bluuebunny/crossref_metadata_2025_split huggingface dataset:
SLFN11 expression (exp) in castration-resistant prostate cancer (CRPC) patients (pts) to predict response to platinum-based chemotherapy (PLT).
Authors: Conteduca Vincenza , Puca Loredana , Ku Sheng-Yu , Hess Judy , Kearney Megan , Fernandez Luisa , Bareja Rohan , Vlachostergios Panagiotis J. , Sigouros Michael , Mosquera Juan Miguel , Sboner Andrea , Nanus David M. , Elemento Olivier , Dittamore Ryan , Tagawa Scott T. , Beltran Himisha 
Published: May 2019

5065 Background: Schlafen family member 11 (SLFN11) sensitizes tumor cells to DNA-damaging agents and has been investigated as a potential predictive biomarker of response to PLT and PARP inhibitors, especially in small cell lung cancer (Lok, CCR 2017; Pietanza, JCO 2018). We aimed to explore the predictive/prognostic role of SLFN11 in PLT-treated CRPC. Methods: We assessed tumor exp of SLFN11 in PLT-treated, metastatic CRPC pts by RNAseq (N=27) and/or CTCs (N=20) (via the Epic Sciences platform). In addition, tumor morphology for neuroendocrine (NE) features and genomic status of select genes (ie, AR, TP53, RB1, BRCA2, BRCA1, ATM) by whole exome sequencing were evaluated. Statistical comparisons used Cox regression analysis and Kaplan Meier method for the association with overall/radiographic progression free survival (OS/rPFS). A dose response curve with PLT was performed in patient-derived organoids using Cell Title Glo according to the manufacturer’s protocol. Results: 41 CRPC (including 20 CRPC-NE) treated with PLT monotherapy (N=3) or PLT combination therapy (N=38) between August 2013 and December 2017 were evaluated. Median age was 67.1 years (range 51-91). Median number of prior therapies was 2 (range 1-7). A longer median rPFS was observed in all SLFN11+ pts treated with PLT (regardless of histology, RB1, TP53, PTEN, or DNA repair status) compared to SLFN11- [5.2 vs 2.3 months, HR 3.5, 95%CI 1.6-7.7, P<0.0001]. No association was reported for OS. On multivariable analysis (Table), SLFN11 was an independent factor associated with rPFS. Organoids derived from patient tumors expressing SLFN11 showed sensitivity to PLT in vitro. Conclusions: SLFN11 exp identifies both CRPC and CRPC-NE pts with a better response to PLT. Patient-derived organoids expressing SLFN11 confirmed increased sensitivity to PLT. Larger prospective evaluation of therapy decisions based on SLFN11 exp is now required. [Table: see text]
Association of plasma DNA repair deficient (DRD) status with clinical outcome of metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with abiraterone acetate (AA) plus prednisone/dexamethasone (+P/D).
