bluuebunny/crossref_metadata_2025_split huggingface dataset:
Landscape of homologous recombination reversion mutations in gynecologic malignancies.
Authors: Domchek Susan M. , Reiss Kim Anna , Nathanson Kate , Bailey Shannon , Danziger Natalie , Thornton James , Hartman Mark , Cui Chenming , Yang Lei , Margolis Matthew , Gornstein Erica , Sokol Ethan , Lin Douglas I. , Schrock Alexa Betzig , Mata Douglas A , Vietz Christine , Ross Jeffrey S. , Oxnard Geoffrey R. , Elvin Julia Andrea , Decker Brennan James 
Published: June 2022

5576 Background: Homologous recombination (HR) reversion mutations (REV) are biomarkers for predicting resistance to platinum and PARP inhibitor therapies. The biologic diversity of REV represents a diagnostic challenge. An automated computational approach was used to detect REV for analysis of genomic features of REV-positive ovarian epithelial, fallopian tube, and peritoneal cancers. Methods: Retrospective study of tissue (n = 23,612) and liquid biopsy (n = 869) samples from patients undergoing hybrid-capture comprehensive genomic profiling during routine clinical care 11/2012-03/2021. A proprietary algorithm tested for seven distinct REV mechanisms in BRCA1, BRCA2, PALB2, RAD51C, or RAD51D. For subjects with multiple samples, the earliest REV-positive sample was used for downstream analyses. Results: Among 23,866 ovarian epithelial, fallopian tube, and peritoneal cancers, 16.4% (n = 3,920) had at least one pathogenic variant (PV) in BRCA1 (10%, n = 2,383), BRCA2 (5.5%, n = 1,320), PALB2 (0.67%, n = 160), RAD51C (0.64%, n = 152), or RAD51D (0.47%, n = 113). 3.9% (154/3,920) of patients with one or more PV had REV. REV were found in tumors with PV in BRCA2 at twice the frequency of BRCA1 (6.0%, [79/1,320] vs 3.0% [71/2,383]; p < 0.001). REV involving RAD51D (1.8%, 2/113), RAD51C (0.7%, 1/152), or PALB2 (0.6%, 1/160) were rarer. A total of 193 REV pairs were identified. The most frequent REV mechanism was an exonic non-frameshift deletion completely encompassing a PV (45%, 87/193). Other recurrent mechanisms included restoration of the reading frame of a frameshift PV (21%, 42/193), replacement of a PV with a benign missense substitution at the same codon (16%, 32/193), and deletion with intronic breakpoints encompassing a PV (15%, 29/193). REV were significantly more prevalent in liquid biopsies than in tissue samples with PV (16% [20/124] vs. 3.5% [134/3,796]; p < 0.001). A range of 1-6 REV pairs were found per sample (liquid: 1-6, tissue: 1-3). Multiple REV per sample was more common in liquid biopsies (35% [7/20] vs. 11% [15/134]; p = 0.011). These differences likely reflect stage of disease and sampling of multiple subclones. Conclusions: BRCA2 PV are most frequently reverted in gynecologic tumors. REV are also common in tumors with BRCA1 PV and can more rarely occur in other HR genes. Liquid biopsy is enriched for detection of polyclonal resistance. Diverse REV mechanisms highlight a need for robust detection to incorporate REV in identifying treatment resistance and guiding downstream therapy selection.
Efficacy of next line of therapy after treatment with lenvatinib (LEN) in combination with pembrolizumab (pembro) versus treatment of physician’s choice (TPC) in patients (pts) with advanced endometrial cancer (aEC): Exploratory analysis of Study 309/KEYNOTE-775.
