bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluating 18F-16B-fluoro-5α-dihydrotestosterone (FDHT) and FDG-PET as a measure of disease progression in metastatic castration resistant prostate cancer (mCRPC).
Authors: Autio Karen A. , Fox Josef J. , Schneider Coursen Walker , Schöder Heiko , Humm John , Rathkopf Dana E. , Slovin Susan F. , Danila Daniel Costin , Haupt Eric C. , Larson Steven M. , Scher Howard I. , Morris Michael J. 
Published: March 2020

5090 Background: Prostate Cancer Working Group 2 defines radiographic progression as new lesions on bone scan. Molecular imaging has potential as a biomarker that reflects both alterations in disease burden and tumor biology. FDG and FDHT PET capture glycolytic activity and androgen receptor (AR) expression and tracer binding, respectively. We examined these tracers in mCRPC patients (pts) at progression (POD) to determine patterns of relapse. Methods: mCRPC pts simultaneously enrolled in imaging and therapeutic clinical trials had FDG and/or FDHT PET scans performed at baseline (BL) and within 4 weeks of treatment (rx) discontinuation for protocol-defined POD. BL characteristics, rx, SUVmax, SUVmaxavg (average of 5 index lesions), and presence of new lesion(s) at POD were collected. ΔSUV was calculated relative to BL. Results: 44 mCRPC pts (86 BL PET scans, 84 scans at POD) receiving novel anti-androgens (eg, enzalutamide) (n=18), abiraterone (abi) (n=10), chemotherapy-based rx (n=5), prednisone (n=4), or other targeted rx (n=7) were included. Of those with PET POD, 75% (24/32) had > 1 new lesion on FDG-PET and 96% (25/26) had > 1 new lesion on FDHT. New lesions on FDHT were seen in 33% (6/18) of pts on novel anti-androgens as compared with 100% (10/10) on abi. Presence of a new FDG avid lesion was similar for both anti-androgens and abi (56% vs 60%). Conclusions: POD on FDG/FDHT is more frequently detected by a new lesion rather than ΔSUV in existing index lesions. This is possibly an underestimate of change as the BL scan and not the post-rx nadir scan were used as a comparator. AR and glycolytic activity at POD may be dependent on individual and treatment factors. Notably, a third of pts on anti-androgens had a new FDHT avid lesion at POD. Full lesional analysis of metastases may enhance our understanding of tumor biology at POD. Clinical trial information: NCT00588185. [Table: see text]
Predictive markers of everolimus efficacy in hormone receptor positive (HR+) metastatic breast cancer (MBC): Final results of the TAMRAD trial translational study.
Authors: Treilleux Isabelle , Arnedos Monica , Cropet Claire , Ferrero Jean-Marc , Abadie Lacourtoisie Sophie , Spaeth Dominique , Levy Christelle , Legouffe Eric , Pujade-Lauraine Eric , WANG Quing , Bachelot Thomas 
Published: March 2020

510 Background: Hormone resistance is linked in part to cross-talk between ER signalling and PI3K/Akt/mTOR pathway. Following results of the BOLERO-2 trial, everolimus (E), a potent mTOR inhibitor, has recently been approved in combination with exemestane in women with HR+ MBC refractory to aromatase inhibitor (AI). However, E is frequently associated with specific toxicities, and predictive markers of efficacy are needed. We report here the final results of translational studies within the TAMRAD randomized Phase II trial, comparing tamoxifen (TAM) to TAM+E in AI pre-treated MBC. Methods: Tumor samples from 51 patients among the 111 treated in the TAMRAD trial were retrieved. Hot spot mutations of PI3K (exon 9-20), and KRAS (exon 2) were described. TMA analysis evaluated IHC expression of PTEN, pAkt, PI3K, LKB1, S6K, pS6K, 4EBP1, p4EBP1, and eIF4E. Exploratory analysis of E efficacy in each biomarker subgroup (high vs low expression defined by median percentage of marked cells) was done. Results: Patients characteristics and treatment efficacy among this sub-population were similar to the results from the whole population: Time to progression was 10 months for the TAM+E treated patients vs. 5.5 months for the TAM treated patients, HR: 0.59 (95% CI 0.33-1.07). PI3K-Akt pathway: All patients derived benefit from E regardless of PI3K mutational status, PTEN or pAkt expression. Surprisingly, E efficacy was greater in patients with low PI3K expression (n=12, HR=0.11, 95%CI 0.01-0.96) than in patients with high PI3K expression (n= 28, HR=0.9; 95%CI 0.49-2.41) PI3K independent pathway: Patients with low expression of the anti-oncogene LKB1 derived greater benefit from E (n=22, HR=0.33; 95%CI 0.13-0.89) than patients with high LKB1 expression (n=25, HR=0.75; 95%CI 0.32-1.74) mTOR downstream effectors: Patients with high p4EBP1 (n=27, HR=0.37; 95%CI 0.15-0.90) or low 4EBP1 (n=21, HR=0.39; 95%CI 0.14-1.08) were the subgroups most likely to benefit from E. Conclusions: Those results are in favor of a better efficacy of E for patients with PI3K independent activation of mTOR. If confirmed, they could have important implications for future patient selection. Clinical trial information: NCT01298713.
A phase II trial of an oral CDK 4/6 inhibitor, PD0332991, in advanced breast cancer.
Authors: DeMichele Angela , Clark Amy Sanders , Heitjan Daniel , Randolph Sophia , Gallagher Maryann , Lal Priti , Feldman Michael D , Zhang Paul J. , Schnader Allison , Zafman Kelly , Domchek Susan M. , Gogineni Keerthi , Keefe Stephen Michael , Fox Kevin R. , O'Dwyer Peter J. 
Published: March 2020

