bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimating survival benefit of adjuvant chemotherapy in postmenopausal women with pT1-2N0 early-stage breast cancer and Oncotype DX recurrence score > 26: A National Cancer Database (NCDB) analysis.
Authors: Cao Lifen , Towe Christopher W. , Stabellini Nickolas , Amin Amanda L. , Montero Alberto J.
Published: June 2022

543

Background: Early validation studies using the Oncotype DX recurrence score (RS) in NSABP B20 demonstrated that women with node negative breast cancer and RS >31 had significant survival benefit from the addition of adjuvant chemotherapy to endocrine therapy (CET). Consequently, in the prospective TAILORx trial, node negative women with RS >26 received CET. These studies did not clearly delineate the magnitude of benefit of adjuvant chemotherapy for post-menopausal node negative women. A recently published well-designed adjuvant trial (RxPONDER) demonstrated that adjuvant chemotherapy was not beneficial in post-menopausal pts with ER+/HER2- breast cancer, 1-3 positive nodes, and RS <25. We hypothesized that CET would be associated with a modest but statistically significant overall survival (OS) in women with hormone receptor positive ER+/HER2- node negative breast cancer with RS >26 compared to endocrine therapy (ET) alone, given that CET is more beneficial in women <50 years of age. Methods: The National Cancer Database (NCDB) was queried to analyze women age > 50 with ER+/HER2- pT1-2N0M0 breast cancer with RS >26, to assess real world utilization. We separated women into two groups based on adjuvant treatment: ET alone or CET. Chi-square and logistic regression analysis determined difference between different systemic treatment groups. OS was analyzed using a multivariable Cox model. Results: A total of 16,745 eligible women who underwent surgery and received ET were identified in the NCDB—4,740 (28.3%) received ET alone and 12,005 (71.7%) received CET. We observed that CET use increased over time. Women were more likely to receive CET if their tumors were moderately differentiated (OR = 1.853, p < 0.001), poorly/undifferentiated tumors (OR = 3.875, p < 0.001), or associated with lymph-vascular invasion (OR = 1.206, p = 0.001). After accounting for demographic and oncologic factors, 5-year OS rates in this cohort were significantly superior in women receiving CET compared to ET alone (95.4% vs 92.0%, Hazard Ratio = 0.680, p < 0.001). Conclusions: Utilizing the NCDB to represent real world outcomes, we observed that women > 50 years with pT1-2N0M0 ER+/HER2- breast cancer, and RS > 26 had a significantly superior 5-year OS when receiving adjuvant chemotherapy provides a measurable OS benefit for post-menopausal women in this setting and should be discussed with patients.
Comparison of predicted benefit using RS clin versus observed benefit in a U.S. registry of stage I ER-positive HER2-negative high oncotype DX RS breast cancer.
Authors: Walden Christopher David , Mosiman Samuel , Borgert Andrew J. , Parsons Benjamin Marshall
Published: June 2022

