bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase 1b/2 study of napabucasin with weekly paclitaxel in advanced, previously treated platinum resistant ovarian cancer.
Authors: Becerra Carlos , Garcia Agustin A. , Hays John L. , Method Michael W. , Richey Stephen Lane , Langleben Adrian , Richards Donald A. , Cote Gregory Michael , Kossler Kimiko , Li Wei , Li Youzhi , Hitron Matthew , Li Chiang 
Published: September 2018

5548 Background: Napabucasin is a first-in-class cancer stemness inhibitor, identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al PNAS 112 (6):1839, 2015). Napabucasin has shown potent synergistic preclinical anti-tumor activity with paclitaxel (PTX). In a phase Ib dose escalation study in patients (pts) with advanced solid tumors, napabucasin plus weekly PTX was well tolerated. A phase II expansion cohort was opened for patients with platinum resistant ovarian cancer. Methods: Pts with advanced ovarian cancer who had disease progression either during or in the 6 months following platinum-based systemic therapy were enrolled. napabucasin was administered orally at a starting dose of 240, 480, or 500 mg twice daily with PTX 80 mg/m2 IV weekly on 3 of every 4 weeks. AEs were evaluated using CTCAE v4.03 and objective assessments were performed per RECIST 1.1 every 8 weeks. Results: A total of 98 pts were enrolled. The average number of prior lines of systemic treatment was 3.5, including prior taxane-based therapy in 100% of patients. Treatment was well tolerated. Related grade 3 adverse events occurring ≥ 5% of pts included diarrhea (12.2%) and vomiting (5.1%). Among pts who received RECIST evaluation (n = 76), the disease control rate (DCR, proportion with SD at 8 weeks + PR + CR) was 65%, and the objective response rate (ORR, PR+CR) was 20%, with complete response in 3 pts (4%). In all patients (ITT, n = 98), the median progression-free survival (mPFS) was 3.0 months and median overall survival (mOS) was 9.3 months. Conclusions: Clinical safety and encouraging signs of anti-cancer activity, including three complete responses, were observed in pts with pre-treated platinum resistant ovarian cancer who received treatment with napabucasin plus weekly PTX. Further clinical evaluation in controlled trials is warranted. Clinical trial information: NCT01325441.
A platinum-resistant subtype of high-grade serous ovarian cancer identified by a network of somatic mutations.
Authors: Shen John P. , Bojorquez-Gomez Ana , Huang Justin , Hofree Matan , Kurnit Katie , Klepper Kristin , Beckett Alex , Kreisberg Jason F , Saenz Cheryl C. , Ideker Trey 
Published: September 2018

5561 Background: High-grade serous ovarian carcinoma (HGS-OvCa) is a heterogeneous entity with a widely variable clinical course even among patients of the same stage and histological subtype. Although most patients will achieve remission with platinum-based chemotherapy, ~20% will display primary platinum resistance. Currently no biomarker exists to identify these platinum resistant patients. Methods: We have recently developed a method called Network-based Stratification (NBS), which combines genome-scale somatic mutation profiles with genetic interaction networks and performs unsupervised clustering of patients into subtypes. Results: Using NBS HGSOC patients were stratified into subtype, in both TCGA (n = 330) and the ICGC (n = 92) a high-risk (HR) subtype consisting of ~20% of the patients was identified (see table). Propagated mutation scores of the HR tumors from TCGA and ICGC cohorts we remarkably correlated (Pearson r2 = 0.94, p < 0.001), relative to the correlation between HR and standard risk subtypes within TGCA cohort (r2 = 0.18). We then identified molecularly matched cell line models for in vitro study, finding that HR cell lines (Kuramochi, Ovkate, OAW28, 59M) were significantly more resistant to cisplatin relative standard risk cell lines (COV318, TYK-NU, OVCAR4), (IC50 14.4 vs. 3.3 µM, p < 0.0001). There was no significant difference in sensitivity to paclitaxel. A genome-wide knockout screen using CRISPR-Cas9 has identified several candidate genes mediating this observed platinum resistance. Conclusions: NBS can be used to identify a molecularly distinct subtype of HGSOC characterized by poor patient survival and primary platinum resistance. [Table: see text]
Impact of genomic heterogeneity on PI3K/AKT/mTOR inhibitors (PAMi) efficacy in gynecologic cancer (GYN) patients (pts).
Authors: Rodriguez Freixinos Victor , Ruiz-Pace Fiorella , Fariñas-Madrid Lorena , Garrido Castro Ana Christina , Villacampa Guillermo , Nuciforo Paolo , Vivancos Ana , Dienstmann Rodrigo , Oaknin Ana 
Published: September 2018

