bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adrenal-permissive HSD3B1 genetic inheritance and risk of estrogen-driven postmenopausal breast cancer.
Authors: Sharifi Nima , Kruse Megan Lynn , McManus Jeffrey , Chung Yoon-Mi , Wei Wei , Bazeley Peter , Nakamura Fumihiko , Hardaway Aimalie , Downs Kelley Erinn , Chandarlapaty Sarat , Thomas Mathew , Moore Halle C. F. , Budd George Thomas , Tang Wai Hong Wilson , Hazen Stanley L. , Bernstein Aaron , Nik-Zainal Serena , Abraham Jame 
Published: June 2021

10503 Background: Genetic factors that contribute to endogenous estrogen synthesis and postmenopausal breast cancer risk are unknown. We set out to test the hypothesis that homozygous inheritance of the common 1245A→C missense-encoding polymorphism in HSD3B1, which is common (8-10%) in White populations, functionally adrenal permissive and increases synthesis of the aromatase substrate, androstenedione, is associated with postmenopausal estrogen receptor-positive breast cancer. Methods: A prospective single institution study of postmenopausal estrogen receptor-driven breast cancer for determination of HSD3B1 genotype, circulating steroid concentrations, and adrenal-permissive genotype frequency compared with the genotype frequency in the general population and in estrogen receptor-negative breast cancer. Validation was performed in 2 breast cancer genomic studies with estrogen receptor documentation. The primary outcome is the adrenal-permissive genotype frequency in postmenopausal estrogen receptor-positive breast cancer and the general population. Genotype comparisons were also done with postmenopausal estrogen receptor-negative breast cancer and the association with circulating adrenal androgen concentrations determined. Results: The prospective and validation studies had 199 and 1628 women, respectively. The adrenal-permissive genotype frequency in postmenopausal White women with estrogen-driven breast cancer in the prospective cohort was 17.5% (21/120) compared with 9.6% (429/4451) in the general population [p = 0.0077]. The adrenal-permissive genotype frequency for estrogen-driven postmenopausal breast cancer was validated using the Cambridge and TCGA genomic datasets together: 14.4% (56/389) compared with 6.0% (9/149) for estrogen receptor-negative breast cancer (p = 0.007) and the general population (p = 0.005). Circulating androstenedione concentration was significantly higher for women with the adrenal-permissive genotype compared with the other genotypes (p = 0.03). Conclusions: The adrenal-permissive genotype is associated with estrogen-driven postmenopausal breast cancer. These findings link genetic inheritance of endogenous estrogen exposure to estrogen-driven breast cancer and have broad implications for risk stratification, prevention, potential biomarkers for hormonal therapy response and possibly other clinical outcomes related to estrogen physiology in postmenopausal women.
Correlation between work productivity loss (WPL) and European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) domains from the MONALEESA-7 (ML-7) trial of premenopausal women with HR+/HER2- advanced breast cancer (ABC).
Authors: Tripathy Debu , Curteis Tristan , Hurvitz Sara A. , Yardley Denise A. , Franke Fabio , Kanakasetty Govind Babu , Wheatley-Price Paul , Im Young-Hyuck , Pencheva Radost , Chandiwana David , Pathak Purnima , Lanoue Brad , Harbeck Nadia 
Published: June 2021

1051 Background: The international, randomized, double-blind, placebo-controlled, Phase III ML-7 trial (NCT02278120) assessed ribociclib + endocrine therapy (ET) vs ET alone in premenopausal women with HR+/HER2– ABC. To our knowledge, the relationship between WPL and domains of the EORTC QLQ-C30 and the tumor-specific module for breast cancer (QLQ-BR23) has not been explored in ABC. In this post hoc analysis (data cutoff, November 30, 2018) of all patients (pts) enrolled in ML-7, we assessed the correlation between the WPL component of the Work Productivity and Activity Impairment: General Health (WPAI:GH) questionnaire