Outcomes in patients with pancreatic and ampullary cancer whose tumors harbor pathogenic APC mutations.
Authors: Christopher Pishvaian, Thomas McPhaul, Dea Cunningham, Lei Zheng, Dan Laheru, Ana De Jesus-Acosta, Dung T. Le, Ilene S. Browner, William Burns, Richard Burkhart, Kelly Lafaro, Amol Narang, Jin He, Valerie Lee, Michael J. Pishvaian
Journal: Journal of Clinical Oncology (2024)

693 Background: APC (adenomatous polyposis coli) is master regulator of the WNT signaling and beta-catenin pathway. Pathogenic (path) mutations in APC are well known for their connection to familial adenomatous polyposis, but germline (G) mutations in APC can give rise to other cancers, and somatic (S) mutations in APC can be found in multiple cancer subtypes. The clinical relevance for tumors that harbor path APC mutations is unknown. Methods: An established database of patients whose tumors have undergone genetic testing (Next-generation DNA sequencing, NGS) was queried for the presence of an APC mutation. Each APC mutation identified was assessed using the NCI Clinvar data base for determination of a path/likely path APC mutation. Patient/disease characteristics and treatment (tx) information were captured from electronic medical record review. Median overall survival (OS) was defined from the time of diagnosis of advanced/metastatic disease until death. Median time to progression (TTP) for each tx regimen was defined from the initiation of tx until documented disease progression. Results: A database of over 13000 patients entered from 2018 to present included 133 patients (1%) with G- or S-APC mutations, of which 41 were identified as path/likely path. Of the 41 patients, 56% were male, 73% were Caucasian and 24% African Americans, with a median age of 67 (range 34-90). Only 32% of patients had known G-APC mutations, but 34% had a second primary cancer, and 37% had a family history of known G-APC mutation-associated cancers. Only one patient had clinical manifestations of a polyposis syndrome. Of the 13 patients with known G-APC mutations, clinical characteristics were similar to the larger group, except that 100% of the G-APC-mutated patients were Caucasian, and the rate of family history of APC-associated cancers was 54%. Fifty-four percent of the overall group of 41 patients had a pathological diagnosis of pancreatic cancer, while the remaining 46% were ampullary or duodenal cancers. (Only 2 patients [5%] had tail of the pancreas cancers). Of the 37 patients who had somatic tumor NGS, only 70% harbored a KRAS gene mutation. For the OS analysis (n=24), the mOS was 11.7 months (range 5.2 – 56.9). Of the 22 patients evaluable for TTP, the mTTP for 5FU-based tx was 5.8 months, and 6.4 months for gemcitabine-based tx. Conclusions: APC-mutated pancreatic and ampullary cancers are uncommon, but exhibit survival rates, as well as TTP on both 5FU and gemcitabine-based txs that are similar to that seen with most pancreatic adenocarcinomas. However, 30% of APC-mutated cancers are KRAS wild type, and may harbor other driving mutations. As the loss of APC function triggers an accumulation of beta-catenin, targeted therapies that inhibit beta-catenin-regulated transcription and downregulate WNT-related signaling could be a promising tx approach for patients whose tumors harbor path/likely path APC mutations.