Disrupting prostate cancer research: Challenge accepted; report from the 2023 Coffey-Holden Prostate Cancer Academy Meeting.

INTRODUCTION: The 2023 Coffey-Holden Prostate Cancer Academy (CHPCA) Meeting, themed "Disrupting Prostate Cancer Research: Challenge Accepted," was convened at the University of California, Los Angeles, Luskin Conference Center, in Los Angeles, CA, from June 22 to 25, 2023. METHODS: The 2023 marked the 10th Annual CHPCA Meeting, a discussion-oriented scientific think-tank conference convened annually by the Prostate Cancer Foundation, which centers on innovative and emerging research topics deemed pivotal for advancing critical unmet needs in prostate cancer research and clinical care. The 2023 CHPCA Meeting was attended by 81 academic investigators and included 40 talks across 8 sessions. RESULTS: The central topic areas covered at the meeting included: targeting transcription factor neo-enhancesomes in cancer, AR as a pro-differentiation and oncogenic transcription factor, why few are cured with androgen deprivation therapy and how to change dogma to cure metastatic prostate cancer without castration, reducing prostate cancer morbidity and mortality with genetics, opportunities for radiation to enhance therapeutic benefit in oligometastatic prostate cancer, novel immunotherapeutic approaches, and the new era of artificial intelligence-driven precision medicine. DISCUSSION: This article provides an overview of the scientific presentations delivered at the 2023 CHPCA Meeting, such that this knowledge can help in facilitating the advancement of prostate cancer research worldwide.

Racial Differences in Germline Genetic Testing Completion Among Males With Pancreatic, Breast, or Metastatic Prostate Cancers.

BACKGROUND: Germline genetic testing is a vital component of guideline-recommended cancer care for males with pancreatic, breast, or metastatic prostate cancers. We sought to determine whether there were racial disparities in germline genetic testing completion in this population. PATIENTS AND METHODS: This retrospective cohort study included non-Hispanic White and Black males with incident pancreatic, breast, or metastatic prostate cancers between January 1, 2019, and September 30, 2021. Two nationwide cohorts were examined: (1) commercially insured individuals in an administrative claims database, and (2) Veterans receiving care in the Veterans Health Administration. One-year germline genetic testing rates were estimated by using Kaplan-Meier methods. Cox proportional hazards regression was used to test the association between race and genetic testing completion. Causal mediation analyses were performed to investigate whether socioeconomic variables contributed to associations between race and germline testing. RESULTS: Our cohort consisted of 7,894 males (5,142 commercially insured; 2,752 Veterans). One-year testing rates were 18.0% (95% CI, 16.8%-19.2%) in commercially insured individuals and 14.2% (95% CI, 11.5%-15.0%) in Veterans. Black race was associated with a lower hazard of testing among commercially insured individuals (adjusted hazard ratio [aHR], 0.73; 95% CI, 0.58-0.91; P=.005) but not among Veterans (aHR, 0.99; 95% CI, 0.75-1.32; P=.960). In commercially insured individuals, income (aHR, 0.90; 95% CI, 0.86-0.96) and net worth (aHR, 0.92; 95% CI, 0.86-0.98) mediated racial disparities, whereas education (aHR, 0.98; 95% CI, 0.94-1.01) did not. CONCLUSIONS: Overall rates of guideline-recommended genetic testing are low in males with pancreatic, breast, or metastatic prostate cancers. Racial disparities in genetic testing among males exist in a commercially insured population, mediated by net worth and household income; these disparities are not seen in the equal-access Veterans Health Administration. Alleviating financial and access barriers may mitigate racial disparities in genetic testing.

Is It Time to Incorporate Liquid Biopsy into High-Risk Cancer Surveillance Protocols in Li-Fraumeni Syndrome?

SUMMARY: In the first prospective study evaluating circulating tumor DNA (ctDNA) for early cancer detection, Wong, Luo, and colleauges demonstrate the feasibility of liquid biopsy as an augmentation to current surveillance protocols for patients with Li-Fraumeni syndrome, an inherited cancer predisposition associated with high cancer risk in both pediatric and adult populations. Though additional clinical validation in larger cohorts is needed, this research highlights that a multimodal approach is likely necessary to improve the sensitivity of liquid biopsy assays for early cancer detection. See related article by Wong, Lou et al., p. 104 (9).

Prevalence of H. pylori and Gastric Intestinal Metaplasia in BRCA1 and BRCA2 Carriers.

