bluuebunny/crossref_metadata_2025_split huggingface dataset:
Historical early treatment effects of adjuvant endocrine therapy for breast cancer in high-risk subgroups: Reanalysis of BIG 1-98, SOFT and TEXT.
Authors: Regan Meredith M. , Niman Samuel M. , Fleming Gini F. , Walley Barbara , Viale Giuseppe , Thurlimann Beat J. K. , Loi Sherene , Colleoni Marco , Pagani Olivia , Francis Prudence A. 
Published: June 2022

508 Background: Clinical trials testing adjuvant endocrine therapy (ET) have not historically limited enrollment to patients with clinically high-risk breast cancer (BC), nor estimated treatment (trt) effects prior to 5 yrs. In light of recent trial results for adjuvant CDK4/6 inhibitors, we estimated early relative and absolute trt effects of aromatase inhibitor (AI) vs tamoxifen (T), with ovarian suppression (OFS) if premenopausal, in high risk subgroups. Methods: From pts enrolled in adjuvant phase 3 randomized clinical trials BIG 1-98 (postmenopausal, 5yr AI v T), TEXT (5yr AI+OFS v T+OFS) and SOFT (5yr AI+OFS v T+OFS v T), we identified subgroups with HR+/HER2- BC and high risk features (≥4 pLN; or 1-3 pLN with grade 3, pT≥5 cm and/or Ki-67≥20% [retrospectively centrally assessed]). TEXT randomized at start of adjuvant trt; BIG 1-98 and SOFT after chemotherapy. Disease-free survival (DFS) was defined from randomization to invasive recurrence at local, regional, distant or contralateral breast, second non-breast malignancy or death. We estimated trt effects as differences in 2, 3 and 5yr DFS Kaplan-Meier estimates (KM diffs at t yrs) and hazard ratios over time intervals of 0-2, 0-3 and 0-5 yrs (HRs over 0 to t yrs) to approximate the maturity of trial results with increasing follow-up. Results: The high-risk HR+/HER2- subgroups were 695/4922, 707/2660 and 526/3047 pts in BIG 1-98, TEXT and SOFT with 202, 122, 142 DFS events observed by 5 yrs since randomization. 60%, 46% and 44% of pts had ≥4 pLNs; 42%, 90% and 92% had chemotherapy. The table summarizes results. Conclusions: In re-analysis of clinical high risk HR+/HER2- subgroups of 3 trials each ̃700 pts, 5 yrs AI vs T had similar magnitude of early trt effects after 2-3 yrs follow-up of all pts vs trt effects observed after 27 mos median follow-up in monarchE trial (HR=0.70; KM diffs 2.7% at 2 yrs, 5.4% at 3 yrs; n=5637). Relative and absolute trt effects sometimes diminished when estimated over 5 yrs rather than over 2 yrs, but meaningful absolute differences remained at 5 yrs in contrast to Penelope-B trial results. Design and interpretation of high risk HR+/HER2- early BC trials may depend on timing of randomization and selection of backbone adjuvant trts; follow-up >5 yrs must remain standard. [Table: see text]
Salvage radiotherapy guided by functional imaging for macroscopic local recurrence following radical prostatectomy: A multicentric retrospective study.