Authors: Shen Dong , Thomas Shibu , Lefresne Florence , Gormley Michael , Urtishak Karen , Lahaye Marjolein , Tombal Bertrand F. , Merseburger Axel S , Parekh Trilok V. , Ricci Deborah S. , Attard Gerhardt 
Published: May 2019

5066 Background: Somatic DRD deficiency in 15-30% of mCRPC pts have been observed and inhibition of enzyme poly ADP ribose polymerase (PARP) could prove beneficial. We aimed to define DRD status using plasma from pts treated on AA and evaluate associations with prospectively-collected outcome measures. Methods: Plasma DNA samples (128 baseline [BL], 134 cycle 2 day 1 [C2D1], 46 progression [PROG]) from chemotherapy-naïve mCRPC pts in a phase 2 study (NCT01867710) evaluating AA+P/D were subjected to custom target-capture next-generation sequencing. DRD assay was optimized and validated to detect pathogenic point mutations, small insertions/deletions, and copy number alternations (DRD+) in 8 DRD genes: BRCA1, BRCA2, FANCA, ATM, CHEK2, HDAC2, BRIP1, and PALB2. Analysis for genomic aberrations was a secondary exploratory objective. Associations with overall survival (OS), progression-free survival (PFS), and radiographic PFS (rPFS) were assessed using Cox regression models and Kaplan Meier analyses. Results: 11.7% of BL and 17.4% of PROG were DRD+. Bi-allelic was observed in 73.3% of BL DRD+ samples. Shorter PFS was observed in BL DRD+ vs DRD- (5.3 vs 15.5 mo; HR: 2.32; 95%CI:1.39-4.28; P < 0.002). Median PFS for BL DRD biallelic + vs DRD biallelic- was 5.1 vs 15.4 mo (HR: 2.49; 95% CI: 1.23-4.38; P < 0.0095). For multivariate analysis using DRD+, ALP, and LDH as covariates, DRD+ (HR: 2.1; 95% CI: 1.18-3.75; P < 0.012) and high ALP (HR: 1.66; 95% CI: 1.08-2.56; P < 0.021) were strongly associated with worse PFS. Median OS for BL DRD+ vs DRD- was 28.8 vs 41.3 mo (HR: 1.67; 95%CI:0.88-3.18; P = 0.116). Median rPFS for BL DRD+ vs DRD- was 16.2 vs 20.9 mo (HR: 1.64; 95%CI:0.83-3.21; P = 0.152). Of 39 Pts with BL, C2D1 and PROG samples, 3 were DRD+ (7.7%) at all 3 timepoints, 3 (7.7%) only at BL, 3 (7.7%) only at PROG (bi-allelic), 2 (5.1%) had extra deletion at PROG. Conclusions: Patients with mCRPC harboring DRD+ have worse outcomes with AA and represent a population with an unmet medical need.
Cell-free DNA as a biomarker for taxane treatment in advanced prostate cancer.
Authors: Sumanasuriya Semini , Seed George , Mehra Niven , Christova Rossitza , Pope Lorna , Goodall Jane , Flohr Penelope , Fowler Gemma , Bianchini Diletta , Rescigno Pasquale , Carreira Suzanne , Yuan Wei , Macé Sandrine , Chadjaa Mustapha , De Bono Johann S. 
Published: May 2019

5070 Background: Antitumor efficacy of chemotherapeutic drugs docetaxel and cabazitaxel against hormone-sensitive and castration-resistant prostate cancer (CRPC) is well recognized. The identification and validation of minimally invasive biomarkers of taxane response remain of paramount importance. Methods: Serial pre-, during and post-treatment plasma samples were collected prospectively from two large Phase III clinical trials, FIRSTANA (NCT01308567) and PROSELICA (NCT01308580). Chemotherapy-naïve patients (pts) were treated with docetaxel (75 mg/m2) or cabazitaxel (20 or 25 mg/m2) in FIRSTANA, and pts previously treated with docetaxel received cabazitaxel (20 or 25 mg/m2) as second-line chemotherapy in PROSELICA. Plasma cell-free DNA (cfDNA) was extracted, low-pass whole genome sequencing (lp-WGS) libraries were prepared using the QIAGEN QiaSeq FX DNA library kit, and samples sequenced on the Illumina NovaSeq 6000. Targeted next-generation sequencing (NGS) on a custom-made AmpliSeq panel of 30 genes, pre-selected for putative roles in taxane resistance, was also performed. lp-WGS copy number (CN) profiles were generated using ichorCNA (v0.1.0) and targeted NGS variant calls derived using IonReporter software. Results: Overall, lp-WGS data was generated from 265 samples (99 pts; 51 treated on the FIRSTANA study, 48 treated on the PROSELICA study), acquired at three time-points (pre-, during and at progression). Average cfDNA input was 10 ng and mean coverage achieved was ~2X (SD 1.2X). We observed changes in lp-WGS tumor purity over time as a result of therapy; samples from non-responding pts exhibited significantly higher tumor purity values post-treatment compared with samples from responding pts (p = 0.02). Targeted NGS results were available from 294 pts (153 from FIRSTANA, 141 from PROSELICA), and changes in tumor purity were also associated with treatment response (p = 0.04). CN frequency of key CRPC genes was similar to previously reported datasets; several aberrant loci associated with response to taxane therapy. Conclusions: cfDNA lp-WGS may have clinical utility in the management of lethal prostate cancer. Funding: Sanofi. Clinical trial information: NCT01308580, NCT01308567.