544

Background: The 21-gene recurrence score assesses the risk of distant breast cancer recurrence and predicts the benefit of adjuvant chemotherapy in ER positive early-stage breast cancer. However, clinicopathologic risk factors continue to impact absolute benefit of adjuvant chemotherapy. Absolute benefit of adjuvant chemotherapy in low clinicopathologic risk Stage I ER positive breast cancer with high Oncotype RS is an important clinical component of shared decision making. The RSClin clinical tool, which integrates the 21-gene recurrence score (RS) and clinicopathologic features, was found to be more prognostic than RS result alone. We assessed RS Clin predicted benefit and compared to absolute benefit in low clinicopathologic risk Stage I ER positive breast cancer with high Oncotype RS as observed in the NCDB. Methods: Using the National Cancer Data Base (NCDB), we identified female patients age 18-75, ER positive and Her 2 negative, 21 gene signature high risk > 25 with negatives surgical margins, <2cm, lymph node negative breast cancers, who had received endocrine therapy with either Tam or AI diagnosed during 2010 - 2017. Clinicopathologic factors and RS were entered into the RSClin calculator, and a predicted benefit of chemotherapy was calculated for each patient. Using NCDB data, Cox proportional hazards regression models were used to project absolute survival benefit at 10 years from diagnosis for those who did vs those who did not receive chemotherapy. NCDB-derived absolute benefit of chemotherapy was compared to estimated absolute benefit as predicted by the RSClin tool. Results: 18,226 patients were identified. Stages T1a = 670(4%), T1b = 4,289(23%), and T1c = 13,267(73%). Median age 59 years (21-75). Race white 84% (15,365), black 10% (1840), and other 1021(6%). AI use 80% (14,711) was greater than Tam use 20% (3515). Chemotherapy was administered in 75% (13,827) of patients. Most patients had high or intermediate grade disease, G3 45% (8225), G2 46% (8328), and G1 9% (1672). Median duration of follow up was 57 months (2-160). Probability of death T1b at 10yrs with chemotherapy was 8.5%, and without chemotherapy was 15.1% with an absolute benefit of 6.6%. Predicted benefit in T1b using RS Clin at 10yrs was 10.8%. Probability of death for T1c at 10yrs with chemotherapy was 15.1%, and without chemotherapy was 23.5% with an absolute benefit of 8.4%. Predicted benefit in T1c using RS Clin at 10yrs was 14%. Conclusions: Patients with stage IB and IC hormone receptor positive HER2 negative breast cancers with high RS had a lower absolute benefit than predicted by RS Clin. The RSClin tool overestimated benefit of therapy in both IB and IC stages requiring caution when using this tool in patients with the lowest clinicopathologic risks.
Bevacizumab in first-line chemotherapy to improve the survival outcome for advanced ovarian clear cell carcinoma: A multicenter, retrospective analysis.
Authors: Seki Toshiyuki , Tate Shinichi , Nishikimi Kyoko , Unno Yoichi , Itoi Mizue , Ikeda Sadatomo , Yoshikawa Nobuhisa , Akashi Hidehiko , Suzuki Eitaro , Tanaka Naotake , Hirakawa Takashi , Kajiyama Hiroaki , Takano Hirokuni , Yoshihara Kosuke , Okamoto Aikou , Shozu Makio
Published: June 2022

5502

Background: Advanced ovarian clear cell carcinoma (ACCC, stage III/IV disease) is a rare tumor characterized by chemoresistance. Bevacizumab (Bev) was approved in November 2013 in Japan and became incorporated in the treatment of advanced ovarian cancer. However, the efficacy of Bev against ACCC remain unknown. We investigated the survival outcomes for ACCC, following first-line chemotherapy with or without Bev. Methods: Patients diagnosed with ACCC at seven institutions between 2008 and 2018 were enrolled in this study. Patients underwent cytoreductive surgery and taxane-carboplatin chemotherapy (78: triweekly regimen; 30: weekly regimen; 25: dose-dense regimen; 12: others) with or without concurrent and maintenance Bev (15 mg/kg/3 weeks). We compared the progression-free survival (PFS) and overall survival (OS) before (group A, n = 102) and after (group B, n = 43) Bev approval, using Kaplan–Meier method and Cox regression model. We excluded patients with poor performance status (PS) in group A, and patients who did not receive Bev due to poor PS or thrombosis in group B. Results: There was no significant difference between two groups in terms of age (p = 0.135) and initial CA125 level (p = 0.674). Thirteen (13%) and 11 (26%) patients had stage IV disease (p = 0.058) and 2 (3%) and 7 (16%) patients were of poor PS (PS ≥2) (p = 0.004) in group A and B, respectively (p = 0.058). More patients (29/43, 67%) in group B were achieved complete resection than in A group (52/102, 51%) (p = 0.068). The median cycle of Bev in B group was 16 (interquartile range: 6-21). The median follow-up time was 36 months. The median PFS increased from 12.5months in A group to 29.7 months in B group (log-rank test: p = 0.023, Wilcoxon test: p = 0.006). The median OS increased from 34.7 months in A group to 51.4 months in B group (log-rank test: p = 0.085, Wilcoxon test: p = 0.027). Multivariate analysis revealed that Bev use (Hazard ratio (HR): 0.54, p = 0.011; HR: 0.54, p = 0.019), PS <2 (HR: 0.33, p = 0.013; HR: 0.29, p = 0.006) and completeness of resection (HR: 0.38, p < 0.001; HR: 0.37, p <0.001) were independent prognostic factors for PFS and OS. Conclusions: Incorporating Bev in first-line chemotherapy may improve PFS in patients with ACCC. [Table: see text]
Staging locally advanced cervical cancer with FIGO 2018 versus FIGO 2008: Impact on overall survival and progression-free survival in the OUTBACK trial (ANZGOG 0902, RTOG 1174, NRG 0274).
Authors: Mileshkin Linda R. , Moore Kathleen N. , Barnes Elizabeth H , Lee Yeh Chen , Gebski Val , Narayan Kailash , Bradshaw Nathan , Diamante Katrina , Fyles Anthony W. , Small William , Gaffney David K. , Khaw Pearly , Brooks Susan , Thompson J Spencer , Huh Warner King , Carlson Matthew , Robison Katina , Rischin Danny , Stockler Martin R. , Monk Bradley J.
Published: June 2022

