Myriad Genetics Research Articles

151P Tumor biology and immunology in patients (pts) with breast cancer occurring during pregnancy (BCP) compared to non-pregnant breast cancer pts

151P Tumor biology and immunology in patients (pts) with breast cancer occurring during pregnancy (BCP) compared to non-pregnant breast cancer pts

Correlates of suicidality among standard rating scales and the Columbia-Suicide Severity Rating Scale (C-SSRS) in adolescents undergoing transcranial magnetic stimulation

Background: Suicide is a leading cause of death in adolescents and young adults.1 This study sought to examine correlations among suicide items of standard rating scales for depression and Columbia-Suicide Severity Rating Scale (C-SSRS)2 scores in adolescents participating in a transcranial magnetic stimulation study. Methods: This study examined data from adolescent patients (N=103) enrolled in a double-blind randomized control trial of transcranial magnetic stimulation (TMS). Total scores and respective individual items assessing suicidality from the Hamilton Depression Rating Scale (HAM-D)3, Montgomery-Asberg Depression Rating Scale (MADRS)4, and Children’s Depression Rating Scale-Revised scale (CDRS-R)5 were compared with C-SSRS total severity and total intensity scores using Pearson correlation coefficients at the end of acute treatment. Results: The suicidality item of the HAM-D scores showed a positive association with C-SSRS total severity and intensity scores at the end of acute treatment for ITT sample (n=103) (r = 0.83; p-value= <0.0001, r = 0.86; p-value=<0.0001), respectively. Similarly, associations were demonstrated with the CDRS-R Item 13 scores and the MADRS scores. Conclusions: Accurate and reliable assessments of suicidality are an ongoing challenge for clinical trials and practice. Suicidality measures of HAM-D and CDRS-R correlated with the C-SSRS suicide assessment scale. These measures can potentially contribute to assessing suicidal risk and be helpful as an outcome measure to monitor treatment response in various clinical settings. Further studies should compare the sensitivity and specificity of suicidality items of HAM-D and CDRS-R. Conflicts of Interests: Dr. Croarkin has received research support from the National Institute of Mental Health, Magventure, Neuronetics, NeoSync, and Pfizer. He has received material support from and provided consultation to Myriad Neuroscience. He has consulted for Procter & Gamble Company. Dr. Elmaadawi receives research support from Duke University and the University of North Western. He receives research funding from Neurocrine, Inc, and Neuronetics. Dr. Aaronson has received research support from Compass Pathways and Neuronetics and serves as a consultant to LivaNova, Neuronetics, Janssen, Genomind, and Sage Therapeutics. He serves on speaker boards for Janssen and Sunovion. Dr. Holbert has received material support (equipment) from Neuronetics. He is also a speaker for Neuronetics. Dr. Demitrack is a consultant to Neuronetics, Inc. and a full-time employee of Trevena, Inc. Dr. Strawn has received research support from Allergan, Neuronetics, Otsuka, the National Institute of Mental Health, National Institute of Child Health and Development, and National Institute of Environmental Health Sciences as well as the Yung Family Foundation. He receives royalties from Springer Publishing and received honoraria from CMEology and Neuroscience Educational Institute. He receives royalties from UpToDate. Finally, he received material support from and provided consultation to Myriad Genetics, Intracellular Therapeutics, and the FDA. The other authors have no disclosures. Funding: This study was funded by Neuronetics, Inc.

The Evolution of CRISPR Technology from Editing to Diagnostics

The Evolution of CRISPR Technology from Editing to Diagnostics

Testing of newly diagnosed advanced high grade ovarian cancer (OC) patients with the Myriad Genetics MyChoice CDx Plus next generation sequencing-based in vitro diagnostic test emphasizes the need for public insurance coverage of genetic testing: Results of a national program by the Hellenic Society of Medical Oncology (HeSMO).

e18520 Background: Homologous Recombination deficiency (HRD) represents a distinct entity in OC. Clinical data suggest that treatment selection can be based on both BRCA1/2 mutations and bearing Genomic Instability Status (GIS). Testing for GIS is critical in order to expand patients’ pool for targeted treatment. Myriad my Choice, is currently the only FDA approved test that can detect HRD by assessing BRCA1/BRCA2 mutation and GIS status in OC tumor specimens using 3 biomarkers: loss of heterozygosity, telomeric allelic imbalance and large-scale state transitions. To address this need, HeSMO has initiated a national program to provide access to myChoice to newly diagnosed patients with high grade stage III/IV OC. Methods: Patients with newly diagnosed stage III/IV high grade OC were eligible to participate in this program. The specific performance characteristics of myChoice CDx assay were determined on FFPE tumor samples by the evaluation of a range of representative tumor BRCA1 and BRCA2 sequence variants (e.g. single nucleotide variants, insertions or deletions and variants in homopolymers), Large Rearrangements (e.g. deletions and duplications affecting single and multiple exons) and a representative range of GIS. The overall results are composed of two major components: GIS Status (positive or negative) and tumor (t) BRCA1/2 Status (positive or negative). The combined results form the basis of the overall interpretation of the myChoice CDx Myriad HRD Status. Results: From December 2020 to January 2022, 454 patients from all over the country were tested within this program. 220 patients (48.46%) had a positive GIS report and 179 (39.43%) had a negative one. Among GIS positive cases, 122 patients were tBRCAwt (26.87%) 78 patients were tBRCA mutated (17.18%) and 10 patients had suspected deleterious BRCA1/2 mutations (2.20%). Inconclusive was the report in 38 specimens (8.37%) and myChoice Lab failed to complete the analysis in 15 cases (3.30%). Furthermore, mutations were also detected in a number of other genes, including but not limited to, ATM, BRIP1, PALB2, RAD51C, RAD51D, FANCL, CHEK2. Conclusions: In our series, 48.46% of the patients with high grade OC tested as BRCA1/2 and/or GIS positive, in accordance with published data, underlying the clinical need to implement GIS testing in OC patients’ molecular evaluation. Apart from the significant implications for treatment possibilities in an expanded patients’ population, these results are important for cancer prevention. We strongly believe that our results will strengthen our efforts for reimbursement of such testing in high grade OC patients, and will serve as a roadmap for the establishment of local HRD testing solutions.

