ABSTRACT
BACKGROUND: Recently approved treatments and updates to genetic testing recommendations for prostate cancer have created a need for correlated analyses of patient outcomes data via germline genetic mutation status. Genetic registries address these gaps by identifying candidates for recently approved targeted treatments, expanding clinical trial data examining specific gene mutations, and understanding effects of targeted treatments in the real-world setting. METHODS: The PROMISE Registry is a 20-year (5-year recruitment, 15-year follow-up), US-wide, prospective genetic registry for prostate cancer patients. Five thousand patients will be screened through an online at-home germline testing to identify and enroll 500 patients with germline mutations, including: pathogenic or likely pathogenic variants and variants of uncertain significance in genes of interest. Patients will be followed for 15 years and clinical data with real time patient reported outcomes will be collected. Eligible patients will enter long-term follow-up (6-month PRO surveys and medical record retrieval). As a virtual study with patient self-enrollment, the PROMISE Registry may fill gaps in genetics services in underserved areas and for patients within sufficient insurance coverage. RESULTS: The PROMISE Registry opened in May 2021. 2114 patients have enrolled to date across 48 US states and 23 recruiting sites. 202 patients have met criteria for long-term follow-up. PROMISE is on target with the study's goal of 5000 patients screened and 500 patients eligible for long-term follow-up by 2026. CONCLUSIONS: The PROMISE Registry is a novel, prospective, germline registry that will collect long-term patient outcomes data to address current gaps in understanding resulting from recently FDA-approved treatments and updates to genetic testing recommendations for prostate cancer. Through inclusion of a broad nationwide sample, including underserved patients and those unaffiliated with major academic centers, the PROMISE Registry aims to provide access to germline genetic testing and to collect data to understand disease characteristics and treatment responses across the disease spectrum for prostate cancer with rare germline genetic variants.
Subject(s)
Germ-Line Mutation , Prostatic Neoplasms , Male , Humans , Prospective Studies , Prostatic Neoplasms/genetics , Prostatic Neoplasms/therapy , Treatment Outcome , RegistriesABSTRACT
BACKGROUND: PARP (poly(ADP-ribose) polymerase) inhibitors (PARPi) are now standard of care in metastatic castrate-resistant prostate cancer (mCRPC) patients with select mutations in DNA damage repair (DDR) pathways, but patients with ATM- and BRCA2 mutations may respond differently to PARPi. We hypothesized that differences may also exist in response to taxanes, which may inform treatment sequencing decisions. METHODS: mCRPC patients (N = 158) with deleterious ATM or BRCA2 mutations who received taxanes, PARPi, or both were retrospectively identified from 11 US academic centers. Demographic, treatment, and survival data were collected. Kaplan-Meier analyses were performed and Cox hazard ratios (HR) were calculated for progression-free survival (PFS) as well as overall survival (OS), from time of first taxane or PARPi therapy. RESULTS: Fifty-eight patients with ATM mutations and 100 with BRCA2 mutations were identified. Fourty-four (76%) patients with ATM mutations received taxane only or taxane before PARPi, while 14 (24%) received PARPi only or PARPi before taxane. Patients with ATM mutations had longer PFS when taxane was given first versus PARPi given first (HR: 0.74 [95% confidence interval [CI]: 0.37-1.50]; p = 0.40). Similarly, OS was longer in patients with ATM mutations who received taxane first (HR: 0.56 [CI: 0.20-1.54]; p = 0.26). Among patients with BRCA2 mutations, 51 (51%) received taxane first and 49 (49%) received PARPi first. In contrast, patients with BRCA2 mutations had longer PFS when PARPi was given first versus taxane given first (HR: 0.85 [CI: 0.54-1.35]; p = 0.49). Similarly, OS was longer in patients with BRCA2 mutations who received PARPi first (HR: 0.75 [CI: 0.41-1.37]; p = 0.35). CONCLUSIONS: Our retrospective data suggest differential response between ATM and BRCA2 mutated prostate cancers in terms of response to PARPi and to taxane chemotherapy. When considering the sequence of PARPi versus taxane chemotherapy for mCRPC with DDR mutations, ATM, and BRCA2 mutation status may be helpful in guiding choice of initial therapy.
