Gastric Cancer Deep Dive

Welcome back to the SO Files! We’re happy to present part 2 of our gastric cancer series. Here we briefly review the historical gastric cancer classifications (Lauren and WHO) and then explain how this has drastically changed over the past 5-10 years with the advent of next-generation sequencing capabilities. We go in depth to evaluate how this applies to the budding surgical oncologist, and what discoveries may lie on the horizon. We also welcome back Dr. Ryan Fields, MD, FACS who is an Associate Professor in the Department of Surgery at Washington University in St. Louis and was recently appointed co-leader of the Solid Tumor Therapeutics Program (STTP) at Siteman Cancer Center.  Dr. Fields talks about the outcomes of several recent trials and how they are helping us to treat gastric cancer patients in the clinic today. As always, all references from the podcast are linked below, enjoy!

Background:

NCCN Guidelines – Gastric Cancer 

An updated, evidence based overview of gastric cancer management. Workup, and    surgical/ medical treatment algorithms discussed.

Relevant Reading:

1. Comprehensive molecular characterization of gastric adenocarcinoma

The Cancer Genome Atlas, Nature 2014

Comprehensive molecular evaluation of 295 primary gastric adenocarcinoma specimens reveals four distinct subtypes of gastric cancer: Epstein – Barr virus (EBV) positive (~10% of tumors), microsatellite unstable tumors (MSI-Hi, ~20% of tumors), genomically stable tumors (~20% of tumors), and chromosome instability tumors (~50% of tumors). 

2. ToGA (Trastuzumab for Gastric Cancer) Trial

Bang et al. The Lancet 2010

International (122 centers in 24 countries), phase 3, RCT comparing chemotherapy versus chemotherapy PLUS trastuzumab in patients with gastric cancer that over-expresses HER2 protein. 594 patients, primary endpoint was overall survival. Median overall survival was 13.8 months in the chemo PLUS trastuzumab group, compared to 11.1 months in the chemo alone group.

Takeaway – Chemo + Trastuzumab > chemo alone for gastric cancer

3. Adjuvant Options for Advanced Melanoma

Melanoma episode with Dr. Andtbacka where we discussed the role of PD-1/PDL1-2 in cancer.

4. PD-1 and Mismatch Repair Deficiency Trial

Le et al., NEJM 2015

Treated 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency with Pembrolizumab (anti-PD 1 immune checkpoint inhibitor). Coprimary end points were immune-related objective response rate and 20-week immune-related progression-free survival rate. Mismatch repair-deficient colorectal carcinomas had 40% and 78% objective response rate and progression free survival respectively. Compared to mismatch repair-proficient tumors, which saw 0% and 11% immune-related objective response rate and immune-related progression-free survival rates respectively. Patients with mismatch repair-deficient noncolorectal cancers had responses similar to those of patients with mismatch repair -deficient colorectal cancer.

Takeaway – MMR status can predict clinical benefit of immune checkpoint blockade with pembrolizumab. 

5. KEYNOTE – 059 Trial

Fuchs et al., JAMA Oncology 2018

International, Phase 2 trial designed to evaluate safety and efficacy of pembrolizumab in patients with previously treated advanced Gastric and GE junction cancer. 259 patients, 16 countries were treated with IV pembrolizumab until disease progression. Primary end points were objective response rate (ORR) and safety. Demonstrated promising activity for all patients (11.6%) which was more prominent in PD-L1+ tumors (15.5% ORR) compared to PD-L1- tumors (6.4%). 

Takeaway – Pembrolizumab demonstrated objective response for all-comers with progressive (failed 2 or more previous chemo regimens) advanced gastric cancer, with especially pronounced response in PD-L1+ tumors.

6. PD-1 Inhibition in Metastatic Gastric Cancer Trial

Kim et al., Nature Medicine 2018

Phase 2 trial that performed molecular characterization of tissues and circulating tumor DNA (ctDNA) from 61 patients with metastatic gastric cancer (mGC); tried to identify determinants of response to salvage pembrolizumab therapy. Saw very high overall response rates in patients with EBV+ tumors (100%) and MSI-high tumors (85.7%). Overall response rate was also higher in patients with PD-L1+ tumors compared to PD-L1 negative tumors, 50% vs 0% respectively

Takeaway – EBV positivity, MSI-high status, and PD-L1 positivity in gastric cancer all predict likely response to pembrolizumab.