Authors: Benziane Ouaritini Nicolas , Zilli Thomas , Ingrosso Gianluca , Pasquier David , renard Penna Raphaelle , Ferrari Victoria , Achard Verane , Pasquier Corentin , Perennec Tanguy , Di Staso Mario , Mihoci Inga , Trippa Fabio , Francolini Giulio , Meyer Emmanuel , Schick Ulrike , Cosset Jean Marc , Martin Etienne , Supiot Stephane , Latorzeff Igor , Sargos Paul 
Published: June 2022

5089 Background: For prostate cancer (Pca), salvage radiotherapy (sRT) with or without androgen deprivation therapy (ADT) is currently the only curative treatment option in case of post-radical prostatectomy (RP) biochemical relapse (BR). Functional imaging techniques have shown that macroscopic recurrence (MR) in the prostate bed (PB) are frequent. In this study, we aimed to assess efficacy and safety of sRT in patients with MR inside the PB proven by functional imaging. Methods: A multicenter retrospective study was conducted in 16 European centers. Patients were included if they displayed BR after RP for Pca, with MR only in the PB proven by functional imaging. All patients had to be eligible for sRT. The overall population was divided along 4 groups according to the delivered treatment: dose escalation on MR (A), dose escalation on PB (B), double dose escalation MR+PB (C), no dose escalation (D). The primary endpoint was progression-free survival (PFS). Secondary outcomes included the metastasis-free survival (MFS), biochemical PFS (bPFS) and overall survival (OS). Grade ≥2 genito-urinary (GU) and gastro-intestinal (GI) acute and late toxicities were collected. Results: Between January 2000 and December 2019, 363 patients with isolated MR after RP for Pca were treated by sRT. The median pre-sRT PSA level was 0.63ng/mL (range, 0.2-23.6). At the time of BR, 266 (73%) patients presented MR in the PB proven by magnetic resonance imaging, and 110 (30%) by positron emission tomography. The median follow-up was 53.6 months (range, 47.52; 58.32). The 5-year PFS and MFS were 70% (95%CI [63.8-75.4]) and 83.7% (95%CI [78.4-87.8]), respectively. Grade ≥2 GU and GI late toxicities were found in 43 (12%) and 11 (3%) patients, respectively. A 5-year PFS benefit was highlighted for groups A, B and C (313 patients) when the MR dose was ≥72Gy: 72,8% (95%CI 64.6-79.4) versus 60.3% (95%CI 48,4-70,3), p = 0.03. Conclusions: In a modern series integrating functional imaging data, we confirmed that sRT is effective in the event of MR inside the PB, with an acceptable toxicity profile. In addition, with the help of functional imaging, we found that dose escalated ≥ 72 Gy on the MR had a significant impact on PFS. Prospective data should further investigate the correlation between MR-targeted dose escalation and PFS.
Racial/ethnic disparities in locoregional recurrence in hormone-receptor positive node-negative breast cancer patients enrolled in the TAILORx trial.
Authors: Kantor Olga , King Tari A. , Freedman Rachel A. , Mayer Erica L. , Chavez Mac Gregor Mariana , Korde Larissa A. , Sparano Joseph A. , Mittendorf Elizabeth A. 
Published: June 2022

515 Background: Whether racial/ethnic disparities in locoregional recurrence (LRR) exist in patients (pts) with similar access to care treated on clinical trials is uncertain. We examined racial/ethnic differences in LRR in hormone-receptor positive HER2-negative (HR+HER2-) node-negative pts enrolled in the TAILORx trial. Methods: 10,273 pts age 18-75 were enrolled in TAILORx, which assigned pts with an OncotypeDx Recurrence Score (RS) <11 to endocrine therapy (ET) alone, those with RS >25 to chemotherapy + ET (CET), and randomized pts with RS 11-25 to ET or CET. Pts with unknown race/ethnicity (n=323) or incomplete treatment adherence information (n=1,168) were excluded from this analysis. Race/ethnicity was self-reported. LRR was defined as ipsilateral invasive in-breast, chest wall, or regional nodal recurrence without distant recurrence. Kaplan-Meier curves were used to estimate 8-year LRR. Cox proportional hazards analysis adjusted for clinical and treatment factors was used to determine factors associated with LRR. Results: 8,782 pts with T1-2N0 HR+HER2- breast