bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical implications of germline genetic testing stratified by ethnicity in a large colorectal cancer cohort.
Authors: Heald Brandie , Coughlin Sarah , Nielsen Sarah M. , Clark Dana , Hatchell Kathryn E. , Katona Bryson W , Esplin Edward D. 
Published: June 2022

10504 Background: Germline genetic testing for patients (pts) with colorectal cancer (CRC) is currently recommended for those diagnosed prior to age 50, as well as other select cases based on personal and/or family history criteria. Whether universal germline multi-gene panel testing (MGPT) should be performed in all pts with CRC remains uncertain given the lack of large-scale studies examining MGPT in CRC across a diverse population. The present study aims to determine the yield, and potential clinical impact, of MGPT across a large CRC cohort. Methods: We conducted a de-identified retrospective cohort study of all pts with CRC who underwent MGPT (excluding patients who underwent testing limited to ≤10 genes) at a commercial laboratory between 03/2015-05/2021. We collected pts demographics from test requisition forms and results of germline MGPT. Clinically actionable PGVs were defined as variants in genes with reported CRC or polyposis risk, as well as other actionable genes associated with clinical management and/or therapeutic implications. Results: A total of 34,210 pts with a history of CRC underwent germline MGPT. These pts were primarily female (60.7%), White (70.6%), and 50 or older (68.8%), with 35.5% reporting an extra-colonic malignancy. Of this cohort, 4,577 (13.4%) were found to carry at least one PGV, with 2,925 (8.6%) having a PGV associated with increased risk of CRC or polyposis. Of all positive pts, 3,038 (66%) had PGVs with precision therapy or clinical trial implications while another 33% had PGVs with published management implications. Among pts under the age of 30 when tested, 23.3% had a clinically actionable PGV compared to 14.7% at age 30-39, 11.7% at 40-49, 12.9% at 50-59, 11.6% at 60-69, 8.9% 70-79, and 7.8% over the age of 80. When compared to pts identified as White, PGVs were more frequently identified in pts of Ashkenazi Jewish descent (p < 0.001) and less frequently identified in those who identified as Hispanic (p < 0.001). VUS was more frequently identified in pts identified as Black, Asian, or Hispanic (p < 0.001). Conclusions: This is the largest study to date examining MGPT in CRC, where we demonstrate high rates of clinically actionable variants across all age groups, self-reported racial/ethnic groups, and panel sizes, with 13% of all CRC pts having a PGV with precision therapy, clinical trial and/or published management implications.This is likely an underestimate as patients with strong clinical suspicion of hereditary CRC (Lynch, FAP) often receive a targeted panel of <10 genes and were excluded. The lower rate of PGVs in Hispanic pts and higher rate of VUS in Black, Asian and Hispanic pts underscores the historical underrepresentation of these pts and ongoing need to mitigate the associated healthcare disparities. Overall, this work supports consideration of broadening germline genetic testing criteria for patients with CRC.
Multicenter retrospective study of clinical genetic testing in patients with sarcoma.
