bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of ERCC1 (rs11615) and DNASE2B (rs3738573) polymorphisms with pathologic complete response to neoadjuvant chemotherapy for HER2-overexpressing breast cancer.
Authors: Ducoulombier Agnes , Dumont Aurelie , Tresch Emmanuelle , Chen Jinying , Pannier Diane , Revillion Francoise , Bonneterre Jacques , Peyrat Jean-Philippe
Published: March 2020

536

Background: Pathological complete response (pCR) is the main prognostic factor after preoperative chemotherapy. Predictive factors of pCR are mainly histological type, hormonal status, HER2 overexpression. Single nucleotide polymorphisms (SNP) in genes encoding drug transporters, drug metabolizing enzymes and target genes can affect drug efficacy and may explain therapeutic failures. The aim of the study was to identify SNPs associated with pCR in breast cancer (BC) patients (PTS) with HER-2 overexpression and treated with sequential neoadjuvant chemotherapy. Methods: Among PTS treated with NCT and included between 2007 and 2012, 46 PTS had HER-2 overexpressing BC, mostly ductal carcinoma (91.3%), greater than or equal to T2 (97.7%) and N1 (65.2%).91.3% of PTS received 3 FEC 100 - 3 Taxotere and 18 cycles of trastuzumab (3-18). Genotyping of 46 SNPs was performed on germline DNA using real time PCR. pCR was correlated with clinicopathologic features and genotypes using logistic regression. Results: pCR was evaluable for 45 PTS according to Sataloff criteria: pCR rate was 40% (95% CI 25.7-55.7%) and was significantly associated with hormonal status: 60.9% in negative hormone receptor tumors and 18.2% in positive hormone receptor tumors (p = 0.004). Four SNPs were significantly associated with pCR. All patients homozygotes CC for ERCC1-rs11615 respond to NCT (p=0.024). The response rate was higher for patients homozygotes TT for NQO2-rs1143684 (59.1%; p=0.018), PTS carrying one or two C allele for DNASE2B-rs3738573 (50%; p=0.025) and PTS carrying one or two C allele for MDR1-rs1045642(51.5%; p=0.012). Conclusions: In this pilot study 4 SNPs were significantly associated with pCR and may be useful to predict response to NCT (Anthracyclines/Taxanes/Trastuzumab regimen) for HER-2 overexpressing breast tumors. Moreover, DNASE2B-rs3738573 and ERCC1-rs11615, two polymorphisms located in genes involved in DNA reparation, have never been described as predictive markers for BC neoadjuvant chemotherapy. (The first 3 authors contributed equally to this work.)
Pro-COL11A1: A biomarker to predict malignant relapse of breast intraductal papillomas.
Authors: Freire Javier , Garcia-Berbel Lucia , Dominguez-Hormaetxe Saioa , Pereda Saray , De Juan Ana , Hens Angela , Fernandez Montes Ana , Simon Laureano , Gomez-Roman Javier
Published: March 2020

540

Background: Breast cancer is currently the most frequent tumor among women. Despite the huge progress achieved in its early diagnosis, there are still many unsolved clinical issues, being the diagnosis, prognosis and treatment of papillary diseases (and specifically intraductal papilloma), one of the highest challenges. Because of its unpredictable clinical behavior, treatment of intraductal papilloma has generated a great controversy. Even though considered as a benign lesion, it presents high rate of malignant recurrence. This is the reason why there are clinicians supporting a complete excision of the papillary lesion, while others support an only expectant follow up. Previous results of our group have suggested that pro-Collagen 11 alpha 1 (pro-COL11A1) expression in cancer associated fibroblasts (CAFs) correlates with an infiltrating phenotype in breast lesions. We have analyzed the correlation between the differential expression of pro-COL11A1 in intraductal papilloma and their risk of malignant recurrence. Methods: Immunohistochemistry of pro-COL11A1 (clone 1E8.33, ONCOMATRIX, Bilbao, SPAIN) was performed in formalin fixed, paraffin embedded Core Needle Biopsy samples of 51 patients with intraductal papilloma. All patients had a minimum follow-up of 5 years. Results: Twenty-three out of 51 cases showed positive staining for COL11A1. Nine patients out of the positive cases relapsed as infiltrating carcinoma, two as intraductal papilloma and the rest had not recurred after five years of follow up. Only one case out of the 28 negative cases relapsed as invasive carcinoma. There were significant differences (p=0.0013) when comparing staining of individuals with malignant recurrence versus non recurrence and benign relapse patients, with a sensitivity of 90% and specificity of 66%. Conclusions: These data suggest that COL11A1 expression in CAFs is a highly sensitive biomarker to predict malignant relapse of intraductal papilloma. The low specificity might be biased by the complete excision of this lesion as the routine treatment or by a short follow-up of the patients.
A new 5-gene signature predictive of risk of relapse in early breast cancer.
Authors: Mustacchi Giorgio , Morandi Luca , Sormani Mariapia , Gennari Alessandra , Zanconati Fabrizio , Bonifacio Daniela , Monzoni Adriana , Bruzzi Paolo
Published: March 2020