Ethical, legal, and sociocultural challenges of genomic research in Jordan: a mixed methods study in patients with breast cancer with Jordanian–Palestinian heritage

BackgroundBreast cancer is a leading cause of morbidity and mortality in women worldwide. At King Hussein Cancer Center (KHCC), Amman, Jordan, 38% of breast cancer diagnoses are in women younger than 45 years, which might reflect a high prevalence of hereditary breast cancer. The aim of this study was to assess the contribution of germline mutations in BRCA1 and BRCA2 to breast cancer treated at KHCC. We also describe our experience in dealing with this delicate cultural issue in a tribal-based country with Palestinian–Jordanian family origins. MethodsPatients treated at KHCC with stage I–IV breast cancer, with a high-risk profile according to US National Comprehensive Cancer Network guidelines, were invited to participate. Patients were interviewed for consent and had full autonomy to decide whether they wanted to know their test result, inform their treating physician, or have a copy of the result placed in their charts. Charts were reviewed for clinical data and tumour pathology. A 10 mL blood sample was obtained for DNA extraction. A detailed three-generation family history was obtained. BRCA sequencing was done at the Myriad Genetics laboratory using BRCAnalysis. BRCA mutations were classified as deleterious, suspected deleterious, variant of uncertain significance (VUS), or favour polymorphism (harmless). The report received for each mutation result contained a detailed description of level of risk associated with the involved variant and estimated lifetime risk of breast and ovarian cancer, risk of second breast cancer or subsequent ovarian cancer, and risk of cancer to first, second, and third-degree family members. Patients were invited to an ad-hoc clinic with the treating physician for disclosure of results and counselling about estimated cancer risk to patient and relatives. Interviews with patients were summarised as text and qualitiative analysis for common themes was done. Challenges encountered during patient consent and disclosure of results were documented, as well as proposed solutions. Ethical approval was granted by the KHCC Institutional Review Board (no 11 KHCC 63). FindingsThe first 102 patients to meet inclusion criteria were invited to participate in the study, of whom 100 enrolled and provided written informed consent. Two patients declined to participate (a response rate of 98%). Six participants were residents of the West Bank and treated at KHCC, and 66 were from families of Palestinian origin residing in Jordan. The remaining patients were Jordanians. Median age was 40 years (range 22–75). 20 patients had deleterious mutations and seven had suspected deleterious mutations in BRCA1 and BRCA2 genes. Seven VUS were detected. All patients with BRCA1 and BRCA2 mutations had a significant family history of breast or ovarian cancer. Nevertheless, many patients with a significant family history (62 of 100) tested negative for BRCA1 and BRCA2 mutations. Many ethical dilemmas were highlighted during patient encounters, mainly relating to the guarantee of confidentiality and privacy in a tribal-based culture, fears of false reassurance, autonomy versus beneficence, and the bounds of physician–patient confidentiality when relatives are at genetic risk of cancer. Potential insurance, employment, and social discrimination implications were also addressed with the patients before testing and in more detail after disclosure of positive mutation results, which flagged a legal void in local genetic testing and data protection regulations. InterpretationOur cohort showed an important incidence of deleterious and suspected deleterious BRCA1 and BRCA2 mutations, suggesting that genetic testing should be discussed and offered to patients with high-risk features. Many high-risk patients tested negative for BRCA1 and BRCA2 mutations, therefore future studies should aim to test for mutations in other breast cancer susceptibility genes (eg, CHEK2, PALB2, and BRIP1). Running culturally sensitive genetic research in a country with limited resources is a challenging exercise and highlights the urgent need for guiding regulations. We recommend establishing a clinical cancer genetics programme, through which unaffected family members would benefit from early breast cancer screening and appropriate risk-reduction measures. FundingSister Institution Network Fund of MD Anderson Cancer Center and KHCC.

The effects of age, sex, weight, and breed on canid methylomes

ABSTRACT Unlike genomes, which are static throughout the lifespan of an organism, DNA methylomes are dynamic. To study these dynamics, we developed quantitative models that measure the effect of multiple factors on DNA methylomes including, age, sex, weight, and genetics. We conducted our study in canids, which prove to be an ideal species to assess epigenetic moderators due to their extreme variability in size and well-characterized genetic structure. We collected buccal swabs from 217 canids (207 domestic dogs and 10 grey wolves) and used targeted bisulphite sequencing to measure methylomes. We also measured genotypes at over one thousand single nucleotide polymorphisms (SNPs). As expected, we found that DNA methylomes are strongly associated with age, enabling the construction of epigenetic clocks. However, we also identify novel associations between methylomes and sex, weight, and sterilization status, leading to accurate models that predict these factors. Methylomes are also affected by genetics, and we observe multiple associations between SNP loci and methylated CpGs. Finally, we show that several factors moderate the relationship between epigenetic ages and real ages, such as body weight, which increases epigenetic ageing. In conclusion, we demonstrate that the plasticity of DNA methylomes is impacted by myriad genetics and physiological factors, and that DNA methylation biomarkers are accurate predictors of age, sex and sterilization status.

