Abstract 4742: APC
WT
/RAS
WT
/BRAF
WT tumors represent an under recognized poor prognostic group of right sided colorectal cancer
Authors: Loree Jonathan M. , Korphaisarn Krittiya K. , Lam Michael , Morris Van K. , Raghav Kanwal P. , Overman Michael J. , Eng Cathy , Dasari Arvind , Kee Bryan K. , Fogelman David , Wolff Robert A. , Shaw Kenna , Broaddus Russell , Routbort Mark J. , Luthra Rajyalakshmi , Maru Dipen M. , Menter David G. , Meric-Bernstam Funda , Kopetz Scott 
Published: July 2017

Abstract
Background: Side of primary tumor has prognostic and predictive significance in metastatic colorectal cancer (mCRC). RAS/BRAF wild type (WT) left (L) sided tumors have improved outcomes with anti-EGFR therapy while right (R) sided tumors do worse. We aimed to identify mutations (MTS) in RAS/BRAF WT patients (pts) which may explain the differing response.
Methods: Using a 46 gene panel, we compared MT frequencies by side in 1880 mCRC pts. Overall survival (OS) was summarized with Kaplan-Meier curves, the log rank test, and Cox models. Microsatellite unstable pts were excluded from univariate OS analysis.
Results: RAS mutant (MT) pts were more likely to be APC MT (OR 1.64, P&lt;0.0001) than RAS WT pts. Presence of APC MTS was associated with improved OS in WT RAS/BRAF (HR 0.58, P=0.0003) and MT RAS/BRAF pts (HR 0.69, P=0.0004). Multivariate analysis confirmed APC MTS were associated with improved OS (HR 0.67, P=0.001) after controlling for RAS/BRAF, side, and MSI.
Given the association of tumor location and OS, we stratified pts by side and compared APC MT/WT pts. Improved OS with APC MTS was independent of side (L-HR 0.70, P=0.0011; R-HR 0.62, P=0.0012), but pts with R APC WT tumors stood out as an extreme risk group with the worst OS of all L/R and APC MT/WT combinations even in RAS/BRAF WT pts (P&lt;0.0001). This group of R sided RAS/BRAF/APC WT pts represents a novel poor prognostic group and its baseline characteristics are summarized below.
When stratifying APC MT by genomic location, only MTS in the mutation cluster region (n=686) that contains axin and β-catenin binding sites remained prognostic in multivariate models (HR 0.63, P&lt;0.0001), while other APC MTS (n=163) were no longer significant (HR 0.82, P=0.27).
Conclusion: APC WT R sided pts represents a group with poor prognosis regardless of RAS/BRAF MT status. Given the difference in CTNNB1 MT rate and importance of MTS in axin/ β-catenin binding sites, WNT signaling differences between L and R sided tumors may be important to explore further.
Baseline Characteristics of Patients with APC/RAS/BRAF Wild Type Right Sided TumorsBaseline CharacteristicRight Sided APC/RAS/BRAF WT (N=88, 15.2%)Other Right Sided Tumors (N=492, 84.8%)P-ValueMedian Age (IQR)56 (47-61)56 (48-64)0.23GenderFemale46 (52.3%)241 (49.0%)0.56Male42 (47.7%)251 (51.0%)MSI-H8 (10.5%)25 (6.5%)0.22HistologyAdenocarcinoma50 (56.8%)366 (74.4%)0.0018Mucinous / Signet38 (43.2%)123 (25.0%)Other03 (0.6%)Average # of Mutations Per Patient (+/- SD)1.38+/- 2.013.10 +/- 1.79&lt;0.0001Synchronous Metastasis76 (86.4%)401 (81.5%)0.36TP53 MT47 (53.4%)275 (55.9%)0.67PIK3CA MT6 (6.8%)111 (22.6%)0.001CTNNB1 MT7 (8.0%)11 (2.2%)0.004
Citation Format: Jonathan M. Loree, Krittiya K. Korphaisarn, Michael Lam, Van K. Morris, Kanwal P. Raghav, Michael J. Overman, Cathy Eng, Arvind Dasari, Bryan K. Kee, David Fogelman, Robert A. Wolff, Kenna Shaw, Russell Broaddus, Mark J. Routbort, Rajyalakshmi Luthra, Dipen M. Maru, David G. Menter, Funda Meric-Bernstam, Scott Kopetz. APCWT/RASWT/BRAFWT tumors represent an under recognized poor prognostic group of right sided colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4742. doi:10.1158/1538-7445.AM2017-4742