tbuckley/cabot-search huggingface dataset:
Validation of a new diagnostic platform for prostate cancer using expression profiling of small non-coding RNAs.
Authors: Winnie Wang, Tucker Conklin, Ilija Aleksic, Igor Sorokin, Hugh A.G. Fisher, Ronald P. Kaufman, Badar Mian, Brian McNeil, Andrew Winer, Raavi Gupta, A. Gregory DiRienzo, Martin Tenniswood
Journal: Journal of Clinical Oncology (2018)

e24151 Background: Confirmation of prostate cancer in men with elevated PSA and suspicious digital rectal exams currently requires a core needle biopsy, which is associated with risks such as infection, among others. The current dilemma associated with prostate cancer diagnosis is the lack of an accurate pre-biopsy screening methodology, resulting in unnecessary biopsies. We describe a non-invasive screening test that interrogates the sncRNAs profiles isolated from urinary exosomes that, in combination with a novel statistical algorithm, accurately classifies patients into those that have prostate cancer versus those that do not. Methods: Urine collected from men with biopsy confirmed prostate cancer status (107 with cancer vs 21 controls without cancer) was used to identify informative sncRNAs Profile specific for prostate cancer using Affymetrix 4.0 arrays, which probes for > 6600 sncRNAs. Urine exosomal RNA, purified from a subsequent patient cohort with unknown cancer status, were screened on a customized platform that interrogates the expression of the top ~120 informative sentinel sncRNAs. The expression profile was then analyzed using a statistical classification algorithm to generate miR-PDx score (prostate diagnostic score). Importantly, the algorithm requires no a priori knowledge of the biological function of the informative sncRNA entities. Results: In a small blinded study of 128 patients designed to mimic prospective prediction of disease status, miR-PDx score generated from the sentinel sncRNAs screening platform correctly identifies patients with prostate cancer with a specificity of 95% (20/21) and a sensitivity of 99% (106/107) in the testing cohort. Conclusions: Implementation of the miR-PDx as an initial screen for prostate cancer, utilized in place of PSA screening would have a major impact on the medical economic costs by substantially reducing the number of unnecessary core needle biopsies. This urine test may also provide a powerful method for longitudinal monitoring of disease stability among men who forego core needle biopsy after initial consultation, and enter active surveillance protocols.
Tappas: An adaptive enrichment phase 3 trial of TRC105 and pazopanib versus pazopanib alone in patients with advanced angiosarcoma (AAS).
Authors: Robin Lewis Jones, Steven Attia, Cyrus R. Mehta, Lingyun Liu, Kamalesh Kumar Sankhala, Steven Ian Robinson, Vinod Ravi, Nicolas Penel, Silvia Stacchiotti, William D. Tap, Delia Alvarez, Richard Yocum, Charles P. Theuer, Robert G. Maki
Journal: Journal of Clinical Oncology (2017)

TPS11081 Background: AAS is an aggressive soft tissue sarcoma (STS) of endothelial cell origin with an expected median overall survival of 8-12 months. Pazopanib (P) is approved for treatment of advanced STS following progression on chemotherapy. In a retrospective study of 40 AAS patients treated with single agent P the median PFS was 3.1 months and median OS 9.9 months with no complete responses. Endoglin is an essential angiogenic receptor expressed on AAS that is upregulated following VEGF inhibition, and TRC105, an endoglin antibody, given with P produced durable complete responses in AAS patients with median PFS of 5.6 months in refractory patients including those receiving prior P. The TAPPAS trial is the first randomized Phase 3 trial performed in AAS, and was initiated following protocol assistance from the EMA and Special Protocol Assessment from the FDA. Methods: TAPPAS is a randomized multicenter study of TRC105/P vs P alone in the United States and Europe that is actively enrolling cutaneous and non-cutaneous AAS patients and incorporates an adaptive enrichment design. Key inclusion criteria: 0, 1 or 2 prior lines of therapy, ECOG ≤ 1. Primary endpoint is PFS and secondary endpoints include ORR and OS. The initial sample size of 124 patients, followed until 95 PFS events, provides more than 80% power to detect a hazard ratio of 0.55. At the time of interim analysis, projected to occur upon the occurrence of 40 events in approximately 70 patients, the result will be classified as belonging to either the favorable, promising, enrichment or unfavorable zones, based on conditional power. The sample size and PFS events will be unchanged in the favorable and unfavorable zones, and will be increased to a total of 200 patients followed for 170 PFS events in the promising zone. The trial will enroll 100 additional patients, with cutaneous disease only, in the enrichment zone and will follow them until 110 events are observed in the total cutaneous population. An independent DMC will follow the trial for safety and futility. The adaptive design requires the enrollment of fewer patients, preserves type-1 error, and protects power to detect a clinically meaningful survival benefit. (NCT 02979899). Clinical trial information: NCT02979899.