Authors: Makker Vicky , Colombo Nicoletta , Santin Alessandro , Miller David Scott , Fujiwara Keiichi , Pignata Sandro , Ray-Coquard Isabelle Laure , Kim Yong Man , Guerra Eva M. , Huang Jie , Barresi Gianmaria , McKenzie Jodi , Lorusso Domenica 
Published: June 2022

5587 Background: In the multicenter, open-label, randomized, phase 3 Study 309/KEYNOTE-775, LEN + pembro had significant PFS and overall survival benefits, and improved objective response rate vs TPC in pts with aEC following systemic platinum-based treatment (Makker 2022, NEJM). These results were seen in all-comer pts and in pts with DNA mismatch repair proficient (pMMR) disease. Here, we assessed PFS on next line of therapy (PFS2) of each arm. Methods: Pts with aEC and 1 prior platinum-based chemotherapy regimen (or up to 2 if 1 was given in neoadjuvant/adjuvant setting) were randomized (1:1) to receive LEN 20 mg orally QD + pembro 200 mg IV Q3W or TPC (doxorubicin at 60 mg/m2 IV Q3W or paclitaxel at 80 mg/m2 IV QW [3 weeks on; 1 week off]). Randomization was stratified by MMR status (determined centrally); pts with pMMR tumors were further stratified by Eastern Cooperative Oncology Group performance status, geographic region, and history of pelvic radiation. In this prespecified exploratory analysis, PFS2 (defined as the time from randomization to disease progression on next line of treatment or death, whichever came first) was analyzed per investigator assessment in the pMMR and all-comer populations. Results: 827 Pts (pMMR, n=697; MMR deficient [dMMR], n=130) were randomized to LEN + pembro (n=411) or TPC (n=416). At data cutoff (October 26, 2020), 567 pts (LEN + pembro, n=282; TPC, n=285) had discontinued study treatment and 315 (LEN + pembro, n=115; TPC, n=200) had received a subsequent systemic anticancer therapy (Table): most commonly doxorubicin (n=58) in the LEN + pembro arm and paclitaxel (n=57) in the TPC arm. Median PFS2 was longer in the LEN + pembro arm vs the TPC arm in the pMMR population (14.4 vs 9.8 mo; HR 0.62, 95% CI 0.50–0.75) and in the all-comer population (16.0 vs 9.5 mo; HR 0.56, 95% CI 0.46–0.67). Additionally, the PFS2 rate at 6 months favored LEN + pembro vs TPC in the pMMR population (82.0% vs 74.8%) and in the all-comer population (81.7% vs 72.5%). Conclusions: Clinically meaningful improvements in PFS2 were seen in the LEN + pembro group compared with TPC in pMMR and all-comer pts. Clinical trial information: NCT03517449. [Table: see text]
Identification of a novel subtype of endometrial cancer with unfavorable outcome using artificial intelligence-based histopathology image analysis.
Authors: Darbandsari Amirali , Farahani Hossein , Abolmaesumi Purang , Leung Samuel , Kommoss Stefan , Huntsman David , Talhouk Aline , Gilks C. Blake , McAlpine Jessica N. , Bashashati Ali 
Published: June 2022

5594 Background: Molecular subtyping of endometrial cancer (EC), unlike histopathological evaluation, offers an objective and reproducible classification system that has strong prognostic value and therapeutic implications. The Proactive Molecular risk classifier for Endometrial cancer (ProMisE) was developed by our team as a pragmatic, cost-effective, and clinically applicable molecular classifier for EC patients. ProMisE has four subtypes: (i) POLE mutant ( POLEmut), (ii) mismatch repair deficient (MMRd), (iii) p53 abnormal (p53abn) by immunohistochemistry, and (iv) NSMP (No Specific Molecular Profile), lacking any of the defining features of the other three subtypes. While ProMisE subtypes are associated with clinical outcomes, within each subtype, there are clinical/prognostic outliers. This is particularly true within the largest ProMisE subtype; NSMP (representing ̃50% of ECs), where a subset of patients experience a very aggressive disease course, comparable to what is observed in patients with p53abn ECs. Methods: We hypothesized that objective assessment of the digitized hematoxylin and eosin (H&E)-stained histopathology slides of the largest and most diverse EC subset, NSMP, could potentially identify clinical outcome outliers. As such, we developed an artificial intelligence (AI)-based image analysis model to identify the NSMP cases that had similar histopathological features to the p53abn subtype, as