546

Background: The aim of this study was look for the "core-genes" of published Signatures in order to find a simpler one Methods: To select candidate genes we used data of NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) including 408 breast cancer cases. Raw intensity data of Affymetrix HU133A and HU133B arrays of the two datasets (GSE1456 and GSE3494) were preprocessed using R/Bioconductor and the supercomputer Michelangelo ( www.litbio.org ). The candidate genes were selected from the “70-gene signature” (van 't Veer, Nature 2002), the “21-gene recurrence score” (Paik, NEJM 2004), the “two-gene–ratio model” (Ma, Cancer Cell 2004) and the “15-gene Insuline Resistence” signature (Gennari , JCO, Vol 25, No 18S, 2007: 10597), for a total of 98 genes.The 20 mRNA more significantly related to DFS were evaluated by quantitative reverse transcriptase PCR on 261 consecutive breast cancer cases, from paraffin embedded sections, split into a training (n 137) and a validation set (n 124). Results: The signature was developed on the training set and a multivariate stepwise Cox analysis selected 5 genes independently associated with DFS: FGF18 (HR=1.13, p=0.05) , BCL2 (HR=0.57, p=0.001), PRC1 (HR=1.51, p=0.001), MMP9 (HR=1.11, p=0.08), SERF1a (HR=0.83, p=0.007). These 5 genes were combined into a linear score weighted according to the coefficients of the Cox model, (0.125 FGF18 - 0.560 BCL2 + 0.409 PRC1 + 0.104 MMP9 - 0.188 SERF1A). The linear score was highly associated with DFS (HR=2.7, 95%CI=1.9-4.0, p<0.001). The signature was then evaluated on the validation set assessing the discrimination ability by a Kaplan Meier analysis, using the same cut offs classifying patients at low, medium or high risk of relapse as defined on the training set. The score resulted highly associated with DFS also in the validation set (p<0.001). Conclusions: Overexpression of BCL2 and SERF1A are related to a higher probability of relapse; overexpression of FGF18, PRC1 and MMP9 to a higher probability of survival without recurrence. The signature has a good discriminating ability and a further clinical validation is planned.
Phase II randomized, open-label study of YM155 (sepantronium bromide) plus docetaxel versus docetaxel alone as first-line treatment for HER2 negative metastatic breast cancer.
Authors: Clemens Michael R. , Keating Anne Therese , Gladkov Oleg , Jie Fei , Steinberg Joyce , Gartner Elaina M. , Crown John , Vladimirov Vladimir Ivanovich
Published: March 2020

548

Background: YM155 (YM) is a small molecule survivin suppressant. In a phase I/II study of YM plus docetaxel (D) in solid tumors evidence of anti-tumor activity was observed in women with human epidermal growth factor 2 non-overexpressing (HER2 negative) metastatic breast cancer (mBC). Methods: This was a randomized study of YM plus D versus D as 1st line treatment in subjects with HER2 negative mBC. Eligibility criteria were: ECOG < 1, no prior chemotherapy for mBC, and at least one measurable lesion. Primary endpoint was progression free survival (PFS); secondary endpoints were: objective response rate (ORR), overall survival (OS), duration of response (DOR), clinical benefit rate (CBR), time to response (TTR) and safety. YM was administered at 5 mg/m2/day as a 168 hr continuous infusion followed by 14 Day (d) observation and D was administered at 75 mg/m2over 1 hr on d1 every 21d. In the control arm, D was dosed per investigator choice q 21d. Results: 101 subjects were randomized (50 YM + D; 51 D). Median (m) age 55 (range: 25 – 79), 25% had triple negative disease, > 60% had bone and lymph mets, 86% had prior therapy for BC. mPFS (days) was 251 (95%CI: 176 – 333) YM + D vs 252 (95%CI: 202-433) D (p=0.34). ORR, CBR and TTR (YM+D; D): 26% vs. 25.5%; 82% vs. 84.3% and 45 vs 59 d. OS data are immature but showed no difference (p=0.911). Adverse events [AEs (> 25%)] [YM + D% vs D %]: neutropenia 83 vs 84, alopecia 62.5 vs 53, fatigue 50 vs 41.2, nausea 35.4 vs 41.2, leucopenia 27 vs 33 and dyspnoea 33 vs 14. Common (>10%) serious AEs [YM + D% vs D%]: febrile neutropenia 21 vs 8 and neutropenia 10 vs 8. Conclusions: Preclinical and clinical evidence suggested the combination of YM + D may offer additional benefit to D alone in subjects with mBC. This study showed no difference in efficacy, but the combination appeared to be well tolerated. Clinical trial information: NCT01038804.
Final results of OV16, a phase III randomized study of sequential cisplatin-topotecan and carboplatin-paclitaxel (CP) versus CP in first-line chemotherapy for advanced epithelial ovarian cancer (EOC): A GCIG study of NCIC CTG, EORTC-GCG, and GEICO.
Authors: Cervantes-Ruiperez Andres , Hoskins Paul , Vergote Ignace , Eisenhauer Elizabeth A. , Ghatage Prafull , Carey Mark , Katsaros Dionyssios , Poveda Andres , Provencher Diane M. , Tu Dongsheng , Stuart Gavin
Published: March 2020

