bluuebunny/crossref_metadata_2025_split huggingface dataset:
Germline alterations in patients with lung cancer.
Authors: Govindan Ramaswamy , Navo Katie , Huang Minxuan , Chao Calvin Y. , Sankararaman Sumithra , BOLTON KELLY L , Cao Yin 
Published: June 2023

10512 Background: Despite extensive knowledge about genomic alterations in tumor cells, less is known about germline alterations in patients with lung cancer. In this study, we explore the association between germline alterations in cancer-predisposition genes across lung cancer patients with different tumor histologies and smoking status. Methods: To compare the alterations in cancer-predisposing genes through germline profiling, we analyzed 11,740 tumors from primary Lung patients (any stage/ subtype) sequenced with Tempus xT tumor/normal matched assay (DNA-seq of 648 genes at 500x coverage, full transcriptome RNA-seq). Prevalence of pathogenic/likely pathogenic (P/LP) germline alterations in 46 genes was compared between smokers and non-smokers, non-smoker somatic EGFR altered (sEGFRalt) and non-smoker somatic EGFR wild-type (sEGFRwt), non-small cell lung histology (NSCLC) and small cell histology (SCLC), and lastly NSCLC sEGFRalt and NSCLC sEGFRwt. Due to the low prevalence of germline, most differences were insignificant, although statistics of interest are reported. Results: Of 10,419 lung cancer patients with known smoking status (89%) 8845 were smokers and 1574 non-smokers. MUTYH germline alterations were detected in 1.3% vs. 1.1%, ATM 0.7% vs. 1.0%, and EGFR < 0.1% vs. 0.4% in smokers and non-smokers with lung cancer respectively. Among non-smokers, 549 were sEGFRalt and 1025 were sEGFRwt. MUTYH germline alterations were detected in 1.1% non-smoker sEGFRalt vs. 1.1% non-smoker sEGFRwt, ATM 0.7% vs. 1.1%, and EGFR 1.1% vs. 0%. Germline EGFR was significant after FDR adjustment (q < 0.037). There were 10115 patients identified with NSCLC histology and 595 with SCLC histology. MUTYH germline alterations were detected in 1.3% NSCLC vs. 0.3% SCLC, ATM 0.8% vs. 0.3%, and BRCA2 0.7% vs. 0%. Of note, SCLC was more likely to be smokers than NSCLC (93% vs. 85%, p < 0.001). Among NSCLC, 1,141 were sEGFRalt and 8,974 were sEGFRwt. MUTYH germline alterations were detected in 1.6% NSCLC sEGFRalt vs. 1.3% NSCLC sEGFRwt, ATM 0.5% vs. 0.8%, EGFR 1.3% vs. 0%, and BRCA2 0.8% vs. 0.6%. Germline EGFR was significant after FDR adjustment (q < 0.001). A separate analysis of the United Kingdom Biobank data found the prevalence of P/LP germline alterations in the same 46 genes in 4.3% of 1132 smokers with lung cancer and 5.1% in 198 never-smokers with lung cancer. The most common germline alterations involved ATM (0.8%), BRCA 2 (0.79%), MUTYH (0.62%) among smokers and MUTYH (1.5%), and CHEK2 (1.01%) among non-smokers. Conclusions: Currently, there are no standard guidelines for germline analysis for patients with lung cancer. The Tempus database enables the identification of pathogenic or likely pathogenic germline alterations in a variety of lung cancer subtypes along with their distribution frequency among various groups. The findings suggest that germline P/LP alterations in the select panel of 46 genes occur infrequently across subgroups of lung cancer.
Famitinib for familial adenomatous polyposis-associated aggressive desmoid tumors: A single-center exploratory study.
