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Impact of an Expanded Definition of Family History on Outcomes of Active Surveillance for Prostate Cancer

2023; Lippincott Williams & Wilkins; Volume: 209; Issue: 6 Linguagem: Inglês

10.1097/ju.0000000000003396

1527-3792

Adam Schneider, Thenappan Chandrasekar, Nicholas Bowler, Ryan Fogg, Joon Yau Leong, Andrew Gusev, Linda Rodgers, Shelley R. McCormick, Douglas M. Dahl, Jason A. Efstathiou, Michael L. Blute, Anthony L. Zietman, Chin‐Lee Wu, Matthew R. Smith, Eliezer M. Van Allen, Adam S. Feldman, Keyan Salari,

Genetic factors in colorectal cancer

Open AccessJournal of UrologyAdult Urology9 Mar 2023Impact of an Expanded Definition of Family History on Outcomes of Active Surveillance for Prostate Cancer Adam C. Schneider, Thenappan Chandrasekar, Nicholas Bowler, Ryan Fogg, Joon Yaa Leong, Andrew Gusev, Linda H. Rodgers, Shelley R. McCormick, Douglas M. Dahl, Jason A. Efstathiou, Michael L. Blute, Anthony L. Zietman, Chin-Lee Wu, Matthew R. Smith, Eliezer M. Van Allen, Adam S. Feldman, and Keyon Salari Adam C. SchneiderAdam C. Schneider Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts Department of Urology, Thomas Jefferson University, Sidney Kimmel Medical College, Philadelphia, Pennsylvania , Thenappan ChandrasekarThenappan Chandrasekar Department of Urology, Thomas Jefferson University, Sidney Kimmel Medical College, Philadelphia, Pennsylvania , Nicholas BowlerNicholas Bowler Department of Urology, Thomas Jefferson University, Sidney Kimmel Medical College, Philadelphia, Pennsylvania , Ryan FoggRyan Fogg Department of Urology, Thomas Jefferson University, Sidney Kimmel Medical College, Philadelphia, Pennsylvania , Joon Yaa LeongJoon Yaa Leong Department of Urology, Thomas Jefferson University, Sidney Kimmel Medical College, Philadelphia, Pennsylvania , Andrew GusevAndrew Gusev Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts , Linda H. RodgersLinda H. Rodgers Center for Cancer Risk Assessment, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts , Shelley R. McCormickShelley R. McCormick Center for Cancer Risk Assessment, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts , Douglas M. DahlDouglas M. Dahl Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts , Jason A. EfstathiouJason A. Efstathiou Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts , Michael L. BluteMichael L. Blute Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts , Anthony L. ZietmanAnthony L. Zietman Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts , Chin-Lee WuChin-Lee Wu Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts , Matthew R. SmithMatthew R. Smith Center for Genitourinary Cancers, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts , Eliezer M. Van AllenEliezer M. Van Allen Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts , Adam S. FeldmanAdam S. Feldman Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts , and Keyon SalariKeyon Salari *Correspondence: Department of Urology, Massachusetts General Hospital, 55 Fruit St, GRB-1106H, Boston, MA 02114 telephone: 617-726-3502; E-mail Address: [email protected] Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts View All Author Informationhttps://doi.org/10.1097/JU.0000000000003396AboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Abstract Purpose: Despite family history being an established risk factor for prostate cancer, the role of a broader definition of family history inclusive of not just prostate cancer but other genetically related malignancies has not been investigated in the active surveillance population. Here, we evaluate the impact of an expanded definition of family history on active surveillance outcomes. Materials and Methods: Patients undergoing active surveillance for prostate cancer at Massachusetts General Hospital from 1997-2019 with detailed data available on family cancer history were identified. Primary outcome was biopsy progression-free survival, and secondary outcomes were treatment-free survival, adverse pathological features at prostatectomy, and biochemical recurrence after treatment. Statistical analyses were conducted using the Kaplan-Meier method and Cox regression. Results: Among 855 evaluable patients, 300 (35.1%) patients had any family history of prostate cancer, and 95 (11.1%) had a family history of related malignancies suggestive of a