Role of PD-L1 expression in triple-negative breast cancer stem cells.
Authors: Massimo A. Di Nicola, Lorenzo Castagnoli, Valeria Cancila, Sandra Romero, Simona Faraci, Claudia Chiodoni, Giovanna Talarico, Giovanni Fucà, Tatiana Volpari, Mario Paolo Colombo, Marilena V Iorio, Elda Tagliabue, Claudio Tripodo, Sabina Sangaletti, Filippo G. De Braud, Serenella Pupa
Journal: Journal of Clinical Oncology (2018)

12081 Background: Triple negative breast cancer (TNBC) is characterized by poor prognosis, lack of specific-targeted agents and is in need of new therapeutics. Immune checkpoint blockers have shown significant efficacy against various tumors, including TNBC. Recent evidences suggested that PD-L1 expression on cancer stem cells (CSCs) might induce immune evasion. We have investigated the role of PD-L1 expression on TNBC stem cells (TNBCSCs). Methods: Formalin-fixed, paraffin embedded (FFPE) samples from TNBC patients treated at our Institution and at Fundación Mexicana de Fomento para la Prevención Oportuna del Cáncer de Mama, were analyzed for PD-L1 and immune gene pathways expression and for cancer stemness features. TNBC cell lines (MDAMB231, MDAMB468, SUM149, SUM159, and BT549) and syngeneic high-grade mammary murine models (SN25A) were used to elucidate the mechanisms behind PD-L1 implication in TNBC stemness. Results: FFPE tumor samples from a total of 158 TNBC patients were sorted according to the high (79 cases; 50%) and low (79 cases; 50%) median level of PD-L1 transcript. In our series, PD-L1 expression was associated with the stemness-score (p = 0.026) and with the up-regulation of CSC-related WNT signaling pathway. Digital fluorescence microscopy analyses revealed a preferential PD-L1 expression in ALDH+ and CD44+ cells. This data was confirmed in vitro, being the significant and constitutive higher expression of PD-L1 associated with ALDH+ and CD44-high TNBCSC subsets but not with their neg/low expressing counterparts. Also, PD-L1+ TNBC cells had a significantly higher mammosphere-forming efficiency than PD-L1- TNBC cells. On the same line, XAV-939, a specific inhibitor of WNT, significantly impaired PD-L1 expression indicating their active cross-talk in sustaining stemness feature. In vivo, we observed that in syngeneic murine high grade mammary tumor models, Sca+ and PD-L1Hightumor elements took close contact with CD8 and CD3 T cells suggesting a direct interaction between CSCs and lymphoid cells. Conclusions: Our study shows that TNBCSCs up-regulate PD-L1 through the activation of the WNT pathway. Unveiling this new mechanism of TNBC immune modulation, we suggest of targeting the WNT pathway to overcome TNBC immune-evasion.
Opportunities for provider education in the use and interpretation of liquid biopsy.
