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Imaging-based prostate cancer screening among BRCA mutation carriers—results from the first round of screening

Open AccessPublished:September 18, 2020DOI:https://doi.org/10.1016/j.annonc.2020.06.025

      Highlights

      • We report the first round of a PCa screening study among male BRCA carriers.
      • We used two novel screening strategies: age-stratified PSA and MRI.
      • We found a high rate of PCa among BRCA carriers (8.5%). Similar risk of PCa for BRCA1 (8.3%) and BRCA2 (8.7%).
      • mpMRI based screening missed 1 of the 16 diagnosed cancers (6%), while age-stratified PSA would have missed 5 (31%).
      • The highest net benefit for screening in young carriers (aged 40–55 years) was MRI; for those aged >55 years it was age-stratified PSA and MRI.

      Background

      Male-carriers of BRCA1/2 gene mutations have an increased risk of prostate cancer (PCa) with a more aggressive phenotype. Current screening-guidelines suggest the use of prostate-specific antigen (PSA) only among BRCA2 carriers. Female carriers have extensive guidelines that include imaging. Our objective was to test the prevalence of PCa among BRCA carriers and examine screening strategies, using PSA and multiparametric magnetic resonance imaging (mpMRI).

      Patients and methods

      We recruited men aged 40–70 years with BRCA1/2 germline mutations and no prior history of prostate biopsy. All men underwent an initial round of screening which included PSA, and prostate mpMRI. PSA was considered elevated using an age-stratified threshold of ≥1 ng/ml for 40–50 years of age, ≥2 ng/ml for 50–60 years of age, and 2.5 ng/ml for 60–70 years of age. Men with elevated PSA and/or suspicious lesion on mpMRI were offered a prostate biopsy. PSA levels, MRI findings, PCa incidence, and tumor characteristics were evaluated. Decision curve analysis was used to compare screening strategies.

      Results

      We recruited 188 men (108 BRCA1, 80 BRCA2), mean age 54 years (9.8). One hundred and ten (57%) had either elevated age-stratified PSA (75; 40%), a suspicious MRI lesion (67; 36%), or both (32; 17%). Of these, 92 (85%) agreed to perform a prostate biopsy. Sixteen (8.5%) were diagnosed with PCa; 44% of the tumors were classified as intermediate- or high-risk disease. mpMRI-based screening missed only one of the cancers (6%), while age-stratified PSA would have missed five (31%). Decision curve analysis showed that mpMRI screening, regardless of PSA, had the highest net benefit for PCa diagnosis, especially among men younger than 55 years of age. We found no difference in the risk of PCa between BRCA1 and BRCA2 (8.3% versus 8.7%, P = 0.91). Ninety percent had a Jewish founder mutation, thus the results cannot be generalized to all ethnic groups.

      Conclusions

      PCa is prevalent among BRCA carriers. Age may affect screening strategy for PCa in this population. Young carriers could benefit from initial MRI screening. BRCA carriers aged older than 55 years should use PSA and be referred to mpMRI if elevated.