5531

Background: The International Federation of Obstetrics and Gynecology staging system for cervical cancer (FIGO 2008) was revised in 2018 to incorporate lymph node involvement (FIGO 2018). OUTBACK is an international, randomized phase 3 trial of adjuvant chemotherapy versus observation after standard of care treatment with chemoradiation for women with locally advanced cervical cancer. OUTBACK found no benefit from the addition of adjuvant chemotherapy. We evaluated the effects of classifying participants with these 2 staging systems in the OUTBACK trial population. Methods: OUTBACK recruited April 2011 to June 2017 and staged participants according to FIGO 2008. Lymph node status, smoking status, age, race and histological subtype were documented at trial entry as important prognostic factors. We assessed the effects of stage grouping into stage I, II, and III/IVa with FIGO 2008 versus FIGO 2018, on progression-free survival (PFS) and overall survival (OS) at 5 years using Kaplan-Meier estimates, and in univariable proportional-hazards regression analyses, and in multivariable analyses adjusting for important prognostic factors and randomly allocated treatment. Results: All 919 study participants had complete data for staging according to the 2 staging systems and most prognostic factors for adjustment. Among all participants, the 5-year outcomes were PFS = 62% and OS = 72%. Classification according to FIGO 2018 rather than FIGO 2008 yielded higher 5-year PFS and OS in each stage group (see table for numbers of participants, PFS and OS for each stage group). Predictors of PFS in multivariable analysis included squamous vs non-squamous histology (HR 0.71 for FIGO 2008 and 0.74 for FIGO 2018), but not nodal involvement when FIGO 2018 was used. Both staging systems were the only independently significant prognostic factors in both univariable and multivariable analyses (all p < 0.0001) for both PFS and OS. Conclusions: Compared to FIGO 2008, reclassifying pts by FIGO 2018 staging resulted in more pts being classified as stage 3 due to the incorporation of nodal status. Staging locally advanced cervical cancer using FIGO 2018 rather than FIGO 2008 resulted in higher PFS and OS in each stage grouping that reflected stage migration, not a true improvement in outcomes. FIGO stage remains the strongest predictor of overall survival after CRT but survival outcomes by stage in trials using the old vs new staging system are not comparable. Clinical trial information: ACTRN12610000732088. [Table: see text]
Prior authorizations for PARP inhibitors in ovarian cancer.
Authors: Hugo Audra , Pena Daniella , Ko Emily Meichun , Haggerty Ashley Ford , Smith Anna Jo Bodurtha
Published: June 2022

