bluuebunny/crossref_metadata_2025_split huggingface dataset:
Breast cancer evaluation and targeted investigational therapy (BEAT-IT): A pilot prospective tissue testing to guide clinical trial selection.
Authors: Pusztai Lajos , Mattair Danielle , Ueno Naoto T. , Valero Vicente , Moulder Stacy L. , Murray James L. , Alvarez Ricardo H. , Chavez-Mac Gregor Mariana , Santiago Lumarie , Avritscher Rony , Sahin Aysegul A. , Hortobagyi Gabriel N. , Symmans William Fraser , Meric-Bernstam Funda , Burton Elizabeth M , Gonzalez-Angulo Ana M. 
Published: March 2020

532 Background: An increasing number of molecularly targeted drugs are now available in Phase I and II clinical trials. Many of these drugs target specific molecular abnormalities such as mutated, amplified or rearranged genes. Our hypothesis is that cancers that carry a molecular abnormality that corresponds to the mechanism of action of a given investigational drug are more sensitive to that particular drug than other cancers. The objective of this study is to perform molecular analysis of metastatic breast cancer biopsies (bx) using methods already established within CLIA approved laboratories, and to use the results to triage pts to various therapeutic clinical trials or standard of care therapy. Methods: Four core needle biopsies (CNB) and 4 fine needle aspirations (FNA), or 8 FNA are obtained from the most safely accessible metastatic site in a single bx session. Pathological confirmation of successful aspiration is performed. Two core bx (or 4 FNA passes) are formaldehyde fixed and paraffin embedded for Immunohistochemistry (IHC), FISH and mutation analysis (CMS11 or CMS46) and 4 FNA are placed in RNA-later and snap-frozen for transcriptional profiles and storage. Samples are transferred to the Molecular Diagnostic, IHC, and Cytogenetics Laboratories. All reports are included in the electronic medical record. Results: FromFeb 2012 to Jan 2013, 142 pts referred, 128 pts registered, 101 bx completed and 78 (77%) bx with available results. Bx sites included: liver (37), lymph node (26), soft tissue (16), bone (13), lung (5), other (4). Successful results were obtained for IHC: PTEN (73%), AR (78%), MET (73%), FISH: EML4-ALK (78%) and MET (74%), and mutation analysis (76%). To date, there have been no reported hospitalizations, ER visits, bleeding, pain, infection or organ dysfunction at the bx sites. 16 pts have been treated on trials with investigational agents hypothesized to result in response based upon the molecular profile of the tumor. Conclusions: Prospective tissue collection to determine the molecular targets and to evaluate pts for clinical trial selection is feasible and safe.
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.