5502

Background: Topotecan was evaluated in a novel combination regimen in comparison to standard therapy in front-line EOC. Methods: Women with newly diagnosed advanced EOC stages IIB-IV, ECOG performance status (PS) 0-1, age < 75, were randomized to either Arm 1: cycles 1 - 4: cisplatin 50 mg/m2 d1 plus topotecan 0.75 mg/m2 d1-5 IV; cycles 5 - 8: paclitaxel 175 mg/m2over 3 hrs d1 followed by carboplatin AUC5 day 1 or Arm 2: paclitaxel plus carboplatin as in Arm 1 for 8 cycles. The primary endpoint was progression free survival (PFS) and secondary endpoints included objective response, overall survival (OS), adverse event (AE) and Quality of Life (QoL). The sample size required 800 pts and 631 events to detect an improvement in PFS from 16 to 20 months (power 80%, 2-sided alpha 0.05). Results with 3.6 years median follow-up (MFU) were reported previously: there was no significant difference in PFS (Hoskins P, JNCI 2010). Final results including OS after MFU of 8.2 years are reported. Results: From 2001 to 2005, 819 pts (409 Arm 1, 410 Arm 2) were randomized. 704 PFS events and 605 deaths have occurred. PFS results are similar to first report: Median (months [mo]): 14.6 (Arm 1) and 16.2 (Arm 2), hazard ratio (HR) 1.03 (95% CI:0.81-1.30; p = 0.83). Median OS is 44.2 mo (Arm 1) and 44.8 mo (Arm 2), HR: 0.92 (95% CI:0.71-1.19; p=0.54). Baseline factors found to be independent predictors of OS in multivariate analysis are: a) pre-randomization surgery (debulking with no macro residual disease (MRD) to no debulking HR: 0.47; 95%CI:0.37-0.58; p < 0.0001; debulking with MRD (<1 cm) to no debulking HR: 0.76; 95%CI:0.61-0.94; p = 0.01), b) Stage (stage II to III or IV HR:0.52; 95%CI:0.36-0.76; p = 0.0007) and c) PS (0 vs 1 HR:0.76; 95%CI:0.63-0.91; p = 0.004). Post-treatment AEs were not significantly different in the two arms. Conclusions: OV16 final results confirm that sequential doublets of topotecan and cisplatin followed by carboplatin and paclitaxel offer no improvement in outcomes compared to carboplatin and paclitaxel. Pretreatment debulking, stage II and PS 0 are predictive of longer OS. Clinical trial information: NCT00028743.
A multicenter phase II study of bevacizumab (B) and temsirolimus (T) in women with recurrent epithelial ovarian cancer (OC): A study of the Mayo, Chicago, California, New York, Southeast, and Princess Margaret Phase II Consortia.
Authors: Morgan Robert , Oza Amit M. , Qin Rui , Fruth Briant , Hirte Hal , Mackay Helen , Tsoref Daliah , Strevel Elizabeth Laureen , Welch Stephen , Sullivan Daniel , Wenham Robert M. , Fleming Gini F. , Brewer Molly , Chen Helen X. , Doyle L. Austin , Gandara David R. , Sparano Joseph A. , Einstein Mark H. , Erlichman Charles
Published: March 2020

5517

Background: Anti-angiogenic therapy is active in OC; the combination of VEGF and mTOR inhibitors is hypothesized to further improve activity. This report is the OC cohort of a multi-histology phase II study assessing the activity and toxicity of B/T. Methods: Patients (Pts) with recurrent epithelial OC who had received ≤ 2 chemotherapy regimens and no prior treatment with a VEGF or mTOR inhibitor were eligible. A two-stage design was used with second stage accrual if >6 pts had objective responses (OR) or >10 pts of the first 25 remained progression-free (PF) at six months (mo). Pre-defined end-points for a recommendation for further clinical trial evaluation included at least 15/50 with OR or 26/50 PF at six mo. Treatment included T 25 mg IV wkly and B 10 mg/kg IV q14 days on 28 day cycles. Results: 58 pts were enrolled (the first 50 pts are used to determine a final recommendation). Median age=62 (range 35-82). A median of 4 (range 1-23) cycles were administered. 24 were platinum-sensitive, 34 resistant. Off-study reasons included 13 adverse events and disease progression in 38. 3 refused further therapy due to toxicity. 14 of the first 50 pts had partial response (PR) (9 platinum-resistant); 25/50 remained PF (8 PR, 15 SD, 2 non-progressing) at 6 mo. Grade (gr) 3/4 toxicities occurring >2 events include: fatigue (4), stomatitis (7), hypertension (5), neutropenia (4), thrombocytopenia (4), hypokalemia (3). One rectal and one vaginal fistula, and two colonic perforations (one gr 2 and one gr 3 during cycles 3 and 1 respectively) were observed. Episodes of gr 1/2 oral, nasal, pulmonary, vaginal and gastrointestinal hemorrhage were also observed. Conclusions: Although the OR and PFS did not reach pre-defined standards, the numbers of OR and 6 mo PFS suggest potential enhanced activity with a combination of mTOR inhibitor with anti-angiogenic therapy. Other combinations of these targeted agents may result in more satisfactory activity with less toxicity. N01-CM-62203 (PMH) N01-CM-62208 (Southeast Phase 2) N01 CM-62209 (CCCP) N01-CM-62204 (NYCC) N01-CM-2011-0071C (Chicago) N01-CM62205 (Mayo) Clinical trial information: NCT01010126.
Targeting p53 mutant ovarian cancer: Phase I results of the WEE1 inhibitor MK-1775 with carboplatin plus paclitaxel in patients (pts) with platinum-sensitive, p53-mutant ovarian cancer (OC).
Authors: Brana Irene , Moore Kathleen N. , Shapira-Frommer Ronnie , Welch Stephen , Jou Ying-Ming , Marinucci Michelle , Freshwater Tomoko , Rose Shelonitda , Oza Amit M.
Published: March 2020

5518

Background: MK-1775 is a highly selective, investigational oral tyrosine kinase inhibitor of WEE1, which regulates G2 cell cycle checkpoint. Functional p53 mutation impairs G1 checkpoint; hence, targeting G2 checkpoint with MK-1775 in p53 mutants should induce synthetic lethality. Methods: Pts with platinum-sensitive disease-recurrent OC who had measurable disease (RECIST 1.1) with loss of function (LOF) p53 mutations by Roche AmpliChip were eligible. All pts received MK-1775 225mg twice daily (BID) D1-D3 (5 doses) plus carboplatin AUC5 + paclitaxel 175mg/m2 every 21 days (CP) for 6 cycles. The objective for the phase I run-in portion of the study was to determine the recommended phase II dose based on safety data. A Toxicity Probability Interval method [Ji et al, Clin Trials 2010; 7(6):653-63] would determine if additional lower doses should be explored. A randomized phase II portion, assessing the efficacy of the combination vs placebo, would start if ≥5 radiological responses and <5 dose-limiting toxicities (DLTs) were observed among the first 13 pts. Results: Of 76 pts screened (26 wt, 43 mutant [24 nonfunctional], 7 undetermined), 19 women had LOF p53 mutations and were eligible. Fifteen consented and were enrolled in the Phase I: median age was 57 (range 38-77); ECOG 0:1 ratio 9:6 pts. Three DLTs were observed: G3 febrile neutropenia, G4 neutropenia, and G4 thrombocytopenia. Diarrhea (84.6%), nausea (76.9%), and fatigue (76.9%) were the most common adverse events (AEs). Seven of 13 pts completed treatment (2 ongoing). Three pts discontinued due to AEs and 3 patients withdrew consent prior to completing treatment. Of 14 evaluable pts by RECIST 1.1 there were 11 partial responses (PRs; 6 confirmed, 5 unconfirmed) and 3 had stable disease; 7 pts were evaluable by CA125 with 3 complete responses and 4 PRs. MK-1775 PK results were similar to those reported for monotherapy studies. Conclusions: The combination of MK-1775 225mg BID x 5 doses with CP is well tolerated, with a preliminary radiological response rate of 78.6%, and has met the safety and efficacy bar for randomized phase II assessment in part 2 of the study. Clinical trial information: NCT01357161.
ADXS11-001 immunotherapy targeting HPV-E7: Preliminary survival data from a P2 study in Indian women with recurrent/refractory cervical cancer.
Authors: Petit Robert G. , Basu Partha
Published: March 2020

