter retrospective analysis of metastatic colorectal cancer (CRC) with high-level microsatellite instability (MSI-H). Ann Oncol 2014;25:1032–8.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Tie J, Lipton L, Desai J, et al. KRAS mutation is associated with lung metastasis in patients with curatively resected colorectal cancer. Clin Cancer Res. 2011;17:1122–30.CrossRefPubMedGoogle Scholar
  20. 20.
    Ghidini M, Personeni N, Bozzarelli S, et al. KRAS mutation in lung metastases from colorectal cancer: prognostic implications. Cancer Med. 2016:5:256–64.CrossRefPubMedGoogle Scholar
  21. 21.
    Lipsyc M, Yaeger R. Impact of somatic mutations on patterns of metastasis in colorectal cancer. J Gastrointest Oncol. 2015;6:645–9.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Yaeger R, Cowell E, Chou JF, et al. RAS mutations affect pattern of metastatic spread and increase propensity for brain metastasis in colorectal cancer. Cancer. 2015;121:1195–203.CrossRefPubMedGoogle Scholar
  23. 23.
    Yokota T, Ura T, Shibata N, et al. BRAF mutation is a powerful prognostic factor in advanced and recurrent colorectal cancer. Br J Cancer. 2011;104:856–62.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Pai RK, Jayachandran P, Koong AC, et al. BRAF-mutated, microsatellite-stable adenocarcinoma of the proximal colon: an aggressive adenocarcinoma with poor survival, mucinous differentiation, and adverse morphologic features. Am J Surg Pathol. 2012;36:744–52.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Russo AL, Borger DR, Szymonifka J, et al. Mutational analysis and clinical correlation of metastatic colorectal cancer. Cancer. 2015;120:1482–90.CrossRefGoogle Scholar
  26. 26.
    Yaeger R. BRAF mutation predicts for poor outcomes after metastasectomy in patients with metastatic colorectal cancer. Cancer. 2014;120:2316–24.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Ogino S, Shima K, Meyerhardt JA, et al. Predictive and prognostic roles of BRAF mutation in stage III colon cancer: results from Intergroup Trial CALGB 89803. Clin Cancer Res. 2012;18:890–900.CrossRefPubMedGoogle Scholar

Copyright information

© Society of Surgical Oncology 2019

Authors and Affiliations

  • M. Bruzzi
    • 1
    Email author
  • E. Auclin
    • 2
    • 13
  • R. Lo Dico
    • 3
  • T. Voron
    • 4
  • M. Karoui
    • 5
  • E. Espin
    • 6
  • F. Cianchi
    • 7
  • J. Weitz
    • 8
  • A. Buggenhout
    • 9
  • R. Malafosse
    • 10
  • F. Denimal
    • 11
  • K. Le Malicot
    • 12
  • D. Vernerey
    • 13
  • R. Douard
    • 1
  • J. F. Emile
    • 14
  • C. Lepage
    • 15
  • P. Laurent-Puig
    • 16
  • J. Taieb
    • 2
  1. 1.Department of General and Digestive Surgery, Georges Pompidou European HospitalAP-HPParisFrance
  2. 2.Department of Digestive Oncology, Georges Pompidou European HospitalAP-HPParisFrance
  3. 3.Department of Digestive and Oncological Surgery, Lariboisière HospitalAP-HPParisFrance
  4. 4.Department of Digestive and General Surgery, Saint Antoine HospitalAP-HP, Sorbonne UniversitéParisFrance
  5. 5.Department of Digestive and Hepato-Pancreato-Biliary Surgery, Pitié-Salpêtrière University HospitalAP-HP, Paris VI University Institute of CancerologyParisFrance
  6. 6.Department of General Surgery, Hospital Valle de HebronUniversitat Autonoma de BarcelonaBarcelonaSpain
  7. 7.Department of Experimental and Clinical MedicineUniversity of FlorenceFlorenceItaly
  8. 8.Department of Visceral, Thoracic and Vascular SurgeryUniversity Hospital Carl Gustav Carus of the Technical University DresdenDresdenGermany
  9. 9.Department of Surgical Gastroenterology, Erasme HospitalUniversité Libre de BruxellesBrusselsBelgium
  10. 10.Department of Digestive Surgery, Ambroise-Paré HospitalAP-HPBoulogneFrance
  11. 11.Department of Digestive SurgeryCentre Hospitalier Départemental VendéeLa Roche Sur YonFrance
  12. 12.Statistical Department, Fédération Francophone de Cancérologie Digestive, EPICAD, INSERM LNC-UMR 1231University of Burgundy and Franche Comté, DijonDijonFrance
  13. 13.Methodological and Quality of Life in Oncology Unit, EA 3181University Hospital of BesançonBesançonFrance
  14. 14.Pathology Department, Ambroise-Paré HospitalAP-HPBoulogneFrance
  15. 15.Hepato-Gastroenterology Department, Dijon University Hospital and EPICAD INSERM LNC-UMR 1231University of Burgundy and Franche ComtéDijonFrance
  16. 16.Department of Biology, European Georges Pompidou HospitalAP-HP, INSERM-UMR-S1147ParisFrance

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