BRCA1 and BRCA2 carriers may be at increased risk for gastric cancer; however, the mechanisms of gastric carcinogenesis remain poorly understood. We sought to determine the prevalence of gastric cancer risk factors Helicobacter pylori (H. pylori) infection and gastric intestinal metaplasia (GIM) among BRCA1/2 carriers to gain insight into the pathogenesis of gastric cancer in this population. A total of 100 unselected BRCA1/2 carriers who underwent endoscopic ultrasound from March 2022 to March 2023 underwent concomitant upper endoscopy with nontargeted gastric antrum and body biopsies. The study population (70% women; mean age 60.1 years) included 66% BRCA2 carriers. H. pylori was detected in one (1%) individual, 7 (7%) had GIM, 2 (2%) had autoimmune atrophic gastritis, and no gastric cancers were diagnosed. Among BRCA1/2 carriers, H. pylori prevalence was low and GIM prevalence was similar to that in the general population; however, identification of H. pylori or GIM may help inform future gastric cancer risk management strategies in BRCA1/2 carriers. Prevention Relevance: Evaluating the burden of H. pylori infection and GIM among BRCA1/2 carriers is warranted to better understand the mechanisms of gastric carcinogenesis and to help inform risk management strategies for gastric cancer among this at-risk population.

Clinical management of TP53 mosaic variants found on germline genetic testing.

BACKGROUND: Germline heterozygous TP53 pathogenic variants (PVs) cause Li Fraumeni Syndrome (LFS, OMIM#151623). TP53 PVs at lower-than-expected variant allele frequencies (VAF) may reflect postzygotic mosaicism (PZM) or clonal hematopoiesis (CH); however, no guidelines exist for workup and clinical management. PATIENTS AND METHODS: Retrospective analysis of probands who presented to an academic cancer genetics program with a TP53 PV result on germline genetic testing. RESULTS: Twenty-one of 125 unrelated probands (17 %) were found to harbor a TP53 PV with VAF<30 % or a designation of "mosaic". A diagnosis of PZM was made in nine (43 %) due to a clinical phenotype consistent with LFS with (n = 8) or without (n = 1) positive ancillary tissue testing. Twelve patients (57 %) were diagnosed with presumed CH (pCH) due to a diagnosis of a myeloproliferative neoplasm, negative ancillary tissue testing, clinical phenotype not meeting LFS criteria, no cancer, and/or no first cancer age<50. Of the 19 patients with biological offspring, nine had either partial or complete offspring testing, all negative. CONCLUSIONS: Determining the etiology of low VAF TP53 PVs requires ancillary tissue testing and incorporation of clinical phenotype. Discerning PZM versus CH is important to provide optimal care and follow-up.

Identification of TP53 germline variants in pediatric patients undergoing tumor testing: strategy and prevalence.

BACKGROUND: TP53 alterations are common in certain pediatric cancers, making identification of putative germline variants through tumor genomic profiling crucial for disease management. METHODS: We analyzed TP53 alterations in 3123 tumors from 2788 pediatric patients sequenced using tumor-only or tumor-normal paired panels. Germline confirmatory testing was performed when indicated. Somatic and germline variants were classified based on published guidelines. RESULTS: In 248 tumors from 222 patients, 284 tier 1/2 TP53 sequence and small copy number variants were detected. Following germline classification, 86.6% of 142 unique variants were pathogenic or likely pathogenic. Confirmatory testing on 118 patients revealed germline TP53 variants in 28 of them (23 pathogenic or likely pathogenic and 5 of uncertain significance), suggesting a minimum Li-Fraumeni syndrome incidence of 0.8% (23/2788) in this cohort, 10.4% (23/222) in patients with TP53 variant-carrying tumors, and 19.5% (23/118) with available normal samples. About 25% (7/28) of patients with germline TP53 variants did not meet Li-Fraumeni syndrome diagnostic or testing criteria, while 20.9% (28/134) with confirmed or inferred somatic origins did. TP53 biallelic inactivation occurred in 75% of germline carrier tumors and was also prevalent in other groups, causing an elevated tumor-observed variant allelic fraction. Somatic evidence, however, including low variant allele fraction correctly identified only 27.8% (25/90) of patients with confirmed somatic TP53 variants. CONCLUSION: The high incidence and variable phenotype of Li-Fraumeni syndrome in this cohort highlights the importance of assessing germline status of TP53 variants identified in all pediatric tumors. Without clear somatic evidence, distinguishing somatic from germline origins is challenging. Classifying germline and somatic variants should follow appropriate guidelines.

Neighborhood Deprivation, Race and Ethnicity, and Prostate Cancer Outcomes Across California Health Care Systems.