hereditary cancer syndrome (family history of hereditary cancer syndrome). Family history of prostate cancer alone was not associated with biopsy progression, whereas family history of hereditary cancer syndrome was associated with a significantly increased risk of biopsy progression (HR 1.43, 95%CI 1.01-2.02), independent of other known clinicopathological risk factors in multivariable analysis. Similarly, family history of hereditary cancer syndrome was associated with significantly lower treatment-free survival (HR 1.58, 95%CI 1.14-2.18) in multivariable analysis. No significant association was found between family history and adverse features on surgical pathology or biochemical recurrence. Conclusions: An expanded family history suggestive of a hereditary cancer syndrome is an independent predictor of biopsy progression during active surveillance. Men with such a family history may still be offered active surveillance but should be counseled regarding the higher risk of disease progression. A family history (FH) of prostate cancer (PC) is a well-established risk factor for the development of PC.1,2 There has been increasing recognition that FH of certain malignancies, such as breast, ovarian, and pancreatic cancer, also increases the risk of being diagnosed with PC, pointing to a shared genetic predisposition.2-6 Indeed, inherited DNA repair-gene mutations (eg, BRCA1/2) result in a hereditary cancer syndrome (HCS) typified by an increased risk of forming breast, ovarian, prostate, and pancreatic cancers. The AUA and National Comprehensive Cancer Network (NCCN) guidelines now recommend germline genetic testing for patients with high-risk or metastatic PC and those with a strong FH suggestive of an HCS.7,8 However, in clinical practice genetic testing for most patients yields negative results, as <5% of men with localized PC are estimated to harbor a pathogenic germline mutation in a known PC risk gene.9 Nonetheless, such patients and their families often remain at elevated risk for PC and other associated malignancies, suggesting the presence of additional, yet to be identified genetic risk factors and/or shared environmental risk factors.10 Thus, FH remains a potentially important tool that encompasses both shared genetic and environmental factors underlying PC risk. While several germline DNA repair-gene mutations increase the risk of aggressive PC,11,12 the extent to which a strong FH suggestive of an HCS may similarly increase the risk of high-grade PC is unknown. This information would be important to inform counseling of patients considering active surveillance (AS) for otherwise seemingly indolent PC. While multiple studies have shown an absence of association between FH of PC and disease progression on AS,13-17 these prior studies focused on a narrower definition of FH of PC alone. We sought to investigate how a broader definition of FH that incorporates genetically related cancer types (ie, breast, ovarian, and pancreatic cancers) impacts the risk of progression in a large institutional AS cohort. Here, we describe the association between an expanded definition of FH and outcomes of AS for PC under the hypothesis that patients at high genetic risk based on their FH are at increased risk of disease progression on AS. MATERIALS AND METHODS Study Population With institutional review board approval, we retrospectively identified patients with PC managed by AS between 1997 and 2019.18,19 Selection guidelines for AS at our institution include cT1-T2a, grade group (GG) 1 (and select low-volume GG2) disease with ≤50% positive cores, and PSA 1, which corresponds to approximately the >90th percentile of S-scores in our cohort (Figure 1) and can be translated clinically to >1 FDR or FDR-equivalent (ie, 1 FDR=2 SDRs=4 TDRs) with relevant cancer history. For example, a father (FDR) with PC and 2 paternal aunts (SDR) with breast cancer would yield S=wFDR*1+wSDR*2=2. Figure 1. A, Overlap of family history of hereditary cancer syndrome–related cancer types. Gray bars indicate the total number of patients in the active surveillance cohort with each family history combination specified in the dot matrix. Orange bar indicates hereditary cancer syndrome+ subset of patients (ie, standard [S] score >1) based on family history of prostate cancer (PC) alone. Red bars indicate hereditary cancer syndrome+ subset of patients