5549

Background: PARP inhibitors improve survival in ovarian cancer, especially in patients with BRCA 1/2 mutations or homologous recombination deficiency (HRD). However, these FDA-approved drugs cost $100,000 annually on average, and concerns have been raised about insurance barriers like prior authorization to such medications. Our objective was to examine the prevalence of prior authorization for PARP inhibitors in ovarian cancer overall, by frontline or recurrent maintenance, and by genetic status. Methods: We performed a retrospective cross-sectional study of ovarian cancer patients prescribed a PARP inhibitor within the University of Pennsylvania oncology practices from May 2020-2021. Using electronic medical records, we assessed the prevalence of prior authorization for PARP inhibitors overall, by frontline or recurrent maintenance, and by BRCA or HRD status. We then assessed the associated approval and appeal rates. Results: We identified 110 patients with ovarian cancer who were prescribed a PARP inhibitor. Of these, 67% (95%CI 57-75) experienced prior authorization for their PARP inhibitor. In contrast, 31 (95%CI 23-40) experienced prior authorization for other components of their gynecologic oncology care. Of patients in the frontline setting, 74 (95%CI 58-86) experienced prior authorization for FDA-approved PARP maintenance. Of patients prescribed PARP maintenance after recurrence, 58 (95%CI 45-71) experienced prior authorization. Of patients with germline BRCA, 70% (95%CI 47-85) experienced prior authorization for PARP inhibitors. Of patients with germline or somatic BRCA or HRD+, 76% (95%CI 61-87) experienced prior authorization. 95% (95%CI 86-94) of prior authorizations for PARP inhibitors were approved on their 1st appeal, and 99% (95%CI 95-100) were approved by the 2nd appeal. Conclusions: Two-thirds of patients of ovarian cancer patients who were prescribed PARP inhibitor experienced prior authorization, including equally high rates among women with germline or somatic BRCA mutations, as well as with HRD-deficient tumors. Given the nearly 100% approval after prior authorization, improvements in insurance processes are needed to streamline PARP inhibitor access in ovarian cancer.
Real-world use, tolerability, and dose modifications of PARP inhibitors in ovarian cancer.
Authors: O'Malley David M. , Arend Rebecca Christian , Alam Naufil , Ozgoren Ozan , McLaurin Kimmie K. , Long Grainne H. , Banerjee Susana N.
Published: June 2022

5552

Background: Tolerability is a key consideration when selecting a PARP inhibitor (PARPi) for ovarian cancer (OC). Here we expand on earlier work (Arend et al 2021) to further characterize real-world tolerability and dose modifications in US patients (pts) with OC receiving PARPi therapy. Methods: A retrospective cohort of OC pts starting olaparib (ola), niraparib (nir) or rucaparib (ruc) between Jan 2017 and Dec 2020 was identified from MarketScan® Commercial/Medicare Supplemental databases, increasing the period covered and number of pts included vs our previous analysis. Pts were followed up from first PARPi prescription (index) for ≥30 days until end of study period, disenrollment or death; baseline was 6 months pre-index. Clinical events of interest (CEIs; acute myeloid leukemia/myelodysplastic syndromes, anemia, leukopenia/neutropenia, thrombocytopenia, acute kidney injury, arthralgia, constipation, diarrhea, nausea, vomiting, dermatitis/rash/photosensitivity, fatigue, hypertension, infection, insomnia, pneumonitis, transaminitis) were identified via ICD-9/10 codes. Multivariable Cox regression compared the likelihood of CEIs, dose modifications and hospitalizations between PARPis, adjusting for baseline CEI, Charlson Comorbidity Index score, prior bevacizumab and cancer-related surgery. Persistence was defined as no PARPi treatment gaps of >90 days in pts with ≥6 months’ continuous enrollment. Results: Overall, 637, 538 and 227 pts received ola, nir and ruc, respectively (median [IQR] follow-up 10.5 [13.4] months). Baseline characteristics were similar across groups. The proportion of pts initiating PARPi at the highest indicated dose was 89.2%, 57.6% and 89.9% for ola, nir and ruc, respectively; 22.6%, 34.8% and 28.6%, respectively, required dose decreases. The likelihood of experiencing CEIs varied across the PARPis after adjusting for a priori confounders as shown in the table. Persistence with index PARPi was higher with ola (83.4%) vs nir (73.3%; P<0.001) and similar vs ruc (80.2%; P>0.05). Among all pts, mean time to non-persistence was shorter with nir vs ola and ruc (6.4 vs 7.9 and 7.6 months, respectively; both P<0.05). CEIs by PARPi dose and calendar year will also be presented. Conclusions: This is the largest real-world comparison of PARPi use in OC pts reported to date. It supports differences between PARPis in persistence with therapy and risk of experiencing a CEI, even after adjusting for confounders. [Table: see text]
A phase Ib study of IN10018 in combination with pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant ovarian cancer.
Authors: Wu Lingying , Wang Jing , Wang Li , Lu Weiguo , Wang Ke , Lin An , Li Ning , Li Li , Su Ning , Xie Shuang , Jiang Jun
Published: June 2022

