bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and unique pharmacokinetic profile of ARX788, a site-specific ADC, in heavily pretreated patients with HER2-overexpresing solid tumors: Results from two phase 1 clinical trials.
Authors: Hurvitz Sara A. , Park Haeseong , Frentzas Sophia , Shannon Catherine M. , Cuff Katharine , Eek Richard Wilhelm , Budd George Thomas , McCartney Amelia , O'Shaughnessy Joyce , Lu Janice M. , Zhang Jian , Ji Dongmei , Shen Weina , Li Matt , Yan Jinchun , Xia Gang , Ji Yanping , Yao Sulan , Xiong Gaozhun , Hu Xichun 
Published: June 2021

1038 Background: ARX788 is a site-specific, homogeneous, and highly stable ADC. The payload AS269 is conjugated to the synthetic amino acids para-acetylphenylalanine (pAF) in a humanized anti-HER2 mAb. ARX788 demonstrated promising activity in HER2-positive, HER2-low, and T-DM1 resistant tumors in preclinical studies. Here we present the phase 1 clinical data evaluating the safety, antitumor activity, and PK of ARX788 in advanced solid tumors. Methods: The standard 3+3 design (0.33 - 1.5 mg/kg; Q3W or Q4W) is used to determine the MTD and/or RP2D in two phase 1 studies in HER2-positive solid tumors in U.S. and Australia (ACE-Pan tumor-01) and in HER2-positive breast cancers in China (ACE-Breast-01). The efficacy endpoints include ORR and DCR. Intensive PK sampling in first 3 cycles is performed to characterize serum PK profiles of ARX788, total Ab, and pAF-AS269. Results: 69 and 34 heavily pretreated patients received ARX788 monotherapy in the ACE-Breast-01 (median 6 prior lines of therapy) and ACE-Pan tumor-01 trial (including breast, gastric/GEJ, NSCLC, ovarian, urothelial, biliary track, endometrial, and salivary gland cancer) respectively. Dose escalation for both studies have been completed with no DLT reported. MTD has not been reached. ARX788 was generally well tolerated with most AEs being grade 1 or 2. The most common grade >3 AEs include ocular AEs (5.7 %) and pneumonitis (4.3%) in the ACE-Breast-01 trial; pneumonitis (2.9%) and fatigue (2.9%) in the ACE-Pan tumor-01 trial. Low systemic toxicities in terms of the incidence rate and grade (as shown in table). No treatment-related death. In the 1.5 mg/kg cohort, ORR was 74% (14/19) and 67% (2/3) for ACE-Breast-01 and ACE-Pan tumor-01, respectively. DCR was 100%. Median DOR or median PFS has not been reached. PK profiles for total antibody and ARX788 were generally comparable across all dose levels. Mean T1/2 for ARX788 and total antibody had approximately 100 hours at the dose of 1.5 mg/kg. Serum pAF-AS269 concentrations peaked with a median time of 168 h. Serum exposure of pAF-AS269 was low with the Cmax and AUC at cycle 1 being approximately 0.1% and 0.18% of those for ARX788 on a molar basis, respectively. Conclusions: High stability of ARX788 and low serum exposure of pAF-AS269 may underlie the low systemic toxicity, which differentiates it from other ADCs. Clinical trial information: NCT032550070 .[Table: see text]
Clinical impact of medical policy supporting universal germline testing for patients with colorectal cancer.
Authors: Nielsen Sarah M. , Dalton Joline , Hatchell Kathryn E. , DaCosta Byfield Stacey , Moretz Chad , Buresh John , Hall Taryn , Nussbaum Robert Luke , Esplin Edward D. 
