bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic predictors of benefit of docetaxel (D) and next-generation hormonal therapy (NHT) in metastatic castration resistant prostate cancer (mCRPC).
Authors: Hamid Anis , Beltran Himisha , Choudhury Atish Dipankar , Sweeney Christopher
Published: May 2019

5018

Background: Predictive genomic biomarkers in mCRPC remain elusive. Prior studies suggest that tumor suppressor (TS) loss is prognostic, and may result in less benefit from NHT, but no impact on D efficacy. We assessed genomic predictors of differential benefit of androgen receptor-targeted therapy and chemotherapy for mCRPC. Methods: Patients with mCRPC and targeted exome sequencing of biopsies obtained after metastatic diagnosis were identified (n=109). Patients with pure small cell histology (n=6) were excluded. Time from NHT or D start to clinical/radiographic progression (time to treatment failure, TTTF) was estimated by Kaplan-Meier method, with censoring at next therapy or last follow-up for non-progressors. Results: 80.1% of patients had bone and/or lymph node-only metastases at mCRPC diagnosis. In total, 87/103 (84.5%) and 61/103 (59.2%) received NHT and D for mCRPC, respectively. Median overall survival was 4.5 years from first mCRPC. The frequency and predictive association of selected recurrently-altered genes are detailed in the table. PTEN alterations (alts) were associated with worse TTTF on NHT, but not D, and a similar trend was observed with BRCA2. Biallelic RB1 loss was strongly predictive, conferring significantly shorter TTTF on both NHT and D. A score based on presence of tumor PTEN alt (1) and/or biallelic RB1 alt (1) was predictive of TTTF on NHT (median TTTF of score 0 vs 1 vs 2: 14.7 vs 12 vs 3.8 months; log rank p=0.003). Conclusions: The presence of single or compound PTEN and RB1 alts predict poorer outcomes with NHT for mCRPC. Chemotherapy may be a preferred therapeutic strategy for this patient population. [Table: see text]
Targeted next-generation sequencing (tNGS) of metastatic castrate-sensitive prostate cancer (M1 CSPC): A pilot molecular analysis in the STAMPEDE multi-center clinical trial.
Authors: Gilson Clare , Ingleby Fiona , Gilbert Duncan C , Parry Marina , Atako Nafisah B , Mason Malcolm David , Malik Zafar , Langley Ruth E , Simmons Andrew , Loehr Andrea , Clarke Noel , James Nicholas , Parmar Mahesh K B , Sydes Matthew Robert , Attard Gerhardt , Chowdhury Simon
Published: May 2019

5019

Background: The STAMPEDE trial recruits men with high risk prostate cancer commencing first line systemic therapy. In a pilot study to ascertain the feasibility of tNGS and the prevalence of common genomic aberrations, we tested a commercial clinically-accredited assay on tumor blocks and present data obtained in the largest cohort of treatment-naïve M1 CSPC to date. Methods: Archival FFPE blocks were retrieved from trial participants and a single block submitted for sequencing by a Foundation Medicine. Inc. tNGS assay that includes 395 genes. Results: We successfully obtained tNGS data on 115 (62%) of 186 patients enrolled between Nov-2011 and April-2017 at 15 UK participating centers. The median age was 70 years (IQR 44-85); 97% had de novo M1 disease and 83% Gleason score ≥8. We observed PTEN deficiency (34%) due to copy-number loss (25%) or mutation (9%); TP53 mutation or loss (33%) and aberrations in PI3K signaling (16%), genes involved in DNA repair (14%), Wnt signaling (14%) and cell cycle control (6%). In total, these aberrations were observed in 76% of patients, with 35% harboring two or more. No androgen receptor ( AR) mutations were detected. Conclusions: The prevalence of PTEN deficiency is comparable with that observed in mCRPC consistent with this being a feature of metastatic disease. In contrast, AR mutations are not observed in this treatment-naïve group. The prevalence of DNA repair deficiency is less than observed in mCRPC but more than reported in prostatectomy cohorts. Although it is possible to use FFPE biopsies for tNGS, the test failure-rate poises challenges to evaluating treatments in low prevalence biomarker-defined groups. These data will inform the design and conduct of biomarker-directed trials.
External validation of a prognostic model for overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Halabi Susan , Dutta Sandipan , Araujo John C. , Logothetis Christopher , Sternberg Cora N. , Armstrong Andrew J. , Carducci Michael Anthony , Chi Kim N. , De Bono Johann S. , Petrylak Daniel Peter , Fizazi Karim , Higano Celestia S. , Small Eric Jay , Kelly William Kevin
Published: May 2019

