Myriad Genetics Research Articles

Clinical significance of germline breast cancer susceptibility gene (gBRCA) testing and olaparib as maintenance therapy for patients with pancreatic cancer

BackgroundGermline breast cancer susceptibility gene (gBRCA) mutation in patients with pancreatic cancer (PC) is not common in clinical practice. Therefore, factors that efficiently show gBRCA mutations and the real-world outcomes of olaparib maintenance therapy have not been fully established. In the present study, we clarified the indicators for the effective detection of gBRCA mutation and the efficacy and safety of olaparib as maintenance therapy.MethodsWe retrospectively analyzed 84 patients with PC who underwent gBRCA testing (BRACAnalysis, Myriad Genetics, Salt Lake City, UT, USA) at our institute between January 2021 and March 2022. For each patient, clinical data were extracted from medical records.ResultsThe median patient age was 64 y (29–85 y), and 41 patients (48.8%) were male. The gBRCA mutations were identified in 10 (11.9%) patients; two patients had BRCA1 mutation and eight had BRCA2 mutation. All patients with gBRCA mutation had a family history of any cancer, and eight of them had a family history of Hereditary Breast and Ovarian Cancer syndrome (HBOC)-related cancer. The gBRCA mutation rate was higher for patients with PC with a family history of HBOC-related cancer compared to that in patients with PC having a family history of other cancers and no family history of cancer (22.9% vs. 4.1%; P = 0.014). In our study, eight out of 10 patients with gBRCA-positive PC received olaparib after platinum-based chemotherapy. The best responses to platinum-based chemotherapy included a complete response in one patient (12.5%) and a partial response in seven patients (87.5%). The median duration of treatment with platinum-based chemotherapy plus olaparib was 17.5 months (8–87 months), and the duration of treatment with olaparib maintenance therapy was 11 months (1–30 months). During olaparib maintenance therapy, three patients showed no disease progression. One of these three patients underwent conversion surgery after receiving olaparib for 12 months.ConclusionsThe gBRCA testing should be considered proactively, especially in patients with PC with a family history of HBOC-related cancer.

Comprehensive molecular profiling of newly diagnosed advanced, high-grade ovarian cancer: Unveiling BRCA1/2 mutations and genomic instability scores to advocate for public insurance coverage of genetic testing—Insights from the Hellenic Society of Medical Oncology (HeSMO) national program.

3146 Background: Homologous recombination deficiency (HRD) in ovarian cancer, indicative of impaired DNA repair, contributes to genomic instability (GIS). Beyond mutations in BRCA1/2 genes, GIS is particularly significant for identifying patients who may benefit from PARP inhibitors. Equivalence between Myriad Genetics' myChoice CDx and the standard diagnostic tests OncoScan and Amoy Diagnostics has been published, prompting HeSMO to launch a national program addressing GIS and BRCA 1/2 mutations in newly diagnosed advanced high grade ovarian cancer patients, with the utilization of these more economically advantageous tests, in order to guide effective therapeutic strategies, since official reimbursement is not yet applicable in our country. Methods: Patients with locally advanced or metastatic high-grade stage III/IV ovarian cancer were eligible for the HeSMO program, submitting an FFPE tissue tumor sample. The evaluation focused on HRD detection (positive or negative) and GIS assessment (high or low), combining results from OncoScan and Amoy Diagnostics. Results: Between August 2022 and December 2023, 511 patients from Greece underwent testing. 48.14% (n=246) tested HRD positive, 46.58% (n=238) HRD negative. High GIS score was observed in 44.81% (n=229), low GIS in 49.71% (n=254). Potential pathogenic mutations in BRCA1/2 genes were found in 19.96% (n=102). BRCA1 mutations (13.70%, n=70) included key mutations: c.190T>C p.(Cys64Arg), c.3700_3704delGTAAA p.(Val1234GlnfsTer8), c.4065_4068del p.(Asn1355LysfsTer10). BRCA2 mutations (6.26%, n=32) comprised of c.1129G>T p.(Glu377Ter), c.3650_3659del p.(Arg1217IlefsTer8), c.7150C>T p.(Gln2384Ter). In 27 samples (5.28%) no result was produced. Conclusions: HRD and GIS are vital genomic instability biomarkers in high-grade ovarian cancer. These metrics provide valuable insights into tumor aggressiveness, guiding therapeutic decisions, including the use of PARP inhibitors. In this study of 511 patients from 50 centers across Greece, 48.14% tested positive for HRD, emphasizing PARP inhibitors' significance and suggesting hereditary implications. Our commitment to enhance patient access to reliable diagnostic biomarker testing in Greece is unquestionable. Furthermore, we believe, our results will strengthen our efforts towards official state reimbursement, paving the way for local HRD testing solutions. [Table: see text]

Impact of American Society of Breast Surgeons (ASBS) guidelines on genetic testing (GT) rates among patients with breast cancer (BC).