based on family history beyond PC. B, Distribution of S scores across entire cohort and patients with S>1 indicated in red. HCS indicates hereditary cancer syndrome. Outcomes The primary outcome of the study was biopsy progression-free survival (BPFS). Biopsy progression was defined by either grade (GG1 to ≥GG2 or GG2 to ≥GG3) or volume (≤50% cores positive and ≤50% maximum core involvement on diagnostic biopsy, progressing to either >50% cores positive or >50% maximum core involvement). Secondary outcomes were adverse pathological features at radical prostatectomy (RP; ≥GG3, pT3-4, or lymph node involvement), treatment-free survival (TFS), and biochemical recurrence (BCR) among patients who underwent delayed definitive treatment after a period of AS. Statistical Analysis Baseline clinicopathological characteristics were compared by FH category using the Mann-Whitney U-test for continuous and Fisher's exact test for categorical variables. Unadjusted Kaplan-Meier estimates of BPFS and TFS by FH category were generated. To estimate the hazard of FH of PC or FH suggestive of an HCS on each time-to-event outcome (BPFS, TFS, BCR), multivariable Cox proportional-hazard models were utilized, adjusting for known clinically associated factors: age, GG, PSA, percent cores positive and maximum percent core involvement on diagnostic biopsy. Follow-up started on the date of diagnosis for BPFS and TFS, and on the date of definitive treatment with surgery or radiation for BCR. Follow-up continued until the relevant event date for each outcome: biopsy demonstrating progression (BPFS), date of treatment (TFS), or date of confirmed PSA recurrence (BCR). Patients were censored on the date of last follow-up if no event had occurred. For sensitivity analysis, the multivariable Cox model of BPFS was repeated restricted to NCCN very low-risk and low-risk patients, adjusted for the same covariates. The same covariates were also adjusted for in a multivariable logistic regression to estimate the odds ratio for adverse pathological features at RP. P value for statistical significance was <.05. All statistical analyses were performed using R. RESULTS Among the 1,268 patients in our institutional AS cohort, we excluded patients with <2 biopsies or 50% cores positive or >50% maximum core involvement; n=103), or missing FH data (n=67). Of the 855 evaluable patients, 300 (35%) had an FH of PC and 95 (11.1%) had FH HCS (ie, S>1; Figure 1). Patient baseline clinicopathological characteristics are presented in Table 1. At least 1 prostate MRI was obtained in 482 (56%) patients, and there were no significant differences between FH categories in the proportion of patients who underwent MRI on AS or number of surveillance biopsies. Table 1. Baseline Clinicopathological Characteristics by Family History Status Variable Overall N = 855 Positive FH PCN = 300 Negative FH PCN = 555 P valuea Positive FH HCSN = 95 Negative FH HCSN = 760 P valuea Age, median (IQR), y 64 (59-69) 63 (58-69) 66 (60-69) <.001 64 (59-70) 64 (59-69) .9 Initial PSA, median (IQR), ng/mL 5.0 (3.8-6.4) 4.6 (3.3-5.9) 5.1 (4.1-6.8) <.001 4.3 (3.1-5.7) 5.0 (4.0-6.6) .001 Prostate volume, median (IQR), mL 42.5 (32.0-58.1) 41.0 (30.0-56.0) 43.2 (33.4-60.0) .046 37.6 (27.8-51.2) 43.5 (33.0-59.0) .008 PSA density, median (IQR), ng/mL2 0.11 (0.08-0.15) 0.11 (0.07-0.15) 0.11 (0.08-0.15) .12 0.11 (0.08-0.16) 0.11 (0.08-0.15) .8 Initial biopsy grade group, No. (%) 1 (3+3) 837 (97.9) 298 (99.3) 539 (97.1) .043 94 (98.9) 743 (97.8) .7 2 (3+4) 18 (2.1) 2 (0.7) 16 (2.9) 1 (1.1) 17 (2.2) Clinical T stage, No. (%) cT1 795 (93.0) 276 (92.0) 519 (93.5) .4 86 (90.5) 709 (93.3) .3 cT2 60 (7.0) 24 (8.0) 36 (6.5) 9 (9.5) 51 (6.7) Prostate MRI on AS, No. (%) Yes 482 (56.4) 178 (59.3) 304 (54.8) .11 59 (62.1) 423 (55.7) 1.0 Positive MRI (PIRADS ≥3) 218 (25.5) 72 (24.0) 146 (26.3) 27 (28.4) 191 (21.5) Negative MRI (PI-RADS <3) 264 (30.9) 106 (35.3) 158 (28.5) 32 (33.7) 232 (34.2) No/Missing 373 (43.6) 122 (40.7) 251 (45.2) 36 (37.9) 337 (44.3) No. biopsies on AS, median (IQR) 2 (2-3) 2 (2-3) 2 (2-3) .9 2 (2-3) 2 (2-3) .7 Abbreviations: AS, active surveillance; FH, family history; HCS, hereditary cancer syndrome; IQR, interquartile range (25th-75th); MRI, magnetic resonance imaging; PC, prostate cancer; PIRADS, Prostate Imaging-Reporting and Data System; PSA, prostate-specific antigen. P values were calculated