821 Post-therapeutic Squamous Cell Transformation of Metastatic Prostatic Adenocarcinoma with Paired Molecular Profiling: A Multi-Institutional Cohort of an Under-reported Entity

Document Type

Conference Proceeding

Publication Date

3-24-2025

Publication Title

Lab Invest

Keywords

epidermal growth factor receptor, prostate specific antigen, adult, aged, cell transdifferentiation, cell transformation, clinical article, cohort analysis, conference abstract, copy number variation, diagnosis, diagnostic error, disease course, drug therapy, gene rearrangement, genetic analyzer, high throughput sequencing, human, human tissue, indel mutation, male, metastasis site, metastatic prostate cancer, microsatellite instability, middle aged, molecular fingerprinting, prostate adenocarcinoma, radiotherapy, single nucleotide polymorphism, squamous cell carcinoma, tumor mutational burden, very elderly

Abstract

Disclosures: Seema Kaushal: None; Jasreman Dhillon: None; Vipra Malik: None; Mahmut Akgul: None; Andres Acosta: None; Anandi Lobo: None; Steven Smith: None; Manju Aron: None; Khaleel Al-Obaidy: None; Sean Williamson: None; Ankur Sangoi: None; Liang Cheng: None; Mahul Amin: None; Tamara Lotan: None; Sambit Mohanty: None Background: Transformation of primary prostatic adenocarcinoma (PCa) to squamous cell carcinoma (SCC) after initial treatment, at the metastatic site, is extremely rare and results in rapid treatment-refractory disease progression and death. Unlike neuroendocrine transdifferentiation of a PCa, scant literature is available on this entity with near absence of comprehensive molecular studies. Design: Patients with SCC transformation at the metastatic site with a primary diagnosis of PCa were collected in an international cohort. The patient's age, PSA levels, tumor's characteristics at the primary and metastatic site and additional clinicopathological details were recorded. Targeted NGS (Illumina® HiSeq 4000) platform was used for DNA and RNA NGS. Single nucleotide variants/substitutions, indels, and copy number variations in 426 cancer-associated genes, and gene rearrangements, microsatellite instability, and tumor mutational burden (TMB) were assessed. The tumors were sequenced to high uniform depth (targeting 500X median coverage with 99% coverage 100X. Somatic genomic alterations were observed in all tumors (both treatment-naive PCa specimen and SCC specimens). Results: Nine patients were collated. The mean age at the primary diagnosis was 66.5 years, with the serum PSA level ranging from 59 to1450 ng/ml. The patients presented with either primary or metastatic disease at the time of initial presentation and received hormonal/androgen-derivation, chemo, and/or radiation therapy. Mean serum PSA at the time of SCC transformation was 0.8 ng/ml (range = 0.04 to 2.13 ng/ml). Duration of SCC transformation ranged from 0.9 to 7 years. Table 1 summarizes the clinicopathologic and molecular characteristics of the cohort. Figure 2 shows a heatmap depicting molecular profiles of paired PCa and SCC samples of the cohort. [Formula presented] [Formula presented] [Formula presented] Conclusions: 1. Post-treatment SCC transformation in a metastatic PCa is rare and portends an aggressive clinical course and treatment resistance. 2. An erroneous misdiagnosis of a secondary SCC can be made, particularly when the clinical data is unavailable. 3. We observed similar mutations in the PCa and subsequent SCC components along with some additional mutational hits involving CCND3, TP53, EGFR, MAP2K7, and PIK3CA genes, which might trigger SCC transformation and be the potential therapeutic targets. 4. Interestingly, presence of TMPRSS2::ERG rearrangement in the SCC component, supports a transformation from the pre-existing adenocarcinoma

Volume

105

Issue

3

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