bluuebunny/crossref_metadata_2025_split huggingface dataset:
A multicentric phase II randomized trial of docetaxel (D) plus enzalutamide (E) versus docetaxel (D) as first-line chemotherapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): CHEIRON study.
Authors: Caffo Orazio , Palesandro Erica , Nole Franco , Gasparro Donatello , Mucciarini Claudia , Aieta Michele , Iacovelli Roberto , De Giorgi Ugo , Rossetti Sabrina , Maruzzo Marco , Fratino Lucia , Sacco Cosimo , Nicodemo Maurizio , Giordano Monica , Sartori Donata , Scapoli Daniela , Verri Elena , Veccia Antonello , Pappagallo Giovanni L. , Aglietta Massimo 
Published: May 2019

5050 Background: D and E demonstrated to be efficacious in the treatment of mCRPC pts. Due to different antitumor mechanism of action of these agents, it could be postulated that their combination can improve disease control. CHEIRON study tried to demonstrate the candidate efficacy of chemo-hormonal combination D+E versus D in mCRPC first-line. Methods: Eligibility criteria included mCRPC diagnosis, ECOG PS ≤ 2, adequate renal, hepatic and hematological functions, no prior treatment for mCRPC. Pts were randomized to receive D 75 mg/m2 IV d1 q3w plus prednisone 5 mg PO BID for 8 courses alone or plus E 160 mg PO daily for 24 weeks. Stratification criteria were presence of pain and visceral metastases. The primary endpoint of the study was the rate of pts without disease progression (according to PCWG2) at 6 mos after randomization. Results: Between 09/2014 and 10/2017, 246 pts (median age 70 years, range 44-88, pain reported by 54 pts, visceral metastases present in 50 pts) were randomized to DE (120) or D (126). The rate of pts without disease progression at 6 mos was significantly higher in DE arm compared to D arm (89.1% vs 72.8%; p = 0.002). Similarly, a higher proportion of DE pts achieved a PSA reduction ≥ 50% compared to the baseline values compared to the D pts (92% vs 69%; p < 0.0001). No differences were observed in terms of objective response rate. Major haematological toxicities consisted of grade 3-4 neutropenia (13 pts DE – 11 pts D); febrile neutropenia was observed in 10 DE pts and in 6 D pts. At a median follow-up of 24 mos, the median progression free survival was 10.1 mos and 9.1 mos in DE and D arm, respectively (p = 0.01). In DE arm the median overall survival was 33.7 mos compared to 29.6 mos of the standard arm (p NS). Conclusions: The present study was the first phase II randomized trial, which tested the addition of a new generation hormone agent to D compared to D alone. From this data, DE improved the 6-mo disease control with a prolongation of PFS compared to the standard chemotherapy. Clinical trial information: NCT02453009.
Clinical and genomic hallmarks of low PSA secretors in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Rubio Romero Gustavo , Weinstein Alana , Friedl Verena , Foye Adam , Playdle Denise , Sabol Alexis , Li Patricia , Huang Jiaoti , Feng Felix Y , Stuart Joshua M. , Small Eric Jay , Aggarwal Rahul Raj 
Published: May 2019

5051 Background: Metastatic disease burden out of proportion to low serum PSA level is frequently used as a clinical surrogate for the diagnosis of treatment-emergent small cell neuroendocrine prostate cancer (t-SCNC), although many t-SCNC patients (pts) have normal or elevated PSA levels. The clinical and genomic characteristics of mCRPC pts who are Low PSA Secretors have not been previously described. Methods: Eligible mCRPC patients (pts) underwent image-guided needle biopsy. Formalin-fixed paraffin embedded tissue was evaluated with targeted next-generation DNA sequencing. Fresh frozen tissue from the same metastatic tumor underwent RNA-seq. A validated AR transcriptional signature was applied. Low PSA Secretors were defined as pts with PSA < 5 ng/mL plus ≥ 6 metastases on conventional imaging at the time of tumor biopsy. Clinical and genomic characteristics were compared between low PSA Secretors and all other pts. Results: Of 89 evaluable pts, 9 (10%) were identified as Low PSA Secretors. There was no difference between Low PSA Secretors and all other pts in: serum PSA at diagnosis, frequency of Gleason ≥ 8 adenocarcinoma at diagnosis, and serum level of LDH, alkaline phosphatase, or hemoglobin at the time of biopsy. Lung and/or liver metastases were more common in low PSA secretors (67% vs. 33%, p = 0.04). There was no difference in serum level of LDH, alkaline phosphatase, or hemoglobin. Tumor biopsies from Low PSA Secretors were more likely to fall within a previously defined t-SCNC transcriptional cluster (80% vs. 6%, p < 0.001). RB1 loss or inactivating mutations appeared to be enriched in Low PSA Secretors (40% vs. 12%, p = 0.09); there was no difference in frequency of TP53 alterations between subgroups. AR transcriptional signature scores were lower in the Low PSA Secretor group (median score -3.63 vs. 0.66, p < 0.001). Conclusions: Low serum PSA levels in relation to metastatic tumor burden may be a reliable surrogate for the detection of mCRPC that harbors the transcriptional and genomic hallmarks of t-SCNC. Validation studies are warranted.