Authors: Wilbur Helen Catherine , Cobain Erin Frances , Wiesner Georgia L. , Davis Elizabeth J. , Chugh Rashmi 
Published: June 2022

10511 Background: Sarcomas are rare and diverse malignancies with a subset developing in the context of heritable cancer predisposition syndromes. Data surrounding the frequency of inheritance and patient/genomic findings are limited. We aimed to describe the characteristics of patients with sarcoma referred for clinical genetic testing and to determine the prevalence of pathogenic/likely pathogenic germline variants (PGV/LPGV). Methods: We performed retrospective chart reviews of patients with sarcoma referred to Michigan Medicine Cancer Genetics Clinic between 12/2006 and 1/2020 and Vanderbilt Hereditary Cancer Clinic between 1/2005 and 1/2019. Reviewers obtained medical/family history, cancer phenotype, and results of germline genetic testing. Descriptive analyses were performed to assess the prevalence of germline variants classified as pathogenic/likely pathogenic according to American College of Medical Genetics criteria. Associations with clinical factors were tested for using Fisher’s exact test or Wilcoxon rank-sum test. Results: One-hundred sixteen patients with sarcoma underwent genetic evaluation during a 15-year period. Mean age at time of visit was 46 years (SD, 17.6 years; range, 1-80 years). Sixty-nine patients (59%) were female. The most common reasons for referral were personal history of multiple malignancies (n = 69, 59.4%), first degree relative (FDR) with malignancy (n = 67, 57.7%) and young age at diagnosis (age ≤ 18, n = 18, 15.5%). Forty-eight patients (41.4%) had both a history of multiple malignancies and a FDR with a malignancy. Eight patients had a FDR with sarcoma (6.9%). Of the 110 patients who underwent germline testing, 53 patients (48.2%) had a PGV/LPGV. Identified germline variants and frequencies are listed in the Table. There was no statistical significance between young age at diagnosis, history of personal malignancies, FDR with sarcoma, FDR with one or more malignancies, or multiple FDRs with malignancy and presence of a PGV/LPGV. Conclusions: In this multicenter study, approximately half of patients with sarcoma referred for cancer genetic testing had a PGV/LPGV associated with hereditary predisposition to cancer. There was no identified positive predictive factor for germline variants. Though TP53 was the most common, over 20 genetic variants were identified, supporting the consideration of multigene panel testing. Our study is limited to patients who were both referred to and attended genetic evaluation. Yet, the high frequency of pathogenic germline variants observed highlights the necessity for further investigation of the prevalence of and predictive factors for germline mutations in all sarcoma patients. Identified germline variants. [Table: see text]
A multicenter study of clinical impact of variant of uncertain significance reclassification in breast, ovarian, and colorectal cancer susceptibility genes.
Authors: Makhnoon Sukh , Levin Brooke , Ensinger Megan , Mattie Kristin , Volk Robert Joseph , Zhao Zhongming , Mendoza Tito R. , Shete Sanjay , Samiian Laila , Grana Generosa , Grainger Andrew V. , Arun Banu , Shirts Brian , Peterson Susan K. 
Published: June 2022

10512 Background: Up to 10% of all cancers are attributable to germline mutations and identifying mutation carriers is critical for cancer prevention. Clinical interpretation of genetic test results is complicated by variants of uncertain significance (VUS) with unknown impact on health, which can be clarified through reclassification. However, there is little empirical evidence regarding VUS reclassification in oncology care settings, including the prevalence and outcomes of reclassification, racial/ethnic differences, and the proportion of patients who undergo cancer preventive healthcare management as a result of VUS reclassification. Methods: Retrospective analysis of persons carrying VUS (with or without an accompanying pathogenic or likely pathogenic [P/LP] variant) in breast, ovarian, and colorectal cancer genes who underwent genetic counseling at four geographically dispersed cancer care settings (in Texas, Florida, Ohio, and New Jersey) between 2013 and 2019, and followed until 2020. Results: Among 2,715 individuals, 3,261 VUS and 313 P/LP variants were reported and 11% (300/2,715) had a P/LP in addition to VUS. In total, 8.1% of all individuals with VUS experienced reclassifications, 87.1% of which were downgraded to benign or likely benign and 12.9% were upgraded to P/LP. Reclassification rates varied significantly among cancer care settings from 4.81% to 20.19% (overall p < 0.001). The reclassification pattern across genes suggests that VUS in most genes underwent reclassification at a rate proportional to their prevalence in the overall sample and occurred commonly in ATM, BRCA2, BRCA1, and CHEK2. Compared to their prevalence in the sample, reclassification rates were higher for Blacks (13.6% vs 19.0%), lower for Asians (6.3% vs 3.5%), and proportional for Whites and Hispanics. Median time to reclassification decreased steadily between 2014 and 2019 from 3.08 to 0.91 years. Overall, 11.3% of all reclassified VUS resulted in clinically actionable findings and 4.6% subsequently changed individuals’ clinical managements including prophylactic surgeries and intensive screenings for cancer prevention and early detection. Conclusions: In this large multisite study, VUS reclassification changed clinical management for 0.4% of all individuals. VUS reclassification may alter clinical management, has implications for precision cancer prevention, and highlights the need for standardized clinical practice guidelines and policies for returning reclassified results to patients.
