Study Suggests Need to Develop Therapeutic Modalities to Target Early-Onset Appendiceal Cancer

A cohort study published in JAMA Network Open suggested that appendiceal cancer diagnosed among younger individuals harbors a distinct genomic landscape, as compared with diagnoses among older individuals.

Given this finding, researchers indicated that there is a need to develop therapeutic modalities that target these unique molecular characteristics in younger patients.

“These findings demonstrate that [appendiceal cancers] diagnosed among young individuals harbor a distinct molecular phenotype compared with late-onset [appendiceal cancers] and yield clinical actionability in future studies that should aim to elucidate distinct molecular phenotypes and mechanisms of early-onset [appendiceal cancer] and to develop and test personalized therapeutic modalities tailored to young patients diagnosed with [appendiceal cancer],” the study authors wrote.

In this study, researchers assessed patients aged 18 years and older who had been diagnosed with pathologically verified appendiceal cancer. Using the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (GENIE), cases which specifically included clinical-grade targeted sequencing data were identified.

“The use of data from the GENIE clinicogenomic data-sharing consortium is a strength of this study because it allowed for pathologically verified cases with clinical-grade sequencing data to be identified from 12 institutions worldwide,” the authors noted.

Overall, 385 patients with appendiceal cancer were evaluated, including 109 patients (28.3%) who were diagnosed with early-onset appendiceal cancer. Importantly, race and ethnicity varied by age at disease onset, with non-Hispanic Black patients accounting for a larger proportion of early-onset compared to late-onset cases (9 of 109 [8.3%] vs 11 of 276 [4.0%]; P = .04).

Moreover, patients with early-onset appendiceal cancer had significantly higher odds of presenting with nonsilent variations in PIK3CA, SMAD3, and TSC2 (PIK3CA: odds ratio [OR], 4.58; 95% CI, 1.72-12.21; P = .002; SMAD3: OR, 7.37; 95% CI, 1.24-43.87; P = .03; TSC2: OR, 12.43; 95% CI, 1.03-149.59; P = .047) when compared with patients aged 50 years or older at diagnosis. Contrastingly, compared with individuals with late-onset appendiceal cancer, those with early-onset appendiceal cancer had 60% decreased odds of presenting with GNAS nonsilent variations (OR, 0.40; 95% CI, 0.21-0.76, P = .006).

When classified by histological subtype, compared with late-onset cases, young patients with mucinous adenocarcinomas of the appendix had 65% decreased odds of variations in GNAS in adjusted models (OR, 0.35; 95% CI, 0.15-0.79; P = .01). Likewise, patients with early-onset nonmucinous appendiceal adenocarcinomas had 72% decreased odds of presenting with GNAS variations when compared with late-onset cases, though these findings did not reach statistical significance (OR, 0.28; 95%CI, 0.07-1.14; P = .08).

Of note, GNAS and TP53 variations were mutually exclusive in appendiceal cancers among early-onset and late-onset cases (P < .05).

“Given that previous studies have revealed that most high-grade [appendiceal cancers] are GNAS wild-type tumors and also that GNAS and TP53 variations tend to be mutually exclusive, these findings suggest that a subset of early-onset [appendiceal cancers] may be more likely to occur de novo rather than progressing from low-grade tumors—emphasizing that distinct pathways may contribute to early-onset [appendiceal cancer],” the authors wrote. “Given this mutual exclusivity for GNAS and TP53 variations and reduced likelihood for young patients with [appendiceal cancer] to have somatic GNAS variations compared with late-onset cases, future studies are also warranted to examine germline TP53 variants and hereditary syndromes among young patients diagnosed with [appendiceal cancer].”

Additionally, the investigators noted with the relatively low somatic variation frequency in TSC2 and SMAD3 observed in the current study cohort, further research is still necessary to explore the mechanistic role of these genes and related pathways, especially in early-onset appendiceal cancer.

Reference:

Holowatyj AN, Eng C, Wen W, Idrees K, Guo X. Spectrum of Somatic Cancer Gene Variations Among Adults With Appendiceal Cancer by Age at Disease Onset. JAMA Network Open. doi: 10.1001/jamanetworkopen.2020.28644