Investigating the utility of extended mutation analysis in gastrointestinal peritoneal metastasis

Abstract

Background and Objectives: Outcomes for gastrointestinal peritoneal metastases (GI-PM) are worse compared to systemic metastases, with a paucity of data exploring extended mutation profiling. An exploratory mutation analysis in GI-PMs was performed as a "proof of concept" of potential predictive values of profiling in GI-PM and rates of actionable mutations. Methods: The study included 40 GI-PM patients: 14 low-grade mucinous carcinoma peritonei and 26 HG-PM (12 colons, 10 appendix, 4 small bowels). Demographics, histologies, peritoneal cancer indexes, cytoreduction scores, and survival data were collected. NGS 50-gene mutation profiling was performed on 38 specimens. The association of mutations with survival was evaluated in high-grade PM. Results: KRAS, TP53, and SMAD4 mutations were observed in 61%, 29%, and 8% of cases across all tumor histologies. In 66% cases >1 mutations occurred, associated with decreased survival in HG-PM: 32 vs 73 months, P = .03. TP53 or SMAD4 mutations were associated with decreased survival in HG-PM: 22 vs 48 months, P = .02. Actionable mutations were detected in 70%. Conclusion: Actionable mutations were detected at high rates. GI-PMs have similar mutational profiles and TP53, SMAD4, and/or >1 mutation were associate with decreased survival in HG-PM. This data supports the concept of the extended mutation profiling utility in GI-PM warranting further investigation.

Exploring the prognostic and therapeutic utility of expanded mutation profiling in appendix peritoneal metastasis managed with CRS/HIPEC

“…26,27 In this analysis TP53 and SMAD4 mutated APMs experienced shorter OS similar to previously reported outcomes in high-grade peritoneal metastasis arising from the colon, appendix, and small bowel. 18 Additionally, the observed impact of TP53 mutation in this series aligns with data reported by Ang et al that included primary and metastatic appendix cancers with a survival of 37 months for TP53 mutation versus 76 months TP53 wildtype. 26 Similarly, in this study the observed TP53 survival was 46 versus 81 months for wildtype p = .003, both studies demonstrating 30-40 month observed survival reduction for TP53 mutated APMs.…”

“…17 A recently published study investigating the utility of NGS extended mutation in peritoneal metastasis arising from colon, high-grade appendix, and small bowel cancers reported that TP53 and SMAD4 mutation detection was associated with decreased survival, as was the detection of more than one mutation. 18 This is a dedicated mutation analysis in APM to investigate the impact of P53, SMAD4, and KRAS mutations on survival outcomes, explore mutation frequency across the spectrum of APM histologies, and identify the rate of actionable mutations based on the TAPUR and MATCH trials. 19,20 2 | METHODS…”

The genetic profile and molecular subtypes of human pseudomyxoma peritonei and appendiceal mucinous neoplasms: a systematic review

“…Two studies did not specify the rates according to histological subtype in their samples of PMP; however, Gleeson et al [44] found a co-occurrence rate of 87% and Pietrantonio et al [51] found a co-occurrence rate of 64%. Other studies comprised of only low-grade samples also documented the co-occurrence of KRAS and GNAS mutations using the same experimental methods [35,38,42,45,48,59]. Using NGS, Foster et al [35] noted a co-occurrence rate of 100% in their sample of LGMCP, Tsai et al [38] identified a co-occurrence rate of 35% in LAMN and 83% in PMP cases caused by LAMN, and Liu et al [59] identified a co-occurrence rate of 40% in their sample of LAMN.…”

“…Other studies comprised of only low-grade samples also documented the co-occurrence of KRAS and GNAS mutations using the same experimental methods [35,38,42,45,48,59]. Using NGS, Foster et al [35] noted a co-occurrence rate of 100% in their sample of LGMCP, Tsai et al [38] identified a co-occurrence rate of 35% in LAMN and 83% in PMP cases caused by LAMN, and Liu et al [59] identified a co-occurrence rate of 40% in their sample of LAMN. Pengelly et al [45] identified a co-occurrence rate of 100% in their sample of LAMN using whole-exome sequencing, and Alakus et al [4] noted a co-occurrence rate of 69% in their sample of LAMN and PMP using PCR.…”

“…Studies (n=17) noted the presence of TP53 mutations in PMP and AMN samples [4, 26, 32, 34, 35, 38-44, 51, 52, 55, 57, 59]. Nine papers noted TP53 expression in only high-grade neoplasms and PMP [4, 26, 32, 38-40, 44, 57, 59], whereas four papers noted TP53 expression in both low-grade and high-grade neoplasms [34,35,42,55] (Table 2). Specifically, Nummela et al [57] noted that P53 protein expression was significantly associated with HAMN (P=0.012).…”