      Trial registration

      Key words

      Introduction

      A higher incidence of prostate cancer (PCa) has been consistently described in BRCA2 carriers and is debatable in BRCA1 carriers.
      • Liede A.
      • Karlan B.Y.
      • Narod S.A.
      Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature.
      • Castro E.
      • Goh C.
      • Leongamornlert D.
      • et al.
      Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer.
      • Nyberg T.
      • Frost D.
      • Barrowdale D.
      • et al.
      Prostate cancer risks for male BRCA1 and BRCA2 mutation carriers: a prospective cohort study.
      The study be Nyberg et al.
      • Nyberg T.
      • Frost D.
      • Barrowdale D.
      • et al.
      Prostate cancer risks for male BRCA1 and BRCA2 mutation carriers: a prospective cohort study.
      reported an increased risk of PCa in both BRCA1 and BRCA2 mutation carriers, the relative risk being higher in BRCA2 than BRCA1. In addition to an increased risk, BRCA mutations may confer a more aggressive phenotype of PCa. Germline BRCA1 and BRCA2 mutations are associated with higher grade and higher stage disease, nodal involvement, and metastases at time of presentation compared with non-BRCA-associated PCa.
      • Castro E.
      • Goh C.
      • Leongamornlert D.
      • et al.
      Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer.
      • Nyberg T.
      • Frost D.
      • Barrowdale D.
      • et al.
      Prostate cancer risks for male BRCA1 and BRCA2 mutation carriers: a prospective cohort study.
      • Gallagher D.J.
      • Gaudet M.M.
      • Pal P.
      • et al.
      Germline BRCA mutations denote a clinicopathologic subset of prostate cancer.
      • Na R.
      • Zheng S.L.
      • Han M.
      • et al.
      Germline mutations in ATM and BRCA1/2 distinguish risk for lethal and indolent prostate cancer and are associated with early age at death.
      Furthermore, BRCA1 and BRCA2 are significantly associated with an increased risk of recurrence, progression to metastatic disease, and PCa-specific death.
      • Castro E.
      • Goh C.
      • Leongamornlert D.
      • et al.
      Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer.
      • Nyberg T.
      • Frost D.
      • Barrowdale D.
      • et al.
      Prostate cancer risks for male BRCA1 and BRCA2 mutation carriers: a prospective cohort study.
      • Gallagher D.J.
      • Gaudet M.M.
      • Pal P.
      • et al.
      Germline BRCA mutations denote a clinicopathologic subset of prostate cancer.
      • Na R.
      • Zheng S.L.
      • Han M.
      • et al.
      Germline mutations in ATM and BRCA1/2 distinguish risk for lethal and indolent prostate cancer and are associated with early age at death.
      • Castro E.
      • Goh C.
      • Olmos D.
      • et al.
      Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in Prostate Cancer.
      The IMPACT study is the first prospective study to evaluate screening in BRCA carriers for PCa.
      • Bancroft E.K.
      • Page E.C.
      • Castro E.
      • et al.
      Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: Results from the initial screening round of the IMPACT study.
      After 3 years of screening, compared with non-carriers, BRCA2 mutation carriers were associated with a higher incidence of PCa, younger age of diagnosis, and clinically significant tumors. Based on these findings, the authors recommend a systematic prostate-specific antigen (PSA) screening for men with a BRCA2 mutation.
      • Bancroft E.K.
      • Page E.C.
      • Castro E.
      • et al.
      Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: Results from the initial screening round of the IMPACT study.
      ,
      • Page E.C.
      • Bancroft E.K.
      • Brook M.N.
      • et al.
      Interim results from the IMPACT study: evidence for prostate-specific antigen screening in BRCA2 mutation carriers.
      In female BRCA carriers, magnetic resonance imaging (MRI) is routinely used as part of the breast cancer screening protocol.
      NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines)
      Breast cancer screening and diagnosis. Version 2.2018.
      ,
      • Paluch-Shimon S.
      • Cardoso F.
      • Sessa C.
      • et al.
      Prevention and screening in BRCA mutation carriers and other breast/ovarian hereditary cancer syndromes: ESMO clinical practice guidelines for cancer prevention and screening.
      The role of MRI screening among males has not been explored. European Association of Urology (EAU) guidelines recommend the use of prostate MRI before biopsy, but specifically state it should not be used for screening. We now report the results of a prospective screening study for PCa among a genetically high-risk population of male BRCA carriers using PSA and MRI.

      Patients and methods

      The study design and methods were previously reported.
      • Margel D.
      • Benjaminov O.
      • Ozalvo R.
      • et al.
      Personalized prostate cancer screening among men with high risk genetic predisposition- study protocol for a prospective cohort study.
      The protocol was approved by the Rabin Medical Center Ethics Committee in Israel. Written informed consent was obtained for all participants.

       Study population

      We recruited men aged 40–70 years with BRCA1 and BRCA2 germline mutation between the years 2014 and 2018. Men were excluded if they had a previous history of PCa and/or prostate biopsy.

       First round screening protocol

      Upon enrolment, all patients underwent PSA and multiparametric (mp) MRI. Patients with an abnormal finding on any of these tests were offered a prostate biopsy.

       PSA thresholds

      Since this was a screening trial for a high-risk, genetically predisposed population, we used strict age-stratified PSA criteria. PSA was considered elevated when: PSA ≥ 1 ng/ml for ages 40–50 years, ≥2 ng/ml for ages 50–60 years,
      • Heidegger I.
      • Fritz J.
      • Klocker H.
      • et al.
      Age-adjusted PSA levels in PCa prediction: updated results of the tyrol prostate cancer early detection program.
      and ≥2.5 ng/ml for ages 60–70 years.
      • Krumholtz J.S.
      • Carvalhal G.F.
      • Ramos C.G.
      • et al.
      Prostate-specific antigen cutoff of 2.6 ng/mL for prostate cancer screening is associated with favorable pathologic tumor features.
      ,
      • Thompson I.M.
      • Goodman P.J.
      • Tangen C.M.
      • et al.
      The influence of finasteride on the development of prostate cancer.

