Prognostic and Predictive Impact of Primary Tumor Sidedness for Previously Untreated Advanced Colorectal Cancer

Author:

Yin Jun1ORCID,Cohen Romain2ORCID,Jin Zhaohui3ORCID,Liu Heshan1,Pederson Levi1ORCID,Adams Richard4ORCID,Grothey Axel5,Maughan Timothy S67ORCID,Venook Alan8,Van Cutsem Eric9,Punt Cornelis10,Koopman Miriam11ORCID,Falcone Alfredo12ORCID,Tebbutt Niall C13,Seymour Matthew T14ORCID,Bokemeyer Carsten15ORCID,Rubio Eduardo Diaz16,Kaplan Richard17ORCID,Heinemann Volker18ORCID,Chibaudel Benoist19,Yoshino Takayuki20,Zalcberg John21ORCID,Andre Thierry22ORCID,De Gramont Aimery23ORCID,Shi Qian1ORCID,Lenz Heinz-Josef24ORCID

Affiliation:

1. Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, USA

2. Department of Medical Oncology, Saint-Antoine Hospital, Paris, France

3. Department of Oncology, Mayo Clinic, Rochester, MN, USA

4. Cardiff University and Velindre Cancer Centre, Cardiff, UK

5. West Cancer Center and Research Institute, OneOncology, Germantown, TN, USA

6. CRUK/MRC Oxford Institute for Radiation Oncology, Oxford, UK

7. St James’s Hospital, University of Leeds, Leeds, UK

8. Department of Medicine, University of California San Francisco, San Francisco, CA, USA

9. Digestive Oncology, University Hospitals Gasthuisberg Leuven, University of Leuven, Leuven, Belgium

10. Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center, the Netherlands

11. Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, the Netherlands

12. Department of Oncology, University of Pisa, Pisa, Italy

13. Department of Medical Oncology, Austin Health, Melbourne, Australia

14. NIHR Clinical Research Network, St James’s Hospital, University of Leeds, Leeds, UK

15. Department of Oncology, Haematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

16. Universidad Complutense Instituto de Investigacion Sanitaria del Hospital Clinico San Carlos, Madrid, Spain

17. MRC Clinical Trials Unit at UCL, University College London, London, UK

18. University Hospital Grosshadern, Ludwig Maximilian University of Munich, Munich, Germany

19. Institut Franco-Britannique, Levallois-Perret, France

20. National Cancer Center Hospital East, Tokyo, Japan

21. School of Public Health and Preventative Medicine, Monash University, Melbourne, Australia

22. Hôpital Saint-Antoine, Paris, France

23. Department of Medical Oncology, Franco-British Institute, Levallois-Perret, France

24. Department of Gastrointestinal Oncology, Keck School of Medicine at USC, Los Angeles, CA, USA

Abstract

Abstract Background Unplanned subgroup analyses from several studies have suggested primary tumor sidedness (PTS) as a potential prognostic and predictive parameter in metastatic colorectal cancer (mCRC). We aimed to investigate the impact of PTS on outcomes of mCRC patients. Methods PTS data of 9277 mCRC patients from 12 first-line randomized trials in the ARCAD database were pooled. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier and Cox models adjusting for age, sex, performance status, prior radiation/chemotherapy, and stratified by treatment arm. Predictive value was tested by interaction term between PTS and treatment (cetuximab plus chemotherapy vs chemotherapy alone). All statistical tests were 2-sided. Results Compared with right-sided metastatic colorectal cancer patients (n = 2421, 26.1%), left-sided metastatic colorectal cancer patients (n = 6856, 73.9%) had better OS (median = 21.6 vs 15.9 months; adjusted hazard ratio [HRadj] = 0.71, 95% confidence interval [CI] = 0.67 to 0.76; P < .001) and PFS (median = 8.6 vs 7.5 months; HRadj = 0.80, 95% CI = 0.75 to 0.84; P < .001). Interaction between PTS and KRAS mutation was statistically significant (Pinteraction < .001); left-sidedness was associated with better prognosis among KRAS wild-type (WT) (OS HRadj = 0.59, 95% CI = 0.53 to 0.66; PFS HRadj =0.68, 95% CI = 0.61 to 0.75) but not among KRAS mutated tumors. Among KRAS-WT tumors, survival benefit from anti-EGFR was confirmed for left-sidedness (OS HRadj = 0.85, 95% CI = 0.75 to 0.97; P = .01; PFS HRadj = 0.77, 95% CI = 0.67 to 0.88; P < .001) but not for right-sidedness. Conclusions The prognostic value of PTS is restricted to the KRAS-WT population. PTS is predictive of anti-EGFR efficacy, with a statistically significant improvement of survival for left-sidedness mCRC patients. These results suggest treatment choice in mCRC should be based on both PTS and KRAS status.

Funder

ARCAD Foundation

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,Oncology

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