Authors: Ge Sai , Li Jian , Shen Lin , Wang Zhenghang , Li Huajun , Wang Xicheng 
Published: June 2023

10513 Background: Desmoid tumour (DT) is a common extra-intestinal manifestation of familial adenomatosis polyposis (FAP), with high risk of recurrence and became the second leading cause of FAP patients’ death. The treatment of FAP-associated DTs are limited. Famitinib is a orally bioavailable, tyrosine kinase inhibitor against VEGFR-2, PDGFR, c-kit, and FGFR, and has shown antitumor activity in these patients (pts). Methods: This is a prospective, single arm study of FAP pts with progressing DT per RECIST v1.1, treated with famitinib 20 mg QD since 11/2021. The primary endpoint was objective response rate (ORR), with secondary endpoints of safety, progression-free survival (PFS), and quality of life (EORTC QLQ C30). We also collected the FFPE slices of DTs to test both genetic and proteomic backgrounds of pts with different therapeutic results. Results: Between Nov 24, 2021 and Aug 8, 2022, 11 pts were enrolled and evaluated every 9 weeks. The median follow-up time was 9.4 m (6.6 to 14.9 m). The median age was 36 (28-53) and 45% were male. Nine pts were diagnosed with intra-abdominal (IA) tumors while two had extra-abdominal (EA) DTs. Eight had stage III-IV DTs with rapid growth and severe symptoms. 10 of them had history of intestinal resection. Two pts were treated with dacarbazine and epirubicin before enrollment, while one patient received radiotherapy before famitinib. Five pts achieved partial response (PR) and six achieved stable disease (SD), with a median time to response of 7.0 months. The ORR was 45.5% and the disease control rate (DCR) was 100%. The 6-month PFS rate was 91%. The ORR of pts with IA DTs was 55.6%. Of adverse events (AEs) with famitinib, 87% were grade 1/2, the most frequently reported being hypertension (73%), neutropenia (64%), bilirubinemia (55%) and proteinuria (36%). Mean global health status/QoL before and after 6 months’ treatment was 58.3 vs 75.8 ( P= 0.09). Of all 11 pts, germline APC mutations scattered from codon 457 to 1578, and five of them detected somatic APC mutations from codon 547 to 1896 in DTs. Correlative study analysis will be presented. Conclusions: Famitinib demonstrated promising efficacy and a favorable safety profile in FAP-associated aggressive DTs.
Real-world outcomes and safety in patients with VHL associated tumors receiving belzutifan.
Authors: Chidharla Anusha , Fleer Ryan , Murphy Madison , Brunk Kelly , Holzbeierlein Jeffrey , Kasi Anup , Parikh Rahul Atul 
Published: June 2023

10515 Background: Belzutifan, a small molecule HIF-2α inhibitor was FDA approved for the treatment of VHL-associated renal cell carcinoma (RCC), CNS hemangioblastomas and pancreatic NET (pNET). The approval was based on the results from the phase 2, open-label, single-group trial, enrolling 61 patients at approximately 12 study sites (Srinivasan, 2021). Objective responses were seen in 49% patients with VHL associated RCC, 63% patients with VHL-associated CNS hemangioblastomas, and 83% of patients with VHL-associated pNET. Common adverse events included anemia, fatigue, renal dysfunction, nausea, and elevated glucose levels. There is currently very limited data on real-world outcomes using belzutifan in VHL patients. Methods: After obtaining IRB approval, we retrospectively evaluated the efficacy and safety of Belzutifan for patients with VHL disease and renal cell cancer and/or VHL-associated tumors who received Belzutifan between August 2021 and January 2023 at KU Cancer center. Results: A total of 16 patients are started on Belzutifan treatment. The baseline characteristics include median age of 45 years, including 8 (50%) females and 8 (50%) males. Patients with VHL-associated RCCs were seen in 15 patients (n = 15), VHL-associated pNET (n = 13), and CNS hemangioblastomas (n = 13). Patients were started on belzutifan 120mg daily. The patients underwent bloodwork and clinic follow-up every 6-8 weeks, and response assessment was done in 11/15 patients who had follow-up scans at 6-month intervals. Objective Response to Belzutifan in any of these VHL-associated tumors was