5567

Background: IN10018 is a highly potent and selective oral inhibitor of focal adhesion kinase (FAK). IN10018 is synergistic with PLD against ovarian cancer in PDX models. This study evaluated the safety, tolerability, and antitumor activities of IN10018 in combination with PLD in patients with platinum-resistant ovarian cancer (PROC). Methods: This is an open-label phase Ib trial in patients with PROC (high-grade serous carcinoma only). Patient were treated with IN10018 in combination with PLD. This study has a dose-confirmation part and a dose-expansion part. Dose-expansion part was conducted at RP2D dose level to evaluate the primary endpoint of objective response rate (ORR). Secondary endpoints included disease control rate (DCR, CR + PR + SD ≥ 6 weeks), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: As of December 31, 2021 (cutoff date for all assessments), a total of 42 PROC patients were enrolled. 92.9% (39/42) patients had 1-3 prior lines of therapy and 14.3% (6/42) had prior bevacizumab use. The RP2D of the combination was determined as IN10018 100 mg QD in combination with PLD 40 mg/m2 Q4W in the dose-confirmation part since no DLTs were observed in 6 patients treated. The safety profile of the combination is comparable to these single agents alone without additive toxicities. No IN10018 related death was observed, and 9.5% (4/42) patients reported IN10018 related SAEs which were also PLD related. The most frequently reported IN10018 related AEs were proteinuria, decreased appetite, fatigue and AEs of gastrointestinal origin such as nausea, diarrhea, vomiting. Majority of these IN10018 related AEs were CTCAE grade 1 and 2, and 14.3% (6/42) had grade 3 AEs. No IN10018 related grade 4 or 5 AEs were reported. Proteinuria was noted asymptomatic, reversible, could be managed with appropriate dose interruption/reduction and only one proteinuria event resulted in IN10018 dose reduction. Antitumor response (as assessed by investigator) was evaluable in 30 patients. 17 patients had best overall response of PR including 13 confirmed PRs and 4 unconfirmed (2 in follow-up to be confirmed). No patient had CR and 9 patients had SD. The ORR is 56.7% (95% CI: 37.4%, 74.5%), the DCR is 86.7% (95% CI: 69.3%, 96.2%), and the median DOR was 4.5 months (95% CI: 2.7 months – NA) and is continuing to mature. Among the 20 efficacy evaluable patients who had at least 6 months of follow up, the ORR is 65.0% (13/20, 95% CI: 40.8%, 84.6%) and the DCR is 90.0% (18/20, 95% CI: 68.3%, 98.8%). In all 42 enrolled patients, the observed median PFS is 6.2 months (95% CI: 6.2 months - NA) and maturing. Conclusions: The combination of IN10018 with PLD showed promising antitumor activities and manageable safety profile in PROC patients. This combination warrants further confirmation in a randomized controlled trial.
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]
Overcoming barriers to tumor genomic profiling through direct patient social media outreach.
Authors: Doe-Tetteh Seyram Adjoa , Camp Sabrina Yvonne , Crowdis Jett , Noronha Anne Marie , Reales Dalicia , Alano Tina , Viale Agnes , Donoghue Mark , Socci Nicholas D. , Berger Michael F. , Al-Ahmadie Hikmat A. , Funt Samuel Aaron , Feldman Darren R. , Diamond Eli L. , Van Allen Eliezer Mendel , Solit David B.
Published: June 2022