       Multiparametric MRI

      mpMRI was carried out with a Philips Ingenia 3.0 Tesla MRI scanner, Eindhoven, Netherlands using an external coil. The imaging protocol included T2-weighted images obtained in three orthogonal planes, axial diffusion-weighted images obtained with multiple b values (0, 100, 1000, and 1500 s/mm2), and axial dynamic contrast-enhanced images. Areas suggestive of PCa were graded by two dedicated uroradiologists (ST, OB) according to the Prostate Imaging-Reporting and Data System, version 2 (PI-RADS v2); suspected lesions with PI-RADS score ≥3 were considered abnormal.
      • Barentsz J.O.
      • Richenberg J.
      • Clements R.
      • et al.
      ESUR prostate MR guidelines 2012.

       Prostate biopsy

      Prostate biopsy was offered only if any screening test was abnormal (i.e. elevated age-stratified PSA or MRI PI-RADS 3 or above). Per institutional review board (IRB) request, we did not perform biopsies to those with normal PSA and imaging.
      All consenting subjects had a 12 core systematic prostate biopsy (BK-flex500, BK Medical, Quickborn, Germany). Subjects with a suspicious MRI lesion (PI-RADS ≥3) underwent additional targeted biopsy during the same session (Navigo, UC-Care, Yokneam, Israel). A dedicated uropathologist reviewed all pathology specimens (YM).

       Statistical analysis

       Primary outcome and sample size calculation

      The primary outcome of this study was to estimate the prevalence of PCa among male BRCA carriers in Israel. To estimate the prevalence of PCa in Israel we utilized the Clalit Health Services databases. Clalit is the largest health insurer in Israel and covers more than half of the Israeli population. We found that the prevalence of PCa among Israeli males aged between 40 and 70 years is 0.65%. Initial results from the IMPACT study suggest that among male BRCA carriers, the prevalence of PCa was 2.8%. To determine that the rate of PCa among BRCA carriers is at least 2.8%, we required a study with 190 carriers.
      • Bancroft E.K.
      • Page E.C.
      • Castro E.
      • et al.
      Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: Results from the initial screening round of the IMPACT study.
      This analysis used a power of 80% and a two-tailed α of 0.05.

       Evaluation of possible screening strategies

      As the criteria we used for biopsy included the lowest PSA threshold or any imaging finding, we were able to compare stricter criteria. These were chosen based on clinical utility. We modeled the possible outcomes of these screening strategies based on the actual results of our cohort. We restricted this analysis to those who carried out a biopsy.
      We calculated the number of biopsies avoided in each screening strategy by subtracting the number of biopsies that would have been carried out from the total number of biopsies actually carried out in our cohort. The numbers of cancers diagnosed and/or missed for each strategy were calculated. Finally, we carried out decision curve analysis to compare the net benefit of each screening strategy. The net benefit is a number that reflects the probability of detecting PCa at the cost of additional biopsies carried out.
      All statistical analyses were carried out with SPSS version 21 IBM, Armonk, NY and decision curve analysis was carried out with Stata version 14.2, College Station, TX.