Published: June 2021

10514 Background: Colorectal cancer (CRC) affects approximately 104,000 patients (pts) annually in the United States, up to 45% of which are estimated to be genetic and/or familial. Aligned with clinical guidelines, in 2020, a large U.S. insurer established Medical Policy allowing for and reimbursing germline genetic testing (GGT) for all CRC pts. This study reports overall uptake of GGT in CRC pts under this inclusive policy, actionable findings and treatment implications for pts tested, stratified by self-reported ancestry/ethnicity. Methods: Two independent de-identified datasets were reviewed, including administrative claims data of commercially insured and Medicare Advantage enrollees, aged 18+ with CRC (≥1 claim with ICD10 C18, C19 or C20 in the first position) who were continuously enrolled (CE) in the health plan from 1/2019-10/2020. Evidence of genetic testing based on CPT codes, was examined during 2020. A second de-identified dataset of CRC pts whose GGT was billed to the insurer under the Medical Policy, was also reviewed. Patient demographics, clinical information and GGT results were descriptively analyzed. Results: Of the >18,000,000 CE enrollees, 55,595 were identified as CRC pts, of whom 1,675 (3%) received GGT. From the GGT dataset, 788 pts had test results available for review. 143 (18%) pts had pathogenic/likely pathogenic (P/LP) variants in genes including MSH2, MLH1, PMS2, MSH6, CHEK2, APC, BRCA2, ATM, MUTYH (biallelic). Of pts with P/LP variants, 96 (67%) were potentially eligible for precision therapy and/or clinical treatment trials. Overall, 133 (93%) had P/LP variants in genes with precision therapy, clinical trial and/or published management implications. In a subset of pts (n=674) with ethnicity data; Asian, Black/African-American and Hispanic pts showed lower relative uptake of germline testing than Caucasians (Table). Conclusions: Despite Medical Policy allowing for GGT for all pts with CRC, only 3% of eligible pts received testing. If all CRC pts had been tested, these data suggest up to 6,705 pts with P/LP variants conferring potential eligibility for precision therapy (PD-1/PD-L1 inhibitors) or clinical treatment trials (PARP inhibitors), and an additional 2,602 pts with mutations in genes with published management recommendations, could have been identified, but were missed. Additional research is needed to identify obstacles to systematic implementation of this Medical Policy, the best timing of GGT to prevent CRC and improve access to underrepresented populations. CRC patients with germline genetic testing.[Table: see text]
Cancer-specific mortality associated with germline genetic testing results among women with breast cancer or ovarian cancer treated with chemotherapy.
Authors: Kurian Allison W. , Abrahamse Paul , Hamilton Ann S. , Deapen Dennis , Gomez Scarlett Lin , Morrow Monica , Berek Jonathan S. , Katz Steven J. , Ward Kevin C. 
Published: June 2021

10517 Background: Breast and ovarian cancer patients increasingly undergo germline genetic testing. While studies suggest a greater chemotherapy benefit for carriers of BRCA1/2 pathogenic variants, little is known about whether pathogenic variants in other genes are associated with cancer mortality. Methods: Georgia and California Surveillance, Epidemiology and End Results (SEER) registry records of women diagnosed with breast cancer or ovarian cancer from 2013-2017 were linked to results of clinical germline genetic testing from four participating laboratories. Patients were included if they linked to a genetic result, had stages I-III breast cancer or I-IV epithelial ovarian cancer and received chemotherapy. Multivariable Cox proportional hazard models were used to examine the association of genetic results, demographic and clinical factors with cancer-specific mortality. Results: 21,348 breast and 4,320 ovarian cancer patients were analyzed with median follow-up of 41 months. Pathogenic variants were present in 12% of patients with estrogen and progesterone receptor-positive, HER2-negative breast cancer, 9% with HER2-positive breast cancer, 17% with triple-negative breast cancer and 18% with ovarian cancer. Pathogenic variants were most common in BRCA1/2, CHEK2, PALB2, ATM and BRIP1. Among triple-negative breast cancer patients, mortality was lower with pathogenic variants in BRCA1 (hazard ratio (HR) 0.27, 95% confidence interval (CI) 0.17-0.45) and genes other than BRCA1/2 (HR 0.33, CI 0.13-0.81) versus no pathogenic variant. Genetic results were not associated with mortality in other breast cancer subtypes. Among ovarian cancer patients, mortality was lower with pathogenic variants in BRCA2 (HR 0.36, CI 0.26-0.49) and in genes other than BRCA1/2 (HR 0.48, CI 0.33-0.70). Conclusions: Among breast and ovarian cancer patients treated with chemotherapy, those with germline pathogenic variants in several cancer-associated genes had equivalent or lower short-term mortality than those testing negative. These results may guide patient counseling and clinical trial design.
