bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of bone scan index (BSI) with prognostic biomarkers and survival in men with metastatic castration-resistant prostate cancer (mCRPC) enrolled in a prospective randomized controlled trial of tasquinimod.
Authors: Armstrong Andrew J. , Kaboteh Reza , Carducci Michael Anthony , Damber Jan-Erik , Stadler Walter Michael , Mats Hansen , Edenbrandt Lars , Forsberg Goran , Nordle Orjan , Pili Roberto , Morris Michael J.
Published: March 2020

5081

Background: Tasquinimod (T) is an oral immunomodulatory and anti-angiogenic agent currently in phase 3 testing in mCRPC. In a randomized, double-blind phase 2 multicenter study, 201 men with mCRPC who received T had improved radiographic PFS vs. placebo (P), with a more pronounced effect seen in men with bone metastases. Given the subjectivity/variability of bone scan measurements, we sought to evaluate the bone scan index (BSI), a quantitative and objective measure of BS activity, over time in this controlled clinical trial. Post-treatment BSI changes were examined given their prior association with survival. Methods: In this retrospective analysis, Exini bone™, an automated software package that generates the BSI (percent tumor involvement) from 99Tc BS, was used to calculate BSI over time from BS collected during central review in this randomized trial of T vs. P. Associations between baseline and on-treatment BSI, survival, prognostic biomarkers, and treatment effect were evaluated. Results: 108 men contributed baseline scans for BSI analysis that met quality control metrics (74 T vs. 34 P), 85 of whom (57 T vs. 28 P) had at least 1 evaluable follow-up week 12 scan. Median baseline BSI was 0.90% and after 3 months median BSI was 1.21%. In univariate analysis (n=85) baseline BSI correlated with OS (HR 1.41; p=0.01). Both baseline BSI (HR 1.62; p=0.006) and week 12 BSI change (HR 1.95; p=0.002) remained associated with OS after adjustment for bone alkaline phosphatase, PSA, pain score, hemoglobin, and treatment arm. BSI correlated with baseline PSA, LDH, bone alkaline phosphatase, and the number of bone lesions. The increase in BSI at week 12 vs. baseline was slower with T vs. placebo (0.16% vs. 0.26% increase). Conclusions: BSI and BSI changes were associated with OS in men with mCRPC in this prospective trial. BSI correlates with known biomarkers of OS, but adds independent prognostic information. While underpowered, a delay in objective radiographic bone scan progression with tasquinimod is suggested and the evaluation of BSI and BSI changes in the context of phase 3 trials of men with mCRPC is warranted. Clinical trial information: NCT00560482.
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.
Bevacizumab (Bev) for treatment of recurrent serous borderline (SB) or low-grade serous (LGS) ovarian cancer: A retrospective review of the Memorial Sloan-Kettering Cancer Center (MSKCC) experience.
Authors: Grisham Rachel N. , Sala Evis , Zhou Qin , Iasonos Alexia , DeLair Deborah , Iyer Gopa , Hyman David Michael , Spriggs David R. , Aghajanian Carol
Published: March 2020