T-DM1 Increases the Risk of SRS-Induced Radiation Necrosis in Her2+ Breast Cancer

Stereotactic radiosurgery (SRS) is an important treatment modality in the management of breast cancer-related brain metastases (BrM). Recent research has found Trastuzumab emtansine (T-DM1) to be effective against Her2+ BrM. However, the risk of radionecrosis (RN) with T-DM1 in combination with SRS is unclear. The objective of this study was to investigate factors associated with RN post-SRS in patients with Her2+ BrM.Patients with Her2+ BrM treated with SRS at the Sunnybrook Odette Cancer Centre between 2010 and 2020 were retrospectively identified. The incidence of RN was determined on a lesion-by-lesion basis using serial brain imaging with or without histological confirmation. Clinical factors associated with RN, such as age, RT dose, lesion volume, intracranial location, total number of BrM, along with history of whole brain RT, and T-DM1 treatment were investigated with univariable and multivariable competing risks regression (MVR) using death from any cause as a competing risk factor. A P-value of < 0.05 in MVR following backward selection was considered statistically significant.67 patients with Her2+ BrM (223 lesions) treated with SRS were identified; among them, 21 (31.3%) were treated with T-DM1 post-SRS, including 14 (20.9%) who received T-DM1 within 12 months of SRS. The median follow-up was 15.6 (IQR 5.4-35.3) months. The 1-year, and 2-year risk of RN post-SRS was 6.7% (95% CI 2.7-10.7%), and 15.2% (95% CI 9.2-21.3%), respectively. MVR identified T-DM1 treatment post-SRS (HR 2.5, 95% CI 1.2-5.3, P = 0.02) and RT dose with a biologically effective dose (BED) > 50.4 Gy (HR 2.4, 95% CI 1.1-5.1, P = 0.02) as independent risk factors of RN. Patients treated with T-DM1 and SRS had a 25.2% (95% CI 12.8-37.6%) risk of RN at both 1- and 2-years post-T-DM1. The median time to RN after T-DM1 among the affected was 4.8 (95% CI: 3.8-25.6) months with 80% of all RN cases occurring within 12 months of T-DM1 treatment.This study demonstrates that T-DM1 exposure post-SRS was independently associated with a higher risk of RN in Her2+ BrM patients. The potential side effects of brain-penetrating agents post-SRS merit greater awareness.B. Id Said: None. H. Chen: None. K. Jerzak: Research Grant; Astra Zeneca, Eli Lilly. Consultant; Amgen, AstraZeneca, Apo Biologix, Eli Lilly, Esai, Genomic Health, Knight Therapeutics, Merck, Myriad Genetics Inc, Pfizer, Roche, Novartis, Purdue Pharma. S.D. Myrehaug: Advisory Board; Novartis AG.C. Tseng: Consultant; Sanofi. Travel Expenses; Elekta. Member; Elekta MR-LINAC.J. Detsky: None. Z.A. Husain: None. A. Sahgal: Research Grant; Elekta AB. Honoraria; Elekta AB, Varian, BrainLAB, Medtronic Kyphon. Consultant; Varian. Travel Expenses; Elekta AB, Varian. H. Soliman: None.

Genetic counseling student rotations in industry: How COVID‐19 magnified the urgency for virtual learning options in diverse training settings

The COVID‐19 pandemic created unprecedented challenges worldwide that required rapid adaptation and transformation across the entire healthcare system. Graduate medical training programs across all specialties have moved to rapidly adjust to the virtual landscape. This created a unique opportunity for genetic counselors who work in industry and within diagnostic laboratories to develop internship and rotation programs that can be offered virtually to meet the needs of genetic counseling training programs. Myriad Genetics, Inc., was contacted by numerous graduate programs in genetic counseling beginning in March 2020 requesting the opportunity for their students to participate in remote laboratory‐based rotations. As a result of these requests, a working group of genetic counselors across Myriad came together to adapt existing experiences to fully remote formats and develop new remote‐based opportunities for students. We describe our experience of expanding genetic counseling student rotations during the COVID‐19 pandemic with the goal of providing examples of remote learning experiences that may be applicable to other diagnostic laboratory industry‐based rotations for genetic counseling students. In 2020, a total of 59 second‐year genetic counseling students, from 21 different genetic counseling training programs, participated in one of five different virtual experiences. Furthermore, two new rotation experiences were created to increase capacity and highlight diversity of industry roles. Genetic counselors in industry are uniquely positioned to provide both remote training opportunities for genetic counseling students and exposure to the variety of roles that genetic counselors can occupy. Increasing the exposure to these roles is important as the genetic counseling workforce continues to expand and diversify, and it is imperative among all programs to enable access to these opportunities.

The Human Patent: What Intellectual Property Rights Does an Individual Have in Their Own Genetic Material, and What Are the Global Biosecurity Implications?

Abstract Under United States patent law, the landmark Supreme Court decision in Diamond v. Chakrabarty established the patentability of human-made life forms, except for those encompassing a human organism. The America Invents Act of 2011, and decisions from lower courts such as Moore v. Regents of University of California, reaffirm the unpatentability of human organisms and limit an individual’s rights to their own genetic material. Prior to Association for Molecular Pathology v. Myriad Genetics, Inc, which struck down the patentability of human genes as well, the decision in Diamond led to the proliferation of gene patents and the growth of the global biotechnology market. While the debate over the patenting of human genetic material, and individual rights, rages on, DNA-gathering companies such as 23andMe and Ancestry.com routinely utilize their customer’s genetic material for multi-million dollar pharmaceutical research. This research not only raises ethical concerns, but can also pose a potentially dangerous biosecurity threat based on the many ways this genetic material can be used to target individuals, groups, and nations.

