Germline APC (I1307K) mutation and clinical outcomes in prostate cancer.
Authors: Economides Minas P. , Nakazawa Mari , Lee Jonathan , Hollifield Lucas , Balar Arjun Vasant , Antonarakis Emmanuel S. , Wise David R 
Published: February 2022

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Background: The germline I1307K mutation in the adenomatous polyposis coli (APC) gene is a well known alteration identified in approximately 6% of the Ashkenazi Jewish population. Individuals with this mutation have an increased risk of developing colorectal and other cancers. The implications of the APC (I1307K) mutation in patients with prostate cancer are unknown. We sought to determine the clinical outcomes of patients with prostate cancer and the germline APC (I1307K) mutation. Methods: We retrospectively reviewed records from New York University and Johns Hopkins University to identify patients with the APC (I1307K) mutation. Eligibility criteria included the identification of the mutation either on germline or somatic tissue testing (when germline testing was not available). Aggressive variant prostate cancer (AVPC) was defined using previously established criteria including: presence of small cell histology, presence of exclusively visceral metastases, bulky prostate mass or lymphadenopathy, low PSA with high-volume ( > 20) bone metastases, neuroendocrine marker positivity or short interval ( < 6 months) to castration resistance. Combined somatic alterations in two or more of following genes were assessed: RB1, TP53, PTEN. These somatic alterations have been previously associated with AVPC. Descriptive statistics were used to summarize patient data. Results: From 2016-2021, 13 patients with the germline APC (I1307K) mutation were identified. At the time of analysis 9 (69%) patients were alive. Most patients (7; 54%) had metastatic disease at presentation. Median PSA at diagnosis was 0.4 ng/mL (range: 0.4-20 ng/mL). The median time to castration resistance among those receiving hormonal therapy was 9 months (range: 3-13 months). Presence of small cell histology was found on initial biopsy in 3 patients and on subsequent biopsy in 1 additional patient (31% overall). Bulky prostate mass or lymphadenopathy was found in 3 (23%) patients. There were 2 (15%) patients who had low PSA with high-volume bone metastases. Four (31%) patients had radiographic progression with no concordant PSA increase. Clinically-defined AVPC was found in 7 (54%) patients and in 100% of those patients with metastatic disease. Combined somatic alterations in two or more of RB1, TP53 or PTEN were identified in 3 (23%) patients. Conclusions: Prostate cancers that develop in the presence of the germline APC (I1307K) mutation appear to be enriched for clinically-defined and molecularly-defined AVPC. Several of these patients demonstrated small cell histology and PSA-independent progression, higher than the expected background rate. This raises the hypothesis that the germline APC (I1307K) mutation influences the somatic genomic and/or epigenomic landscape of prostate cancer. Larger studies to validate the increased risk of AVPC in APC (I1307K) carriers, and to elucidate the somatic alteration landscape in these patients, are ongoing.