5569 Background: Aberrant PI3K/AKT/mTOR activation is common in GYN. Predictive biomarkers to PAMi in GYN have yet to be identified. Methods: Advanced GYN pts with available genomic data, treated with PAMi in phase I/II clinical trials were selected. Mutation (mut) allele fractions (MAFs) were corrected for tumor purity and defined as clonal (cl) (≥ 0.4) or subclonal (scl) ( < 0.4). PAMi efficacy: (i) time to progression (TTP); (ii) clinical benefit rate (CBR: complete/partial response or stable disease > 4 months [m]); and (iii) ratio TTP on PAMi/ TTP on non-standard chemotherapy pre- or post-PAMi (PAMi/nsChemo TTP). Results: From 2010 to 2016, 264 GYN pts (152 ovarian(OC); 75 endometrial(EC); 37 cervical(CC)) had genomic analysis; 50 pts (24 OC [11 PIK3CA mut, 5 KRAS mut], 15 EC [6 PIK3CA mut, 5 PTEN mut, 4 KRAS mut], and 11 CC [9 PIK3CA mut, 3 KRAS mut]) received PAMi (17 pan-PI3K/mTOR or AKT inh, 17 α-PI3K inh, 16 PAMi targeted combos). PAMi therapy was matched (MA) to PIK3CA/PTEN mut in 30 pts (60%). Median age was 57 years (30-70); median number of prior lines was 2 (1-6) and 34 pts (68%) received nsChemo. Efficacy of PAMi: (i) median TTP (3.27 m [95% CI 2.1-4.4] with trend for longer TTP in OC compared to others [3.93 vs. 2.1 m, HR 0.57; p = 0.08], without differences according to MA status [p = 0.26] or regimen [p = 0.5]); (ii) CBR (42% [95% CI 27-58%], without differences according to tumor type [p = 0.47], MA status [p = 1] or regimen [p = 0.86]); and (iii) TTP PAMi/nsChemo ≥ 1.3 (42% [95% CI 24-63%], without differences according to tumor type [p = 0.53], MA status [p = 0.23] or regimen [p = 0.41]). Partial responses were seen in 5 pts (4 PIK3CA mut on single agent PAMi; 1 KRAS mut on PI3K + MEK inh). Of 4 KRAS mut pts, none had CBR with single agent PAMi. PIK3CA mut were cl in 63% of OC, 17% of EC and 40% of CC. Clonal exon 20 PIK3CA mut were more frequent in OC (p = 0.03). We found longer TTP for cl PIK3CA events (4.0 vs. 1.5 m in scl, HR 5.1, p = 0.006) and a trend for exon 20 events (4.4 vs. 1.4 m in exon 9, HR 1.7, p = 0.25). Conclusions: Regardless of PIK3CA/PTEN mut status, PAMi confer CBR in almost 40% of GYN pts. Functionality and clonality of PIK3CA mut impact on TTP and interact with tumor type. Coexisting KRAS mut may drive resistance to single agent PAMi.
Primary operation in synchroneous metastasized invasive breast cancer patients: First oncologic outcomes of the prospective randomized phase III ABCSG 28 POSYTIVE trial.
Authors: Fitzal Florian , Balic Marija , Bjelic-Radisic Vesna , Hubalek Michael , Singer Christian F. , Steger Guenther G. , Marth Christian , Schrenk Peter , Knauer Michael , Haid Anton , Wette Viktor , Luisser Irmgard , Greil Richard , Fuegger Reinhold , Swoboda Ursula , Soelkner Lidija , Gnant Michael 
Published: September 2018