5545

Background: LGS ovarian cancer is a rare subtype of ovarian cancer, accounting for 10% of ovarian cancer cases. Patients typically present at an early age, exhibit a protracted clinical course, and have response rates to chemotherapy of < 4%. Limited clinical data suggests that bev may have activity in this disease. The objective of this study was to determine the response rate to treatment with bev in patients with SB or LGS ovarian cancer treated at MSKCC. Methods: Following IRB approval, all patients with a diagnosis of SB or LGS ovarian or primary peritoneal cancer treated with ≥ 1 dose of bev for persistent or recurrent disease were identified. 17 patients were treated at MSKCC between July 2005 and June 2012. Diagnosis was confirmed by a gynecologic pathologist. All imaging was independently reviewed by the study radiologist and response was determined by RECIST 1.1 criteria. Results: 17 patients, 10 with LGS ovarian cancer, 3 with LGS primary peritoneal cancer, and 4 with SB disease were included in the analysis. The mean number of prior therapies was 3.4 (range: 1-9, median: 2). Two patients were treated with bev alone, the remainder (15) received bev in combination with paclitaxel (Pac, 6), topotecan (1), pemetrexed (1), oral cyclophosphamide (3), gemcitabine (Gem, 2), Gem and carboplatin (Carbo) (1), or Pac and Carbo (1) .Two patients were not evaluable for response due to termination of treatment prior to first radiographic assessment. The median duration of bev treatment was 23 weeks (mean: 32.2; range 6-79.4). Conclusions: This data suggests that the addition of bev to cytotoxic chemotherapy may produce dramatically higher response rates than chemotherapy alone in patients with SB and LGS ovarian cancer. A prospective study of bev for treatment of this chemotherapy resistant disease is warranted. [Table: see text]
The role of CHFR expression in ovarian cancer and response to taxane therapy.
Authors: Wahner Hendrickson Andrea Elisabeth , Visscher Daniel W. , Goergen Krista M. , Negron Vivian , Lingle Wilma L. , Oberg Ann L. , Kalli Kimberly , Hartmann Lynn C. , Maurer Matthew J. , Kaufmann Scott H.
Published: March 2020

5546

Background: CHFR, an E3 ubiquitin ligase that regulates Aurora A and Pololike Kinase 1, plays a critical role in the cellular response to mitotic stress. In particular, cells containing CHFR arrest in G2 when microtubule dynamics are disrupted. Conversely, low CHFR expression is associated with hypersensitivity to mitotic spindle poisons in breast cancer cell lines. Despite the extensive use of taxanes in front line treatment of epithelial ovarian cancer (EOC), little is known about CHFR expression in this disease. We examined CHFR expression and its relationship with clinical characteristics and outcome in women with EOC. Methods: Pretreatment EOC samples from women enrolled in the Mayo Clinic Biospecimen Resource for Ovarian Cancer Research who underwent initial surgical debulking between 1999-2009 were stained in triplicate with anti-CHFR antibodies. Samples were scored in a blinded fashion for CHFR expression. Associations between CHFR staining and histology, grade, and stage were assessed using chi-squared tests; associations between CHFR and overall survival (OS) or time to disease recurrence (TTR) were assessed using Cox proportional hazards models. Results: Samples from 354 women were stained; median age at diagnosis was 60.5 (range 21-93). At a median follow-up of 67 months, 221 women (62%) had died. Across all patients, moderate/strong CHFR staining was associated with poor OS (HR = 1.39, 95% CI: 1.07-1.81, p = 0.015). Moreover, moderate/strong CHFR expression was strongly associated with serous histology (p < 0.0001), high grade (p < 0.0001) and advanced stage (p = 0.0002). To assess whether the association between CHFR expression and OS was related to taxane sensitivity, a subgroup analysis was performed in the subset of patients (N=131) with high-grade serous EOC who received initial platinum/taxane chemotherapy. Moderate/strong CHFR expression failed to correlate with OS (HR=0.91, 95% CI: 0.57-1.45, p = 0.68) or TTR from the start of chemotherapy (HR = 0.85, 95% CI: 0.55-1.31, p = 0.55) in this subset. Conclusions: CHFR expression is associated with poor OS and adverse clinical characteristics in patients with EOC but does not appear to be related to taxane sensitivity in high-grade serous tumors.
Analysis of clinical features of ovarian cancer (OC) and breast cancer (BC) among BRCA-mutated (BRCA+) and sporadic (NH) double tumours.
Authors: Nicoletto Maria Ornella , Rocchetto Marco , Artioli Grazia , Perin Alessandra , Ghiotto Cristina , Borgato Lucia , Fiduccia Pasquale , Dalla Palma Maurizia , Koussis Haralabos , Zustovich Fable , Ercoli Alfredo , Litta Pietro , Nardelli Giovanni B. , Zagonel Vittorina
Published: March 2020

