bluuebunny/crossref_metadata_2025 huggingface dataset:
A multivariate analysis of low-dose CT lung cancer screening in a Michigan community hospital network.
Authors: Law Jason , Hrinczenko Borys
Published: June 2023

10576

Background: Lung cancer is the leading cause of cancer deaths in the United States. The USPSTF recommended screening for lung cancer with low-dose chest computer tomography (LDCT) in 2013. This was based on the National Lung Screening Trial (NLST) which showed a 20% relative reduction in mortality from LDCT compared with chest radiography in high-risk individuals. The major NLST eligibility criteria were age 55-74, a 30 + pack year smoking history and current smoking status or having quit in the last 15 years. The impact of other risk factors on screening results besides inclusion criteria is unknown. We sought to identify other factors for the risk of lung cancer detection in screened individuals. Methods: This was a retrospective cohort study employing a Michigan based McLaren Hospital Network Lung Cancer Screening Program (LCSP) database from 2015-2022. Participant eligibility in screening was the USPSTF criteria except for an age range of 50-80. Analyses were stratified by BMI, smoking pack-years, insurance status, smoking status, sex, other CT findings, pre- vs. during COVID pandemic (before and after January 2020). Multivariate logistic regression analysis was used for odds ratios (OR) with 95% confidence intervals (CI) as estimates of the relative risk of an elevated Lung-RADS category ≥3 (high risk of detecting lung cancer). Results: A total of 2638 subjects, 49.91% females, 50.09% males, mean BMI 29.50 ± 7.17 (SD), pack-years 44.52 ±18.29, Medicaid 6.66%, Medicare 32.01%, Private Insurance 57.62%, Self-pay /unknown 3.71%. Current smoker 65.49%, Former smoker 34.51%, other CT findings 51.99%, pre-COVID 46.08%, during COVID pandemic 53.92%. Lung-RADS category 0 (0.04%), 1 (35.33%), 2, (50.61%), 3 (6.56%), 4a (4.85%), 4b (1.55%), 4x (1.06%). A statistically significant association with a Lung-RADS category ≥3 was found with lower BMI, OR=0.980 (95% CI, 0.969-0.991), p=0.0005, and female gender, OR=1.232 (95% CI, 1.039-1.462), p=0.0166 (Table). Conclusions: In our study cohort a lower-than-average BMI and also female gender were statistically correlated with an elevated Lung-RADS category ≥3. These findings might be incorporated into a risk stratification model, however further larger studies are needed to validate our findings. [Table: see text]
Effect of colorectal cancer screening on 1-year mortality and medical costs: Real-world evidence from the largest commercial medical claims database in the US.
Authors: Nguyen Chi Mai , Su Jing
Published: June 2023

10579

Background: Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the United States with increasing trends in both mortality and incidence in individuals under age 50. Whether CRC screening reduces mortality recently becomes controversial in some observational studies due to a lack of data and a possibility of screenings confounded with social determinants of health (SDoH) and patient characteristics that were not properly addressed. Methods: We used the Optum’s de-identified Clinformatics Data Mart Database that provides information of healthcare plan, major SDoH, the CRC diagnosis, treatments, medical service and prescription charges, and survival data since 2007 for over 75 million patients to re-examine benefits of CRC screenings. Our CRC study cohort (N=99,704) included persons first diagnosed with CRC between 2010 – 2020, with 3-year pre-diagnosis continuing insurance coverage to identify pre-diagnosis screening, and 1-year follow-up to identify death and associated costs. Primary outcomes are 1-year mortality, the post-diagnosis medical and prescription cost increments, and health plan change after CRC diagnosis. Augmented inverse probability weighting (AIPW) models were employed to estimate the benefits of CRC screening, adjusting the probabilities of pre-diagnosis screenings due to insurance cover types (commercial/employer, Medicare advantage, and dual Medicare-Medicaid or low-income subsidy (LIS) covers), and healthcare plans (pre-paid, only-in-network, pay-less in-network, and fee-for-service plans), ages, sex, race, residential states, and calendar year. Results: In the study cohort, 37.8% have pre-diagnosis screening records, 18% died within 1 year. Women, persons under age 45, and persons with dual covers were more present in the non-screening group than the screening one. CRC screening was associated with a significant reduction of one-year mortality after adjusting for age, sex, race, health plans, and other factors (death rates in the non-screening group vs the screening one were 23% vs 12%, adjusted OR = 0.57, 95%CI = 0.55 - 0.59). Persons with no screening records experienced higher one-year medical cost increases than those who had pre-diagnosis screenings (17.8% vs 14.8%). No significant difference in health plan changes and/or disruption among the two groups was obvious for persons having either dual- or commercial-cover beneficiaries, yet the screenings slightly induced more these plan changes in the Medicare advantage beneficiaries (OR = 1.06, 95%CI = 1.01 - 1.11). Conclusions: The real-world evidence from the US largest medical claims database suggested that, after adjusting for the screening probability due to healthcare plans and other confounders, CRC screening dramatically reduced one-year death risk, and slightly eased the 1-year financial burdens after CRC diagnosis.
Colorectal cancer screening with blood-based tests: Estimated impact of a 1-, 2-, or 3-year screening interval compared with annual FIT and triennial mt-sDNA strategies.
Authors: Fendrick A. Mark , Kisiel John B. , Ebner Derek W. , Ozbay A. Burak , Vahdat Vahab , Estes Chris , Limburg Paul J.
Published: June 2023