e22537 Background: Identifying patients with pathogenic germline genetic variants can inform clinical decision-making and risk assessment. Previous studies have suggested low rates of GT in BC patients overall and disproportionately lower rates of GT among black patients. This may be explained in part by clinicians failing to understand the current National Comprehensive Cancer Network (NCCN) GT guidelines, which are complex. In February 2019, the ASBS released updated guidelines recommending GT for all patients with a personal history of BC. The objective of this study was to evaluate the impact of the ASBS guideline change on GT utilization for all BC patients, and for black BC patients in particular. Methods: This retrospective cohort study included 4386 BC patients who were diagnosed and/or treated at the Siteman Cancer Center (SCC) in St. Louis, MO from January 1, 2017 to December 31, 2020. The pre-guideline period included those patients diagnosed between January 1, 2017 and July 25th, 2019 and the post-guideline period included those diagnosed between July 26, 2019 and December 31, 2020. Within the study period, Myriad Genetics was used almost exclusively for GT by breast oncologists and surgeons at SCC. Myriad data was queried to identify all BC patients at SCC with GT. Data including self-reported race/ethnicity, BC subtype (triple negative breast cancer (TNBC) vs other), insurance type (public vs private), and family history of BC (yes vs no) was collected from the electronic medical record (EMR) independently by authors. Multivariate logistic regression analyses and difference in difference (DiD) analyses were performed to compare GT rates pre- and post-guideline change. Results: There was no significant difference in the rate of GT among BC patients pre- vs post-guideline change (17% vs 14.8%, p = 0.05). Similarly, there was no significant difference in GT rates pre- vs post-guideline change for non-Hispanic black (NHB) (14.6% vs 13.1%) and non-Hispanic white (NHW) subgroups (17.8% vs 15.2%) using DiD analysis (p = 0.96). Patients with a family history of BC (odds ratio (OR) 1.41, 95% confidence interval (CI) 1.17-1.69, p < 0.01) and TNBC (OR 1.47, 95% CI 1.15-1.86, p < 0.01) were more likely to receive GT. Patients aged greater than 50 years (OR 0.44, 95% CI 0.37-0.54, p < 0.001) and those with public insurance were less likely to receive GT (OR 0.82, 95% CI 0.67-1.02, p = 0.07). DiD analyses identified no significant differences pre- and post-guideline change for these subgroups. Conclusions: Despite the recent broadening of GT guidelines by ASBS, GT rates remain low among patients with BC. We found no significant impact of the guideline change on the uptake of GT among our population of BC patients overall or by race/ethnicity, family history, BC subtype, age, or insurance status. Multidisciplinary efforts are needed to improve guideline implementation and uptake of GT in BC patients.

Comparison of primary versus metastatic tumor tissue sources when designing panels for whole genome–based tumor-informed ctDNA assays in clear cell renal cell carcinoma.

3039 Background: Due to low shedding and low tumor-mutation burden, metastatic clear cell renal cell carcinoma (ccRCC) is poorly modeled by current cell-free circulating tumor DNA (ctDNA) assays. Second generation tumor-informed ctDNA approaches may demonstrate improved sensitivity in ccRCC, where somatic variants identified by whole-genome sequencing (WGS) of tumor tissue are tracked in probe panels to monitor molecular residual disease (MRD) in patient plasma. However, intertumoral genomic heterogeneity of input tissue may hinder optimal panel design. Here we evaluated the concordance of ctDNA results using panels designed from primary nephrectomy or metastatic tumors in ccRCC. Methods: In five patients with oligometastatic ccRCC (≤5 lesions of metastatic disease; median of 1, range 1-4), 13 primary tumor, 24 metastatic lesion subsites and matched buffy coat samples were collected. Baseline plasma was collected prior to radiotherapy. Samples were tested with Myriad Genetics High-Definition MRD assay. Briefly, tumor and normal DNA were whole-genome sequenced (median coverage 30x). A sub-panel with up to 1000 somatic variants was designed for each lesion subsite; variants could be common across sub-panels. Sites were enriched using hybridization capture from patient plasma-derived cfDNA and sequenced to high depth. A statistical model of variant allele counts was used to assess the presence or absence of ctDNA (MRD status) and infer quantitative tumor fraction. Results: Median time from nephrectomy or most recent metastasis sample collection to baseline plasma collection was 146 months (71-169) and 32 months (7-48), respectively. Median panel probe count per patient was 4,311 (3,400-5,000) and per tumor sample was 1,545 (102-2,158). Confident calls were emitted for tumor fractions ranging from 0.0004% to 0.027%. Baseline MRD status was fully concordant across sub-panels derived from primary tumor lesion subsites and metastases in three of five patients (3/5; 60%). Of the patients with discordant calls, a single metastasis-derived sub-panel (comprising 20%-25% of metastatic sub-panels) called MRD discordantly in each. Of the three patients MRD positive at baseline, only one was alive at last follow up. All patients MRD negative at baseline are still alive. Conclusions: A tumor-informed, WGS MRD assay for ccRCC showed comparable performance between probe capture panels designed from primary tumor and metastatic lesion subsites despite differences in anatomical location and time from plasma collection. This result suggests that intertumoral genomic heterogeneity may not be consequential in MRD assays that leverage large panels to detect ctDNA variants, obviating the need for repeat biopsies of metastatic sites. Work is underway to validate this MRD assay in a larger cohort of patients with ccRCC before and after treatment.