Authors: Christine Elaine Lee, Ashley M Wells, Neil Sheehy, Rebecca J Nagy, Richard B. Lanman
Journal: Journal of Clinical Oncology (2018)

11017 Background: Increasingly affordable comprehensive genomic profiling (CGP) has exponentially expanded the amount of data available to oncologists, and liquid biopsy has made CGP more accessible. Given comprehensive liquid biopsy has only been commercially available since 2014, and the average age of a practicing oncologist is 52, liquid biopsy education was not a component in the majority of providers’ formal training. Data from both community and academic settings suggests physicians’ confidence around interpretation of genomic tests may play a critical role in clinical decision making. Physician knowledge is also a strong predictor of physicians’ anticipated use of testing. Although liquid biopsy has gained in popularity and acceptability, little is known about providers’ confidence in interpreting these results. Methods: Between 1/2016 and 1/2018, we prospectively documented provider calls with test-related questions. We then attempted to characterize major themes in provider inquiries related to genomic testing and liquid biopsy. Results: 811 consecutive provider contacts were recorded. Of those, 434 included completed survey data. Approx. 75% of these contacts originated from community-based practices and almost 70% of contacts were from providers who had ordered 5 or less tests. Of genomic questions, 49% were specific to liquid biopsy and most providers had ≥ 2 questions. Common questions about cfDNA results included: Is there enough mutation present to warrant treatment? (13%), What is the ideal timing of testing? (11%), Could this mutation be hereditary? (11%), What does mutant allele fraction mean? (8%). Interestingly, over 25% of all providers surveyed had questions regarding basic genomic principles not specific to liquid analysis. The remainder of questions varied, but many were related to NGS technology. Conclusions: Providers in both community and academic centers sought genomics support when interpreting a comprehensive liquid biopsy result. Questions regarding general genomics and liquid biopsy were asked at similar rates in this analysis. Though liquid analysis is an emerging field, our data suggests there is still a need for basic genomic education across provider types.
A multicenter retrospective analysis of nivolumab in advanced melanoma during the French Temporary Authorization Use.
Authors: Sandrine Monestier, Stéphane Dalle, Laurent Mortier, Caroline Dutriaux, Sophie Dalac-Rat, Nicolas Meyer, Marie Thérèse Leccia, Sandrine Mansard, Jean-Philippe Lacour, Philippe Saiag, Patrick Combemale, Bernard Guillot, François Skowron, Pascal Joly, Nathalie Beneton, Ewa Hainaut, Nabahet Ameur, Emilie Varey, Amir Khammari, Brigitte Dreno
Journal: Journal of Clinical Oncology (2018)

e21598 Background: Nivolumab was the first anti-PD1 therapy to receive a European marketed authorization for the treatment of advanced (unresectable or metastatic) melanoma. To collect and evaluate real-life clinical data and use of nivolumab, an observational retrospective study (CA 209-555) was conducted in patients with advanced melanoma treated during the French Temporary Authorization Use (ATU) with 2-years of follow-up (NCT03325257). Methods: Data from 342 patients included in the ATU program by 17 participating French centers were collected via the RIC-Mel database. Demographic characteristics, efficacy and safety of nivolumab (3mg/kg every 2 weeks) were assessed in patients who received at least one dose, between Sept. 2014 and Dec. 2015. Results: Patients were most commonly diagnosed with cutaneous melanoma (70%); the median age was 66 years, 61% were male, 34.5% had BRAF V600 mutations and 84% had ECOG performance status of 0 or 1. The majority of patients (71%) had stage IV M1c (7th AJCC) and approximatively 50% had > 2 metastatic sites. Most patients (82.7%) were pretreated with ≥ 1 line of therapy; and the mean nivolumab treatment duration was 9.7 months. One and 2-year overall survival (OS) rates were 55.7 and 38%, respectively, with a median OS of 14.3 months (95% CI, 12.1-18.6). The overall response rate (ORR) was 32% with a 11.9% complete response rate and a disease control rate of 53%. Of note, subgroup analysis in older patients ( > 75 years) and those with brain metastases showed 39% and 23% ORR, respectively; and 2-year OS rates of 38% and 25%, respectively. The incidence of grade ≥3 adverse events (AE) was 14%, the most frequent being gastrointestinal (3.5%) and pulmonary (3.5%). Discontinuation of nivolumab due to AEs occurred in 8% of patients. Conclusions: Results from this first french real-life analysis confirm efficacy and safety observed with Nivolumab in phase 3 clinical studies in patients with treatment-naive (CA209-066) and pre-treated (CA209-037) advanced melanoma. Moreover, they provide additional information on subgroup populations with high unmet need that are typically excluded from clinical trials, including older patients and those with brain metastases.