using Mann-Whitney U-test for continuous and Fisher's exact test for categorical variables. There were 330 patients who experienced biopsy progression while on AS. The median follow-up time for patients who did not progress was 6.3 years. There were 165 patients who underwent RP at a median of 2.3 years (IQR 1.6-3.8 years) after diagnosis, 38 of whom had adverse pathological features on final surgical pathology. A total of 360 patients progressed to treatment with either surgery or radiation, with biopsy progression being the most common reason for treatment irrespective of FH. Only 12 (1.4%) patients in our AS cohort have undergone germline genetic testing and 2 had a pathogenic variant identified in a PC risk gene (1 BRCA2 and 1 MSH6); neither experienced disease progression during the follow-up of this study. One additional patient who had an FH of a germline BRCA2 mutation but had not personally undergone genetic testing did experience disease progression. Each FH category was evaluated for association with disease progression on AS. No significant association was found between FH of PC alone and BPFS in multivariable Cox regression (HR 1.13, 95%CI 0.90-1.42, P = .3; Table 2), and Kaplan-Meier estimates were similar between patients with vs without FH PC (Figure 2). However, FH HCS was associated with a significantly increased hazard of biopsy progression; in multivariable analysis, FH HCS was a statistically significant predictor of biopsy progression, after adjusting for known clinically associated factors (HR 1.43, 95%CI 1.01-2.02, P = .046; Table 2 and Figure 3). We found no significant difference in biopsy progression based on whether patients underwent a prostate MRI while on AS (P = .66) and no significant difference between FH categories with respect to MRI utilization or number of biopsies on AS (Table 1). Table 2. Multivariable Cox Proportional Hazards Models of Biopsy Progression-free Survival and Treatment-free Survival Variable Biopsy progression-free survival Treatment-free survival Hazard ratio (95% CI) P value Hazard ratio (95% CI) P value PC No FH - - - - FH PC 1.13 (0.90-1.42) 0.3 1.20 (0.96-1.49) 0.10 HCS No FH (S=0) - - - - FH (0 1) 1.43 (1.01-2.02) 0.046 1.58 (1.14-2.18) 0.006 Abbreviations: CI, confidence interval; FH, family history; HCS, hereditary cancer syndrome; PC, prostate cancer; S, standard score. Multivariable models adjusted for age, Gleason grade, prostate-specific antigen, percent cores positive, and maximum percent core involvement at diagnosis. Figure 2. Kaplan-Meier curve of biopsy progression-free survival (PFS) for patients with vs without any family history (FH) of prostate cancer (PC). Figure 3. Kaplan-Meier curve of biopsy progression-free survival (PFS) for patients with vs without a strong family history (FH) suggestive of a hereditary cancer syndrome (HCS). We next examined the impact of FH on progression to treatment (Table 2). Similar to BPFS, no significant difference was observed in TFS between patients with vs without FH PC, whereas FH HCS was significantly associated with worse TFS. In multivariable analysis, FH HCS was a statistically significant predictor of TFS (HR 1.58, 95%CI 1.14-2.18, P = .006; Table 2). Regarding adverse pathology at RP, no significant association was found with FH PC (P = .8) or FH HCS (P = .7). Similarly, there were no statistically significant differences in the hazards of BCR between FH categories among the subset of patients (n=337) who underwent delayed treatment after a period of AS (all P > .4; 5-year BCR rates: 84% FH PC- vs 93% FH PC+ and 87% FH HCS- vs 90% FH HCS+), though this analysis was likely underpowered due to few BCR events (n=27). Finally, our sensitivity analysis restricted to NCCN very-low-risk (n=405) and low-risk (n=381) PC demonstrated FH HCS (but not FH PC alone) was associated with an increased hazard for biopsy progression (HR 1.37, 95%CI 0.96-1.96, P = .087), consistent with the overall cohort results but not reaching nominal statistical significance in this subgroup analysis. DISCUSSION We found that patients with a strong FH suggestive of an HCS (but not those with FH PC alone) have an increased hazard of biopsy progression and coming to treatment on AS compared to patients without such FH. However, the subset of FH HCS patients who underwent delayed definitive treatment after a period of AS did not