seen in 9 of 11 patients (81%), and 1/11(9%) had progressive disease (PD). Objective response in patients with VHL-associated RCC was observed in 8/11 (72%) patients and 2/11 (18%) with partial response (PR), and 6/11 (54%) with stable disease (SD). Responses observed in patients with pancreatic lesions were 1/11 patients (9%) with CR, 1/11 (9%) with PR, and 5/11 (45%) with SD. Patients with CNS hemangioblastomas 4/9 (44%) had SD. Safety was assessed in all the patients. The predominant side effect was anemia 12/16 (75%) and fatigue 11/16 (68%). Other side effects reported are fogginess 4/16 (25%), nausea 2/16 (12.5%), dizziness 2/16 (12.5%), and shortness of breath 2/16 (12.5%). Dose reduction to 80mg was needed in 2/16 (12.5%) patients due to moderate fatigue, hypoxia in one, and dysgeusia, respectively. Conclusions: Our real-world outcomes analysis of patients with VHL-associated tumors who are treated with Belzutifan shows an improved objective response when compared to the initial clinical trials, which is promising for patients. The analysis based on our real-world data shows the superior objective response in VHL-associated RCCs with Belzutifan, with a manageable safety profile. These findings reinforce Belzutifan as an effective treatment option for this patient population but warrant confirmation in a larger sample.
Early real-world (RW) experience with a multi-cancer early detection (MCED) test.
Authors: Westgate Candace , Kingsbury Dallas , Poliak Martin , Lipton Jordan , McMillin Matthew , Malinow Louis B. , Matrana Marc Ryan , Beausang John F. , Stanley Geoff , Shaknovich Rita , Venstrom Jeffrey M. , Kurtzman Kathryn , Shukla Vershalee 
Published: June 2023

10519 Background: An MCED test (Galleri, GRAIL, LLC, Menlo Park, CA) intended to complement recommended screening has been in clinical use since 04/2021. Here, we report RW clinical experience across age, sex, ordering site, and use case with the initial ~53,000 tests. Methods: This cell-free DNA-based MCED test uses a targeted methylation assay and a machine learning classification algorithm to detect a cancer signal (CS) and predict CS origin (CSO). This report includes tests returned from 04/20/2021 to 12/31/2022 on individuals aged ≥22 years (yrs) and excludes tests from clinical studies and sites limiting external data sharing, and repeat tests. Systematic collection of outcomes for cases with a “CS detected” (CSD) result was completed for a limited subset and continues via a rigorously controlled quality assurance (QA) program. Results: Tests were ordered and processed from across all US states (results returned, 98.9%; mean turnaround time, 6.7 business days). Among the 53,134 tests with results returned, CSD rate (CSDR) was was 1.0% (95% CI, 0.9-1.0; 510/53134), generally higher in males (1.1% [1.0-1.2; 313/29201]) vs females (0.8% [0.7-0.9; 197/23933]), and comparable to expected CSDR (males 1.07%; females 0.96%) as modeled based on MCED test performance and cancer incidence from SEER. CSDR increased with age (Table), which was a significant predictor of CSDR (p < 2e-13). In males and females, 67.4% and 61.9% of CSOs represented cancers without (w/o) recommended population screening, respectively. Early data from the QA program from an initial limited subset of CSD cases showed that a CSD result was associated with a diagnosis of invasive cancer across multiple cancers (eg, anus, breast, esophagus, head and neck, liver/bile duct, lymphoma, ovary, pancreas, plasma cell neoplasm, prostate, sarcoma), including stage I and II cancers. Conclusions: RW experience with the MCED test was consistent with previous large-scale clinical studies with an average CSDR of 1.0%, which increased with age. The test detected a CS and predicted CSO across multiple cancers, including early-stage cancers and cancers w/o recommended screening. This indicates that the MCED test can reliably detect a CS, which is essential to support population screening. Follow-up of CSD cases is ongoing through the QA program and will allow for future reporting of RW outcomes. [Table: see text]
HER2 persistence after treatment with T-DXd in breast and gastrointestinal cancers.
