bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rates of potentially actionable germline variants in homologous recombination repair genes in a large international cohort outside of the United States.
Authors: Nielsen Sarah M. , Heald Brandie , Ngeow Joanne YY , Chavarri Guerra Yanin , Russell Emily M. , Esplin Edward D. , Pineda Alvarez Daniel Esteban 
Published: June 2023

10590 Background: Identification of pathogenic germline variants (PGVs) in homologous recombination repair (HRR) genes among patients (pts) with breast (BC), ovarian (OC), pancreatic (PaC), and prostate cancer (PrC) is critical to determine potential eligibility for targeted therapies such as PARP inhibitors (PARPi). It is important to evaluate the frequency and patterns of PGVs across different regions of the World to help inform the counseling of pts and implementation of precision medicine. Methods: A retrospective analysis of pts with BC, OC, PaC, and/or PrC cancer undergoing GGT through a single laboratory was conducted. The location of the ordering provider determined the assigned region, which included: Asia-Pacific (APAC), Latin America (LATAM), Middle East and African (MEA), and United Kingdom and Europe (UKEU). Analyses were limited to pts tested for PARPi-eligible (in the US) HRR genes and PGV analysis to the 10 most frequent genes for that cancer type. Descriptive statistics and Chi square with Yates correction were utilized. Significance was set at p<0.05. Results: The cohort consisted of 40,539 pts with an average age at testing of 51 years, the majority of whom had BC (81%) (Table). The median number of genes tested ranged from 14-85 (Table). BRCA1 and BRCA2 were the most frequent genes with PGVs (3,358 pts, 8%). LATAM BC pts had significantly higher rates of BRCA1/2 PGVs (10%) than the other 3 regions ( p <0.0007). OC BRCA1/2 rates were high, and statistically similar, across regions (15-17%, p>0.08). Rates of BRCA1/2 and PALB2 in PaC pts did not differ between regions (4-7%, p>0.08), nor did rates of BRCA1/2, CHEK2, ATM, and PALB2 in PrC pts (7-11%, p>0.16) (Table). In sum, 3,434 pts (9% of those tested for the eligible genes) had PGVs in the above PARPi-eligible HRR genes. A notable limitation is that pts were ascertained by cancer type but information on other PARPi eligibility, namely metastatic/advanced disease, was not available. Conclusions: 1 in 12 pts were found to carry PARPi-eligible PGVs across the 4 cancer types and regions analyzed. Knowledge of these PGVs can help inform public health policies, current and future treatment strategies, and identify at-risk family members. In some countries, GGT may represent a more cost-effective and accessible pathway to targeted therapies compared to tumor profiling due to ease of sample collection and lower cost of testing. [Table: see text]
A pan-cancer statistical study of microsatellite instability and Lynch syndrome–associated mismatch repair genes germline mutations.
Authors: Cao Huiya , Peisu Suo , Zhang Weishuang , Fang Guizhen , Li Yingmei , Chen Shifu , Chunze Zhang 
Published: June 2023

10593 Background: Lynch Syndrome (LS), known as hereditary nonpolyposis colorectal cancer (HNPCC1), is caused by germline mutations in the mismatch repair (MMR) genes ( MLH1, MSH2, PMS2, MSH6), or epigenetic silencing of MSH2 which caused by deletion of 3-prime exons of the EPCAM gene and intergenic regions directly upstream of the MSH2 gene. DNA mismatches commonly occur in regions of repetitive nucleotide sequences called microsatellites, and the status of microsatellite instability (MSI) is the key feature in LS-associated cancers. Although there are sporadic reports of MSI and LS in certain cohorts, the real-world status of MSI in large pan-cancer cohort remains to be analyzed. Methods: We retrospectively reviewed all 18189 solid tumor patients from August 1, 2020 to February 5, 2023 from HaploX Genomic Sequencing Center and analyzed their germline mutations in MMR genes ( MLH1,MSH2,PMS2,MSH6 and EPCAM). MSI status was determined using Sanger sequencing or Next-generation sequencing, with tumor MSI status classified as microsatellite instability-high (MSI-H), or microsatellite-stable (MSS). Results: LS-associated germline mutations were detected in 0.313% (n = 57) of patients, and75.4% (n = 43) of patients were identified as MSI-H, and 24.6% (n = 14) of patients were MSS. The patients were grouped into CRC/EC group (colorectal cancer and endometrial cancer) and non-CRC/EC (lung cancer, central nervous system tumor, gastric cancer, esophageal cancer, hepatological cancer, pancreatic adenocarcinoma, small bowel carcinoma, kidney cancer, etc.). Among MSI-H patients, the CRC/EC group accounted for 90.7% (n = 39) and the non-CRC/EC group accounted for 9.3% (n = 4). In MSS patients, the CRC/EC patients accounted for 35.7% (n = 5), and the non-CRC/EC patients accounted for 60% (n = 9). Among patients with MSS, the most frequently mutated gene was MSH6 (n = 9): MSH6 (NM_000179) c.3261dup (p.F1088Lfs*5) mutation was detected in 4 patients, of which 2 patients were paternal and both were diagnosed as colorectal cancer; MSH6 c.718C > T (p.R240*) mutation was detected in 2 patients with available MMR IHC results, and one of them was MSH6 negative in IHC staining. Conclusions: Traditionally, a family history of colorectal cancer or endometrial cancers was the primary clinical feature to diagnose Lynch syndrome. Once it was recognized that Lynch-associated CRCs were microsatellite unstable, tumor testing became an additional tool for identification of Lynch syndrome. Some previous studies also reported Lynch syndrome mutations, primarily MSH6 and PMS2, were present in a few MSS patients. Thus, MSI status or family history as diagnostic factor alone may result in Lynch syndrome under-recognized, and additional NGS test on MMR genes should facilitate more accurate diagnosis.