Chemoprotective effect of metformin against HR+/HER2- breast cancer among women with type-2 diabetes.
Authors: Chikermane Soumya , Abughosh Susan M. , Sharma Manvi , Trivedi Meghna V. , Aparasu Rajender R. , Johnson Michael L. 
Published: June 2021

10518 Background: Type-2 diabetes mellitus (T2DM) increases the risk of breast cancer among postmenopausal women. Metformin has demonstrated a chemoprotective effect in breast cancer, however its role in HR+/HER2- breast cancer (HR+/HER2- BC), the most common subtype, has not been studied among older women with T2DM in the United States. This study evaluated if increased exposure to metformin is associated with a reduced risk of HR+/HER2- BC among postmenopausal women with T2DM. Methods: A case-control study was performed using the Surveillance, Epidemiology, and End Results (SEER)-Medicare data (2008-2015). Those diagnosed with HR+/HER2- BC as their first/only cancer after incident T2DM diagnosis were cases. The event date was the date of HR+/HER2- BC diagnosis in cases, and randomly assigned to non-cancer T2DM controls based on the distribution in cases. Cases were matched to up to 4 controls each using incidence density sampling with replacement. Metformin exposures were defined as cumulative dose, average intensity and adherence, measured during the 1-year lookback period prior to the event date. Dose (mg) was categorized as: 0, 0-30,000, 30,001-136,000, 136,001-293,000, and > 293,000. Average intensity per day (mg/day) was categorized as: 0, 1-500, and > 500. To evaluate adherence, those without metformin claims during the lookback period were excluded. Adherence measures were: binary proportion of days covered (PDC) (≥0.80, < 0.80) and adherence trajectories. Group based trajectory modeling was used to identify trajectories (adherent, slow decline, rapid decline, and early discontinuation). The Anderson Behavioral Model was used to guide selection of covariables: demographic and clinical variables (diabetes severity, metabolic syndrome, comedications, and health status). Conditional logistic regression was used to evaluate the association between exposure to metformin and the risk of HR+/HER2- BC. Results: The main cohort included 690 cases and 2747 controls. A decremental reduction in odds of HR+/HER2- BC in the highest cumulative dose (OR = 0.72, 95% CI: 0.55-0.95; OR = 0.60, 95% CI: 0.42-0.85) and intensity (OR = 0.61, 95% CI:0.46-0.82) categories of metformin was observed compared to the no-metformin group. Those non-adherent to metformin had 45% (OR = 1.45, 95% CI: 1.08-1.94) increased odds of HR+/HER2- BC compared to those adherent. The risk of HR+/HER2- BC in the adherent (OR = 0.67, 95% CI: 0.39-1.14), slow decline (OR = 0.75, 95% CI: 0.43-1.32) and rapid decline (OR = 0.73, 95% CI: 0.41-1.31) trajectories was not statistically significant compared to the early discontinuation trajectory. Conclusions: This retrospective study based on SEER-Medicare found an association between high dose and intensity of metformin use with reduced odds of incidence of HR+/HER2- BC among postmenopausal women with T2DM. Adherence to metformin also showed protective effect against HR+/HER2- BC.
Reductions in cancer screening: The consequence of changes in routine care during the COVID-19 pandemic.