Subject(s)
Poly(ADP-ribose) Polymerase Inhibitors , Prostatic Neoplasms, Castration-Resistant , Male , Humans , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Retrospective Studies , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/pathology , Treatment Outcome , Taxoids/therapeutic use , BRCA2 Protein/genetics , Ataxia Telangiectasia Mutated Proteins/geneticsABSTRACT
BACKGROUND: Among men with metastatic prostate cancer, about 10% have germline alterations in DNA damage response genes. Most studies have examined BRCA2 alone or an aggregate of BRCA1/2 and ATM. Emerging data suggest that ATM mutations may have distinct biology and warrant individual evaluation. The objective of this study is to determine whether response to prostate cancer systemic therapies differs between men with germline mutations in ATM (gATM) and BRCA2 (gBRCA2). METHODS: This is an international multicenter retrospective matched cohort study of men with prostate cancer harboring gATM or gBRCA2. PSA50 response (≥50% decline in prostate-specific antigen) was compared using Fisher's exact test. RESULTS AND LIMITATIONS: The study included 45 gATM and 45 gBRCA2 patients, matched on stage and year of germline testing. Patients with gATM and gBRCA2 had similar age, Gleason grade, and PSA at diagnosis. We did not observe differences in PSA50 responses to abiraterone, enzalutamide, or docetaxel in metastatic castration resistant prostate cancer between the two groups; however, 0/7 with gATM and 12/14 with gBRCA2 achieved PSA50 response to PARPi (p < .001). Median (95% confidence interval) overall survival from diagnosis to death was 10.9 years (9.5-not reached) versus 9.9 years (7.1-not reached, p = .07) for the gATM and gBRCA2 cohorts, respectively. Limitations include the retrospective design and lack of mutation zygosity data. CONCLUSIONS: Conventional therapies can be effective in gATM carriers and should be considered before PARPi, which shows limited efficacy in this group. Men with gATM mutations warrant prioritization for novel treatment strategies.
Subject(s)
Androstenes/therapeutic use , Ataxia Telangiectasia Mutated Proteins/genetics , BRCA2 Protein/genetics , Benzamides/therapeutic use , Docetaxel/therapeutic use , Medication Therapy Management/standards , Nitriles/therapeutic use , Phenylthiohydantoin/therapeutic use , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Prostatic Neoplasms, Castration-Resistant , Antineoplastic Agents/therapeutic use , Germ-Line Mutation , Humans , Male , Middle Aged , Neoplasm Grading , Neoplasm Staging , Patient Selection , Prostate-Specific Antigen/blood , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/mortality , Prostatic Neoplasms, Castration-Resistant/pathology , Prostatic Neoplasms, Castration-Resistant/therapy , Retrospective Studies , Survival AnalysisABSTRACT
BACKGROUND: The goal of this study is to evaluate germline genetic variants in African American men with metastatic prostate cancer as compared to those in Caucasian men with metastatic prostate cancer in an effort to understand the role of genetic factors in these populations. METHODS: African American and Caucasian men with metastatic prostate cancer who had germline testing using multigene panels were used to generate comparisons. Germline genetic results, clinical parameters, and family histories between the two populations were analyzed. RESULTS: A total of 867 patients were included in this retrospective study, including 188 African American and 669 Caucasian patients. There was no significant difference in the likelihood of a pathogenic or likely-pathogenic variants (PV/LPVs) between African American and Caucasian patients (p = .09). African American patients were more likely to have a variant of unknown significance than Caucasians (odds ratio [OR] = 1.95; p < .0001). BRCA1 PV/LPVs were higher in African Americans (OR = 4.86; p = .04). African American patients were less likely to have a PV/LPV in non-BRCA DNA repair genes (OR = 0.30; p = .008). Family history of breast (OR = 2.09; p = .002) or ovarian cancer (OR = 2.33; p = .04) predicted PV/LPVs in Caucasians but not African-Americans. This underscores the limitations of family history in AA men and the importance of personal history to guide germline testing in AA men. CONCLUSIONS: In metastatic prostate cancer patients, PV/LPVs of tested genes did not vary by race, BRCA1 PV/LPVs were more common in the African American subset. However, PV/LPVs in non-BRCA DNA repair genes were less likely to be encountered in African Americans. Family history associated with genetic testing results in Caucasians only.
