bluuebunny/crossref_metadata_2025_split huggingface dataset:
N0937(Alliance): Final clinical results and correlative data from the phase II trial of cisplatin (C) and the novel agent brostallicin (B) in patients with metastatic triple-negative breast cancer (mTNBC).
Authors: Moreno-Aspitia Alvaro , Liu Heshan , Hillman David W. , Rowland Kendrith M. , Geiger Xochiquetzal , Stella Philip J. , Kourlas Peter , Gross Howard M. , Karlin Nina J. , Bury Martin J. , Soori Gamini S. , Nassar Aziza , Perez Edith A. ,   Alliance for Clinical Trials in Oncology
Published: March 2020

1059 Background: Relapsed TNBC is characterized by its poor prognosis. B is a synthetic DNA minor groove binding non-cross resistant agent that is fully active against DNA-mismatch repair deficient tumor cells. C increases GSH/GST in which enhances the efficacy of B. Methods: Phase II study in pts with mTNBC. C Day 1 followed by B Day 2, repeated every 21 days. Aim: Efficacy of C + B in mTNBC. Primary endpoint: PFS at 3 mo. Secondary endpoints include ORR, duration of response (DOR), 6-mo PFS, OS and AE profile. Tertiary endpoints include assessment of baseline GSH levels, prevalence of BCRA1 mutation and pERK, and correlations with outcome. Results: Closed 3/2012. 48 pts accrued (1 ineligible pt). Median f/u 11.4 mo (6.6-14.8); 2 pts still on treatment. 47 pts evaluable for the PFS endpoint and AEs. 49% received therapy as 3rd-5th line. Median number of cycles = 4 (range 1-15). There are currently 9 confirmed responses (8 PR and 1 CR); DOR = 2.6-14.5 mo. The 3-mo PFS = 51%; 6-mo PFS = 28%; the median TTP is 3.2 mo. AE data: 75% G3/4 hematologic AE: febrile neutropenia 19%. Non-hematologic AEs included G3 (47%) and G4 (15%): G3 fatigue 17%; and no G5 non-heme AE. No correlation of GSH/GST levels with outcome was found. Among 35 pts with evaluable data, no association between BRCA1 expression and outcomes was found. pERK expression was negatively associated with 3-mo PFS, but not 6-mo PFS. Cytoplasmic pERK expression was negatively associated with tumor response (p=0.03). No significant effect of BRCA-1 or pERK expression was found on OS. Conclusions: This trial showed B + C is an active regimen, especially in heavily pretreated mTNBC pts. Correlative data demonstrated a negative association between pERK expression and outcomes. A randomized phase II trial is in development. Clinical trial information: NCT01091454.
Efficacy and safety of metronomic capecitabine and gefitinib in heavily pretreated metastatic triple-negative breast cancer.
Authors: Ranade Anantbhushan , Govind Babu Kanaka , Parikh Purvish M. , Singh Jk , Singh Manisha , Bhattacharyya Gouri Shankar 
Published: March 2020

1071 Background: Metronomic chemotherapy regimens have shown efficacy in patients with metastatic breast cancer by antiangiogenic mechanisms. When used metronomically the toxicity profile of capecitabine is low. Triple negative breast cancer is a common problem in India and developing countries. Approximately 30% of triple negative breast cancer express EGFR and its mutation. Methods: Since October 2003 to December 2011 we objectively tested response rates, clinical benefit, and safety of gefitinib and capecitabine administered with a metronomic schedule of 500 mg thrice daily in heavily pretreated metastatic breast cancer patients with gefitinib 250 mg once daily. 300 patients were screened for EGFR expression. Among 85 enrolled patients with EGFR positivity, 76 were evaluable. ECOG performance status (PS) was 0-2, median age 52 years (range 36-65), bone plus visceral metastasis in 40% of patients. Rest had only visceral metastasis. All the patients were pretreated with anthracyclines and taxanes. The combination was administered for a median duration of 32 weeks (range 12-166). Results: We observed 18 partial responses (PR: 24%), 42 (55%) stable disease (SD). Median time to progression was 53 weeks, (95% CI, range 12-166 weeks). Safety of metronomic capecitabine with gefitinib was excellent. Neither grade 2-4 haematological or clinical side effects were recorded. Only 12 patients experienced grade I (WHO) hand-foot syndrome. Conclusions: Treatment with metronomic capecitabine and gefitinib was effective and minimally toxic in heavily pretreated breast cancer patients.
Etirinotecan pegol (EP) target-specific pharmacodynamic (PD) biomarkers measured in circulating tumor cells (CTCs) from patients in the phase III BEACON study in patients with metastatic breast cancer (mBC).
Authors: Hoch Ute , Fry Dennis G. , Chia Yen Lin , Caygill Katie , Hannah Alison L. , Perez Edith A. , Cortez Javier , Awada Ahmad , O'Shaughnessy Joyce , Twelves Christopher , Rugo Hope S. , Im Seock-Ah , Xu Binghe , Anderes Kenna Lynn , Davis Darren W. 
Published: March 2020