Importance: Non-Hispanic Black (hereafter, Black) individuals experience worse prostate cancer outcomes due to socioeconomic and racial inequities of access to care. Few studies have empirically evaluated these disparities across different health care systems. Objective: To describe the racial and ethnic and neighborhood socioeconomic status (nSES) disparities among residents of the same communities who receive prostate cancer care in the US Department of Veterans Affairs (VA) health care system vs other settings. Design, Setting, and Participants: This cohort study obtained data from the VA Central Cancer Registry for veterans with prostate cancer who received care within the VA Greater Los Angeles Healthcare System (VA cohort) and from the California Cancer Registry (CCR) for nonveterans who received care outside the VA setting (CCR cohort). The cohorts consisted of all males with incident prostate cancer who were living within the same US Census tracts. These individuals received care between 2000 and 2018 and were followed up until death from any cause or censoring on December 31, 2018. Data analyses were conducted between September 2022 and December 2023. Exposures: Health care setting, self-identified race and ethnicity (SIRE), and nSES. Main Outcomes and Measures: The primary outcome was all-cause mortality (ACM). Cox proportional hazards regression models were used to estimate hazard ratios for associations of SIRE and nSES with prostate cancer outcomes in the VA and CCR cohorts. Results: Included in the analysis were 49 461 males with prostate cancer. Of these, 1881 males were in the VA cohort (mean [SD] age, 65.3 [7.7] years; 833 Black individuals [44.3%], 694 non-Hispanic White [hereafter, White] individuals [36.9%], and 354 individuals [18.8%] of other or unknown race). A total of 47 580 individuals were in the CCR cohort (mean [SD] age, 67.0 [9.6] years; 8183 Black individuals [17.2%], 26 206 White individuals [55.1%], and 13 191 individuals [27.8%] of other or unknown race). In the VA cohort, there were no racial disparities observed for metastasis, ACM, or prostate cancer-specific mortality (PCSM). However, in the CCR cohort, the racial disparities were observed for metastasis (adjusted odds ratio [AOR], 1.36; 95% CI, 1.22-1.52), ACM (adjusted hazard ratio [AHR], 1.13; 95% CI, 1.04-1.24), and PCSM (AHR, 1.15; 95% CI, 1.05-1.25). Heterogeneity was observed for the racial disparity in ACM in the VA vs CCR cohorts (AHR, 0.90 [95% CI, 0.76-1.06] vs 1.13 [95% CI, 1.04-1.24]; P = .01). No evidence of nSES disparities was observed for any prostate cancer outcomes in the VA cohort. However, in the CCR cohort, heterogeneity was observed for nSES disparities with ACM (AHR, 0.82; 95% CI, 0.80-0.84; P = .002) and PCSM (AHR, 0.86; 95% CI, 0.82-0.89; P = .007). Conclusions and Relevance: Results of this study suggest that racial and nSES disparities were wider among patients seeking care outside of the VA health care system. Health systems-related interventions that address access barriers may mitigate racial and socioeconomic disparities in prostate cancer.

Distinct genomic and immunologic tumor evolution in germline TP53-driven breast cancers.

Pathogenic germline TP53 alterations cause Li-Fraumeni Syndrome (LFS), and breast cancer is the most common cancer in LFS females. We performed first of its kind multimodal analysis of LFS breast cancer (LFS-BC) compared to sporadic premenopausal BC. Nearly all LFS-BC underwent biallelic loss of TP53 with no recurrent oncogenic variants except ERBB2 (HER2) amplification. Compared to sporadic BC, in situ and invasive LFS-BC exhibited a high burden of short amplified aneuploid segments (SAAS). Pro-apoptotic p53 target genes BAX and TP53I3 failed to be up-regulated in LFS-BC as was seen in sporadic BC compared to normal breast tissue. LFS-BC had lower CD8+ T-cell infiltration compared to sporadic BC yet higher levels of proliferating cytotoxic T-cells. Within LFS-BC, progression from in situ to invasive BC was marked by an increase in chromosomal instability with a decrease in proliferating cytotoxic T-cells. Our study uncovers critical events in mutant p53-driven tumorigenesis in breast tissue.

BRCA1, BRCA2, and Associated Cancer Risks and Management for Male Patients: A Review.

Importance: Half of all carriers of inherited cancer-predisposing variants in BRCA1 and BRCA2 are male, but the implications for their health are underrecognized compared to female individuals. Germline variants in BRCA1 and BRCA2 (also known as pathogenic or likely pathogenic variants, referred to here as BRCA1/2 PVs) are well known to significantly increase the risk of breast and ovarian cancers in female carriers, and knowledge of BRCA1/2 PVs informs established cancer screening and options for risk reduction. While risks to male carriers of BRCA1/2 PVs are less characterized, there is convincing evidence of increased risk for prostate cancer, pancreatic cancer, and breast cancer in males. There has also been a rapid expansion of US Food and Drug Administration-approved targeted cancer therapies, including poly ADP ribose polymerase (PARP) inhibitors, for breast, pancreatic, and prostate cancers associated with BRCA1/2 PVs. Observations: This narrative review summarized the data that inform cancer risks, targeted cancer therapy options, and guidelines for early cancer detection. It also highlighted areas of emerging research and clinical trial opportunities for male BRCA1/2 PV carriers. These developments, along with the continued relevance to family cancer risk and reproductive options, have informed changes to guideline recommendations for genetic testing and strengthened the case for increased genetic testing for males. Conclusions and Relevance: Despite increasing clinical actionability for male carriers of BRCA1/2 PVs, far fewer males than female individuals undergo cancer genetic testing. Oncologists, internists, and primary care clinicians should be vigilant about offering appropriate genetic testing to males. Identifying more male carriers of BRCA1/2 PVs will maximize opportunities for cancer early detection, targeted risk management, and cancer treatment for males, along with facilitating opportunities for risk reduction and prevention in their family members, thereby decreasing the burden of hereditary cancer.