cancer were included. Race/ethnicity was non-Hispanic White (NHW) in 6,932 (78.9%), non-Hispanic Black (NHB) in 629 (7.2%), Hispanic in 818 (9.3%), and Asian in 403 (4.6%). Treatment adherence was high across groups over time, with a 9.1% crossover in treatment arms. Average duration of ET was 63.8 +/- 0.3 months. Radiation therapy was planned in 96.0% of pts after breast conservation and 12.7% after mastectomy. At a median follow-up of 8 years, LRR rates were 1.9% in NHW, 4.2% in in NHB, 3.2% in Hispanic, and 3.9% in Asian pts (p<0.01). LRR rates broken down by RS are shown in the Table. On adjusted analyses, NHB and Asian (vs. NHW) pts were more likely to have LRR (HR 1.94 for NHB, HR 2.04 for Asian, p<0.05 for both). Additional statistically significant factors associated with LRR included age <50 (HR 1.85), T2 tumors (HR 1.43), higher grade (HR 2.30 for grade 3), and high RS (HR 3.13 for RS>25). Treatment receipt (chemotherapy, ET duration, and radiation) was not associated with LRR in this population. Conclusions: Racial/ethnic differences in LRR were seen in T1-2N0 HR+HER2- breast cancer pts enrolled in the TAILORx trial despite high rates of treatment adherence in this clinical trial population, with highest LRR rates in NHB and Asian pts. Further study in needed to understand racial/ethnic patterns in LRR by breast cancer subtype and if failure to rescue after LRR may contribute to differences in breast cancer mortality.[Table: see text]
Adjuvant abemaciclib for high-risk early breast cancer (EBC): Factors increasing the rate of treatment discontinuations in monarchE.
Authors: Tolaney Sara M. , Johnston Stephen R.D. , Wei Ran , Andre Valerie AM , Shahir Ashwin , Harbeck Nadia , Martin Miguel 
Published: June 2022

527 Background: Adjuvant abemaciclib plus endocrine therapy (ET) demonstrated clinically meaningful improvement in reducing the risk of recurrence in patients (pts) with HR+, HER2– high risk EBC. In monarchE, 25.6% pts discontinued abemaciclib before completing the 2-year treatment period due to reasons other than recurrence. This exploratory analysis evaluates the impact of baseline factors on time to discontinuation for abemaciclib-treated patients with an aim to identify pts at higher risk of discontinuation. Methods: Time to discontinuation(TTD) was defined as time from first dose to the discontinuation of abemaciclib or all treatment due to reasons other than recurrence. These exploratory analyses evaluated the association between TTD and baseline demographics, disease characteristics, and the extent of pre-existing medical comorbidities. Factors with p-value <0.05 in the univariate Cox model were considered as potentially associated with TTD and then fitted into a multivariate Cox model with stepwise variable selection, with entry and retaining p-value threshold of 0.05. Discontinuation rates at selected timepoints (6-month, 12-month, 18-month, 24-month) within each subgroup were estimated using the Kaplan-Meier method. Results: The following variables were significantly associated with higher risk of discontinuation in the multivariate model: Age ≥65 yr, enrolled in North America or EU, ECOG PS=1, post-menopausal, 1-3 positive nodes, or 4 or more pre-existing comorbidities. The majority of discontinuations occurred within the first 6 months of the treatment period; thus, this timepoint was selected to estimate discontinuation rates for factors independently associated with TTD (Table). Complete results on discontinuation rates at other timepoints will be reported in the presentation. Conclusions: This exploratory analysis identified several factors associated with a greater risk of discontinuation. These results illustrate the importance of close monitoring and dose adjustments early on, particularly for patients with an increased risk of discontinuation prior to completing the 2-yr treatment period of abemaciclib. Clinical trial information: NCT03155997. [Table: see text]
Breast density reduction as a predictor for prognosis in premenopausal women with hormone receptor–positive breast cancer: A retrospective analysis of the ASTRRA study.