Association between endocrine adjuvant therapy intake timing and disease-free survival in patients with high-risk early breast cancer: results of a sub-study of the UCBG- UNIRAD trial

Circadian rhythms regulate cellular physiology and could influence the efficacy of endocrine therapy (ET) in breast cancer (BC). We prospectively tested this hypothesis within the UNIRAD adjuvant phase III trial (NCT01805271). 1278 patients with high-risk hormonal receptor positive (HR+)/HER2 negative (HER2-) primary BC were randomly assigned to adjuvant ET with placebo or everolimus. Patients prospectively reported in a diary the daily timing of ET intake among four 6-h slots (06:00-11:59 (morning), 12:00-17:59 (afternoon), 18:00-23:59 (evening), or 24:00-05:59 (nighttime). The association between ET timing and disease-free survival (DFS) was a prespecified secondary endpoint of the trial and the results of this observational study are reported here. ET timing was recorded by 855 patients (67.2%). Patients declaring morning (n=465, 54.4%) or afternoon (n=45, 5.4%) ET intake were older than those declaring evening (n=339, 39.6%) or nighttime (n=5, 0.6%) intake. With a median follow-up of 46.7 months, 118 patients had a local (n=30) or metastasis relapse (n=84), and 41 patients died. ET intake timing was not associated with DFS in the whole population (HR=0.77, 95% CI [0.53-1.12]). The association between ET intake timing and DFS according to the stratification factors revealed interactions with ET agent (tamoxifen versus Aromatase inhibitors (AI) with an increased DFS in the group of evening/nighttime versus morning/afternoon tamoxifen intake (HR=0.43, 95% CI [0.22-0.85]), while no association was found for AI intake (HR=1.07, 95% CI [0.68-1.69]). The interaction between ET intake timing and ET agent remained in multivariable analysis (HR=0.38 [0.16-0.91]). Tamoxifen intake in the evening/nighttime could be recommended in patients with high-risk HR+/HER2- BC while awaiting for results from further ET timing studies. UNIRAD was Supported by a grant from the French Ministry of Health PHRC 2012 and received funding from La Ligue contre le Cancer, Cancer Research-UK, Myriad Genetics, and Novartis.

High positive predictive value 22q11.2 microdeletion screening by prenatal cell-free DNA testing that incorporates fetal fraction amplification.

22q11.2 deletion syndrome (DS) is a serious condition with a range of features. The small microdeletion causing 22q11.2DS makes it technically challenging to detect using standard prenatal cfDNA screening. Here, we assess 22q11.2 microdeletion clinical performance by a prenatal cfDNA screen that incorporates fetal fraction (FF) amplification. The study cohort consisted of patients who received Prequel (Myriad Genetics, Inc.), a prenatal cfDNA screening that incorporates FF amplification, and met additional eligibility criteria. Pregnancy outcomes were obtained via a routine process for continuous quality improvement. Samples with diagnostic testing results were used to calculate positive predictive value (PPV). 379,428 patients met study eligibility criteria, 76 of whom were screen-positive for a de novo 22q11.2 microdeletion. 22 (29.7%) had diagnostic testing results available, and all 22 cases were confirmed as true positives, for a PPV of 100% (95% CI 84.6%-100%). This performance was based on cases that ranged broadly across FF (5.9%-41.1%, mean 23.0%), body mass index (22.3-44.8, mean 29.9), and gestational age at testing (10.0w-34.6w, median 12.7w). Ultrasound findings in screen-positive pregnancies were consistent with those known to be associated with 22q11.2DS. 22q11.2 microdeletion screening that incorporates FF amplification demonstrated high PPV across both general and high-risk population cohorts.

Clinical evaluation of a low-coverage whole-genome test for detecting homologous recombination deficiency in ovarian cancer

BackgroundThe PAOLA-1/ENGOT-ov25 trial showed that maintenance olaparib plus bevacizumab increases survival of advanced ovarian cancer patients with homologous recombination deficiency (HRD). However, decentralized solutions to test for HRD in clinical routine are scarce. The goal of this study was to retrospectively validate on tumor samples from the PAOLA-1 trial, the decentralized SeqOne assay, which relies on shallow Whole Genome Sequencing (sWGS) to capture genomic instability and targeted sequencing to determine BRCA status. MethodsThe study comprised 368 patients from the PAOLA-1 trial. The SeqOne assay was compared to the Myriad MyChoice HRD test (Myriad Genetics), and results were analyzed with respect to Progression-Free Survival (PFS). ResultsWe found a 95% concordance between the HRD status of the two tests (95% Confidence Interval (CI); 92%−97%). The Positive Percentage Agreement (PPA) of the sWGS test was 95% (95% CI; 91%−97%) like its Negative Percentage Agreement (NPA) (95% CI; 89%−98%). In patients with HRD-positive tumors treated with olaparib plus bevacizumab, the PFS Hazard Ratio (HR) was 0.38 (95% CI; 0.26–0.54) with SeqOne assay and 0.32 (95% CI; 0.22–0.45) with the Myriad assay. In patients with HRD-negative tumors, HR was 0.99 (95% CI; 0.68–1.42) and 1.05 (95% CI; 0.70–1.57) with SeqOne and Myriad assays. Among patients with BRCA-wildtype tumors, those with HRD-positive tumors, benefited from olaparib plus bevacizumab maintenance, with HR of 0.48 (95% CI: 0.29–0.79) and of 0.38 (95% CI: 0.23 to 0.63) with the SeqOne and Myriad assay. ConclusionThe SeqOne assay offers a clinically validated approach to detect HRD.

The Myriad Decision at 10.