5529

Background: ADXS11-001 immunotherapy is a live attenuated Listeria monocytogenes (Lm) bioengineered to secrete a HPV16-E7 fusion protein targeting HPV transformed cells. The Lm vector serves as its own adjuvant and infects APC where it naturally cross presents, stimulating both MHC class 1 and 2 pathways resulting in specific T-cell immunity to tumors. Here we describe the preliminary survival data associated with ADXS11-001 administration in Lm-LLO-E7-015, a randomized P2 study being conducted in India in 110 patients with recurrent/refractory cervical cancer who have been treated previously with chemotherapy, radiotherapy or both. Methods: Patients were randomized to either 3 doses of ADXS11-001 at 1 x 109 cfu or 4 doses of ADXS11-001 at 1 x 109cfu with cisplatin chemotherapy. Naprosyn and oral promethazine were given as premedications and a course of ampicillin was given 72h after infusion. Patients received CT scans at baseline and 3, 6, 9, 12 and 18 months. The primary endpoint is overall survival. Results: As of February 2013, the trial has completed enrollment and 110 patients have received 264 doses of ADXS11-001. The percentage of patients alive at 6 months is 63% (67/107); at 9 months is 46% (49/106); at 12 months is 34% (30/87) and at 18 months is 15% (8/54). Tumor responses have been observed in both treatment arms with 6 CRs and 6 PRs; 36 additional patients had stable disease > 3 months, for a disease control rate of 44% (48/110). Activity against different high risk HPV strains has been observed. Three serious adverse events and 69 mild-moderate adverse events possibly related/related to ADXS11-001 treatment have been reported in 41% (45/110) of patients. The non-serious adverse events consisted predominately of transient, non-cumulative flu-like symptoms associated with infusion that either resolved on their own or responded to symptomatic treatment. Conclusions: ADXS11-001 can be safely administered to patients with advanced cancer alone and in combination with chemotherapy. ADXS11-001 is well tolerated and presents a predictable and manageable safety profile. Final 12-month OS, updated safety and translational analyses will be presented at the meeting.
Tumor-associated CD66b+ neutrophil and CD8+ lymphocyte densities as independent prognostic factors for recurrence in localized cervical cancer: Automated digital image analysis and observer-assisted stereological assessments.
Authors: Carus Andreas , Ladekarl Morten , Nielsen Patricia Switten , Hager Henrik , Nedergaard Bettina S , Steiniche Torben , Donskov Frede
Published: March 2020

5532

Background: The prognostic impact of tumor-associated immune cells in cervical cancer is unclear. Methods: Automated digital image analysis (DIA) software and observer-assisted stereological (OAS) assessments were used to obtain densities of immunostains for CD66b+ neutrophils, CD163+ macrophages, and CD8+lymphocytes in scanned whole slide images of tumor sections from 101 patients with FIGO stage IB and IIA cervical cancer. Primary end-point was recurrence-free survival (RFS). Results: The highest densities of CD66b+ neutrophils and CD163+ macrophages were observed by OAS in the peritumoral compartment (median 53.1 cells/mm2 and 1.3% area fraction, respectively). DIA required far less human resources than OAS assessments. We observed high correlations between DIA and OAS variables of corresponding parameters; spearman ρ was 0.79 for CD8+ lymphocytes , 0.85 for CD66b+ neutrophils, and 0.92 for CD163+ macrophages (all p <0.0001). Hazard rates for DIA assessments in the global tumor area were comparable with the prognostically strongest OAS assessments in the peritumoral compartment. In multivariate analysis, high density of CD66b+ neutrophils (HR 2.6; 95% CI 1.2–5.7; p = 0.02), low density of CD8+ lymphocytes (HR 2.3; 95% CI 1.1–4.9; p = 0.03), and presence of lymph node metastases (HR 2.6; 95% CI 1.2–5.5; p = 0.02) were independent predictors of poor RFS, whereas FIGO stage and CD163+macrophage density were not. The CD66b/CD8 immunostain index obtained by DIA had excellent discriminatory power for each quartile with 5-year RFS of 92%, 80%, 65%, and 48% for quartile I (<0.019), II (0.02-0.05), III (0.06-0.24), and IV (>0.25), respectively (p = 0.001). Conclusions: High tumor-associated CD66b+ neutrophil and low CD8+ lymphocyte densities are independent prognostic factors for short recurrence-free survival in cervical cancer assessed by DIA and OAS. Combined CD66b+ neutrophil/CD8+ lymphocyte immunostain index obtained by DIA is a strong and cost-efficient prognostic variable with potential for routine application.
Ovarian cancer distribution of histology, stage, and screening performance.
Authors: Eiriksson Lua R , Reade Clare J , Lennox Genevieve , Mojtahedi Golnessa , Murphy Joan , Ferguson Sarah E , Bernardini Marcus Q
Published: March 2020