Hereditary breast and ovarian cancer syndrome: A misnomer?
Authors: Weiss Jessica M. , Ahsan Muhammad Danyal , Webster Emily M. , Levi Sarah R. , Qazi Murtaza , Harvey Benedict , Cantillo Evelyn , Holcomb Kevin , Chapman-Davis Eloise , Sharaf Ravi N. , Frey Melissa Kristen 
Published: June 2023

10594 Background: Germline pathogenic gene variants (PGV) in homologous recombination deficiency (HRD) genes are traditionally associated with breast, ovarian, pancreatic, prostate and melanoma skin cancer. Recent evidence suggests other cancers may also be associated with these genes. We analyzed the prevalence of somatic HRD mutations in common, traditionally non-hereditary breast and ovarian cancer (HBOC) associated incident cancers in the US. Methods: Data were collected from the American Association for Cancer Research’s (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database version 13.0 via cBioPortal (http://genie.cbioportal.org). This is a publicly available, multi-institutional database of next-generation sequencing (NGS) genomic profiles of tumor samples. The database was queried for all cancers with at least 20,000 incident cases in 2022, as reported by the American Cancer Society, excluding well established HBOC associated cancers – breast, ovarian, prostate, pancreatic, melanoma. Frequencies of somatic PGVs were reported for nine HRD genes currently included in National Comprehensive Cancer Network (NCCN) management guidelines for HBOC: ATM , BARD1, BRCA1, BRCA2, BRIP1, CHEK2, PALB2, RAD51C and RAD51D. Results: A total of 78,285 tumor samples across 12 cancer types were included. At least 1 somatic HRD was found in 6.8% of all included tumors. At least 1 HRD PGV was most common in: Uterine Cancer (694/5,760, 12.1%), Non-Melanoma Skin Cancer (127/1,209, 10.5%), Bladder Cancer (462/4,605, 10.0%), Colorectal Cancer (1306/14,625, 8.9%) Non-Hodgkin’s Lymphoma (5/58, 8.6%), Esophagogastric Cancer (356/4,649, 7.7%), Hepatobiliary Cancer (219/3,325, 6.6%), Lung Cancer (1,480/23,621, 6.3%), Kidney Cancer (113/2,564, 4.4%), Brain Cancer (420/10,206, 4.1%), Thyroid Cancer (89/2,246, 4.0%) and Leukemia (80/5,417, 1.5%). The most common PGVs across all cancer types were BRCA1/2 and ATM (Table). Conclusions: A pan-cancer analysis using NGS data demonstrates a substantial rate of somatic HRD PGVs in common, traditionally non-HBOC associated cancers in the US. These data raise the possibility that germline pathogenic variants in HRD genes could be associated with several more cancers than currently known, underscoring the need for studies evaluating risks of the aforementioned cancers in germline PGV carriers. Additionally, these findings present opportunities for trials evaluating the efficacy of HRD-targeting therapies in these cancers. [Table: see text]
A randomized controlled trial evaluating pretest cancer genetics educational video or in-person genetic counseling.