appear to experience higher rates of adverse pathology at RP or BCR. Our study represents one of the largest cohorts in which the impact of FH on AS outcomes has been investigated.13-17 Unique to our study is the broader definition of FH considered to be clinically relevant to men on AS, including an FH of not only PC, but also other malignancies with shared genetic underpinnings (ie, breast, ovarian, and pancreatic cancers). Further, we present a novel FH scoring metric that aggregates affected relatives across multiple generations while accounting for degree of relatedness. Over the past decade, the relationship between FH of PC and disease progression on AS has been investigated in 5 studies to our knowledge,13-17,21 all generally concluding that FH of PC is not associated with disease progression on AS. Notable differences between our study and prior studies that might account for the discordant findings include smaller sample size of previously examined AS cohorts (n=200-471); varying definitions for disease progression (biopsy-detected vs biomarker-detected) among prior studies; lack of a standardized definition of positive FH; and perhaps most importantly, the prior studies focused on FH of PC alone and did not include related malignancies that raise suspicion for an HCS. Our results are consistent with previous studies, where FH of PC alone was not associated with a higher risk of biopsy progression. Only when an expanded definition of FH that includes related malignancies was employed did we observe FH to be associated with an increased risk of progression on AS. Most recently, Jibara et al examined the association between FH of prostate and other cancer types with clinicopathological outcomes in their institutional AS cohort.22 Their analysis of 3,211 patients (with median follow-up of 3.7 years) demonstrated an increased risk of biopsy grade progression on AS among patients with strong FH of PC but not among those with strong FH of other cancers. Notably, in their study FH HCS was defined based on NCCN Guidelines criteria as ≥3 relatives from the same side of the family with any of a dozen different cancer types.23 We believe this definition is likely too broad to enrich for a shared genetic predisposition for PC and may in part explain the discordant results. Nonetheless, our studies reach similar conclusions in that strong FH does not appear to increase risk of adverse pathology at RP and thus AS can still be safely offered to such patients. In our AS cohort, while all 95 patients with FH HCS meet germline genetic testing criteria per NCCN Guidelines,23,24 the vast majority of patients have not undergone testing. Determining the germline mutation status of our AS patients will be a focus of future work, but we expect the carrier rates of DNA repair-gene mutations to be quite low (<5%) in localized PC (vs ∼12% in metastatic PC9,25). Indeed, in a combined analysis of 2 independent AS cohorts,26 pathogenic mutations in a three-gene panel (BRCA1, BRCA2, ATM) were found in only 26 of 1211 patients (2.1%). However, patients harboring a mutation in any of these genes (particularly BRCA2) carried a significantly higher risk of grade reclassification. Even among highly pre-selected patients, 1 study of a prospective genetic testing database found germline mutations in only 19.5% of 169 probands with FH suggestive of HCS that includes PC.10 Together, these studies suggest that germline DNA repair-gene mutations likely account for a small minority of AS patients with strong FH or those experiencing biopsy progression. Our results underscore the added value of a detailed FH as an inexpensive tool for assessing the independent risk conferred by FH on biopsy progression. While patients in our study with FH HCS experienced a higher risk of disease progression, no association was found with adverse pathology at RP or BCR after treatment, suggesting that with timely intervention curative treatment is likely not compromised. It is likely that our observed association between FH and biopsy progression results from a combination of occult, undersampled high-grade cancer present at diagnosis and progression from low- to high-grade disease over time. This is consistent with a recent study identifying an increased risk of high-grade PC among patients referred for prostate biopsy with FH of both prostate and breast