5543

Background: Survival in women with ovarian cancer is strongly influenced by stage of disease at diagnosis. As such, strategies have been investigated to identify biomarkers for early detection. This premise assumes a progression of disease from early to late stage. Varying histologic subtypes in ovarian cancer have distinct etiologies. It is likely that early detection strategies will need to be subtype specific. This study sought to evaluate histologic subtypes, stage of disease, and screening performance in a cohort of women diagnosed with ovarian cancer. Methods: This analysis was performed as an REB approved sub-study of a single institution ovarian cancer tumor banking protocol for which all patients presenting with suspected ovarian cancer, since February 2011, were eligible. This analysis included all patients with confirmed ovarian cancer. Patients were identified and tracked prospectively. Results: There were 135 patients with ovarian cancer (mean age 57 ± 12 years). 67% were post-menopausal. The distribution of histologic subtypes was 42% high-grade serous (HGS), 18% endometrioid, 12% clear cell, 6% low-grade serous (LGS), 6% sex-cord stromal, 5% germ cell, 3% mucinous, 3% mixed, 3% carcinosarcoma, and 2% other. 64 (47%) women presented with advanced disease with a median CA 125 of 260 (range 14 – 21 782), of whom 43 (68%) were found to have HGS histology. 46 (34%) patients presented with stage I disease with a median CA 125 of 41 (range 3 – 9305). Of these, the distribution of histologic subtypes included 13 (28%) endometrioid, 9 (20%) clear cell, 5 (11%) sex-cord stromal, 5 (11%) HGS, 3 (7%) mucinous and 23% other. Risk of Malignancy Index (RMI) scoring for women with stage I disease (N = 35) revealed a false negative rate of 31%, including 4 clear cell, 2 LGS, 2 endometrioid and 1 each of HGS, mucinous, and mixed (clear cell and endometrioid) histologies. Conclusions: Stage I ovarian cancer consists primarily of non-serous histologies, which are not reliably detected using CA 125 and ultrasound markers. Current approaches to screening for early stage disease may require the identification of biomarkers unique to clear cell and endometrioid histologies and novel strategies for the identification of patients at risk for HGS carcinomas.
Tasisulam-sodium in combination with liposomal doxorubicin in patients with ovarian cancer.
Authors: McMeekin D. Scott , Rosen Lee S. , Bessudo Alberto , Tai Datchen Fritz , Ilaria Robert L. , Chen Jian , Turner P. Kellie , Krueger Sandia , Gordon Michael S.
Published: March 2020

5551

Background: Tasisulam-sodium (TASI) is a novel, highly albumin-bound small molecule that induces tumor cell apoptosis and has antiangiogenic activity. This phase 1b study was designed as a dose-finding study for TASI in combination with liposomal doxorubicin (DX) in patients (pts) with advanced solid tumors, followed by a dose-confirmation phase in platinum-resistant DX-naïve ovarian cancer (OvCa) pts. However, the study was stopped early for business reasons. Nonetheless, the dataset allowed partial characterization of the safety and antitumor activity of TASI + DX among OvCa pts who achieved an albumin-corrected exposure (AUCalb) within a hypothesized therapeutic range identified in phase II monotherapy trials. Methods: In the dose-escalation phase (3+3 schema), pts received TASI (escalating Cmax targets of 300-380 μg/mL, 2-h IV) plus DX (40 mg/m2, 1-h IV) every 28 days. Pharmacokinetic and safety analyses identified an AUCalb target of 3500 h*μg/mL for the dose-confirmation phase. We analyzed data for OvCa pts from both phases who achieved TASI AUCalbof 1200-6400 h*μg/mL in cycle 1. Results: Of the 13 OvCa pts who completed the dose-escalation phase and 6 OvCa pts who completed the dose-confirmation phase, 10 had AUCalbof 1200-6400 h*μg/mL in cycle 1. For these pts, the most common possibly drug-related Grade 3-4 adverse event was neutropenia (see table). Although no pt achieved complete response, 2 pts achieved partial response. Data from the other OvCa pts will also be presented. Conclusions: The early closure of the study did not allow complete assessment of TASI in combination with DX; however, acceptable tolerability and some antitumor activity were observed for OvCa pts with TASI AUCalbwithin the hypothesized therapeutic range. Clinical trial information: NCT01214668. [Table: see text]
Phase II study of trabectedin in pretreated patients with recurrent epithelial ovarian cancer (REOC).
Authors: Marinaccio Marco , Mele Emilia , Lorusso Vito , Fumarulo Valeria Vincenza , Sozzi Fausta , Cicinelli Ettore
Published: March 2020

5559

Background: The prognosis of patients with REOC is extremely poor after several lines of chemotherapy. The choice and timing of therapies must be individualized to optimize survival and quality of life. This open-label, nonrandomized, phase II study was aimed at evaluating efficacy and toxicity of Trabectedin as a single-agent therapy in patients with preteated Recurrent Epithelial Ovarian Cancer (REOC). Methods: Sixteen patients (median age 51 yrs, range 44 – 71) with REOC who progressed after 2 (18.7%), 3 (56.3%) or 4 (25.0%) previous lines of chemotherapy were treated with Trabectedin at the dose of 1.1 mg/m2 via a 3-hour i.v. infusion with dexamethasone pretreatment every 3 weeks until disease progression, unacceptable toxicity or when a stability of disease was reached. Clinical objective response was the primary efficacy endpoint; the secondary one was safety. Response to treatment was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST, version 1.1), and toxicities were graded according to NCI Common Toxicity Criteria, version 2.0. Results: The median number of treatment cycles per patients was 5 (range, 2-9 cycles). A total of 81 cycles were administered. A dose reduction was never required. Main toxicities included anemia (20.9%), leucopenia (15.0%), thrombocytopenia (4.5%) and asthenia (22.2%). No deaths were attributable to therapy. No one showed complete response, while 9/16 partial response (56.2%) and 4/16 stable disease (25.0%) were observed. 3/19 pts (18.8%) progressed on therapy. The median progression-free interval was 18 weeks in patients with partial response; stable disease was maintained for a median time of 12 weeks. Conclusions: Trabectedin 1.1mg/m2 given as a 3-hour i.v. infusion every 3 weeks was well tolerated and has confirmed a very interesting antitumor activity in this heavily pretreated population and it seems also to be a very tolerable regimen. The co-treatment with dexamethasone improves the safety of Trabectedin by reducing drug-induced myelosuppression and hepatotoxicity. Trabectedin has a manageable toxicity profile, and can be safely administered thanks to its secure action profile also in patients with no other viable therapeutic options.
An open label, randomized, parallel, phase II trial to evaluate the efficacy and safety of cremophor-free, polymeric micelle formulation of paclitaxel compared to paclitaxel in subjects with ovarian cancer.
Authors: Kim Yong-Man , Lee Shin-Wha , Cho Chi Heum , Hur Soo-Young , Kim Byoung-Gie , Kim Jae Hoon , Kim Seung Cheol , Kim Seok-Mo , Kim Young-Tae , Ryu Hee Sug , Kang Soon-Beom
Published: March 2020