Prevalence of <i>EGFR</i> gene fusions in a large cohort of Chinese patients with non-small cell lung cancer (NSCLC).
Authors: Chunwei Xu, Wen xian Wang, Yu Chen, You-cai Zhu, Yueping Liu, Hong Wang, Wu Zhuang, Xiaohui Chen, Yun-jian Huang, Jinhuo Lai, Meiyu Fang, Zhenghua Zhang, Ye Tao, Shuguang Xu, Xue Qian, Hongyu Zhao, Jing Ma, Gang Chen, Tangfeng Lv, Yong Song
Journal: Journal of Clinical Oncology (2018)

e13538 Background: Currently, with the advances in detection techniques, such as next generation sequencing (NGS), more and more rare or atypical EGFR mutations had been identified. Such as exons 18-25 kinase domain duplications (KDD) and EGFR fusions (EGFR-RAD51 or EGFR-PURB), the importance of EGFR signaling in the pathogenesis of lung cancer and the efficacy of EGFR-TKI treatment had been demonstrated. The aim of this study was to evaluate the prevalence of EGFR fusions in Chinese NSCLC patients, and to study the association between these molecular alterations and clinicopathological characteristics in these patients. Methods: A multicenter study in China was initiated from February 2014, and NSCLC patients have been enrolled as of December 2017. A total of 2410 patients with NSCLC (non-squamous/squamous =2061/349) were screened by using next-generation sequencing (NGS)-based 381 genes panel assay for detecting EGFR fusions. Results: Of this entire cohort, just two (0.08%) patients were identified with an EGFR-SEPT14 fusion and an EGFR-RAD51 fusion. These two patients was that a 62-year-old never smoking female, who was diagnosed with lung adenocarcinoma and a 48-year-old male with a 32 pack-year smoking history, who was diagnosed with lung adenocarcinoma. The first patient: EGFR-SEPT14 fusion driven NSCLC responding to icotinib, there were no treatment-related adverse events, including abnormal hepatic, renal function, gastrointestinal reactions, rashes, and cordis damage. Thus far, after several months, the disease is stable and she is continuing treatment with icotinib; The second patient: EGFR-RAD51 fusion driven NSCLC responding to erlotinib will be presented. The patient was considered to have a partial response (PR) to erlotinib. During treatment with erlotinib, no abnormal hepatic and renal function occurred. Conclusions: The frequency of EGFR fusions in Chinese patients with NSCLC is extremely rare (0.08%). The NGS assay provides a novel diagnostic tool. In the future, we can explore differences in the acquired mechanism underlying EGFR TKIs between sensitive EGFR mutations and other uncommon variant NSCLC patients.
Association of race, reproductive factors, and lifestyle factors with tumor subtype defined by Oncotype DX recurrence score.