A decade ago, the US Supreme Court decided Association for Molecular Pathology v. Myriad Genetics, Inc., concluding that isolated genes were not patentable subject matter. Beyond being a mere patent dispute, the case was a political and cultural phenomenon, viewed as a harbinger for the health of the biotechnology industry. With a decade of perspective, though, Myriad's impact seems much narrower. The law surrounding patentable subject matter-while greatly transformed-only centered on Myriad in small part. The case had only a modest impact on patenting practices both in and outside the United States. And persistent efforts to legislatively overturn the decision have not borne fruit. The significance of Myriad thus remains, even a decade later, hidden by larger developments in science and law that have occurred since the case was decided. Expected final online publication date for the Annual Review of Genomics and Human Genetics, Volume 25 is August 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Tumour-based Mutational Profiles Predict Visceral Metastasis Outcome and Early Death in Prostate Cancer Patients

BackgroundVisceral metastases are known to occur in advanced prostate cancer, usually when the tumour is resistant to androgen deprivation and, have worse outcomes regardless of therapies. ObjectiveTo analyse genomic alterations in tumour samples according to their lymphatic, bone, and visceral metastatic stages and overall survival. Design, setting, and participantsWe selected 200 patients with metastatic prostate cancer. Genomic profiling of 111 genes and molecular signatures (homologous recombination deficiency [HRD], microsatellite instability, and tumour burden mutation) was performed with the MyChoice test (Myriad Genetics, Inc, Salt Lake City, UT, USA). Outcome measurements and statistical analysisThe association between genomic profiles and visceral metastatic evolution was evaluated using logistic regression. Kaplan-Meier and Cox proportional hazard analyses were used for analyses of early death. Results and limitationsA total of 173 (87%) genomic profiles were obtained. Eighty-four (49%) patients died during the follow-up period (median duration = 76 mo). TP53 was the most frequently mutated gene, followed by FANC genes, including BRCA2, and those of the Wnt-pathway (APC/CTNNB1). TP53 gene mutations were more frequent in patients of European (42%) than in those of African (16%) ancestry. An HRD score of >25 was predictive of FANC gene mutations. The mutational status of TP53 (p < 0.001) and APC (p = 0.002) genes were significantly associated with the risk of visceral metastases. The mutational status of CTNNB1 (p = 0.001), TP53 (p = 0.015), BRCA2 (p = 0.027), and FANC (p = 0.005) genes were significantly associated with an earlier age at death. The limitations are the retrospective study design based on a selection of genes and the low frequency of certain molecular events. ConclusionsMutations in the TP53 gene and genes (APC/CTNNB1) related to the Wnt pathway are associated with metastatic visceral dissemination and early death. These genomic alterations could be considered as markers to identify prostate cancer patients at a high risk of life-threatening disease who might benefit from more intensified treatment or new targeted therapies. Patient summaryIn this report, we evaluated the relationships between genomic profiles (gene mutations and molecular signatures) of tumour samples from patients with metastatic prostate cancer and early death. We found that mutations of specific genes, notably TP53 and APC/CTNNB1 related to the Wnt pathway, are associated with visceral metastatic progression and an earlier age at death.

Real-World Concordance between Germline and Tumour BRCA1/2 Status in Epithelial Ovarian Cancer.

Patients diagnosed with epithelial ovarian cancer may undergo reflex tumour BRCA1/2 testing followed by germline BRCA1/2 testing in patients with a positive tumour test result. This testing model relies on tumour BRCA1/2 tests being able to detect all types of pathogenic variant. We analysed germline and tumour BRCA1/2 test results from patients treated for epithelial ovarian cancer at our specialist oncological referral centre. Tumour BRCA1/2 testing was performed using the next-generation sequencing (NGS)-based myChoice® companion diagnostic (CDx; Myriad Genetics, Inc.). Germline BRCA1/2 testing was performed in the North West Genomic Laboratory Hub using NGS and multiplex ligation-dependent probe amplification. Between 11 April 2021 and 11 October 2023, 382 patients were successfully tested for tumour BRCA1 and BRCA2 variants. Of these, 367 (96.1%) patients were tested for germline BRCA1/2 variants. In those patients who underwent tumour and germline testing, 15.3% (56/367) had a BRCA1/2 pathogenic variant (36 germline and 20 somatic). All germline BRCA1/2 pathogenic small sequencing variants were detected in tumour DNA. By contrast, 3 out of 8 germline BRCA1/2 pathogenic large rearrangements were not reported in tumour DNA. The overall concordance of germline BRCA1/2 pathogenic variants detected in germline and tumour DNA was clinically acceptable at 91.7% (33/36). The myChoice® CDx was able to detect most germline BRCA1/2 pathogenic variants in tumour DNA, although a proportion of pathogenic large rearrangements were not reported. If Myriad's myChoice® CDx is used for tumour BRCA1/2 testing, our data supports a testing strategy of germline and tumour BRCA1/2 testing in all patients diagnosed with epithelial ovarian cancer aged < 79 years old, with germline BRCA1/2 testing only necessary for patients aged ≥ 80 years old with a tumour BRCA1/2 pathogenic variant.

Validation of the Clinical Use of GIScar, an Academic-developed Genomic Instability Score Predicting Sensitivity to Maintenance Olaparib for Ovarian Cancer.