5568

Background: Cremorphor EL, used to enhance drug solubility, may add to paclitaxel’s toxicities such as hypersensitivity reactions or peripheral neuropathy. This multi-institutional phase II trial is to evaluate the efficacy and safety of Cremophor-Free, Polymeric Micelle Formulation of Paclitaxel (Genexol-PM) compared to Paclitaxel (Genexol) as a combined chemotherapy with carboplatin in patients with advanced epithelial ovarian cancer. Methods: In this phase II, randomized, parallel study, patients with FIGO stage IC-IV epithelial ovarian cancer after debulking surgery received intravenously Genexol-PM 260 mg/m2 or Genexol 175 mg/m2 combined with carboplatin iv (AUC 5) on day 1 of every 3-week cycle for a maximum of six cycles. The primary endpoint was composite response by GCIG CA-125 Response and Response Evaluation Criteria In Solid Tumors (RECIST). Secondary and exploratory endpoints included overall survival, progression-free survival, time to tumor progression, and safety and tolerability. Results: A total of 102 patients were randomized to Genexol-PM plus carboplatin (n = 51) or Genexol plus carboplatin (n = 51). Composite response rate in patients with or without measurable disease was 88.0% in the Genexol-PM plus carboplatin group and 77.1% in the Genexol plus carboplatin group. Noninferiority of Genexol-PM plus carboplatin compared with Genexol plus carboplatin was confirmed for composite response rate by CA-125/RECIST criteria. There were no differences in progression-free survival and overall tumor progression between the groups. Although there was a higher rate of grade 3 neutropenia in the Genexol-PM plus carboplatin group, the overall rate of hemodynamic adverse events was comparable between the 2 groups. There was no difference in peripheral neuropathy and hypersensitivity. No unexpected safety concerns were identified in this study. Conclusions: High-dose of Genexol-PM in combination with carboplatin was well tolerated, and its response rate was noninferior to that of Genexol plus carboplatin in patients with advanced epithelial ovarian cancer. Clinical trial information: NCT01276548.
Chemotherapy-induced myelosuppression in ovarian cancer patients with germline BRCA1/2 mutations: A case control study.
Authors: Christie Alan , Che Bakri Amalina , Roxburgh Patricia , Khan Muhammad Imtiaz , Iqbal Yousuf , Rye Tzyvia , Mitchell Paul , Rye Ronald , Nussey Fiona , Mackean Melanie J. , Reed Nicholas , Glasspool Rosalind Margaret , Ferguson Michelle , Gourley Charlie
Published: March 2020

5571

Background: Ovarian cancer patients with germline BRCA1 or BRCA2 (gBRCA1/2) mutations frequently respond to multiple lines of chemotherapy. Having noticed significant myelosuppression during chemotherapy in gBRCA1/2 patients we wished to determine whether this was a chance finding or related to a heterozygous gene dosage effect in the bone marrow. Methods: gBRCA1/2 ovarian cancer patients from Edinburgh, Glasgow and Dundee were identified and matched for chemotherapy regimen, dose and age to controls from the Edinburgh Ovarian Cancer Database. Case notes and transfusion service records were analysed for chemotherapy details, haematology results, G-CSF use, red cell and platelet transfusions during first line chemotherapy. Results: Of 91 gBRCA1/2 patients, 35 patients were excluded who had previously received cytotoxic chemotherapy (mostly for breast cancer) or unusual chemotherapy regimens unable to be matched to controls. 56 were matched to controls. Baseline haematological indices were similar. There was a significant difference in the fall in haemoglobin levels from baseline to cycle 4 in gBRCA1/2 patients compared to controls (12.23% v 5.14%, p = 0.0005) and gBRCA1/2 patients had longer delays during their chemotherapy (mean 7.73 v 4.51 days, p = 0.0375) and more dose reductions for haemotoxicity (14 v 4 p = 0.0011). gBRCA1/2 were more likely to have a red cell transfusion (19 v 11, p = 0.099), and received more red cells (69 v 31 units, p = 0.0318). G-CSF was required in 3 BRCA patients versus 0 controls. Differences in platelet and white cell counts at cycle 4 were not significant. Conclusions: Patients with ovarian cancer and germline BRCA1/2 mutations were more likely to have significant falls in haemoglobin levels and require red cell transfusions and to experience delays during chemotherapy. This susceptibility to anaemia may be a hemizygous BRCA1/2 gene dosage effect manifest in the bone marrow and may have implications for the optimisation of cytotoxic and PARP inhibitor therapy in this patient group.
A panel of biomarkers to improve specificity in presurgical assessment of adnexal masses for risk of ovarian malignancy.
Authors: Zhang Zhen , Li Danni , Sokoll Lori J. , Sun Xiaer , Bristow Robert , Chan Daniel W
Published: March 2020