557 Background: The ABCSG 28 Posytive trial compared primary surgery versus primary systemic therapy without surgery in stage IV breast cancer patients. The primary aim was to investigate whether immediate resection of the primary tumor followed by standard systemic therapy improves median survival compared with no surgical resection (NCT01015625). The trial had to be stopped early due insufficient recruitment. Methods: Untreated stage IV breast cancer patients with the primary in situ were randomly assigned to either surgery of the primary versus no surgery followed by systemic therapy between 2011 and 2015 in 15 breast health centers in Austria. Systemic therapy included endocrine therapy or chemotherapy. Patients were routinely followed every 3-6 months. Primary endpoint was median survival. Results: 90 patients (45 with surgery, 45 with primary systemic therapy without surgery) were randomized. Stratification criteria were age, endocrine responsiveness, her2 expression, planned first line therapy and bone only versus other metastases. Patients in the surgery arm had more cT3 breast cancer (22% versus 7%) and more cN2 staging (16% versus 4%) as well as more her2 positive breast cancer cases (27% versus 18%). The median follow up was 37.5 months and immunohistochemical subtype analysis showed 9% basal like, 22% her2 positive, 51% luminal A and 13% luminal B cancers. Both groups were well balanced regarding first line treatment (endocrine versus chemotherapy) however, there were more taxane treated patients in the no surgery group (24.4 versus 15.6%). The median survival in the surgery arm was 34.6 months versus 54.8 months in the no surgery arm without statistical significance (HR 0.691 CI 0.358 – 1.333; p=0.267). Time to distant progression was insignificantly longer in the no surgery arm (surgery arm 13.9 versus no surgery arm 29.0 months). Conclusions: This first analysis of the prospective randomized phase III trial POSYTIVE-ABCSG-28 demonstrated no benefit in overall survival for immediate surgery of the primary in de novo stage IV breast cancer patients. Clinical trial information: NCT01015625.
Neoadjuvant BEP regimen in the treatment of extensively advanced yolk sac tumor: A single institutional experience.
Authors: Zhang Gong-Yi , Zhang Rong , Wu Ling-Ying , Li Shu-min , Li Bin 
Published: September 2018

5570 Background: Due to the highly aggressive biological behavior and early intra-abdominal spread potential of ovarian yolk sac tumor (YST), a considerable proportion of patients were inoperalbe at initial diagnosis. The aim of this study was to investigate the role of neoadjuvant chemotherapy (NACT) in this cohort of patients. Methods: Between July 1982 and December 2015, 58 patients diagnosed as YSTs were initially treated at Cancer Hospital of China Academy of Medical Science (CAMS), among which 18 were evaluated to be inoperable and received NACT. They were either too debilitated by the disease (ECOG ps≥2) to undergo a major surgery, or were with too extensively disseminated lesions to be optimally debulked. Massive ascites, pleural effusion, dyspnea, neoplastic fever, hypoproteinemia, or electrolyte disturbance were also common in these 18 patients. This cohort of patients was retrospectively reviewed. Results: One or 2 cycles of BEP regimens were prescribed to the majority of patients preoperatively. At the completion of NACT, all the 18 patients had ECOG ps≤1 . Seventeen of them (94.4%) exhibited clinical partial tumor regression and 1(5.6%) had clinical stable disease. Pathological complete tumor regression was observed in 2 (11.1%) patients, whereas the remaining 16(88.9%) had nearly complete pathological response. All these 18 patients were rendered operable at the completion of NACT, yielding a resection rate of 100%. Seventeen patients (94.4%) were cytoreduced to no macroscopic residual disease, 1 (5.6%) patient was cyto-reduced to macroscopic residual disease ≤2 cm. No major surgical complications occurred in our series. After a median follow-up of 83.5 months, 17 patients were free of recurrence. Five-year DFS and OS were both 94.4%. Fertility-sparing surgery was carried out in all the 17 patients with fertility desire, and 5 infants were delivered in 6 patients who attempted conception. Conclusions: One or 2 cycles of NACT followed by early cyto-reductive surgery offers a chance for cure in patients with extensively advanced YSTs. It allows for a more through and safe cyto-reductive surgery, improves survival outcomes, and helps pave the way for fertility-sparing surgery.
A phase I dose-escalation study of intraperitoneal (IP) cisplatin, IV/IP paclitaxel, IV bevacizumab, and oral olaparib for newly diagnosed adenxal carcinoma.
Authors: Konner Jason A. , Boucicaut Nicole N , O'Cearbhaill Roisin Eilish , Zamarin Dmitriy , Makker Vicky , Sabbatini Paul , Tew William P. , Cadoo Karen Anne , Grisham Rachel N. , Aghajanian Carol 
Published: September 2018