Double jeopardy? A closer look at cancer histories of individuals with multiple germline pathogenic variants.
Authors: Horton Carolyn , Lo Min-Tzu , Yussuf Amal , Young Colin , Carraway Cassidy , Agaoglu Nihat Bugra , Bychkovsky Brittany L. , Rana Huma Q. 
Published: June 2022

10514 Background: Germline multigene panel testing has led to the increased detection of multiple co-occurring pathogenic variants (PV) in the same individual. As this occurrence is still relatively rare, reports of these individuals have been limited. Therefore, we sought to describe the clinical features of individuals with multiple PV identified at a single high-volume diagnostic laboratory. Methods: We performed a retrospective review of demographics and clinical data for individuals with > 1 pathogenic or likely pathogenic variant (PV) who underwent hereditary cancer panel testing (5-67 genes) between May 2012 and April 2017. In recessive genes (i.e. MUTYH), PV were only included when biallelic. PVs with reduced penetrance ( APC p.I1307K; CHEK2 p.I157T, p.S428F, p.T476M) were excluded. In individuals with the most common combinations of genes, personal cancer history and age at cancer diagnosis was evaluated. Results: A total of 555 individuals were identified with multiple PVs. Most individuals were female (85.1%), had a personal history of cancer (73.3%) and 26.3% had two or more primary cancers. CHEK2 was most often seen in co-occurrence with a PV in a different gene (137 observations), followed by ATM (120 observations), BRCA2 (110 observations), and BRCA1 (88 observations). Among cases in which clinical information was provided (n = 545), the five most frequent co-occurring combinations were in ATM/CHEK2 (25), ATM/BRCA2 (23), BRCA1/CHEK2 (19), CHEK2/CHEK2 (16), and BRCA2/CHEK2 (14). Individuals with co-occurring PVs in CHEK2/CHEK2 had the youngest age at first cancer diagnosis (mean = 41.5y; median = 42y), the highest rate of breast cancer diagnoses and other cancer diagnoses (100.0% and 70.6% of individuals, respectively), and the highest proportion of individuals with > 1 primary cancer (52.9%). Conclusions: Our results indicate that individuals with two PVs in CHEK2 have an average age of cancer onset that is similar to individuals with either a BRCA1 or BRCA2 concurrent PV. Additionally, individuals with two PVs in CHEK2 were more likely to have multiple primary cancers as compared to others in the cohort with concurrent PVs including those with either a BRCA1 or BRCA2 concurrent PV (Table). Continued studies, including comparisons to individuals with one PV, will provide valuable insight to aid in counseling and management of individuals with multiple germline PV. [Table: see text]
Lung cancer risk prediction nomogram in Chinese female non-smokers.
Authors: Lan-Wei Guo 
Published: June 2022

10530 Background: About 53% of lung cancers in females are not attributable to smoking worldwide. The aim was to develop and validate a simple and non-invasive model which could assess and stratify lung cancer risk in female non-smokers in China. Methods: A large-sample size, population-based study was conducted under the framework of a population-based Cancer Screening Program in Urban China (CanSPUC). Data on the lung cancer screening in Henan province, China, from October 2013 to October 2019 were used and randomly divided into the training and validation sets. Related risk factors were identified through multivariable Cox regression analysis, followed by establishment of risk prediction nomogram. Discrimination [area under the curve (AUC)] and calibration were further performed to assess the validation of risk prediction nomogram in the training set, and then validated by the validation set. Results: A total of 151,834 eligible subjects were included, with a mean age of 55.34 years. Subjects were randomly divided into the training (75,917) and validation (75,917) sets. Elder age, history of chronic respiratory disease, first-degree family history of lung cancer, menopause, and history of benign breast disease were the independent risk factors for lung cancer. Using these five variables, we plotted 1-year, 3-year, and 5-year lung cancer risk prediction nomogram. The AUC was 0.762, 0.718, and 0.703 for the 1-, 3- and 5-year lung cancer risk in the training set, respectively. In the validation set, the model showed a good predictive discrimination, with the AUC was 0.646, 0.658, and 0.650 for the 1-, 3- and 5-year lung cancer risk. Conclusions: We developed and validated a simple and non-invasive lung cancer risk model in female non-smokers. This model can be applied to identify and triage patients at high risk for developing lung cancers in female non-smokers.
