bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of clinical risk category on prognosis and prediction of chemotherapy benefit in early breast cancer (EBC) by age and the 21-gene recurrence score (RS) in TAILORx.
Authors: Sparano Joseph A. , Gray Robert James , Makower Della F. , Lively Tracy G. , Saphner Thomas James , Keane Maccon M. , Gomez Henry Leonidas , Reddy Pavan S. , Goggins Timothy F. , Mayer Ingrid A. , Toppmeyer Deborah , Brufsky Adam , Goetz Matthew P. , Hayes Daniel F. , Dees Elizabeth Claire , Pritchard Kathleen I. , Geyer Charles E. , Olson John A. , Albain Kathy S. , Sledge George W. 
Published: May 2019

503 Background: TAILORx established that endocrine therapy (ET) alone is non-inferior to adjuvant chemotherapy (CT) plus ET in EBC and a 21-gene RS of 11-25, with some benefit if ≤50 years (y) with RS 16-25 (PMID: 29860917). We evaluated whether clinical risk (tumor size & histologic grade) provides additional prognostic information to RS, a secondary trial objective. Methods: Clinical risk by was assessed by Adjuvant! (version 8.0) using MINDACT criteria (PMID 27557300), defined as low clinical risk (LCR - tumor ≤3 cm and low grade, <2 cm and intermediate grade, or ≤1 cm and high grade) or high clinical risk (HCR -not meeting LCR criteria). Results: Of 9427 women with RS and clinical risk information, 70% were LCR and 30% HCR, with comparable distribution by age ( ≤50 vs. >50). The RS was 26-100 in 9% of LCR and 27% of HCR patients, with similar distributions by age. Although LCR/HCR provided additional prognostic information in each RS category for iDFS, including RS 0-10 (9-year rates 86.7% vs. 75.7% LCR vs. HCR), 11-25 (85.4% vs. 78.9%), and 26-100 (82.0% vs. 70.4%), iDFS rates were similar irrespective of CT (no vs. yes) in the entire RS 11-25 cohort whether LCR (85.8% vs. 85.1%) or HCR (79.8% vs. 77.9%). DRFI rates were also similar irrespective of CT in the RS 11-25 cohort or > 50y group whether LCR (96.0% vs. 96.1% overall; 96.5% vs. 96.0% > 50y) or HCR (92.3% vs. 89.9% overall; 91.7% vs. 90.7% >50y). For women ≤50y, the absolute reduction in distant recurrence from CT with a RS of 16-20 (N=923) was -0.2% (standard error [SE]±2.1%) for LCR vs. 6.5%(SE±4.9%) for HCR (vs. 1.6%[SE±1.9%] overall), whereas for a RS 21-25 (N=492) it was 6.4% (SE±4.9%) for LCR vs. 8.6% (SE±6.2%) for HCR (vs. 6.5%[SE±3.7%] overall). Conclusions: Clinical risk stratification provides additional prognostic information to the 21-gene RS, but not prediction of CT benefit in the overall TAILORx population or those > 50y, and facilitates more refined estimates of absolute CT benefit for women ≤50y with a RS 16-25. (Funded by National Cancer Institute, Komen Foundation, Breast Cancer Research Foundation). Clinical trial information: NCT00310180.
Genomic characteristics of deleterious BRCA1 and BRCA2 alterations and associations with baseline clinical factors in patients with metastatic castration-resistant prostate cancer (mCRPC) enrolled in TRITON2.