Authors: Bae Soong June , Kim Hyun-Ah , Ryu Jai Min , Park Seho , Lee Eun-Gyeong , Im Seock-Ah , Jung Yongsik , Park Min Ho , Park Kyong Hwa , Kwang Su Hwan , Park Eunhwa , Kim Sung Yong , Lee Min Hyuk , Kim Lee Su , Lee Anbok , Noh Woo Chul , Ahn Sei-Hyun , Kim Seonok , Kim Hee Jeong , Jeong Joon 
Published: June 2022

531 Background: While the relationship between mammographic breast density (MD) decline and anti-hormone therapy efficacy has been reported in estrogen-receptor (ER)-positive breast cancer, it is still unclear in premenopausal women and in the case of adding ovarian function suppression (OFS) to anti-hormone therapy. We aimed to investigate the MD reduction (MDR) rate and impact of MDR on prognosis stratified by treatment from the updated result of the ASTRRA trial. Methods: ASTRRA trial, a randomized phase 3 study, showed that adding ovarian function suppression (OFS) to tamoxifen (TAM) improved survival in premenopausal women with ER+ breast cancer after chemotherapy. We updated survival outcomes with a median follow-up of 108 months. We assessed mammography taken before treatment and the follow-up mammography taken annually for up to five years after initiation of treatment. MD was classified into four categories based on the Breast Imaging Reporting and Data System. MDR positivity was defined as a downgrade in MD among follow-up mammography up to two years after randomization, with the pretreatment MD grade as a reference. Results: Among the 1,293 patients from ASTRRA trial, we successfully evaluated MDR in 947 patients, of which 796 (83.4%) belong to high MD (grade C or D). The patient characteristics were similar between the entire ASTRRA trial and the subgroup with available MDR. There was no difference in MDR-positive rate between two treatment groups (106 of 477 [22.2%] in TAM-only group vs. 87 of 470 [18.5%] in TAM + OFS group, P =.156). MDR-positivity was significantly associated with better disease-free survival (DFS) in TAM + OFS group (estimated 8-year DFS: 92.9% in MDR-positive vs. 82.2% in MDR-negative, P =.013), but did not in TAM-only group (estimated 8-year DFS: 80.3% in MDR-positive vs. 80.2% in MDR-negative, P =.927; Pinteraction =.025). Simialr trends were observed in terms of recurrence-free survival, distant metastasis-free survival (DMFS), locoregional-free survival, and overall survival. In addition, MDR-positivity was an independent factor for favorable DFS (adjusted hazard ratio [HR], 0.37; 95% CI, 0.16 to 0.86; P =.021) and DMFS (adjusted HR, 0.35; 95% CI, 0.13 to 0.98; P =.045) in TAM + OFS group. Conclusions: Although the proportion of patients with MDR-positive was comparable between the two treatment groups, MDR-positive was independently associated with favorable outcomes only in TAM + OFS group. Future work is warranted to verify the mechanism by which the association between MDR and clinical benefit differs according to the treatment group. Clinical trial information: NCT00912548.
Dostarlimab in advanced/recurrent (AR) mismatch repair deficient/microsatellite instability–high or proficient/stable (dMMR/MSI-H or MMRp/MSS) endometrial cancer (EC): The GARNET study.