1087 Background: EP is a unique topoisomerase 1 inhibitor that provides continuous exposure to SN38. EP demonstrated a 29% overall response rate in patients with mBC, leading to a phase III global BEACON study in patients with mBC. CTCs in patient blood samples provide a minimally invasive approach to detect PD markers of drug activity. We developed quantitative multiplex immunofluorescent assays to measure target-specific PD biomarkers for EP in CTCs isolated pre- and post-treatment. Methods: Assays for Top1, Top2, g-H2Ax, Rad51, ABCG2, and Ki-67 were developed using control (0.1% DMSO) and drug-treated (SN38, 10 uM) tumor cell lines (HCT116, MCF7, A549, SKBr3) and PBMCs from healthy donors. The optimal antibody for each biomarker was then multiplexed in a panel with antibodies against cytokeratin, CD45 and DAPI for phenotypic identification of CTCs. For analysis of BEACON pts, serial 7.5 mL whole blood samples were drawn and shipped ambient to Apocell (Houston, TX) for further processing. PBMCs were separated and CTCs were isolated using ApoStream technology. CTCs were stained for PD markers and analyzed using an iCys laser scanning cytometer equipped with image analysis software. Results: Antibodies bound to tumor cells showed staining confined to the nucleus (Top1, Top2, g-H2AX, Ki-67) or membrane (ABCG2), exhibited defined peak separation from their isotype controls, and signal strength correlated with cellular expression of high and low levels of markers. To date, ~ 80% of BEACON pts consent to participate in the CTC sub-study. As of 30 Oct 2012, data from 167 pre-dose blood samples from BEACON pts were available. 99% of blood samples were successfully processed. 93% had detectable CTCs, yielding a median of 216 CTCs (range: 7.5-14816). Staining was positive for Top1, Top2, g-H2Ax, Rad51, ABCG2, and Ki-67 in 82%, 89%, 16%, 53%, 31%, 52% of samples, respectively. Conclusions: EP target-specific pharmacodynamic biomarkers can be reliably measured in CTCs isolated from patients participating in BEACON. Sample collection and analysis of pre- and post-treatment samples is ongoing. Clinical trial information: NCT01492101.
Integrating molecular profiling into cancer treatment decision making: Experience with over 35,000 cases.
Authors: Gatalica Zoran , Millis Sherri , Chen Sting , Basu Gargi Dan , Wen Wenhsiang , Paul Les , Bender Ryan P. , Von Hoff Daniel D. 
Published: March 2020

11001 Background: Molecular profiling of both common and rare cancer types provides for the identification of actionable targets for chemotherapy with many unexpected associations. Methods: Caris Life Sciences database of >35,000 profiled cancers was reviewed for well-established driver gene mutations and copy number alterations, and protein expression patterns that are relevant for selection of targeted therapy. Based on the published literature, these tumor characteristics were then associated with potential benefit or no benefit to the specific therapeutic agents. All relevant published studies were evaluated using the USPSTF grading scheme for study design and validity. Assay methodologies included sequencing (Sanger, pyrosequencing), PCR, FISH, CISH, and immunohistochemistry. Results: All common malignancies (10 most common cancer types in men and women) and 10 rare cancer types were well represented (minimum of 100 cases in each individual cancer type). Well established driver mutations and protein expression in common cancers were all identified with expected frequencies (e.g. HER2 amplification in breast, PIK3CA mutations in ER+ breast cancer, EGFR mutations in NSCLC, etc.). Importantly, unexpected new and potentially actionable targets were identified in common (e.g., 6.7% HER2 amplification in NSCLC, 1.6% KRAS mutation in prostatic adenocarcinoma) and rare cancers (e.g., 8.3% ALK alteration in soft tissue sarcomas, 10.5% c-MET and 26.4% EGFR gene amplification in melanomas, 16.3% KRAS mutation in cholangiocarcinomas, 10% AR expression in STS), as well in cancers of unknown primary site (approximately 4% of all tested cases). Conclusions: This review of the large referral cancer profiling database provided an unparalleled insight in the distribution of common and rare genetic and protein alterations with direct and potential treatment implications. Numerous targets were discovered that had a potential to be treated by the conventional chemotherapy as well as targeted therapy not usually considered for the cancer type. Comparison between an individual patient tumor profile and database for the matched cancer type provides additional level of support for targeted treatment choices.
The genetic landscape of clinical resistance to RAF inhibition in melanoma.
Authors: Van Allen Eliezer Mendel , Wagle Nikhil , Carter Scott L. , Sucker Antje , Farlow Deborah Norman , Hodis Eran , Taylor-Weiner Amaro , Berking Carola , Egberts Friederike , Hassel Jessica Cecile , Gogas Helen , Gutzmer Ralf , Goldinger Simone M. , Loquai Carmen , Ugurel Selma , Zimmer Lisa , Gabriel Stacey B. , Getz Gad , Garraway Levi A. , Schadendorf Dirk ,   DeCOG
Published: March 2020