Development of a Prognostic Model That Predicts 3- and 5-Year Overall Survival in Multiple Myeloma Using the Connect® MM Patient Registry

Introduction: Novel therapies have improved the median overall survival (OS) for newly diagnosed multiple myeloma (NDMM). In an unselected population of NDMM patients, the estimated rates of 5-year OS were 77%, 53%, and 19% for revised international staging system (R-ISS) Stage I, II, and III, respectively (Kastritis, 2017). However, the improvements have not been uniform, and prognosis varies considerably based on several baseline characteristics. Because of this clinical heterogeneity it is helpful to have a clear idea of risk factors involved in OS of patients with NDMM. Connect MM is the first and largest US-based, multicenter, prospective observational registry of patients with NDMM. Using data from the Connect MM registry, an unselected patient population reflective of the heterogeneity seen in routine clinical practice, we developed a prognostic tool to identify factors predictive of 3- and 5-year OS.Methods: The Connect MM registry is designed to describe baseline characteristics, patterns of care, and outcomes for NDMM in clinical practice. Patients were enrolled in Cohort 1 (n = 1493) between Sept 2009 and Dec 2011. Enrollment for Cohort 2 (n = 1518) began Dec 2012 and was completed April 2016. Data cut-off was July 7, 2016. Multivariate analyses of patient- and disease-related characteristics were conducted using Cohort 1 data to identify key predictors of OS. A series of univariate Cox regression models were used to identify variables significantly associated with 3-year and 5-year OS in patients ≤75 years and >75 years, as 75 years was determined to be the most discriminating age cut point, using Connect MM data, in identifying independent factors significantly associated with 3-year and 5-year OS. Prediction matrices for OS were constructed from the Cox model. Models were evaluated using the concordance (C)-index, a goodness of fitness measure. Internal validation of the logistic model in predicting the probability of survival was performed on data from Cohort 1. External validation of the model was performed on data from Cohort 2 and the Celgene-sponsored randomized phase III NDMM trials, MM-015 (N = 459) and FIRST (N = 1623).Results: Characteristics associated with late survival identified by multivariate analyses (P < 0.05) were: age, EQ-5D mobility, del(17p), ISS stage, platelet count, solitary plasmacytoma, Eastern Cooperative Oncology Group performance status, history of diabetes, creatinine category, and triplet therapy use (Figure). The C-index results were robust and consistent in the external validations: Connect MM Cohort 2 (C-statistic = 0.698), MM-015 (C-statistic = 0.649) and MM-020 (C-statistic = 0.647), thereby confirming model validity.Conclusions: This is the first assessment of long-term survival using data from the Connect MM patient registry. Our study highlighted factors known to impact OS, including, mobility, del(17p) and ISS stage. We have developed a model that allows for robust prediction of long-term survival in patients with NDMM based on a variety of baseline characteristics. For clinicians, identifying patients with an increased likelihood of longer survival may be a useful tool to identify patient specific risk factors to better inform treatment decisions. [Display omitted] DisclosuresTerebelo:Celgene: Consultancy; Janssen: Speakers Bureau; Takeda: Speakers Bureau; Pharmacyclics: Speakers Bureau. Abonour:Celgene: Other: Steering committee, Research Funding; Takeda: Other: Steering committee, Research Funding; Prothena: Research Funding. Gasparetto:Janssen, BMS, Celgene, Takeda: Honoraria; Janssen, BMS, Celgene: Other: Travel, accommodations, or other expenses paid or reimbursed; Celgene: Research Funding; Janssen, BMS, Celgene: Consultancy. Toomey:Celgene: Consultancy; Myriad Genetics: Speakers Bureau; Dava Oncology: Other: Travel. Durie:Takeda: Consultancy; Janssen: Consultancy. Hardin:Celgene: Consultancy. Jagannath:Celgene: Consultancy; Merck: Consultancy; Novartis: Consultancy; Bristol-Meyers Squibb: Consultancy; Medicom: Speakers Bureau; MMRF: Speakers Bureau. Wagner:EveryFit: Consultancy; Gilead: Consultancy; Janssen: Consultancy. Narang:Celgene: Consultancy, Speakers Bureau; Janssen: Speakers Bureau. Srinivasan:Celgene: Employment. Yue:Celgene: Employment. Zafar:Celgene: Employment. Kitali:Celgene: Employment. Agarwal:Celgene Corporation: Employment. Rifkin:Amgen: Consultancy; Boehringer Ingelheim: Consultancy; Celgene: Consultancy; EMD Serono: Consultancy; Sandoz: Consultancy; Takeda: Consultancy; McKesson: Other: Stock.

Baseline Disease Characteristics and Diagnostic Patterns for NDMM of the Connect® MM Registry: Observations over Time in Cohort 1 (2009-2011) and Cohort 2 (2012-2016)