Examination of the additive value of CTC biomarkers of heterogeneity (Het) and chromosomal instability to nuclear-localized (nl) AR-V7+ CTCs in prediction of poor outcomes to androgen receptor signaling inhibitor (ARSi) in metastatic castration resistant prostate cancer (mCRPC).
Authors: Scher Howard I. , Schonhoft Joseph , Graf Ryon P , Jendrisak Adam , Barnett Ethan , Jayaram Anuradha , Winquist Eric , Landers Mark , Wang Yipeng , Allan Alison L , Attard Gerhardt , Dittamore Ryan 
Published: May 2019

5075 Background: Prediction of ARSi benefit in mCRPC is an unmet medical need. Recently, the Epic Sciences CTC based nl AR-V7 test validated as a predictive biomarker in two multi-center validation studies and has received Medicare coverage for use in mCRPC. While the nl AR-V7 biomarker is highly specific to resistance and predictive of improved response with taxane Rx, it is a measure of just one mechanism of resistance to ARSis. CTC Het measured by the Shannon Index and CTC chromosomal instability measured by predicted number of Large Scale Transitions (pLST) have both been associated with poor OS to ARSis in previous analysis. Here we investigate the relationship of Het and pLST to nlAR-V7 in order to assess multi-clonal resistance and determine if these biomarkers can provide added sensitivity in the nlAR-V7 negative patient population. Methods: 275 blood samples from 2nd+ line mCRPC patients prior to treatment with ARSi (n=148) or taxanes (n=137) were obtained between 2012 and 2017 from 3 clinical centers. Detectable CTCs in each blood sample were assayed for nlAR-V7, Het, and pLST using the Epic Sciences platform. Biomarkers were analyzed in context of each other and outcomes including clinical co-variates. Results: 94% of samples had detectable CTCs, 84% were evaluable for Het analysis (> 2 CTCs), and 76% were evaluable for pLST (> 3 CTCs). Conclusions: Addition of CTC Het (Shannon Index) and CTC chromosomal instability (pLST) biomarkers to nlAR-V7 identifies an additional 15% of mCRPC pts (38% of total) that are predicted to have poor survival to AR signaling inhibitors. [Table: see text][Table: see text]
Clinical and safety outcomes of TALAPRO-2: A two-part phase III study of talazoparib (TALA) in combination with enzalutamide (ENZA) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Agarwal Neeraj , Shore Neal D. , Dunshee Curtis , Karsh Lawrence Ivan , Sullivan Beth , Di Santo Nicola , Elmeliegy Mohamed , Lin Xun , Czibere Akos Gabor , Fizazi Karim 
Published: May 2019

5076 Background: TALA is a dual-mechanism PARP inhibitor that inhibits PARP catalytic activity and traps PARP on DNA. ENZA is a novel hormonal therapy approved to treat castration resistant prostate cancer. TALA + ENZA may improve clinical outcomes for men with mCRPC. However, TALA, is a substrate for efflux drug transporters P-gp and BCRP. Prior to the initiation of TALAPRO-2 part 1, the in vivo effect of ENZA on exposure of P-gp and BCRP substrates, such as TALA, had not been evaluated. Methods: TALAPRO-2 part 1 was designed to determine TALA starting dose based on safety and pharmacokinetics (PK) evaluation of TALA + ENZA. Pts were ≥18 yrs of age, had ECOG PS ≤1, with no prior systemic treatment for mCRPC. The starting dose of TALA in the first 13 pts was 1 mg once daily (QD) + ENZA 160 mg QD (1 mg QD cohort). Based on safety review of prespecified target safety events and PK data, TALA dose was reduced to 0.5 mg QD; additional pts were treated with a starting dose of TALA 0.5 mg QD + ENZA 160 mg QD (0.5 mg QD cohort). Results: 