Molecular Insights into Gastric Cancer: A Comparative Analysis of Asian and White Populations

 

  • Authors: Saar Peles, Roy Khalife, Anthony Magliocco

  • Presented at: San Antonio Breast Cancer Symposium 2024, San Antonio, TX

  • Journal: Cancer Diagnosis & Prognosis. 2025 Jun 30;5(4):429–436

  • Publication Date: 2025/6/30

Background:

Breast cancer is a heterogeneous disease with many biological subtypes. Invasive lobular carcinoma (ILC) is a rarer subtype of increasing clinical importance, with distinct clinical pathological and molecular features that are not fully understood. The incidence of ILC is increasing compared to ductal carcinoma in the US. While the incidence of breast cancer is lower in African American/Black (AA/B) women compared to White women (W), mortality rates are disproportionately higher. The reasons for this disparity are unclear. The aim of this study is to better characterize the molecular features of lobular breast cancer and determine if differences exist between AA/B women compared to W women. Methods: The Cancer Genome Atlas firehose data set was analyzed in cBioPortal, comparing AA/B (n=16) and W (n=166) women with lobular breast cancer. Statistical tests including linear cox regression, Fisher’s exact test, and chi square analysis were performed using R (version 4.4.1, 2024). Variables included race, stage, age, and hormone receptor status. Analysis compared differences in overall and disease-free survival and interpreted molecular differences between the two groups. ClinVar was used to determine frequency of germline mutations in the general population. Results: There were no differences for distribution of age or stage between racial subgroups. Proportions for stage were 18.7% AA and 15.7% W for stage 1, 62.5% AA and 50.3% W for stage 2, and 18.8% AA and 33.9% W for stage 3. The median age was 59.3 for AA/B and 62.0 for W. Overall survival at 36 months was worse (76.7%) in AA/B compared to (94.6%) in W women with ILC (p=0.056). In this cohort, age and stage were not associated with differences in overall survival. Estrogen receptor (ER) negative status was more prevalent in AA/B subgroup with ILC (22%) compared to W women with ILC (2%). Overall survival at 36 months for patients with ER negative ILC was shortened compared to ER positive ILC (50% vs 98% respectively, p=0.0001). However, when separated by racial subgroup, ER status was not associated with differences in overall survival for AA/B vs. W. Patients with ER negative ILC were 14.29 times more likely to have a TP53 alteration compared to ER positive ILC (p= 0.002). TP53 mutation was more prevalent in AA/B (37.6%, n=6) compared to W (3.6%, n=6) in lobular cancer. Within the AA subgroup, disease free survival at 36 months for patients with TP53 alterations was 25% (n=5) compared to 100% for patients with unaltered TP53 (n=11) (p=0.0004). Within the W subgroup, patients with TP53 alterations were less common and associated with longer disease-free survival at 3 months (100%, n=6 for altered) compared to unaltered TP53 (89.5%, n=160) (p=0.50). Among the 6 AA/B patients with TP53 alterations, four had allele frequencies of 0.4-0.7, possibly suggestive of germline mutation. A search of ClinVar revealed two out of the four TP53 mutations were previously seen in Li Fraumeni syndrome (R248W, L255 del). Conclusion: Overall survival for ILC was worse in AA/B women compared to their W counterparts, consistent with existing literature. Differences in hormone status and inherited and somatic gene mutations were identified between racial subgroups. Among ILC there is an aggressive subtype characterized by ER negativity and TP53 mutations. This subtype may be more common in AA/B. These results suggest that some TP53 mutations in AA/B may be inherited; this could have implications for future targeted TP53 therapy in AA/B. However, analysis is limited by small sample size for AA/B women with ILC, and absence of detailed sociodemographic, treatment and outcome data. Future studies should include a larger size of AA/B, and control for sociodemographic and treatment variables.

 
Anthony Magliocco