assessed by H&E stain. We used a discovery cohort of 182 and an external validation cohort of 195 NSMP ECs. Results: Our AI-based image analysis model, based on deep convolutional neural networks, identified 21 (11.5%) out of the 182 NSMP cases with similar histopathological features as p53abn cases. We refer to these cases as ‘p53abn-like’ NSMPs. Compared to the rest of the NSMP cases, these cases had markedly inferior disease-specific survival (DSS) (10-year DSS 58.9% vs. 93.1% ( p<3.44e-8)) and progression-free survival (PFS) (10-year PFS 55.1% vs. 91.4% ( p<3.76e-6)). These findings were confirmed in our validation cohort, with 10.7% of the 195 patients categorized as ‘p53abn-like’ tumors with 10-year DSS of 82% vs. 51.3% ( p<5.28e-5) and PFS of 89.3% vs. 56.6% (p<2.15e-4). Conclusions: Utilizing an AI-based approach for histopathology image analysis, we have discovered ‘p53abn-like’ NSMPs, a novel subtype of NSMP ECs with morphological features similar to p53abn cases. ‘p53abn-like’ NSMPs exhibit similar clinical behavior as p53abn, having noticeably inferior outcome compared to the rest of the NSMP cases in two independent cohorts. These findings warrant further molecular investigation of this novel subtype of EC to identify the biological underpinning and future therapeutic strategies.
Interaction of race and socioeconomic status as risk modulators of treatment delay and cancer-specific mortality in uterine cancer.
Authors: Mattei Larissa H , Polan Rosa Miller , Ruterbusch Julie J. , Cote Michele L. 
Published: June 2022

5595 Background: The majority of studies of uterine cancer combine high and low-grade histologies and do not sample a diverse cohort of patients. In many studies race is treated as biologic construct, when it may be better thought of as a proxy for socioeconomic inequity and deprivation. Socioeconomic (SE) deprivation may play a significant role in the disease trajectory of women with uterine cancer. Methods: Data were drawn from the Metropolitan Detroit Cancer Surveillance System which covers a tri-county area of approximately 4 million people. We included non-Hispanic Black (NHB) and White (NHW) women diagnosed with uterine cancer between 2010 and 2018. Poorly differentiated and undifferentiated endometrioid, serous, clear cell, mixed, carcinosarcoma and mucinous histologies were considered high grade. Patients diagnosed by death certificate, or with unknown stage or histology were excluded. Socioeconomic status was assessed using the Yost Score, an area-level composite measure of socioeconomic deprivation derived from census-tract data at cancer diagnosis. Lower Yost quintile indicates higher deprivation. Competing risk analysis was used to determine risk of uterine cancer specific mortality (reported as subdistribution hazard ratio [SHR]) and to assess statistical interaction between race and Yost score. Results: A total of 4,840 patients were identified. Race conferred significant increased risk of cancer-specific mortality (SHR 2.11, p < 0.0001). Race and Yost score interacted to increase risk of cancer-specific mortality in NHB women in the lowest Yost quintile (SHR 2.23, p < 0.0001) compared to NHW and NHB women in the highest quintiles. The interaction between race and Yost score persisted only among women with low grade cancers (SHR 1.7, p = 0.04). Time from diagnosis to surgery increased as Yost score decreased. Women in the lowest Yost quintile had lower likelihood of receiving surgery within 6 weeks of diagnosis (OR 0.74, p = 0.001). This effect persisted among women with low grade cancer (NHB OR 0.75, p = 0.014; lowest Yost quintile OR 0.68, p < 0.0001). An association between race, Yost score and delays in time to surgery was not seen among women with high grade cancers. Conclusions: Race and Yost score, an area-based measure of socioeconomic deprivation, are associated with increased cancer-specific mortality risk among women with low grade cancer. NHB race and high socioeconomic deprivation are associated with delayed primary surgery. The interaction between race and socioeconomic deprivation may underlie known disparities in uterine cancer survival, particularly in low grade disease where there is the greatest opportunity for timely curative surgery.