Authors: Halei Benefield, Katherine Elizabeth Reeder-Hayes, Stephanie B. Wheeler, Lisa A. Carey, Andrew F Olshan, Melissa Troester
Journal: Journal of Clinical Oncology (2018)

e13581 Background: A variety of patient factors have been shown to affect breast cancer risk and prognosis. Recent studies have suggested that these factors may also be associated with quantitative genomic measures. We investigated associations between race, reproductive factors, and lifestyle factors and 21-gene Recurrence Score (RS) from the Oncotype DX test. Methods: We retrospectively reviewed medical histories, pathology reports, and Oncotype DX results of patients with stage I or II estrogen receptor (ER) positive, HER2 negative breast cancer in the population-based Carolina Breast Cancer Study Phase 3 (2008 – 2013). We used linear binomial regression to estimate the prevalence differences (PD) of breast cancer risk factors among tumors categorized as low (RS < 18), intermediate (RS 18 – 30), and high risk (RS > 30). Association between race and RS was adjusted for age and stage, all other associations were adjusted for age, stage, and race. Hormone therapy (HT) was examined only in postmenopausal women. Results: Of 603 total patients, 322 (53%) had low risk, 226 (37%) had intermediate risk, and 60 (10%) had high risk tumors. 213 (35%) were African American (AA). Median age at diagnosis was 51 years (range 28 – 74). AA women had a significantly higher prevalence of high versus low risk tumors (PD 8.35%, 95% CI 0.19%, 16.5%). Smoking was associated with a significantly lower prevalence of intermediate versus low risk tumors (PD -12.4%, 95% CI -20.6%, -4.2%). Among postmenopausal women (n = 347) HT was associated with a significantly higher prevalence of intermediate versus low risk tumors (PD 12.6%, 95% CI 1.0%, 24.2%). No significant associations were found for age, body mass index, waist-hip ratio, alcohol use, oral contraceptive use, parity, lactation, or menopausal status. Conclusions: Consistent with prior reports, AA women present with high risk tumors more frequently than non-AA women. Smoking and HT, known to modulate estrogen metabolism, may impact the RS through ER gene expression, which is included in the RS algorithm. Additional tumor data, such as quantitative ER, may help interpret these findings. Future research should evaluate whether these exposures modify the predictive value of RS.
Adjuvant versus salvage radiation therapy in men with high risk features after radical prostatectomy: Survey of North American genitourinary expert radiation oncologists.
Authors: Shearwood McClelland, Kiri A. Sandler, Catherine Degnin, Yiyi Chen, Timur Mitin
Journal: Journal of Clinical Oncology (2018)

e17078Background: Management of patients with high-risk features after radical prostatectomy is controversial. Adjuvant radiation therapy (RT) improves survival when compared to no treatment and is...
Phase I/II trial of pembrolizumab(P) and vorinostat(V) in recurrent metastatic head and neck squamous cell carcinomas (HN) and salivary gland cancer (SGC).
Authors: Cristina P. Rodriguez, Vicky Wu, Jenna M. Voutsinas, Jonathan P Fromm, Venu Gopal Pillarisetty, Sylvia Lee, Rafael Santana-Davila, Bernardo H. L. Goulart, Christina S. Baik, Laura Quan Man Chow, Keith D. Eaton, Renato G. Martins
Journal: Journal of Clinical Oncology (2018)

6025 Background: Epigenetic modification is increasingly recognized as a mechanism for tumor immune evasion. This clinical trial explored the activity of P with the HDAC inhibitor V in HN and SGC. Methods: Patients(pts) with progressing incurable HN and SGC with ECOG ≤1, no prior immunotherapy, RECIST 1.1 measurable disease, and normal organ function were eligible. Controlled brain metastases were permitted. PDL1 expression was not an eligibility criterion. P 200mg was given IV q21 days (d) , with V 400mg QD PO, 5d on and 2d off, both started on d1 of each cycle. The primary endpoint was safety according to CTCAE v. 4.03. Secondary endpoints were RECIST 1.1 objective response rates and biomarker collection. Results: From 11/2015 to 8/2017, 25 HN and 25 SGC pts were enrolled. Among all 50 pts, median age was 61 (range 33-86) yrs, 39 (78%) were male, 21(62%) were never smokers, 27 (54%) had ECOG 0. In HN, primary sites were oropharynx 17 (68%), nasopharynx 4 (16%), oral cavity 1(4%), skin 2 (8%) and unknown 1 (4%). Thirteen(52%) were p16+ oropharynx HN. SGC histologies were adenoid cystic (ACC) 12(48%), acinic cell (AciC) 3(12%), mucoepidermoid 3(12%), ca ex. pl. adenoma 2(8%). There was 1(4%) pt each with adenocarcinoma, salivary duct, epithelial-myoepithelial, clear cell, parotid lymphoepithelioma-like(LEL-C) carcinoma. The median (range) treatment cycles received in HN was 6 (1-33), and SGC 9 (1-34). Adverse events regardless of cause (AEs) in all pts were: 27 (54%) Grade ≥1, 18(36%) Grade≥ 3. Nine(18%) pts required V dose reductions. The most common AEs in all pts were renal insufficiency in 7(14%), fatigue 6 (12%) and nausea 3 (6%). There were 3 (12%) deaths on study, 1 aspiration pneumonia, 1 myocardial infarction, and 1 presumed pneumonitis from P. Responses in HN were: complete response (CR) 0, partial response(PR) 8 (36%), stable disease(SD) 5 (20%). Efficacy in SGC:CR 0, PR 4 (16%) in 1 LEL-C, 2 AciC and 1 ACC, SD 14(56%). With a median follow up of 8.7 mos for all pts, in HN median PFS was 4.5 mos, median OS, 12.6 mos; in SGC median PFS was 7 mos, and median OS 13 mos. Conclusions: P+V demonstrated activity in HN, with fewer responses in SGC. Serum and tissue biomarker analyses are ongoing. Clinical trial information: NCT02538510.