19 pts were enrolled in part 1 (1 mg QD cohort, 13; 0.5 mg QD cohort, 6). The median (range) age was 71 yrs (52-82). As of the analysis cutoff date, the median treatment duration was 25 and 11 wks for the 1 mg QD and 0.5 mg QD cohorts, respectively. Treatment-emergent adverse events (TEAEs) occurred in 19 pts. The most common TEAE, anemia, occurred in 76.9% and 33.3% of pts in the 1 mg QD and 0.5 mg QD cohorts, respectively. TEAEs that led to TALA dose reduction occurred in 6 pts (46.2%) and 0 pts in the 1 mg QD and 0.5 mg QD cohorts, respectively. In the 1 mg QD cohort, target safety events were reported for 7 pts (53.8%) vs 0 in the 0.5 mg QD cohort. 92% and 100% of pts had a 50% decline from baseline in PSA in the 1 mg QD and 0.5 mg cohorts, respectively, demonstrating preliminary anti-tumor activity. PK data showed that ENZA increased TALA exposure and that TALA 0.5 mg QD + ENZA maintained similar TALA exposure to that achieved with 1 mg QD monotherapy. Conclusions: TALA 0.5 mg QD + ENZA 160 mg QD had a manageable safety profile in pts with mCRPC and will be the starting dose for the randomized portion of TALAPRO-2. Clinical trial information: NCT03395197.
Evaluation of the patient-reported outcomes common terminology criteria for adverse events (PRO-CTCAE) with abiraterone acetate plus prednisone (AAP), degarelix (D), or the combination in men with biochemically recurrent prostate cancer (BCRPC).
Authors: Autio Karen A. , Antonarakis Emmanuel S. , Baser Raymond , Stein Mark N. , Shevrin Daniel H. , Vaishampayan Ulka N. , Mayer Tina M. , Morris Michael J. , Slovin Susan F. , Heath Elisabeth I. , Tagawa Scott T. , Rathkopf Dana E. , Milowsky Matthew I. , Harrison Michael Roger , Beer Tomasz M. , Balar Arjun Vasant , Armstrong Andrew J. , Paller Channing Judith , Basch Ethan M. , Scher Howard I. 
Published: May 2019

5080 Background: Patient-reported symptoms using the PRO-CTCAE provide insights into the patient experience with care. Earlier use of AAP (an androgen biosynthesis inhibitor plus prednisone) with androgen deprivation therapy in castration sensitive disease may lead to increased symptoms. We previously reported a randomized phase 2 trial of intermittent AAP, D, or AAP+D in BCRPC (NCT01751451) and now share the PRO-CTCAE results. Methods: Men were randomized 1:1:1 to AAP, D, or AAP+D for 8 months, then entered follow up with PSA, testosterone, and safety monitoring. PRO-CTCAE was elicited from patients monthly for hot flashes (HF), fatigue, arthralgias, myalgias, anxiety, depression, sexual function, plus overall QOL. Changes from baseline to end of treatment were compared between groups. AUCs were calculated for each item as a measure of symptom severity over time. Results: 110 men were included. Compliance with PRO-CTCAE reporting from baseline to EOT was 93%. HF did not differ between AAP+D and D, but were increased relative to AAP (all p < 0.05). These differences were consistent when HF were measured as an AUC (all p < 0.01). Fatigue severity did not differ between groups however men receiving AAP reported a small worsening in activity interference from fatigue as compared to AAP+D (p < 0.05). Overall QOL scores were high and did not differ with AAP+D relative to AAP or D. Conclusions: Collection of PRO-CTCAE was feasible and did not demonstrate differences in fatigue, HF, or QOL between AAP+D and D. Comparisons of PRO-CTCAE to matched clinician-reported AEs, and changes in PRO-CTCAE with testosterone recovery during follow up are planned. Clinical trial information: NCT01751451.
