tbuckley/cabot-search huggingface dataset:
Prostate cancer enhanced mRNA detection assay in whole blood as predictive biomarker of tumor sensitivity to targeted androgen inhibition for men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Daniel Costin Danila, Shibu Thomas, Yashoda Rani Rajpurohit, Amrita Herkal, Michael Gormley, Erica Simone Dayan, Nicole A. Schreiber, Martin Fleisher, Deborah S. Ricci, Howard I. Scher
Journal: Journal of Clinical Oncology (2016)

5038 Background: Enzalutamide (ENZ) and abiraterone + prednisone (AA) have transformed the care of pts with mCRPC. Qualified predictive biomarkers are needed to guide treatment selections. Studies of androgen receptor (AR) splice variants, especially ARv7, may predict resistance to ENZ and AA. We report on analytical validation and testing of whole blood ARv7 assay for pts with mCRPC starting AR-targeted therapies. Methods: Men with progressive mCRPC were enrolled prospectively on a biomarker protocol to collect blood in PAXgene tubes before starting treatment with ENZ or AA. An RTPCR based assay to detect KLK2, KLK3, HOXB13, GRHL2, FOXA1 and ARv7 in whole blood was analytically validated in 2 independent laboratories. VCaP spikes established the limit of detection, and healthy volunteers were used as controls. Samples were independently tested with the validated signature. Results: A standard operating protocol was generated and applied to 45pts starting ENZ (AA- and chemo- naïve) and 33pts starting AA (prior ENZ >6 months; 22 pts were chemo-naïve; 8 pts progressed on ENZ cohort). ARv7 detection trended at higher levels in pts with prior ENZ exposure (Ct=26) compared to patients starting ENZ (Ct=30.5). Conclusions: In our study, ARv7+ve pts starting AA after ENZ had <50% PSA declines, but did not predict de novo resistance to ENZ. Further analysis of ARv7 status as a predictive biomarker, in parallel with other biomarkers, is ongoing. Treatment N ARv7 status N (%, 95%CI) ≥50%PSA decline N (%, 95%CI) PSA response from baseline Time on therapy mos Mean (range) Overall survival, HR (95%CI) True responder (≥50% max decline) Acquired resistance (rise after ≥50% max decline) De novo resistance (<50% decline) ENZ cohort (AA-naïve) 45 pts ARv7+ve 7 (16%, 8-29) 6 (86%, 49-97) 4 (57%, 25-84) 2 (29%, 8-64) 1 (14%, 3-51) 28 (2.8-61.3) 1.1 (0.2-1.2) ARv7–ve 38 (84%, 71-92) 28 (74%, 58-85) 19 (50%, 35-65) 9 (24%, 13-39) 10 (26%, 15-42) 24 (0.1-103.8) AA cohort (prior ENZ) 33 pts ARv7+ve 7 (21%, 11-38) 0 0 0 7 (100%, 65-100) 9 (1.6-39.2) 1.3 (0.4-4) ARv7–ve 26 (79%, 62-89%) 5 (19%, 9-38) 3 (12%, 4-29) 2 (8%, 2-24) 21 (81%, 62-91) 5 (0.6-21.5)
Molecular matching and treatment strategies for lung cancer at Dartmouth-Hitchcock Medical Center: A three year review of a molecular tumor board.
Authors: Erica Bernhardt, Mary D. Chamberlin, Ivan P Gorlov, Francine B Blumental de Abreu, Katarzyna J Bloch, Jason D Peterson, Gregory J. Tsongalis, Keisuke Shirai, Konstantin H. Dragnev, Todd W. Miller, Laura J. Tafe
Journal: Journal of Clinical Oncology (2017)