Authors: Chavarri Guerra Yanin , Morales Alfaro Andrea , Alcacio Vzquez Cesar , Carrillo Bedoya Araceli , Arteaga Jazmin , Peñafort Zamora Jose Carlos , Sánchez-Román Sofía , Ramirez Maza Daniela , Villarreal-Garza Cynthia , Reynoso Nancy , Mohar Alejandro , Calva Mercado Juan Jose 
Published: June 2023

10597 Background: Cancer genetic testing indications are rapidly expanding to determine treatment eligibility for patients with cancer, to identify individual cancer risk as well as to select family members at higher cancer risk when a pathogenic variant (PV) has been identified in the family. Currently, international guidelines recommend that all candidates for genetic testing should have genetic counseling to make an informed decision for genetic testing. However, with the increased demand for genetic testing, innovative ways to deliver pretest information are needed, especially in limited resource settings, where genetic cancer professionals’ availability is scarce. Methods: This is a non-inferiority trial comparing a pretest educational video to in-person genetic counseling. Participants referred for genetic cancer risk assessment at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán in Mexico City were enrolled if they met international cancer genetic testing criteria and did not previously have genetic testing and/or counseling. The primary outcome was the uptake of genetic testing. Secondary outcomes included changes in genetic cancer knowledge, anxiety, and satisfaction using validated tools. Results: A total of 250 participants were included: 124 were randomized to the in-person genetic counseling arm and 126 to the educational video arm. Mean age was 47.9 years (SD 12.7), 86.4% were women, 37.2% had high-school or less and 86.4% had personal history of cancer (70% breast cancer). Overall, test acceptance was 100% in both arms. Cancer genetics knowledge improved in both groups: in-person from. 53 to .74 (diff .20; 95%CI .24-.26; p < 0.05) and video from .51 to .68 (diff .16; 95%CI .20-.12; p < 0.05). However, the in-person arm had a higher post counseling knowledge score (p 0.001). 43.5% and 42% of participants in the in-person and video arms had moderate-severe baseline anxiety. After intervention, both groups had a decrease in anxiety score: in-person from 5.2 to 4.7 (diff .58; 95% CI .09-1.08; p 0.01) and video from 4.9 to 4.1 (diff .75; 95%CI 0.42-1.08; p < 0.05). Both groups were satisfied with genetic services (97.5% and 92.5%, respectively; p 0.34). Conclusions: A pretest educational video was non-inferior regarding genetic testing acceptance. It was also associated with improved genetic cancer knowledge and decreased anxiety levels. These results support the use of educational videos before genetic testing where in-person genetic counseling availability is limited. Clinical trial information: pending .
A comprehensive analysis of clinical characterization in 149 Chinese patients with Lynch syndrome.
Authors: Lin Junqiong , Kong Rongrong , Han Tiantian , Guo Didi , Dong Yuwei , Chen Siqi , Chen Yang , Deng Wanglong , Ding Ran , Bu Fanfeng , Wang Mengjuan 
Published: June 2023

10606 Background: Lynch syndrome (LS) caused by germline pathogenic variants (PVs) in mismatch repair (MMR) genes, which increased risk of malignancy in different organs. LS-related tumors included colorectal, endometrial, gastric, ovarian, pancreas, urinary system, biliary tract, central nervous system, skin and small intestinal carcinomas (CRC, EC, GC, OC, PC, UST, BTC, CNST, SC, SIC). As sequencing technology becomes more economical and widespread, more MMR PVs were detected in LS-unrelated tumors. The aim of this study was to explore the clinical characterization in Chinese real-world LS solid tumor. Methods: We applied next-generation sequencing (NGS) screening to detect the germline mutation in MMR (include MLH1, MSH2, MSH6, PMS2), tumor mutation burden (TMB) and microsatellite instability (MSI) in Chinese solid tumor patients (pts). In the cohort, lung cancer (LC) was the most common cancer type, followed by CNST, CRC, hepatic carcinoma (HC). Results: 149 LS pts were observed in our cohort, among which 81.2% (121/149) carried LS-related tumors (44 CRC, 47 CNST, 9 EC, 9 BTC, 4 UST, 3 OC, 2 GC, 2 SC, 1 SIC), 18.8% (28/149) carried with LS-unrelated tumors(18 LC, 5 HC, 3 sarcoma, 1 ampullary carcinoma, 1 peritoneal cancer), and the age showed no significant difference between LS-related tumors and LS-unrelated tumors (average age: 48 vs 53, p=0.08). The distribution of MMR PVs were as follows: MLH1 (37, 24.8%), MSH2 (46, 30.9%), MSH6 (34, 22.8%), PMS2 (32, 21.5% ), and comparative analysis showed that LS-related tumors tended to carry MLH1 and MSH2 PVs (60.3%, 73/121), while LS-unrelated tumors tended to carry MSH6 and PMS2 PVs (67.9%, 19/28) ( p<0.05). 46.3% LS pts had MSI-H, concentrated in MLH1 or MSH2 PVs carriers. MSI-H showed a higher detection rate in LS-related tumors other than LS-unrelated tumors(56.1% vs 3.6%, p<0.005). Among LS-related tumors, the top 3 prevalence of MSI-H were CRC (93.2%, 41/44), BTC (55.6%, 5/9) and EC (44.4%, 4/9), which were lower in CNST (31.9%, 15/47). In addition, we found that the rate of TMB-H in LS-related tumors was also higher than LS-unrelated tumors ( p<0.001). Conclusions: In our dates, 18.8%(28/149) LS pts carried with LS-unrelated tumors, which emphasized the importance of germline genetic assessment for LS in pan-cancer. In addition, MSI-H, TMB-H and MMR PVs distributions were significantly different in LS-related tumors and LS-unrelated tumors. The differences about LS clinical characterization associated with MMR genes require further study.