Authors: Kim Ashley , Gitlin Matthew , Fadli Ela , McGarvey November , Cong Ze , Chung Karen 
Published: June 2021

10550 Background: The COVID-19 pandemic imposes significant impact on daily activities with regard to public health orders and individual responses to the pandemic. Much of the direct or indirect impact is potentially in reductions in healthcare encounters for services such as preventive care. Here, we quantified changes in cancer screening rates to better understand the impact of the evolving COVID-19 implications and shifts in health-seeking behaviors. Methods: We conducted a retrospective analysis of cancer screening rates during March-June 2019 (pre-COVID-19) and March-June 2020 (post-COVID-19 restrictions), using Optum’s de-identified Clinformatics Data Mart Database which includes Medicare and commercially insured members. Members meeting age and/or sex criteria as detailed in the United States Preventive Services Task Force recommendations for breast, colorectal, lung, prostate, and cervical cancer screening represented the eligible membership for screening. Procedure and laboratory services were used to identify those who received cancer screening. Analyses were conducted cross-sectionally by cancer screening type. Results: Eligible cohorts were identified from insured members within March-June 2019 and 2020 (2019: 17,931,318; 2020: 17,521,411). The percent of eligible members screened in March-June 2019 was 19.3%, 9.4%, 16.7%, 0.4%, and 7.8% for breast, cervical, prostate, lung, and colorectal cancer, respectively. Changes in screening rates from 2019 to 2020 are summarized in Table, with the sharpest decline in April. The percent change from 2019 to 2020 during the combined March-June period for each cancer screening type was statistically significant (p<0.0001). Conclusions: Routine cancer screening rates from March-June 2020 showed meaningful reductions when compared to the same period in 2019, with substantial declines during the initial peak of the pandemic in April. These declines may be impacted by variations in regional restrictions with tighter restrictions leading to larger screening declines and loosening restrictions reflecting catch-up screening. Efforts to promote cancer screening in a safe and timely manner are crucial given individual risk factors, to reduce later stage cancer diagnoses and improve clinical outcomes.[Table: see text]
Young-onset colorectal cancer: A call for action.
Authors: Baraibar Iosune , Salva Francesc , Comas Raquel , Ros Javier , Garcia Ariadna , Sanchis Mireia , Cuadra Jose Luis , Saoudi Nadia , Valdivia Augusto , Mulet Nuria , Virgili Ana , Hernando Jorge , Capdevila Jaume , Martí Marc , Landolfi Stefania , Verdaguer Helena , Espin Eloy , Nuciforo Paolo , Tabernero Josep , Elez Elena 
Published: June 2021

10563 Background: Young-onset colorectal cancer (YOCR) is defined as diagnosis below the age of 50. Over the past decades, the incidence of YOCRC has increased at an alarming rate, but causes and pathogenesis still remain unknown. Early detection of colorectal cancer (CRC) has demonstrated to improve survival. Despite these facts, adults < 50 years old are not yet included in screening programs and YOCRC is not well characterized. We aimed to characterize the clinical and molecular characteristics of YOCRC in patients (pts) diagnosed at our institution. Methods: Consecutive pts with a diagnosis of CRC below the age of 50 visited for the first time at Vall d’Hebron University Hospital in Spain between January 2017 and October 2020 were included in the analysis. Data of clinicopathologic features and treatment were collected retrospectively from medical records. Results: 205 pts met the inclusion criteria, 111 (54%) were females, 8 (4%) presented a personal history of cancer at diagnosis and 109 (53%) a family history of cancer. Age at diagnosis was: < 30: 10 (5%), {30 – 40): 52 (25%), {40-45): 51 (25%), {45-50): 92 (45%). Site of primary tumor was: right colon: 50 (24%), left colon: 107 (52%): rectum: 48 (24%). Stage at diagnosis was I: 3 (1%), II: 14 (7%), III: 60 (29%), IV: 128 (63%). 6 of 14 (43%) and 44 of 60 patients (73%) with stage II and III CRC presented disease progression after initial treatment, respectively. Molecular status was: KRAS mutation: 74 (36%), NRAS mutation: 7 (3%), BRAF mutation: 12 (6%), MSI-H: 12 (6%). 43 pts (21%) had documentation of genetic counseling. Median (range) number of lines of treatment for metastatic disease was 3 (1-7), 53 pts (30%) received at least 4 lines of treatment. Median (range) number of metastatic sites was: 2 (1-6). 114 patients (55.6%) had died at the cut-off timepoint. Conclusions: YOCR is usually diagnosed with a more advanced stage than standard-onset CRC, with a poorer course of the disease. Further studies in young adults with CRC should address this phenomenon to understand the underlying causes, and prioritize genetic counseling. Our results support the unmet need of initiating screening programs in adults younger than 50 years, the urgency for a global consensus and a call for action.
