Mutational Patterns Drive Metastatic Aggressiveness of Appendiceal Adenocarcinomas

A comprehensive molecular analysis performed in patients with appendiceal adenocarcinomas revealed distinct molecular subtypes: a clinically indolent RAS-mutated/GNAS-wild-type/TP53-wild-type subtype; a chemotherapy-resistant GNAS-mutated predominant subtype; and an aggressive, highly aneuploid TP53-mutated predominant subtype. The study findings highlight the value of performing somatic tumour profiling for this relatively rare malignancy. Different molecular subtypes of appendiceal adenocarcinomas have distinct clinical and biological behaviours that may be useful in guiding treatment decision making regarding whether to offer cytoreductive surgery and/or systemic therapy. The results are published by Dr. Andrea Cercek of the Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center in New York, NY, US and colleagues on 9 December 2022 in the Journal of Clinical Oncology.

The authors wrote in the background that appendiceal adenocarcinomas encompass diverse, rare tumours that comprise up to 1% of all gastrointestinal cancers. Appendiceal adenocarcinomas are conventionally defined by histology. Mucinous appendiceal adenocarcinoma is the most common subtype, identified by tumour cells highly enriched in surrounding mucin, while goblet cell adenocarcinoma exhibits mixed glandular and neuroendocrine features, and intestinal or colonic-type adenocarcinoma is morphologically similar to colorectal cancer.

Appendiceal adenocarcinomas are usually managed by using colorectal cancer treatment paradigms. Given high appendiceal adenocarcinomas peritoneal tropism, management often involves extensive peritoneal-based cytoreductive surgeries to remove visible disease.

Many patients with metastatic appendiceal adenocarcinoma exhibit decades long disease indolence with a low peritoneal cancer index tumour burden; these patients can experience long treatment-free intervals following cytoreductive surgeries. Other patients with similar histologic features exhibit aggressive, unresectable disease, poor overall survival (OS), and low chemotherapy responsiveness. Given the shortcomings of histopathologic appendiceal adenocarcinoma features to predict clinical outcomes, the study team determined whether co-occurring genomic alterations can identify molecular subtypes with conserved clinical behaviour.

A comprehensive molecular analysis was performed in patients with appendiceal adenocarcinoma to define molecular subtypes. Associations between molecular subtype and OS, intraoperative peritoneal cancer index, and first-line chemotherapy response were assessed adjusting for histopathologic and clinical variables using multivariable Cox proportional hazards, linear regression, and logistic regression models. 

The study team defined distinct molecular lineages of mucinous appendiceal adenocarcinoma from co-occurring mutations in GNAS, RAS, and TP53. Of 164 mucinous appendiceal adenocarcinomas, 24 were RAS-mutated predominant (RAS-mutated/GNAS-wild-type/TP53-wild-type) with significantly decreased mutations and chromosomal alterations compared with tumours with GNAS mutations (GNAS-mutated predominant) or TP53 mutations (TP53-mutated predominant).

No patient with RAS-mutated predominant subtype metastatic mucinous appendiceal adenocarcinoma died of cancer, and OS in this subgroup was significantly improved compared with patients with GNAS-mutated (p = 0.05) and TP53-mutated (p = 0.004) predominant subtypes.

TP53-mutated predominant subtypes were highly aneuploid; increased tumour aneuploidy was independently (p = 0.001) associated with poor prognosis. The findings retained significance in patients with any metastatic appendiceal adenocarcinoma.

RAS-mutated predominant metastases exhibited reduced peritoneal tumour bulk (p = 0.04) and stromal invasion (p < 0.001) compared with GNAS-mutated or TP53-mutated predominant tumours.

Patients with RAS-mutated predominant mucinous appendiceal adenocarcinoma responded more to first-line chemotherapy (50%) compared with 6% of patients with GNAS-mutated predominant tumours (p = 0.03).

The study team found that activating mutations in GNAS and RAS are common in appendiceal adenocarcinoma with relatively fewer TP53 mutations compared with sporadic colorectal cancer. The results demonstrate that the clinical course of appendiceal adenocarcinoma is linked to specific mutational profiles. The profiles show that RAS mutations likely occur early in mucinous appendiceal adenocarcinoma oncogenesis followed by acquisition of mutations in GNAS or TP53 in a near mutationally exclusive pattern.

Analysis of molecular subtypes defined by these mutational patterns reveals the associated progressive aneuploidy and adverse patient outcomes that accompany this mutational evolution. The findings offer a new perspective on molecular complexity as a driver of appendiceal adenocarcinoma metastatic aggressiveness and demonstrate the potential value of key mutational patterns in the clinical management of this disease.

The study was supported by the Glades Foundation, funding from the US National Institutes of Health, the Conquer Cancer—Boehringer Ingelheim Endowed Young Investigator Award in Gastrointestinal Cancer, the US National Cancer Institute grant, and by the Marie-Josée and Henry R. Kravis Center for Molecular Oncology. The Conquer Cancer Foundation is administered by the American Society of Clinical Oncology.

Reference

Foote MB, Walch H, Chatila W, et al. Molecular Classification of Appendiceal Adenocarcinoma. JCO; Published online 9 December 2022. DOI: 10.1200/JCO.22.01392

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