Authors: Abida Wassim , Bryce Alan Haruo , Vogelzang Nicholas J. , Amato Robert J. , Percent Ivor John , Shapiro Jeremy David , McDermott Raymond S. , Hussain Arif , Patnaik Akash , Petrylak Daniel Peter , Ryan Charles J. , Stanton Thomas S. , Zhang Jingsong , Loehr Andrea , Simmons Andrew , Despain Darrin , Golsorkhi Anthony A. , Watkins Simon Paul , Scher Howard I. , Chowdhury Simon 
Published: May 2019

5031 Background: The phase 2 TRITON2 study (NCT02952534) is evaluating the PARP inhibitor rucaparib in patients with mCRPC who have a deleterious germline or somatic alteration in BRCA ( BRCA1 or BRCA2) or 1 of 13 other DNA damage repair genes. Here we present analyses of tumor genomics and baseline clinical characteristics in mCRPC patients with a deleterious alteration in BRCA. Methods: Plasma (baseline) and tissue (archival or baseline) samples from patients with a deleterious alteration in BRCA were analyzed using Foundation Medicine next-generation sequencing assays. The alterations and zygosity of the alterations that were detected, as well as the somatic/germline status from Color Genomics testing, were summarized. Associations between genomic alterations, DNA yield, allele frequency, and baseline clinical characteristics were investigated. Results: Results are shown in the Table for a cohort of 40 BRCA2 and 5 BRCA1 patients enrolled in TRITON2 (Abida W et al. Presented at ESMO 2018. Abst 793PD). A biallelic alteration was observed in 21 of the 22 BRCA2 patients (95%) for whom alteration zygosity could be determined. Among the 5 BRCA1 patients, 1 alteration was monoallelic and 4 were of unknown zygosity. Co-occurring alterations in cancer-related or DNA damage repair genes were observed in many patients with BRCA alterations. At baseline, cell-free DNA (cfDNA) yield correlated positively with the sum of target lesions (STL; P= 0.04), but not with prostate-specific antigen (PSA) levels ( P= 0.86). No correlation was observed between allele frequency of the BRCA alteration baseline STL ( P= 0.68) or PSA levels ( P= 0.97). Conclusions: Patients with a BRCA mutation enrolled in TRITON2 demonstrate a profile of genomic alterations consistent with that of prior studies of patients with mCRPC. Plasma cfDNA profiling showed a correlation between baseline cfDNA yield and measurable tumor burden, but not baseline PSA. Clinical trial information: NCT02952534. [Table: see text]
Personalized peptide vaccination for castration-resistant prostate cancer progressing after docetaxel chemotherapy: A randomized, double-blind, placebo-controlled, phase III trial.
Authors: Noguchi Masanori , Fujimoto Kiyohide , Arai Gaku , Uemura Hiroji , Hashine Katsuyoshi , Matsumoto Hiroaki , Fukasawa Satoshi , Nakatsu Hideomi , Takenaka Atsushi , Fujisawa Masato , Uemura Hirotsugu , Naito Seiji , Egawa Shin , Fujimoto Hiroyuki , Hinotsu Shiro , Itoh Kyogo , Kohjimoto Yasuo 
Published: May 2019

5033 Background: To develop a new treatment modality, we conducted a phase III randomized trial of personalized peptide vaccination (PPV) for human leukocyte antigen (HLA) -A24 positive patients with castration-resistant prostate cancer (CRPC) who failed docetaxel chemotherapy. Methods: Patients were randomly assigned in a 2:1 ratio to receive PPV or placebo. Four of 12 warehouse peptides selected based on preexisting peptide-specific immunoglobulin G levels or the corresponding placebo were subcutaneously injected 6 doses weekly followed the maximum of 30 doses bi-weekly until disease progression. The primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS) and immune responses. Results: From August 2013 to April 2016, 310 patients were randomly assigned (207 to PPV and 103 to placebo), and 306 patients were analyzed by the full analysis set (204 to PPV and 102 to placebo). Baseline characteristics were balanced between groups. Estimated median OS was 16.1 months (95% CI, 13 to 18.2) with PPV and 16.9 months (95% CI, 13.1 to 20.4) with placebo (HR, 1.04; 95%CI, 0.79 to 1.37; P = 0.77). Median PFS was also not significantly different among them. Median Grade ≥ 3 adverse events were observed in 41% in both groups. The analysis of treatment arm effects among various subgroups revealed a lower HR for OS in favor of the PPV arm in patients with a < 64% neutrophil proportion (HR, 0.55; 95%CI, 0.33 to 0.93), with a significant interaction test ( P = 0.003). Conclusions: PPV did not prolong either OS or PFS in HLA-A24 positive patients with CRPC progressing after docetaxel chemotherapy. Clinical trial information: 0000113088.
