Universal germline genetic testing in unselected patients with gastric, gastroesophageal junction and esophageal cancers was able to identify PGV in 15.6% of patients with the majority in high and moderate penetrance genes, including those in DNA damage repair pathways where precision targeted therapies exist. The incidence of PGVs was higher in GEJ tumors when compared to gastric and esophageal cancers. The population frequency of PGVs in BRCA1, BRCA2, CDH1, PALB2, SDHA, ATM, HOXB13, MITF, and FH is estimated to be less than 1%, and for MUTYH heterozygotes to be 1–2% [15,16,17]. Accordingly, the frequencies of PGVs in this cohort in high penetrance genes BRCA1, BRCA2, CDH1, PALB2 and SDHA, moderate penetrance genes ATM, HOXB13 and MITF, and low penetrance/recessive genes MUTYH (monoallelic) and FH all appear to be overrepresented in these patients with cancer compared to the general population.
Importantly, 80% of the PGV would not have been detected using current (2020) guidelines for genetic testing from national societies or professional organizations. For example, NCCN guidelines for considering germline genetic testing of individuals with gastric cancer require patients meet a complicated combination of criteria for eligibility . This includes any one of the following: being diagnosed with diffuse gastric cancer (DGC) before 50 years of age without a family history, having a personal or family history of DGC and lobular breast cancer (one diagnosed < 70 years of age), two gastric cancer cases in a family (one confirmed DGC regardless of age), two cases of lobular breast cancer in family members < 50 years of age, DGC in any age in individuals of Maori ethnicity (or with personal or family history of cleft lip/cleft palate), or bilateral lobular breast cancer < 70 years of age.
For patients with GEJ or esophageal cancers, the NCCN does not have any guidelines recommending germline genetic testing, indicating that, “Although early age of onset, multiple family members with the same or related cancer, and individuals with multiple primary cancers are all signs of hereditary cancer, specific referral guidelines for esophageal and [GEJ] cancers risk assessment are not possible at this time.” Accordingly, none of the patients with GEJ or esophageal cancers would be recommended for germline genetic testing because the NCCN does not have guidelines that apply to these patients .
The incidence of gastric cancer worldwide is relatively low in countries such as the USA and highest in East Asian countries such as Japan. However, the rate of germline mutations in CDH1 in patients with gastric cancer varies inversely with the incidences of gastric cancer, with high CDH1 mutation detection rates in the USA and low detection rates in Japan . Prior to identification of CDH1 germline mutations in Japanese patients, nearly all cases of gastric cancer were attributed to past exposure to H. pylori or some other carcinogen such as food and smoking, in the setting of a widely implemented screening program for gastric cancer. Identification of CDH1 PGVs in Japanese gastric cancer patients, though low in frequency, led to the recommendation to screen for CDH1 PGVs, as part of medical management in gastric cancer patients in Japan . However, due in part to low rates of detection for CDH1 PGVs in countries such as Japan, genetic testing is often under-utilized. The higher rate of PGVs in CDH1 and other cancer risk genes in US patients, as reported here, may provide motivation to offer germline genetic testing to all patients with gastric, GEJ and esophageal cancers.
Although the majority of gastric cancer cases are felt to be sporadic, up to 20% of gastric cancer patients may also have relatives with gastric cancer suggesting a familial risk. From those patients, only 3–5% are found to have an inherited germline variant detected [20, 21]. Multiple cancer predisposition syndromes may be associated with the development of gastric cancers such as Li Fraumeni syndrome, Lynch syndrome and CDH1-associated hereditary diffuse gastric cancer [20, 22, 23]. Most patients with families that meet clinical criteria for hereditary diffuse gastric cancer will harbor CDH1 germline mutations . However, for CDH1-mutation negative patients, application of targeted sequencing has identified pathogenic variants in other related genes including CTNNA1, BRCA1, BRCA2, STK11, SDHB, PRSS1, ATM, MSR1, RAD51 and PALB2 [24,25,26,27,28,29,30]. DDR genes are of particular interest considering possible targeted treatment strategies in this group of patients with homologous recombination deficient tumors, including platinum-based therapies and poly-ADP-ribose polymerase (PARP) inhibitors such as olaparib. In the current manuscript, application of a universal multi-gene panel testing found 17.6% of gastric cancer patients harbored a PGV. Interestingly along with a PGV in the gene CDH1, PGV in DDR genes including BRCA1 and BRCA2 were identified. Exploiting DDR genes have already been the subject of a randomized trial in ATM-negative metastatic gastric cancer . However, the combination paclitaxel plus olaparib did not improve overall survival . Nowadays other combinations with olaparib are being developed, including with anti-programmed death-ligand 1 (PD-L1) durvalumab and anti-vascular endothelial growth factor receptor-2 (VEGFR2) ramucirumab [31,32,33].
Among patients with esophageal and GEJ cancers, PGV were identified in 10.8 and 20% with the majority being in DDR-related genes including ATM, BRCA2 and PALB2. Some esophageal cancers have been found to be related to hereditary cancer predisposition syndromes such as tylosis, familial Barrett’s esophagus, Bloom syndrome and Fanconi anemia, with the latter related to BRCA2 and PALB2 [34,35,36,37]. The association between BRCA and esophageal cancer (both squamous cell carcinoma and adenocarcinoma) was also observed by other groups [38,39,40]. However, currently, referral to a cancer genetics professional is recommended only for patients fulfilling criteria for a known high-risk syndrome. Considering current guidelines including NCCN, NSCG or ACMG in the year 2020, only 20% of patients with a PGV would have been detected. This limits the opportunities for future cancer prevention in the proband and their relatives. Several tumor agnostic trials are already underway or being developed for patients that harbor a deleterious mutation in homologous recombination repair (HRR) genes. As an example, a phase II study evaluating the efficacy of rucaparib (PARP inhibitor) for advanced solid tumors that have a deleterious mutation (germline or somatic) in BRCA1, BRCA2, PALB2, RAD51C, RAD51D, BARD1, BRIP1, FANCA, NBN, RAD51 or RAD51B (NCT04171700). With this new horizon of options for patients with advanced and recurrent disease, this study in unselected gastric and esophageal cancer patients highlights the usefulness of universal germline testing. Despite major advances in the systemic treatment of metastatic gastric and esophageal cancers with the incorporation of immunotherapy in the first line of systemic treatment, median overall survival remains poor, with most patients with advanced disease dying within 2 years of diagnosis [41,42,43].
Some limitations of the current study include the demographic characteristics of patients seen at the multiple Mayo Clinic sites participating, as they may not reflect populations in other areas of the USA or other countries. Further, no integrative somatic tumor analysis was performed. The combination of universal germline and somatic testing may detect additional HRR deficient tumors. Due to a limited number of cases with positive PGV in each of the three different primary tumor locations, an analysis and comparison of outcomes and response to treatments was not permissible. Larger cohorts are necessary to address important questions related to treatment outcomes of gastric, esophageal, and GEJ cancer patients with PGVs.
In this prospective, multi-site study in unselected patients with gastric, esophageal, and GEJ cancers, implementation of universal germline testing identified that 1 in 6 patients carry a PGV. Incorporation of universal germline testing in these patients could improve development of protocols for cancer risk assessment, personalized medicine, and family counseling.