Abstract B138: Prognostic value of PTEN loss for second-line paclitaxel treatment efficacy in metastatic gastric cancer

Abstract

Abstract Introduction: For recurrent and metastatic gastric cancer, systemic chemotherapy is used for palliative purposes, and a paclitaxel- or irinotecan-based regimen is typically used in the second-line setting. Recent advances in research including the TCGA project now enable gastric cancer to be divided into four molecular subgroups, yet whether there are differences in chemotherapy response for each molecular subgroup remain largely unknown. Our aim in this study is to retrospectively compare the efficacy of paclitaxel as second-line chemotherapy according to molecular subtype and to evaluate prognostic value for these markers. Method: A total of 235 metastatic gastric cancer (mGC) patients who have been treated with second-line paclitaxel-containing regimen (paclitaxel monotherapy, FL/paclitaxel) between 2005-2017 were assessed. Archived formalin-fixed, paraffin-embedded tissue blocks obtained before the start of paclitaxel treatment were examined for EGFR, HER2, and PTEN status using immunohistochemistry (IHC). HER2 positivity was defined as either IHC 3+ or 2+ with amplification confirmed by FISH/SISH, and EGFR positivity was defined as IHC 3+. PTEN loss was defined as having complete loss of PTEN expression. MSI-H and EBV-positive group was excluded in this study. Treatment response was based on CT images taken every 2 to 3 cycles of chemotherapy and evaluated according to the RECIST criteria. Overall survival (OS) and progression-free survival (PFS) were calculated based on the starting point of second-line chemotherapy until death or disease progression, respectively. Those negative for all three markers (HER2, EGFR, PTEN loss) were categorized as genome stable (GS)-like molecular group. Result: Patients were classified into subgroups based on HER2, EGFR, and PTEN expression; 19.6% (46/235) were HER2 positive, 15.0% (26/173) were EGFR positive, and PTEN loss was observed in 11.6% (20/173). Expression status for the three markers showed tendency towards mutual exclusivity. When coexpression rates were taken into account, 35.3% (61/173) showed positivity in at least one of the markers, and 64.7% (112/173) were negative for all three. This latter group, categorized as GS-like molecular group, showed a tendency towards poor overall survival compared with patients positive for at least one molecular marker, with median survival of 5.7 vs 8.8 months (P=0.012). There were no significant differences in OS or PFS in terms of HER2 and EGFR status. However, patients with PTEN loss had significantly longer overall survival than those with intact PTEN expression, with median survival time of 12.0 months (95% confidence interval [CI], 7.0 - 21.2) and 6.2 months (95% CI, 4.7-7.2), respectively (P=0.003). Conclusion: In mGC patients treated with second-line paclitaxel chemotherapy, HER2 and EGFR status had no predictive or prognostic value. Contrary to the general association of PTEN loss with poor prognosis in many solid cancers including gastric cancer, PTEN loss group showed better survival outcome for second-line paclitaxel treatment in our study. Indirect association of PTEN with other pathways of multidrug resistance or cell cycle-related molecules that ultimately affect the PI3K/Akt pathway may play a role. Further investigation is needed for specific mechanisms and factors that lead to increased paclitaxel sensitivity in the PTEN loss group. Citation Format: Kyoo Hyun Kim, Jeong Hyun Jo, Sejung Park, Minkyu Jung, Woo Sun Kwon, Jee Hung Kim, Hyo Song Kim, Seung-Hoon Beom, Hyun Cheol Chung, Sun Young Rha. Prognostic value of PTEN loss for second-line paclitaxel treatment efficacy in metastatic gastric cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B138.