      Results

      We recruited 188 men with a mean age of 54 years (9.8). Of these, 108 subjects had a BRCA1 mutation and 80 had a BRCA2 mutation (Table 1). Most patients (187, 99.5%) had a familial history of cancer and 24% had a familial history of PCa. Ninety percent of subjects had one of the three Ashkenazi Jewish founder mutations (BRCA1: 185delAG n = 84; 5382inSC n = 17 patients; BRCA2: 6174delT n = 69).
      Table 1Baseline characteristics of the study cohort
      VariableTotal (N = 188)BRCA1 (n = 108)BRCA2 (n = 80)P value
      P value for the comparison between BRCA1 and BRCA2 mutation carriers. P value calculated by chi-square test.
      Mean age in years (± SD)54 (± 9.8)55.4 (± 9.5)52.1 (± 9.9)0.02
      P value calculated by Student's t-test.
      Type of mutation N (%)
       185delAG84 (44)
       5382inSC17 (9)
       Tyr987X4 (2)
       6174delIT69 (36)
       8765delAG4 (2)
       Other3 (2)7 (4)
      Patients with familial history of cancer N (%)
       Any cancer187 (99.5)107 (99.5)80 (100)0.53
       Prostate45 (24)23 (21.5)22 (27.5)0.43
       Ovary74 (40)42 (39.3)32 (40.0)0.91
       Breast151 (80)90 (84.1)61 (76.3)0.22
       Pancreas41 (22)19 (17.8)22 (27.5)0.15
       Colon46 (25)30 (28)16 (20)0.27
       Melanoma23 (12)13 (12.1)10 (12.5)0.94
      Patients with personal history of cancer N (%)
       Any cancer24 (12.8)11 (10)13 (16)0.21
       Melanoma8 (4.3)4 (3.7)4 (5)0.66
       Non-melanoma skin caner8 (4.3)4 (3.7)4 (5)0.66
       Breast3 (1.6)1 (0.9)2 (2.5)0.39
       Non-BRCA related5 (2.7)2 (1.8)3 (3.7)0.42
      SD, standard deviation.
      P value for the comparison between BRCA1 and BRCA2 mutation carriers. P value calculated by chi-square test.
      ∗∗ P value calculated by Student's t-test.
      For initial screening we carried out PSA on 187 subjects and MRI on 177 subjects in our cohort (Figure 1). Sixty-nine subjects (37%) had both normal MRI and normal age-adjusted PSA. All other subjects (110; 57%) had either elevated age-stratified PSA (75; 40%), a suspicious MRI lesion (67; 36%), or both (32; 17%). Of these, 92 (85%) agreed to perform a prostate biopsy (Figure 1).
      Figure thumbnail gr1
      Figure 1CONSORT diagram.
      Study enrollment and flow—first round of screening. MRI, magnetic resonance imaging; PSA, prostate-specific antigen.
      Median PSA was 1 (interquartile range 0.6–1.8) and median prostate volume was 30 (interquartile range 22–44); both increased with age (Table 2). Forty percent of our cohort had an elevated age-stratified PSA. This was equal across age groups. We detected a suspicious MRI lesion in 67 (36%) subjects (PI-RADS 3, 18%; PI-RADS 4, 14%; PI-RADS 5, 3%). Subjects between 40 and 50 years of age had significantly less findings on prostate MRI (P = 0.005) (Table 3).
      Table 2Summary of initial PSA results from the first round of prostate cancer screening stratified by age
      40–50 n = 8150–60 n = 4160–70 n = 66P value
      P value for comparison between age groups calculated by Kruskal–Wallis test.
      Total

      N = 188
      PSA, ng/ml (median, IQR)0.7 (0.5–1)1 (0.6–1.7)2 (1–4.1)<0.0011 (0.6–1.8)
      PSA density, ng/ml2 (median, IQR)0.03 (0.01–0.05)0.03 (0.02–0.05)0.04 (0.02–0.07)0.0190.03 (0.02–0.05)
      Prostate volume, ml (median, IQR)23 (19–29)33 (25–42)45 (33–69)<0.00130 (22–44)
      Patients with age-specific elevated PSA
      PSA value was considered elevated if ≥1 ng/ml for ages 40–50 years, ≥2 ng/ml for ages 50–60 years, and ≥2.5 ng/ml for ages 60–70 years.
      (no. pts., %)
      31 (38)13 (31)31 (47)0.2775 (40)
      IQR, interquartile range; no. pts., number of patients; PSA, prostate-specific antigen; PSAD, prostate-specific antigen density.
      a PSA value was considered elevated if ≥1 ng/ml for ages 40–50 years, ≥2 ng/ml for ages 50–60 years, and ≥2.5 ng/ml for ages 60–70 years.
      P value for comparison between age groups calculated by Kruskal–Wallis test.
      Table 3Summary of mpMRI findings from the first round of prostate cancer screening stratified by age
      Age group (years)40–50 n = 8150–60 n = 4160–70 n = 66Total

      N = 188
      mpMRI findings
      Highest score given among all lesions found on mpMRI.
      (no. pts., %)
      P value for comparison between age groups = 0.008 (chi-square test).
      No MRI5 (6)1 (2)5 (8)11 (6)
      Normal MRI56 (69)18 (44)36 (55)110 (59)
      PI-RADS 311 (14)10 (24)13 (20)34 (18)
      PI-RADS 49 (11)9 (22)9 (14)27 (14)
      PI-RADS 503 (7)3 (5)6 (3)
      no. pts., number of patients; mpMRI, multiparametric magnetic resonance imaging; PI-RADS, Prostate Imaging-Reporting and Data System.
      a Highest score given among all lesions found on mpMRI.
      P value for comparison between age groups = 0.008 (chi-square test).
      We detected a total of 16 PCa (8.5%), out of which 7 cases (44%) were Gleason grade group 2 (GG2) and above (Table 4). Eleven of 16 cancers (69%) and 4 of the 7 GG2 and above cancers (57%) were detected only by MRI-targeted biopsies (Table 5). Three cancers had intraductal carcinoma (Table 5). Among subjects between 40 and 50 years of age, we detected three cases of PCa (3.7%); all were GG1. All these cases had PSA levels <1, and were sent to biopsy based only on MRI findings. Among subjects aged more than 50 years, we detected 13 (12.1%) cases of PCa, (six cases of GG1; five of GG2; one of GG3; and one of GG5). There were no differences between the 50–60 years and 60–70 years age groups in PCa prevalence or in the percentage of GG2 and above cancers (Table 4).
      Table 4Summary of biopsy findings from the first round of prostate cancer screening stratified by age
      Age group (years)40–50 n = 8150–60 n = 4160–70 n = 66Total