5572 Background: IP cisplatin (Cis) plus IV/IP paclitaxel (Tax) is a standard therapy for optimally debulked adnexal cancer. We previously demonstrated the feasibility of combining bevacizumab (Bev) with this IV/IP regimen. In this study IP Cis, IV/IP Tax, and IV Bev are combined with olaparib (Ola) as front-line therapy. Methods: Patients with newly diagnosed adnexal (ovarian, fallopian tube, or primary peritoneal) carcinoma, acceptable organ function, and KPS ≥ 70% are eligible. Patients receive 6 cycles of chemotherapy plus Bev: Tax 135 mg/m2 IV over 3 hours on Day 1, Bev 15 mg/kg IV on Day 1 (starting cycle 2), Cis 75 mg/m2 IP on Day 2, Tax 60 mg/m2 IP on Day 8. Bev is continued every 3 weeks for 21 treatments after chemotherapy is complete. In addition, Ola is given at escalating doses (50/100/200mg tabs BID) on Days 2-8 during cycles 1-6, and then 300mg BID Daily during cycles 7-22. The primary objective is to evaluate the MTD and safety/tolerability of Ola when combined with IP Cis, IV Bev and IV/IP Tax using a 3+3 dose escalation scheme. Results: Seventeen women have been treated [median age 57 (47-73)]: 8 in cohort 1 (50mg), 3 in cohort 2 (100mg) and 6 in cohort 3 (200mg). Thirteen (76%) completed all 6 cycles of IV/IP cis/tax; 2 (12%) experienced IP port malfunction (both were removed and replaced); 2 (12%) switched from IP Cis to IV carboplatin due to nephrotoxicity (via ATN and/or OCT-2 inhibition). Grade 3/4 toxicities have included: neutropenia (50%), hyperglycemia (12.5%), leukopenia (12.5%), anemia (18.8%), fatigue (12.5%), and lymphopenia (31.3%). There were 2 occurrences of related grade 3 small bowel obstructions (12.5%), during cycles 2 and 7, respectively. There were no perforations or fistulae. Maintenance therapy with Bev + Ola was generally well tolerated. Conclusions: The addition of Ola to this IV/IP regimen appears to be feasible. Ola may increase the risk of creatinine elevation and myelotoxicity. The MTD of intermittent dosing of Ola tabs concurrent with chemotherapy appears to be 200mg BID, while maintenance bev + full-dose ola at 300mg BID continuous appears feasible following IV/IP. Updated results will be presented. Clinical trial information: NCT02121990.
Circulating tumor DNA analysis using targeted sequencing of 508 clinically actionable genes in patients with high grade serous ovarian cancer.
Authors: Färkkilä Anniina , Salminen Liina , Huhtinen Kaisa , Hietanen Sakari , Grenman Seija Elisa , Lehtonen Rainer , Hynninen Johanna , Carpen Olli , Hautaniemi Sampsa 
Published: September 2018

5582 Background: The prediction of tumor chemoresponse and treatment toxicity is crucial for optimal patient care in high grade serous ovarian cancer (HGSC). We employed a targeted sequencing panel of 508 clinically annotated cancer genes to screen for actionable genetic variants in tumor tissue and ctDNA of patients with advanced HGSC. Methods: Tumor tissue, and serial plasma samples at diagnosis and during primary therapy were obtained from five patients with FIGO Stage IIIc HGSC. All patients were surgically debulked and received standard carboplatin and paclitaxel chemotherapy. DNA isolated from tumor tissue and plasma was analyzed for genetic alterations by targeted deep-sequencing of 508 previously annotated cancer genes. Somatic variants were systematically reported for alterations related to drug sensitivity and treatment toxicity, and analyzed with respect to clinical parameters and primary therapy outcomes. Results: In tumor tissues, and the corresponding pre-treatment ctDNA, oncogenic mutations were detected at a median of 13.0 and 1.6 allelic frequencies, respectively. The mutation frequency was higher, and also more unique mutations were detected in ctDNA of patients presenting with high tumor spread. Interestingly, a de-novo ctDNA MAPK1 mutation was detected in a sample taken during chemotherapy with partial response, while, no new mutations emerged in a patient with complete response. Analysis of the pretreatment plasma ctDNA revealed profiles of low and high drug sensitivities consistent with the clinical course of the patients. In two patients, increased risk profiles for treatment toxicities were identified via e.g. GSTP1. Consistently, these two patients were forced to discontinue standard therapy. Conclusions: Panel-based targeted sequencing of ctDNA identified potentially actionable mutations, and reflected tumor heterogeneity of HGSC. Further, the ctDNA gene panel annotations showed concordance with the chemoresponse- and treatment toxicity profiles, suggesting that ctDNA gene panel maybe a feasible approach to individualize treatment of HGSC patients.
Utility of multi-gene panel testing with next generation sequencing in women with endometrial cancer.
Authors: Chern Jing-Yi , Madden Nigel , Lee Jessica , Gerber Deanna , Cantor Anna , Asgari Shabnam , Martineau Jessica , Pothuri Bhavana 
Published: September 2018