Subject(s)
BRCA2 Protein/genetics , Black or African American/genetics , Germ-Line Mutation , Neoplasm Metastasis/genetics , Prostatic Neoplasms/genetics , White People/genetics , Humans , Male , Middle Aged , Neoplasm Metastasis/pathology , Prostatic Neoplasms/pathologyABSTRACT
Gender parity within academic oncology is important. We hypothesized that gender differences exist in subspecialty choice and academic rank among medical oncologists. We performed a cross-sectional study of adult medical oncologists at the top 15 cancer centers. Gender, rank, subspecialty (breast, thoracic, gastrointestinal, and genitourinary) and board certification year were recorded. 570 medical oncologists were identified (60% men; 40% women). More women practice breast oncology (OR 3.1, p < 0.001), but less practice genitourinary oncology (OR 0.37, p < 0.001). 22% of women were full professors vs 34% of men (OR 0.55, p = 0.001). Gender differences persist in academic adult medical oncology.
Subject(s)
Oncologists/organization & administration , Sex Characteristics , Cross-Sectional Studies , Faculty , Female , Humans , MaleABSTRACT
The results of multiple studies have shown that a substantial proportion of men with advanced prostate cancer carry germline DNA repair mutations. Germline testing in prostate cancer may inform treatment decisions and consideration for clinical trials. There are 2 FDA approved PARP inhibitors (PARPi), olaparib (Lynparza) and rucaparib (Rubraca), for the treatment of advanced prostate cancer with DNA repair deficiency. Increasing demand for germline testing in prostate cancer and a shortage of genetic counselors have created a need for alternative care models and encouraged oncologists to take a more active role in performing germline testing. This article summarizes recommendations for germline testing in prostate cancer and describes care models for providing counseling and testing.
Subject(s)
DNA Repair/genetics , Germ-Line Mutation , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/genetics , Genetic Counseling , Genetic Predisposition to Disease , Genetic Testing , Humans , Male , Neoplasm Grading , Practice Guidelines as Topic , Prostatic Neoplasms/pathologyABSTRACT
With the promise and potential of clinical next-generation sequencing for tumor and germline testing to impact treatment and outcomes of patients with cancer, there are also risks of oversimplification, misinterpretation, and missed opportunities. These issues risk limiting clinical benefit and, at worst, perpetuating false conclusions that could lead to inappropriate treatment selection, avoidable toxicity, and harm to patients. This report presents 5 case studies illustrating challenges and opportunities in clinical next-generation sequencing interpretation and clinical application in solid tumor oncologic care. First is a case that dissects the origin of an ATM mutation as originating from a hematopoietic clone rather than the tumor. Second is a case illustrating the potential for tumor sequencing to suggest germline variants associated with a hereditary cancer syndrome. Third are 2 cases showing the potential for variant reclassification of a germline variant of uncertain significance when considered alongside family history and tumor sequencing results. Finally, we describe a case illustrating challenges with using microsatellite instability for predicting tumor response to immune checkpoint inhibitors. The common theme of the case studies is the importance of examining clinical context alongside expert review and interpretation, which together highlight an expanding role for contextual examination and multidisciplinary expert review through molecular tumor boards.
Subject(s)
High-Throughput Nucleotide Sequencing , Neoplastic Syndromes, Hereditary , Genetic Predisposition to Disease , Germ-Line Mutation , Humans , Microsatellite Instability , Mutation , Neoplastic Syndromes, Hereditary/diagnosis , Neoplastic Syndromes, Hereditary/geneticsABSTRACT
PURPOSE OF REVIEW: This review summarizes recent advances in prostate cancer (PCa) genetics. RECENT FINDINGS: Upwards of 20% of metastatic castration-resistant prostate tumors (mCRPC) carry homologous recombination (HR) repair gene mutations, of which ~ 10% are germline (inherited). Another ~ 5% exhibit microsatellite instability (MSI-H) and/or mismatch repair deficiency (MMRd). Pembrolizumab is approved for tumors with MMRd, thus patients with mCRPC and MMRd are candidates for pembrolizumab. Emerging data indicate that platinum chemotherapy and poly ADP-ribose polymerase inhibitors (PARPi) are effective in PCa exhibiting HR deficiency. NCCN guidelines now recommend germline and somatic tumor testing in specific clinical scenarios due to treatment and family implications. Genetic testing in PCa patients may inform prognosis, treatment options, and have implications for family counseling. PARPi, platinum chemotherapy, and immune checkpoint inhibitors are promising targeted therapies for PCa with specific molecular features. Therapeutic advances, along with importance to relatives, are driving genetic testing in prostate cancer.