5022

Background: We have previously developed and externally validated a prognostic model of OS in men with mCRPC treated with docetaxel (D), which included eight predictors: opioid analgesic use, ECOG performance status, albumin, disease site, LDH, hemoglobin, PSA, and alkaline phosphatase. We have used this model to develop prognostic risk groups. We sought to externally validate this model in a broader group of men with mCRPC and in specific subgroups (White, Black, Asian patients, different age groups) and to validate the two and three prognostic risk groups in this large dataset. Methods: Data from 5,790 mCRPC men randomized on 5 phase III trials were utilized to validate the prognostic model of OS: D +/- zibotentan (ENTHUSE), D +/- lenalidomide (MAINSAIL), D +/- dasatinib (READY), D+/- custirsen (SYNERGY), and tasquinimod/placebo)). We applied the estimated parameters from the prognostic model to each of the five data sets and computed a risk score. We assessed the predictive performance of the model by computing the time-dependent area under the receiver operating characteristic curve (tAUC) and validated the two-risk (low, high) and three-risk prognostic risk groups (low, intermediate, high) that were defined by the model. Results: The tAUC for the different groups is presented in the table. Race, age, and treatment subsets had similar results. For the two prognostic risk groups, the median OS in the low and high groups were 27.6 months (95% CI = 26.6-28.7) and 13.8 months (95% CI = 13.3-14.4). For the three prognostic risk group, median OS in the low, intermediate and high groups were 29.7 months (95% CI = 28.3-31.4), 19.0 month (95% CI = 18.3-20.4) and 12.1 months (95% CI = 11.5-12.9), respectively. Conclusions: This prognostic model for OS in men with mCRPC has been validated in a larger dataset, yields similar results across race, age and treatment groups. The model is robust and can be used to identify prognostic risk groups of patients for stratification and enrichment trials. Clinical trial information: NCT00626548. [Table: see text]
Efficacy of apalutamide (APA) plus ongoing androgen deprivation therapy (ADT) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) and baseline (BL) comorbidities (CM).
Authors: Small Eric Jay , Saad Fred , Chowdhury Simon , Oudard Stephane , Hadaschik Boris A. , Graff Julie Nicole , Olmos David , Mainwaring Paul N. , Lee Ji Youl , Uemura Hiroji , Lopez-Gitlitz Angela , Londhe Anil , Bhaumik Amitabha , Cheng Shinta , Rooney Oliver Brendan , Smith Matthew Raymond
Published: May 2019

5023

Background: The addition of APA to ongoing ADT in pts with nmCRPC significantly prolonged metastasis-free survival (MFS), time to symptomatic progression (SymProg), and second progression-free survival (PFS2) in SPARTAN. We assessed the impact of APA on these end points in pts with or without BL CM. Methods: Using Cox proportional hazards models, treatment effect of APA was evaluated in SPARTAN pts with CM at BL, stratifying by the presence of BL diabetes/hyperglycemia (D/H), cardiovascular disease (CVD), hypertension (HTN), and renal insufficiency (RI). Results: Of 1207 SPARTAN pts, 1062 (88%) had ≥ 1 BL CM, including 703/806 (87%) APA pts and 359/401 (90%) PBO pts. A total of 226 (19%), 398 (33%), 798 (66%), and 774 (64%) pts had D/H, CVD, HTN, and RI, respectively; 323 (27%), 412 (34%), 259 (21%), and 68 (6%) pts had 1, 2, 3, and 4 CM, respectively. Incidence of CM was balanced between arms. Pts with CM were older than pts with no CM (median age, 75 vs 69 yrs, APA; 74 vs 69 yrs, PBO). MFS, SymProg, and PFS2 benefit with APA was significant in all CM subgroups, except PFS2 for pts with D/H (Table) and regardless of the number of CM. The incidence of any treatment-emergent AE was balanced between pts with and without CM. AEs with APA were not affected by any CM. Clinical trial information: NCT01946204. Conclusions: The benefit of APA + ongoing ADT in pts with nmCRPC was maintained in pts with D/H, CVD, HTN, and RI. The safety profile of APA was not affected by any CM.[Table: see text]
Targeting IGF-1/2 with xentuzumab (Xe) plus enzalutamide (En) in metastatic castration-resistant prostate cancer (mCRPC) after progression on docetaxel chemotherapy (DCt) and abiraterone (Abi): Randomized phase II trial results.
Authors: Hussain Syed A. , Maroto Pablo , Climent Miguel Ángel , Bianchini Diletta , Jones Robert Hugh , Lin Chia-Chi , Wang Shian-Shiang , Dean Emma , Crossley Kate , Schlieker Laura , Bogenrieder Thomas , De Bono Johann S.
Published: May 2019