11009 Background: Although single-agent RAF inhibition has proved effective in metastatic BRAFV600-mutant melanoma, most patients relapse and some are intrinsically resistant. While several genetic resistance effectors have been identified, a comprehensive assessment of the genetic resistance spectrum in a large patient cohort may further inform resistance patterns and treatment strategies. Methods: Pre-treatment and post-relapse biopsies were obtained from BRAFV600melanoma patients treated with vemurafenib or dabrafenib. Whole exome sequencing of tumor and normal samples was performed to identify exome-wide mutations, insertion/deletions, and chromosomal copy number alterations. Since somatic allelic fraction comparisons across treatment time points must account for variable stromal admixture between biopsies, novel algorithms were applied to impute purity and tumor cell ploidy, thus determining the “cancer cell fraction” (CCF) of each alteration. Those with enriched CCF in post-relapse samples were nominated as potential resistance effectors. Results: 30 patients (towards a goal of 77) were sequenced to a mean depth of 145-fold coverage. In acquired resistance patients (on drug ≥ 12 weeks, n=18), NRAS Q61R (28%) and BRAF amplifications (6%) were observed. The remaining patients had multiple clonally enriched alterations in the post-relapse tumors that may drive resistance, including MEK1 mutations at residues previously noted in an in vitro mutagenesis screen for vemurafenib resistance. In the intrinsic resistance cohort (on drug < 12 weeks, n=12), multiple putative resistance mutations not previously observed in the setting of acquired resistance were identified. Conclusions: In addition to reported genetic resistance mechanisms, we identified new MEK1 mutations in resistant samples. For the majority of patients (67%) without events in these genes, computational algorithms identified new candidate drivers of RAF inhibitor resistance. Alterations that predict intrinsic or acquired resistance may also inform new approaches to melanoma therapy. Future studies incorporating longitudinal biopsies and genetic profiling will underpin a robust assessment of clinical resistance in melanoma and other cancers.
Fusion transcript discovery in formalin-fixed paraffin-embedded human breast cancer tissues and its relation to tumor progression.
Authors: Ma Yan , Ambannavar Ranjana , Stephans James , Jeong Jennie , Dei Rossi Andrew , Morlan John , Liu Mei-Lan , Levy Samuel , Baker Joffre , Sinicropi Dominick , Qu Kunbin 
Published: March 2020

