bluuebunny/crossref_metadata_2025_split huggingface dataset:
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 .
Geographical impact on prostate cancer genetic testing eligibility: A preliminary study from an academic cancer center.
Authors: Beck Samantha , Tward Jonathan David , Gammon Amanda , Greenberg Samantha 
Published: June 2023

10618 Background: Germline testing (GT) for prostate cancer (PCa) helps to determine treatment selection and other cancer risk, which guides screening recommendations. Patients with PCa that is high risk group by NCCN and greater stage should receive genetic counseling (GC) referral. There is limited data on differences in genetic services given the rurality of PCa patients. This study aims to determine the geographical distribution of PCa patients meeting GC referral and GT criteria. Methods: A retrospective analysis evaluated data from electronic medical records of PCa patients at an NCI-designated cancer research facility. Data was abstracted from new PCa patients seen in 2019 and 2021, years before and after the COVID-19 pandemic. Data includes demographic information, cancer staging, and pathology results. Regions of urbanicity, urban and non-urban (rural/frontier), were categorized through zip codes and defined by Utah Department of Health and Human Services. Criteria for GT followed NCCN guidelines (v.1.2023). Statistical methods for descriptive and comparative analysis done using Chisquare, Fisher’s exact, and Mann Whitney tests in R*Stats to compare 2019 and 2021 cohorts. Results: Out of 525 PCa patients' initial treatment at HCI in 2019 (n = 346) and 2021, (n = 179) 94% self-reported as White (p = 0.164) with a median age of 66 (p = 0.690) and 51% being employed (p = 0.396) at time of first treatment. Of these, 414 (79%) were from an urban area and 111 (21%) from a non-urban area (p = 0.883). The cohort was primarily from 2019 (66%), with 274 (79%) and 72 (21%) of the PCa patients living in urban and non-urban areas, respectively. In 2021 (34%), 140 (78%) and 39 (35%) patients were from urban and non-urban areas. Criteria for GT were met in 37% (n = 196) of PCa patients (p = 0.595). Regions were independently compared by race, age, employment, and year. No statistical difference across all variables was found (p > 0.05). Geographical regions did not impact GT eligibility. Conclusions: This preliminary study shows that geographical region does not impact GT eligibility in PCa patients seen at HCI during 2019 and 2021. The years analyzed is a proxy for differences in aggressiveness by rurality. The results show 37% of the PCa patients met criteria for GT. No significant differences were identified by geographical region, race, age, employment, or the year of initial treatment. Further research is being conducted to determine if access to PCa GC uptake is impacted by geography and differing service delivery models after criteria for GT has been met.
Endocrine therapy resistance (ETR) in hormone receptor-positive, HER2-negative metastatic breast cancer (HR+, HER2– mBC): Prevalence, biomarker characteristics, and outcomes.
Authors: Jeselsohn Rinath , Chen Lu , Chaudhary Nayan , Martinalbo Jorge , Fasching Peter A. , Hafner Marc , Luhn Patricia , Montero Alberto J. , Pérez-Moreno Pablo Diego , Wander Seth Andrew , Kalinsky Kevin 
Published: June 2023

1062 Background: ETR to prior adjuvant ET poses challenges to first-line treatment (1L tx) of HR+, HER2– mBC. Understanding patient (pt)/disease heterogeneity is crucial for developing new txs that target specific ETR mechanisms to improve pt outcomes. We investigate ETR, including prevalence, genomic profiles, and survival outcomes in pts with HR+, HER2– mBC treated in the 1L setting. Methods: This retrospective two-cohort study of pts initiating 1L systemic tx for mBC (diagnosed after Jan 1, 2015) used data from the Flatiron Health (FH) electronic health record-derived de-identified database (FH cohort), and FH-Foundation Medicine, Inc. (FMI) clinico-genomic