e20585 Background: Matching of actionable tumor mutations with targeted therapy has been shown to increase response rates and prolong survival in lung cancer patients. Drug development and trials targeting genetic alterations are expanding rapidly. We describe the role of a Molecular Tumor Board (MTB) in the design of molecularly informed treatment strategies in our lung cancer patient population. Methods: DNA from tumor specimens was sequenced to identify coding mutations using a 50-gene targeted next-generation sequencing panel (Ampliseq v2). Cases were evaluated by a multidisciplinary MTB that included medical oncologists, hematologists, molecular and anatomic pathologists, genetic counselors, and basic science researchers who suggested a course of treatment based on the patient’s molecular findings. Results: During a three-year period, 88 patients were presented to the MTB. Of these, 21 patients had lung cancer (23.9%). All patients lacked common (indicated for FDA approved drug) activating EGFR and ALK mutations. One patient was stage IIIb, all others were stage IV; 18 had previously received at least one prior line of therapy (range 0-5). Suggestions for treatment with a targeted therapy were made for 19 of 21 (90.5%) and four patients underwent treatment with a MTB-suggested targeted agent (21.1%); two as part of a clinical trial. One patient received targeted therapy for 27 months before his disease eventually progressed. Barriers to treatment with targeted therapy included: ineligibility for study (n = 2), lack of interest in study/distance to travel (n = 2), lack of disease progression (n = 2), death/hospice enrollment (n = 5), decision to treat with immunotherapy (n = 3), and unknown (n = 1). Conclusions: For the majority of lung cancer patients, the MTB was able to provide suggestions based on targetable genetic alterations. The largest barriers to treatment were death and hospice enrollment indicating that molecular testing and presentation to the MTB at earlier stages of disease may increase the number of patients who ultimately are eligible for treatment with a targeted agent.
Next generation sequencing for DLBCL classification.
Authors: Monica Madden Reinholz, Debrah Thompson, Ihab Botros, Paul Sportmann, Qian Liu, Pat Roche, Zijun Xu-Monette, Ken H Young, Bonnie LaFleur
Journal: Journal of Clinical Oncology (2016)

11559 Background: Diffuse large B-cell lymphoma (DLBCL) can be molecularly classified as germinal center (GCB) and activated (ABC) B-cell-like, which traditionally define low- and high-risk patient groups when treated with chemotherapy. The HTG EdgeSeq system combines HTG's proprietary quantitative nuclease protection assay chemistry with Next Generation Sequencing (NGS) to enable semi-quantitative analysis of hundreds of targeted probes in a single assay. We developed a novel HTG EdgeSeq DLBCL Cell of Origin (COO) Assay that simultaneously measures the transcript levels of 96 genes using small clinical samples with an objective for accurate subtyping of GCB and ABC DLBCL using NGS. Methods: The EdgeSeq DLBCL COO assay was run on 257 de-identified FFPE tissue samples (approximately 5 mm2of tissue) previously characterized for ABC/GCB subtyped by gene expression profiling (GEP) using Affymetrix GeneChip microarray. A model-based classifier was developed using these expression data, 172 samples as part of a training set (86 GCB/86 ABC) and 85 for a test set (49 GCB/36 ABC). The resulting classifier identified three mutually exclusive subtypes, ABC, GCB and “unclassified”. The unclassified designation is used for cases where the expression pattern does not fall within either sub-type with certainty. The resulting classifier and assay was then validated on 90 samples (40 ABC, 40 GCB, and 10 unclassified/borderline samples). Results: Bootstrap resampling of the classifier in the training set showed low over-fitting with less than 1% based on 200 bootstrap resamples of Area Under the Curve. Misclassification rate in the classification test set was 9% (8/85). For the system validation study average overall agreement with GEP was 96% and conditional ABC and GCB agreement was 93% and 95%, respectively. Additionally, we had a low (averaged less than 3%) of samples with lower than expected sequencing quality (based on alignment rate and sample-level quality control metrics). Conclusions: We developed a classifier for DLBCL ABC/GCB sub-typing based on targeted NGS and demonstrated a high degree of agreement with GEP and a low sample failure rate, despite low tissue input requirements.
Efficacy and safety of obinutuzumab in the frontline treatment of CLL patients with comorbidities: The real-world results of Polish Adult Leukemia Group (PALG) retrospective analysis.
Authors: Monika Dlugosz-Danecka, Wojciech Jurczak, Ewa Łątka, Marta Morawska, Krzysztof Gawroński, Anna Wiśniewska, Marek Dudziński, Ewa Wąsik-Szczepanek, Ewa Chmielowska, Anna Łabędź, Kamil Wdowiak, Iwona Hus
Journal: Journal of Clinical Oncology (2018)