Authors: Drago Joshua Z. , Pareja Fresia , Jhaveri Komal L. , Walsh Elaine M. , Ku Geoffrey Yuyat , Maron Steven Brad , Janjigian Yelena Y. , Robson Mark E. , Reis-Filho Jorge S. , Modi Shanu , Razavi Pedram , Chandarlapaty Sarat 
Published: June 2023

1052 Background: T-DXd is a HER2-targeted antibody drug conjugate approved for treatment of advanced HER2-positive breast and gastroesophageal cancers and HER2-low breast cancers. The prevalence of HER2 loss after exposure to T-DXd is unknown and has implications for treatment strategies in refractory patients. Methods: We investigated clinically reported HER2 immunohistochemistry (IHC) scoring on post-treatment tissue biopsies from patients who received at least 2 cycles of T-DXd as of 2/2023. IHC was performed using mAB clone 4B5 (Ventana) and scored by ASCO/CAP guidelines on a scale of 0 to 3+. MSK-IMPACT next generation sequencing (NGS) was performed on paired pre- and post-treatment samples when available. Statistics are descriptive. Results: A total of 62 patients with breast, gastroesophageal, or colon cancer had available post-treatment biopsies. The majority (n = 51) had breast cancer, including 32 with HER2-positive and 19 with HER2-low disease. Median time on therapy was 30 weeks in HER2-positive and 21 weeks in HER2-low breast cancer. All 32 patients with HER2-positive breast cancer had detectable HER2 expression by IHC on post-treatment biopsies (median IHC score 2+; range 1+ to 3+). Of those with HER2-low breast cancer, 12 (63.1%) patients had detectible IHC after treatment. Of the 7 with IHC scores of zero, 3 also had scores of zero on the most proximal pre-treatment biopsies. Seven patients with gastroesophageal and 3 with colorectal cancer were included, with a median time on therapy of 12 and 9 weeks respectively, of which 1 (9%) exhibited HER2-loss after treatment. Among all patients with HER2-positive cancers, the rate of complete HER2-loss by IHC after exposure to T-DXd was 2.3%. Thirty-two patients had paired genomic analysis, including 25 breast and 7 gastrointestinal cancers. No change was observed in the fraction of genome altered (p = 0.0736, q = .327) or tumor mutational burden (p = 0.139, q = .487) with T-DXd exposure. Changes in ERBB2 copy number did not show clear directionality, with 15 patients (46.7%) exhibiting ERBB2 amplification pre-treatment and 12 (37.5%) post-treatment, the sum of 3 temporal gains and 6 losses of ERBB2 amplification across the threshold of 1.8. Conclusions: HER2 remained detectable by IHC in the majority of patients treated with T-DXd in this cohort, especially those with HER2-positive cancers. These findings suggest that resistance to T-DXd may occur via target-independent factors, and that HER2 could still be exploited therapeutically in these populations. Further prospective studies using quantitative assays are needed to confirm these hypotheses. [Table: see text]
Prevalence of unexpected actionable germline pathogenic variants identified on broad-based multi-gene panel testing in a cohort of cancer patients.
