P-45 Microsatellite instability and HER2 status in radically resectable locally advanced esophago-gastric adenocarcinoma: A single-center experience

Abstract

Peri-operative systemic chemotherapy significantly improved the prognosis of patients with resectable locally advanced gastric cancer (LAGC) but, despite that, relapse-related death remains a major challenge. Neoadjuvant chemotherapy (NAC) plays a crucial role and is currently recommend by international guidelines. Several biomarkers, including human epidermal growth factor receptor-2 (HER2) and mismatch repair (MMR) or microsatellite instability (MSI) are crucial for treatment decision in metastatic setting. However, currently, no biomarkers can guide the choice of NAC in clinical practice. In addition, most of available data derived from surgical specimens, harboring potential confusing factors after NAC. Our aim was to evaluate correlations between MSI and HER2 status and clinical outcomes in resectable LAGC treated with perioperative chemotherapy. We conducted a retrospective cohort study of resectable LAGC patients treated with NAC and surgery +/- adjuvant chemotherapy from 2006 to 2018, for whom endoscopic pre-NAC and surgical post-NAC samples were available. A uniform small cohort of patients receiving adjuvant chemotherapy only was added for general prognostic analyses. Clinical parameters were collected including patient and tumor characteristics. Determinations of HER2 and MMR status were carried out on endoscopic pre-NAC and surgical samples. Pathologic complete response (pCR) rate, Overall survival (OS) and event-free survival (EFS) were estimated and evaluated for association with histologic downstaging and MSI status using Cox proportional hazard models. Moreover, in dMMR cases, a custom in-house Next-Generation Sequencing (NGS) (Ion Torrent S5) panel was performed, assessing mutational status of 26 tumor-genes (EGFR, MET, ALK, RET, KRAS, NRAS, HRAS, BRAF, KIT, PDGFR α/β, GNAQ, GNA11, PIK3CA, AKT1, MAP2K1, MAP2K2, TP53, ERBB2, SMAD4, PTEN, STK11, CTNNB1, NOTCH1, POLE, ESR1). We selected 76 out 90 patients, with a median age at diagnosis of 61 years. Fifty-nine patients received NAC, while 17 were treated with adjuvant chemotherapy alone. Overall, dMMR/MSI-H counted for 8% of cases, entirely consistent between endoscopic and surgical samples. Six percent of tumors were HER2 positive on endoscopic tumor assessment and 4% on surgical samples. Tumor downstaging was observed in 52.5% of the population, with 3 pCR (5.1%), none of them in MSI-H cancers. According to MSI status and pCR, EFS and OS were better for MSI-H patients and MSS achieving pCR compared to MSS without pCR [EFS NR vs NR vs 30.0 months (95% CI 16.8 – NR.), P = .08; OS NR vs NR vs 39.6 (95% CI 27.6 – NR) P = .10]. Considering the entire population, EFS and OS were analyzed according to MSI status with a better outcome for MSI-H patients [EFS NR vs 48.0 months (95% CI 25.2 – 229.4), P = .121; OS NR vs 62.4 (95% CI 28.8 – 229.4) P < .143]. The most common alteration in MSI-H cases was TP53 mutation (4/6), other mutations detected were KRAS, SMAD4, ERBB2, BRAF, PIK3CA, RET and PTEN. Our work confirms the positive prognostic effect of MSI-H in the curative setting of LAGC, not correlated with the rate of pathologic tumor response to NAC. Prospective ad-hoc trial focused on dMMR/MSI-H and more accurate molecular profiling are strongly needed in resectable LAGC.