5548

Background: The clinical outcome of double OC and BC is specifically unknown either BRCA+ and in double tumours NH patients. Methods: The present databases made of 106 patients, 67 cases of NH (negative, no-tested or ongoing test for BRCA1/2 mutations) and 39 of BRCA+, were constituted to identify the clinical and pathological features of BC and OC. The primary endpoint was to evaluate biological characteristics of both cancers and clinical outcome of OC in coexistence with BC. Patients were censored at last follow-up or death (any cause) for determination of overall survival (OS). OS were determined using the Kaplan-Meier method and log-rank test to compared the different levels of a variable. Pearson Chi-Square or Fisher’s exact test were used to compare relationship between variables in to groups and Mann-Whitney U test to compare the medians. Results: 32/39 (82 %) BRCA+ and 44/67 (66 %) NH had BC as their first malignancy. As regards the genetic test on NH patients, 28 were BRCA negative, 22 have not been tested and in 10 patients the test is still in progress. All BRCA2 patients had BC as first malignancy, while 20/22 of BRCA1. Bilateral BC was more frequent in BRCA+ than in NH (33 % vs 9 %), resulted in a fivefold higher risk (p = 0.002). III-IV stage OC at diagnosis was 79% in BRCA+ vs 55 % in NH (p = 0.013); indeed BRCA+ patients have a threefold higher risk (however moderate) to develop an advanced stage OC. Death for progression of ovarian cancer involved both groups, and third neoplasm was involved in death cause in 1/1 of BRCA and 5/6 of NH. Two BRCA1 with OC as first neoplasm are alive. Conclusions: III-IV stage OC is more frequent in BRCA+ than in NH, and the main cause of disease progression and death is due to OC. Eventually the most relevant conclusive assessment is the suggestion of a more conserving management for BC and an intensive follow-up for OC in patients with double tumours, irrespective of their pathological or genetic features. Prospective trials are also indicated.
A prognostic factor (PF) index for overall survival in a HER2-negative endocrine-resistant metastatic breast cancer (MBC) population: Analysis from the ATHENA trial.
Authors: Llombart-Cussac Antonio , Pivot Xavier B. , Biganzoli Laura , Cortes-Funes Hernan , Pritchard Kathleen I. , Pierga Jean-Yves , Smith Ian E. , Thomssen Christoph , Palacios Gemma , Srock Stefanie , Sampayo Miguel , Cortes Javier
Published: March 2020

555

Background: Chemotherapy is the standard of care for patients (pts) with HER2-negative endocrine-resistant MBC. The considerable variability in overall survival (OS) within this population relates essentially to prognostic factors (PF). Increasingly, large studies based on progression-free survival (PFS) as a primary endpoint are now being questioned. An accurate PF index may help in designing innovative trials with appropriate pts selection according to overall survival (OS) prognosis. Methods: The ATHENA trial assessed the safety of first-line bevacizumab combined with non-anthracycline-containing therapy in 2264 pts treated in 37 countries from 2006 to 2009. Pt characteristics, safety, and efficacy have been reported [Breast Cancer Res Treat 2011;130:133-43]. Sixty-one HER2-positive pts were excluded. A multivariate Cox regression model selected PF generating a simple PF index. Of note, skin, lymph node, ipsi-/contra- breast, or other soft tissue involvement was scored as a single organ. Results: After a median follow-up of 20.1 months and 1171 OS events (53% of pts), median OS for the entire sample and triple-negative (TNBC) and non-TNBC subgroups was 25.2 (95% CI 23.9–26.3), 18.3 (16.3–19.7) and 27.3 (26.3–29.3) months, respectively. PF most closely associated with poorer OS were: liver mets or >2 involved organs (HR 1.6; 95% CI 1.5–1.8); DFI ≤24 months (HR 1.7; 1.5–2.0); adjuvant anthracyline and/or taxane (HR 1.1; 1.2–1.4); and TNBC (HR 1.6; 1.4–1.8). A predictive model was designed stratifying by number of PF present (0/1 vs 2 vs 3/4). The model was consistent in both TNBC and non-TNBC populations (Table). Conclusions: A PF index may estimate figures and balance arms in future trials considering OS as primary objective. A well-defined group of non-TNBC accounting for 37% of patients has an OS estimate similar to the most aggressive TNBC. [Table: see text]
Polyvalent vaccine-KLH conjugate and OPT-821 with bevacizumab (BEV) in patients with ovarian cancer in second or greater remission.
Authors: O'Cearbhaill Roisin Eilish , Iasonos Alexia , Zhou Qin , Durany Robert , Aghajanian Carol , Hensley Martee Leigh , Konner Jason A. , Makker Vicky , Tew William P. , Fleisher Martin , Sabbatini Paul
Published: March 2020