Phase 1 study of pasotuxizumab (BAY 2010112), a PSMA-targeting Bispecific T cell Engager (BiTE) immunotherapy for metastatic castration-resistant prostate cancer (mCRPC).
Authors: Hummel Horst-Dieter , Kufer Peter , Grüllich Carsten , Deschler-Baier Barbara , Chatterjee Manik , Goebeler Maria-Elisabeth , Miller Kurt , De Santis Maria , Loidl Wolfgang C. , Buck Andreas , Wittemer-Rump Sabine , Koca Goekben , Boix Oliver , Doecke Wolf-Dietrich , Stienen Sabine , Sayehli Cyrus , Bargou Ralf C. 
Published: May 2019

5034 Background: mCRPC has a poor prognosis and immunotherapies are largely ineffective. PSMA is a promising therapeutic target in mCRPC, and pasotuxizumab is a PSMA x CD3 BiTE that mediates tumor cell killing. Methods: NCT01723475 was a first-in-human, multicenter, dose-escalation study in patients (pts) with mCRPC refractory to standard therapy. Pts received pasotuxizumab as a continuous intravenous infusion in cohorts of 3–4 pts. Dose-escalation followed a continuous reassessment methodology design. The primary objective was to determine safety and maximum tolerated dose (MTD); secondary objectives included pharmacokinetics, biomarkers, and tumor response. Results: 16 pts were enrolled into 5 dosing cohorts (5 µg/d, n = 3; 10 µg/d, n = 4; 20 µg/d, n = 3; 40 µg/d, n = 4; 80 µg/d, n = 2). All pts had ≥1 AE of any grade; most common were fever (94%), chills (69%), and fatigue (50%). 13 pts (81%) had ≥1 AE of grade ≥3; most common were decreased lymphocytes and infections (both 44%). No grade 5 AE occurred. A serious AE related to study drug was reported for 1 pt (fatigue, 20 µg/d). No anti-drug antibodies were observed. Recruitment was stopped before MTD was reached to facilitate initiation of a new study sponsored by Amgen. Antitumor activity as indicated by PSA serum level decline was dose dependent, with a mean best PSA change per dosing cohort versus baseline of +0.74% (5 µg/d), –17.9% (10 µg/d), –37.4% (20 µg/d), –42.5% (40 µg/d) and –54.9% (80 µg/d). PSA decreases of ≥50% occurred in 3 pts (n = 1 each in 20 µg/d, 40 µg/d, and 80 µg/d cohorts). One long-term PSA responder was treated for 14 months (40 µg/d) and one for 19.4 months (80 µg/d). The latter pt showed a complete regression of soft-tissue metastases and marked regression of bone metastases as assessed by PSMA-PET/CT, > 90% reduction in PSA and alkaline phosphatase, and a significant and durable improvement in disease related symptoms. Conclusions: Pasotuxizumab had an acceptable safety profile and dose-dependent clinical activity in mCRPC pts. There were two long term responders in the dose escalation. This is the first clinical study showing that a BiTE immunotherapy can be efficacious in solid tumors. Clinical trial information: NCT01723475.
Genomic landscape of metastatic hormone sensitive prostate cancer (mHSPC) vs. metastatic castration-refractory prostate cancer (mCRPC) by circulating tumor DNA (ctDNA).