and domains of the EORTC QLQ-C30/BR23. Methods: We analyzed EORTC and WPAI:GH data from all pts enrolled in ML-7 who were employed at any point during the trial (N = 329 of 672 total pts). Domains of the EORTC QLQ-C30 and QLQ-BR23 that had the greatest correlation (pairwise Pearson correlation) with WPL were prioritized for analysis. Separate univariable mixed-model repeated-measures regression models were fitted for each domain, with WPL as the dependent variable and each EORTC domain as a single fixed-effect covariate. Linear and quadratic relationships were considered. Model selection was based on the Akaike information criterion (AIC). Results: Linear models were favored over quadratic models. WPL was negatively correlated with global health status (GHS) and the physical, role, social, and emotional functioning domains and was positively correlated with the fatigue and pain domains of the QLQ-C30 ( P <.001; Table). The coefficients indicated the estimated mean change in WPL was associated with a 1-unit increase in each QLQ-C30 domain. For example, a 10-point increase in GHS was associated with an estimated mean decrease of 7.8% (95% CI, 7.1%-8.5%) in WPL. Conclusions: Greater WPL was associated with higher levels of fatigue and pain and with lower levels of overall quality of life and physical, role, social, and emotional functioning among pts with HR+/HER2− ABC in ML-7. Further investigation of the correlation with QLQ-BR23 and multivariable analysis could determine which EORTC domains and items independently drive these findings. Clinical trial information: NCT02278120 .[Table: see text]
Limitations of direct-to-consumer (DTC) genetic testing for hereditary breast and ovarian cancer.
Authors: Desai Neelam Vijay , Barrows Elizabeth Dominic , Nielsen Sarah M. , Hatchell Kathryn E. , Esplin Edward D. , Tung Nadine M. , Isaacs Claudine 
Published: June 2021

10515 Background: With the advent of DTC genetic testing, individuals have access to genetic testing without input from a healthcare professional. DTC testing now exists for the 3 Ashkenazi Jewish (AJ) BRCA1/2 founder variants. DTC testing may provide false reassurance to individuals that they do not carry a pathogenic or likely pathogenic variant (PLPV) in BRCA1/2 or other cancer-risk genes. Methods: Multi-panel genetic testing was performed in 348,692 individuals for a clinical indication of hereditary breast/ovarian cancer (Clinical cohort) and 7,636 self-referred ostensibly healthy individuals (Healthy cohort) by a clinical testing laboratory. The primary analysis evaluated PLPVs for Group 1 genes: BRCA1/2 AJ founder variants and Group 2: full sequence BRCA1/2. Secondary analyses assessed PLPVs in Group 3: high-risk breast cancer genes ( BRCA1/2, CDH1, PALB2, PTEN, STK11, TP53), Group 4: all breast or ovarian cancer-risk genes (Group 3 genes plus ATM, BARD1, BRIP1, truncating CHEK2, EPCAM, MLH1, MSH2/6, NF1, PMS2, RAD51C/D) and Group 5: 41 cancer-risk genes; these analyses were limited to participants who tested for all 41 genes. Potentially mosaic variants were excluded. Results: Table illustrates PLPVs found in both cohorts. The BRCA1/2 AJ founder variants account for only ̃11% (1513/13,987) and ̃30% (19/64) of the BRCA PLPVs in the Clinical and Healthy cohorts, respectively. Even among AJ individuals, testing only for the 3 founder variants will miss ̃10% (52/513) of all BRCA1/2 PLPVs. Evaluating only the BRCA AJ founder variants missed a higher percentage of PLPVs in other cancer-risk genes. Conclusions: The 3 BRCA1/2 AJ founder variants analyzed by DTC testing account for a small fraction of PLPVs in cancer-risk genes in the general population, and miss 10% of BRCA PLPVs even among AJ individuals. Greater public education is needed to dispel the misconception that DTC tests are equivalent to clinical assessment and comprehensive genetic testing. PLPVs identified in Clinical and Healthy Cohorts.[Table: see text]
Pan-cancer evaluation of homologous repair deficiency somatic mutations and response to first-line anti-neoplastic therapy.