519 Background: The G1/S checkpoint of the cell cycle is frequently dysregulated in breast cancer (BC). Initial efficacy of PD0332991, a potent oral inhibitor of cyclin-dependent kinases (CDKs) 4/6 was shown in a variety of solid tumors and in combination with letrozole in a randomized phase II trial. Methods: We performed a phase II, single arm trial of PD0332991 in women with advanced BC. The primary objectives were safety and efficacy. Eligible patients had histologically-confirmed, stage IV BC with primary or metastatic tumor positive for retinoblastoma (Rb) protein expression, measureable disease by RECIST and adequate organ function/performance status. PD0332991 was given at 125 mg orally, days 1 – 21 of a 28-day cycle. Tumor was assessed every 2 cycles. A two-stage statistical design was employed. Secondary objectives included predictive biomarker assessment. Results: 36 patients were enrolled; 28 who completed cycle 1 are reported: 18 (64%) HR+/Her2-, 2 (7%) HR+/Her2+ and 8 (29%) HR-/Her2-. 90% had prior chemotherapy for metastatic disease (median 3 lines); 78% had prior hormonal therapy (median 2 lines). Grade 3/4 toxicities were limited to transient neutropenia (50%) and thrombocytopenia (21%). One episode of neutropenic sepsis occurred in cycle 1 in patient with 6 prior chemo regimens. All other toxicities were grade 1/2. Treatment was interrupted in 7 (25%) and dose reduced in 13 (46%) pts for cytopenias. For response data see table. Responses occurred at dose levels as low as 50 mg. Median PFS (months, 95% CI) was 4.1 (2.3,7.7) for ER+/Her2-, 18.8 (5.1,∞) for ER+/Her+ and 1.8 (0.9,∞) for ER-/Her2-. 27/28 patients discontinued study for progressive disease (PD); 1 due to patient preference. Conclusions: Therapy with PD0332991 alone is well-tolerated and demonstrates response or prolonged stable disease (SD) in patients with BC despite prior hormonal and chemotherapy. Expansion within subtypes and molecular predictors of response are being investigated. Clinical trial information: NCT01037790. [Table: see text]
Integration of Ki67 with residual cancer burden (RCB) compared to Ki67 or RCB alone to predict long-term term outcome following neoadjuvant chemotherapy.
Authors: Sheri Amna , A'Hern Roger , Jones Robin Lewis , Symmans William Fraser , Nerurkar Ashutosh , Hills Margaret , Detre Simone , Johnston Stephen R. D. , Dowsett Mitchell 
Published: March 2020