10580

Background: Blood-based tests are an emerging option for non-invasive colorectal cancer (CRC) screening for which the Centers for Medicare & Medicaid Services (CMS) has proposed coverage every 3 years for average-risk individuals. Analyses with the CRC-AIM microsimulation model demonstrated that triennial screening with blood-based tests with CMS minimum performance often yields inferior outcomes to stool-based CRC screening (fecal immunochemical test [FIT] and multi-target stool DNA [mt-sDNA]). CRC-AIM was used to explore the impact of blood-based screening intervals, using reported performance characteristics from the ECLIPSE study (Guardant Health, Inc.)1, on estimated clinical outcomes vs FIT and mt-sDNA screening. Methods: Outcomes were simulated for average-risk individuals screened between ages 45-75 years. Intervals were set at 1, 2, or 3 years for blood-based, 3 years for mt-sDNA and annually for FIT screening. The blood-based test was modeled at 83% CRC sensitivity, 13% advanced adenoma sensitivity, and 90% specificity. Perfect adherence (100%) was modeled for blood-based tests and real-world adherence rates used for CRC initial screening tests (mt-sDNA=65.6%; FIT=42.6%) and follow-up colonoscopy (mt-sDNA=72.1%; FIT=46.0%). Primary outcomes were life-years gained (LYG) and colonoscopies (COL) per 1000 individuals for blood-based screening compared to mt-sDNA and FIT. As a secondary analysis, estimates were generated with perfect (100%) adherence assumed for initial screening and follow-up colonoscopy for mt-sDNA and FIT as well. Results: Blood-based testing at a 3-year interval with 100% adherence led to 11% fewer LYG than mt-sDNA at RWE adherence (240 vs 270, respectively), and 9% more COL (1402/1000 vs 1288/1000). Meanwhile, blood-based testing at a 1-year interval and perfect adherence (best case scenario) resulted in the lowest LYG per COL ratio across all scenarios (16% more LYG and 87% more COL compared to mt-sDNA at RWE adherence). Blood-based test results showed similar trends when compared to FIT. Conclusions: Outcomes for blood-based screening every 3 years based on reported test performance characteristics and unrealistic perfect adherence demonstrate fewer LYG as compared to either mt-sDNA or FIT. When compared to real-world adherence for mt-sDNA and FIT, blood-based tests with 1- and 2-year intervals and perfect adherence had higher LYG with the tradeoff of a greater number of diagnostic colonoscopies. [Table: see text]
The role of molecular biomarker CDKN-2A in early diagnosis of colorectal cancer.
Authors: Ten Yakov , Nigmatovich Mirzagaleb , Ziyaev Yakhyo , Islamov Hurshid , Zakhirova Nargiza Nematovna
Published: June 2023

