Magnetic Resonance Imaging-based Prostate Cancer Screening in Carriers of Pathogenic Germline Mutations: Interim Results from the Initial Screening Round of the Prostate Cancer Genetic Risk Evaluation and Screening Study.

BACKGROUND: The risk of early-onset and clinically aggressive prostate cancer is elevated in carriers of certain rare pathogenic germline mutations. The utility of augmenting traditional prostate-specific antigen (PSA)-based screening measures with multiparametric magnetic resonance imaging (MRI) in this population is not yet known. OBJECTIVE: To evaluate MRI-based screening in comparison with traditional PSA-based screening among individuals at an elevated genetic risk for prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: Male germline carriers of pathogenic/likely pathogenic variants in any of 19 prostate cancer risk genes between the ages of 35 and 74 yr with no prior history of prostate cancer were recruited. Intervention Enrolled participants underwent screening with annual PSA, digital rectal examination (DRE), and triennial multiparametric MRI. Individuals with abnormal DRE, elevated age-adjusted PSA (>1.5 ng/ml for 35-49 yr, >2.0 ng/ml for 50-54 yr, and >3.0 ng/ml for 55-74 yr), or suspicious multiparametric MRI (Prostate Imaging Reporting and Data System [PI-RADS] ≥3 lesion) were offered prostate biopsy. Outcome measurements and statistical analysis Endpoints were diagnosis of any and clinically significant prostate cancer, and alternative screening strategies were compared by a decision curve analysis. RESULTS AND LIMITATIONS: To date, 101 males have completed the first round of screening. The greatest proportion of participants are carriers of BRCA2 (n = 44), BRCA1 (n = 35), and ATM (n = 7) variants. Twenty-one have undergone biopsy, resulting in the detection of nine cases of cancer (seven clinically significant). For the detection of clinically significant prostate cancer, abnormal MRI (PI-RADS ≥3) demonstrated 100% sensitivity (7/7) with a negative predictive value (NPV) of 100%, whereas PSA-based screening alone had 57% (4/7) sensitivity with an NPV of 73%. Of six screening strategies evaluated in the decision curve analysis, MRI-based screening alone achieved superior net benefit at all threshold probabilities compared with PSA screening-detecting one additional cancer case per 7.5 patients, while avoiding more unnecessary biopsies at the same threshold probability. CONCLUSIONS: Disease prevalence is high among carriers of prostate cancer-associated pathogenic germline mutations. Early results suggest that MRI-based screening enhances early detection of clinically significant disease beyond PSA screening alone. PATIENT SUMMARY: In this study, we present the interim results from the PROGRESS prostate cancer screening trial. We found that in certain germline carriers of prostate cancer risk mutations, magnetic resonance imaging-based screening enhances detection of prostate cancer while reducing biopsies triggered, in comparison with traditional prostate-specific antigen screening strategies.

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

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 prostate cancer alone was not associated with biopsy progression, whereas family history suggestive of a 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 suggestive of a 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.

Motivation and family communication in hereditary prostate cancer genetic testing: Survey of patients from a US tertiary medical center.

Identification of a hereditary prostate cancer in an affected individual can guide treatment and may also impact cancer screening and surveillance for patients and their relatives. This study aimed to determine the factors that are associated with the decision-making process of individuals with prostate cancer regarding whether to pursue genetic testing as well as how, why, and with whom genetic test results are shared. We surveyed 113 patients diagnosed with prostate cancer who received cancer genetic counseling through a United States tertiary medical center, inquiring about genetic testing motivations and family communication about results. Among those who pursued genetic testing, (1) learning about my family's possible cancer risk (98%), (2) learning information that may guide cancer treatment (93%), and (3) learning if I am at risk for future cancers (92%) were most frequently identified as slightly or very important factors in their decision. Participants shared their genetic test results in a higher proportion to male first-degree relatives than female first-degree relatives; however, no significant difference was found (p = 0.103). Our study may suggest sex differences related to family communication about genetic testing results. Such findings indicate a critical need for genetic counselors to clearly communicate the impact of genetic test results on both male and female relatives. Further research on motivation and family communication about genetic test results in diverse cohorts is needed.

Transition to telephone genetic counseling services during the COVID-19 pandemic.

The COVID-19 pandemic has significantly disrupted the delivery of healthcare services, including oncology. To ensure continuity of cancer genetic counseling at a large academic medical center while also promoting the safety of patients and staff, our team transitioned to fully remote telephone genetic counseling and testing services within 48 hr. We compare differences in the six weeks following the shift to telephone genetic counseling (post-COVID) to the six weeks preceding the pandemic (pre-COVID). We maintained 99% of our total visit capacity and saw a decrease in patient no-show rate from 9.5% to 7.3%. Of all patients who received telephone genetic counseling, fewer consented to genetic testing as compared to patients seen in-person prior to the pandemic (79% pre-COVID v. 72% post-COVID; p = .012). Four weeks after this cohort was closed for analysis, 96 out of 303 samples (32%) had not been received by the genetic testing laboratory, despite at least one reminder phone call to the patient. In 13 reported instances, a second sample was required (quality not sufficient, lost or mislabeled sample), thus delaying test results. We conclude that a rapid transition to remote genetic counseling and testing allowed uninterrupted access to cancer genetics services during to the COVID-19 pandemic. Patient compliance with sample return and higher rates of sample failure emerge as potential barriers to timely genetic testing under this service delivery model.