GeparOLA: A randomized phase II trial to assess the efficacy of paclitaxel and olaparib in comparison to paclitaxel/carboplatin followed by epirubicin/cyclophosphamide as neoadjuvant chemotherapy in patients (pts) with HER2-negative early breast cancer (BC) and homologous recombination deficiency (HRD).
Authors: Fasching Peter A. , Jackisch Christian , Rhiem Kerstin , Schneeweiss Andreas , Klare Peter , Hanusch Claus , Huober Jens Bodo , Link Theresa , Untch Michael , Schmatloch Sabine , Denkert Carsten , Stefek Andrea , Uleer Christoph , Doering Gabriele , Engels Knut , Seither Fenja , Blohmer Jens Uwe , Loibl Sibylle 
Published: May 2019

506 Background: The efficacy and toxicity of olaparib in early BC pts with homologous DNA repair deficiency (here defined as HRD score high tumors +/- germline (g) or tumor (t) BRCA mutation) is not well described. GeparOLA investigates olaparib in HER2 negative early BC with HRD. Methods: GeparOLA (NCT02789332) randomized 102 pts to either paclitaxel 80 mg/m² weekly (Pw) plus olaparib 100 mg twice daily for 12 weeks (PwO n = 65) or Pw plus carboplatin (Cb) AUC2 weekly for 12 weeks (PwCb n = 37), both followed by EC. Randomization was stratified by hormone receptor-status (HR+ vs HR-) and age ( < 40 vs ≥40 years). Pts with untreated primary cT2 - cT4a-d or cT1c with either cN+ or pNSLN+ or triple negative or Ki-67 > 20% were included, with either g/t BRCA mutation and/or high HRD score. The primary endpoint is pathological complete response (pCR; ypT0/is ypN0). A one group χ2-test was planned to exclude the pCR rate of ≤55% in PwO→EC arm. Secondary endpoints are other pCR definitions, breast conservation rate, clinical and imaging response, tolerability and safety. Results: A total of 107 pts were randomized between 9/2016 and 7/2018; 106 started treatment. Median age was 47.0 years [range 25.0-71.0]; 36.2% of pts had cT1, 61.0% cT2, 2.9% cT3, and 31.8% cN-positive tumors; G3: 86.8%; Ki-67 > 20%: 89.6%; TNBC 72.6%; confirmed g /tBRCA 1/2 mutation: 60.4%. pCR rate with PwO was 55.1% (90%CI 44.5%-65.3%) vs PwCb 48.6% (90%CI 34.3%-63.2%). Analysis for the stratified subgroups showed higher pCR rates with PwO in the cohorts of pts < 40 years and HR+ pts Clinical trial information: NCT02789332. Conclusions: GeparOla could not exclude a pCR rate of ≤55% in the PwO arm. Subgroup analysis is hypothesis generating and need further confirmation.[Table: see text]
Multi-gene hereditary cancer testing, family history and prognosis in men with prostate cancer.
Authors: Vlachostergios Panagiotis J. , Schaap Ariel , Sun Michael , Sternberg Cora N. , Molina Ana M. , Nanus David M. , Barbieri Christopher , Tagawa Scott T. 