5030

Background: Insulin-like growth factor receptor-1 (IGF-1R) signaling activates the PI3K/AKT pathway and may lead to androgen receptor (AR) transactivation and progression to endocrine treatment resistance. Xe, an IGF-ligand-neutralizing antibody, binds to IGF-1 and IGF-2 and inhibits IGF-1R signaling. This multi-center randomized phase II trial (NCT02204072) evaluated anti-tumor activity of Xe plus En in mCRPC. Methods: Men with histologically/cytologically confirmed mCRPC and progression after DCt+Abi were randomized to receive Xe 1000mg IV QW + En 160mg/day oral, or En alone (28-day cycles until progression or intolerable adverse events [AEs]). Primary endpoint: progression-free survival by investigator assessment (PFS-IA); secondary: PFS by central review (PFS-CR), overall survival (OS), AEs. Results: Overall, 43 patients were randomized per arm; 70% Caucasian and 29% Asian (median age 70 y; range 46–88). At baseline (BL) the two arms were generally well balanced, although 33% v 47% were ECOG PS O, and 72% v 56% had a Gleason total score ≥8. By data cut-off (23 October 2017), 39/43 (Xe+En) and 38/43 patients (En) had discontinued, most due to disease progression. The median PFS-IA was 7.4 m for Xe+En (95% CI: 3.5–8.7) and 6.2 m for En (3.5–11.1) [HR = 0.99 (0.56–1.73); p = 0.96]. The results were similar after adjusting for BL ECOG PS and Gleason score. The median PFS-CR was 3.6 m for Xe+En (3.5–8.1) and 6.2 m for En (3.6–8.3) (HR = 1.22 [0.70–2.13]; p = 0.48). OS data are immature. For the two arms, prostate-specific antigen (PSA) response rates were 21% and 19%; maximum decline in PSA: -20 v -9 μg/L; PSA change at week 12: 19% v 18%; maximum decline in circulating tumor cells (CTC): -52% v -35%; and CTC response: 16% v 11%. The most frequently reported AEs were: fatigue 67% v 49%; decreased appetite 56% v 54%; weight reduction 37% v 12%; anemia 33% v 44%; back pain 30% v 37%. Nine patients discontinued Xe due to AEs. Conclusions: Addition of Xe to En did not prolong PFS in mCRPC compared with En alone. There were no notable differences in PSA-related endpoints and CTC between arms. Clinical trial information: NCT02204072.
Overall survival (OS) of African-American (AA) and Caucasian (CAU) men who received sipuleucel-T for metastatic castration-resistant prostate cancer (mCRPC): Final PROCEED analysis.
Authors: Sartor A. Oliver , Armstrong Andrew J. , Ahaghotu Chiledum , McLeod David G. , Cooperberg Matthew R. , Penson David F. , Kantoff Philip W. , Vogelzang Nicholas J. , Hussain Arif , Pieczonka Christopher Michael , Shore Neal D. , Quinn David I. , Small Eric Jay , Heath Elisabeth I. , Tutrone Ronald F , Schellhammer Paul F. , Harmon Matthew , Chang Nancy N. , Freedland Stephen J. , Higano Celestia S.
Published: May 2019