Somatic profiling guides germline genetic testing in patients with mutations in cancer predisposition genes.
Authors: Darabi Sourat , Homer Jeanne , Weatherill Chelsey , Zuazo Carlos E , Dalili-Shoaie Valentina , Demeure Michael J. , Braxton David R. 
Published: June 2023

10608 Background: 15% of patients with advanced cancer have an inherited predisposition to cancer. Over a third of patients carrying a pathogenic germline variant would not qualify for genetic testing based on current National Comprehensive Cancer Network genetic testing guidelines. Supplementing the current practice of somatic sequencing with germline testing would improve treatment decisions and be informative of the risk of developing subsequent cancers in the individual. It may also extend the benefits of high-risk screening programs to family members. Offering genetic testing to patients with the highest likelihood of carrying a germline mutation is preferable to unselected sequencing given the current environment. Methods: We developed a list of genes to help identify patients whose somatic mutations were more likely to be found in the germline as well. We classified these genes into 3 tiers based on the likelihood of germline pathogenicity. All somatic sequencing panel results were reviewed based on the IRB-approved protocol for our designated Tier One genes ( ATM, BAP1, BMPR1A, BRCA1, BRCA2, BRIP1, MSH2, MSH6, MUTYH, MYH11, PALB2, RUNX1, SDHAF2, SDHB, SDHC, and known founder mutations in additional genes). Treating physicians for patients whose tumors harbored a mutation in one of these genes were contacted and, if they agreed, patients were offered participation in this ongoing study. Enrolled patients had genetic counseling and testing for a multi-gene panel at no cost to them. Results: We reviewed 3621 somatic test results, and 339 (9.4%) patients were eligible for the study. 34 (10.03%) eligible patients were enrolled, and 33 (9.73%) completed testing. Of these, 16 had positive germline results (48.5%, though they may not all be in the originally identified genes), 8 had a variant of uncertain significance (24.2%), and 9 had negative testing (27.3%). Some patients were not referred by their treating physicians based on their own clinical assessment. Others were hesitant to enroll due to concerns about the privacy of genetic information. Other confounding factors may have affected our accrual, including the pandemic. Conclusions: Implementing a somatic profiling-based screening program to identify inherited cancer predisposition syndromes is feasible in patients who may not meet current germline genetic testing guidelines. Our study showed 9.73% of eligible patients underwent genetic counseling and testing, and an inherited predisposition to cancer was confirmed in almost 50% of these patients. In addition, family members were offered cascade testing. Germline genetic evaluation remains underutilized even when payor constraints are removed as a barrier. To increase the identification of patients with inherited predispositions to cancer other barriers such as a lack of referrals by treating oncologists need to be overcome.
Interim analyses (IA) of the giredestrant (G), G + abemaciclib (A), and G + ribociclib (R) arms in MORPHEUS Breast Cancer (BC): A phase I/II study of G treatment (tx) combinations in patients (pts) with estrogen receptor-positive, HER2-negative locally advanced/metastatic BC (ER+, HER2– LA/mBC).