11018 Background: While several recently discovered gene fusions already play an important role in personalized cancer treatment, many cancer gene fusions remain to be discovered. Next generation sequencing has enabled identification of many rare gene fusion events in fresh or frozen solid tumors. There is a need to detect gene fusions in transcriptomes of formalin-fixed paraffin-embedded (FFPE) tumor tissue, for which there is long-term clinical outcome data. We therefore sought to develop bioinformatics methods to detect fusion transcripts in FFPE tissue and to characterize their association with clinical outcomes. Methods: RNA sequencing libraries were created and sequenced from tumor biopsy tissues (Plos One 2012 7(7): e40092) of two ER+ breast cancer cohorts consisting of 136 and 77 patients, for which clinical outcomes were available. The fusion junctions were nominated by the RNA-seq aligner GSNAP and further filtered to consider discontinuous expression patterns at exon/intron levels. Results: A total of 108 candidate fusion transcripts were detected and RT-PCR assays confirmed 89% of the top ranking fusion transcript candidates. The majority (82%) of identified fusion gene partners are listed in the COSMIC database of known cancer sequence variations. Of note, several patients expressed multiple fusion transcripts that are significantly associated with tumor progression (P<0.001), including genes associated with cell proliferation and cellular metabolism. Furthermore, these patients also harbored inter-chromosomal gene fusions. It is noteworthy that several gene fusions were present in multiple patients. In one of these recurrent fusions the estrogen receptor gene acts as the fusion pair donor. Conclusions: Novel bioinformatics approaches developed here demonstrate the ability to detect fusion transcripts as biomarkers from archival FFPE tissues that associate with breast cancer progression. Some gene fusions were common in multiple patients and deserved further study.
ROR1 mRNA expression in EGFR-mutant non-small-cell lung cancer (NSCLC) patients (p) with the T790M mutation: A potential therapeutic target.
Authors: Karachaliou Niki , Drozdowskyj Ana , Costa Carlota , Molina-Vila Miguel Angel , Gimenez Capitan Ana , Vergnenegre Alain , Massuti Bartomeu , Moran Teresa , Majem Margarita , Felip Enriqueta , Carcereny Costa Enric , Garcia-Campelo M. Rosario , Viteri Ramirez Santiago , Heidecke Cordula Nicole , Estrada-Tejedor Roger , Teixido Jordi , Bivona Trever Grant , Giannikopoulos Petros , Ono Mayumi , Rosell Rafael ,   Spanish Lung Cancer Group
Published: March 2020

11027 Background: Progression-free survival (PFS) is short in NSCLC driven by EGFR mutations treated with erlotinib alone, due to crosstalk with other signaling pathways that can cause secondary dependency. ROR1 knockdown inhibited the growth of NCI-H1975 cells (with EGFR L858R and T790M mutations). A pro-survival function for ROR1/MEK/ERK signaling has been demonstrated, with cooperation with AKT. In a subset of 95 p in the EURTAC trial (clinicaltrials.gov NCT00446225), 65% had pre-treatment T790M mutations. We have assessed ROR1 expression in 45 of these 95 p. Methods: The T790M mutation was determined by Taqman with a PNA to inhibit amplification of the wild-type (wt) allele. Tumor samples were run in octuplicates; this method can detect 1 mutated allele among 10,000 wt alleles. ROR1 mRNA expression was examined by quantitative RT-PCR and categorized by terciles. p were classified as having low/intermediate or high ROR1 expression. The impact of ROR1 expression on outcome was examined in all 45 p and in a subset of 15 p with concomitant T790M mutations. Results: Median age 65; 68.9% female; 57.8% never-smokers; 95.6% ECOG PS <2; 91.1% adenocarcinoma; 68.9% exon 19 deletion. No differences in baseline characteristics were observed according to ROR1 expression levels. 24 p (53.3%) were treated with erlotinib and 21 p (46.7%) with chemotherapy. 10 (41.7%) erlotinib-treated p and 6 (28.6%) chemotherapy-treated p had ROR1 mRNA levels in the top tercile. Among erlotinib-treated p, response rate was 40% for p with high ROR1 levels vs 71.4% for p with low/intermediate levels (P=0.0918). Among chemotherapy-treated p, only p with low ROR1 levels responded (6.7%). PFS was 11.8 months (m) for erlotinib-treated p with low/intermediate ROR1 levels vs 5.8 m for p with high levels. PFS for chemotherapy-treated p was 5.6 and 9 m, respectively (P=0.033). Among 15 erlotinib-treated p with concomitant T790M mutations, PFS was10.8 m for p with low/intermediate ROR1 levels vs 2.7 for p with high levels (P=0.0174). Conclusions: HighROR1 expression significantly limits PFS in p with T790M mutations. ROR1-directed therapies can enhance the efficacy of erlotinib in EGFR-mutant NSCLC p overexpressing ROR1. Clinical trial information: NCT00446225.
Low cytokeratin- and low EpCAM-expressing circulating tumor cells in pancreatic cancer.
Authors: Adams Daniel , Tsai Susan , Makarova Olga V. , Zhu Peixuan , Li Shuhong , Amstutz Platte T. , Tang Cha-Mei 
Published: March 2020