Published: May 2019

5073 Background: Multi-gene hereditary cancer testing is common in prostate cancer (PC). We assessed the frequency of pathogenic mutations (mt) and examined associations with family history (FH), cancer recurrence, and overall survival (OS). Methods: Men with clinically localized or metastatic PC consented to germline DNA testing using a validated panel of 30 genes associated with elevated risk for common cancers (Color Genomics). Chi-square test and Fisher’s exact test were used to compare pathogenic mt and clinical characteristics. The Kaplan-Meier method was used to evaluate the associations of mt status with PSA recurrence and OS. Results: 315 men (median age 69, range 38-89) were included; 140 (44.4%) with localized and 175 (55.6%) with metastatic PC. 215 (68.3%) reported a FH of any cancer in one and 101 (32.1%) in ≥ 2 first-degree relatives. Genomic testing detected 12.1% of pts possessed a pathogenic mt (39 mt in 38 pts): BRCA2 (n = 12, 3.8%), CHEK2 (n = 10, 3.2%), APC (n = 7, 2.2%), MUTYH (n = 3, 0.9%), ATM (n = 2, 0.6%), and 1 each (0.3%) with NBN, PALB2, RAD51D, MSH2, and PMS2. Variants of uncertain significance were detected in 52 (16.5%). Men with FH of prostate, breast, ovarian, pancreatic cancer or/and melanoma (182/315, 58%), were more likely to have BRCA2 pathogenic mt (P = 0.049). Median age of diagnosis was 55 with BRCA2 versus 62 in non-carriers (P = 0.01). No association was found between FH of Lynch-associated cancers (colon, endometrial, gastric) and mismatch repair gene variants. The prevalence of pathogenic mt was significantly higher with visceral metastases (P = 0.001) but did not differ between localized and advanced PC pts (P = 0.602). In men with clinically localized PC at diagnosis (n = 226, 71.7%), pathogenic mt were associated with a shorter time to recurrence (30 vs 53 months, P = 0.004). Men with advanced PC (n = 175) and germline APC or MUTYH mt had worse median OS (44 vs 318 months, P = 0.004). Conclusions: Our findings confirm the incidence of men with non-PC FH associated with DNA repair gene mt and support testing in early stage pts. Further, our data support the prognostic significance of germline genetic alterations which deserves study in a larger cohort of pts.
Exome analysis of oncogenic pathways and tumor mutational burden (TMB) in triple-negative breast cancer (TNBC): Results of the translational biomarker program of the neoadjuvant double-blind placebo controlled GeparNuevo trial.
Authors: Loibl Sibylle , Sinn Bruno Valentin , Karn Thomas , Untch Michael , Sinn Hans-Peter , Weber Karsten Ernst , Hanusch Claus , Huober Jens Bodo , Staib Peter , Lorenz Ralf , Blohmer Jens Uwe , Marmé Frederik , Schmitt Wolfgang D , Rhiem Kerstin , van Mackelenbergh Marion , Fasching Peter A. , Wu Song , Higgs Brandon W. , Schneeweiss Andreas , Denkert Carsten 
Published: May 2019

509 Background: GeparNuevo (G9) showed a numerical increase in pCR rate of 53% vs 44%; p = 0.287 compared to placebo in TNBC with the addition of the anti-PD-L1 antibody durvalumab (D) to a neoadjuvant anthracycline-taxane containing chemotherapy (Loibl S et al. ASCO 2018). Somatic mutations in malignant cells manifest over the evolutionary history of a tumor. Reports in selected tumor types suggest that TMB may predict clinical outcomes on immune-checkpoint inhibitors (ICI). The clinical relevance of TMB in breast cancer has not been studied widely. Here, we investigated the hypothesis that TMB predicts response to ICI. Methods: Whole exome sequencing was conducted on patient-matched fresh-frozen core biopsies and blood samples with Illumina (n = 149/174). SNVs and indels were called with Mutect and pureCN was used for copy number calls. Mutational signatures were identified as described by Alexandrov et al. (Cell Rep. 3, 2013). Data from G9 were compared to The Cancer Genome Atlas (TCGA) TNBC cohort. Results: A similar genomic landscape was observed between G9 and TCGA with primary mutations in TP53 (69%), c-MYC (26%), BRCA1 (13%), BRCA2 (6%), PIK3CA (11%) and PTEN (11%). Median TMB was 1.52 mut/MB. TMB in G9 was slightly lower than TCGA TNBC. TMB correlated with older age, higher mutation rates in BRCA2, ARID1A, and TP53, and higher burden in variant signatures such as DDR, HRD, GFRs, APOBEC and Alexandrov’s signatures 3 and 6. Continuous TMB predicted pCR in univariate (OR = 1.62, 95%-CI: 1.20 - 2.20, p = 0.0018) and multivariate (OR = 2.06, 95%-CI: 1.33 - 3.20, p = 0.0012) logistic regression models, but did not predict a D effect. After dichotomisation of TMB at the top tertile, 50 patients had high TMB and 29 of these (58%) achieved a pCR, while 99 had low TMB and only 38 of these (38%) had a pCR (p = 0.0242). Conclusions: Results show that TMB may predict pCR in primary TNBC. The trial was financially supported by Astra Zeneca and Celgene. Clinical trial information: NCT02685059.