      N = 188
      Prostate biopsy results (no. pts., %)
      P value for comparison between age groups = 0.22 (chi-square test).
      PCa GG13 (3.7)2 (4.9)4 (6)9 (4.8)
      PCa GG22 (4.9)3 (4.5)5 (2.7)
      PCa GG31 (1.5)1 (0.5)
      PCa GG4
      PCa GG51 (2.4)1 (0.5)
      TOTAL3 (3.7)5 (12)8 (12)16 (8.5)
      GG, Gleason grade group; no. pts., number of patients; PCa, prostate cancer.
      P value for comparison between age groups = 0.22 (chi-square test).
      Table 5Summary of PSA, MRI, and biopsy findings of the PCa cases diagnosed
      CaseAge (years)BRCA typeMutationPSAPI-RADSGG groupIntraductal carcinoma – cribiform patternIdentified by systematic/fusionGG in fusion biopsyGG in systemic biopsy
      140.726174delIT0.941noFusion only1BPH
      243.015382inSC0.531noFusion only1BPH
      349.61185delAG0.241noFusion only1BPH
      453.026174delIT1.242noFusion only2BPH
      554.51185delAG7.952noFusion only2BPH
      657.21185delAG4.131noFusion only1BPH
      759.51185delAG5.151noFusion and systematic11
      859.528765delAG6.055yesFusion and systematic55
      960.726174delIT3.042noFusion only2BPH
      1063.926174delIT8.431noFusion only1BPH
      1166.11185delAG4.531noFusion only1BPH
      1267.01185delAG6.11noSystemic only
      Patient unable to perform mpMRI due to medical reasons.
      1
      1367.328765delAG6.242noFusion and systematic21
      1468.01185delAG1.531noFusion only1BPH
      1570.026174delIT10.652yesFusion only2BPH
      1670.11185delAG5.043yesFusion and systematic33
      BPH, benign prostatic hyperplasia; GG, Gleason grade group; PCa, prostate cancer; PI-RADS, Prostate Imaging-Reporting and Data System; PSA, protein specific antigen.
      a Patient unable to perform mpMRI due to medical reasons.
      We found no difference between PCa detection rates of BRCA1 carriers (8.3%) and BRCA2 carriers (8.8%; P = 0.91). However, 23% of the BRCA1 cancers were GG2 or above, compared with 71% of BRCA2 cancers (P = 0.049) (Supplementary Table S3, available at https://doi.org/10.1016/j.annonc.2020.06.025). Data stratified by BRCA type and age is presented in Supplementary Tables S1–S3, available at https://doi.org/10.1016/j.annonc.2020.06.025.
      Among the 92 men who underwent a prostate biopsy, we tested five possible screening strategies using different PSA thresholds with or without prostate MRI (Table 6). All strategies that included MRI as a screening tool were more effective than PSA alone in detecting PCa. The best strategy that detected 15 out 16 cancers (94%) was the use of MRI only without PSA as a screening tool. However, this comes at a cost of performing many unnecessary biopsies {positive predictive value (PPV) = 23.8% [95% confidence interval (CI) 20.2–27.9]}. The second-best strategy that detected 10 out of 16 cases (63%) was based on elevated age-stratified PSA followed by MRI. Although this strategy missed six cases, five of them were GG1.
      Table 6Impact summary of the five strategies used to detect prostate cancer in BRCA carriers
      Biopsies avoided
      Biopsies avoided was calculated as the total number of biopsies done in the cohort minus the number of biopsies that would have been done if the specific strategy was used.
      n, (% from a total of 92 carried out)
      Any cancer detected n, (% from total of 16 cancers)Any cancer missed n, (% from total of 16 cancers)Negative predictive value %, (95% CI)Positive predictive value %, (95% CI)
      Strategy 167 (73)5 (31)11 (69)83.6 (78.1–87.9)20 (9.9–36.2)