11046 Background: To date, detecting circulating tumor cells (CTCs) in the peripheral blood of pancreatic patients using standard immuno-capture techniques has met with limited success. As pancreatic cancer is prone to metastasize at distant sites, and therefore should have high numbers of CTCs, it is possible that immuno-capture methods are not suitable for this disease. Using a microfiltration approach, we show that CTCs are present in the peripheral blood in over 75% of pancreatic cancer patients, and that two distinct subtypes can be identified. Methods: Pancreatic patient samples were provided by Medical College of Wisconsin, Milwaukee, WI. CellSieve microfilters, with precision 7 micron diameter pores distributed in uniform arrays were employed. 7.5 mL of whole blood was diluted in pre-fixation solution and filtered through CellSieve microfilters. CTCs collected by this size exclusion technique were fixed, permeabilized, and stained with DAPI, an antibody cocktail against cytokeratin 8, 18 and 19 (FITC), EpCAM (PE), and CD45 (Cy5). CTCs, defined as cytokeratin positive and CD45 negative, were found in two distinct subtypes. One subtype had the “classic” characteristics of a CTC, with high EpCAM and cytokeratin expression, identifiable cytokeratin filamentation, and a cancer-like nuclear structure. The second subtype is indicative of a CTC undergoing epithelial-mesenchymal transition (EMT), with low or no EpCAM, weak cytokeratin expression, and a smooth oval nuclear structure. Results: The “classic” CTCs were found in ~20% (n=40) of patient samples. The EMT-like CTCs were found in ~75% of the same patient cohort. Neither cell was present in any healthy subjects (n=30). EMT-like CTCs consistently lacked EpCAM expression and commonly presented as multi-cell clusters, or microemboli, in ~40% of the cases. Conclusions: We show that two distinct CTC subtypes circulate in the blood of most pancreatic patients. The low expression of cytokeratin and EpCAM of the EMT-like subtype implies that immuno-capture based CTC isolation methods have limited utility for pancreatic cancer. Further, this subtype provides a useful strategy for tracking pancreatic CTCs over the course of treatment.
The prognostic impact from the difference of surgical procedure after ipsilateral breast cancer recurrence.
Authors: Yoshida Atsushi , Arima Nobuyuki , Nakatsukasa Katsuhiko , Okumura Yasuhiro , Iwase Takuji , Shien Tadahiko , Masuda Norikazu , Tanaka Satoru , Tanabe Masahiko , Tanaka Takehiro , Komoike Yoshifumi , Taguchi Tetsuya , Nishimura Reiki , Inaji Hideo , Yamauchi Hideko , Ishitobi Makoto 
Published: March 2020

1106 Background: Mastectomy is the current standard of surgical procedure for ipsilateral breast cancer recurrence (IBTR). However, there is little evidence about a prognostic impact of surgical procedure after IBTR, due to small number of incidence of IBTR. Methods: A total of 271 consecutive patients who had histologically confirmed IBTR without distant metastases and underwent definitive surgery for the IBTR between 1989 and 2008 were included from eight institutions as a scientific research from the Japanese Breast Cancer Society. Distant Disease free survival (DDFS) rates were calculated by the Kaplan-Meier method. Univariate analysis was performed using the log rank test and multivariate analysis by Cox's proportional hazard model. Results: Of the 271 patients, 149 patients (55%) underwent lumpectomy and 122 patients (45%) underwent mastectomy after IBTR. One hundred thirty four patients (49%) did not receive radiation therapy after initial lumpectomy (52% in lumpectomy patients and 47% in mastectomy patients). The median follow-up period from definitive surgery for IBTR was 55 months. Seventy-six patients (28.2%) relapsed after IBTR (23.7% of lumpectomy patients, 33.6% of mastectomy patients). In comparing groups by type of surgery, patient and tumor demographics in each group were significantly less positive HER2 status and smaller tumor size of IBTR, and more receiving adjuvant endocrine therapy and less adjuvant chemotherapy for IBTR in lumpectomy patients compared with mastectomy patients. On univariate analysis, lumpectomy group was significantly longer DDFS than mastectomy group (p=0.012), but this difference was not appeared on multivariate analysis (p=0.35). Furthermore, only using small IBTR (<2cm) population, this difference was not appeared (p=0.71). On multivariate analysis, the time intervals from initial surgery to IBTR (<5years) (HR, 1.93; 95%CI, 1.01-3.67; p=0.047) and lymphovascular invasion of the IBTR (HR, 2.31; 95%CI, 1.18-4.52; p=0.015) were independent predictive factor for poor DDFS. Conclusions: Our study suggests that the type of surgical procedure after IBTR does not affect DDFS. Further analyses are needed. (UMIN-CTR number UMIN000008136).