Authors: Landry Kara K. , DeSarno Michael , Kipnis Lindsay , Barquet Ramos Farid , Breen Katelyn , Patton Kaleigh , Morrissette Audrey , Buehler Ryan , Ukaegbu Chinedu , Rohanizadegan Mersedeh , Yurgelun Matthew B. , Syngal Sapna , Rana Huma Q. , Garber Judy Ellen 
Published: June 2023

10523 Background: Broad-based germline multi-gene panel testing (MGPT) for inherited predisposition has become increasingly common for cancer patients. Both indications for germline testing and the spectrum of genes on MGPT have expanded. We sought to examine the frequency of an unexpected pathogenic/likely pathogenic variant (P/LPV) in patients with a variety of solid and hematologic malignancies undergoing MGPT. Methods: A retrospective review of patients with a history of cancer who underwent MGPT at a single institution from 2015 to 2021 with MGPT of > 20 cancer predisposition genes. Low penetrance genes and genes with a recessive inheritance pattern were excluded. Deidentified pedigrees were analyzed by genetic counselors for clinical diagnostic criteria and gene-specific national testing guidelines to determine whether clinical suspicion of the P/LPV was present. Results: 10,975 cancer patients underwent MGPT. 1,180 (10.9%) patients were found to have > 1 P/LPV in a moderate or highly penetrant cancer susceptibility gene. 357 (3.3%) of the P/LPV were unexpected based on patient’s personal cancer history alone. 208 (1.9%) of the P/LPV remained unexpected after patient and family cancer histories were considered. Most common cancer subtypes with an unexpected P/LPV were breast [1.5% (83/5691)], prostate [2.1% (28/1300)], colorectal [2.2% (18/823)], ovarian/fallopian [1.7% (13/781)] and uterine [ 2.8% (10/352)] cancer. Most frequent unexpected P/LPV were PMS2 (n = 19), MITF (n = 18), ATM (n = 18), BRIP1 (n = 17), CHEK2 (n = 14), HOXB13 (n = 13), SDHA (n = 12), BRCA2 (n = 7), MSH6 (n = 7), SDHC (n = 7), TP53 (n = 7), and PALB2 (n = 6). No predictor of having an unexpected P/LPV was identified in multivariable logistic regression analysis. Low penetrance or recessive variants were found in 521 (4.8%) patients. Variants of uncertain significance (VUS) were found in 3,774 (35.0%) patients. Conclusions: This large retrospective analysis of cancer patients undergoing MGPT identified an overall rate of 1.9% of P/LPV in actionable cancer predisposition genes. Findings were more often unexpected (3.3%) when considering only the patient cancer history, endorsing the importance of family cancer history for consideration of more targeted genetic testing. Identification of moderate or highly penetrant P/LPV in cancer patients is increasingly important in guiding treatment decisions, cancer screening in survivors and testing of at-risk family members. These findings may justify consideration of broader MGPT panels especially when family cancer history is uncertain or unavailable. MGPT also detected a high rate of VUS, reinforcing the importance of physician education to ensure appropriate interpretation and management.
Cardiorespiratory fitness and BMI in youth and site-specific cancer mortality in men: A population-based cohort study with register linkage.
Authors: Onerup Aron , Mehlig Kirsten , af Geijerstam Agnes , Ekblom Bak Elin , Kuhn Hans-Georg , Lissner Lauren , Åberg Maria , Börjesson Mats 
Published: June 2023

10534 Background: There is insufficient evidence on the associations between cardiorespiratory fitness (CRF), body mass index (BMI), and site-specific cancer mortality. Methods: We collected data on all men who underwent military conscription 1968-2005 in Sweden at ages 16-25. CRF was assessed as maximal aerobic workload on a cycle ergometer test and classified as low, moderate, or high. BMI (kg/m2) was classified as underweight ( < 18.5), normal weight (18.5-24.9), overweight (25-29.9), or obesity (≥30). Data was cross-linked on individual level through the Swedish identification number with national registers with high validity for information on cancer mortality. Follow-up was from conscription until death, emigration, or end of follow-up (12/31/2019). Cox regression analyses included CRF and BMI as well as age, year, and site of conscription, parental education, and muscle strength. Primary analyses tested linear trends for CRF and BMI, with effect sizes for categorical comparisons for interpretation. Results: 1,083,738 men were included in the analyses and were followed for a mean of 33 years, during which 8,912 cancer-specific deaths occurred. Lower CRF and higher BMI were linearly associated with any cancer mortality as well as with several site-specific cancer mortalities (table). However, death in some major cancer sites (prostate, CNS) were not associated with CRF or BMI and higher CRF was associated with higher mortality from malignant skin cancer. Conclusions: Higher CRF and lower BMI was associated with lower cancer mortality for some, but not all cancer sites. These results could be used as a further incentive for working with modifiable risk factors in public health. [Table: see text]
Obesity and breast cancer in women under age 40.