Authors: Lavery Jessica A , Brown Samantha , Riely Gregory J. , Bedard Philippe L. , Park Ben Ho , Warner Jeremy Lyle , Kehl Kenneth L. , Lepisto Eva M , Rizvi Hira , LeNoue-Newton Michele , McCarthy Caroline G. , Yu Celeste , Kundra Ritika , Mastrogiacomo Brooke , Schultz Nikolaus , Rudolph Julia Elizabeth , Sweeney Shawn , Schrag Deborah , Panageas Katherine ,   AACR GENIE Consortium
Published: June 2021

10535 Background: Homologous recombination is a major mechanism of defective DNA repair, but it remains uncertain whether homologous repair deficient (HRD) tumors have favorable prognosis or are more/less likely to respond to treatment than tumors lacking such mutations. Objective: To determine whether lung (NSCLC) and colorectal (CRC) HRD+ tumors have better survival or response to chemotherapy than HRD- tumors. Methods: Patients with de novo stage IV NSCLC or CRC who had next generation sequencing (NGS) between 2015-2018 from one of four cancer centers were identified. Records were curated using the PRISSMM framework to ascertain treatment, overall survival (OS) and progression free survival based on imaging (PFS-I) and oncologists’ notes (PFS-M). Each NSCLC or CRC tumor was categorized as HRD+ if NGS revealed an oncogenic/likely oncogenic mutation in: ATM, BAP1, BARD1, BLM, BRCA1, BRCA2, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN, PALB2, RAD50, RAD51, RAD51C, RTEL1, or MRE11A based on the OncoKB database. The tumor was categorized as HRD- if no oncogenic mutation in any of these genes was evident and HRD indeterminate (HRD?) if no mutation was identified but the panel did not include all genes. OS, PFS-I and PFS-M from start of first line therapy were reported by HRD status. The percentage with a good response to first line therapy (≥2x the median) and exceptional response (≥3x the median) was estimated for each endpoint. Results: For NSCLC 4% were HRD+, 59% HRD- and 37% HRD?. For CRC there were 5% HRD+, 60% HRD- and 35% HRD?. There were no significant differences for any survival endpoint between patients who were HRD+ vs HRD- in univariable analyses. The proportion of good and exceptional responders to first line systemic chemotherapy also did not vary by HRD status, though patients with HRD+ CRC were potentially more likely to be exceptional responders. Similarly, no differences between HRD+ and HRD- tumors were apparent for the subgroup receiving platinum containing therapy. Conclusions: NSCLC and CRC patients with somatic mutations in HRD oncogenic genes did not differ from patients lacking such a mutation with respect to OS or PFS. CRC patients with HRD+ tumors may be more likely to be exceptional responders, but sample sizes are limited. By May, the analysis will include breast and pancreatic cancer cases.[Table: see text]
Identification and characterization of de novo TP53 mutation carriers in Li-Fraumeni syndrome families: A single institution experience.
Authors: Vera Recio Carlos Christian , Corredor Jessica , Dodd-Eaton Elissa , Gutierrez-Barrera Angelica M. , Daw Najat C. , Arun Banu , Wang Wenyi 
Published: June 2021

10538 Background: Li-Fraumeni syndrome (LFS) is an inherited cancer syndrome mainly caused by a deleterious mutation in TP53. An estimated 48% of LFS patients present due to a deleterious de novo mutation (DNM) in TP53. The knowledge of DNM status, DNM or familial mutation (FM), of an LFS patient requires genetic testing of both parents which is often inaccessible, making de novo LFS patients an understudied population. Famdenovo.TP53 is a Mendelian Risk prediction model used to predict DNM status of TP53 mutation carriers based on the cancer-family history and several input genetic parameters, including disease-gene penetrance. The good predictive performance of Famdenovo.TP53 was demonstrated using data collected from four historical US cohorts. We hypothesize that by incorporating penetrance estimates that are specific for different types of cancers diagnosed in family members, we can develop a model with further improved calibration, accuracy and prediction. Methods: We present Famdenovo.CS, which uses cancer-specific penetrance estimates that were derived previously using a Bayesian semi-parametric competing risk model, to calculate the DNM probability. We use our model to analyze 101 families recently collected from the Clinical Cancer Genetic program at MD Anderson Cancer Center (CCG-TP53) that includes 20 families with known DNM status and 81 families with unknown DNM status. We used the concordance index (AUC), observed:expected ratios (OE) and Brier score (BS) to measure our model’s discrimination, calibration and accuracy, respectively. We estimate the proportion of probands that present a DNM and compare DNM to FM carriers in several areas including: cancer types diagnosed, age at diagnosis, number of primary cancers diagnosed, sex, amino acid change caused by mutation in TP53. Results: Famdenovo.CS showed equally good discrimination and calibration performance to Famdenovo.TP53, while improving the overall accuracy, demonstrated by a decrease in the Brier score of -0.09 (95% CI: [-0.02, -0.19]). Of the 101 probands in the CCG-TP53 cohort, we predict 39 to be DNMs and 62 to be FMs. The cancer types and ages of diagnosis observed in FMs and DNMs are similarly distributed. Conclusions: Famdenovo.CS shows improved model accuracy in the CCG cohort. DNMs in TP53 are a prevalent cause of LFS and we did not find differences in the clinical characteristics of DNM and FM carriers. Our model allows for a systematic identification and characterization of TP53 DNM carriers.