Authors: Hahn Andrew W , Lin Edwin , Esther John , Anderson Neysi , Rathi Nityam , Yandell Mark , Maughan Benjamin Louis , Agarwal Neeraj 
Published: May 2019

5043 Background: mCRPC carries a poor prognosis, and targeted therapies have had minimal success in mCRPC. Novel genomic targets could improve drug development. To date, large ctDNA studies in metastatic prostate cancer have been descriptive with limited or no clinical annotation. Herein, we hypothesize that profiles of genomic alterations (GAs) in ctDNA not only differ significantly between, but can also be used to predict mCRPC vs. mHSPC. These findings could help identify new drug targets for mCRPC treatment. Methods: Men with mHSPC or mCRPC who underwent NGS of ctDNA using G360 (Guardant Health Inc.) at the Huntsman Cancer Institute were included. Men were classified as mCRPC or mHSPC (patients with current or no prior ADT). G360 detects somatic mutations in selected exons of 73 genes, amplifications in 18 genes, and selected fusions in 6 genes. Two-sided students t-test was used to compare the %cfDNA and total GAs. The Chi squared test was used to compare the frequency of each GA. Machine learning (ML) algorithms were trained on GAs and benchmarked by cross-validated performance. GAs contributing to mCRPC vs. mHSPC classification were measured by ML feature importance (e.g. odds ratios, regression coefficients). Results: Of the 259 men included, 119 men had mHSPC and 140 had mCRPC. Men with mCRPC had more GAs (4.5 vs. 1.86, p<0.0001) and higher %cfDNA (9.56% vs. 5.02%, p=0.02). In mHSPC, there was no significant difference in the number of GAs or %cfDNA between men on ADT and those who hadn’t yet started ADT. ML algorithms used GAs to predict mCRPC with 78.1% sensitivity, 64.0% specificity, 76.7% PPV, 65.1% NPV, and 70.3% overall accuracy. mCRPC was enriched with GAs in AR, ARID1A, BRAF, BRCA2, CCNE1, CTNNB1, EGFR, FGFR1, KIT, MET, MYC, PDGFRB, PIK3CA, and TP53. Of note, many of these genes are involved in MAP/ERK signaling. Conclusions: Men with mCRPC have more GAs, higher %cfDNA, and enrichment of GAs in the MAP/ERK pathway compared to men with mHSPC. The distinct GAs seen in mCRPC represent novel therapeutic targets, especially in the MAP/ERK pathway. We also show that machine learning can differentiate mHSPC and mCRPC based on GAs detected in ctDNA.
Interim results from a phase 2 study of olaparib (without ADT) in men with biochemically-recurrent prostate cancer after prostatectomy, with integrated biomarker analysis.
Authors: Antonarakis Emmanuel S. , Wang Hao , Teply Benjamin A. , Kelly William Kevin , Willms Jamie , Sullivan Rana , King Serina , Marshall Catherine Handy , Lotan Tamara L. 
Published: May 2019

5045 Background: Pts with biochemically-recurrent (BCR) prostate cancer after local therapy with a PSA doubling time (PSADT) of ≤6 mo are likely to develop metastases and death from their disease. We hypothesized that the PARP inhibitor olaparib would be effective as a non-hormonal therapy for biomarker-unselected pts with BCR after prostatectomy, the first study of PARP inhibition in the hormone-sensitive setting. We report pre-specified interim results from the first stage of the trial. Methods: This investigator-initiated multicenter study (NCT03047135) enrolled pts with non-metastatic BCR after prostatectomy, with a PSADT of ≤6 mo. PSA had to be ≥1.0 ng/mL, with T ≥150 ng/dL. Pts received olaparib 300 mg twice daily (without ADT), until a doubling of their PSA or metastatic progression. The primary endpoint was confirmed ≥50% PSA decline (PSA50 response). Secondary endpoints included safety, minor PSA response (1-50% reduction), and PSA progression-free survival. Integrated biomarker analyses included somatic DNA sequencing, RNA expression analysis and IHC for DNA damage markers, using prostatectomy specimens. The study was designed to enroll a biomarker-unselected population using a staged-adaptive design, with up to 50 pts. In the first stage, ≥3 PSA50 responses out of 20 pts were required to proceed to the second stage; otherwise enrichment with biomarker-selected pts would occur. Results: Between 5/2017 and 11/2018, 20 men (median age, 65) enrolled in the first stage, with a median follow-up of 6 (range, 3-16) mo. Median PSADT was 3.1 mo, and 55% had Gleason ≥8 cancers. Seven men (35%) had BRCA2/ATM mutations. Three men (15%) had PSA50 responses (all had BRCA2 muts – 2 had complete PSA responses), and 4 other men (20%) had minor PSA responses. Median PSA progression-free survival was greater in men with vs. without BRCA2/ATM muts (9 vs. 4 mo; P= 0.02). Common toxicities of olaparib included fatigue, nausea, anemia and leukopenia; 2 men required a dose reduction. Conclusions: Olaparib (without ADT) was tolerable and showed activity in hormone-sensitive BCR prostate cancer, especially in men with BRCA2 muts. Second-stage enrolment is ongoing. Clinical trial information: NCT03047135.