NSABP B-41, a randomized neoadjuvant trial: Genes and signatures associated with pathologic complete response (pCR).
Authors: Swain Sandra M. , Tang Gong , Brauer Heather Ann , Goerlitz David , Lucas Peter C. , Harris Brent T. , Robidoux Andre , Geyer Charles E. , Rastogi Priya , Mamounas Eleftherios P. , Wolmark Norman 
Published: May 2019

511 Background: NSABP B-41 randomly assigned 529 patients (pts) with HER2 positive breast cancer to neoadjuvant trastuzumab (T), lapatinib (L), or combination (T+L), with weekly paclitaxel following doxorubicin and cyclophosphamide. No significant differences in pCR were found, but overall survival was significantly increased for pCR. Methods: RNA was extracted from FFPE tumor specimens, run on the NanoString Breast Cancer 360 Plus panel. Gene counts were normalized to include housekeeping genes, 33 biological signatures from 776 genes across 23 pathways and transformed into logarithm scale with base two. Univariate logistic regression was used to screen candidate genes and signatures that are prognostic of pCR, with false discovery rate controlled at 0.1. Multivariable logistic regression with lasso regularization was used for model selection. Results: 194 core biopsy samples were available; 69 treated with T, 64 with L and 61 with T+L. 20 prognostic genes are selected for trastuzumab-based regimens (TBR), including the epithelial-mesenchymal transition (HEMK1, GRB7, ERBB2, TMPRSS4), adhesion and migration (ITGB6, COL27A1, NRCAM), JAK-STAT (SOCS2), Hedgehog (LRP2), ER signaling (ELOVL2, MAPT), DNA damage and repair (NPEPPS, PRKDC), MAPK (DUSP6, PRKCB), Apoptosis (BCL2), proliferation (TFDP1). ERBB2 expression are associated with pCR in patients on TBR (OR = 1.73), but not for patients on L (interaction p = 0.01). HER2-Enriched correlation (p < 0.001), ESR1 (OR = 0.78, 95% CI = 0.69-0.88, p < 0.001), PD1 (OR = 1.68, 95% CI = 1.12-2.52, p = 0.01) and Tumor Inflammation Score (OR = 1.58, 95% CI = 1.18-2.11, p = 0.002) are associated with pCR in TBR. No genes or signatures were found to be predictive of treatment benefit from L added to T. Conclusions: BC360 highlighted tumor progression and signaling genes prognostic for TBR. HER2-Enriched correlation, ERBB2 and PD1 expression, and immune activation signatures were associated with pCR in TBR and may provide personalized treatment guidance.
Ki67 during and after neoadjuvant trastuzumab, pertuzumab and palbociclib plus or minus fulvestrant in HER2 and ER-positive breast cancer: The NA-PHER2 Michelangelo study.