5573

Background: OVA1 is a panel of biomarkers cleared by FDA currently in clinical use for pre-surgical assessment of adnexal masses for risk of ovarian malignancy. To further improve the specificity of OVA1, we evaluated biomarkers using a designed set of clinical samples enriched with OVA1 false positive benign patients and selected insulin-like growth factor binding protein 2 (IGFBP2), interleukin 6 (IL6), and follicle-stimulating hormone (FSH) to be further evaluated along with the original five biomarkers of OVA1 on a prospectively collected clinical sample set. The inclusion of FSH was to eliminate the need for menopause-specific cutoffs. Methods: Consecutive patients with a documented pelvic mass planned for surgical intervention were prospectively enrolled at 27 sites. Exclusion criteria included a diagnosis of malignancy in the previous 5 years or initial enrollment by a gynecologic oncologist. At the time of analysis, 384 subjects had all biomarker values. Among them 69 were ovarian cancer cases (13 LMPs, 27 stages 1/2, 19 serous, 11 endometrioid , 5 mucinous, and 4 clear cell). Biomarkers were tested by ELISA and reported as continuous values. Using a subset of the samples, the biomarkers were first selected for inclusion in a final panel based on contributions in multivariate models estimated by bootstrap. The selected biomarkers were further assessed for ability to improve specificity of risk stratification at a fixed sensitivity over that of OVA1 using the full data set. This was done by cross-validation of multivariate models with 50/50 split between training and testing. Results: The final panel of biomarkers consisted of CA125II, prealbumin, IGFBP2, IL6, and FSH. At a fixed sensitivity of 90%, the mean and median specificity of models using the new panel in testing were 78.2% (95% CI: 76.7 – 79.8%), and 80.6%, respectively. The mean and median absolute improvements over that of OVA1 were 18.6% (95% CI: 16.4% – 20.9%) and 20.3%, respectively. Conclusions: The new panel demonstrated the potential to significantly improve specificity over that of the first-generation OVA1 algorithm, while maintaining a high sensitivity in pre-surgical assessment of adnexal masses for risk of malignancy.
Is uterine serous carcinoma a part of hereditary breast cancer syndrome?
Authors: Rafii Saeed , Dawson Philip , Williams Sarah , Pascoe Jennifer S. , Nevin James E. , Sundar Sudha
Published: March 2020

5587

Background: Whilst the association between breast cancer and uterine serous carcinoma (USC) is attributed to tamoxifen treatment, few studies have reported that this increased risk is independent of tamoxifen. Methods: To further investigate the relationship between breast cancer and USC, we retrospectively studied 216 patients from 5 hospital trusts in Birmingham, UK who were diagnosed with USC between 1993 and 2012. We collected personal history of cancer in these cases before or after USC diagnosis. In addition FIGO staging, clinical and survival data were collected from our local cancer registry and patients’ clinical records. Results: In this case series, 56 patients (25.9%) had personal history of at least one cancer before and 18 patients (8.3%) had history of at least one cancer after the diagnosis of USC. Within the group of patients with the history of cancer before the USC, 38 patients (68%, 17.5% of all cases) had personal history of breast cancer prior to the development of USC, higher than the UK expected age standardised relative incidence of breast cancer (350 in 100,000, CRUK 2006-2008). Although 27/38 cases (71%) had endocrine treatment for their primary breast cancer, 11/38 patients (29%) did not have any tamoxifen treatment due to hormone receptor negative breast cancer. Additionally the median age of breast cancer diagnosis for the hormone receptor negative group was significantly lower than those patients who had hormonal treatment for their breast cancer (56 vs. 64 years, p :0.036) compatible with the younger age at diagnosis expected of the familial (BRCA mutated) or triple negative breast cancer. Of 18 patients with a second cancer after diagnosis of USC, 6 patients (33%) were diagnosed with breast/ovarian cancer. This group also had no treatment with tamoxifen. Conclusions: Lack of exposure to tamoxifen and younger age at diagnosis in this subgroup suggest that other factors such as a common underlying genetic predisposition may be responsible for the development of both malignancies. We propose that at least a subgroup of USC may be a part of hereditary breast cancer syndrome. This may have implications in prevention (prophylactic hysterectomy) or trials of targeted treatments (PARP inhibitors) for a subgroup of USC patients.
Tissue sampling frequency and breast pathology diagnoses following mammography: Time trends and age group analysis from the Breast Cancer Surveillance Consortium (BCSC).
Authors: Allison Kimberly H. , Abraham Linn A , Weaver Donald L. , Tosteson Anna NA , Onega Tracy , Geller Berta M , Kerlikowske Karla , Carney Patricia A , Ichikawa Laura E , Buist Diana SM , Elmore Joann G
Published: March 2020

559

Background: Pathology diagnoses in a well-characterized population of women can be used to identify tissue sampling and diagnosis trends following mammography. Methods: Screening and diagnostic mammography, patient characteristics, and pathology reports from the BCSC performed from 1996-2008 were identified. Diagnosis was based on the most severe pathology interpretation in the same breast within 60 days of a post-mammogram tissue sample. Age, mammogram year and type, breast density, and family history of breast cancer were evaluated for associations with tissue sampling and most severe pathology diagnosis. Results: 4,022,506 mammograms (88.5% screening; 11.5% diagnostic) were performed in 1,288,886 women; 76,567 (1.9%) were followed by tissue sampling (1.2% screening; 7.1% diagnostic). Tissue sampling frequency following diagnostic mammography increased over time in women over 50 but remained stable following screening mammography. The frequency of invasive cancer increased with age and was more common following a diagnostic (29.3%) vs screening (19.8%) mammogram; the frequency of high risk lesions (ADH; lobular neoplasia) was highest in women aged 50-59. For tissue sampling following screening mammograms, the frequency of DCIS increased over time while benign diagnoses decreased. No significant time trends were noted for diagnoses associated with diagnostic mammograms. Women aged 40-59 with dense breasts and a tissue sampling following screening mammogram had a significantly higher frequency of DCIS (40-49: 4.8% vs 3.2%, P< 0.001; 50-59: 7.0% vs 5.7%, P=0.007). Women aged 40-59 with > 1first degree relative with breast cancer vs none that had a tissue sampling following screening mammogram had a significantly higher frequency of invasive cancer (40-49: 11.4% vs 9.4%, p=0.008; 50-59: 19.8% vs 18.2%, p =0.086) and DCIS (40-49: 6.2% vs 4.0%, p< 0.001; 50-59: 8.2% vs 6.2%, p< 0.001). Conclusions: There was an increase in DCIS and a decrease in benign diagnoses in tissues samples after screening mammography over time. No trends were seen following diagnostic mammography. DCIS was also more frequent in women with dense breasts.
Gene scoring model to predict recurrence in low- and intermediate-risk uterine endometrial cancer: Establishment of uterine print.
Authors: Chiyoda Tatsuyuki , Ito Yoichi M , Kataoka Fumio , Yamagami Wataru , Nomura Hiroyuki , Tsuda Hiroshi , Tanaka Hideo , Takano Masashi , Nishimura Sadako , Iguchi Yoko , Hashimoto Shiho , Yoshihama Tomoko , Susumu Nobuyuki , Aoki Daisuke
Published: March 2020