Awareness of the link between HPV, cervical cancer, and HPV vaccination: An online survey among Polish women.
Authors: Kotowski Artur , Kotowska Maja Dominika , Zadroga Aleksandra , Hernas Katarzyna , Szymusik Iwona , Fal Andrzej Mariusz 
Published: June 2022

10538 Background: In 2019 cervical cancer (CC) was the 7th most common malignant neoplasm in Polish women. Its incidence has been declining over the years, nonetheless the 5-year survival rate is still significantly lower than the EU average. Vaccination against human papillomavirus (HPV) is not included in the mandatory immunization schedule in Poland and is not reimbursed yet. The aim of the study was to assess women's awareness of the risk factors of CC (including the role of HPV) and the possibility of cancer prevention through HPV vaccination. Methods: The questionnaire prepared by the study team was aimed at women and conducted online using social network sites. The single/multiple-choice questions included knowledge about CC, HPV and HPV vaccination. Statistical analyses were performed using MS Excel 2016 and Medistica pvalue.io 2021 software in general population and age- dependent subgroups. Results: The total number of 3262 women participated in the study. The age subgroups were: aged ≤ 18 years (group 1): 1090 (33.4%), aged 19-25 years (group 2): 1615 (49.5%) and > 25 years (group 3): 557 (17.1%). Overall 81.4% of the respondents correctly associated HPV as the key factor of CC, 85.0% believed that CC could be prevented and 80.0% had heard of HPV vaccination before. In the last two parameters a statistically significant difference in age subgroups was observed (p < 0.001). Only 21.2% of the total number of respondents were vaccinated (26.2%, 22.0% and 9.2% in age groups 1, 2 and 3 respectively, p < 0.001). In all studied populations the following factors had the greatest influence on the decision to get vaccinated: parents’ advice – 54.8%, pediatrician recommendation – 15.7%, possibility of free vaccination offered by municipality – 11.6%, teachers’ advice - 9.7%, gynecologist recommendation - 8.2%. The main reasons behind not getting vaccinated were: high price (63.0%) and disbelief in efficacy (41.5%); only 12.2% respondents were afraid of possible side effects. 65.0% of the unvaccinated respondents declared willingness to get vaccinated in the future (71.5%, 66.1% and 52.0% in age groups 1, 2 and 3 respectively p < 0.001), 28.5% of the respondents were not confident of their decision at the time of submitting answers. Conclusions: As oncogenic types of human papillomavirus play a vital role in pathogenesis of CC, the HPV vaccination and cytological screening together with awareness-raising campaigns should be considered the best strategy for the prevention of CC, its early detection and increase in survival rates. Vaccine willingness remains at high level especially among young women, however the effectiveness of vaccination should be emphasized and the HPV free vaccination programs should be introduced by the state. The educational role of gynecologists needs to be enhanced.
Trends in the incidence of early-onset invasive colorectal cancer between 1990 and 2018, stratified by race/ethnicity, gender, and anatomic sub-sites among Pennsylvania residents.
Authors: Jackson Inimfon , Bley Edward , Goldberg Michael , Behme Matthew , Dourado Claudia M. 
