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

Abstract

Introduction: Interrogation of cancers with next-generation sequencing (NGS) mutation panels has become widely utilized, identifying prognostic and actionable mutations. This study explored the value of expanded mutation analysis in appendix peritoneal metastases (APM). Methods: Forty-eight APM patients treated 2013-2018 were retrospectively collected from a registry. Fifty-gene NGS analysis was performed in CLIA approved lab to obtain mutation profiles. All patients underwent cytoreductive surgery (CRS)/hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C. Peritoneal cancer index (PCI), optimal CRS, survival (overall survival [OS] and progression-free survival [PFS]) data were collected. Survival analyses were performed on all APM, high-grade (HG), and low grade (LG) subsets, evaluating the impact of specific mutations on the outcome.Results: Eighty-three percent of APM had a mutation identified. KRAS was most frequent, 65% (88% LG 42% HG) with GNAS identified in 92% of LG-APM. SMAD4 and/or TP53 mutations occurred in 25% of APM with observed decreased OS (46 vs. 81 months p = .0029); worse in HG-APM (26 vs. 49 months p = .0451).SMAD4 was associated with the most significant reduction in PFS in APM (p = .0085). Actionable mutations were identified in 73% of APM patients.Conclusions: Most frequent mutations were KRAS, TP53, and SMAD4, and actionable mutation detection was common. SMAD4 and TP53 were associated with decreased OS. NGS mutation profiling has potential utility in APM.

Peritoneal metastases from primary appendiceal and colorectal carcinomas demonstrate distinct molecular identities on comprehensive tumor analysis

“…Finally, pCRC harbored higher rates of VUS in SMAD4 . Davison et al associated SMAD4 protein expression loss with higher tumor grade and worse prognosis in disseminated appendiceal mucinous neoplasms, similar to findings by Zhang et al 35,36 One possible explanation for the increased rates of VUS in pCRC is the higher rates of MSI seen in these samples.…”

The contemporary management of peritoneal metastasis: A journey from the cold past of treatment futility to a warm present and a bright future

“…Identifying surrogate factors that can be identified before CRS/HIPEC will be important tools in the future. Some potential tools actively being investigated include serologic markers and mutation profiles 2,29,70,71,72 …”

“…These tools currently have a role in colon cancer to identify tumors unresponsive to anti‐EGFR therapy that harbor KRAS and BRAF mutations in metastatic CRC as well as emerging data that, when combined with primary tumor sidedness, may have a predictive role in metastatic CRC outcome 190‐193 . Recent exploratory studies in appendix cancer PM has identified SMAD4 and P53 as surrogates of more aggressive biology 70 …”

“…[190][191][192][193] Recent exploratory studies in appendix cancer PM has identified SMAD4 and P53 as surrogates of more aggressive biology. 70 Circulating tumor cells and genomic serum assays as biologic surrogate tools for response to therapy and early detection of recurrence are actively being investigated and could further expand the tools available to improve the overall management of patients with PM. 194,195 Ongoing investigations of these tools could potentially improve early detection of low-burden disease, identify signatures that predict or measure response to therapy, and improve early detection of recurrence disease.…”

“…Some potential tools actively being investigated include serologic markers and mutation profiles. 2,29,70,71,72 Colorectal Peritoneal Metastasis Management…”