5035

Background: Prostate cancer risk and mortality are higher in AAs versus CAUs. Post-hoc analyses of pooled Phase 3 data (n = 737) suggested substantial OS benefit for AA men receiving sipuleucel-T (n = 33) vs placebo (n = 10) (McLeod 2012). Compared with pooled placebo patients (n = 249), number needed to treat for OS benefit at 3 years was 3 for AAs and 8 for all sipuleucel-T-treated patients (n = 488) (Moses 2019). Herein we analyzed PROCEED (NCT01306890), a large real-world registry, in which all patients received sipuleucel-T. Methods: In PROCEED, 1902 mCRPC patients received ≥1 sipuleucel-T infusion. OS of all AA (n = 221) and CAU (n = 1649) men were compared. Baseline prostate-specific antigen (PSA), the most important prognostic variable for OS after sipuleucel-T (Schellhammer 2013), substantially differed by race. Thus, OS for a PSA-matched cohort (n = 219 AA; n = 438 CAU) was compared and univariable/multivariable analyses were performed. Post-sipuleucel-T use of OS-prolonging anticancer interventions was also assessed. Results: After a median follow-up of 46.6 mo, median OS was 35.2 (all sipuleucel-T-treated AAs) and 29.9 mo (all sipuleucel-T-treated CAUs): HR 0.81, 95% CI 0.68–0.97; P = 0.03. In the PSA-matched cohort, median OS was 35.3 and 25.8 mo, respectively (HR 0.70, 95% CI 0.57–0.86; P < 0.001). Sipuleucel-T-treated AAs with lower baseline PSA had markedly longer median OS vs sipuleucel-T-treated CAUs. Among those with ≤ median baseline PSA (29.48 ng/ml), median OS was 54.3 mo (AA) vs. 33.4 (CAUs); HR 0.52, 95% CI 0.37–0.72; p < 0.001. Along with other known prognostic factors, AA race was independently associated with prolonged OS on detailed multivariable analyses (HR 0.60, 95% CI 0.48–0.74; p < 0.001) and confirmed on sensitivity analyses. Post-sipuleucel-T life-prolonging anti-cancer therapies were balanced between groups. Conclusions: Sipuleucel-T-treated AAs had significantly improved OS vs sipuleucel-T-treated CAUs. This analysis marks the largest known racial difference in OS in response to any therapy for mCRPC, a finding with implications for both prostate cancer pathophysiology and cancer immunotherapy. Clinical trial information: NCT01306890.
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.
Factors associated with osteonecrosis of the jaw in women with breast cancer receiving high-dose bisphosphonates to prevent breast cancer metastases as part of the SWOG 0307 trial.
Authors: Kizub Darya , Miao Jieling , Schubert Mark M. , Paterson Alexander H. G. , Clemons Mark J. , Dees Elizabeth Claire , Ingle James N. , Falkson Carla Isadora , Barlow William E. , Hortobagyi Gabriel N. , Gralow Julie
Published: May 2019

552

Background: Bisphosphonates reduce the risk of bone metastases in postmenopausal women with early-stage breast cancer but carry the risk of osteonecrosis of the jaw (ONJ). We used the data collected in the S0307 trial to describe factors associated with provoked and unprovoked ONJ. Methods: In S0307, 6097 patients with Stage I-III breast cancer who had surgery were randomized to receive zoledronic acid (ZA) 4mg IV monthly for 6 months, then every 3 months, clodronate (CL) 1600mg daily, or ibandronate (IB) 50mg daily for three years, with no difference in bone metastases or disease-free survival. Patients completed dental procedures prior to and had a dental exam at enrollment. Pearson’s Chi-squared and Student’s T-test were used to test differences in categorical and continuous variables, respectively; logistic regression was used test independent association. Results: Of 5836 evaluable women, 48 developed ONJ, which was associated with bisphosphonate type (28/2124 (1.26%) for ZA, 8/2185 (0.36%) for CL and 12/1527 (0.77%) for IB (p = 0.002). Median time to onset of ONJ was 24.9 (1.4-66.6) for ZA, 41.2 months (range 33.8-67.4) for CL, 23.9 (2.1-75.3) for IB (p = 0.0447). Infection was present in 21 (43.8%) and absent in 20. ONJ was considered unprovoked in 20 (41.7%) and provoked by dental extraction in 20 (41.7%), periodontal disease in 14 (29.2%), denture trauma in 6 (12.5%), other dental surgery in 3 (6.3%). ONJ was associated with dental calculus (OR 2.03 (95% CI: 1.08-3.81), gingivitis (OR 2.11, 95% CI: 1.12-3.98), and periodontal disease (OR 2.87, 95% CI 1.45-5.53) that were moderate/severe and > 4mm periodontitis (OR 2.20, 95% CI 1.18-4.08). Patients with provoked and unprovoked ONJ had similar amounts of dental disease and lesion location. ONJ was not associated with dentures, plaque, chemotherapy, corticosteroids or renal adverse events. In multivariate analysis (limited by small sample), only bisphosphonate type was associated with ONJ. Conclusions: ONJ prevalence was low, likely due to patients completing dental procedures before enrollment. ZA carried a higher risk of ONJ (though current adjuvant dosing interval recommendations are less frequent), with time to onset similar to IB. Oral CL and IB (not currently available in the United States) are thus likely more appropriate for patients with poor dental health. Clinical trial information: NCT00127205.
Omission of adjuvant therapy in stage I clear cell ovarian cancer: Review of the British Columbia (BC) cancer experience.
Authors: Liu Shiru Lucy , Tinker Anna
Published: May 2019