Universal screening of both endometrial and colon cancers increases the detection of Lynch syndrome.

BACKGROUND: Lynch syndrome (LS) is the most common hereditary cause of colorectal cancer (CRC) and endometrial cancer (EC). Screening of all CRCs for LS is currently recommended, but screening of ECs is inconsistent. The objective of this study was to determine the added value of screening both CRC and EC tumors in the same population. METHODS: A prospective, immunohistochemistry (IHC)-based screening program for all patients with newly diagnosed CRCs and ECs was initiated in 2011 and 2013, respectively, at 2 centers (primary and tertiary). Genetic testing was recommended for those who had tumors with absent mutS homolog 2 (MSH2), MSH6, or postmeiotoic segregation increased 2 (PMS2) expression and for those who had tumors with absent mutL homolog 1 (MLH1) expression and no v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutation or MLH1 promoter methylation. Amsterdam II criteria, revised Bethesda criteria, and scores from prediction models for gene mutations (the PREMM1,2,6 and PREMM5 prediction models) were ascertained in patients with LS. RESULTS: In total, 1290 patients with CRC and 484 with EC were screened for LS, and genetic testing was recommended for 137 patients (10.6%) and 32 patients (6.6%), respectively (P = .01). LS was identified in 16 patients (1.2%) with CRC and in 8 patients (1.7%) with EC. Among patients for whom genetic testing was recommended, the LS diagnosis rate was higher among those with EC (25.0% vs 11.7%, P = .052). The Amsterdam II criteria, revised Bethesda criteria, and both PREMM calculators would have missed 62.5%, 50.0%, and 12.5% of the identified patients with LS, respectively. CONCLUSIONS: Expanding a universal screening program for LS to include patients who had EC identified 50% more patients with LS, and many of these patients would have been missed by risk assessment tools (including PREMM5 ). Universal screening programs for LS should include both CRC and EC. Cancer 2018. © 2018 American Cancer Society.

A tailored approach to BRAF and MLH1 methylation testing in a universal screening program for Lynch syndrome.

To determine the correlation between BRAF genotype and MLH1 promoter methylation in a screening program for Lynch syndrome (LS), a universal screening program for LS was established in two medical centers. Tumors with abnormal MLH1 staining were evaluated for both BRAF V600E genotype and MLH1 promoter methylation. Tumors positive for both were considered sporadic, and genetic testing was recommended for all others. A total 1011 colorectal cancer cases were screened for Lynch syndrome, and 148 (14.6%) exhibited absent MLH1 immunostaining. Both BRAF and MLH1 methylation testing were completed in 126 cases. Concordant results (both positive or both negative) were obtained in 86 (68.3%) and 16 (12.7%) cases, respectively, with 81% concordance overall. The positive and negative predictive values for a BRAF mutation in predicting MLH1 promoter methylation were 98.9% and 41%, respectively, and the negative predictive value fell to 15% in patients ≥70 years old. Using BRAF genotyping as a sole test to evaluate cases with absent MLH1 staining would have increased referral rates for genetic testing by 2.3-fold compared with MLH1 methylation testing alone (31% vs 13.5%, respectively, P<0.01). However, a hybrid approach that reserves MLH1 methylation testing for BRAF wild-type cases only would significantly decrease the number of methylation assays performed and reduce the referral rate for genetic testing to 12.7%. A BRAF mutation has an excellent positive predictive value but poor negative predictive value in predicting MLH1 promoter methylation. A hybrid use of these tests may reduce the number of low-risk patients referred to genetic counseling and facilitate wider implementation of Lynch syndrome screening programs.

Which individuals undergoing BRACAnalysis need BART testing?

Deleterious mutations in BRCA1 and BRCA2 include those identified by sequencing technology as well as large genomic rearrangements (LGR). The main testing laboratory in the United States, Myriad Genetics Laboratory (MGL), has defined criteria for inclusion of LGR testing (i.e., BRACAnalysis Rearrangement Test, or BART™) when BRCA1 and BRCA2 testing is ordered. We were interested in determining how many of our patients with LGR mutations in BRCA1 and BRCA2 fulfilled these MGL criteria. A retrospective chart review was performed on all individuals who underwent genetic testing at our institution since August 2006. Individuals who underwent LGR testing were classified as either having or not having a LGR in BRCA1 or BRCA2. Each individual's history was classified as meeting MGL defined LGR criteria, meeting criteria using third-degree relatives, or not meeting criteria. A total of 257 BART tests were ordered at our institution from August 2006 to August 2009. Five individuals (1.9%) had an LGR mutation. Two LGR were identified in patients who met MGL defined LGR criteria. One LGR was identified in a patient that met MGL defined LGR criteria only when using third-degree relatives. Two LGR were identified in individuals who did not meet MGL defined criteria. LGR are present in individuals who do not have a high pretest probability of carrying a mutation in BRCA1 or BRCA2. These data suggest that when BRCA1 and BRCA2 genetic testing is performed, testing should always include LGR testing so that the results are the most comprehensive and reliable.