Early-onset metastatic and clinically advanced prostate cancer is a distinct clinical and molecular entity characterized by increased TMPRSS2–ERG fusions

Chalmers, Zachary R.; Burns, Michael C.; Ebot, Ericka M.; Frampton, Garrett M.; Ross, Jeffrey S.; Hussain, Maha; Abdulkadir, Sarki A.

doi:10.1038/s41391-020-00314-z

Cited by 12 publications

(11 citation statements)

References 43 publications

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“…2 Androgens and the androgenregulated transmembrane protease, serine 2 (TMPRSS2) play an important role in prostate cancer cell invasion, tumor growth, and metastasis. 3,5 The TMPRSS2:ERG gene fusion is the most frequent genomic alteration in prostate cancer, leading to an androgen-regulated fusion oncogene. 6,7 The TMPRSS2 protein also plays a central role in SARS-CoV-2 pathogenicity; the viral spike glycoprotein is cleaved by TMPRSS2, activating SARS-CoV-2 for virus-cell fusion.…”

Section: Introductionmentioning

confidence: 99%

“…It has been hypothesized that the observed sex differences may be mediated through androgen regulation of cellular processes . Androgens and the androgen-regulated transmembrane protease, serine 2 (TMPRSS2) play an important role in prostate cancer cell invasion, tumor growth, and metastasis . The TMPRSS2:ERG gene fusion is the most frequent genomic alteration in prostate cancer, leading to an androgen-regulated fusion oncogene .…”

Section: Introductionmentioning

confidence: 99%

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Association Between Androgen Deprivation Therapy and Mortality Among Patients With Prostate Cancer and COVID-19

et al. 2021

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IMPORTANCEAndrogen deprivation therapy (ADT) has been theorized to decrease the severity of SARS-CoV-2 infection in patients with prostate cancer owing to a potential decrease in the tissuebased expression of the SARS-CoV-2 coreceptor transmembrane protease, serine 2 (TMPRSS2). OBJECTIVE To examine whether ADT is associated with a decreased rate of 30-day mortality from SARS-CoV-2 infection among patients with prostate cancer. DESIGN, SETTING, AND PARTICIPANTS This cohort study analyzed patient data recorded in the COVID-19 and Cancer Consortium registry between March 17, 2020, and February 11, 2021. The consortium maintains a centralized multi-institution registry of patients with a current or past diagnosis of cancer who developed COVID-19. Data were collected and managed using REDCap software hosted at Vanderbilt University Medical Center in Nashville, Tennessee. Initially, 1228patients aged 18 years or older with prostate cancer listed as their primary malignant neoplasm were included; 122 patients with a second malignant neoplasm, insufficient follow-up, or low-quality data were excluded. Propensity matching was performed using the nearest-neighbor method with a 1:3 ratio of treated units to control units, adjusted for age, body mass index, race and ethnicity, Eastern Cooperative Oncology Group performance status score, smoking status, comorbidities (cardiovascular, pulmonary, kidney disease, and diabetes), cancer status, baseline steroid use, COVID-19 treatment, and presence of metastatic disease. EXPOSURES Androgen deprivation therapy use was defined as prior bilateral orchiectomy or pharmacologic ADT administered within the prior 3 months of presentation with COVID-19. MAIN OUTCOMES AND MEASURESThe primary outcome was the rate of all-cause 30-day mortality after COVID-19 diagnosis for patients receiving ADT compared with patients not receiving ADT after propensity matching. RESULTSAfter exclusions, 1106 patients with prostate cancer (before propensity score matching: median age, 73 years [IQR, 65-79 years]; 561 (51%) self-identified as non-Hispanic White) were included for analysis. Of these patients, 477 were included for propensity score matching (169 who received ADT and 308 who did not receive ADT). After propensity matching, there was no significant difference in the primary end point of the rate of all-cause 30-day mortality (OR, 0.77; 95% CI, 0.42-1.42).

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Association Between Androgen Deprivation Therapy and Mortality Among Patients With Prostate Cancer and COVID-19

et al. 2021

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“…Advanced disease stages at diagnosis 297,298 Poor differentiation, perineural invasion 228,[295][296][297][298] Prostate cancer Metastatic disease, resistance to androgen-deprivation therapy, and shorter OS [299][300][301][302] Genomic and epigenomic aberrations seen in patients with early-onset prostate cancer might be distinctly different from those seen in patients with later-onset disease 303,304 ; for example, clinically advanced early-onset prostate cancers might be associated with TMPRSS2::ERG fusions and fewer AR, SPOP and ASXL1 alterations 305…”