Authors: Oaknin Ana , Pothuri Bhavana , Gilbert Lucy , Sabatier Renaud , Ghamande SharadA. , Gravina Adriano , Calvo Emiliano , Banerjee SusanaN. , Miller Rowan , Pikiel Joanna , Mirza MansoorRaza , Duan Tao , Zildjian Sybil , Zografos Eleftherios , Veneris JenniferLynnTaylor , Tinker Anna 
Published: June 2022

5509 Background: Dostarlimab is a programmed death 1 (PD-1) inhibitor approved in the U.S. as a monotherapy in patients (pts) with dMMR AR EC that has progressed on or after treatment with a platinum-containing regimen or dMMR solid tumors that have progressed on or after prior treatment, with no satisfactory alternative treatment options; and in the E.U. as a monotherapy in pts with dMMR/MSI-H AR EC that has progressed on or after treatment with a platinum-containing regimen. Here, we report on efficacy and safety in the 2 expansion cohorts of the GARNET trial that enrolled pts with EC. Methods: GARNET is a multicenter, open-label, single-arm phase 1 study. Pts were assigned to cohort A1 (dMMR/MSI-H EC) or cohort A2 (MMRp/MSS EC) based on local assessment. Pts received 500 mg of dostarlimab IV Q3W for 4 cycles, then 1,000 mg Q6W until disease progression, discontinuation, or withdrawal. The primary endpoints are ORR and DOR by blinded independent central review using RECIST v1.1. Results: For this third interim analysis, 153 dMMR/MSI-H and 161 MMRp/MSS pts were enrolled and dosed. Of these, 143 dMMR/MSI-H and 156 MMRp/MSS pts had measurable disease at baseline and ≥ 6 mo of follow-up and were included in the efficacy-evaluable population. ORRs were 45.5% (dMMR/MSI-H) and 15.4% (MMRp/MSS; Table). Median (m) DORs were not reached (NR; dMMR/MSI-H) and 19.4 mo (MMRp/MSS). Probability of PFS at 6, 9, and 12 mo was 49.5%, 48.0%, and 46.4% in dMMR/MSI-H EC and 35.8%, 31.3%, and 29.4% in MMRp/MSS EC, respectively. mOS was NR (dMMR/MSI-H) and 16.9 mo (MMRp/MSS). Overall, 27 pts (8.6%) discontinued treatment because of a treatment-related adverse event (TRAE; 13 dMMR/MSI-H, 14 MMRp/MSS). The majority of TRAEs were grade 1 or 2. The most common any-grade TRAEs were fatigue (56; 17.8%), diarrhea (46; 14.6%), and nausea (43; 13.7%). No deaths were attributed to dostarlimab in the EC cohorts. Hypothyroidism (12; 8%) was the most common any-grade immune-related TRAE. Conclusions: Dostarlimab demonstrated durable antitumor activity in both dMMR/MSI-H and MMRp/MSS AR EC. dMMR/MSI-H was associated with better outcomes: a higher response rate and longer PFS and OS. Safety was consistent with other PD-1 antibodies. Clinical trial information: NCT02715284. [Table: see text]
IGNITE: A phase II signal-seeking trial of adavosertib targeting recurrent high-grade, serous ovarian cancer with cyclin E1 overexpression with and without gene amplification.
Authors: Au-Yeung George , Bressel Mathias , Prall Owen , Surace Daniela , Andrews John , Mongta Sally , Lee Yeh Chen , Gao Bo , Meniawy Tarek , Baron-Hay Sally E. , Black Allison Jane , Kichenadasse Ganessan , Ananda Sumitra , Fox Peter , Bowtell David , Mileshkin Linda R. 
Published: June 2022

5515 Background: Cyclin E1 gene amplification and protein over-expression is a marker of platinum resistance in high grade serous ovarian, fallopian tube or primary peritoneal cancer (HGSC), and may predict response to WEE1 inhibition. Adavosertib, a WEE1 inhibitor, has demonstrated activity in unselected women with recurrent ovarian and serous endometrial cancer. We aimed to evaluate the efficacy of adavosertib in women with recurrent platinum resistant HGSC with cyclin E1 over-expression, with and without gene amplification. Methods: IGNITE is a multicentre, phase 2 trial with 2 cohorts of women with recurrent platinum resistant HGSC. Tumors were assessed for cyclin E1 protein expression by IHC and CCNE1 copy number by FISH. Patients were assigned to Cohort 1 if tumors were cyclin E1 over-expressed (H-score>50) and amplified (≥8 copies), and Cohort 2 if tumors were overexpressed and nonamplified. Patients with evaluable disease by RECIST v1.1 or GCIG CA-125 criteria were included. Adavosertib 300mg PO was given daily on days 1-5 and 8-12 of a 21-day cycle. The primary endpoint was investigator assessed clinical benefit (CB) defined as absence of progression for ≥ 18 weeks. Here we present the 18-week response data for the first 32 patients treated from Cohort 2, with a data cut-off of August 2021. Results: Between Jan-2020 and May-2021, 32 patients were accrued to Cohort 2. Median age was 62 years (range 42-77) and 84% had received ≥2 prior lines of chemotherapy. Median cyclin E1 IHC H-score was 120 and 28 patients (88%) had measurable disease by RECIST. Median number of cycles commenced was 8 (range 1-19). Overall response rate (ORR) was 53% and CB rate was 61% for all evaluable patients. Seventeen patients (53%) required a dose reduction, most commonly for neutropenia or fatigue. Seventeen patients experienced ≥Grade 3 treatment related adverse event, and 4 patients (15%) discontinued due to toxicity. Conclusions: The efficacy results in a biomarker-selected cohort of patients are promising with a higher response rate than reported in previous studies of adavosertib in unselected women with recurrent HGSC. Duration of response and progression free survival data will be presented as data matures. Clinical trial information: ACTRN12619001185156P. [Table: see text]
A phase 1 trial of the PARP inhibitor fuzuloparib in combination with the anti-angiogenic apatinib in recurrent ovarian or triple-negative breast cancer.