Effect of neoadjuvant versus adjuvant chemotherapy on ipsilateral breast tumor recurrence after breast-conserving surgery and whole-breast irradiation.
Authors: Cheun Jong-Ho , Kim Hong-Kyu , Lee Han-Byoel , Moon Hyeong-Gon , Han Wonshik 
Published: June 2022

604 Background: Early Breast Cancer Trialists’ Collaborative Group conducted a large meta-analysis and reported that patients who underwent neoadjuvant chemotherapy (NAC) had higher ipsilateral breast tumor recurrence (IBTR) rate than those with adjuvant chemotherapy. However, since the study was conducted with patients treated two decades ago, the results could not reflect the advance in treatments and IBTR rate was much higher than in recent studies, Thus, we investigated the association between chemotherapy settings and IBTR rates in breast cancer patients. Methods: We retrospectively reviewed the data of 5,307 patients who underwent breast conserving surgery followed by whole breast irradiation between January 2004 and December 2018 in a single institution. Patients who underwent mastectomy or omitted chemotherapy were excluded. Results: The 1,473 patients who underwent NAC showed significantly higher IBTR rate than the 3,564 patients who underwent adjuvant chemotherapy (10-year risk: 4.5% vs. 4.0%; log-rank p=0.045, hazard ratio 1.42 [95%CI,1.01-1.99]). The difference was more evident for patients with hormone receptor (HR) positive and human epidermal growth factor receptor-2 (HER2) negative tumor (unadjusted p=0.001, hazard ratio 2.27 [95%CI,1.37-3.74; adjusted p=0.002, hazard ratio 2.80 [95%CI,1.45-5.42]], and the statistical significance was still remained after 1:1 propensity score matching (p=0.026). In contrast, patients with other subtypes did not show significant differences between two groups. Conclusions: Patients who underwent NAC for HR+/HER2- tumors carry increased risk of IBTR than those who underwent adjuvant chemotherapy. Our observation supports the need for considering tumor subtypes in initial treatment. In addition, more intensive surveillance would be needed for patients with HR+/HER2- tumors after NAC.
The Medicaid expansion of the Affordable Care Act and participation of patients with Medicaid in cancer clinical trials.
Authors: Unger Joseph M. , Xiao Hong , Vaidya Riha , Hershman Dawn L. 
Published: June 2022

6505 Background: The Affordable Care Act (ACA) Medicaid Expansion (ME) resulted in increased use of Medicaid insurance nationwide. However, the impact of the ACA ME on access to clinical trials has not been examined. Methods: We examined the number and proportion of patients insured by Medicaid at enrollment over time using data from the SWOG Cancer Research Network. We examined all patients 18-64 years old enrolled to treatment trials between April 1, 1992 to February 28, 2020 using Medicaid vs. private insurance. Interrupted time-series analysis was used; first implementation of the ACA ME (in 2014) was the independent exposure variable. Segmented logistic regression was used to estimate the difference between actual enrollment of patients using Medicaid to the expected rate had the ACA ME not been implemented. To account for secular trends related to economic conditions, we adjusted for the monthly unemployment rate using data from the Bureau of Labor Statistics. Indicator variables to reflect administrative differences in Medicaid by presidential administration were included. Results: In total, 47,042 patients age < 65 years were analyzed, including 31,565 (67.1%) females, 18,987 (40.4%) age < 50 years, and 4,709 (10.0%) with Medicaid coverage. Overall, a 20% (OR = 1.20, 95% CI, 1.11-1.30, p <.001) increase per year in the odds of patients using Medicaid was detected following the ACA ME. Based on pre-ACA patterns, the proportion of patients using Medicaid decreased during periods of economic growth and low unemployment; thus, the model-based estimate of the proportion of patients with Medicaid insurance had the ACA ME not occurred was only 7.4% (95% CI, 4.8%-9.5%) at the end of the study period (February 2020), when national unemployment was low (3.5%). In contrast, the actual rate was 20.8% (95% CI, 17.1%-25.0%). Patterns