Subject(s)
Genetic Testing/methods , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/genetics , Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/genetics , Clinical Trials, Phase II as Topic , Clinical Trials, Phase III as Topic , Genomics , Germ-Line Mutation , Humans , Male , Molecular Targeted Therapy , Precision Medicine , Prostatic Neoplasms/pathology , Randomized Controlled Trials as TopicABSTRACT
It is increasingly important for clinicians involved in the management of prostate cancer to understand the relevance of heritable (germline) mutations that, for select patients, affect prostate cancer risk and cancer biology, and acquired (somatic) mutations that occur in prostate cancer cells. In the advanced disease setting, mutations in homologous recombination repair genes (eg, BRCA1, BRCA2, ATM, CHEK2, PALB2) suggest candidacy for platinum chemotherapy and PARP inhibitor trials. Similarly, microsatellite instability and mismatch repair deficiency, which may arise in the setting of MLH1, MSH2, MSH6, and PMS2 mutations, suggest potential vulnerability to PD-1 inhibitors. Germline genetic testing has potential importance in the treatment and assessment of familial risk, and tumor-directed somatic sequencing may guide treatment decision-making. This review provides clinicians with knowledge of basic genetic terminology, awareness of the importance of family history of cancer (not limited to prostate cancer), contrasts between the different but potentially related objectives of germline versus somatic testing of tumor tissue, and indications for genetic counseling. Specific clinical scenarios, objectives of testing, and nature of the assays are reviewed. Germline and somatic mutations of known and potential relevance to prostate cancer are discussed in the context of treatment options, and algorithms to assist clinicians in approaching this area are proposed.
Subject(s)
Germ-Line Mutation , Mutation , Prostatic Neoplasms/diagnosis , Prostatic Neoplasms/genetics , Genetic Predisposition to Disease , Genetic Testing , Humans , MaleABSTRACT
Genetic testing is an integral part of the workup of metastatic prostate cancer, in part, because the results can have a profound impact on the subsequent management of this disease. There are now several Food & Drug Administration (FDA) approved therapeutics available for patients with prostate cancer and certain genetic abnormalities - most notably, mutations in DNA damage repair (DDR) pathways such mismatch repair (MMR) and homologous recombination repair (HRR). In this review of the current literature, we discuss the indications for somatic and germline testing, the genetic changes of particular clinical relevance, the associated therapeutic options, and the clinical data supporting their use. We also highlight select trials-in-progress and future directions for the field.
Subject(s)
Germ-Line Mutation , Mutation , Prostatic Neoplasms , Humans , Male , Prostatic Neoplasms/genetics , Prostatic Neoplasms/therapy , Prostatic Neoplasms/pathology , Genetic Testing/methodsABSTRACT
This report aims to shed light on the intricate challenges encountered during the diagnosis and treatment of an uncommon variant of prostate cancer-mixed adenosquamous cell carcinoma of the prostate. Prostate cancers of this nature pose distinctive diagnostic and therapeutic dilemmas due to their rarity and complex histological composition. We present a case of a 63-year-old man with metastatic prostate cancer, featuring adenocarcinoma with squamous cell differentiation, who underwent a multimodal treatment approach. The patient responded to first-line carboplatin, docetaxel, and androgen deprivation therapy, followed by androgen receptor pathway inhibitor (ARPI) maintenance. However, disease progression led to radiation therapy and a subsequent switch to Lutetium (177Lu) vipivotide tetraxetan after chemotherapy challenges. Comprehensive genetic profiling revealed shared mutations in the prostate and liver lesions, emphasizing the role of targeted therapies. Prostate-specific membrane antigen (PSMA)-targeted therapy resulted in a notable PSA decline. This case highlights the evolving treatment landscape for rare prostate cancers, integrating genetic insights for tailored interventions. In conclusion, squamous cell carcinoma (SCC) of the prostate is rare, emphasizing the imperative for enhanced comprehension in diagnosis and management. Our case suggests the potential efficacy of ARPI and PSMA-targeted therapies. Our findings advocate for a more nuanced approach to the management of this rare prostate cancer variant, leveraging genomic insights for personalized treatment strategies. This exploration serves as a foundation for further research and clinical considerations in addressing the challenges posed by mixed adenosquamous cell carcinoma of the prostate.
