Prognostic significance of the localization of the primary tumor and HER2-receptor expression in KRAS wild-type metastatic colorectal cancer treated with anti-EGFR therapy

Abstract

Background: Treatment of metastaƟ c colorectal cancer (mCRC) remains a clinical challenge since a certain percentage of paƟ ents with RAS/RAF wild type (wt) tumor do not respond to anƟ -EGFR therapy. The reasons may be a consequence of primary or secondary resistance or the excessive expression of HER2 receptors in paƟ ents with mCRC. The localizaƟ on of the primary tumor (LPT) can also contribute to variable treatment response and disease outcomes since segments of the large bowl represent disƟ ncƟ ve molecular enƟƟ es. The aim of this study was to examine the prognosƟ c value of LPT, as well as to invesƟ gate the role of HER2-receptor expression in paƟ ents with mCRC. PaƟ ents and Methods: This study included 181 paƟ ents (101 leŌ LPT and 80 right LPT) with KRASwt mCRC, who received anƟ -EGFR therapy at the Oncology InsƟ tute of Vojvodina. KRAS mutaƟ on status was determined using Real-Time PCR methodology, while HER2-receptor expression was detected immunohistochemically. The eff ect of anƟ -EGFR anƟ body therapy was analyzed using progression-free survival (PFS) and overall survival (OS) in relaƟ on to the LPT and the HER2-receptor expression. Results: The median OS in paƟ ents with leŌ -side tumors was signifi cantly beƩ er than in paƟ ents with rightside localized tumors (43 vs. 33 months, Mantel-Cox p=0.005; Breslow p=0.001), as well as median PFS (6 vs. 3 months, Mantel-Cox p <0.001; Breslow p<0.001). According to the mulƟ variate Cox regression analysis of OS and PFS, right tumor localizaƟ on also represents an independent prognosƟ c factor (p=0.022; HR 1.46; 95% CI 1.06-2.01; p=0.004; HR 1.60; 95% CI 1.16-2.21, respecƟ vely). The OS of HER2 posiƟ ve paƟ ents is worse than in HER2 negaƟ ve paƟ ents (p = 0.339), while the PFS of HER2 posiƟ ve paƟ ents was signifi cantly worse (p<0.001) compared to HER2 negaƟ ve paƟ ents (despite a relaƟ vely small number of HER2 posiƟ ve paƟ ents). Conclusion: LocalizaƟ on of the primary tumor is an important prognosƟ c marker in the KRASwt mCRC paƟ ents since results demonstrated that paƟ ents with right-sided primary tumors have a staƟ sƟ cally signifi cantly shorter PSF and OS. The role of HER2 receptor expression requires further examinaƟ on, although we noted a low expression level of HER2 receptor in KRASwt mCRC; these paƟ ents also had a shorter PFS and OS.