Early-Onset Metastatic and Clinically Advanced Prostate Cancer Is a Distinct Clinical and Molecular Entity Characterized by Increased TMPRSS2-ERG Fusions

Prostate cancer is the leading cancer diagnosis among men in the United States with an estimated 248,530 new cases expected and is the second most common cause of cancer death for men in the United States, responsible for an estimated 34,130 deaths in 2021.¹ It is a heterogeneous disease with locoregional cancers carrying an excellent five-year overall survival of nearly 100% in stark contrast to aggressive and lethal phenotypes that carry poor outcomes despite advances in systemic therapy. The rising incidence of young men presenting with aggressive disease phenotypes has been particularly challenging for the medical community,² and our study, therefore, sought to describe the clinical and molecular features of early-onset prostate cancer on a large scale.

In our manuscript,³ we detail the landscape of molecular alterations that drive clinically advanced early-onset prostate cancer and define the clinical and molecular features that distinguish this aggressive phenotype from typical-onset disease in older patients. To accomplish this we employed a big data approach with over 10,000 cases to correlate clinical information including age, race, and disease spread, with genomic profiling data. Together, this provided us with the largest dataset of early-onset prostate cancer patients to analyze and powered our study to find differences between early- and typical-onset groups at lower frequencies than prior work.

Our cohort included 439 patients with prostate cancer diagnosed at or before 50 years old (4.3%), as well as 1,928 patients from 51 to 59 years old (18.9%), and 7,822 patients 60 years old and greater (76.8%). A diverse patient population was represented including nearly 1000 patients with African ancestry and over 2,700 patients without clear European ancestry. As expected, the most common metastatic biopsy sites included lymph node, liver, and bone specimens although a diversity of metastatic sites were observed.

The majority of patients (97.4%) harbored at least one pathogenic alteration (median = 4). When we examined more closely what genes were involved, we discovered alterations in common oncogenes (MYC, MLL2, RAD21, SPOP, PIK3CA, MLL3, CDK12, and CTNNB1), tumor suppressors (TP53, PTEN, BRCA2, APC, RB1, and ATM), as well as prostate cancer-specific molecular alterations in the androgen receptor (AR) and TMPRSS2–ERG fusions. When patients were stratified by age it became readily apparent that patients ≤50 years old harbored significantly more TMPRSS2–ERG fusions than patients ≥60 years old. Additionally, AR copy number alterations, as well as SPOP and ASXL1 mutations, were significantly less frequent in the older patients.

With respect to markers of sensitivity to immunotherapy, both microsatellite instability (MSI) and tumor mutation burden (TMB) were found to be associated with increasing age. This finding was not unexpected as both oncogenic and passenger mutations may increase with age; however, its significance is not yet clear as immunotherapy has shown limited benefit in prostate cancer patients to date.

Patients with early-onset, aggressive prostate cancer phenotypes are challenging to manage due to the paucity of literature characterizing their disease; their requirement for multiple lines of therapy; and the absence of data guiding optimal management. This study demonstrates the diverse presentations of prostate cancer, both clinical and genomic, and describes the molecular alterations of early-onset disease using the largest collection of early-onset cases ever reported. As a unique clinical subgroup, patients with early-onset prostate cancer harbor tumors that are characteristically driven TMPRSS2–ERG fusions and fewer AR, SPOP, and ASXL1 alterations. Now that this aggressive disease is defined both clinically and molecularly as distinct from typical-onset prostate cancer, we propose prospective controlled trials be designed to optimize the clinical management of patients with early-onset, clinically advanced prostate cancer.

Written by: Zachary R. Chalmers, BS, Medical Scientist Training Program, Michael C. Burns, MD, PhD, Division of Hematology-Oncology, Sarki Abba Abdulkadir, MD, PhD, Department Of Urology, Maha Hussain, MD, Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois

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