6532

Background: Tumor genomic profiling is increasingly used to identify actionable genomic alterations as a guide to therapy selection. To overcome barriers to genomic testing for patients with rare cancers, we initiated a program to offer free clinical tumor genomic testing worldwide to patients with select rare cancer subtypes. Methods: Patients were recruited through social media outreach, engagement with disease advocacy groups, or via physician referral, with a focus on recruiting patients with histiocytosis, germ cell tumors and rare pediatric cancers. Tumor and patient-matched germline DNA were analyzed using the MSK-IMPACT targeted sequencing next generation sequencing panel with return of results to patients and their local physicians. Whole exome recapture of MSK-IMPACT DNA sequencing libraries was performed for patients with female germ cell tumors to define the genomic landscape of this rare cancer subtype. Results: 359 cancer patients expressed interest in the Make-an-IMPACT program, of whom 333 were enrolled. Tumor tissue was received for 288 (86.4%), with 250 (86.8%) having tumor DNA of sufficient quantity and quality for MSK-IMPACT testing. 14 histiocytosis patients have received genomically guided therapy to date, of whom 13 (93%) have had clinical benefit based on local MD response assessment with a mean treatment duration of 16.7 months (range 3-32+). Whole exome sequencing of ovarian GCTs identified a subset with fully haploid genotypes, a phenotype rarely observed in other cancer types. Actionable genomic alterations were rare in ovarian GCT (28%), however, 2 ovarian GCTs and squamous transformation had high tumor mutational burden, one of whom had a complete response to pembrolizumab. Conclusions: Social media outreach can facilitate the assembly of cohorts of rare cancers of sufficient size to define their genomic landscape. By profiling tumors in a clinical laboratory, results could be reported to patients and their local physicians where they could be used to guide treatment selection. This can also open the door to diversifying and being able to study the genomic landscape in a diverse cohort.
Population-based impact of rurality and neighborhood-level socioeconomic disadvantage on pediatric cancer mortality in Washington State.
Authors: Ohlsen Timothy James Daeeun , Doody David R , Desai Arti D , Mueller Beth A , Chow Eric Jessen
Published: June 2022

6537

Background: Emerging evidence suggests mortality among children with cancer differs based on socioeconomic factors. The effects of residential location in relation to these factors are not well-characterized. We examined associations of rurality and neighborhood-level socioeconomic (SE) disadvantage with mortality in pediatric patients with cancer. Methods: We conducted a retrospective cohort study using Washington State (WA) Cancer Registry data (1992-2013) linked to state birth (1974-2013) and death records (1992-2013) to identify all children born in WA diagnosed with cancer < 20 years. We defined rural residence as patient addresses within 2010 census tract level rural-urban commuting area (RUCA) codes of ≥4.0 at diagnosis. Neighborhood-level socioeconomic disadvantage was determined using 2010 census block-group level Area Deprivation Index (ADI) quintiles normalized to WA. Patient addresses within the highest ADI quintile were categorized as having SE disadvantage. children in four mutually exclusive groups was compared using Kaplan-Meier analysis, pairwise log rank testing, and Cox proportional hazard ratios (HR): non-rural with SE disadvantage, rural without SE disadvantage, rural with SE disadvantage, and non-rural without SE disadvantage (). Models were adjusted for sex, race and ethnicity, age at diagnosis, birth year, and cancer type. Results: We identified 4,417 children for analysis. Median length of follow up among survivors was 5.0 years (inter-quartile range: 1.0-11.5). SE disadvantaged and 13% were rural. Pairwise log rank tests showed mortality differences among children living in rural, SE disadvantaged, or rural and SE disadvantaged neighborhoods when compared with children without either factor (individual p-values all < 0.005); no other differences were noted. Relative to children in non-rural areas without SE disadvantage, the mortality HR for those in non-rural areas with SE disadvantage was 1.68 (95% confidence intervals [CI] 1.37-2.07). The HR for children in rural areas without SE disadvantage was 1.59 (95% CI 1.19-2.12). The HR for children in rural areas with SE disadvantage was 1.56 (95% CI 1.20-2.03). In sub-analyses, associations for rurality and SE disadvantage remained significant for leukemia mortality, but CNS and solid tumor mortality was only associated with SE disadvantage (but not rural) status. Acute lymphoblastic leukemia mortality was associated with rural (but not SE disadvantage) status. Conclusions: Children with cancer living in socioeconomically disadvantaged and/or rural neighborhoods at diagnosis had higher mortality relative to those in non-rural areas with lower neighborhood deprivation. Associations varied by disease type. The individual effects of SE disadvantage and rurality suggest that interventions should be designed to target both factors.