5550

Background: We previously completed a phase I study of a polyvalent vaccine containing GM2, Globo-H, LeY, Tn-MUC1, Tn(c), STn(c) and TF(c) antigens (AGs) individually conjugated to KLH and mixed with adjuvant OPT-821. We showed safe induction of antibody (ab) responses to 5 of the 7 vaccine AGs. Data has shown that tumor vaccine efficacy may be enhanced through disruption of angiogenesis thus providing a rationale for combining BEV with the polyvalent vaccine. We conducted an IRB-approved pilot study to evaluate the safety and immunogenicity of the poly-KLH-vaccine when given with BEV in OC in remission. Methods: Pts with recurrent OC in ≥2nd complete or partial remission were enrolled from 12/2010-03/2012. Pts received 6 vaccines and BEV over 17 weeks. BEV was continued beyond the vaccination phase. Treatment was continued until disease progression or toxicity. Serologic IgM and IgG responses were measured by ELISA against each AG. Wilcoxon signed rank test was used to test changes in cytokines (CKs): FGFβ, IL-8, PDGF, VEGF measured by angio multiplex assay. Results: n=21 Median age 56yrs (51-70). 2, 8, 8, 3 pts were in 2nd, 3rd, 4th, 5th remission, respectively. 1 DLT (gr 4 fever post vaccine #2). Immune Results: n=19 IgG +/or IgM: ≥3 AGs in 17pts. IgM: ≥1 AG in 19pts, ≥3 AGs in 15pts. IgG: ≥1 AG in 17pts, ≥3 AGs in 3pts. CK Results: In 10 pts who completed 6 vaccines there was a mean (median) decrease in VEGF of 144 (111) pg/ml at the 17-week timepoint compared to baseline (p=0.05). For 8 pts who did not complete all 6 vaccines there was a mean (median) increase of 76 (69) pg/ml compared to baseline at the off-study visit (p=0.16). There was no statistically significant change in the other CKs compared to baseline values. At last follow-up, 18 pts had recurred and 3 pts had died. The median PFS was 5.6mths. Conclusions: 89% of pts responded to ≥3 AGs comparable to the 89% response in our prior phase I trial without BEV. BEV and polyvalent-KLH vaccine can be safely administered together with retention of the vaccine’s immunogenicity. Serum VEGF levels decreased in patients on continued BEV therapy. Clinical trial information: NCT01223235. [Table: see text]
A phase II study of oral metronomic combination therapy in relapsed epithelial ovarian cancer.
Authors: Gupta Sudeep , Goyal Gautam , Ghosh Jaya , Bhosale Bharatsinha Baburao , Bajpai Jyoti , Maheshwari Amita , Kerkar Rajendra , Deodhar Kedar , Rekhi Bharat , Menon Santosh , Banavali Shripad
Published: March 2020