5588 Background: Lynch syndrome (LS) accounts for 2-6% of all endometrial cancers (EC), and women with a germline mutation in the mismatch repair (MMR) genes ( MLH1, MSH2, MSH6, and PMS2) have an average lifetime risk of EC of 40%. As with breast and ovarian cancer syndromes, there are likely other genes implicated in the development of EC outside of the MMR genes. Multi-gene panel testing (MGPT) with next generation sequencing (NGS) allows for simultaneous analysis of numerous genes.We sought to evaluate the characteristics and incidence of gene mutations in women with newly diagnosed EC. Methods: We conducted a review of EC patients diagnosed from 6/2013 to 12/2016 who had MGPT at our institution. Demographics, family history, genetic testing results, and tumor characteristics were collected and analyzed using χ2 tests. Results: Of the 129 patients who had MGPT, 13 (10%) had a mutation and only 5 (38%) were in patients < 50 years old. The median age of EC diagnosis is 55 (31-100) years and median BMI = 27.5 (21-59). Majority were stage 1, 76 (59%) and grade 1, 50 (39%). Patients with additional primary cancers, breast or colon were not more likely to have a mutation. However, patients with a family history of gynecologic cancer were more likely to have a mutation identified, 10 (77%) mutation vs no mutation 34 (29%), p = 0.003. Among all patients tested, 8 (6%) had a mutation in LS genes, and 6 (5%) had mutations in other genes ( BRCA1, BRCA2, RAD51C, MUTYH, CHEK2); 1 (0.8%) had both MSH2 and CHEK2 mutation. Three patients had prior testing for breast cancer; 2 were found to have a BRCA1/ 2 mutation and the other was on Tamoxifen and BRCA negative. IHC was performed on 7 of 13 patients, and 5 (71%) had a loss of MMR protein expression. Variants of uncertain significance were noted in 35/129 (27%) of patients tested. Conclusions: Majority of EC patients with a mutation detected with NGS were > age 50. We identified additional new mutations in non-LS genes including, CHEK2, RAD51C, and MUYTH with MGPT. These accounted for 29% of the mutations and would have not been not detected using classic LS gene testing. These genes are implicated in breast, ovary or colon cancer. MGPT testing is feasible and useful in identifying additional actionable gene mutations.
High-intermediate risk endometrial cancer: Can gene expression predict recurrence?
Authors: Tawfik Cindy , Kim Beomjy , Londono Angelina , Katre Ashwini A. , Della Manna Deborah L , Huh Warner King , Yang Eddy Shih-Hsin , Bevis Kerri S. , Straughn John Michael , Leath Charles A. , Arend Rebecca Christian 
Published: September 2018

5591 Background: Studies have shown that adjuvant therapy increases progression free survival, but does not affect overall survival in patients with high-intermediate risk (H-IR) endometrial cancer (EMCA). Our objective was to develop a gene expression signature that may help identify H-IR EMCA patients with the highest risk of recurrence to help guide treatment strategies. Methods: Data was collected on all patients that met H-IR EMCA criteria diagnosed between 2000-2010 at UAB (n = 292). Of the patients that did not receive adjuvant treatment, 13 patients that recurred were matched to 13 patients that did not recur and original tumor was compared. Of those that recurred, 5 patients had original and recurrent tumor available for analysis. Gene expression data was collected using the Nanostring nCounter PanCancer Pathway 770 gene panel. Data was analyzed using nSolver Advanced Analysis Software. A fold change (FC) of ≥ ± 2 (p < 0.05) was used to identify genes with a significant expression difference. Results: Comparing the 13 patients that recurred to the 13 that did not, there were 5 genes with FC ≥ +2: BAIAP3, PLCB1, IL1R1, NOS3 and RAD50. There were 29 genes with FC ≥ -2; the top 3 genes with decreased expression (FC ≥ -10) were: BMP7, FGF18, WNT7A. Genes in the Cell Cycle (CC) pathway were significantly different in the patients that recurred (p = 0.02). There were 61 genes with FC ≥ +2 when comparing the original tumor to recurrent tumor; the top 3 genes with increased expression (FC ≥ 10) were: FGF18, CCND1, HIST1H3H (p < 0.05). There were 50 genes with FC ≥ -2; the top 3 genes with decreased expression (FC ≥ -1000) were: HOXA11, LEFTY2 and SFRP4. Wnt, Hedgehog, Chromatin Modification, DNA repair, TGF-β, MAPK, and CC pathways were significantly different in the recurrent samples compared to the original tumor (p < 0.05). Conclusions: Our data suggests that gene expression panels could better identify patients that warrant adjuvant treatment. The CC pathway, which is significantly different in the original tumor from those that recurred and those that did not, was further altered in the recurrent tumor samples. Additional studies are on-going to validate these findings and to further investigate DNA mutation differences in larger cohort of patients.