      Strategy 232 (35)5 (31)11 (69)84.4 (71.1–92.2)18.3 (13.4–24.5)
      Strategy 329 (32)15 (94)1 (6)96.6 (80.4–99.5)23.8 (20.2–27.9)
      Strategy 474 (80)9 (56)7 (44)90.6 (84.5–94.4)50 (32.1–67.9)
      Strategy 561 (66)10 (63)6 (27)90 (82.5–94.5)31.3 (21.3–43.3)
      Strategies:
      CI, confidence interval; MRI, magnetic resonance imaging; PI-RADS, Prostate Imaging-Reporting and Data System; PSA, prostate-specific antigen.
      a Biopsies avoided was calculated as the total number of biopsies done in the cohort minus the number of biopsies that would have been done if the specific strategy was used.
      We used decision curve analysis to compare the net benefit of each approach (Figure 2A). When the probability for PCa is low, the highest net benefit is imaging regardless of PSA; MRI for every patient and fusion biopsy in case there is a lesion. When the probability of PCa increases and reaches approximately 20%, the highest net benefit stems from triaging imaging using PSA first. PSA without imaging shows a linear line and has the same low net benefit.
      Figure thumbnail gr2
      Figure 2Decision curve analysis comparing five possible screening strategies.
      (A) Decision curve analysis for prediction of prostate cancer diagnosis, comparing PSA only screening (PSA > 3 and age-stratified cut-offs), MRI only screening, and PSA triage before MRI screening (PSA > 3 and age-stratified cut-offs). X-axis (threshold probability) is the probability of prostate cancer diagnosis. Y-axis is the net clinical benefit for the different clinical strategies. The lines for both PSA only strategies are identical. Analysis carried out on data from 92 subjects with biopsy. (B) Decision curve analysis for prediction of prostate cancer diagnosis in subjects younger than 55 years, comparing PSA only screening (PSA > 3 and age-stratified cut-offs), MRI only screening, and PSA triage before MRI screening (PSA > 3 and age-stratified cut-offs). X-axis (threshold probability) is the probability of prostate cancer diagnosis. Y-axis is the net clinical benefit for the different clinical strategies. The lines for 'diagnose none' and the two PSA only strategies are identical. Analysis carried out on data from 92 subjects with biopsy. (C) Decision curve analysis for prediction of prostate cancer diagnosis in subjects older than 55 years comparing PSA only screening (PSA > 3 and age-stratified cut-offs), MRI only screening, and PSA triage before MRI screening (PSA > 3 and age-stratified cut-offs). X-axis (threshold probability) is the probability of prostate cancer diagnosis. Y-axis is the net clinical benefit for the different clinical strategies. The lines for both PSA only strategies are identical. Analysis carried out on data from 92 subjects with biopsy. PI-RADS, Prostate Imaging-Reporting and Data System; PSA, prostate-specific antigen.
      To identify a clinical parameter that may be useful to optimize the screening protocol for BRCA carriers, we stratified our cohort based on age. Figure 2B shows that for BRCA subjects less than 55 years of age, MRI regardless of PSA has the highest net benefit. Conversely, for subjects aged more than 55 years old, PSA screening added value, and age-stratified PSA followed by MRI had the highest net benefit for diagnosis of PCa (Figure 2C). Of note, for young carriers (less than 55 years old), the net benefit for the PSA only strategies was zero, meaning MRI was vital for diagnosis at this age group.