535 Background: RCB and Ki67 after neoadjuvant chemotherapy have each been shown to predict long-term outcome. Their combined use might provide greater prognostic information. RCB requires collection of data beyond that in routine pathological work-up of residual disease, which may not be required when Ki67 is added. Aims: (i) To test the hypothesis that combining Ki67 and RCB as the residual proliferative cancer burden (R-P-CB) provides significantly more prognostic information than either alone. (ii) To determine if a simplified algorithm integrating Ki67 and standard characteristics of residual disease can provide as much information. Methods: Cases at the Royal Marsden Hospital between 2002-2010 were identified and residual disease assessed. The primary endpoint of the study was time to recurrence. The primary analysis compared the prognostic information from Ki67, RCB and R-P-CB. Analyses employed a Cox proportional hazards model. Prognostic indices (PIs) were also created adding Ki67, grade and ER to the RCB and AJCC staging. Leave-one-out cross validation was used to reduce bias. The overall change in chi-square (ΔX2) of the best model for each index was used to compare the prognostic ability of the different indices a ΔX2 of more than 3.84 indicates statistical significance. Results: A total of 222 evaluable patients were included in the study, median age was 50 with a median follow up of 60 months. The addition of Ki67 improved the prognostic power of all indices. The R-P-CB (ΔX2=69.5) was significantly more prognostic than the RCB alone (ΔX2=35) and Ki67 alone (ΔX2=41.4). A novel proliferative residual cancer index (PRECI) using post-treatment values of T size, number of involved lymph nodes, grade, ER status (±) and Ki67 gave ΔX2=81.1 and performed similarly to a model including the RCB, Ki67, ER and grade (ΔX2=80.2). Conclusions: Addition of Ki67 to RCB improved prediction of long-term outcome. In this study, a novel index the PRECI provided as much prognostic information as a more complex assessment involving RCB and warrants further investigation for estimating post-neoadjuvant risk of recurrence.
A phase II study of combined fulvestrant and everolimus in metastatic estrogen receptor (ER)+ breast cancer after aromatase inhibitor (AI) failure.
Authors: Massarweh Suleiman Alfred , Romond Edward H. , Croley Jessica Jones , Black Esther P. , Chambers Mara D. , Stevens Mark , Shelton Brent , Kadamyan Vera , Elledge Richard M. 
Published: March 2020

541 Background: Fulvestrant, an ER downregulator, can be effective in metastatic ER+ breast cancer but resistance is a problem. Everolimus inhibits mTOR; a key pathway in endocrine resistance. We hypothesized that everolimus may delay resistance to fulvestrant and thus improve its efficacy. Methods: We enrolled postmenopausal women with ER+ breast cancer who experienced disease relapse or progression within 6 months of AI use and had measurable/evaluable disease. Fulvestrant was given at 500 mg IM on day1, 250 mg d14, d28, and monthly thereafter. Everolimus was given at 10 mg po daily. Primary endpoint was time to progression (TTP) and secondary endpoints included safety, response, and biomarker analysis. A sample size of 40 patients was calculated to meet a median TTP of 7 vs. 3.7 months for fulvestrant alone as reported in the EFECT trial. Tumor blocks were collected and biopsies done for accessible disease. Results: 33 patients were enrolled. 2 were ineligible and are excluded from analysis. Median age was 54 years (range 40-85). Most common disease sites were bone 84%, liver 62%, and lung 55%. 81% of patients received prior tamoxifen, 71% had prior chemotherapy and 23% had multiple AIs. Median TTP is currently 7.4 months with 4 patients remaining on therapy. Responses include complete response 3%, partial response 10%, and stable disease 42%. 32% of patients had primary refractory disease and 13% discontinued therapy before disease assessment. Most common adverse events were elevated AST 81% or ALT 68%, hyperglycemia 61%, anemia 61%, elevated cholesterol 60%, hypokalemia 52%, mucositis 48%, and weight loss 48%. The majority of adverse events were grade I/II. Fasting lipid profile data is summarized. Conclusions: These results suggest that adding everolimus to fulvestrant improves its efficacy in heavily pretreated ER+ metastatic breast cancer. Toxicity was manageable but needs close monitoring. Biomarker analysis is ongoing in order to identify patients not likely to benefit from this treatment strategy. Clinical trial information: NCT00570921. [Table: see text]
Distinct copy number alteration patterns as prognostic of endometrial cancer outcomes.
Authors: Pashtan Itai Max , Neuberg Donna S. , Beroukhim Rameen , Salvesen Helga B , Cherniack Andrew 
Published: March 2020