The optimal application of maintenance PARP inhibitor therapy for ovarian cancer requires accessible, robust, and rapid testing of homologous recombination deficiency (HRD). However, in many countries, access to HRD testing is problematic and the failure rate is high. We developed an academic HRD test to support treatment decision-making. Genomic Instability Scar (GIScar) was developed through targeted sequencing of a 127-gene panel to determine HRD status. GIScar was trained from a noninterventional study with 250 prospectively collected ovarian tumor samples. GIScar was validated on 469 DNA tumor samples from the PAOLA-1 trial evaluating maintenance olaparib for newly diagnosed ovarian cancer, and its predictive value was compared with Myriad Genetics MyChoice (MGMC). GIScar showed significant correlation with MGMC HRD classification (kappa statistics: 0.780). From PAOLA-1 samples, more HRD-positive tumors were identified by GIScar (258) than MGMC (242), with a lower proportion of inconclusive results (1% vs. 9%, respectively). The HRs for progression-free survival (PFS) with olaparib versus placebo were 0.45 [95% confidence interval (CI), 0.33-0.62] in GIScar-identified HRD-positive BRCA-mutated tumors, 0.50 (95% CI, 0.31-0.80) in HRD-positive BRCA-wild-type tumors, and 1.02 (95% CI, 0.74-1.40) in HRD-negative tumors. Tumors identified as HRD positive by GIScar but HRD negative by MGMC had better PFS with olaparib (HR, 0.23; 95% CI, 0.07-0.72). GIScar is a valuable diagnostic tool, reliably detecting HRD and predicting sensitivity to olaparib for ovarian cancer. GIScar showed high analytic concordance with MGMC test and fewer inconclusive results. GIScar is easily implemented into diagnostic laboratories with a rapid turnaround.

Ovarian high-grade serous carcinoma with transitional-like (SET) morphology: a homologous recombination-deficient tumor

Thirteen years ago, we pointed out that ovarian transitional cell carcinomas (TCCs) and conventional high-grade serous carcinomas (HGSCs) had similar genetic alterations and clinical behavior. Consequently, ovarian TCC is now classified as a morphologic variant of HGSC. Defective homologous recombination, resulting from genetic or epigenetic inactivation of DNA damage repair genes, such as BRCA1/2, occurs in approximately 50% of the HGSCs. Although BRCA mutations have been associated with HGSCs with solid, pseudoendometrioid or transitional (SET) features, little is known about the role of non-BRCA homologous recombinationrepair (HRR) genes and the HRR status in these tumors. Using two commercially available assays (Myriad Genetics MyChoice CDx Plus test and SOPHiA Dx Homologous Recombination Deficiency Solution), we study mutations of BRCA1/2 and non-BRCA HRR genes (ATM, BARD1, BRIP1, CDK12, CHEK1/2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L), and the HRR status in 19 HGSCs with SET features and 20 HGSCs with classic morphology. We also studied, as control cases, 5 endometrioid carcinomas, 1 clear cell carcinoma, 2 low-grade serous carcinomas, and 1 malignant Brenner tumor. Seven HGSCs with SET features (7/19; 37%) showed BRCA mutations (4 BRCA1, 2 BRCA2, and 1 BRCA1/2). Mutations in non-BRCA HRR genes were found in ATM (1/15; 7%), BARD1 (1/15; 7%), and BRIP1 (1/19; 5%). MostHGSCs with SET features (17/19; 90%) were considered to be homologous recombination-deficient tumors. Three HGSCs with classic morphology (3/20; 15%) showed BRCA2 mutations. Mutations in non-BRCA HRR genes were found in CDK12 (2/14; 14%), FANCL (1/14; 7%), RAD51B (1/14; 7%), and RAD54L (1/14; 7%). Eleven HGSCs with classical morphology (11/20; 55%) were considered to be homologous recombination deficient. In contrast, all ovarian carcinoma control cases (5 endometrioid carcinomas, 1 clear cell carcinoma, 2 low-grade serous carcinomas, and 1 malignant Brenner tumor) were homologous recombination proficient and did not have BRCA mutations. Our results show that the majority of HGSCs with SET features are homologous recombination-deficient tumors independently of the BRCA status and highlight the importance of the HRR tumor testing, especially in BRCA wild-type tumors. Recognition of transitional cell variant of HGSCs may help to identify patients most likely to benefit from PARP inhibitors.

The diagnostic landscape of HRD testing based on cross-sectional survey of physicians and molecular biologists conducting testing (INDICATOR ONE).

5585 Background: Homologous recombination deficiency (HRD) occurs in approximately 50% of epithelial ovarian cancer (OC) cases. As HRD-positive tumors are more sensitive to poly(ADP-ribose) polymerase inhibitors (PARPi), HRD testing (determined by BRCAm and genomic instability score) identifies advanced ovarian cancer (AOC) patients who will benefit most from PARPi treatment . The value of these tests is recognized by guidelines to inform PARPi maintenance treatment decisions following first-line chemotherapy. This study characterizes the current testing landscape. Methods: This non-interventional, cross-sectional, web-based survey will be repeated in three waves, 9-12 months apart. Reported results are from Survey Wave 1 open from July to November 2022 and conducted among physicians and clinical laboratory heads/molecular biologists in the US and Europe (UK, France, Germany, Austria). Participants were recruited from clinical sites/laboratories known to be conducting HRD testing and via a standing physician panel. Results: Responses were received from 287 eligible participants (representing invitees from ~9% sites and &lt; 2% panelists), 265 of whom completed the full survey (Europe: 153, US: 112; 228 physicians, 37 clinical laboratory heads/molecular biologists). Physicians ordered HRD testing for 70% ± 27% (mean ± SD) of newly diagnosed AOC patients. Nearly all physicians ordered the test to inform treatment decisions (n = 222; 97%). Physicians were most likely to conduct testing at stage 3 or 4 of OC diagnosis (Europe: n = 89, 64%; US: n = 63, 71%), followed by OC diagnosis regardless of stage (Europe: n = 51, 37%, US: n = 51, 57%). When European participants selected all types of tests used MyChoice CDx, Myriad Genetics (n = 82, 54%) was most commonly selected, followed by FoundationOne CDx, Foundation Medicine (n = 38, 25%). US participants used FoundationOne CDx (n = 62, 55%), followed by MyChoice CDx (n = 49, 44%), and QIAGEN QIASeq HRD (n = 38, 34%). Test costs were often partially (Europe: n = 47; 27%; US: n = 125; 53%) or fully covered (Europe: n = 89; 51%; US: n = 48; 21%). Results were received within 10 ± 6 (mean ± SD) working days in the US and 16 ± 11 working days in Europe. Testing guided treatment decisions ‘always/often’ (Europe: n = 117, 84%; US: n = 65, 73%) or ‘sometimes’ (Europe: n = 21, 15%; US: n = 23, 26%). Most European (n = 108, 78%) and US (n = 71, 80%) institutions offered genetic counselling. Conclusions: Among physicians and molecular biologists known to be conducting HRD testing, most newly diagnosed AOC patients were tested for HRD, and results usually played a role in treatment decisions. Variations in testing between the US and Europe include test types, test cost coverage, and time to receive results. Differences indicate potential areas for improvement in HRD testing to further benefit patients.