Section: Breast Cancermentioning

confidence: 99%

Is early-onset cancer an emerging global epidemic? Current evidence and future implications

et al. 2022

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Cancer is a multifactorial disease that most commonly affects people ≥50 years of age. However, evidence indicates that the incidence of cancers of various organs (including those of the breast, colorectum, endometrium, oesophagus, extrahepatic bile duct, gallbladder, head and neck, kidney, liver, bone marrow (multiple myeloma (MM)), pancreas, prostate, stomach and thyroid) has been rising in adults <50 years of age in many parts of the world 1-13 . This trend is also observed in analyses using Global Cancer Observatory (GLOBOCAN; https://gco.iarc.fr/) data (Fig. 1 provides data on selected countries; more comprehensive data are provided in Supplementary Table 1). We herein use the term 'early-onset' to describe cancers diagnosed in adults <50 years of age, and a contrasting term, 'later-onset' , for cancers diagnosed in those ≥50 years of age. Cancers diagnosed during childhood and adolescence (<20 years of age) are out of the scope of this Review.The rise of early-onset cancer has considerable personal, societal and economic implications. Survivors of early-onset cancers have a higher risk of long-term health problems such as infertility, cardiovascular disease and secondary cancers [14][15][16] . Owing to this increasing cancer burden among young adults, which might be referred to as the 'early-onset cancer epidemic' , the US National Cancer Institute listed this phenomenon as a research priority in one of its 'Provocative Questions' for 2020-2021 (reF. 17).Differences in epidemiology and clinical, pathological, and molecular characteristics clearly exist between early-onset and later-onset cancers, although these features are not likely to change dramatically at exactly 50 years of age 18 . Furthermore, early-onset cancer in any given organ is not a homogeneous entity but rather encompasses a variable range of clinical and pathological features 18,19 . We acknowledge the limitations of applying a dichotomy at 50 years of age, although we selected this cut-off point to enable consistent collection and interpretation of current evidence on early-onset cancers. In reality, we also need to consider heterogeneity within Is early-onset cancer an emerging global epidemic? Current evidence and future implications

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“…It has been suggested that early-onset metastatic and clinically advanced prostate cancer, characterized by a higher incidence of TMPRSS2:ERG fusions, is a distinct clinical and molecular entity. 58 Racial disparities in the distribution of TMPRSS2:ERG fusions are well documented, with Black patients less likely to have these alterations compared to White patients. 59 The causes of this difference are unclear, potentially due to genetic susceptibility, hormone levels, lifestyle factors, and healthcare access.…”

Section: Discussionmentioning

confidence: 99%

Incorporating Real-World Clinico-Genomic Insights to Inform Diversity Enrollment Targets in Oncology Trials

De La Vega,

Pouliot,

Rhead

2024

Preprint

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The passage of the US Food and Drug Administration (FDA) Omnibus Reform Act of 2022 underscores a national commitment to enhancing diversity in clinical trials. This commitment recognizes not only the ethical imperative of inclusivity but also the practical necessity to ensure the safety and efficacy of medications across all demographic groups. Particularly for Phase 3 and pivotal clinical trials, the FDA has issued draft guidance that recommends sponsors to develop diversity plans with race and ethnicity (R/E) enrollment targets informed by the epidemiological landscape of the disease in the therapy's target population. For biomarker-driven oncology trials, real-world data (RWD), especially when enriched with multimodal clinico-genomic information, holds immense promise for informing these R/E enrollment goals. However, leveraging RWD comes with hurdles, including the overrepresentation of insured patients, significant non-random missingness in R/E data, and disparities between R/E distributions in RWD and disease incidence databases - often attributed to healthcare access and socioeconomic disparities. Here, we propose a robust methodology to harness clinico-genomic RWD, addressing these challenges through strategies that include accurate R/E imputation and incidence adjustment factors. Our approach then utilizes clinical data and biomarker prevalence in RWD to derive a data-driven R/E distribution for clinical trial enrollment targets. Through a case study on a hypothetical biomarker-driven clinical trial targeting prostate adenocarcinoma and leveraging a cohort from the Tempus clinco-genomic database, we demonstrate the application of our methodology. This example illustrates the potential of RWD to offer enrollment target scenarios, grounded in disease epidemiology and empirical R/E distributions adjusted for biomarker prevalence. Such data-driven targets are pivotal for the development of informed and equitable diversity plans in oncology clinical trials, paving the way for more representative and generalizable research outcomes.

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Early-onset metastatic and clinically advanced prostate cancer is a distinct clinical and molecular entity characterized by increased TMPRSS2–ERG fusions

Cited by 12 publications

References 43 publications

Association Between Androgen Deprivation Therapy and Mortality Among Patients With Prostate Cancer and COVID-19

Association Between Androgen Deprivation Therapy and Mortality Among Patients With Prostate Cancer and COVID-19

Is early-onset cancer an emerging global epidemic? Current evidence and future implications

Incorporating Real-World Clinico-Genomic Insights to Inform Diversity Enrollment Targets in Oncology Trials

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