bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of mevalonate pathway inhibitors on outcomes of patients (pts) with HER2-positive early breast cancer (BC) in the ALTTO trial.
Authors: De Angelis Carmine , Veeraraghavan Jamunarani , Sethunath Vidyalakshmi , Ameye Lieveke , Paesmans Marianne , El-Abed Sarra , Choudhury Anup , Napoleone Sylvia , Chumsri Saranya , Piccart-Gebhart Martine J. , Moreno-Aspitia Alvaro , Gomez Henry Leonidas , Viale Giuseppe , Hilsenbeck Susan G. , Rimawi Mothaffar F. , Osborne C. Kent , de Azambuja Evandro , Schiff Rachel 
Published: June 2022

522 Background: Our preclinical findings suggest a role for the mevalonate pathway (MVA) in treatment resistance in HER2+ BC by providing alternative growth and survival signaling to bypass potent HER2 blockade, which could be overcome by the MVA inhibitors statins and nitrogen-containing bisphosphonates (NBs). Here we explored the effect of MVA inhibitors’ use on pts’ outcomes in the ALTTO trial (BIG2-06; NCT00490139). Methods: In the ALTTO trial, 8381 pts with HER2+ BC were randomized to 1 year of adjuvant lapatinib (L), trastuzumab (T), L+T, or T→L. All pts with documented treatment start with statins or NBs < 1 year after randomization were considered as MVA inhibitors users. Survival curves, with a median follow-up of 6.9 years, for disease-free survival (DFS), distant relapse-free interval (DRFI), BC-specific survival (BCSS), and overall survival (OS) according to MVA inhibitors use were estimated by the Kaplan Meier method and Log-rank test. All multivariate survival analyses employed a Cox proportional hazards regression model, adjusting for tumor size, nodal status, hormonal receptor (HoR), menopausal status, BMI, timing of chemo, and randomization arm. We considered interactions terms in Cox’s model between MVA inhibitors use and randomization arm, hormonal status, and BMI group. Results: Among the 8381 pts included in this study, 493 and 299 were statins or NBs users, respectively. Table 1 summarizes the significant differences in pts’ characteristics according to MVA inhibitors use ( P <.005). In multivariate survival analyses, only NBs use was associated independently with better BCSS (HR, 0.44; 95% CI, 0.23 - 0.84; P = 0.014). Statin use was not independently associated with prognosis but only in interaction with pts characteristics: worse DFS, BCSS and OS in pts treated with L+T, worse DRFI and OS in pts treated with HoR+ BC (respective interaction P-values <0.05 in the Cox’s model). Conclusions: NBs independently predicted improved BC-specific outcome in pts with HER2+ BC treated with adjuvant anti-HER2 therapy. Statin use was associated with an inferior outcome in pts with HoR+ disease and/or those treated with L+T. Whether this inferior association in statin users may reflect the underlying predisposition factors that can weaken the efficacy of anti-HER2 treatments and whether this effect was observed only in the L+T arm due to the more potent inhibition of the HER2 signaling pathway remain open questions. Further clinical investigations on the impact of MVA inhibitors on the outcome of pts with HER2+ BC are warranted. [Table: see text]
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.