were consistent by age but not by sex, with a stronger 29% (OR = 1.29, 95% CI, 1.17-1.42, p <.001) annual increase in the proportion of Medicaid use for female patients compared to only 7% (OR = 1.07, 95% CI, 0.94-1.23, p =.26) for males. The increase per year of Medicaid use for patients from states that implemented the ME in 2014 or 2015 was 27% (OR = 1.27, 95% CI, 1.16-1.41, p <.001) compared to 7% for patients from other states (OR = 1.07, 95% CI, 0.94-1.22, p =.28). Conclusions: The implementation of the ACA ME was associated with nearly a threefold increase (20.8% vs. 7.4%) in the proportion of patients using Medicaid in cancer clinical trials by early 2020. Improved access to clinical trials for more vulnerable patients is critical for improving confidence that trial findings apply to the general cancer population. These findings suggest that the recently enacted Cancer Treatment Act – which mandates that state Medicaid programs cover the routine care costs of clinical trial participation – may continue to improve access to clinical trials for those with Medicaid insurance.
A health insurance navigation intervention tool (HINT) for survivors of childhood cancer: Randomized pilot trial results from the Childhood Cancer Survivor Study.
Authors: Park Elyse R. , Kirchhoff Anne C. , Kuhlthau Karen A. , Perez Giselle K. , McDonald Aaron , Galbraith Alison A. , Battaglia Tracy Ann , Ponzani Colin , Foor Allyson , Mann Karely , Waters Austin R. , Armstrong Gregory T. , Leisenring Wendy M. , Bliss Cayley C. , Wang Cathy , Lopez Ana , Donelan Karen 
Published: June 2022

6508 Background: Childhood cancer survivors are vulnerable to being underinsured and health insurance-related financial burden. Low health insurance literacy reduces survivors’ ability to utilize health insurance. We conducted a pilot randomized controlled trial (RCT) to assess a virtually delivered health insurance navigation tool (HINT) intervention to improve health insurance literacy (HIL) and decrease financial burden. Methods: Using a multiphase, mixed methods design, we developed and tested a theoretically-driven 4-session intervention that included: 1) Learning About Survivorship Healthcare Needs, 2) Learning About Your Plan in Relation to Policy, 3) Navigating Your Plan and Obstacles, and 4) Managing Care Costs. Eligible CCSS participants were insured and had wireless device access. We assessed feasibility and preliminary efficacy of HINT versus enhanced usual care (EUC; health insurance booklet) on HIL (16-item instrument assessing knowledge and confidence with health insurance terms and activity, ACA provisions knowledge (8-items), psychological financial burden (7-items assessing worry due to medical costs), and satisfaction with health insurance coverage (1 item) using multivariable linear regression. Results: From 8/20 to 5/2021, 82 participants enrolled (39.7% participation rate); 53.7% female; 82% white, 7% Hispanic, and 7% black; 52.4% <40 years of age; and 57.3% from a Medicaid expansion state. 25.6% reported previously being uninsured. 57.3% were diagnosed <10 years of age, and 40.1% had ≥1 severe chronic health condition. There were gaps in health insurance literacy (HIL mean 28.5, sd=9.0; 16-60 (high-low); 39.0% were not familiar with the Affordable Care Act (ACA), and many lacked ACA provisions knowledge (e.g., appeals for coverage denials (56.1%). 82% completed 4 sessions; 92.6% completed the 5-month follow-up survey. Compared to EUC, HINT significantly improved HIL, ACA provisions knowledge, psychological financial hardship, and health insurance satisfaction (p’s ≤ 0.03). Conclusions: Findings affirm health insurance literacy gaps among a national sample of insured long-term survivors. Results support the feasibility and preliminary efficacy of HINT on improving health insurance literacy, satisfaction, and psychological financial burden. HINT is the first intervention to demonstrate improvements in long-term survivors’ health insurance literacy and psychological financial burden. Clinical trial information: NCT04520061. [Table: see text]
Disparities in speed to BMT consult and allograft in 279 adults with AML.