TNF-alpha immunosuppressive use and future malignancy risk.
Authors: Driscoll Conor , O'Shea Kaitlyn , Zhang Hui , Rich Jordan , Yang Christopher , Isaacson Dylan , Li Eric , Siddiqui Mohammad , Kundu Roopal , Schaeffer Edward M. , Kundu Shilajit ,   TNF Alpha ASCO 2021
Published: June 2021

10558 Background: Tumor Necrosis Factor Alpha (TNF-a) inhibitors suppress the immune system in patients with systemic inflammatory conditions. Long term data assessing future cancer risk for these patients is not known. We assessed long term risk of malignancy in patients with Rheumatoid Arthritis [RA], Inflammatory Bowel Disease [IBD], Psoriasis [PS], and Ankylosing Spondylitis [AS], who were or were not exposed to a TNF-a inhibitor. Methods: This was a retrospective, cohort study conducted using electronic medical record data for patients with complete demographic and treatment data at Northwestern Medicine from years 1998 to 2020 (RA: n = 10763; IBD: n = 12106; PS: n = 1920; AS: n = 5103). Inverse Probability of Treatment Weighting (IPTW) was used to balance the distributions of age, race, gender, smoking status, and follow-up time across exposure groups within each inflammatory condition type. Relative risk (RR) of malignancy based on TNF-a exposure was assessed using logistic regression. Results: 2583 (24.0%) of RA, 2185 (18.0%) of IBD, 1811 (94.3%) of PS, 572 (11.2%) of AS patients had TNF-a exposure. Median follow-up for patients was 43 months. The RR for any cancer was higher for patients exposed to a TNF-a agent with rheumatoid arthritis (RR 1.121 (95% CI 1.02-1.23, p = 0.015) and psoriasis (RR 1.763 (95% CI 1.32-2.37, p < 0.001). The relative risk of any cancer was lower in patients exposed to a TNF-a agent with IBD (RR 0.858 (95% CI 0.78-0.94, p = 0.001). No significant difference in relative risk associated with TNF-a exposure was detected with ankylosing spondylitis (RR 0.929 (95% CI 0.8-1.08, p = 0.344). Conclusions: Patients with RA or PS and TNF-a exposure had higher RR of overall malignancy. Patients with IBD and TNF-a exposure had lower risk of overall malignancy. TNF-a immunosuppression may alter cancer risk differently based on the disease states for which it is being used. This information is critical when counseling patients on long term risk and screening strategies when considering TNF-a inhibition.
Young patients with cancer related to modifiable behaviors in the United States: What can we learn from them?