Predicting absolute benefit in risk of metastasis of androgen deprivation therapy added to radiation therapy in patients with newly diagnosed prostate cancer using Prolaris.

5030 Background: Most patients would defer using androgen deprivation therapy (ADT) with radiation therapy (RT) when the number-needed-to-treat (NNT) exceeds 25 persons to prevent 1 from developing metastasis, corresponding to an absolute benefit of 4%.1 However, no tools for estimating personalized NNT or absolute benefit from ADT exist. We aimed to quantify personalized absolute benefit and NNT for persons receiving ADT added to single modality RT. Methods: The clinical cell-cycle risk (CCR) score combines the University of California, San Francisco’s Cancer of the Prostate Risk Assessment and the cell cycle progression molecular score to accurately assess prostate cancer aggressiveness. The effect of ADT added to RT was modeled using a 10-year risk of metastasis as a function of continuous CCR score for patients treated with RT alone. The relative benefit of ADT added to RT to reduce distant metastasis was modeled using published data from The Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) which utilized several prospectively randomized RT±ADT trials.2 The average absolute benefit was calculated for patients with CCR scores above and below a prespecified multimodality treatment threshold (MTT) using the distribution of scores in a cohort of patients commercially tested by Myriad Genetics. Results: The commercially tested cohort consisted of 56,485 patients spanning all National Comprehensive Cancer Network risk categories (33.7% very low/low risk, 29.8% favorable intermediate risk, 25.6% unfavorable intermediate risk, 11.0% high/very high risk), with 87.2% having CCR scores at or below the MTT and 12.7% with CCR scores above the threshold. The average absolute benefit of ADT treatment was 0.86% (NNT=116) for patients with CCR scores below the MTT and 8.2% (NNT=12) for patients with CCR scores above the MTT. Patients with CCR scores at precisely the MTT had a predicted absolute benefit of 3.7% (NNT=27). Conclusions: The Prolaris test can accurately predict an individual's benefit of adding ADT to RT, and the risk threshold is consistent with patient attitudes about when to use or omit ADT. 1. Spratt DE, Tward JD: IJROBP 108:899-902, 2020. 2. Kishan AU, Sun Y, Hartman H, et al. Lancet Oncol 23:304-316, 2022.

(384) International Clinical Guidelines for Sexual Health Care in Prostate Cancer Survivorship