5536

Background: Standard guidelines recommend adjuvant chemotherapy for stage I clear cell ovarian cancer (CCOC), despite data demonstrating excellent outcomes. Since 2012, the BC Cancer provincial treatment guidelines for surgically staged stage IA/B and IC1 (defined by intraoperative rupture only) CCOC has been to offer observation only. We reviewed the clinical outcomes of stage I CCOC patients since policy implementation. Methods: A retrospective, population-based cohort study of all stage I CCOC patients operated on between April 2012 and December 2017 was conducted. Patient, tumor, surgical and clinical outcome data were collected. Survival analysis was conducted using Kaplan-Meier methods. Results: 78 patients with stage I disease were identified (see Table). Among stage IC1 patients, 9 received adjuvant therapy despite provincial policy, 6 of which were due to sharp dissection. 40 patients with stages IA/B and IC1, who underwent post-operative observation, were included in the analysis. Median duration of follow-up was 36 months. Median age at diagnosis was 55 years and >50% patients had a Charlson Comorbidity Index of 0 (N= 26) and an Eastern Cooperative Oncology Group performance status of 0 (N=28) prior to diagnosis. Lymph node dissection was not performed in 20 patients. All 16 cases tested immunohistochemically for mismatch repair were intact, and 2 of 6 cases with tumour genomic sequencing had an AURKA aberration. There were 4 recurrences (10%), 3 of which were metastatic. 5-year disease-free survival is 90%, and 5-year overall survival is 95% for stage IA/B and 90% for stage IC1 (p=0.645). In comparison, 5-year overall survival for stage IC2 (surface involvement) and IC1 with sharp dissection (all received chemotherapy) is 82% and for stage IC3 (positive washings) is 23% (p<0.001). Conclusions: Outcomes of patients with stage I A/B and C1 CCOC remain excellent. Adjuvant therapy can be safely omitted, with low recurrence rates and survival over 90% at 5 years. Consideration of disease substage is valuable in predicting the clinical outcomes of stage I CCOC. [Table: see text]
First-in-human (FIH) phase 1 (Ph1) study of MORAb-202 in patients (pts) with advanced folate receptor alpha (FRA)-positive solid tumors.
Authors: Shimizu Toshio , Fujiwara Yutaka , Yonemori Kan , Koyama Takafumi , Shimomura Akihiko , Tamura Kenji , Iwasa Satoru , Sato Jun , Kitano Shigehisa , Ikezawa Hiroki , Nomoto Maiko , Nakajima Ryo , Miura Takuma , Yamamoto Noboru
Published: May 2019