10581

Background: Polyps are considered as obligate precancerous disease. The percentage of malignization ranges from 20% in single polyps to 95% in diffuse polyposis. Current research examines the results of the early diagnosis of colon cancer by using the biomarker CDKN2A for development of molecular-biological methods of prognostication. The correlation with the molecular-biological indicators were studied. It is also planned to develop an effective system for development prognostication of CRC and the formation of "risk groups" for evidence-based counselling for families which are highly predisposed to colorectal cancer. Methods: Investigations were carried out in 30 patients during the period 2016-2022, the study included patients with single polyps, multiple polyps, polyposis of the colon, as well as patients without a history of either familial or sporadic cancer. 12 patients had multiple polyps, 9 polyposis and 9 single colon polyps. The levels of methylation of the gene CDKN2A were determined in 10 patients. The material for the isolation of DNA was a serum obtained from venous blood, and biopsy material. DNA extraction was held according to standards. After the conversion of DNA methyl-specific PCR was done. Results: Among 30 patients with polyps and polyposis of the colon, serum gene CDKN2A methylated DNA was detected in 10 patients. In 4 patients malignization of the polyp was determined. If patients without malignization surgical intervention was limited with resection of the intestine without lymph dissection. In 20 patients the test result was negative. We did not perform surgical intervention to these patients and they were sent to dynamic observation. Thus, the diagnostic efficacy of detecting colorectal cancer in early diagnosis of by means of methylated DNA of the gene CDKN2A was - 33.3%. Conclusions: If there is a positive test for methylation of the CDKN2A-gene, the risk of colorectal cancer is considered very high and these patients underwent surgical treatment. Application of the molecular biological marker CDKN2A may be an effective method in early diagnosis of malignization of polyps.
Genetic testing into survivorship after diagnosis of breast cancer.
Authors: Katz Steven , Hodan Rachel , Abrahamse Paul , Tocco Rachel , Hofer Timothy , Wallner Lauren P. , Kurian Allison W.
Published: June 2023

10583

Background: Support for universal genetic testing after diagnosis of breast cancer is growing because of concerns that targeted guidelines fail to identify all patients who could benefit from genetic risk evaluation (GRE). Little is known about use of genetic testing in survivors of breast cancer over time. Methods: Women who were diagnosed with breast cancer in 2014-15 and reported to the SEER registries of Georgia and Los Angeles County completed a baseline survey about 9 months after diagnosis (N=2502). We performed a follow-up survey (FUPs) about 6 years after diagnosis among survivors (N=2347), of whom 1423 responded (60% response rate). We asked women about their receipt of clinical germline genetic testing and results, communication with relatives about cancer genetic testing, and use of direct-to-consumer testing (DTCt) after diagnosis. We categorized women into indications (yes/no) for GRE based on National Comprehensive Cancer Network guidelines at time of diagnosis (GRE indication baseline) and at the time of the follow-up survey (GRE indication FUPs only). Results: We present results for a preliminary sample (N=1272). About half of the respondents (44.6%) had indications for GRE over the study period; 28.0% at baseline; and an additional 16.6% at time of the follow-up survey (FUPs only). The Table below shows patient-reported testing at FUPs by GRE indication category (baseline, FUPs only, no indication). About two thirds of those with a baseline indication for GRE received genetic testing over the observation period: 66.5% vs 43.9% with indication at FUPs only vs 35.0% of those with no indication (p<.001). A substantial proportion of those who reported testing received the test during the survivorship period (1 to 6 years post-diagnosis): approximately one-third of those with baseline indications vs over half of those with GRE indication at FUPs only. Testers with a pathogenic variant result (n=59) were much more likely to have talked to most or all of their first-degree adult relatives about genetic testing than those with a variant of unknown significance (n=40) or a negative finding (n=382): 64.3% vs 35.0% and 37.1%, respectively (p<.001). Overall, there was very little interest in DTCt for cancer risk: 5.0% researched DTCt online somewhat to a lot; and only 3.5% had DTCt. Conclusions: The proportion of patients with indications for GRE after diagnosis of breast cancer markedly increases into survivorship but many patients do not receive genetic testing. Lack of survivor interest in DTCt for cancer risk is reassuring that patients are not substituting DTCt for clinical testing. [Table: see text]
Analysis of ATM germline mutations in solid tumors from Chinese patients.
Authors: Fu Tao , Zhao Yaping , Guo Didi , Chen Siqi , Han Tiantian , Ding Ran , Deng Wanglong , Bu Fanfeng
Published: June 2023