Authors: Fingrut Warren Benjamin , Gyurkocza Boglarka , Davis Eric , Flynn Jessica , Scaradavou Andromachi , Chinapen Stephanie , Naputo Kristine , Quach Sean , Cho Christina , Giralt Sergio , Papadopoulos Esperanza Bouza , Perales Miguel-Angel , Shaffer Brian C. , Politikos Ioannis , Barker Juliet Naomi 
Published: June 2022

6523 Background: Whether patient (pt) ancestry impacts the time to BMT is not established. Methods: We hypothesized that non-European (non-EURO) ancestry AML pts are at increased risk of delayed time to transplant. Thus, we analyzed time to allograft (Allo) by ancestry defining delayed (late) times as: Allo Indication to BMT Consult (Ind. – Consult) > 90 days, Consult – BMT > 120 days & Allo Indication to BMT (Ind. - BMT) > 180 days. We studied pts < 70 yrs transplanted 1/2016-7/2021. Results: In 279 AML pts (median 56 yrs, range 19-69), BMT indication was date of diagnosis if ELN 2017 intermediate/ high risk &/or high risk mutations &/or sAML in 261 (94%) pts, or date of refractory/ relapsed disease in 18 (6%) pts. European (EURO) pts (n = 195, 70%; median 60 yrs) were older than non-EURO pts (n = 84, 30%; median 49 yrs), p <.001. Most HLA-matched sibling (SIB) (27/33, 82%) & 8/8 HLA-matched unrelated donor (mURD, 113/138, 82%) recipients were EURO; more non-EURO pts received HLA-disparate grafts [cord blood (CB)/ haplo/ mmURD]: 48/84 (57%) vs 55/195 (28%), p <.001. Overall, median (range) times for BMT Ind. - Consult, Consult - BMT, & Ind. - BMT were 45 (1-1127), 86 (13-1628), & 135 (23-1683) days. 15% of pts had late BMT Ind. - Consult, 27% late Consult – BMT, & 28% late Ind. - BMT. In multivariate analysis (significant variables in Table), more older pts had late Consult - BMT & Ind. - BMT; more non-EURO pts had late Ind. - Consult, Consult - BMT & Ind. – BMT; & despite mostly being non-EURO (35/67, 52%), fewer CB recipients had late Consult - BMT. In mURD pts, BMT Ind. - BMT time was delayed in non-EURO (median 182 days) vs EURO (median 128 days) pts (p = 0.04); there was no difference in CB pts (BMT Ind. - BMT EURO pt median 118 vs non-EURO pt median 108 days, p = 0.42). During the pandemic, as compared with EURO pts BMT delays were further exacerbated in non-EURO pts (Ind. - Consult median 13 & Ind. - BMT median 33 days). Conclusions: Few older non-EURO pts are allografted. Matched SIB & 8/8 mURD transplants predominantly serve EURO pts; the majority of non-EURO pts receive HLA-disparate grafts. Older age & non-EURO ancestry are associated with delayed BMT. CB transplants (CBT) are the fastest regardless of ancestry. Finally, the pandemic further exacerbated delays for non-EURO pts. Strategies to mitigate referral barriers (esp. for older non-EURO pts), prompt adult donor evaluations, efficient URD searches, & utilization of all alternative donors are critical to ensure timely BMT for all. Given the rapid availability, CBT should have high priority in high-risk or urgent pts & speedy graft procurement can compensate for late referral. [Table: see text]