Authors: Chan John , Caesar Michelle Ann P. , Chan Chloe , Richardson Michael , Kapp Daniel Stuart , Francoeur Alex Andrea , Liao Cheng-I 
Published: June 2021

10560 Background: We proposed to examine trends in modifiable behaviorally related cancers among younger men and women in the United States. Methods: Alcohol-associated cancers, HPV-associated, obesity-associated, physical inactivity-associated, and tobacco-associated were defined using ICD-O-3 site codes. From 2001 and 2017, registry data were obtained from the United States Cancer Statistics database. SEER*Stat 8.3.8 and Joinpoint regression program 4.8.0.1 were used to calculate the trends of associated cancers expressed per 100,000. Results: Of the young women (ages 20-49 years) the incidence of cancers in 2017 associated with alcohol, smoking and obesity were 89/100,000, 43/100,000 and 64/100,000 respectively. Based on analysis of trends of women from 2001 to 2017, obesity, physical inactivity and alcohol related cancers increased with an annual percent change (APC 2.31%, 1.67%, 0.46%, p < 0.001). Using a projection model, in Hispanic women, obesity related cancers will become the highest incidence cancers by 2035, surpassing alcohol and physical inactivity. Of the young men (ages 20-49 years) the incidence of cancers in 2017 associated with alcohol, obesity, and tobacco were 23/100,000, 36/100,000 and 44/100,000 respectively. On trends analysis, obesity, physical inactivity, and alcohol related cancers have increased (APC 2.0%, 1.65%, 0.17%, p < 0.001, p < 0.001, p = 0.044), whereas tobacco-related cancers are decreasing with an APC of -0.44% (p < 0.001). When examining different regions, the highest APC for obesity and physical inactivity related cancers was 2.43% in the Midwest (p < 0.001). Using a prediction model, obesity is predicted to surpass alcohol and physical inactivity related cancers for men 20-49 years old by 2035. Conclusions: In women, most modifiable factors associated with cancer are increasing except in HPV related cancers. In men, these rates of cancer are increasing except in tobacco related cancers. However, rates of obesity related cancers are on the rise in Hispanic women and younger men in southern U.S. regions. Obesity is projected to become the major modifiable factor for many associated cancers.
Rate of incidental germline findings detected by tumor-normal matched sequencing in cancer types lacking hereditary cancer testing guidelines.
Authors: Yap Timothy A. , Ashok Arya , Stoll Jessica , Schwarzbach Anna Ewa , Blackwell Kimberly L. , Li Tianhong , Kang Hyunseok , Garber Judy Ellen , Meric-Bernstam Funda 
Published: June 2021

10582 Background: Up to 10% of all cancers are associated with hereditary cancer syndromes; however, guidelines for germline testing are currently limited to patients and families with specific cancer types (ovarian, breast, prostate, pancreatic, etc.). Although germline alterations have been shown in genes associated with cancers such as bile-duct, head & neck, brain, bladder, esophageal, and lung cancers, genetic testing is not routinely offered (PMID: 28873162). In such cancers, a guidelines-based approach may fail to detect cancer risk variants found by tumor-normal (T/N) matched sequencing. Here, we report the prevalence of incidental germline findings in patients with the aforementioned 6 cancer types and highlight frequently mutated genes by cancer type. Methods: We retrospectively analyzed next-generation sequencing data from de-identified records of 19,630 patients tested using Tempus|xT T/N matched assay. Incidental germline findings (i.e., single nucleotide variants and small insertions/deletions) detected in 50 hereditary cancer genes were determined for: bile duct (n = 466), head & neck (n = 673), esophageal (n = 395), brain (n = 1,391), bladder (n = 810), and lung (n = 5,544), where n = total patients. For comparison, we also included 4 cancer types that frequently undergo germline testing: ovarian (n = 2,042), breast (n = 3,542), prostate (n = 2,146), and pancreatic (n = 2,621). Results: We detected incidental pathogenic/likely pathogenic germline variants (P/LPV) in 6.5% (601/9,279) of patients diagnosed with the 6 selected cancer types lacking hereditary cancer testing guidelines. The highest prevalence of P/LPV was identified in patients with bladder (8%), brain (6.9%), and lung (6.5%) cancers. Frequently mutated genes (Table) include ATM (n = 62), BRCA2 (n = 60), BRCA1 (n = 33), APC (n = 27), and CHEK2 (n = 21). Of note, the Ashkenazi Jewish variant (p.I1307K) was the most frequent mutation in APC. For cancer types where patients frequently undergo germline testing, the rates of incidental germline findings in descending order were ovarian (15%), breast (12%), prostate (9.4%), and pancreatic (8.5%) cancers. Conclusions: In addition to enhanced variant calling, T/N matched sequencing may identify germline variants missed by a guidelines-based approach to testing. The identification of such germline findings may have clinical implications for the patient, as well as at-risk family members, thereby resulting in the opportunity for genetic counseling and risk-stratified intervention.[Table: see text]