5554

Background: Etoposide (E), cyclophosphamide (C) and tamoxifen (T) have been used as single agents in relapsed epithelial ovarian cancer (EOC) patients. We tested a low dose, continuous, daily, oral metronomic regimen that combined these 3 agents. Methods: This single centre prospective study included patients of relapsed EOC with exposure to at least 2 prior lines of chemotherapy (CT) and at least partial as the best response to most recent regimen. Study regimen comprised daily oral administration of E (50 mg/m2) and C (50 mg/m2) for 21 of a 28 day cycle plus T (20 mg/m2, twice per day) continuously. The primary endpoint was serological (CA-125) progression-free survival (PFS) as per Rustin Criteria and secondary endpoints were radiological (RECIST) PFS, overall survival (OS), duration of response (DOR), response rates and toxicity. The data cut-off date was 15 Jan 2013. Results: 26 patients with a median age of 48 years were accrued, of whom 21 had received 2 prior lines of CT and 5 had received 3 lines. 25 patients who were evaluable for analysis received a median of 6 (1-19) cycles of metronomic regimen. The median delivered relative dose intensities of E, C and T were 0.71, 0.71 and 0.97 respectively. 13 (52%) patients needed dose reduction after a median of 3 (1-9) cycles. Most common grade 3 or 4 toxicities included anemia, neutropenia, febrile neutropenia, nausea, vomiting and diarrhea in 44%, 36%, 12%, 16%, 16% and 12% patients respectively. 19 (76%) patients had serological CR or PR with a median time to response (TTR) and DOR of 1.8 (0.83-2.96) and 7.0 (95% CI, 5.8-8.2) months respectively. 11 (45.8%) of the 24 evaluable patients achieved radiological CR or PR with median TTR and DOR of 3.7 (1.8-7.2) and 5.5 (95% CI, 3.9-7.2) months respectively. 17, 18 and 7 patients have respectively experienced serological progression, radiological progression and death at the time of analysis. The median serological PFS, radiological PFS and OS are 7.9 (95% CI 7.2-8.6), 7.97 (95% CI, 5.95-9.98) and 22.3 (95% CI, 17.4-27.3) months, respectively. Conclusions: The oral metronomic combination of E, C and T has substantial and durable activity in relapsed EOC and is worthy of further evaluation in a larger randomized study.
Does aggressive primary debulking surgery influence survival in ovarian cancer?
Authors: Segev Yakir , Rosen Barry , Murphy Joan , Laframboise Stephane , Dodge Jason Esli , Ferguson Sarah E , Bernardini Marcus , Charles Brendan , Sun Ping , Narod Steven
Published: March 2020

5561

Background: Evidence comparing outcomes in patients receiving primary debulking surgery (PDS) to those receiving neoadjuvant chemotherapy (NACT) for advanced stage ovarian carcinoma is conflicting. We conducted a retrospective survival analysis of all patients with stage IIIC and IV serous ovarian cancer treated at our institute by either PDS or NACT. Methods: Data was extracted from patient synoptic OR reports and medical records between January 2003 and December 2011. Survival comparisons between patients receiving NACT and PDS were made according to aggressiveness of surgery and residual disease following surgery. Aggressive surgery was defined by one of the following procedures; pelvic peritonectomy, any bowel resection, diaphragm resection, diaphragm peritonectomy and splenectomy. Results: Out of 342 patients, 143 (41%) had NACT and 199 (59%) had PDS. Patients undergoing PDS had a median survival (MS) of 58 months compared to 34 months for NACT. Patients undergoing PDS with > 10mm and <10mm residual disease, had a MS of 33 and 55 months, respectively; whereas those with microscopic disease have not yet reached their MS. In the NACT group, MS for < and > 10 mm residual disease was 30 months for both, compared with 39 months for those with microscopic disease. Within the PDS group, those undergoing limited surgery had a MS of 48 months whereas MS has not been reached for those undergoing aggressive surgery. Over 60% of patients undergoing PDS with microscopic residual were alive at 7 years. In the NACT group, there was no difference in survival according to extent of surgery. Conclusions: Patients withPDS, whether debulked to < 10mm or to microscopic disease have a significant and lengthy survival advantage over patients receiving NACT.
Continuous low-flow ascites drainage and sequential non-invasive tumor-cell sampling through the urinary bladder via the alfa-pump closed system in platinum-resistant ovarian cancer (PROC): First clinical experience in a cancer patient.
Authors: Fotopoulou Christina , Spiers Laura , Pickford Emily , Dina Roberto , Blagden Sarah Patricia , Habib Nagy A , Gabra Hani
Published: March 2020