5590

Background: Endometrial cancers (ECs) classified as low-, intermediate-, and high-risk, based on clinical and pathological features (CPF: Lurain, 2007) associated with 5%, 15%, and 25% risk of recurrence, respectively. The need for adjuvant chemotherapy in intermediate-risk patients is controversial. We examined whether gene expression profiling can more accurately predict the prognosis of ECs, excluding the CPF-based high-risk group. Methods: Tumor specimens were obtained from 136 ECs including 14 recurrences, excluding high-risk cases. Gene expression profiles were achieved using a custom array consisting of 85 genes associated with EC recurrence and 20 internal controls that were previously screened. We established the gene scoring model (GSM) for recurrence by the logistic regression model in randomly selected 68 ECs including 7 recurrences, and evaluated the accuracy of GSM in other 68 ECs including 7 recurrences. This process was repeated 100 times. We calculated the mean accuracy of GSM and compared it with the accuracy of CPF. We also compared GSM and CPF with respect to progression-free survival (PFS) by use of the log-rank test. Results: Median age of all cases was 58 (29-86) years, and stage, histologic grade, and risk classification based on CPF were as follows: (I, 107; II, 15; III, 14), (G1, 69; G2, 57; G3, 10), and (low, 67; intermediate, 69). The median follow-up period was 1830 (1626-3444) days. The GSM was established based on the expression of 4 genes (PRCC, SPC25, PXDN, and LBXCOR1) and 10 internal controls. The area under the receiver operating characteristic curve of GSM to predict recurrence was 0.87 in 68 test cases. Based on the CPF, 68 cases were classified as 30 low-risk and 38 intermediate-risk, and the sensitivity and specificity of CPF was 86% and 48% each in the 68 test cases. When sensitivity of GSM was fixed at 86%, specificity of 67% was achieved, and 68 cases were classified as 42 risk (-) and 26 risk (+). PFS was significantly related with GSM (p = 0.006); however, it was not related with CPF (p = 0.09). Conclusions: GSM can predict the prognosis of ECs (low- and intermediate-risk) more precisely than CPF.
Ethnic differences in tumor proliferation in women with early-stage breast cancer.
Authors: Kalinsky Kevin , Lim Emerson A. , Andreopoulou Eleni , Desai Avni Mukund , Wang Antai , Maurer Matthew A. , Crew Katherine D. , Greenlee Heather , Hibshoosh Hanina , Sparano Joseph A. , Hershman Dawn L.
Published: March 2020

560

Background: Hispanic women have a higher mortality rate and lower incidence of breast cancer (BC) compared to Caucasian women. Studies report higher tumor proliferation in African American (AA) women compared to Caucasian women. The 21-gene assay (OncotypeDX) Recurrence Score (Score) is based on the expression of 16 cancer related genes, including 5 proliferation genes that are grouped to provide the proliferation axis score (PAS). We evaluated the differences in the Score and PAS between Hispanic and Caucasian women with early-stage BC in a matched cohort analysis. Methods: Women with early-stage BC who had a Score obtained from 2005- 2011 were identified. Hispanic women were matched to Caucasians in a 1:2 ratio, based on age (+/- 10 years), stage, and nodal status. Lymphovascular invasion (LVI) and grade were collected. The Score result, 10-year distant recurrence, ER/PR/HER2 expression, and PAS were obtained from the OncotypeDX assay. Assuming equal variances, we expected > 90% power to detect a difference in the mean PAS between Hispanic and Caucasian women Results: We identified 219 women who had OncotypeDX testing (74 Hispanic: 145 Caucasian). Of the 74 Hispanic women, 84% were from the Dominican Republic or Puerto Rico. Mean age was similar between groups (56.3 and 56.8). All but 8 patients were node(-). Mean PAS was higher in Hispanic (5.53, range: 3.9-7.8) vs Caucasian women (5.26, 3.7-7.3) (p=0.03, 95% CI: 0.03-0.51). The mean Score was 18.3 (0-54) and 16.3 (1-50) for Hispanic vs Caucasian women. There was no statistical difference in Score (p= 0.17) or 10-year distant recurrence (p=0.13) between groups. No differences were observed in median ER (9.8% vs 9.9%: Hispanic vs Caucasian), PR (7.3% vs 7.6%), or HER2 (9.1% vs 9.0%) by RT-PCR. Rates of LVI and grade 3 tumors were also not statistically different. Conclusions: Similar to higher PAS in AA women, Hispanic women with ER/PR(+), HER2(-) early-stage BC have higher tumor proliferation markers, measured by RT-PCR in the Oncotype DX assay, than Caucasian women. This may contribute to ethnic differences in BC mortality. We plan to evaluate ethnic differences in the 5 single PAS genes (CCNB1, MKI17, MYBL2, BIRC5, AURKA) to determine which are driving proliferation differences.