O-014 - High BRAF mutation frequency and marked survival differences in subgroups according to KRAS/BRAF mutation status and tumor tissue availability in a...

Date 04 July 2015
Event WorldGI 2015
Session Oral and LBA abstracts
Topics Colon Cancer
Rectal Cancer
Pathology/Molecular Biology
Presenter H. Sorbye
Citation Annals of Oncology (2015) 26 (suppl_4): 108-116. 10.1093/annonc/mdv235
Authors H. Sorbye1, P. Pfeiffer2, C. Qvortrup2, A. Dragomir3, M. Sundstrom1, U. Thunberg3, M. Bergfors3, K. Aasebo4, G. Eide1, F. Ponten1, B. Glimelius5
  • 1University of Bergen, Bergen/NO
  • 2Odense University Hospital, Odense/DK
  • 3Uppsala University Hospital, Uppsala/SE
  • 4Haukeland University Hospital, Bergen/NO
  • 5Uppsala University, Uppsala/SE

Abstract

Introduction

RAS and BRAF mutations impact treatment and prognosis of metastatic colorectal cancer patients (mCRC). The molecular studies behind these results are based on tumor specimens from patients included into trials. However, trial patients may be selected and not representative for the general cancer population. The aim of the study was: i: To decide the true incidence of BRAF mutations in unselected mCRC patients ii: To investigate if BRAF mutations alone could explain the very poor prognosis for mCRC patients with poor PS, iii: To characterize patients without available tumor tissue for molecular analyses, to decide generalizability of prior TMA studies, and iv: To study heterogeneity of survival for unselected mCRC patients in comparison to selected trial patients.

Methods

Patient characteristics, treatment and efficacy according to KRAS, BRAF and MSI status and tumour tissue availability were analyzed in a prospectively collected unselected Scandinavian population-based cohort of non-resectable mCRC patients.

Results

The cohort contained of 798 patients, many with poor performance status (39% PS 2-4) and elderly (37% age >75), groups usually not included in clinical trials. Tissue micro array (TMA) was possible to produce from 462 of 701 collected cases (58% of initial 798 cases), whereas the remaining 239 patients had biopsies being too small or containing necrotic tissue. Patients without available tissue micro array (TMA) (42%) had worse prognostic factors and shorter survival in all patients (7m vs 11m, log-rank p < 0.001) and in chemotherapy-treated patients (12m vs 17m, log-rank p < 0.001). The 92 patients (21%) with a BRAF mutation had a poor prognosis regardless of microsatellite instability, but initial chemotherapy treatment did not differ. In patients aged < 75 years with good performance status (PS), survival was longer with wildtype KRAS/BRAF compared to mutated KRAS. Median survival varied from 1 month in BRAF mutated patients not given chemotherapy to 26 months in wildtype KRAS/BRAF patients <75 years in good PS.

Conclusion

The observed 21% BRAF mutation incidence is higher than the previously and repeatedly reported incidence of 6-10% in mCRC. Screening for BRAF mutations before selection of treatment strategy is therefore relevant for many patients, especially outside clinical trials. A BRAF mutation only partly explained the very poor prognosis of many mCRC patients. Survival in unselected metastatic colorectal cancer patients is extremely variable and subgroups have an extremely short survival compared to trial patients. Patients without available TMA had worse prognostic factors and shorter survival, which questions the total generalizability of present TMA studies and implies that we lack information on the biologically worst mCRC cases. Lack of available tissue is an important underexposed issue that introduces sample bias, and this should be recognized more clearly when conclusions are made from translational studies of mCRC trial patients.

Figure: O-014