cancers.27 Overall, we believe such patients can still be safely offered AS but should be counseled about the higher risk of biopsy progression. Our study has several important limitations. First, while our median follow-up time of 6.3 years is longer than previous studies investigating FH in AS, it limits our evaluation to short- to intermediate-term outcomes of AS. Longer follow-up will be required to assess late outcomes of AS (BCR, metastasis and PC-specific mortality). Second, only 18 patients in our analysis had GG2 disease, and therefore our results may not be generalizable to this subset of men on AS. Third, our data partially predate the introduction of MRI into our AS program, and it is possible that patients with strong FH might be more likely to have a positive MRI and be excluded from AS. However, our data suggest no differences in the proportion of patients with positive MRIs between FH categories. Fourth, we introduce a novel FH scoring metric, which warrants validation in future studies. Finally, because FH was not systematically obtained by a genetic counselor, differences in documenting FH data could lead to observer bias. For example, if patients with higher risk disease were asked in more depth about extended family history, this could bias our results towards a higher risk estimate. Ascertainment bias may also be possible if retrospectively reviewed cases where FH was negative were recorded as missing. However, this would have biased our results towards a lower risk estimate. Additionally, given in clinical practice patients undergoing AS are not routinely evaluated by genetic counselors, our results are likely more generalizable to standard clinical practice. CONCLUSIONS We demonstrate that a strong FH suggestive of an HCS is associated with a significantly increased hazard of biopsy progression and progression to treatment for men on AS for PC. However, no association was identified between FH and the probability of adverse pathological features at RP or BCR among patients who ultimately underwent definitive treatment. Therefore, such patients can still be safely offered AS but should be counseled about the higher risk of biopsy progression and warrant closer monitoring compared to patients without a strong FH. These data support the wider inclusion of an expanded definition of FH in patient counseling and clinical decision-making for patients considering AS. Further research is warranted to investigate the underlying genetic factors that increase the risk of disease progression on AS. REFERENCES 1. . Epidemiology of prostate cancer. World J Oncol.2019; 10(2):63-89. Crossref, Medline, Google Scholar 2. . Risk of prostate cancer associated with familial and hereditary cancer syndromes. J Clin Oncol.2020; 38(16):1807-1813. Crossref, Medline, Google Scholar 3. . First-degree family history of breast cancer is associated with prostate cancer risk: a systematic review and meta-analysis. BMC Cancer.2019; 19(1):871. Crossref, Medline, Google Scholar 4. . Family history of cancer and risk of pancreatic cancer: a pooled analysis from the Pancreatic Cancer Cohort Consortium (PanScan). Int J Cancer.2010; 127(6):1421-1428. Crossref, Medline, Google Scholar 5. . Familial clustering of breast and prostate cancer and risk of postmenopausal breast cancer in the Women's Health Initiative Study. Cancer.2015; 121(8):1265-1272. Crossref, Medline, Google Scholar 6. . Family history of breast or prostate cancer and prostate cancer risk. Clin Cancer Res.2018; 24(23):5910-5917. Crossref, Medline, Google Scholar 7. . NCCN guidelines updates: management of prostate cancer. J Natl Compr Canc Netw.2019; 17(5.5):583-586. Medline, Google Scholar 8. . Clinically localized prostate cancer: AUA/ASTRO/SUO guideline. Part I: risk stratification, shared decision making, and Care options. J Urol.2018; 199(3):683-690. Link, Google Scholar 9. Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell.2015; 163(4):1011. Crossref, Medline, Google Scholar 10. . Prevalence of suspected hereditary cancer syndromes and germline mutations among a diverse cohort of probands reporting a family history of prostate cancer: toward informing cascade testing for men. Eur Urol Oncol.2020; 3:291-297. Crossref, Medline, Google Scholar 11. . Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol.2013; 31(14):1748-1757. Crossref, Medline, Google Scholar 12. . Elevated risk of prostate cancer among men with Lynch syndrome. J Clin Oncol.2013; 31(14):1713-1718. Crossref, Medline, Google Scholar 13. . Clinical and demographic characteristics associated with prostate cancer progression in patients on active surveillance. J Urol.2012; 187(5):1594-1600. Link, Google Scholar 14. . Impact of race on selecting appropriate patients for active surveillance with seemingly low-risk prostate cancer. Urology.2015; 85(2):436-441. Crossref, Medline, Google Scholar 15. . Clinical implications of family history of prostate cancer and genetic risk single nucleotide polymorphism (SNP) profiles in an active surveillance cohort. BJU Int.2013; 112(5):666-673. Crossref, Medline, Google Scholar 16. . Family history of prostate cancer in men being followed by active surveillance does not increase risk of being diagnosed with high-grade disease. Urology.2015; 85(4):742-747. Crossref, Medline, Google Scholar 17. . Urinary TMPRSS2:ERG and PCA3 in an active surveillance cohort: results from a baseline analysis in the Canary Prostate Active Surveillance Study. Clin Cancer Res.2013; 19(9):2442-2450. Crossref, Medline, Google Scholar 18. . Active surveillance for low-risk prostate cancer: need for intervention and survival at 10 years. Urol Oncol.2015; 33(9):383.e9-383.e16. Crossref, Medline, Google Scholar 19. . Active surveillance of prostate cancer is a viable option for men younger than 60 years. J Urol.2019; 201(4):721-727. Link, Google Scholar 20. . Association of Neo-Family History Score with pathological complete response, safety, and survival outcomes in patients with breast cancer receiving neoadjuvant platinum-based chemotherapy: an exploratory analysis of two prospective trials. EClinicalMedicine.2021; 38:101031. Crossref, Medline, Google Scholar 21. . Prostate cancer family history and eligibility for active surveillance: a systematic review of the literature. BJU Int.2017; 120(4):464-467. Crossref, Medline, Google Scholar 22. Association of family history of cancer with clinical and pathological outcomes for prostate cancer patients on active surveillance. J Urol.2022; 208(2):325-332. Link, Google Scholar 23. National Comprehensive Cancer Network. Prostate Cancer (Version 1.2023). Google Scholar 24. National Comprehensive Cancer Network. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (Version 2.2023). Google Scholar 25. . Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med.2016; 375(5):443-453. Crossref, Medline, Google Scholar 26. . Germline mutations in ATM and BRCA1/2 are associated with grade reclassification in men on active surveillance for prostate cancer. Eur Urol.2019; 75(5):743-749. Crossref, Medline, Google Scholar 27. Defining the impact of family history on detection of high-grade prostate cancer in a large multi-institutional cohort. Eur Urol.2022; 82(2):163-169. Crossref, Medline, Google Scholar Support: This work was supported in part by the Urology Care Foundation Research Scholar Award Program (KS), a Prostate Cancer Foundation Young Investigator Award (KS) and PCF-Movember Challenge Award (EVA), and a Mark Foundation Emerging Leader Award (EVA). Conflict of Interest: Jason A. Efstathiou: Advisory/Consulting: Blue Earth Diagnostics, Boston Scientific, AstraZeneca; Honorarium: Genentech; Advisory boards: Merck, Roviant Pharma, Myovant Sciences, Janssen, Bayer Healthcare. Eliezer M. Van Allen: Advisory/Consulting: Tango Therapeutics, Genome Medical, Genomic Life, Enara Bio, Janssen, Manifold Bio, Monte Rosa; Research support: Novartis, BMS; Equity: Tango Therapeutics, Genome Medical, Genomic Life, Syapse, Enara Bio, Manifold Bio, Microsoft, Monte Rosa; Patents: Institutional patents filed on chromatin mutations and immunotherapy response, and methods for clinical interpretation; intermittent legal consulting on patents for Foaley & Hoag; Editorial Boards: JCO Precision Oncology, Science Advances. Adam S. Feldman: Advisory/Consulting: Olympus, Vessi Medical; Research Funding: Convergent Genomics. Keyan Salari: Research Funding: Convergent Genomics. Ethics Statement: This study received Institutional Review Board approval (IRB No. 2021P002912). Publication History: This study was presented in part at the Society of Urologic Oncology Annual Meeting, December 3-5, 2020; Genitourinary Cancers Symposium, February 11-13, 2021; and the AUA Annual Meeting, September 10-13, 2021. This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.