5511 Background: Endometrial cancer is classified by tumor stage, histologic subtype and grade. However, a substantial proportion of presumed non-high risk cases recur, supporting the need for improved tools of prognostication. Methods: Using clinical and Affymetrix SNP 6.0 data from The Cancer Genome Atlas (TCGA) endometrial carcinoma project, we identified 4 somatic copy number alteration (SCNA) subtypes, established their prognostic value and validated them in an independent, population-based cohort from Norway. Patients had endometrioid, uterine papillary serous carcinoma (UPSC) or mixed histology tumors. Progression-free survival (PFS) was defined as time from diagnosis to recurrence or progression, and estimated by the Kaplan-Meier method. Results: Four groups of SCNA patterns were identified using hierarchical clustering: low SCNA, moderate SCNA, SCNA dominated by 1q amplification (1q amplified) and high SCNA level (serous-like). Their prognostic value was assessed in all TCGA patients (N = 292) and in a low risk subset with endometrioid histology, stage 1 disease (N = 210). In the full TCGA cohort, patients with low SCNA (reference group) had excellent 2-year PFS of 94%, while for moderate SCNA it was 84% (hazard ratio[HR] 2.7, p = .08). The 1q amplified and serous-like groups had significantly worse outcomes with 2-year PFS of 74% (HR 5.9, p= .002) and 74% (HR 6.0, p <.001), respectively. On multivariable analysis, adjusting for variables including stage and grade, 1q amplified and serous-like SCNA patterns remained independently prognostic (respectively, adjusted HR 6.2, p = .002 and 4.7, p = .02). Similar results were found in the low risk subset. The prognostic value of the SCNA patterns was validated in an independent group of patients with low risk disease (N = 57). 5-year PFS was 91% for low SCNA, 83% for moderate SCNA (HR 2.0, p = .58), 72% for 1q amplified (HR 3.7, p = .11) and 50% for the serous-like SCNA group (HR 6.7, p = .04). Conclusions: Four subtypes of DNA SCNA patterns in endometrial cancer were identified and validated to be prognostic of outcome. These novel biomarkers may be useful in guiding therapeutic decisions, and shed insight on the biology of more, or less, aggressive endometrial cancer.
Adult granulosa cell tumors (GCT): 56 years of clinicopathologic outcomes including FOXL2 mutational status.
Authors: Wilson Michelle , Rosario Roseanne , Chrystal Kathryn F. , Payne Kathryn , Evans Barrie David , Shelling Andrew , Fong Peter C.C. 
Published: March 2020

5536 Background: GCT account for 2-3% of ovarian cancers with a tendency for late relapse. Treatment is primarily surgical. The role of chemotherapy and hormonal therapy is more controversial. The FOXL2 mutation (402C→G) has been identified as a potential driver mutation and may be useful in diagnosis and treatment. Methods: We performed a retrospective review of GCT patients (pts) referred to the Auckland Gynae-Oncology Multidisciplinary Team from 1955 to 2011. Baseline characteristics, clinical course, histopathology and survival data was recorded. FOXL2 mutation status was determined by DNA sequencing, and correlated with clinical data. Results: 56 GCT pts were identified. Median (med) age 48.6 years (y) (22-86). Stage I were 82.1%. 48% of tumours were ≥10cm. Med follow up was 10.0y (0.2-40.4). 25 pts progressed, med time to progression (TTP) was 4.5y (0.1-17.7). Med progression free survival was 14.5y. Med overall survival (OS) was 21.8y but med disease specific survival was not reached. 9/18 pts died of disease. Stage III GCT and size ≥10cm had a higher risk of relapse (RR 3.1 and 2.9) and death (RR 8.2 and 8.6) respectively. 17/46 (37%) Stage I pts progressed. Med TTP was 8.3y (1.3 to 17.7), med OS was 29.0y. Stage I relapse rate was higher in tumours ≥10cm (RR 3.9 p<0.01). 12/17 1st relapses were treated with surgery. 10/17 pts received ≥1 line of chemotherapy and 7 ≥1 hormonal therapy. Clinical benefit rates (CR, PR and SD>6m) for first-line chemotherapy was 25% and 71% for hormones. All 7 Stage III pts progressed with med OS of 6.3yr (0.2-12.3y). Currently the FOXL2 mutation statuses are known for 18 patients. 89% carried the mutation. Homozygous, heterozygous and wild-type mutations had no difference in risk of relapse or death. Further FOXL2 mutation analysis is ongoing. Conclusions: This long term series confirms the protracted natural history of this disease. Early stage GCT, despite progression has a good prognosis with med OS >25y. Stage and tumour size remain the most consistent prognostic factors. Whilst surgery remains the mainstay of therapy, the high response rate to hormonal therapy deserves investigation. Currently the FOXL2 mutation status does not appear prognostic but this needs further research.
Phase I study of combination chemotherapy with irinotecan and gemcitabine for taxane/platinum resistant ovarian, fallopian tube, or primary peritoneal cancer.
Authors: Yoshino Kiyoshi , Kamiura Shoji , Ogawa Haruki , Tokuhira Atsushi , Takemura Masahiko , Sawada Kenjiro , Ueda Yutaka , Mabuchi Seiji , Fujita Masami , Tsutsui Tateki , Kimura Tadashi ,   Gynecologic Oncology Group of Osaka (GOGO)
Published: March 2020