Introduction: Patients with multiple myeloma (MM) experience clinical manifestations of hypercalcemia, renal insufficiency, anemia, or bone lesions. The National Comprehensive Cancer Network (NCCN) recommends specific testing as part of the initial workup of patients suspected of having MM. Connect MM is the first and largest US-based, multicenter, prospective observational registry of patients with newly diagnosed MM (NDMM). This registry includes patients with NDMM treated in community, academic, and government practices, thus allowing a reasonable generalizability to diagnostic patterns for the US. Previous work characterized baseline characteristics for patients enrolled in the first cohort of the registry (Rifkin, Clin Lymph Myeloma Leuk, 2014). The primary objectives of this analysis were to describe the baseline demographic and disease characteristics and to analyze the completion of diagnostic work-up of NDMM patients enrolled from 2009 to 2016.Methods: Connect MM (NCT01081028) was initiated in September 2009 at 250 community and academic sites. Patients were enrolled sequentially in 2 cohorts. Cohort 1 enrolled 1493 patients with NDMM from September 2009 to December 2011, and Cohort 2 enrolled 1518 patients with NDMM from December 2012 to April 2016. This current analysis was conducted in the populations of treated patients in Cohort 1 (n = 1450) and Cohort 2 (n = 1462). Baseline demographics and disease characteristics for Cohorts 1 and 2 individually were evaluated. The usage of NCCN-suggested diagnostic work-up as part of the initial diagnostic characterization of NDMM was also examined.Results: Across both cohorts, most patients (84%) were treated at community sites, with some in academic (15%) and government (1%) centers. The data cutoff date was April 2017. The median follow-up for Cohort 1 is 39.3 months and for Cohort 2 is 21.4 months. Baseline characteristics are listed in the Table. Cohorts 1 and 2 were similar in age (median 67 years), sex (57% male), and race (83% white). Patients with a documented history of MGUS, smoldering myeloma, or asymptomatic myeloma were uncommon (<10%) in both cohorts. Notably, ISS staging at baseline was reported for 59% and 51% of patients in Cohorts 1 and 2, respectively. The Figure lists the completed NCCN recommended diagnostic procedures. Significant differences were detected between the two cohorts in five assessments. The assessment of β2-microglobulin was reported for 74% (1070 of 1450) of patients in Cohort 1 compared with 66% (961 of 1462) in Cohort 2. Protein electrophoresis was assessed more frequently in Cohort 2 (99%; 1447 of 1462) vs Cohort 1 (78%; 1131 of 1450). Likewise, the serum free light chain ratio was assessed more frequently in Cohort 2 (72%; 1050 of 1462) than Cohort 1 (62%; 900 of 1450). Conventional cytogenetic analysis and FISH analysis were performed more frequently in Cohort 2 than in Cohort 1: 75% vs 64% and 77% vs 60%, respectively.Conclusions: This analysis outlines the diagnostic patterns from a real-world, multi-institutional registry of NDMM in the US. Results from this analysis indicate that the baseline demographics were largely unchanged from Cohort 1 and Cohort 2, which supports the pooling of data for future analyses. The multicenter nature of these data may better reflect clinical practice compared with single-center databases. The baseline testing of key factors required for accurate diagnosis and assessment, and adequate monitoring of patients with NDMM to guide therapy decisions is variable. Missing baseline diagnostic work-up assessments may impact ISS staging and risk stratification. Our findings suggest a better adherence to guidelines and adoption of diagnostic testing as standard of care over time. [Display omitted] DisclosuresNarang:Celgene: Consultancy, Speakers Bureau; Janssen: Speakers Bureau. Abonour:Takeda: Other: Steering committee, Research Funding; Prothena: Research Funding; Celgene: Other: Steering committee, Research Funding. Durie:Takeda: Consultancy; Janssen: Consultancy. Gasparetto:Janssen, BMS, Celgene, Takeda: Honoraria; Celgene: Research Funding; Janssen, BMS, Celgene: Consultancy; Janssen, BMS, Celgene: Other: Travel, accommodations, or other expenses paid or reimbursed. Toomey:Myriad Genetics: Speakers Bureau; Dava Oncology: Other: Travel; Celgene: Consultancy. Hardin:Celgene: Consultancy. Jagannath:Medicom: Speakers Bureau; Novartis: Consultancy; MMRF: Speakers Bureau; Celgene: Consultancy; Merck: Consultancy; Bristol-Meyers Squibb: Consultancy. Terebelo:Janssen: Speakers Bureau; Takeda: Speakers Bureau; Pharmacyclics: Speakers Bureau; Celgene: Consultancy. Wagner:EveryFit: Consultancy; Gilead: Consultancy; Janssen: Consultancy. Srinivasan:Celgene: Employment. Flick:Celgene: Employment. Zafar:Celgene Corporation: Employment. Kitali:Celgene: Employment. Agarwal:Celgene Corporation: Employment. Rifkin:Celgene: Consultancy; EMD Serono: Consultancy; Sandoz: Consultancy; Takeda: Consultancy; McKesson: Other: Stock; Boehringer Ingelheim: Consultancy; Amgen: Consultancy.

Development of a Predictive Model of Multiple Myeloma (MM) Patient (pt) Outcomes Based on Treatment Class Transitions Using the Connect® MMpatient Registry

Development of a Predictive Model of Multiple Myeloma (MM) Patient (pt) Outcomes Based on Treatment Class Transitions Using the Connect® MMpatient Registry

Differential Effect of t(11;14) Abnormality on Survival and Depth of Response in African American (AA) and Non-AA (NAA) Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) in the Connect® MM Registry

Differential Effect of t(11;14) Abnormality on Survival and Depth of Response in African American (AA) and Non-AA (NAA) Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) in the Connect® MM Registry

Neoadjuvant talazoparib (TALA) in patients (pts) with germline BRCA1/2 (gBRCA1/2) mutation-positive, early HER2-negative breast cancer (BC): Exploration of tumor BRCA mutational status and zygosity and overall mutational landscape in a phase 2 study.