Point of care genetic testing in a breast cancer survivorship clinic.
Authors: Ranallo Lori , Nye Lauren Elizabeth , Williams Mary , Fabian F.A.S.C.O Carol J. , O'Dea Anne , Klemp Jennifer R. 
Published: June 2021

10580 Background:: Breast cancer survivorship care (BCSC) includes the ongoing assessment of personal and family cancer history and offering genetic education, counseling and testing to survivors who meet NCCN, ASBrS and Medicare guidelines for germline genetic testing. It is reported that approximately 8% of patients with breast cancer (BC) will have a clinically actionable germline mutation. However, lower than expected rates of testing are seen in both the acute and extended phases of BCSC. We sought to identify the number of patients seen in a long-term survivorship clinic who had previously undergone or currently qualified for germline testing, and the prevalence of germline variants in BC survivors. Methods: In a Nurse Practitioner (NP) led clinic, 2,184 non-selected BC survivors were screened to determine if: germline testing was previously completed or if update germline testing or initial germline testing is needed (with a 3-generation review of family history). BC survivors eligible for initial or update germline testing (411 patients) were provided with genetic education, counseling, and offered multigene panel testing. Seven (7) BC survivors declined testing. Results: From May 2019 – January 2021, 2,184 BC survivors were seen in the clinic. The average age of survivors = 60.2 yrs; average time since diagnosis = 10.7 yrs; and average age at diagnosis = 50.1 yrs, gPV were identified in 10.4%. Out of pocket cost on average was $50.00 for 2.0% of those tested. Conclusions: Within a comprehensive Breast Cancer program where genetic testing is common practice, there is an ongoing need to screen breast cancer (BC) survivors for genetic testing eligibility. A significant number of BC survivors will test positive for a pathogenic mutation (10.4%) a decade after an initial diagnosis. Genetic testing is a necessary step to stratify a BC survivors’ risk of developing secondary cancers, appropriate screening and prevention strategies, cascade testing, and for some, treatment planning. This individualized approach to BCSC is often described, but difficult to put into action. Time/access and drop rates with a referral model are barriers. Incorporating a point of care genetic testing model requires additional support (genetic extender), professional development, education, and a commitment to provide patient centric care.[Table: see text]
Germline testing and somatic tumor testing for BRCA1/2 pathogenic variants in ovarian cancer: What is the optimal sequence of testing?