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Background: Malignant ascites in PROC causes significant impairment in quality of life. The Sequana Medical alfapump System (AP), a remotely controlled device connecting the patients’ peritoneal cavity to their urinary bladder, has been evaluated for the continuous drainage of ascites in liver cirrhosis, but not as yet for malignant ascites. Methods: We implanted the AP in the peritoneal cavity of a 67y old heavily pretreated PROC patient with recurrent malignant ascites requiring 3-5 liters drained 3 times/month. The AP was evaluated for its ability to drain ascites into the urinary bladder using an electronic download of recorded volume pumped, cross correlated with weekly ultrasound, symptomatic scores and QoL evaluation. Early morning urine for evaluation of urinary cytology and tumor-cell molecular analysis was collected weekly. Results: The implantation was performed under general anaesthesia in a 60 minute procedure. Before insertion the patient had 3 liters of malignant ascites; 2 liters were drained during surgery. The pump, draining 350ml ascites per day successfully drained the ascites to dryness after 3 days. The patient underwent weekly sonography and monthly cystoscopies. She did not report pollaki- or dysuria, only an increased micturition volume. Histopathological analysis of the urine revealed rich malignant cell content, used to create FFPE cell blocks weekly for molecular- pathological profiling with sequential Caris Target Now analysis and full exome sequencing. Conclusions: On initial evaluation, the AP represents a tolerable and effective means of diverting peritoneal ascites into the urinary bladder and thus preventing its recumulation in PROC. This innovative approach not only addresses an area of unmet need for the control of malignant ascites but also provides a method of collecting tumor tissue and evaluating longitudinal change in molecular tumor characterization. A EUTROC multicenter European randomized trial (AMAZE) is planned for evaluation of clinical and translational implications of the AP in PROC.
Exploratory analysis of nibrin in advanced ovarian cancer (AOC) patients treated in the phase III OVA-301 trial.
Authors: Aracil Avila Miguel , Nieto Antonio , Tanovic Adnan , Monk Bradley J. , Kaye Stanley B. , Poveda Andres , Herzog Thomas J. , Parekh Trilok V. , Badri Nadia , Galmarini Carlos
Published: March 2020

5566

Background: Nibrin (p95/NBS1) is a protein with an essential function in DNA double-strand break repair by homologous recombination. Therefore, we have investigated its value as a possible biomarker in patients with AOC by immunohistochemistry (IHC). Methods: IHC staining was performed in 138 samples from a subset of patients that have participated in the phase III OVA-301 trial, in which the combination of trabectedin plus pegylated liposomal doxorubicin (PLD) or PLD alone were randomly administered for advanced disease after failure of platinum-based chemotherapy (Monk 2010; Monk 2012). A computerized image analysis system was used to calculate the total percentage of nibrin-positive cells. Nibrin expression was considered as a continuous variable. The analysis of overall response rate (ORR) and progression-free survival (PFS) was based on independent oncologist assessment. Overall survival (OS) was defined from randomization to death/last contact. All the comparisons had an exploratory nature; an alpha cut-off value of 0.05 (two-sided) was established as statistically significant. Results: For PFS, there was a statistically significant correlation between high levels of nibrin and short PFS (HR = 1.014, 95% CI: 1.004-1.024, p=0.0047). Similarly, for OS, there was a statistically significant correlation between high levels of nibrin and worse OS (HR = 1.009, 95% CI: 1.001-1.017, p = 0.0295). A multivariate analysis showed that high levels of nibrin were independently correlated to a worse PFS (HR = 1.012, 95% CI: 1.002-1.022, p = 0.0147) and to a worse OS (HR = 1.010, 95% CI: 1.002-1.018, p=0.0192). After stratification according to platinum-sensitivity, high nibrin showed a significant correlation with lower ORR (ORR = 1.02, 95% CI: 1.01-1.03, p=0.0009), short PFS and OS values only in the platinum-sensitive patients. Conclusions: The results point out the potential importance of nibrin expression in the clinical outcome of patients with AOC. In particular, high protein expression of nibrin seems to be associated with a worse clinical outcome. Prospective clinical trials evaluating the clinical usefulness of this marker with other standard of care treatments are warranted. Clinical trial information: NCT00113607.