Published: June 2022

10543 Background: Recent data report a rising incidence of colorectal cancer in the younger population and epidemiological evidence is useful to enable clinicians understand evolving trends and better counsel patients on the potential risks/benefits of early screening. We explored the trends in incidence of early-onset invasive colorectal cancer by race/ethnicity, gender, and anatomic sub-sites. Methods: Repeated cross-sectional analyses were conducted among adults < 50 years diagnosed with invasive colorectal cancer between 1990-2018 in Pennsylvania using data from the Pennsylvania Department of Health Cancer Registry. Temporal trends in invasive cancer with age adjusted incidence rates according to race/ethnicity, gender, and anatomical sub-sites were assessed using the Enterprise Data Dissemination Informatics Exchange (EDDIE). Results: 16,154 cases of early-onset invasive colorectal cancer were diagnosed between 1990 and 2018. There was an increased incidence of invasive colorectal cancer in the general population especially when stratified by gender, race/ethnicity and among those < 40 years of age. While rates among Whites nearly doubled from 5.4 per 100,000 (95% Confidence Interval (CI): 4.9–6.0 per 100,000) population to 9.0 per 100,000 (95% CI: 8.2– 9.7 per 100,000) population, the rates in the Black population have been decreasing in recent years from a peak of 10.4 per 100,000 (95% CI: 8.4–12.7 per 100,000) population in 2011 to 7.3 per 100,000 (95% CI: 5.7–9.3 per 100,000) population in 2018. However, the Hispanic rates have remained stable. Across anatomical subsites, the rectum, rectosigmoid and sigmoid colon were found to have rising trends in incidence rates over time. Conclusions: There is increased awareness on the need for early diagnosis of colorectal cancer in the young Black population. However, we found trends toward increasing incidence rates among Whites while rates in the Black population are now decreasing. These findings accentuate the need for quality provider-patient communication during primary care visits with a goal to improve adherence to the new colorectal cancer screening guidelines regardless of race/ethnicity.
Interception versus prevention in cancer screening in a Medicare population: Results from the CRC-MAPS model.
Authors: Putcha Girish , Carroll Lauren N , Chandra Tarun , Piscitello Andrew 
Published: June 2022

10546 Background: This study examines the impact of detecting cancer (interception) versus adenomas and cancer (prevention + interception) on clinical outcomes in a screen-naive Medicare cohort for a hypothetical colorectal cancer (CRC) screening test or a multicancer early detection (MCED) test that includes CRC. Methods: CRC-MAPS, a validated microsimulation model of the adenoma-carcinoma pathway that reproduced incidence reduction (IR) and mortality reduction (MR) consistent with CISNET models and a randomized controlled trial, was used to simulate perfect adherence to a hypothetical annual screening test among previously unscreened individuals free of diagnosed CRC. Four scenarios were examined: two cancer interception and two cancer prevention + interception. Individuals were screened from age 65 to 75. CRC IR and MR outcomes compared to no screening were aggregated from age 65 until death. Threshold analysis (#5) identified the ≥10mm adenoma sensitivity needed for a base-case cancer interception test (#1) to yield CRC MR equivalent to a near-perfect cancer interception test (#2). Results: The base-case interception scenario (#1) resulted in 5.6% CRC IR and 21.7% MR compared to 5.2% CRC IR and 25.9% MR for the near-perfect interception scenario (#2). The threshold analysis demonstrates that when the base-case interception scenario's ≥10mm adenoma sensitivity is increased from 1% to just 2.43% (#5), the resulting MR is equivalent to a near-perfect interception test. Accordingly, the cancer prevention + interception scenarios (#3, #4) resulted in CRC IR and MR outcomes 9.7-12.9x and 2.5-3.4x (respectively) as favorable as either cancer interception scenario due to adenoma detection. Conclusions: This analysis highlights that even small improvements in the detection of precancerous lesions for certain cancers (e.g., adenomas for CRC), which enable cancer prevention, can yield clinical benefits that meaningfully exceed those from tests that primarily detect cancer. Future studies will explore both benefits and burdens of different screening tests. Moreover, this approach will be applied to better understand the clinical utility of MCED tests. [Table: see text]