Subject(s)
Carcinoma, Adenosquamous , Liver Neoplasms , Prostatic Neoplasms , Humans , Male , Liver Neoplasms/secondary , Middle Aged , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , Carcinoma, Adenosquamous/genetics , Carcinoma, Adenosquamous/pathology , Carcinoma, Adenosquamous/drug therapy , Carcinoma, Adenosquamous/secondaryABSTRACT
Prostate cancer (PCa) seldom metastasizes to the thyroid gland, and only a limited number of cases are documented in the literature. The application of a relatively recent and highly sensitive imaging technique, prostate-specific membrane antigen (PSMA) positron emission tomography-computed tomography (PET/CT), has enhanced the identification of metastatic disease. Nevertheless, as PSMA is expressed in various tissue types, the clinical importance of a PSMA-avid thyroid lesion remains largely uncertain. A minor, yet noteworthy, percentage of these lesions are ultimately determined to be malignant. Here we describe the case of a 70-year-old man with a past medical history of Lynch syndrome who presented to an outpatient oncologic clinic for management of very high risk localized PCa. He developed metastatic recurrence and his disease progressed through several lines of therapy, including immunotherapy and targeted treatments. He was found to have a new, intense PSMA uptake in an existing, previously benign thyroid nodule. Sonographic evaluation revealed changing morphology despite grossly stable size. Repeat biopsy confirmed the unusual finding of PCa metastasis to a known thyroid nodule. The shift in PSMA avidity played a pivotal role in discerning this metastatic deposit. There is a potential risk that such lesions may be inadequately acknowledged. The impact of the patient's Lynch syndrome on this presentation remains uncertain.
ABSTRACT
PURPOSE: There are limited data available on the real-world patterns of molecular testing in men with advanced prostate cancer. We thus sought to evaluate next-generation sequencing (NGS) testing in the United States, focused on single versus serial NGS testing, the different disease states of testing (hormone-sensitive v castration-resistant, metastatic vs nonmetastatic), tissue versus plasma circulating tumor DNA (ctDNA) assays, and how often actionable data were found on each NGS test. METHODS: The Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort clinical-genomic database was used for this retrospective analysis, including 1,597 patients across 15 institutions. Actionable NGS data were defined as including somatic alterations in homologous recombination repair genes, mismatch repair deficiency, microsatellite instability (MSI-high), or a high tumor mutational burden ≥10 mut/MB. RESULTS: Serial NGS testing (two or more NGS tests with specimens collected more than 60 days apart) was performed in 9% (n = 144) of patients with a median of 182 days in between test results. For the second NGS test and beyond, 82.1% (225 of 274) of tests were from ctDNA assays and 76.1% (217 of 285) were collected in the metastatic castration-resistant setting. New actionable data were found on 11.1% (16 of 144) of second NGS tests, with 3.5% (5 of 144) of tests detecting a new BRCA2 alteration or MSI-high. A targeted therapy (poly (ADP-ribose) polymerase inhibitor or immunotherapy) was given after an actionable result on the second NGS test in 31.3% (5 of 16) of patients. CONCLUSION: Repeat somatic NGS testing in men with prostate cancer is infrequently performed in practice and can identify new actionable alterations not present with initial testing, suggesting the utility of repeat molecular profiling with tissue or blood of men with metastatic castration-resistant prostate cancer to guide therapy choices.