database (CGDB cohort; solid biopsy FMI test required). The de-identified data originated from ~280 US cancer clinics (~800 sites of care). Pts with ETR to prior adjuvant ET were defined per ESMO guidelines (table footnote); primary ETR (1ETR) was divided into pts relapsing within 1 year (yr) or 1–2 yrs of adjuvant ET. Genomic profiles were assessed in the CGDB cohort. In both cohorts, real-world (rw) progression-free survival (PFS) and overall survival (OS) were estimated in pts who received 1L tx with fulvestrant (F) + CDK4/6 inhibitor (CDK4/6i). Results: In the FH cohort (N = 4052), 16.1% of pts had 1ETR (ET <1 yr: 7.9%) and 33.9% had secondary ETR (2ETR). In the CGDB cohort (N = 696), ESR1 mutations (ESR1m) were present in 10.8% of 158 pts with 1ETR (ET <1 yr: 4.2%; 1–2 yrs: 16.1%) and 19.9% of 317 pts with 2ETR. In pts who received 1L F + CDK4/6i, shorter median (m) rwPFS (statistically significant) and OS (not significant) were seen in pts with 1ETR vs. 2ETR, but outcomes were not affected by the presence of ESR1m in pts with 2ETR. Conclusions: Overall, half of pts with 1L HR+, HER2– mBC have ETR to prior adjuvant ET. Pts with ETR have tumors with heterogeneous genomic profiles and varied survival outcomes. ESR1m are infrequent in pts with 1ETR and <1 yr of adjuvant ET but are more common in 2ETR. In pts treated with 1L F + CDK4/6i, PFS and OS were worse with 1ETR than 2ETR. This study highlights the importance of further understanding the heterogeneity in molecular profiles and outcomes within ETR. [Table: see text]
Risk of death among lung cancer patients before and during the COVID-19 pandemic.
Authors: Lee Teddy Tai Loy , Zheng Danyang , Wang Sichao , Wai Abraham Ka Chung , Kong Feng-Ming Spring 
Published: June 2023

10625 Background: The survival of lung cancer patients in Hong Kong before and during the COVID-19 pandemic is poorly understood. Methods: Patients diagnosed with lung cancer from January 1 2010 to October 31 2022 were recruited from all 43 public hospitals in Hong Kong. Patients who died on the day of cancer diagnosis were excluded. Patients between 2020-2022 (pandemic) were matched with patients diagnosed between 2010-2019 (pre-pandemic) using 1:1 propensity score matching, based on demographics and comorbidities such as age, sex, and Charlson Comorbidity Index (CCI), to study survival before and during the pandemic. The outcomes were 1-year and 6-month all-cause mortality. In subgroup analysis, patients were categorized into 12 groups, from 2010 to 2022, based on the year of first diagnosis of lung cancer to investigate yearly changes in mortality. Patients with confirmed diagnosis of COVID-19 infection were also analyzed. Results: A total of 42102 lung cancer patients (66.0% male, age 72±12 years (median±SD), CCI 7.00±2.42) were recruited from 2010 to 2021 with 1-year follow up. Only 36 patients were confirmed COVID-19 positive. The matched cohort consisted of 4958 pandemic patients (68.6% male, age 72±12 years, CCI 8.00±2.43) and 4958 pre-pandemic patients (67.7% male, age 73±12 years, CCI 7.53±2.48). 2782 (56.1%) and 3846 (77.6%) pandemic patients died within 6 months and 1 year respectively, compared to 2338 (47.2%) and 3194 (64.4%) pre-pandemic patients. In subgroup analysis by year of lung cancer diagnosis, patients diagnosed in 2021 had highest risk of 1-year mortality (85.1%). There was no significant difference in mortality between patients with and without confirmed COVID-19 positivity. The cohort of 2022 lung cancer patients, with higher COVID-19 positivity, was still undergoing follow-up and will be included in the analysis at the time of presentation. Conclusions: Lung patients diagnosed during the COVID-19 pandemic are associated with higher risk of death within the first year compared to that of pre-pandemic patients, and is likely not associated with COVID-19 positivity. [Table: see text]
Inverse association of post-transplant malignancy and graft failure on survival outcome following double lung transplantation.