© 2023 The Author(s). Published on behalf of the American Urological Association, Education and Research, Inc.FiguresReferencesRelatedDetails Supplementary Materials Advertisement Copyright & Permissions© 2023 The Author(s). Published on behalf of the American Urological Association, Education and Research, Inc.Keywordsneoplastic syndromesprostate cancerprostatic neoplasmswatchful waitinghereditaryfamilialMetricsAuthor Information Adam C. Schneider Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts Department of Urology, Thomas Jefferson University, Sidney Kimmel Medical College, Philadelphia, Pennsylvania More articles by this author Thenappan Chandrasekar Department of Urology, Thomas Jefferson University, Sidney Kimmel Medical College, Philadelphia, Pennsylvania More articles by this author Nicholas Bowler Department of Urology, Thomas Jefferson University, Sidney Kimmel Medical College, Philadelphia, Pennsylvania More articles by this author Ryan Fogg Department of Urology, Thomas Jefferson University, Sidney Kimmel Medical College, Philadelphia, Pennsylvania More articles by this author Joon Yaa Leong Department of Urology, Thomas Jefferson University, Sidney Kimmel Medical College, Philadelphia, Pennsylvania More articles by this author Andrew Gusev Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts More articles by this author Linda H. Rodgers Center for Cancer Risk Assessment, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts More articles by this author Shelley R. McCormick Center for Cancer Risk Assessment, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts More articles by this author Douglas M. Dahl Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts More articles by this author Jason A. Efstathiou Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts More articles by this author Michael L. Blute Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts More articles by this author Anthony L. Zietman Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts More articles by this author Chin-Lee Wu Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts More articles by this author Matthew R. Smith Center for Genitourinary Cancers, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts More articles by this author Eliezer M. Van Allen Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts More articles by this author Adam S. Feldman Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts More articles by this author Keyon Salari Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts *Correspondence: Department of Urology, Massachusetts General Hospital, 55 Fruit St, GRB-1106H, Boston, MA 02114 telephone: 617-726-3502; E-mail Address: [email protected] More articles by this author Expand All Support: This work was supported in part by the Urology Care Foundation Research Scholar Award Program (KS), a Prostate Cancer Foundation Young Investigator Award (KS) and PCF-Movember Challenge Award (EVA), and a Mark Foundation Emerging Leader Award (EVA). Conflict of Interest: Jason A. Efstathiou: Advisory/Consulting: Blue Earth Diagnostics, Boston Scientific, AstraZeneca; Honorarium: Genentech; Advisory boards: Merck, Roviant Pharma, Myovant Sciences, Janssen, Bayer Healthcare. Eliezer M. Van Allen: Advisory/Consulting: Tango Therapeutics, Genome Medical, Genomic Life, Enara Bio, Janssen, Manifold Bio, Monte Rosa; Research support: Novartis, BMS; Equity: Tango Therapeutics, Genome Medical, Genomic Life, Syapse, Enara Bio, Manifold Bio, Microsoft, Monte Rosa; Patents: Institutional patents filed on chromatin mutations and immunotherapy response, and methods for clinical interpretation; intermittent legal consulting on patents for Foaley & Hoag; Editorial Boards: JCO Precision Oncology, Science Advances. Adam S. Feldman: Advisory/Consulting: Olympus, Vessi Medical; Research Funding: Convergent Genomics. Keyan Salari: Research Funding: Convergent Genomics. Ethics Statement: This study received Institutional Review Board approval (IRB No. 2021P002912). Publication History: This study was presented in part at the Society of Urologic Oncology Annual Meeting, December 3-5, 2020; Genitourinary Cancers Symposium, February 11-13, 2021; and the AUA Annual Meeting, September 10-13, 2021. Advertisement Advertisement PDF downloadLoading ...