Abstract Introduction During the past 20 years, researchers have studied various aspects of the impact of prostate cancer therapies on patients, partners and couples. Patients and partners reported distress and negative consequences for their relationships resulting from treatment-related sexual side-effects of prostate cancer therapies. Research on rehabilitation strategies in prostate cancer survivorship has focused largely on biomedical interventions although psychosexual intervention research is also gaining ground. This research has never been summarized in such a way that clinicians can use the findings to provide evidence-based support for prostate cancer patients and their partners in survivorship. Objective An international panel of experts has developed a guideline that informs clinicians, patients and partners about the impact of prostate cancer therapies on the sexuality of patients and partners, and on their sexual relationships. It provides guidance for biopsychosocial rehabilitation strategies that help patients and partners recover sexual intimacy after prostate cancer therapy. Methods The guideline panel included international, multidisciplinary clinical experts and researchers in prostate cancer, a reference librarian and a guideline methodologist. A systematic review of the literature, using the Ovid MEDLINE, Scopus, CINAHL, PsychINFO, LGBT Life, and Embase databases was conducted (1995-2022). The review was conducted according to the Cochrane Handbook for Systematic Reviews of Interventions. Study selection is reported, based on PRISMA guidelines. Evidence for each statement was assigned a strength (A-C) and a level of recommendation (strong, moderate, conditional) which was based on benefit/risk balance. Data synthesis included meta-analyses of high-quality studies (determined by the Cochrane Risk of Bias tool). Results The guideline is contextualized within cultural, ethnic and racial diversity. The needs of individuals with diverse sexual orientations and gender identities are also recognized. Forty-seven statements were generated, guided by a theoretical model of sexual recovery after prostate cancer therapies and by principles that promote clinician-initiated discussion of realistic expectations of sexual outcomes and mitigation of sexual side-effects through biopsychosocial rehabilitation. The statements focus on counseling about the impact of prostate cancer therapies on patients’ and partners’ sexuality and couples’ relationships as well as on biomedical and psychosocial treatment strategies for sexual dysfunction. The guideline statements address the assessment of sexual function and distress, and barriers to providing sexual health care in prostate cancer survivorship in globally varied health care systems. Conclusions The guideline documents the distressing sexual sequelae of prostate cancer therapies and makes evidence-based recommendations for sexual rehabilitation in prostate cancer survivorship. Areas for future research are also outlined. The guideline was supported and funded by the Movember Foundation. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Author disclosures 1. Capogrosso 2. Northouse 3. Matthew 4. Elliott 5. Mulhall 6. Capellari 7. Incrocci 8. Faraday 9. Loeb 10. Mehta 11. Howell 12. McPhail J 13. McPhail S 14. Brandon 15. Paich 16. Erickson 17. Shifferd 18. Duby 19. Yap 20. Goltz 21. Odiyo 22. Salter 23. Nelson 24. McLeod 25. Trost 26. Wittmann – 10% salary paid by Movember 27. Bober – honorarium from UpToDate 28. Bennett - Endo Pharma - speaker 29. Coloplast - speaker, training grant. 30. Glode – Janssen, Aurora Oncology, Bayer, Exelixis, ProTechSure Scientific, Gonex, Patents, Seattle Genetics 31. Kirby – Lilly, Astra Zeneca, GSK, others 32. Wang – Boston Scientific, Teleflex, Coloplast 33. Pollack – Gilead 34. Burnett - Grant/research support: Endo Pharmaceutical, Boston Scientific, NIH Consultant/advisor: Boston Scientific, Coloplast, Reflexonic, Astellas, Novartis, Futura Medical, Comphya SA, Myriad Genetics Patent Holder: MHN Biotech Boards: UCF, AUA PAC, Mentoring Mae teens in the Hood Editor/editorial board: Urology Practice, Andrology, Canadian Journal of Urology, International Urology and Nephrology, Urology Times Other: UroMissionsWorks Inc (Non-profit) 35. Skolarus – UpToDate 36. Koontz - receives research funding from Janssen Scientific Affairs, Merck Pharmaceuticals, Blue Earth Diagnostics, and has received personal fees (ie advisory board) for Blue Earth Diagnostics.

Abstract 6113: Predictive value of HRD testing on the response to PARP inhibitors in ovarian cancer preclinical models

Abstract Since the introduction of Poly(ADP-ribose)polymerase inhibitors (PARPi) in the clinical practice, the search of biomarkers to distinguish homologous recombination defective tumors, eligible for PARPi therapy, has become a priority. Along with testing for BRCA mutations, commercially available tests, such as MyChoice® assay (Myriad Genetics), exploit scores calculated from genomic scarring patterns. Platinum sensitivity is also considered a surrogate marker of PARPi efficacy. However, the prognostic accuracy remains a challenge because these tests can only infer homologous recombination functionality but not directly measure it. Moreover, the association between platinum and PARPi response is imperfect since not all platinum-sensitive patients benefit from PARPi and PARPi response has been observed in platinum-resistant cancers. A panel of 20 high-grade serous ovarian carcinoma patient-derived xenografts (OC-PDXs) were molecularly and pharmacologically characterized to assess predictive markers of response to PARPi therapy. Genomic DNA and total RNA were sequenced searching for BRCA1/2 alterations or sent to Myriad Genetics to obtain HRD scores. Absolute BRCA1 mRNA expression was measured by RT-qPCR. OC-PDXs growing subcutaneously or orthotopically in nude mice were treated with the PARPi olaparib or platinum to test drug sensitivity. The molecular analyses revealed that nearly 90% (17/20) of OC-PDXs are TP53 mutated, thus reflecting the clinical scenario. 50% (10/20) of OC-PDXs harbor mutations in BRCA1/2 genes, while 10% (2/20) lack BRCA1 mRNA expression. MyChoice® assay showed that 65% (13/20) of OC-PDXs score higher than 42, which is the currently used threshold to classify HRD-positive tumors. Correlation analysis confirmed that the HRD score is highly associated with the presence of mutations in BRCA1/2 genes. Preclinical testing showed that 50% of OC-PDXs are sensitive to olaparib. Notably, in 20% of cases the therapeutic response was incorrectly predicted considering either BRCA1/2 mutations or HRD score. 30% of platinum-sensitive OC-PDXs were not responsive to olaparib, confirming that platinum sensitivity not always correlate with response to PARPi. Our results show that tumor genotype and HRD score are strongly associated. Further analyses are required to improve the predictive value of currently used tests to select patients who will benefit the most from PARPi treatment while sparing toxicities in patients that are unlikely to respond. Citation Format: Giulia Dellavedova, Alessandra Decio, Laura Formenti, Luca Porcu, Carmen Ghilardi, Raffaella Giavazzi, Maria Rosa Bani. Predictive value of HRD testing on the response to PARP inhibitors in ovarian cancer preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6113.