10586

Background: Ataxia-telangiectasia mutated (ATM) is a tumor suppressor genes and plays an important role in the repair of DNA double-strand breaks (DSBs). Germ-line mutations of ATM gene result in the well-characterized ataxia telangiectasia syndrome, which manifests with an increased cancer predisposition, including a 20% to 30% lifetime risk of lymphoid, gastric, breast, central nervous system, skin, and other cancers. Novel therapies are in development that may improve the response to therapy of patients with ATM-deficient cancers including targeted therapy and immunotherapy. Nevertheless, the knowledge of incidence of ATM germline mutations in solid tumor remains poorly understood. Methods: We identified 19248 malignant solid tumors patients without selecting age or family history in a retrospective cohort. The pathogenicity of germline mutations was categorized based on American College of Medical Genetics and Genomics (ACMG) guidelines.The patients were divided into two groups, P/ LP group (with pathogenic or likely-pathogenic mutations), and Non-P/LP group (neither pathogenic nor likely-pathogenic mutation). Results: In 19248 patients with pan-cancer, 76 patients were found 76 heterozygous pathogenic or likely pathogenic germline mutations in ATM gene and the mutation frequency was 0.39%.Among these 76 carriers, 71 (93.4%) carried frameshift, nonsense or splice mutations (33 for frameshift,21 for missense and 17 for splice mutations). 4 carried missense mutations and 1 carried intron mutations. Eliminated a few types of cancers that had a smaller number (less than 50), the higher frequency of mutations contained cancers were pancreatic cancer (1.0%,7/692), breast cancer (0.71%,3/423), gastric cancer (0.6%,7/1094), The median age of group P/LP and non-P/LP group was 64 and 63 in pancreatic cancer，62 and 53 in breast cancer and 62 and 61 in gastric cancer. The three genes with the most somatic mutations were TP53, MUC16 and KRAS in P/LP group and were TP53, MUC16 and EGFR in non-P/LP group. There was no significant difference in mutation frequency of the four genes. The media TMB in P/LP group and non-P/LP group were 3.55 and 2.84 respectively and there was no statistical difference. In P/LP group，only one patients is high microsatellite instability who carryied a MLH1 and a ATM pathogenic mutation. Conclusions: This was the first report of the incidence of ATM germline mutations in Chinese solid tumors which expanded the understanding of ATM and provided a direction for clinical trial design of novel therapies. The relationship between germline mutations and cancer susceptibility will be studied in the future.
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]
Impact of early testing and analysis of germline genetic mutation patterns in patients with breast cancer: A single institution experience.
Authors: Reddy Aswanth , Nwankwo Nkolika , Milam Kathleen
Published: June 2023

10613

Background: Approximately 3% of patients with breast cancer have a pathogenic or likely pathogenic variant (mutation) in a high-risk breast cancer gene, such as BRCA1, BRCA2and PALB2, which increases breast cancer risk more than fourfold. Approximately 3% have a germline mutation in a moderate-penetrance breast cancer gene, such as ATM or CHEK2, which confers a two- to threefold increased risk of breast cancer. Methods: In 2020 we started offering germline genetic testing to all newly diagnosed breast cancer patients at the time of diagnosis irrespective of their family history. Our objectives included the following: Prevalence of mutations in breast cancer patients treated at our institution. Germline mutations in patients with Ductal carcinoma in situ (DCIS). To identify if early universal germline testing affected the surgical modality. Results: A total of 525 patients were seen in the oncology clinic from January 2020 to December 2022 with a breast cancer diagnosis. The median age of diagnosis is 66 (32-91) years. Invasive ductal cancer (IDC 66 %) was the most common subtype, followed by DCIS (18%) (Table 1). Most patients had estrogen-positive cancer (82% vs. 18%), and approximately 13% had HER2-positive disease (61% HER2 low). Mutation in CHEK2 (9 patients) was our cohort's most common pathogenic mutation, followed by BRCA1 (6 patients) and MUYTH (6 patients) genes. Predominant germline mutations were identified in patients with IDC, followed by DCIS. One patient with a pure mucinous subtype had a germline pathogenic mutation (RECQL4 gene). We identified a higher percentage of pathogenic breast cancer-related mutations in patients above 60 years (63% vs. 37%) and all CHEK2 mutations were in patients above 60. Out of 41 patients with pathogenic mutations, 17 underwent a partial mastectomy, 12 had a bilateral mastectomy, and two had a unilateral mastectomy. All patients with BRCA1/2 mutation chose bilateral mastectomy, and all patients with a CHEK2 mutation underwent a partial mastectomy. Several variants of unknown significance (VUS) mutations were identified, and they followed a similar pattern, being more common in patients with IDC. VUS mutations in the ATM gene were the most reported abnormality. Conclusions: Pathogenic mutation in the CHEK2 gene is more prevalent, and we hypothesize that this finding could be related to the demographic population treated in our institution. Also, CHEK2 mutation was only identified in patients older than 60, which argues for more testing in patients in this age group. Approximately 9% of all IDC patients had a germline mutation compared to 4.2 % in patients with DCIS. Our review identifies that patients with BRCA1/2 mutations tend to undergo prophylactic mastectomy, and early testing likely impacted this decision. From our study, we believe that germline genetic testing should be offered to all breast cancer patients.
Utility of multi-gene panel-based germline analysis following genomic profiling and cascade testing in advanced solid tumors: An initial report of the BRANCH study.
Authors: Kuwata Takeshi , Nakamura Yoshiaki , Nishina Tomohiro , Takahashi Naoki , Narimatsu Hiroto , Cho Hourin , Inagaki Chiaki , Kadowaki Shigenori , Okugawa Yoshinaga , Matsuzaki Sawako , Tomita Naohiro , Yasui Hisateru , Sunakawa Yu , Matsukawa Manami , Kimura Kaori , Hiraoka Yumie , Hirata Makoto , Imoto Issei , Kosugi Shinji , Yoshino Takayuki
Published: June 2023