554 Background: TALA is a poly(ADP-ribose) polymerase inhibitor approved as monotherapy for adult pts with g BRCA1/2-mutated HER2-negative locally advanced/metastatic BC. We report biomarker analyses from a phase 2, nonrandomized, single-arm, open-label study (NEOTALA; NCT03499353) evaluating the efficacy and safety of TALA in the neoadjuvant setting for pts with early g BRCA1/2-mutated HER2− BC. Efficacy and safety results are presented separately. Methods: The biomarker analysis population was all pts treated with TALA for whom biomarker results are available. To support molecular eligibility, blood was tested using BRCAnalysis CDx (Myriad Genetics). Baseline tumor tissue was retrospectively tested using FoundationOne CDx, with BRCA1/2 zygosity assessed using somatic-germline-zygosity (SGZ; Sun et al. JCO PO, 2018). Germline mutational status of 14 non- BRCA DNA damage response (DDR) genes was retrospectively assessed in baseline saliva samples using Ambry CustomNext-Cancer. Mutations were defined as known/likely pathogenic/deleterious variants, including copy number alterations (CNAs). Association between mutational status of MYC or RAD21 and primary endpoint pathological complete response (pCR) as per Independent Central Review was investigated with logistic regression. Results: Of 52 evaluable tumor samples from 61 treated pts, 39 (75%) and 13 (25%) pts exhibited BRCA1 and BRCA2 mutations, respectively; 1 (2%) pt exhibited mutations in both genes, and 1 (2%) pt had mutations in neither. BRCA loss of heterozygosity (LOH) was seen in 42/43 (98%) evaluable BRCA-mutant tumors. Of 45 pts evaluable centrally for both germline and tumor, 44/45 (98%) pts exhibited the same BRCA mutation in tumor as originally detected in germline, with the remaining pt exhibiting a g BRCA1 mutation, but lacking a tumor BRCA mutation. None of 49 saliva-evaluable pts exhibited non- BRCA germline DDR mutations. TP53 (51 [98%] pts) was the most frequently mutated gene in tumors. MYC and RAD21 (each 14 [27%] pts) were the most frequent CNAs. No evidence of association between mutational status of MYC or RAD21 and pCR was found (odds ratio=0.39, 95% CI 0.12-2.30). Based on a cutoff of ≥16%, genomic LOH was elevated in 24/27 (89%) tumors evaluable for both gLOH and pCR, precluding assessment of the potential association of gLOH high/low status with pCR. Conclusions: Tumor BRCA mutations were evident in nearly all pts in the biomarker analysis population, with BRCA LOH evident in all but 1 BRCA-mutated tumor. No pts had non- BRCA germline DDR gene mutations; tumor TP53 mutations were near-universal. MYC and RAD21 each exhibited CNAs in 27% of tumors, with no association with pCR. These results support the central role of BRCA mutations in tumor pathobiology in this indication. Clinical trial information: NCT03499353.

Maintenance vigil immunotherapy in newly diagnosed advanced ovarian cancer: Efficacy assessment of homologous recombination proficient (HRP) patients in the phase IIb VITAL trial.

5502 Background: In the VITAL (NCT02346747) trial, maintenance therapy with Vigil, an autologous tumor cell vaccine transfected with a DNA plasmid encoding GMCSF and bi-shRNA-furin for TGFβ expression control, following frontline platinum-based chemotherapy led to a recurrence-free survival (RFS) benefit in patients with advanced high-grade ovarian cancer (HR=0.69, 90% CI 0.44–1.07, p=0.078) and significantly in BRCA-wt patients (HR=0.51, 90% CI 0.30-0.88, p=0.020) ( Rocconi et al. Lancet Oncol. 2020). Here we report post-hoc HR deficiency (HRD) subgroup analysis and identification of an additional molecular subgroup sensitive to Vigil therapy involving STRING analysis. Methods: This double-blind, placebo-controlled, Phase 2b study randomized 92 patients with newly diagnosed stage III/IV ovarian cancer with a complete clinical response (CR) to frontline surgery and chemotherapy. Patients received 1 x 10e7 cells/ml of Vigil or placebo intradermally once a month for up to 12 doses or disease progression. RFS was the primary endpoint assessed by blinded independent central review. HRD status was determined according to the Myriad Genetics myChoice CDx assay (HRD score &lt; 42 for proficient). Using tumor annotated DNA polymorphism data, a protein-protein interaction network was constructed using the STRING database. Properties of this network including topological distance and the identification of hub genes were used to predict a target molecular population sensitive to Vigil. Results: In the per-protocol population (PP, n=91), 62 BRCA-wt patients were tested for HRD status. Forty-five patients were HR proficient (HRP) and 17 patients were HR deficient (HRD). No HRP patients in the Vigil group reported treatment related Grade 3 or higher adverse events. From the time of study randomization median RFS was improved with Vigil (n=25) in HRP patients compared to placebo (n=20) (Table 1). Similarly, overall survival (OS) benefit was observed in the Vigil group compared to placebo (Table 1). Improved RFS was demonstrated for a subset of patients with STRING predicted molecular profile. Conclusions: Vigil immunotherapy as frontline maintenance in Stage III/IV ovarian cancer is well tolerated and showed clinical benefit in both BRCA-wt and HRP molecular profile patients. Results suggest a unique molecular network that enhances sensitivity to Vigil therapy. Clinical trial information: NCT02346747. [Table: see text]

Gemogenovatucel-T (Vigil) immunotherapy demonstrates clinical benefit in homologous recombination proficient (HRP) ovarian cancer

ObjectiveRecently, Vigil showed significant clinical benefit with improvement in relapse free (RFS) and overall survival (OS) in pre-planned subgroup analysis in stage III/IV newly diagnosed ovarian cancer patients with BRCA wild type (BRCA-wt) molecular profile. Here we analyze homologous recombination (HR) status of patients enrolled in the Phase 2b VITAL study and determine clinical benefit of Vigil in HR proficient (P) patients. MethodsPatients were previously enrolled in a Phase 2b, double-blind, placebo-controlled trial. All were in complete response with Stage III/IV high grade serious, endometroid or clear cell ovarian cancer. HR status was determined using MyChoice®CDx score (<42 = HRP) (Myriad Genetics, Inc., UT). Post-hoc analyses were carried out using Kaplan Meier and restricted mean survival time (RMST) analysis to evaluate RFS and OS based on HR deficiency (D) status. ResultsRFS was improved with Vigil (n = 25) in HRP patients compared to placebo (n = 20) (HR = 0.386; 90% CI 0.199–0.750; p = 0.007), results were verified by RMST (p = 0.017). Similarly, OS benefit was observed in Vigil group compared to placebo (HR = 0.342; 90% CI 0.141–0.832; p = 0.019). Results with OS were also verified with RMST (p = 0.008). ConclusionVigil exhibited clinical benefit in HRP molecular profile patients.

Local Laboratory Testing of Germline BRCA Mutations vs. Myriad: A Single-Institution Experience in Korea.