Subject(s)
Antineoplastic Agents , Circulating Tumor DNA , Prostatic Neoplasms , Male , Humans , Retrospective Studies , Prostatic Neoplasms/diagnosis , Prostatic Neoplasms/genetics , Prostatic Neoplasms/drug therapy , Circulating Tumor DNA/genetics , Antineoplastic Agents/therapeutic use , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , High-Throughput Nucleotide Sequencing/methodsABSTRACT
PURPOSE: Germline mutations in DNA repair genes are present in approximately 10% of men with metastatic prostate cancer (mPC), and guidelines recommend genetic germline testing. Notable barriers exist, including access to genetic counseling, insurance coverage, and out-of-pocket costs. The GENTleMEN study was designed to determine the feasibility of an Internet-based, patient-driven germline genetic testing approach for men with mPC. PATIENTS AND METHODS: In this prospective cohort study, men with mPC provided informed consent via an Internet-based platform and completed a questionnaire including demographics and family cancer history. Supporting medical data were also collected. Genetic testing was performed using the Color Genomics 30-gene targeted panel of cancer predisposition genes on a mailed saliva sample. Men whose test results identified a germline pathogenic or likely pathogenic variant received results by phone or telehealth genetic counseling; other participants received results by email with an option for phone-based or telehealth genetic counseling. RESULTS: As of August 18, 2021, 816 eligible men were consented, of whom 68% (551) completed genetic testing, and 8.7% (48 of 551) were found to carry a pathogenic or likely pathogenic variant in a germline DNA repair gene: CHEK2 (17), BRCA2 (15), ATM (6), NBN1 (3), BRCA1 (2), PALB2 (2), PMS2 (2), and MSH6 (1). Participants were more likely to complete the testing process if they were non-Hispanic White, married, highly educated, or from a higher-income bracket. CONCLUSION: Here, we show the feasibility of delivering germline (inherited) genetic testing by a voluntary, patient-driven, Internet-based platform to men with mPC. Preliminary results show rates of germline DNA repair mutations, consistent with other cohorts. Although feasible for some, reduced steps for participation, more dedicated diverse outreach and participant support, and identification and addressing of additional barriers is needed to ensure equitable access and optimization.
Subject(s)
Genetic Testing , Prostatic Neoplasms , Humans , Male , DNA Repair/genetics , Germ Cells/pathology , Prospective Studies , Prostatic Neoplasms/diagnosis , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , Neoplasm MetastasisABSTRACT
BACKGROUND AND OBJECTIVE: BRCA2 mutations in metastatic castration-resistant prostate cancer (mCRPC) confer sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. However, additional factors predicting PARP inhibitor efficacy in mCRPC are needed. Preclinical studies support a relationship between speckle-type POZ protein (SPOP) inactivation and PARP inhibitor sensitivity. We hypothesized that SPOP mutations may predict enhanced PARP inhibitor response in BRCA2-altered mCRPC. METHODS: We conducted a multicenter retrospective study involving 13 sites. We identified 131 patients with BRCA2-altered mCRPC treated with PARP inhibitors, 14 of which also carried concurrent SPOP mutations. The primary efficacy endpoint was prostate-specific antigen (PSA) response rate (≥50% PSA decline). The secondary endpoints were biochemical progression-free survival (PSA-PFS), clinical/radiographic progression-free survival (PFS), and overall survival (OS). These were compared by multivariable Cox proportional hazard models adjusting for age, tumor stage, baseline PSA level, Gleason sum, prior therapies, BRCA2 alteration types, and co-occurring mutations. KEY FINDINGS AND LIMITATIONS: Baseline characteristics were similar between groups. PSA responses were observed in 60% (70/117) of patients with BRCA2mut/SPOPwt disease and in 86% (12/14) of patients with BRCA2mut/SPOPmut disease (p = 0.06). The median time on PARP inhibitor treatment was 24.0 mo (95% confidence interval [CI] 19.2 mo to not reached) in this group versus 8.0 mo (95% CI 