5538 Background: Development of new regimen is required to overcome platinum resistant ovarian cancer. Irinotecan and gemcitabine have a synergistic effect to inhibit the growth of ovarian cancer cell line in vitro. The objective is to evaluate the feasibility of combination chemotherapy with irinotecan and gemcitabine for taxane/platinum resistant recurrent ovarian, fallopian tube or peritoneal cancer and to determine the recommended dose. Methods: Nine patients with measurable disease (age range 51-70 years) were enrolled. Patients were treated with irinotecan and gemcitabine on days 1 and 8 every 3 weeks with starting dose of level 1. Dose levels included irinotecan/gemcitabine: 65/650 (level 0), 80/800 (level 1), 100/1000 (level 2), mg/m2 respectively. Level 2 is defined as the maximum dose as used in other malignancies. Dose-limiting toxicity (DLT) was assessed during the first cycle; toxicities were monitored throughout the treatment according to the CTCAE v4.0. Treatment continued until disease progression or unacceptable toxicity. Results: In level 1 (n = 6), grade 3/4 neutropenia was observed in 5 patients. Grade 3 nausea and vomiting was observed in 1, grade 3 diarrhea in 1. One patient of level 1 experienced DLTs. In level 2 (n = 3), grade 3/4 neutropenia are observed in 3, anemia in 1, and thrombocytopenia in one patient. Other toxicities were mild. Three patients who received level 2 did not show DLT. The objective response was CR/PR/SD/PD, 0/2/5/2. Conclusions: The dose level of irinotecan 100 mg/m2 and gemcitabine 1000 mg/m2 on day 1 and 8 every 3 weeks is recommended for a phase II study. Clinical trial information: UMIN000005926.
Feasibility and safety of front-line bevacizumab (BEV)-containing therapy after neoadjuvant (NA) chemotherapy (CT) for ovarian cancer (OC): The ROSiA experience.
Authors: Korach Jacob , Colombo Nicoletta , Davidenko Irina , Mendiola Cesar , Selle Frédéric , Gonzalez-Martin Antonio , De Censi Andrea , Pautier Patricia , Meirovitz Mihai , Petru Edgar , Ghatage Prafull , Hegg Roberto , Bamias Aristotelis , Gocze Peter , Chmielowska Ewa , Zvirbule Zanete , Bollag David T. , Freudensprung Ulrich , Oza Amit M. ,   ROSiA Investigators
Published: March 2020

5541 Background: BEV significantly improved the efficacy of front-line CT for OC in the GOG-0218 and ICON7 phase III trials. The ongoing single-arm ROSiA study, which has completed recruitment of 1039 patients (pts), is assessing BEV + CT in routine oncology practice. Unlike GOG-0218 and ICON7, prior NACT is permitted. We assessed the surgical safety of BEV + CT in the subgroup of pts with prior NACT. Methods: Inclusion criteria include: FIGO stage IIb–IV or grade 3 stage I–IIa epithelial ovarian, fallopian tube, or primary peritoneal carcinoma; no prior post-surgical therapy for OC; and ECOG PS 0–2. Pts with uncontrolled hypertension or clinical signs/symptoms of GI obstruction or history of abdominal fistula, GI perforation, or intra-abdominal abscess in the preceding 6 mo are excluded. Pts in the NA subgroup were enrolled into the study after up to 4 cycles of NACT without BEV. After interval debulking, pts received BEV 15 mg/kg q3w (or 7.5 mg/kg at the investigator’s discretion) in combination with CT (paclitaxel [175 mg/m2 d1 q3w or 80 mg/m2 qw] + q3w carboplatin [AUC 5 or 6]), to a maximum total of 8 cycles including the pre-study NA cycles. Single-agent BEV was continued until progression, unacceptable toxicity, or for up to 36 cycles in total. The primary objective is evaluation of safety (CTCAE v4.03). Additional endpoints include efficacy (including PFS, response rate, OS) and exploratory translational research. Results: Of the 1039 pts enrolled in ROSiA, 150 (14%) had received NACT. Of these, most had stage IIIc (60%) or IV (29%) disease; 65% had residual disease ≤1 cm; and 19% underwent bowel resection. At the data cut-off 22 mo after enrollment began, median follow-up from post-surgery study entry was 12.6 mo; 69 patients (46%) remained on BEV therapy. At cut-off, pts had received a median of 13 cycles of BEV (range 1–31), including 4 cycles (range 1–6) of BEV in combination with CT after surgery. To date, no pts have had grade ≥3 wound-healing complications during study therapy; 1 pt experienced grade 4 GI perforation 10 weeks after surgery (3 weeks after the first BEV dose), which resolved within 4 weeks. Conclusions: NACT followed by BEV + CT was feasible and tolerable. Clinical trial information: NCT01239732.