Authors: Lee Jeeyeon , Kim Hye Sung , Lee Yunjoo , Chung Liam Il-Young , Yang Won Jun , Yu Jisang , Bharat Ankit , Chae Young Kwang 
Published: June 2023

10629 Background: Graft failure (GF) and post-transplant malignancy (PTM) are common causes of death in lung transplantation. Immunosuppression to prevent graft failure is known to lead to de novo malignancies after solid organ transplantation. Here, we assess the relationship between graft failure and de novo malignancies after double lung transplantation (DLT). Methods: Data extracted from the Organ Procurement Transplantation Network (OPTN) registry were analyzed. DLT cases for non-cancerous diseases were selected. We evaluated the overall survival (OS) of recipients with or without PTM (PTM+ or PTM-), and that of recipients with or without GF (GF+ or GF-) after DLT. The association between GF and PTM was investigated. Results: Among 23,935 DLT recipients, there were 5,629 cases (23.5%) of PTM+ and 18,306 cases (76.5%) of PTM -, and 2,316 cases (9.7%) of GF+ and 21,619 cases (90.3%) of GF- following DLT. Among GF+ cases, the prevalence of acute, hyperacute, and chronic rejection after DLT was 1,962 cases (84.7%). The OS in recipients with GF+ was worse than that in recipients with GF- (p < 0.001). However, inversely, the OS in recipients with PTM+ was better than that of recipients with PTM- (p < 0.001). When patients were categorized into four categories by each factor (GF-, GF+, PTM+, PTM-), the GF rate was lower in recipients with PTM+ than in those with PTM- [GF+/PTM+ (n = 368, 1.5%) versus GF+/PTM- (n = 1,948, 8.1%)] (p < 0.001), and the PTM+ rate was higher in recipients with GF- than in those with GF+ [GF-/PTM+ (n = 5,261, 22.0%) versus GF+/PTM+ (n = 368, 1.5%)] (p < 0.001). And the GF-/PTM+ group showed the best prognosis with 97.3 months of median OS, and the GF+/PTM- group showed the worst prognosis with 36.8 months of median OS (p < 0.001). Conclusions: Recipients who developed PTM following DLT had longer OS compared with those who did not. And the GF rate was significantly lower in recipients with PTM compared to those without PTM. Further research is needed to investigate the underlying mechanism of the inverse association between PTM and GF in DLT recipients.
Outcomes with first-line (1L) ribociclib (RIB) + endocrine therapy (ET) vs physician’s choice combination chemotherapy (combo CT) by age in pre/perimenopausal patients (pts) with aggressive HR+/HER2− advanced breast cancer (ABC): A subgroup analysis of the RIGHT Choice trial.
Authors: El Saghir Nagi S. , Yap Yoon Sim , Eralp Yesim , Im Seock-Ah , Azim Hamdy A. , Rihani Julie , Volkov Nikita , Chen Shin-Cheh , Harputluoglu Hakan , Sunpaweravong Patrapim , Chang Yuan-Ching , Delgar Alfaro Teresa , Wu Jiwen , Hu Huilin , Gao Ming , Lu Yen-Shen 
Published: June 2023

1063 Background: The progression-free survival (PFS; primary endpoint) results from the Phase II RIGHT Choice trial demonstrated a statistically significant median PFS (mPFS) benefit of ≈1 y with RIB + ET over combo CT (mPFS, 24.0 vs 12.3 mo; hazard ratio [HR], 0.54; 95% CI, 0.36-0.79; P = .0007) in pts with aggressive HR+/HER2− ABC. Younger pts with aggressive ABC have a worse prognosis, which impacts treatment (tx) decisions. Hence, a subgroup analysis of key efficacy endpoints from RIGHT Choice by age (< 40 vs ≥ 40 y) was undertaken. Methods: Pre/perimenopausal pts (aged 18-59 y) with HR+/HER2− ABC and no prior systemic therapy for ABC were randomized 1:1 to either RIB with letrozole/anastrozole + goserelin or investigator’s choice of combo CT (docetaxel + capecitabine, paclitaxel + gemcitabine, or capecitabine + vinorelbine). Pts in the trial had ABC not amenable to curative therapy and for which combo CT was clinically indicated by physician’s judgment (ie, symptomatic visceral metastases, rapid progression of disease or impending visceral compromise, or