Authors: Gianni Luca , Colleoni Marco , Bisagni Giancarlo , Mansutti Mauro , Zamagni Claudio , Del Mastro Lucia , Zambelli Stefania , Frassoldati Antonio , Barlera Simona , Valagussa Pinuccia , Viale Giuseppe 
Published: May 2019

527 Background: Downregulation of Ki67 by neoadjuvant endocrine therapy predicts activity of endocrine treatments in hormone receptors positive breast cancer. NA-PHER2 is an exploratory phase II study (NCT02530424) assessing Ki67 changes in patients with HER2+ and ER+ breast cancer undergoing dual HER2 block and palbociclib. Cohort A of the NA-PHER2 showed significant decrease of Ki67 at week 2 and at surgery and pathological complete response (pCR) in 27% of patients (Lancet Oncol 2018). Methods: After completing cohort A two additional cohorts were started. In Cohort B cases with HER2 3+ or amplified unilateral breast cancer received therapy with dual block and palbociclib without fulvestrant. In Cohort C tumors with Ki67 >20% and HER2 low (1+/2+, no amplification) received also fulvestrant. Trastuzumab and pertuzumab q3 wks were dosed for 6 cycles and palbociclib for 5 cycles (125 mg po q.d. 3q4 wks). Fulvestrant in Cohort C was given im 500 mg q4 wks for 5 cycles. Primary endpoint was Ki67 change from baseline to 2 weeks and at surgery. Results: 26 eligible patients in cohort B and 23 in cohort C with centrally confirmed HER2 and ER status were recruited. Ki67 was centrally assessed. Main results are reported in the table. Clinical trial information: NCT02530424. The most frequent G >=3 adverse events were neutropenia (36%) and gastrointestinal disorders (12%). Conclusions: Dual block of HER2 and palbociclib caused robust persistent decrease of Ki67 as in cohort A. In cohort B without endocrine therapy there also were pCR and high objective response rate. Effects on Ki67 and ORR were similar in HER2 low tumors. The chemo-free approach of NA-PHER2 leads to promising therapeutic effects and deserves investigation in ER+ HER2+ tumors to spare the toxicity of chemotherapy, and in HER2-low tumors, in which functional activation of HER2 may lead to resistance to endocrine therapy. Supported in part by unrestricted grants of Pfizer Italia S.r.l. and Roche S.p.a. Italia.[Table: see text]
The prognosis of patients with recurrent or persistent ovarian clear cell carcinoma: Results from a randomized phase III study (JGOG3017/GCIG).
Authors: Kondo Eiji , Tabata Tsutomu , Suzuki Nao , Aoki Daisuke , Tokuyama Osamu , Kato Kiyoko , Hamano Tetsutaro , Kotera Yoshio , Fujiwara Keiichi , Kimura Eizo , Terauchi Fumitoshi , Sumi Toshiyuki , Okamoto Aikou , Yaegashi Nobuo , Enomoto Takayuki , Sugiyama Toru 
Published: May 2019

5515 Background: There are currently no concise data on prognosis in patients with recurrent or persistent clear cell carcinoma (CCC). The JGOG3017/GCIG was a randomized phase III trial to compare paclitaxel plus carboplatin (TC) to CPT-11 plus cisplatin (CPT-P) for stage I to IV CCC patients who have been diagnosed by central pathological review (CPR). A total of 619 patients were eligible for efficacy analyses. The aim of this study was to investigate prognosis of these patients with recurrent or persistent CCC. Methods: We estimated median and restricted mean survival time (RMST) of post-progression survival (PPS) of patients with recurrent or persistent CCC by platinum sensitivity, treatment arm, crossover chemotherapy, primary stage, residual tumor, performance status and ethnicity. PPS rates at 6, 12, 18 and 24-month were also calculated. Results: Among the 619 patients, the recurrence rate of stages was as follows: 6.3% (6/96) in stage IA/IB, 14.6% (46/315) in stage IC, and 54.8% (114/208) in stage II- Ⅳ. The recurrence rate of surgical situations was as follows: 19.4% (106/544) in complete surgery, 75% (27/36) in optimal, and 84.6% (33/39) in suboptimal. Overall, 166 of 619 patients had recurrent disease. The median PPS were 14.0 months (95% confidence interval [CI], 12.6 – 17.9) for all patients, 13.5 months (95% CI, 11.4 – 19.6) in the TC group (n=77) and 14.4 months (95% CI, 11.0 - 18.8) in the CPT-T group (n=89), with no significant difference between the two groups (hazard ratio, 1.02; 95% CI, 0.71 - 1.47, log-rank P = 0.898). The RMST of PPS for all patients was 14.6 months (95% CI, 13.3 - 15.8). Median PPS for patients with platinum-resistant (44.6%, n=74) and platinum-sensitive (53.0%, n=88) disease were 10.9 months (95% CI, 8.9 - 13.3) and 18.8 months (95% CI, 15.0 - 28.7) (HR, 1.88; 95% CI, 1.30-2.72, p<0.001), respectively. Conclusions: The median PPS of patients with platinum-resistant recurrence was significantly shorter than that of patients with platinum-sensitive recurrence. Data on PPS in patients with recurrent CCC that will be the basis of a future clinical trial in such patients were obtained.