5544

Background: MORAb-202 is an antibody drug conjugate consisting of farletuzumab (a humanized monoclonal antibody that binds to FRA) paired with a cathepsin B-cleavable linker to eribulin mesylate (a microtubule dynamics inhibitor). We report preliminary results from a FIH Ph1 study of MORAb-202 in pts with FRA-positive solid tumors. Methods: This open-label, ongoing, FIH study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, maximum tolerated dose, and/or the recommended dose of MORAb-202 (Part 1: Dose finding part with accelerated modified toxicity probability interval design; Part 2: Expansion part). Eligible pts had FRA-positive solid tumors who failed standard therapy and an ECOG PS of ≤1. MORAb-202 was administered by intravenous injection once every 3 weeks and dose-limiting toxicities (DLTs) were assessed during the first 21-day cycle. Efficacy endpoints were assessed with RECIST v1.1 by investigator assessment. Results: As of Nov 16, 2018, 16 pts with confirmed FRA-positive tumors were enrolled and treated with MORAb-202 across 4 dose levels in Part 1 (0.3mg/kg: n = 3 [2 endometrial and 1 ovarian], 0.45mg/kg: n = 3 [3 ovarian], 0.68mg/kg: n = 3 [1 NSCLC, 1 ovarian, and 1 TNBC], 0.9mg/kg: n = 7 [4 ovarian, 1 endometrial, 1 NSCLC, and 1 TNBC]); all completed > 1 cycle. One pt in the 0.9mg/kg cohort experienced DLTs of alanine aminotransferase increased (grade 3) and gamma-glutamyl transferase increased (grade 3). Treatment-emergent adverse events (TEAEs) occurred in 15 pts (93.8%). The most common TEAEs were leukopenia and neutropenia (50% each). The objective response rate based on RECIST v1.1 was 37.5% (6/16 pts) in Part 1 with 1 complete response (ovarian) at 0.9mg/kg and 5 partial responses including 2 pts (both ovarian) at 0.9mg/kg, 1 pt (endometrial) at 0.3mg/kg, and 2 pts (1 TNBC and 1 NSCLC) at 0.68mg/kg. The disease control rate was 75% (12/16 pts). Exposure to MORAb-202 was dose proportional across the dose range investigated. Conclusions: MORAb-202 escalation to 0.9mg/kg was manageable with encouraging initial antitumor activity in pts with FRA-positive solid tumors. Clinical trial information: NCT03386942.
Risk factors for progression or death in ovarian cancer patients who completed first-line platinum treatment.
Authors: Westin Shannon Neville , Louie-Gao Melinda , Badamgarav Enkhe , Bala Mohan V. , Thaker Premal H.
Published: May 2019

5548

Background: Limited real-world information is available in ovarian cancer (OC) regarding prognostic factors for disease progression or death after initial treatment. Here, we assessed potential prognostic risk factors in OC patients (pts) who completed first-line (1L) platinum-based chemotherapy (CT) using real-world data. Methods: This retrospective study identified 5535 pts diagnosed with OC from January 2011–October 2018 from the Flatiron database, a longitudinal, demographically and geographically diverse database derived from health records from > 265 cancer clinics and > 2 million US cancer pts. Stage III/IV OC pts who completed 1L platinum-based CT after primary debulking or interval debulking surgery were included. Pts who received a poly(ADP-ribose) polymerase inhibitor (PARPi) in 1L treatment or as maintenance therapy after 1L treatment were excluded. Cox proportional hazards model was used to assess the association between baseline factors (neoadjuvant CT, disease stage, residual disease, BRCA status, ECOG, age, platelet count, hemoglobin, and neutrophil count) and time to next treatment (TTNT; a proxy for progression-free survival) or overall survival (OS) in these pts. Results: 1064 of 5535 pts were eligible per our inclusion/exclusion criteria. Neoadjuvant treatment, stage of disease, residual disease after surgery, and BRCA mutation ( BRCAmut) status were significant prognostic factors for either TTNT or OS. Neoadjuvant chemotherapy pts had a shorter TTNT (hazard ration [HR] = 1.37; P= .001) and OS (HR = 1.64; P= .0002) than pts who underwent primary surgery after adjusting for other covariates. Stage IV pts had a shorter TTNT (HR = 1.26; P= .01) and OS (HR = 1.24; P= .09) than stage III pts. OS was also worse in pts with vs without residual disease (HR = 1.27; P= .04) and worse in BRCAwt than BRCAmut pts (HR = 1.37; P= .10). Conclusions: In this retrospective analysis of a real-world data set, BRCAwt status was associated with higher risk of death. Receipt of neoadjuvant CT, higher stage of disease at diagnosis, or presence of residual disease after surgery were also associated with a shorter TTNT or higher risk of death. These real-world data confirm previously identified prognostic factors.