Targeting backdoor androgen synthesis through AKR1C3 inhibition: A presurgical hormonal ablative trial in high risk localized prostate cancer (PC).
Authors: Graham Laura , Reder Nicholas , Gulati Roman , Grivas Petros , Wright Jonathan L. , Yu Evan Y. , Hou Wendy , Nega Katie , Yezefski Todd , Montgomery Robert B. , Mostaghel Elahe A. , Ellis William J. , True Lawrence D. , Lin Daniel W. , Nelson Peter , Schweizer Michael Thomas 
Published: May 2019

5081 Background: Studies have shown that localized PCs may resist neoadjuvant androgen receptor (AR)-targeted therapies as a result of persistent intraprostatic androgens, likely arising through upregulation of steroidogenic enzymes. Therefore, we sought to evaluate clinical effects of combinatorial AR-targeted therapy, including indomethacin (Indo) to inhibit the steroidogenic enzyme AKR1C3, in men with high risk PC undergoing radical prostatectomy (RP). Methods: This was an open label, single-site, Phase II neoadjuvant trial in men with localized high to very-high risk PC, as defined by NCCN criteria. Patients received 12 weeks of neoadjuvant apalutamide (Apa), abiraterone (Abi) plus prednisone, degarelix, and Indo at their respective FDA-approved doses followed by RP. The primary objective was to determine the pathologic complete response (pCR) rate. Secondary objectives included assessing for minimal residual disease (MRD) (i.e. ≤0.25 cm3 tumor volume corrected for cellularity), measuring intraprostatic androgens and assessing molecular features associated with drug resistance. Twenty evaluable patients provided 91% power (one-sided alpha = 7.5%) to detect a difference in pCR rate of 5% (H0) vs. 25% (H1). Results: Twenty-two patients enrolled and 20 were evaluable for the primary endpoint (1 patient came off to pursue stereotactic radiosurgery; 1 was removed after developing grade 2 transaminitis). At baseline, the median PSA was 10.1 ng/mL (4.4-159.4), 4 (20%) patients had Gleason grade group (GG) 4 disease and 16 had GG 5 disease. At RP, 1 (5%) patient had a pCR, 6 (30%) had MRD, 18 (90%) had ypT3 disease and 7 (35%) had lymph node (LN) metastases. Treatment was generally well tolerated and adverse events were consistent with each individual drug’s known safety profile. Additional follow up data and correlative work will be presented at the meeting. Conclusions: In our cohort of men with high-risk PC, pCR rates remained low even with combinatorial AR-directed therapy. Ongoing pharmacodynamic studies aimed at determining if Indo effectively inhibited AKR1C3 will provide important insights regarding the utility of targeting this steroidogenic enzyme. Clinical trial information: NCT02849990.
Is there a role for testosterone replacement therapy in reducing biochemical recurrence following radical prostatectomy?