ARCHES: Efficacy of androgen deprivation therapy (ADT) with enzalutamide (ENZA) or placebo (PBO) in metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Armstrong Andrew J. , Szmulewitz Russell Zelig , Petrylak Daniel Peter , Holzbeierlein Jeffrey M. , Villers Arnauld , Azad Arun , Alcaraz Antonio , Alekseev Boris Yakovlevich , Iguchi Taro , Shore Neal D. , Rosbrook Brad , Baron Benoit , Chen Lucy F. , Stenzl Arnulf 
Published: May 2019

5048 Background: ENZA has demonstrated benefit in men with metastatic and nonmetastatic castration-resistant prostate cancer (CRPC). ARCHES assessed the efficacy of ENZA with ADT in men with mHSPC, including pre-specified subgroups based on prior therapy. Methods: ARCHES, a multinational, double-blind, Phase 3 study (NCT02677896), randomized patients (pts) with mHSPC 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT, stratified by disease volume (CHAARTED criteria) and prior docetaxel (doce) use. Primary endpoint was radiographic progression-free survival (rPFS; centrally assessed radiographic progression or death within 24 weeks of treatment discontinuation). Secondary endpoints included time to initiation of new antineoplastic therapy and overall survival (OS). Treatment continued until disease progression or unacceptable toxicity. Results: 1150 men were randomized to ENZA (n = 574) or PBO (n = 576). Overall, 63% had high-volume disease, 18% had prior doce, and 91% had prior ADT or orchiectomy (orch). Median follow-up was 14.4 mo. ENZA + ADT significantly improved rPFS (Table); significant improvements in rPFS were also reported in prior treatment subgroups. Secondary endpoints improved with ENZA + ADT (Table), with no significant impact in time to deterioration in urinary symptoms. OS data are immature. Grade 3–4 adverse events (AEs) were reported in 23.6% of ENZA pts vs. 24.7% of PBO pts with no unexpected AEs. Conclusions: ENZA + ADT significantly improved rPFS and other efficacy endpoints vs. PBO + ADT in men with mHSPC. Preliminary safety analysis appears consistent with the safety profile of ENZA in previous CRPC clinical trials. Clinical trial information: NCT02677896. [Table: see text]
Trans-aTTom: Breast Cancer Index for prediction of endocrine benefit and late distant recurrence (DR) in patients with HR+ breast cancer treated in the adjuvant tamoxifen—To offer more? (aTTom) trial.