6.1-10.9 mo) in patients with BRCA2 mutation alone (p = 0.05). In an unadjusted analysis, patients with BRCA2mut/SPOPmut disease experienced longer PSA-PFS (hazard ratio [HR] 0.33 [95% CI 0.15-0.72], p = 0.005) and clinical/radiographic PFS (HR 0.4 [95% CI 0.18-0.86], p = 0.02), and numerically longer OS (HR 0.4 [95% CI 0.15-1.12], p = 0.08). In a multivariable analysis including histology, Gleason sum, prior taxane, prior androgen receptor pathway inhibitor, stage, PSA, BRCA2 alteration characteristics, and other co-mutations, patients with BRCA2mut/SPOPmut disease experienced longer PSA-PFS (HR 0.16 [95% CI 0.05-0.47], adjusted p = 0.001), clinical/radiographic PFS (HR 0.28 [95% CI 0.1-0.81], adjusted p = 0.019), and OS (HR 0.19 [95% CI 0.05-0.69], adjusted p = 0.012). In a separate cohort of patients not treated with a PARP inhibitor, there was no difference in OS between patients with BRCA2mut/SPOPmut versus BRCA2mut/SPOPwt disease (HR 0.97 [95% CI 0.40-2.4], p = 0.94). In a genomic signature analysis, Catalog of Somatic Mutations in Cancer (COSMIC) SBS3 scores predictive of homologous recombination repair (HRR) defects were higher for BRCA2mut/SPOPmut than for BRCA2mut/SPOPwt disease (p = 0.04). This was a retrospective study, and additional prospective validation cohorts are needed. CONCLUSIONS AND CLINICAL IMPLICATIONS: In this retrospective analysis, PARP inhibitors appeared more effective in patients with BRCA2mut/SPOPmut than in patients with BRCA2mut/SPOPwt mCRPC. This may be related to an increase in HRR defects in coaltered disease. PATIENT SUMMARY: In this study, we demonstrate that co-alteration of both BRCA2 and SPOP predicts superior clinical outcomes to treatment with poly (ADP-ribose) polymerase (PARP) inhibitors than BRCA2 alteration without SPOP mutation.
ABSTRACT
Recent studies show that the prevalence of germline pathogenic and likely pathogenic variants (also known as mutations) in DNA repair genes in metastatic prostate cancer is higher than previously recognized and higher than in unaffected men. Specific gene dysfunction is important in prostate cancer initiation and/or evolution to metastases. This article reviews key literature on individual genes, recognizing BRCA2 as the gene most commonly altered in the metastatic setting. This article discusses the importance of representative and diverse inclusion, and efforts to advance management for at-risk carrier populations to maximize clinical benefit.
Subject(s)
Neoplasm Metastasis/genetics , Neoplasm Metastasis/pathology , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , Antineoplastic Agents/therapeutic use , DNA Damage , Genetic Predisposition to Disease , Genetic Testing , Germ-Line Mutation , Humans , Indoles/therapeutic use , Male , Neoplasm Metastasis/drug therapy , Phthalazines/therapeutic use , Piperazines/therapeutic use , Prostatic Neoplasms/drug therapyABSTRACT
Chelation therapy is sometimes used after potential exposures to plutonium to increase urinary excretion of the radionuclide to improve the accuracy of bioassay measurements. The purpose of this report is to describe the enhancement of urinary excretion of plutonium during and after the administration of the trisodium salt of calcium diethylenetriaminepentaacetate (Ca-DTPA) daily for 3 d to a group of male and female plutonium workers from the Mayak Production Association in Ozyorsk, Russia. One-hundred and two cases (18 females and 84 males) were selected where urinary contents of plutonium, prior to chelation, exceeded the detection threshold. Daily urine collections were obtained during the 3 d of Ca-DTPA treatments. In addition, 58 of these cases had urine bioassays at 1-45 d after chelation. The daily enhancement over baseline values excretion of plutonium was found to be 50.4×/1.4 (geometric mean and geometric standard deviation); 58.9×/1.2; 72.9×/1.4 in the first, second and third days of Ca-DTPA administration. The mean enhancement for the 3-d period was 60.1×/1.7. The rate of plutonium excretion from 1 to 45 d after chelation decreased with a half-period of 3.9 d and the chelation enhancement factor (Ðenh-i) is described by the function Ðenh-i = (0.79 ± 0.24) + (42.9 ± 1.2) × e-(0.18 ± 0.01) × day.