A randomized double-blind placebo-controlled phase II trial comparing gemcitabine monotherapy to gemcitabine in combination with adavosertib in women with recurrent, platinum resistant epithelial ovarian cancer: A trial of the Princess Margaret, California, Chicago and Mayo Phase II Consortia.
Authors: Lheureux Stephanie , Cabanero Michael , Cristea Mihaela C. , Mantia-Smaldone Gina , Olawaiye Alexander , Ellard Susan , Weberpals Johanne I , Wahner Hendrickson Andrea Elisabeth , Fleming Gini F. , Welch Stephen , Dhani Neesha C. , Piskorz Anna , Tan Susie , Chang Karen , Wang Lisa , Kunos Charles , Pugh Trevor John , Brenton James D. , Oza Amit M. 
Published: May 2019

5518 Background: Platinum resistant ovarian cancer (OC) remains a therapeutic challenge. High grade serous OC (HGSOC) harbors TP53 mutations leading to increased dependency on S- and G2-phase checkpoints. Wee1 inhibition with Adavosertib (AZD 1775) (A) induces G2 checkpoint escape. Gemcitabine (G) is an antimetabolite therapy and blocks the progression of cells through the G1/S phase. We hypothesized that combining G+A would be synergistic and overcome resistance. Methods: We conducted a multicentre double-blind 2:1 randomized phase 2 trial to assess the progression free survival (PFS) in women with recurrent platinum-resistant/refractory HGSOC receiving G+A or G+placebo (P) (NCT02151292). Eligibility required measurable disease and feasibility of paired tumor biopsies; no limitation in prior lines of therapy. Non HGSOC histologic subtypes were enrolled in a separate non-randomized exploratory cohort. A/P was given orally at 175mg QD on D1-2, D8-9 and D15-16 with G 1000mg/m² IV D1, D8 and D15 in a 28-day cycle until progression or unacceptable AE. Tumor staging was scheduled every 8 weeks. TP53 mutations were analyzed on archival tissue with Sanger sequencing, TAm-Seq and IHC. TP53 mutation will be also assessed in circulating tumor DNA (ctDNA). Whole exome and RNA sequencing were performed on paired tumor tissues. Results: 124 patients (pts) with median of 3 prior lines of therapy (range 1-10) from 12 centres across Canada and US were enrolled between Sep 2014 to May 2018, with 99 pts randomized (65 in Arm G+A and 34 in G+P). 5 pts were ineligible; 64 pts have died. The median follow-up was 14.3 months. Main related AE was hematologic toxicity (Anemia G≥3: 31% in G+A vs 18% in G+P; Thrombocytopenia G≥3: 31% vs 6%; Neutropenia G≥3: 62% vs 30%). PFS was significantly improved from 3.0 to 4.6 months (HR 0.56 (95%CI: 0.35-0.90, p=0.015 Log rank). There was a significant improvement in overall survival (OS) from 7.2 to 11.5 months (HR 0.56 (95%CI: 0.34-0.92, P=0.022). Partial response by RECIST 1.1 was observed in 13 (21%) and 1 (3%) pts for Arms G+A and G+P, respectively (p=0.02). From the 25 pts in the exploratory cohort, 3 (12%) partial responses were observed. Final results will be reported at the meeting. Conclusion: Addition of adavosertib to gemcitabine in women with platinum resistant/refractory OC improved response rate, PFS and OS with manageable toxicity. Clinical trial information: NCT02151292.