Genetic diagnosis for human epidermal growth factor receptor 2-negative metastatic breast cancer patients with the germline BRCA (gBRCA) mutation has been emphasized since the development of polyadenosine diphosphate-ribose polymerase inhibitors. Myriad Genetics, Inc.’s (Salt Lake City, UT, USA) companion diagnostics service is almost exclusively used for genetic testing. The aim of this study was to compare the results of germline BRCA mutation tests returned by a local laboratory and those performed by Myriad. Between April 2014 and February 2018, 31 patients with gBRCA 1/2 mutation test results from both Samsung Medical Center (Seoul, Korea) and Myriad were enrolled. “Discordant: Opposite classification” was observed for only one among 27 (3.7%). This discrepancy was due to the detection of a deleterious large genomic rearrangement of BRCA 1 by Myriad. Samsung Medical Center performed multiple ligation-dependent probe amplifications (MLPA) to detect large genomic rearrangements only in high-risk patients. This one case was not suspected as high risk and MLPA was not performed. The concordant rate was 74.1% for all 27 patients. “Discordant: Laboratory’s uncertain classification” was found in 22.2% of the sample (six patients). All discrepancies were generated during interpretation of BRCA 2 gene sequencing. Further studies and standardization of genetic testing for BRCA 1/2 genes are required.

Cell cycle progression score and PTEN as prognostic factors for metastasis in intermediate- and high-risk prostate cancer overall, and in those who also received salvage radiotherapy.

247 Background: The cell cycle progression (CCP) score and PTEN have never been evaluated together as prognostic markers for risk of metastasis in a radical prostatectomy (RP) cohort of men with National Comprehensive Cancer Network intermediate- and high-risk prostate cancer (PCa), nor in such patients who also received salvage radiation (SRT) alone or with androgen deprivation (SRT+ADT). This study evaluated CCP score and PTEN in both settings. Methods: Participants were treated with RP at Johns Hopkins from 2007-2015. Paraffin-embedded RP tissue was analyzed blind to clinical outcome at Myriad Genetics, for CCP score using qRT-PCR, and PTEN by immunohistochemistry. For overall evaluation of CCP and PTEN in intermediate- and high-risk men a case-cohort sample was selected. Intermediate- and high-risk men with biochemical recurrence who received SRT or SRT+ADT were also sampled to provide a population at particularly high risk. Metastasis-free survival (MFS) was analyzed with the proportional hazards model, weighted for case-cohort design for the overall analysis, and adjusted for CAPRA-S. The clinical cell-cycle risk (CCR) score, a fixed algorithm combining CCP and CAPRA-S was also analyzed in both contexts. Data were analyzed independently by Johns Hopkins and Myriad Genetics. Results: The case-cohort consisted of 209 men, including 47% with Gleason score &gt;4+3, 48% extra-prostatic extension, and 18% with seminal vesicle or lymph node involvement; 42 (20%) developed metastasis. In univariate analyses CCP, CAPRA-S, and PTEN were all highly significant. In multivariable analysis, only CCP and CAPRA-S retained significance (Table section A). CCR was also strongly prognostic, HR=7.9 (95% CI 4.4, 14.5) per unit change, p&lt;0.00001. SRT (56%) or SRT+ADT (44%) were received by 172 men, of whom 78% had Gleason &gt;4+3, 48% extra-prostatic extension, and 34% seminal vesicle or lymph node involvement; 19 (11%) developed metastases. Again, CCP and CAPRA-S, but not PTEN, were statistically significant (Table section B). CCR was also statistically significant, HR=1.7 (95% CI 1.2, 2.4), p=0.002. Conclusions: This is the first comparison, in a recent cohort of intermediate- and high-risk men, of CCP score and PTEN as risk factors for metastasis, and first evaluation in such men receiving SRT. In both multivariable settings, CCP score, but not PTEN, was significantly associated with MFS, adjusted for CAPRA-S. CCR, a fixed algorithm that combines CCP and CAPRA-S was also significant in both settings. [Table: see text]

Abstract PD10-01: Trends in genetic testing and results for women diagnosed with breast cancer or ovarian cancer, 2013-2017

Abstract Background: Genetic testing is increasingly important for breast and ovarian cancer risk reduction and treatment. However, little is known about trends and disparities in receipt of testing in the community and test results after diagnosis. Methods: We linked records of all women with breast cancer or ovarian cancer diagnosed from 2013-2017 in Georgia and California and reported to Surveillance, Epidemiology and End Results (SEER) registries to genetic testing results from four laboratories that did most clinical testing in the studied regions (Ambry Genetics, GeneDx, Invitae, Myriad Genetics). We combined test results performed by all laboratories over 2012-2019 with SEER data. We measured use of any test, median number of genes tested, rates of variants of uncertain significance (VUS) and pathogenic variants (PVs). Results: A total of 25.2% of 187,535 breast cancer patients, and 34.3% of 14,689 ovarian cancer patients, had genetic testing. Testing increased annually by 2% while the median number of genes tested increased annually by 28%. Among tested patients diagnosed with breast cancer in 2017, 5.2% had BRCA1/2 PVs while 4.9% had PVs in genes associated with a recognized cancer syndrome (APC, CDH1, MLH1, MSH2, MSH6, NF1, PMS2, PTEN, RET and TP53) or with emerging evidence for an increased risk of breast cancer and/or ovarian cancer (ATM, BARD1, BRIP1, CHEK2, NBN, PALB2, RAD51C and RAD51D). Among tested patients diagnosed with ovarian cancer in 2017, 11.0% had BRCA1/2 PVs while 2.3% had PVs in a syndromic gene (APC, MLH1, MSH2, MSH6, NF1, PMS2, and TP53) or an emerging breast/ovarian cancer gene (ATM, BARD1, BRIP1, CHEK2, NBN, PALB2, RAD51C and RAD51D). PVs in other tested genes were rare (generally &amp;lt;1%). VUS rates increased from patients diagnosed in 2013 (11.2% breast, 11.2% ovarian) to 2017 (26.4% breast, 26.8% ovarian) and were higher in racial/ethnic minorities (47.8% Asian, 46.0% Black, 40% Hispanic versus 24.6% non-Hispanic Whites diagnosed with ovarian cancer in 2017; p&amp;lt;.001). Conclusions: A substantial gap persists in testing ovarian cancer patients (34.5% versus nearly 100% recommended) while testing more genes was associated with a substantial racial/ethnic gap in VUS. Most clinically relevant PVs occurred in the 17 genes (ovarian cancer patients) to 20 genes (breast cancer patients) reported above; testing only these genes may optimize the clinically salient PV-to-VUS ratio, particularly for racial/ethnic minorities. Citation Format: Allison W Kurian, Monica Morrow, Steven Katz. Trends in genetic testing and results for women diagnosed with breast cancer or ovarian cancer, 2013-2017 [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-01.