Authors: Kwon Janice S. , Tinker Anna , Santos Jennifer , Compton Katie , Sun Sophie , Schrader Kasmintan A. , Karsan Aly 
Published: June 2021

10585 Background: In 2020 ASCO recommended that all women with epithelial ovarian cancer have germline testing (GT) for BRCA1/2 mutations, and those without a germline pathogenic variant (PV) should have somatic tumor testing (TT), to determine eligibility for PARP inhibitor (PARPi) therapy (GT-TT strategy). An alternate strategy is to start with tumor testing first, and to conduct germline testing only in those with a PV in the tumor, or a significant family history (TT-GT strategy). The objective was to conduct a cost-effectiveness analysis comparing the 2 testing strategies. Methods: A Markov Monte Carlo simulation model compared the costs (USD) and benefits of the 2 testing strategies. According to local empiric data, a sufficient tissue sample for TT was available in 99% of cases, otherwise the patient would only have GT. Sensitivity of TT was 99% for detecting germline PV. Only those with BRCA1/2 PV were eligible for PARPi. Primary outcomes included the number of women eligible for PARPi, with progression-free years of life (PFLY) gained based on SOLO1 data, and the incremental cost-effectiveness ratio (ICER). Monte Carlo simulation estimated the number of women who would have GT and TT, and the total with germline or somatic BRCA1/2 PV eligible for PARPi. Sensitivity analyses accounted for uncertainty around various parameters. Results: The GT-TT strategy was more effective but more costly than TT-GT in identifying patients eligible for PARPi. Table summarizes the average lifetime costs, benefits, and Monte Carlo simulation estimates for 10,000 women diagnosed with advanced epithelial ovarian cancer annually in the USA. The incremental benefit from the GT-TT strategy would be achieved at substantial cost to the health care system, with an ICER of $119,340 per PFLY gained relative to the TT-GT strategy. The results were highly sensitive to the sensitivity of TT to detect germline PV, and the costs of GT and TT. Assuming that GT was less than 50% of the cost of TT, the sensitivity of TT had to exceed 98% for the TT-GT strategy to be cost-effective. Conclusions: Although the ASCO recommended strategy of BRCA germline testing followed by tumor testing for those without a pathogenic variant may be more effective in identifying ovarian cancer patients for PARP inhibitor therapy, it is more costly. The ASCO strategy is justified if the sensitivity of tumor testing is not sufficiently high. However, assuming high tumor testing performance rates, tumor testing first followed by germline testing if there is a PV in the tumor and/or family history is a cost-effective strategy.[Table: see text]
Multicancer hereditary syndrome testing: Genetic counselors’ perspectives.
Authors: Weldon Christine B. , Liang Su-Ying , Phillips Kathryn A , Douglas Michael P , Scheuner Maren Theresa , Kurian Allison W. , Schaa Kendra , Roscow Breanna , Erwin Deanna , Trosman Julia Rachel 
Published: June 2021

10594 Background: The accessibility of cancer hereditary syndrome testing has increased, and the cost has declined significantly in the past few years. We conducted a national, quantitative survey of genetic counselors (GCs) to assess their perspectives on what influences hereditary cancer genetic testing decisions and practices, with a focus on cost. This survey was funded by NIH, conducted by UCSF TRANSPERS, and supported by the National Society of Genetic Counselors (NSGC). Methods: The survey was developed through literature review, expert interviews, and a pilot. Sent to the NSGC Cancer Special Interest Group via email. Chi-square tests were used to examine variability. Results: The survey response rate was 56% (202/363). Multiple hereditary cancer syndrome tests are discussed often/always by 86% of genetic counselors (GCs). The existence of an institutional protocol on multiple hereditary cancer syndrome testing was reported by 35.4% of GCs. When asked about GC counseling encounters, GCs report insurance rarely/never pays for: 25.2% pre-test in-person, 39.7% for pre-test tele-genetics, 35.4% post-test in-person, and 52.9% post-test tele-genetics. GCs rated clinical factors higher than cost as influencing decision for multiple hereditary syndrome cancer testing (table); the total cost of the test was least important. These patterns were similar across the GCs institution types and years in practice. Conclusions: We found consistent use of multiple hereditary cancer syndrome tests, with less focus on cost, out-of-pocket, and insurance coverage and more of a focus on clinical indicators. GCs reported challenges with reimbursement for GC counseling encounters. The shift toward more genetic counseling encounters via tele-genetics necessitates evaluation of insurance reimbursement.[Table: see text]