Sexual Difference Matters: Females with High Microsatellite Instability Show Increased Survival after Neoadjuvant Chemotherapy in Gastric Cancer

Abstract

We aimed to investigate patients with gastric/gastro-esophageal adenocarcinomas for sex- and age-specific differences regarding overall survival (OS) and response to neoadjuvant chemotherapy (CTx) under consideration of tumor specific molecular subtypes. Overall, 717 patients were analyzed, including 426 patients treated with and 291 treated without neoadjuvant CTx. Microsatellite instability (MSI) and Epstein-Barr virus positivity (EBV+) were determined previously. Females demonstrated a significantly increased OS (p = 0.035), particularly in the subgroup treated with CTx (p = 0.054). No significant differences regarding age were found. In the molecular subgroups, no sex-related differences were observed in the non-CTx group. However in the CTx group, females with MSI-high (H) tumors showed the best OS (p = 0.043), followed by the male MSI-H (p = 0.198) and female MSS (p = 0.114) compared to the male MSS group as reference. The interaction between sex and MSI in this patient group was noticeable (p = 0.053) and was included as a relevant factor in multivariable analyses. In conclusion, our results show an effect of sex on OS in gastric/gastro-esophageal cancer specifically for patients treated with neoadjuvant CTx. The superior survival of women with MSI-H tumors after neoadjuvant CTx implies that combined consideration of these factors could contribute to an individualized treatment of the patients.

Elevated microsatellite instability at selected tetranucleotide (EMAST) repeats in gastric cancer: a distinct microsatellite instability type with potential clinical impact?

“…DNA from formalin‐fixed paraffin‐embedded (FFPE) normal and tumour tissues was isolated after manual microdissection as described previously and was used for analysis [ 8 , 9 ]. Samples with a tumour cell content of at least 10% were included for MSI analysis according to the described limit of detection for MSI [ 25 ].…”

“…Tumours with only instability at two dinucleotides were additionally analysed using three mononucleotides (NR‐21, NR‐24, and NR‐27). Tumours were classified as MSI‐H if at least two markers of the Bethesda panel were unstable including at least one unstable mononucleotide marker or if at least two of the five mononucleotide markers showed instability essentially as described [ 9 ].…”

“…MSI‐H is due to defects in the DNA MMR proteins, MLH1, MSH2, MSH6, or PMS2, which normally correct the frequent replication errors occurring at short repetitive microsatellite sequences. MSI‐H has been identified as an important, distinct molecular subtype in 10–22% of gastric carcinomas (GC) and an association with specific clinical characteristics such as intestinal histotype, distal tumour location, female sex, and older age has been demonstrated [ 5 , 6 , 7 , 8 , 9 ]. Of note, MSI‐H has been related to increased survival in the majority of studies [ 7 , 10 ].…”

“…Of note, MSI‐H has been related to increased survival in the majority of studies [ 7 , 10 ]. For patients treated with neoadjuvant chemotherapy (CTx), controversial results have been reported, as a negative prognostic effect of MSI‐H as well as an association of MSI‐H with favourable prognosis, specifically for females, have been shown in this therapeutic setting [ 8 , 9 , 11 ].…”

“…In recent studies, we performed a comprehensive molecular characterisation in large GC cohorts, including determination of the molecular subgroups MSI and Epstein–Barr virus positive (EBV+), encompassing patients treated with and without neoadjuvant platinum/5‐fluorouracil (5‐FU)‐based CTx [ 8 , 9 , 21 ]. MSI and EBV‐positive tumours are two of the molecular subtypes described by the Cancer Genome Atlas Consortium (TCGA) [ 5 ].…”