Authors: Cattie Rabia , Chung Victoria , Henry Marcia , Alberti Matthew , Peeples James , Yuan Helen , Saxena Raina , Olet Susan , Taylor Caitlin , Sheen Melanie Anne 
Published: June 2023

10536 Background: Obesity is a well-established risk factor for postmenopausal hormone-receptor positive breast cancer (BC). The role of obesity in premenopausal BC, especially in women under the age of 40, is not well understood. Multiple studies have shown a decreased rate of premenopausal BC with increasing body mass index (BMI), notably for estrogen receptor positive tumors. Even though there is an inverse association between obesity and premenopausal BC, it has been suggested that obesity has a negative prognostic role in premenopausal BC. This may be explained if premenopausal obese women develop more aggressive tumors. Obesity is associated with triple negative and Luminal B cancers in premenopausal women. We sought to evaluate the relationship between premenopausal breast cancer and obesity in a diverse patient population. Methods: We assembled a 10-year database of women diagnosed with breast cancer before age 40 in a single health system. Data collected included age at diagnosis, self-identified race, breast cancer subtype, BMI, and stage at diagnosis. The control group was all women under the age of 40 presenting to our health system in the same time period. Stratification analysis was performed using Mantel-Haenszel Risk Estimation. Results: The risk ratio between the standardized estimates of BC patients under 40 with BMI ≤ 30 to BMI > 30 is 0.7924, 95% CI (0.683 – 0.920), P = 0.0022. This implies that young BC patients are more likely to be obese than all young women presenting to our health system. There are more obese Black patients compared to White patients. The effect of obesity on BC diagnosis was more pronounced in Black patients, with a risk ratio of 0.59 compared to 0.96. Conclusions: The data presented here challenge previous research which had shown that obesity seemed to be protective against breast cancer in premenopausal women. Here, we see a statistically significant increase in obesity among young women < 40 years presenting with breast cancer. The increased risk of breast cancer diagnosis was particularly pronounced in obese Black women. Previous studies have had a very low proportion of Black women represented, which may cause underestimation of risk in this patient population. These data suggest that obesity is a risk factor for breast cancer in young women, especially in Black patients. [Table: see text]
The impact of high body mass index on hepatocellular carcinoma in viral hepatitis and cirrhosis.
Authors: Kim Moonho , Jun Baek Gyu , Shin Hwang Sik , Yi Sang-Wook 
Published: June 2023

10537 Background: The impact of a high body mass index (BMI) on hepatocellular carcinoma (HCC) has been unclear in patients with viral hepatitis and liver cirrhosis (LC). Our aim is to investigate the association between BMI and HCC in patients with viral hepatitis and LC. Methods: We conducted a population-based cohort study. In total, 156,143 Korean adults who underwent routine health examinations during 2003-2006 were followed up until December 2019 via linkage to the national hospital discharge records. Multivariable-adjusted hazard ratios (HRs) per each 5 kg/m2 increase in BMI for HCC risk were calculated using Cox proportional hazard models. Results: BMI was positively associated with HCC in hepatitis B virus (HBV) patients with BMI range of 27.5~29.9 kg/m² and BMI ≥30 kg/m² and LC patients with a BMI range of 27.5~29.9 kg/m². Assuming linear associations, HRs were 1.17 for HBV, 1.08 for hepatitis C virus (HCV), and 1.11 for LC. In the subgroup analysis for the LC, the HR were 1.19 in the HBV-LC, 1.38 in the HCV-LC, 1.36 in the alcoholic LC, and 1.59 in the fatty liver LC. Women showed stronger positive associations between BMI and HCC than men in the HBV (HR, 1.45 vs 1.06) and LC (1.27 vs. 1.02). The positive association seemed to be stronger in younger age ( < 65 years) in HBV (1.17 vs 1.05) and HCV (1.33 vs 0.77) patients compared to older age ( > 65 years). Conclusions: In the BMI range of ≥25 kg/m2, a higher BMI was associated with an increased risk of HCC in LC and HBV. The associations between BMI and HCC risk are different according to liver disease, sex and age.