      Discussion

      This is the first trial to use prostate-MRI as a screening tool for a high-risk population. In this first round of screening, PCa prevalence among BRCA carriers was 8.5%. We found that the most effective screening strategy was MRI, regardless of PSA values. This was most prominent among males younger than 55 years of age. The prevalence of PCa was similar between BRCA1 (8.3%) and BRCA2 (8.75%) carriers.
      The IMPACT study was the first prospective study evaluating the role of PCa screening in an international cohort of men with BRCA1/2 mutations.
      • Bancroft E.K.
      • Page E.C.
      • Castro E.
      • et al.
      Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: Results from the initial screening round of the IMPACT study.
      ,
      • Page E.C.
      • Bancroft E.K.
      • Brook M.N.
      • et al.
      Interim results from the IMPACT study: evidence for prostate-specific antigen screening in BRCA2 mutation carriers.
      They used PSA > 3 as a cut-off for prostate biopsy. Patients underwent systematic biopsy. The mean age at enrollment was 54 years, similar to our cohort. In the first round of screening, they reported a diagnostic rate of 2.3% (BRCA1) and 3.3% (BRCA2).
      • Bancroft E.K.
      • Page E.C.
      • Castro E.
      • et al.
      Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: Results from the initial screening round of the IMPACT study.
      Implementing this strategy in our study (i.e. PSA > 3 and systematic biopsy, our Strategy 1), we would have detected a similar rate (five cancers, 2.7%). The IMPACT based their screening on PSA alone. Recent studies have shown a benefit for using MRI before performing prostate biopsy. Data from the PRECISION trial,
      • Kasivisvanathan V.
      • Rannikko A.S.
      • Borghi M.
      • et al.
      MRI-targeted or standard biopsy for prostate-cancer diagnosis.
      MRI-FIRST, and 4M support the use of MRI before prostate biopsy, but not as a screening tool.
      • Rouvière O.
      • Puech P.
      • Renard-Penna R.
      • et al.
      Use of prostate systematic and targeted biopsy on the basis of multiparametric MRI in biopsy-naive patients (MRI-FIRST): a prospective, multicentre, paired diagnostic study.
      ,
      • Van der Leest M.
      • Cornel E.
      • Israël B.
      • et al.
      Head-to-head comparison of transrectal ultrasound-guided prostate biopsy versus multiparametric prostate resonance imaging with subsequent magnetic resonance-guided biopsy in biopsy-naïve men with elevated prostate-specific antigen: a large prospective multicenter clinical study.
      To the best of our knowledge, only one previous study evaluated MRI as a screening tool for PCa in the general population. Nam et al.
      • Nam R.K.
      • Wallis C.J.D.
      • Stojcic-Bendavid J.
      • et al.
      A pilot study to evaluate the role of magnetic resonance imaging for prostate cancer screening in the general population.
      carried out a pilot study among unselected men. They recruited 47 men and detected 18 cancers (38.3%). They found that MRI was a stronger predictor of PCa compared with PSA.
      Current guidelines specifically object to the use of MRI as a screening tool for PCa. In contrast, all guidelines recommend breast MRI as a screening tool for BRCA female carriers.
      NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines)
      Breast cancer screening and diagnosis. Version 2.2018.
      ,
      • Paluch-Shimon S.
      • Cardoso F.
      • Sessa C.
      • et al.
      Prevention and screening in BRCA mutation carriers and other breast/ovarian hereditary cancer syndromes: ESMO clinical practice guidelines for cancer prevention and screening.
      This, despite several studies that found the PPV of breast MRI is only between 10% and 42%,
      • Chiarelli A.M.
      • Prummel M.V.
      • Muradali D.
      • et al.
      Effectiveness of screening with annual magnetic resonance imaging and mammography: results of the initial screen from the Ontario High Risk Breast Screening Program.
      • Helvie M.
      Surveillance of BRCA1 and BRCA2 carriers.
      • Leach M.O.
      • Boggis C.R.
      • Dixon A.K.
      • et al.
      Screening with magnetic resonance imaging and mammography of a UK population at high familial risk of breast cancer: a prospective multicentre cohort study (MARIBS).
      leading to many needless biopsies. In our study, MRI was the most effective screening strategy for PCa. This came at a cost of performing many unnecessary prostate biopsies [PPV = 23.8% (95% CI 20.2–27.9)]. Given the ratio of PCa incidence to PCa-related mortality, performing unnecessary biopsies in the general population may be unacceptable. However, data suggest that PCa among BRCA carriers has the worst prognosis and may be a more deadly disease,
      • Castro E.
      • Goh C.
      • Leongamornlert D.
      • et al.
      Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer.
      • Nyberg T.
      • Frost D.
      • Barrowdale D.
      • et al.
      Prostate cancer risks for male BRCA1 and BRCA2 mutation carriers: a prospective cohort study.
      • Gallagher D.J.
      • Gaudet M.M.
      • Pal P.
      • et al.
      Germline BRCA mutations denote a clinicopathologic subset of prostate cancer.
      • Na R.
      • Zheng S.L.
      • Han M.
      • et al.
      Germline mutations in ATM and BRCA1/2 distinguish risk for lethal and indolent prostate cancer and are associated with early age at death.
      • Castro E.
      • Goh C.
      • Olmos D.
      • et al.
      Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in Prostate Cancer.
      underscoring the need to diagnose these cancers at an early, curable stage.