Subject(s)
Occupational Exposure , Plutonium , Biological Assay , Chelating Agents , Female , Humans , Male , Occupational Exposure/analysis , Pentetic Acid , Plutonium/analysisABSTRACT
IMPORTANCE: Cell-free DNA (cfDNA) testing is increasingly used in the treatment of patients with advanced prostate cancer. Clonal hematopoiesis of indeterminate potential (CHIP) can interfere with cfDNA testing and cause incorrect interpretation of results. There is an urgent need to better understand this problem following recent US Food and Drug Administration approval of poly(ADP) ribose polymerase inhibitors (PARPi) for metastatic prostate cancer based on variants in DNA repair genes that can be affected by CHIP. OBJECTIVE: To determine the prevalence of clinically relevant CHIP interference in prostate cancer cfDNA testing. DESIGN, SETTING, AND PARTICIPANTS: We report a case series of 69 patients with advanced prostate cancer (metastatic disease or with rising PSA following localized therapy) who had cfDNA variant testing with a large panel cancer next generation sequencing assay (UW-OncoPlexCT). To determine the source of variants in plasma, we tested paired cfDNA and whole blood control samples. The study was carried out in an academic medical center system reference laboratory. MAIN OUTCOMES AND MEASURES: Prevalence and gene spectrum of CHIP interference in patients with prostate cancer undergoing cfDNA testing. RESULTS: We detected CHIP variants at 2% or more variant fraction in cfDNA from 13 of 69 men with prostate cancer (19%; 95% CI, 10%-30%). Seven men (10%; 95% CI, 4%-20%) had CHIP variants in DNA repair genes used to determine PARPi candidacy, including ATM (n = 5), BRCA2 (n = 1), and CHEK2 (n = 1). Overall, CHIP variants accounted for almost half of the somatic DNA repair gene variants detected. Participant CHIP variants were exponentially correlated with older age (R2 = 0.82). CHIP interference variants could be distinguished from prostate cancer variants using a paired whole-blood control. CONCLUSIONS AND RELEVANCE: In this case series, approximately 10% of men with advanced prostate cancer had CHIP interference in plasma cfDNA in DNA repair genes that are used for eligibility of PARPi therapy, most frequently in ATM. Clinical cfDNA testing should include a paired whole-blood control to exclude CHIP variants and avoid misdiagnosis.
Subject(s)
Cell-Free Nucleic Acids , Prostatic Neoplasms , Cell-Free Nucleic Acids/genetics , Clonal Hematopoiesis , DNA Repair/genetics , High-Throughput Nucleotide Sequencing , Humans , Male , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/geneticsABSTRACT
Two poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and rucaparib) are US Food and Drug Administration-approved for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring BRCA1/2 mutations, but the relative efficacy of PARP inhibition in BRCA1- versus BRCA2-altered mCRPC is understudied. METHODS: We conducted a multicenter retrospective analysis involving 12 sites. We collected genomic and clinical data from 123 patients with BRCA1/2-altered mCRPC who were treated with PARP inhibitors. The primary efficacy end point was the prostate-specific antigen (PSA) response (≥ 50% PSA decline) rate. Secondary end points were PSA progression-free survival (PSA-PFS), clinical or radiographic PFS, and overall survival. We compared clinical outcomes, and other genomic characteristics, among BRCA1- versus BRCA2-altered mCRPC. RESULTS: A total of 123 patients (13 BRCA1 and 110 BRCA2) were included. PARP inhibitors used were olaparib (n = 116), rucaparib (n = 3), talazoparib (n = 2), and veliparib (n = 2). At diagnosis, 72% of patients had Gleason 8-10 disease. BRCA1 patients were more likely to have metastatic disease at presentation (69% v 37%; P = .04). Age, baseline PSA, metastatic distribution, and types of previous systemic therapies were similar between groups. There were equal proportions of germline mutations (51% v 46%; P = .78) in both groups. BRCA1 patients had more monoallelic (56% v 41%; P = .49) and concurrent TP53 (55% v 36%; P = .32) mutations. PSA50 responses in BRCA1- versus BRCA2-altered patients were 23% versus 63%, respectively (P = .01). BRCA2 patients achieved longer PSA-PFS (HR, 1.94; 95% CI, 0.92 to 4.09; P = .08), PFS (HR, 2.08; 95% CI, 0.99 to 4.40; P = .05), and overall survival (HR, 3.01; 95% CI, 1.32 to 6.83; P = .008). Biallelic (compared with monoallelic) mutations, truncating (compared with missense) mutations, and absence of a concurrent TP53 mutation were associated with PARP inhibitor sensitivity. CONCLUSION: PARP inhibitor efficacy is diminished in BRCA1- versus BRCA2-altered mCRPC. This is not due to an imbalance in germline mutations but might be related to more monoallelic mutations and/or concurrent TP53 alterations in the BRCA1 group.