10615

Background: Genetic testing for pathogenic germline variants (PGVs) is performed to identify hereditary cancer syndromes (HCS) and to evaluate the application of targeted therapies in clinical oncology. Multi-gene panels (MGPs) have become popular for identifying HCS; however, their clinical utility in therapeutic applications and confirmatory germline testing for presumed PGVs and in cascade testing are not well established. Methods: BRANCH [UMIN000046085] is a multicenter clinical study to confirm PGVs in: i) patients with advanced solid tumors in whom a presumed PGV has been detected by comprehensive genomic profiling (CGP) (cohort A); ii) patients who received a germline BRCA (gBRCA) test (cohort D); and iii) first-degree relatives of patients with PGVs identified in this study (cohort C). PGVs were examined in 35 HCS genes using an MGP combined with digital multiple-ligation-dependent probe amplification. Results: MGP results were available for 75 patients in cohort A and 83 in cohort D (3 February 2023). The most common cancer in cohort A was colorectal cancer (13%) followed by ovarian (12%) and breast (11%) cancers. Of 103 tested presumed PGVs, 46 (45%) were confirmed as PGVs, with the highest germline conversion rates in BRCA1 (8/8, 100%), followed by PALB2 (5/6, 83%) and BRCA2 (15/19, 79%) among the genes tested in ≥3 patients. In tissue-based CGP, true PGVs had a higher variant allelic frequency (median 55.7% [range, 31.9-96.8]) than non-PGVs (37.0% [9.3-86.9]). In cohort D, 61 (74%) patients had breast cancer, including one with both breast and ovarian cancers. All BRCA PGVs identified by gBRCA test were identified by MGP in 28 BRCA-positive patients. Intriguingly, among 55 patients (66%) in whom no BRCA PGV was detected by gBRCA test, non-BRCA PGVs were identified in 6 (11%) patients (2 PALB2 and 1 each of ATM, CHEK2, MSH2 [large deletion], and TP53). Thirty relatives in 18 pedigrees received MGP-based cascade testing in cohort C. The most frequent target genes were BRCA2 followed by BRCA1 and PALB2. The same PGVs as the probands were confirmed in 11 (37%) individuals and novel PGVs were identified in 2 (7%) relatives, leading to double PGVs in homologous recombination genes ( PALB2+ BRCA2 and BRCA2+ ATM), respectively . Conclusions: MGP successfully determined germline variants among presumed PGVs identified by CGP in patients with advanced solid tumors, and detected non-BRCA PGVs in 10% of gBRCA-negative patients. Furthermore, MGP-based cascade testing has the potential to identify other PGVs in addition to those detected in the probands. Clinical trial information: UMIN000046085 .