Authors: Oliveira Mafalda , Sonnenblick Amir , Rugo Hope S. , Jung Kyung Hae , Yam Einav Gal , Hurvitz Sara A. , Hernando Cristina , Im Seock-Ah , Breton Vanessa , Collier Ann , Schwab Richard B. , Zhu Jing , Sohn Joohyuk 
Published: June 2023

1061 Background: Limitations of current approved endocrine therapies (ETs), a mainstay tx for ER+ BC, include incomplete ER signaling inhibition. Novel ETs, such as selective estrogen receptor antagonists and degraders (SERDs), may help overcome this. G, a potent, nonsteroidal, oral (PO) SERD, is well tolerated and has shown robust ER occupancy and encouraging antitumor activity as monotherapy and in combination with the cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) palbociclib (P). MORPHEUS BC (NCT04802759) is evaluating the safety and efficacy of G tx combinations in ER+, HER2– LA/mBC. We present results from the 16-week IA of G and G + CDK4/6i (A or R). Methods: Eligible pts had disease progression on 1–2 lines of ET (including a CDK4/6i) for LA/mBC. Pts were randomized 1:6 (planned n = 15 per arm) to receive G (30 mg PO QD; control arm), G + A (150 mg PO BID), or sequentially, G + R (600 mg PO QD) until disease progression/unacceptable toxicity. The study was not designed to make explicit power and type I error considerations for a hypothesis test. Primary endpoints were safety and objective response rate; other endpoints included progression-free survival, overall survival, clinical benefit rate, disease control rate (DCR), duration of response, and pharmacokinetics. Genetic alterations were defined using baseline circulating tumor DNA. Results: As of Feb 4, 2022, 15 pts were enrolled in the G + A arm; 73% received one prior line of tx in the LA/mBC setting; 27% received prior fulvestrant; 73% had liver metastases at baseline (BL). As of Sept 22, 2022, 11 and 16 (of whom 14 were evaluable) pts were enrolled in the G and G + R arms, respectively; 64%/86% received one prior line of tx in the LA/mBC setting; 73%/36% received prior fulvestrant; 73%/57% had liver metastases at BL. Three pts had a partial response (PR; G + A, n = 1; G + R, n = 2); 19 had stable disease (G, n = 5; G + A, n = 7; G + R, n = 7). DCRs were 36% (G), 40% (G + A), and 50% (G + R). Safety is shown. Conclusions: G combined with a CDK4/6i (A or R) was well tolerated, with no unexpected safety signals. Three PRs were seen in this heavily pretreated population of pts with disease progression post-CDK4/6i tx. This study provides the first data supporting the combinability of G with the CDK4/6is A and R, in addition to P as seen in prior studies. G can therefore be combined with all three approved CDK4/6is. Clinical trial information: NCT04802759 . [Table: see text]
Beyond the standards: The impact of provider collaboration on referrals to genetic counseling.
Authors: Fowler Eric S , Moreno Laura , Markman Maurie 
Published: June 2023

10611 Background: The Commission on Cancer standards require institutions to monitor genetic assessment for a selected cancer site, providing an opportunity to increase referrals to genetic counseling. Genetic counseling, risk assessment, and testing improve patient care, outcomes, and facilitate cascade testing in families. This study investigated how collaboration with referring providers through education, feedback, and ongoing communication impacted referrals to genetic counseling. Methods: Study participants included new patients with colorectal cancer (CRC) diagnosed under age 50 presenting to our institution from July 2021 to September 2022. Patients were excluded if they did not return after initial visits. Baseline and intervention time periods were compared. Interventions to increase referrals included communication with the medical staff through memoranda co-authored by genetic counselors and physician champions, presentations by genetic counselors at tumor board, medical oncology, cancer committee meetings, and emails providing quarterly and final outcomes. Descriptive statistics were utilized to review categorical data, with baseline and intervention referral rates compared with the Pearson Chi-Square Test. Results: 133 patients met referral criteria with ages at diagnosis ranging from 19-49 years old. Mean (and median) patient ages were comparable between baseline and intervention study periods: 42.5 (45) and 43.0 (45), respectively. In the baseline period, 10/32 (31.3%) patients were referred to genetic counseling. In the intervention period, 58/101 (57.4%) patients were referred to genetic counseling representing a 26.1% increase over baseline. The Pearson Chi-Square Test yielded a p-value of 0.01. Referral rates varied by quarter (collaboration/education began in mid-Q2): Q1 - 26.7%, Q2 - 45.8%, Q3 - 77.8%, Q4 - 60.0%, and Q5 - 34.4%. Conclusions: Collaboration and communication with referring providers resulted in statistically and clinically significant increases in referrals to genetic counseling. The increase in referrals was most pronounced immediately after collaboration began and declined by the last quarter. This study highlights the importance of genetics educational initiatives and ongoing communication in the oncology setting, and the need for alternative and more sustainable strategies to maintain and increase referrals to genetic counseling. Referrals to genetic counseling facilitate the provision of cancer screening guidelines for patients and their families, based on genetic test results and personal/family histories, and reinforce the importance of cascade testing where appropriate. [Table: see text]