Authors: Bartlett John , Sgroi Dennis , Treuner Kai , Zhang Yi , Piper Tammy , Salunga Ranelle C. , Ahmed Ikhlaaq , Basnet Kristen M , Brachtel Elena , Pirrie Sarah , Schnabel Catherine A. , Rea Daniel William ,   on behalf of the Trans-aTTom Study Group
Published: May 2019

505 Background: The aTTom study is a prospective phase III trial that randomized 6953 HR+ women to stop or continue tamoxifen (TAM) for 5 more years after completing at least 4 years of prior TAM. Results at 9 years of median follow-up demonstrated fewer breast cancer recurrences (21% vs 25%; RR= 0.86 [95% CI 0.77-0.96]; P = 0.006) and reduced breast cancer mortality (13% vs 15%; HR= 0.91 [95% CI 0.80-1.04]; P = 0.18) but increased incidence of endometrial cancer with longer TAM use (P < 0.0001). The Breast Cancer Index (BCI) is a gene expression–based signature that stratifies patients based on the risk of overall (0-10y) and late (post-5y) DR and predicted the likelihood of benefit from extended endocrine therapy in MA.17. This Translational aTTom (Trans-aTTom) study is a large-scale validation of the predictive ability of BCI for extended endocrine therapy (EET) benefit. Methods: Patients treated in the aTTom trial with available primary tumor tissue were eligible for this multi-institutional prospective-retrospective study. Primary and secondary endpoints were recurrence-free interval (RFI) and disease-free interval (DFI), respectively. Statistical significance level for RFI was set at 0.0336 as per statistical plan. Kaplan-Meier and Cox proportional hazards regression analysis with time-varying coefficients were used to test the predictive activity of BCI by HoxB13/IL17BR (H/I) status (High vs Low). Likelihood ratio test based on Cox regression was used to evaluate treatment by biomarker interaction. Results: 2637 tumors were centrally assessed for ER, PR and HER2 status leading to 1822 HR+ patients analyzed (1018 N0, 583 N+). Initial results from patients with N+ disease at 12 years of median follow-up showed 287 (49%) were classified as H/I-High and 296 (51%) were classified as H/I-Low. H/I High patients showed a statistically significant benefit of 9.8% in RFI with 10y vs 5y of TAM (HR=0.35 [95% CI 0.15-0.85]; P=0.027), whereas H/I Low patients showed no benefit (-0.2% RFI; HR=1.07 [95% CI 0.69-1.65]; P=0.77). A statistically significant interaction between continuous BCI and treatment was demonstrated (P = 0.02). Conclusions: These data provide further validation and establish level 1B evidence for BCI as a predictive biomarker for preferential benefit from EET in HR+ breast cancer.
Results from a phase Ib/II study of enzalutamide and metformin in men with castration resistant prostate cancer (CRPC).
Authors: Parikh Mamta , Robles Daniel , Pan Chong-xian , Lara Primo , Yang Joy C , Gao Allen , Evans Christopher P. 
Published: May 2019

5054 Background: Preclinical models have shown that autophagy is a cell survival mechanism to overcome treatment-induced stress and facilitate progression and resistance in CRPC. Metformin (met) demonstrates autophagy inhibition and resensitizes CRPC tumors to enzalutamide (enza) as a combination in in vitro models. A Phase Ib/II trial was conducted to evaluate the combination. Methods: Eligible patients (pts) had established CRPC, ECOG 0-2, adequate hematologic and organ function, and ≤ 2 prior treatments for CRPC. Major exclusion criteria included prior enza or met treatment, presence of brain metastases, history of DM2 or seizures. An initial cohort of 3 pts were treated with enza 160 mg PO daily and met 500 mg PO bid (DL1), with met dose escalated to 1000 mg PO bid (DL2) in subsequent 3 pts if dose-limiting toxicity (DLT) was observed in ≤1 pt in DL 1, and cycles of 28 days. Once primary objective of maximum tolerated dose (MTD) was established, additional pts were enrolled at MTD for a total of 24 evaluable pts. Secondary objectives of the study included PSA response and safety. Results: From 8/24/16-12/31/18, a total of 3 pts were enrolled to DL1, with no DLTs observed in that cohort, with an additional 21 enrolled to DL2; 12 remain on trial. Median age was 71, with 8/24 (33%) and 3/24 (12.5%) with prior docetaxel and abiraterone treatment, respectively. One DLT due to Grade 3 abdominal pain was observed at DL2 prior to establishing MTD. Grade 3 AEs observed in 1/24 (4%) of pts were diarrhea, fatigue, hypertension, lower GI bleed, myalgia; 2/24 (8%) had abdominal pain. One pt had Grade 4 hallucinations. Among pts who discontinued, 8 were discontinued for progression, 3 withdrew consent, and 1 experienced an SAE (seizure). Pts received median of 11 cycles (1-31) of treatment. PSA response ≥ 50% was observed in 19/24 (79%) pts. Conclusions: The combination of enzalutamide 160 mg PO daily and metformin 1000 mg PO bid is well-tolerated, and clinically active. Clinical trial information: NCT02339168.