Clinical development of asciminib (ABL001) in chronic myeloid leukemia (CML): A randomized phase 3 study vs. bosutinib.
Authors: Michael J. Mauro, Fabian Lang, Dong-Wook Kim, Jorge E. Cortes, Timothy P. Hughes, Andreas Hochhaus, Hironobu Minami, Carla Boquimpani, Yosuke Minami, Daniel J. DeAngelo, Massimo Breccia, Moshe Talpaz, Yeow-Tee Goh, Oliver Ottmann, Manu Sondhi, Stephan Hois, Véronique Bédoucha, Shu-Fang Hsu Schmitz, Delphine Rea
Journal: Journal of Clinical Oncology (2018)

TPS7081 Background: Several tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 ATP-binding site are available to treat CML. However, new options are needed for patients (pts) with resistance/intolerance to these TKIs or who do not achieve treatment goals with them. Asciminib is a novel, potent and specific BCR-ABL1 inhibitor that targets the myristoyl pocket (Wylie, Nature 2017). Due to its distinct binding site, asciminib maintains activity against BCR-ABL1 mutants that confer resistance to ATP-binding site TKIs and offers the possibility for combination therapy with these TKIs. It therefore has the potential to address unmet needs in CML, including use in pts for whom ATP-binding site TKIs have failed or for combination with these TKIs in earlier lines, and in Philadelphia chromosome–positive acute lymphoblastic leukemia. In an ongoing phase 1 study in pts with resistance/intolerance to ≥ 2 TKIs (Hughes, Blood 2016 [abst 625]), asciminib has been well tolerated; 42% of pts achieved a major molecular response (MMR) by 12 mo with single-agent twice-daily asciminib. A recommended dose for asciminib monotherapy was identified for pts without T315I mutations (40 mg twice daily); in separate cohorts, dosing in select pt groups and combination dosing with ATP-binding site TKIs continues to be evaluated. Now, a phase 2 study of asciminib add-on therapy in pts without a deep molecular response on long-term frontline imatinib is planned, and a randomized phase 3 study of asciminib monotherapy vs bosutinib (an ATP-binding site TKI approved for third-line therapy) in the third or later line is enrolling. Here we describe this ongoing, open-label, phase 3 study (NCT03106779). Methods: Pts with CML in chronic phase (planned enrollment, N = 222) are randomized 2:1 to receive asciminib 40 mg twice daily or bosutinib 500 mg once daily. Eligible pts are ≥ 18 y old, previously treated with ≥ 2 TKIs, with failure/intolerance to the previous TKI, and have BCR-ABL1IS ≥ 1%. Pts with T315I or V299L mutations are excluded. MMR rate at 24 wk will be compared between arms (primary objective). The 96-wk MMR rate, progression-free and overall survival, safety, tolerability, and asciminib pharmacokinetics will also be evaluated. Clinical trial information: NCT03106779.