Abstract GS3-05: Classification of triple negative breast cancer (TNBC) by DNA damage immune response (DDIR) signature and homologous recombination deficiency (HRD) status: Analysis of SWOG S9313 adjuvant trial

Abstract Introduction/Aims: DDIR signature, HRD, and stromal tumor infiltrating lymphocytes (sTIL) have each been associated with favorable outcomes in early stage TNBC. We assessed the overlap between these markers and created prognostic categories based on their combined use in a prospective trial of TNBC patients uniformly treated with adjuvant doxorubicin (A) and cyclophosphamide (C) on the SWOG S9313 trial. Methods: SWOG S9313 trial accrued 3,125 women with early stage breast cancer to two alternative dose schedules of AC, with no difference in outcomes between the two arms. 425 centrally determined TNBC cases from S9313 were identified. DDIR signature (score ≥ 0.3681 = DDIR+, Almac Diagnostic Services), HRD status (score ≥ 42 = HRD+, Myriad Genetics), and sTIL were assessed. Gene expression data (Xcel™ array) was subjected to claraT V3.0.0 biological signature analysis (Almac Diagnostic Services), and co-expression cluster analysis was used to identify signatures associated with DDIR and HRD status. The impact of dual classification by DDIR and HRD status (Group 1: DDIR+/HRD+, Group 2: DDIR+/HRD-, Group 3: DDIR-/HRD+, Group 4: DDIR-/HRD-) on disease free survival (DFS) and overall survival (OS) was examined using Cox regression with adjustment for randomized treatment assignment and nodal status. Results: For the 425 patients, median age was 45 years, 33% were node-positive, and 5-year DFS and OS were 74% and 82%, respectively. DDIR and HRD status was available for 89% each, sTIL% was available for 99%, and all three markers were available for 77% (328/425) of patients. 60% were DDIR+ and 65% HRD+. Among DDIR- tumors, 58% were HRD+. sTIL% was associated with DDIR status (P&amp;lt;0.0001) but not with HRD status (P=0.75). The proportion of patients in each group, median sTIL%, and 5-year DFS and OS for each group are outlined in Table 1. DFS and OS were similar for Groups 1, 2, and 3 but significantly lower for Group 4. As expected, cluster analysis showed that immune response signatures dominated Groups 1 and 2 regardless of HRD status. Group 3 tumors were characterized by over-representation of genomic instability signatures, a paucity of immune-related signatures, and low sTIL infiltration. Despite this immune-depleted phenotype, the 5-year OS for Group 3 was similar to that of the immune-enriched DDIR+ groups. Signatures associated with epithelial-mesenchymal transition, mast cell infiltration, and xenobiotic metabolism were over-represented in Group 4. Conclusions: Forty percent of patients with early stage TNBC demonstrate immune-deplete (DDIR-) phenotype, and within this phenotype, more than half demonstrate HRD+ status. HRD+ status within the immune-deplete phenotype predicts for better DFS and OS with adjuvant AC, probably due to underlying genomic instability and increased sensitivity to DNA damaging chemotherapy. Sixty percent of early stage TNBC patients demonstrate an immune-enriched (DDIR+) phenotype, and this phenotype is associated with improved survival with adjuvant AC chemotherapy regardless of HRD status. These findings provide important insights for patient selection and stratification in ongoing and future trials assessing DNA damaging therapy (e.g. PARPi, anthracyclines, platinum agents), immunotherapy, and their combinations in TNBC. Table 1Immune-Enriched GroupsImmune-Deplete GroupsGroup 1 DDIR+/HRD+ N=137 (42%)Group 2 DDIR+/HRD- N=59 (18%)Group 3 DDIR-/HRD+ N=77 (23%)Group 4 DDIR-/HRD- N=55 (17%)5-year DFS82%74%74%56%P=0.001 (Group 1 vs 4); P=0.006 (Group 2 vs 4); P=0.016 (Group 3 vs 4); P=NS (Groups 1 vs 2, 1 vs 3, and 2 vs 3)5-year OS88%86%83%69%P=0.001 (Group 1 vs 4); P=0.003 (Group 2 vs 4); P=0.026 (Group 3 vs 4); P=NS (Group 1 vs 2, 1 vs 3, and 2 vs 3)Median sTIL (%)20%20%5%5%P&amp;lt;0.0001 (Group 1 vs 3); P&amp;lt;0.0001 (Group 2 vs 3); P=NS (Group 1 vs 2, 3 vs 4) Citation Format: Shane R Stecklein, William Barlow, Lajos Pusztai, Kirsten Timms, Richard Kennedy, Sunil Badve, Yesim Gökmen-Polar, Peggy Porter, Hannah Linden, Debu Tripathy, Gabriel N Hortobagyi, Andrew K Godwin, Alastair Thompson, Daniel Hayes, Priyanka Sharma. Classification of triple negative breast cancer (TNBC) by DNA damage immune response (DDIR) signature and homologous recombination deficiency (HRD) status: Analysis of SWOG S9313 adjuvant trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS3-05.