Authors: Li Huiping , Zhang Jiayang , Yin Rutie , Song Nan , Zhang Youzhong , Zhang Yu , Zhang Keqiang , Pan Hongming , Wang Ke , Lou Ge , Guiling Li , Zhang Ben , Wang Quanren , Gao Yunong 
Published: June 2022

5539 Background: The combination of an anti-angiogenic agent with a poly (ADP-ribose) polymerase (PARP) inhibitor has demonstrated improved clinical outcomes as treatment/maintenance treatment in gynecological cancers. Here we aimed to characterize the safety profile and recommended phase 2 dose (RP2D) of the combination of fuzuloparib (formerly fluzoparib), a PARP inhibitor, and apatinib, a VEGFR inhibitor in recurrent ovarian cancer (OC) or triple-negative breast cancer (TNBC). Methods: This was a dose-escalation and PK-expansion phase 1 trial conducted in China. Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer or metastatic TNBC were eligible. No prior PARP/VEGFR inhibitors were allowed. The study used a standard 3+3 dose-escalation design, with additional patients (a total of 8-12 patients per dose level) enrolled for PK assessment. Patients received orally a single dose of fluzoparib on D1 and apatinib on D4, followed by continuous dosing of fluzoparib (bid) plus apatinib (qd) starting on D8. Endpoints were RP2D, safety, PK, and anti-tumor activity. Results: Between 03/17/2017 and 03/02/2021, 52 patients (30 OC, 22 TNBC) were enrolled to 7 dose levels (up to fuzuloparib 100 mg plus apatinib 500 mg). A total of 2 DLTs occurred: grade 4 decreased white blood cell count (WBC)/febrile neutropenia (fuzuloparib 100 mg plus apatinib 250 mg) and grade 4 thrombocytopenia (fuzuloparib 100 mg plus apatinib 375 mg). No maximum tolerated dose was reached. The most common treatment-related grade ≥3 toxicities included hypertension, anemia/decreased hemoglobin, thrombocytopenia, and decreased WBC. In PK analysis, steady-state plasma concentrations of apatinib was decreased when combined with fuzuloparib, as compared with apatinib alone. Higher dose of apatinib in combination with fuzuloparib 100 mg was associated with higher exposure and improved clinical activity. The ORR was 44% (95% CI, 32-58; OC, 60% [95% CI, 42-75]; TNBC, 23% [95% CI, 10-43]) across all dose levels and 62.5% (95% CI, 31-86) at fuzuloparib 100 mg plus apatinib 500 mg (all OC), which was determined to be the RP2D. Conclusions: Fuzuloparib plus apatinib has acceptable safety in patients with recurrent ovarian cancer and triple-negative breast cancer. With the promising clinical activity observed in ovarian cancer, this combination is warranted to be further explored as a potential alternative to chemotherapy. Clinical trial information: NCT03075462.