Abstract P5-03-03: Variant Classification Discordance: A real-world experience of genetic test results in a community-based setting

Abstract BACKGROUND Accurate interpretation of hereditary cancer germline genetic variants is critical to ensuring appropriate care. Myriad Genetics has developed tools that are instrumental in the accurate classification of variants, including a previously described history-weighting algorithm (Pheno), mutation co-occurrence statistical analysis (MCO), and in trans haplotype analysis. Differences in classification are known to occur among commercial testing laboratories, however the rate at which a single provider may observe variants with a different classification has not been reported. Here, we compared genetic test results from multiple laboratories ordered by a single surgical community-based practice with the classifications from Myriad’s testing laboratory. METHODS Variants initially reported as a “variant of uncertain significance” (VUS) on hereditary cancer test results from multiple commercial laboratories ordered by a single surgeon at a community-based, comprehensive breast center from June 2013 to May 2021 were evaluated and compared to the classifications from Myriad. In total, 212 variants were submitted for comparison. After review, 42 variants were excluded because they had not been observed previously in Myriad-tested patients. Therefore, 170 variants were eligible for comparison. Variants were classified as pathogenic/likely pathogenic, VUS, and benign/likely benign for comparison. Descriptive statistics were used for analysis. RESULTS Discordant classification was observed between Myriad and other testing laboratories for 28.2% (48/170) of the variants compared. Initially, all 170 variants were classified and reported by other testing laboratories as VUS, however, 15 variants (8.8%) were subsequently reclassified by other testing laboratories (N=13 were reclassified as benign/likely benign; N=2 were reclassified as pathogenic/likely pathogenic). Among all variants compared, 23.5% (40/170) were definitively classified by Myriad as benign/likely benign. For 90.0% (36/40) of these variants, evidence driving the classification relied upon Pheno (32 variants), MCO (4 variants), and in trans haplotype analysis (8 variants), with some variants having multiple lines of evidence. Other in-house specific rules were used for the remaining classifications (4/40;10%). Fifty-five percent (22/40) of the discordant classifications were seen in high-risk genes including APC, BRCA1/2, MLH1, MSH2, MSH6, PMS2, PALB2 and STK11, and 45% (18/40) were in moderate-risk genes including ATM, BARD1, BRIP1, CHEK2, and RAD51C. Of the 13 variants reclassified by other testing laboratories as benign/likely benign, six were classified as VUS by Myriad. Notably, two variants classified by Myriad as VUS were reclassified by other laboratories as pathogenic/likely pathogenic. CONCLUSIONS These data indicate that even in a single practice, significant discordance in variant classification exists based on the chosen laboratory. Myriad definitively classified nearly one-quarter of variants classified as VUS by other laboratories, likely due to the use of Myriad’s laboratory-developed classification tools. The degree of discordance observed here reflects the need for continuous laboratory investment in variant classification tools and evaluation of genetic variants, enabling physicians and patients to receive accurate results to facilitate appropriate medical management decisions. Citation Format: Shelly Cummings, Erin Mundt, Ann Marie Miller, TinaMarie Bauman, Thomas Slavin, Robert Maganini. Variant Classification Discordance: A real-world experience of genetic test results in a community-based setting [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-03-03.

38MO Validation study of the ShallowHRDv2 assay for homologous recombination deficiency (HRD) detection in high-grade ovarian carcinomas (HGOC) in the first-line setting, from the phase III PAOLA-1/ENGOT-ov25 trial

The bevacizumab(bev)/olaparib(ola) maintenance regimen was approved for women affected with BRCA-mutated (BRCAm) and HRD HGOC, based on a greater progression-free survival (PFS) compared to bevacizumab alone in the PAOLA-1/ENGOT-ov25 trial (NCT02477644). HRD status in this trial was determined by the centralized MyChoice CDx test by Myriad Genetics (MG test). Belonging to the second part of the ENGOT HRD European initiative we evaluated the analytical and clinical validity of the ShallowHRDv2 test, an assay that analyzes the genome-wide copy number alterations, as compared with the MG test on PAOLA-1/ENGOT-ov25 tumor samples. We performed shallow Whole Genome Sequencing (sWGS) with a mean coverage of ∼1x (XT-HS capture kit; Agilent) on 449 tumor DNAs from the PAOLA-1/ENGOT-OV25 trial. HRD status was determined using the shallowHRDv2 bio-informatics pipeline with a single cut-off at 20 Large scale Genomic Alterations. We further evaluated our test on 109 prospective samples from our routine practice. In the PAOLA-1 cohort, positive agreement for the ShallowHRDv2 vs. MG test status was 95% (196/206), negative agreement was 92% (173/188) and the overall agreement was 94% (369/394). Patients with shallowHRDv2-HRD-positive (including BRCAm) tumors showed a significantly prolonged PFS with bev/ola versus bev/placebo (median PFS: 44.8 vs. 20.3 months, hazard ratio (HR): 0.35 [95% CI, 0.23–0.54]). This benefit was still significant after exclusion of BRCAm tumors (41.7 vs. 18.6 months, HR: 0.47 [95% CI, 0.27–0.84]). Less non-contributive analyses were observed with the ShallowHRDv2 test (15/449; 3%) than with MG test (51/449; 11%). We confirmed the high overall percentage agreement of 91% (86/94) between ShallowHRDv2 and MG tests in the prospective cohort, with less non contributive results for ShallowHRDv2 (5% vs. 12%). The ShallowHRDv2 test is a robust, cost-effective, clinically validated & highly performant test for HRD determination and is a valid alternative to MG to detect HRD in ovarian cancers.

The Impact of Gene Patent Decision and the Changing IP Strategies of Myriad Genetics

The Impact of Gene Patent Decision and the Changing IP Strategies of Myriad Genetics

Systematic mapping review of guidelines for BRCA1/2 genetic testing globally: investigating geographic and regional disparities in health equity for women and families at risk for hereditary ovarian cancer

ObjectiveIdentification of persons at risk for hereditary syndromes through genetic testing prior to cancer diagnosis may proactively reduce the cancer burden morbidity and mortality. Using a framework of health equity,...