Authors: A T Edward , Huynh Linda My , Towe Maxwell M , See Kaelyn , El Khatib Farouk , Yafi Faysal A 
Published: May 2019

5085 Background: Historically, the use of testosterone replacement therapy (TRT) has not been recommended in men with a history of prostate cancer (PC). However, low testosterone levels are significantly associated with metabolic complications, decreased sexual function, and (more recently) high-grade PC. In 2009, in hopes of improving sexual function outcomes in men following radical prostatectomy (RP), we began treating low-risk patients with TRT. The current study examines the impact of TRT on biochemical recurrence (BCR). Methods: Between December 2009 and June 2018, a cohort of 850 patients underwent RP by a single surgeon. 152 (18%) men were postoperatively placed on TRT for recovery of sexual function. All data was prospectively collected and retrospectively analyzed. TRT patients were proportionately matched to 419 control patients by pathologic Gleason Grade Group (GGG) and stage. Univariate and multivariate comparisons were used to compare rates and time to BCR (two consecutive PSAs ≥ 0.2 ng/dl); Cox regression modeling was used to generate a survival function at the mean of covariates. Results: There were no statistically significant differences in preoperative PSA, age, prostate weight, pathologic GGG and stage between the control versus TRT groups. Median follow-up time was 3 years in both groups. 7/152 (4.6%) and 39/419 (9.3%) patients experienced BCR in the TRT versus control groups, respectively (unadjusted, p=0.068). In adjusted time to-analysis, TRT was an independent predictor of recurrence-free survival, after controlling for GGG, p-stage, preoperative FT and PSA. A patient on TRT was approximately 53% less likely to experience a BCR (OR: 0.534, 95%CI: 0.288-0.993). Conclusions: After accounting for pathologic GGG, stage, and other significant covariates, the use of TRT independently reduced recurrence post-RP. These results suggest the need for a multi-center randomized control trial.
Patient-reported outcomes (PROs) from KATHERINE: A phase III study of adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab (H) in patients (pts) with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer.
Authors: Schneeweiss Andreas , Loibl Sibylle , Mamounas Eleftherios P. , Minckwitz Gunter von , Mano Max S. , Untch Michael , Huang Chiun-Sheng , Rastogi Priya , Conte Pier Franco , D'hondt Veronique , Redondo Andres , Stamatovic Ljiljana , Bonnefoi Herve R. , Castro Salguero Hugo Raul , Fischer Hans Holger , Wahl Tanya A. , Song Chunyan , Blotner Steven , Trask Peter , Geyer Charles E. 
Published: May 2019

513 Background: The phase 3 KATHERINE (NCT01772472) study, met its primary endpoint by demonstrating significantly improved invasive disease-free survival with adjuvant T-DM1 compared to H in pts with residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy. PROs are reported here. Methods: Eligible pts had HER2-positive early breast cancer, received taxane- and H-containing neoadjuvant therapy (with/without anthracyclines) followed by surgery, and had residual invasive disease in the breast and/or axillary nodes. Pts were randomized to 14 cycles of adjuvant T-DM1 (3.6 mg/kg IV q3w) or H (6 mg/kg IV q3w) and adjuvant endocrine and radiation therapy per standard of care. The EORTC Quality of Life Questionnaire–Core 30 (QLQ-C30) and QLQ–Breast Cancer (QLQ-BR23) were completed at screening, at day 1 of cycles 5 and 11, within 30 days after study drug completion, and at 6 and 12 months’ follow-up. Results: Of 1,486 pts randomized (T-DM1, n = 743; H, n = 743), 612 (82%) and 640 (86%), respectively, had valid baseline and ≥1 post-baseline PRO assessments. During the study, pts in both arms had similar mean scores on the QLQ-C30 and QLQ-BR23 function and symptom scales. There was no clinically meaningful change (≥10 points) from baseline in the mean scores in either arm, including on symptoms similar to AEs seen with T-DM1 (eg, fatigue). While more pts in the T-DM1 arm reported clinically meaningful deterioration in role functioning (49% vs 41%), appetite loss (38% vs 28%), constipation (47% vs 38%), fatigue (66% vs 61%), nausea/vomiting (39% vs. 30%), and systemic therapy side effects (49% vs 36%) at ≥1 assessment, the proportion reporting clinically meaningful change in functioning was similar between arms at any given assessment. Conclusions: Mean scores showed only small deterioration from baseline in patient-reported treatment-related symptoms in both study arms. While more pts in the T-DM1 arm reported deterioration at some point in several symptoms, baseline global health status and functioning were generally maintained in both arms over the treatment course. Clinical trial information: NCT01772472.