markedly symptomatic non-visceral disease). Results: In total, 70 pts were aged < 40 y and 152 were aged ≥ 40 y. In the combo CT arm, pts aged < 40 y fared worse and had a shorter mPFS, shorter median time to tx failure (mTTF), and higher 3-month tx failure rate (TFR) than pts aged ≥ 40 y. Pts aged < 40 y showed a significant PFS benefit with RIB + ET vs combo CT (mPFS, not reached [NR] vs 10.2 mo; HR, 0.38). This PFS benefit with RIB + ET over combo CT was also observed in pts aged ≥ 40 y (21.2 vs 16.0 mo; HR, 0.71). Regardless of age, the mTTF was longer and the 3-month TFR was lower in the RIB + ET arm than the combo CT arm. The median time to response (mTTR), overall response rate (ORR), and clinical benefit rate (CBR) were similar between the two tx arms in both age groups. Conclusions: This analysis demonstrated a clinically meaningful PFS benefit and improved secondary outcomes with 1L RIB + ET over combo CT along with similar treatment responses in both tx arms in pts aged < 40 y as well as in those ≥ 40 y with aggressive HR+/HER2− ABC. This analysis supports RIB + ET as a preferred tx option in this pt population, including younger pts aged < 40 y. Clinical trial information: NCT03839823 . [Table: see text]
Prevalence of pathogenic germline variants in a cohort of patients with early onset non-small cell lung cancer (EOLUNG).
Authors: Jove Maria , Gausachs Mireia , Bosch-Barrera Joaquim , Carcereny Enric , Teulé Alex , Mosteiro Miguel , Pineda Marta , Tornero Eva , Hijazo-Pechero Sara , Ruffinelli Jose Carlos , Brenes Jesús , Hernandez Alejandro I. , Fina Claudia , Sais Elia , Brunet Joan , Doménech Marta , Saigi Maria , Moran Teresa , Lazaro Conxi , Nadal Ernest 
Published: June 2023

10630 Background: Patients with early onset lung cancer might be more likely to carry pathogenic (or likely-pathogenic) germline variants (PGV) in genes associated with cancer predisposition. However, germline testing is not recommended in this population. We designed this study to determine the prevalence of PGVs in patients with early onset lung cancer. Methods: This prospective, multicenter cohort study assessed PGV in patients younger than 51 years diagnosed with non-small cell lung cancer (NSCLC) in 3 sites at the Catalan Institute of Oncology between June 2018 to May 2022. Genomic DNA was sequenced using a custom-designed NGS panel covering 164 cancer-predisposing genes and results were discussed in a multidisciplinary tumor board. Results: 138 patients were included. Median age was 45.5 (28-50) years; 49% were females; 79% were ever-smokers with a median packs-year of 24 and median age of tobacco initiation of 16 years old. Most patients had non-squamous histology (88%) and had stage IV (62%) at diagnosis. Somatic oncogenic drivers were found in 74 patients (54%): EGFR 27 (20%); ALK 22 (16%); KRAS 20 (14%); RET 3 (2%); ROS1 1 (1%); BRAF V600E 1 (1%). Only 4% had past personal history of cancer and 50% had family history of cancer in a first-degree relative, being lung and breast cancer the most common tumors. Overall, 20 patients (14%) carried PGVs involving 12 genes associated with cancer predisposition: PARK2 (n=4); SBDS (n=3); NBN (n=2); ATM (n=2); TSC1 (n=2) and BLM, FANCA, MCPH1, PMS2, POLH, SDHA, RECQL4 (n=1, each). Four patients (3%) fulfilled criteria to be referred to genetic counseling clinic. There were no significant differences in clinical and molecular characteristics among patients with PGVs compared to their counterparts (Table). Conclusions: In this prospective cohort, 14% of patients with early onset NSCLC harbored germline PGVs. As clinicopathological and genomic features were not associated with PGVs, germline testing might be considered in addition to comprehensive genomic characterization of tumor tissue in young patients with NSCLC. However, only a minority of PGVs were deemed clinically actionable.[Table: see text]