      We used stringent criteria for prostate biopsies. We offered a biopsy to subjects with either abnormal MRI or elevated age-stratified PSA. PSA cut-offs were selected based on previous studies showing that PSA higher than 1 ng/ml before the age of 50 years was associated with PCa mortality. This may have led to a higher rate of GG1 cancers diagnosed (9/16 cases, 56%). GG1 PCas may be indolent in the general population; however, there is a debate regarding the clinical significance of these cancers among BRCA carriers. Taylor et al.
      • Taylor R.A.
      • Fraser M.
      • Livingstone J.
      • et al.
      Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories.
      ,
      • Taylor R.A.
      • Fraser M.
      • Rebello R.J.
      • et al.
      The influence of BRCA2 mutation on localized PCa.
      have shown that BRCA2 carriers develop PCa with high mutational load at early stages, higher tumor instability, and are more likely to harbor intraductal carcinoma, even in GG1 cancers. A recent study by Carter et al.
      • Carter H.B.
      • Helfand B.
      • Mamawala M.
      • et al.
      Germline mutations in ATM and BRCA1/2 are associated with grade reclassification in men on active surveillance for PCa.
      explored the rate of upgrading during active surveillance for carriers of BRCA1/2. In their study, the hazard ratio for grade progression among BRCA2 carriers compared with non-carriers was 2.74 (95% CI = 1.26–5.96, P = 0.01). Combined, these data suggest that early detection of any grade PCa among carriers may be vital.
      In the recent publication from the IMPACT study, the detection rate of PCa among BRCA1 carriers (2.6%) was lower than among BRCA2 carriers (2.8%), and even comparable with non-carriers (1.8%).
      • Page E.C.
      • Bancroft E.K.
      • Brook M.N.
      • et al.
      Interim results from the IMPACT study: evidence for prostate-specific antigen screening in BRCA2 mutation carriers.
      In our study, the PCa detection rate of BRCA1 carriers was similar to that of BRCA2 carriers (8.3% versus 8.8%). However, PCa among BRCA1 was mostly of lower grade (GG1). These differences may be accounted for by the unique mutational landscape of our cohort. Most of the BRCA1 carriers in our study (78%) have the 185delAG Jewish founder mutation. Data regarding possible clinical differences between mutation types are limited. Others have found a possible link between cancer risk and mutation type in BRCA.
      • Rebbeck T.R.
      • Mitra N.
      • Wan F.
      • et al.
      Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer.
      • Agalliu I.
      • Gern R.
      • Leanza S.
      • et al.
      Associations of high-grade prostate cancer with BRCA1 and BRCA2 founder mutations.
      • Patel V.L.
      • Busch E.L.
      • Friebel T.M.
      • et al.
      Association of genomic domains in BRCA1 and BRCA2 with prostate cancer risk and aggressiveness.
      Our data might suggest that 185delAG mutation may be associated with a higher risk of lower grade PCa.
      Our study design allowed us to test the clinical utility of different screening strategies. Traditionally, screening strategies are compared using sensitivity and specificity or area under the curve. However, these measures are statistical abstractions and are not directly translated to inform clinical decision-making. We chose to compare the different screening strategies using decision curve analysis and net benefit. PCa screening involves a trade-off between diagnosing patients with cancer versus unnecessary biopsy for those who are healthy. This is even more pronounced in our high-risk population, where the stakes are higher. The net benefit is an increasingly reported decision analytic measure that puts benefits and harms on the same scale.
      • Van Calster B.
      • Wynants L.
      • Verbeek J.F.M.
      • et al.
      Reporting and interpreting decision curve analysis: A guide for investigators.
      This is achieved by specifying an exchange rate, a clinical judgment of the relative value of benefits (i.e. detecting cancer), and harms (i.e. unnecessary biopsy).
      Using this analysis we found that the screening strategy with the highest net benefit for threshold probability lower than 20% was MRI. However, in higher threshold probabilities, the highest net benefit was triaging with PSA before MRI. To enable clinical decision-making, we stratified our cohort by age. Among patients younger than 55 years, PSA values in our cohort were low, and not useful for prediction, thus MRI had the highest net benefit. However, in older carriers, PSA triaging before MRI had better clinical utility.
      Our study has several limitations. First, this is a single-arm study, without a non-carrier group. As prostate biopsies may be harmful, applying our stringent biopsy protocol among non-carriers seemed unethical. For a similar reason, we did not biopsy carriers with both normal PSA and MRI. Thus, we cannot rule out PCa in these subjects.
      Generalizability of our findings may be hampered, as a vast majority of our carriers had a Jewish founder mutation. Thus, our results may be limited to this population. However, when comparing similar strategies, our detection rate is comparable with the multinational IMPACT study. Finally, the ultimate outcome of screening is overall mortality, and not cancer detection. This is the first report of our screening study, and we are continuing to monitor these subjects.

      Conclusions

      We found a high rate of PCa in the first round of screening of BRCA-carriers. We employed a contemporary screening-strategy with both imaging and biomarkers. We found that among carriers younger than 55Y, mpMRI had the best clinical utility and that in older carriers; PSA should be used first to triage before mpMRI.

      Funding

      This work was supported by ASCO CDA grant [grant number 8259 to DM]. The funding organization had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication

      Disclosure

      The authors have declared no conflict of interests.

      Supplementary data

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