e19513 Background: The current first-line treatment for fit chronic lymphocytic leukemia (CLL) patients remains fludarabine-based therapy. Elderly patients with numerous comorbidities, poorly tolerate such regimen and pose a huge challenge. In our analysis, we investigated the efficacy and safety obinutuzumab-chlorambucil combination in elderly and unfit patients. Methods: We include in our analysis 86 elderly (median age 74), treatment-naïve CLL patients with significant burden of coexisting comorbidities. All patients presented the Cumulative Illness Rating Scale (CIRS) score greater than 6 and/or creatinine clearance (CrCl) of 30–69 ml/min. Obinutuzumab was infused intravenously at 1000 mg on days 1, 8 and 15 of cycle 1 and on day 1 of cycles 2–6 (28-day cycles) with first infusion split over 2 days for patients’ safety. Chlorambucil was administered orally at a dose of 0.5 mg per kilogram of body weight on days 1 and 15 of each cycle. Results: Overall response rate (ORR) at 2 months after treatment completion was 95,35% with CR rate of 43,02 % and partial remission (PR) rate of 56,98%. Stable disease (SD) or progressive disease (PD) were not observed after the end of therapy. The median progression free survival (PFS) was 13,05 months. The relapses occurred in 9 patients (10,46%) with 3 patients (3,49%) completing treatment with CR, 3 (3,49%) with PR and another 3 (3,49%) with SD. The most frequent adverse events (AE) were infusion-related reactions (IRR) and neutropenia. Grade 3 IRR occurred in 2,3 % of patients, grade 2 in 12,8% (in 81,8% of patients only during the first infusion of monoclonal antibody). Grade 3 neutropenia was reported in 11,6% of patients, grade 2 in 22,1% with any incidence of febrile neutropenia. There were no AE of grade 4 and 5 or related deaths. Conclusions: Our data confirms that obinutuzumab-chlorambucil is an effective and well-tollerated regimen in untreated CLL patients with coexisting comorbidities.
Case-control study of PD-1, PD-L1 and B7-H3 expression in lung cancer (CA) patients (pts) with and without human immunodeficiency virus (HIV) infection.
Authors: Katherine Ann Scilla, Dan Paul Zandberg, Soren Bentzen, Jonathon Heath, Olga B. Ioffe, Ashley L Cellini, Candace Barette Mainor, Martin J. Edelman, David Riedel, Josephine Louella Feliciano
Journal: Journal of Clinical Oncology (2017)

11606 Background: PD-1, PD-L1 and B7-H3 are co-signaling molecules involved in CA immunology. There are limited data on expression of these molecules in HIV-infected (HIV+) lung CA pts and these pts are routinely excluded from immunotherapy trials. Methods: We reviewed archived lung CA tissue samples from HIV+ cases (n = 13) and HIV-uninfected controls (n = 13) from 2001-2015. Cases and controls were matched by histology and stage. Baseline demographics were collected for all pts. CD4 count and HIV RNA viral load (VL) were collected for HIV+ pts. Immunostained tumor sections were analyzed for percent of tumor cells expressing PD-L1 and B7-H3 (Abcam), and percent of tumor-infiltrating lymphocytes (TIL) expressing PD-1 and PD-L1 (Abcam). Positive expression was defined as &gt; 5%. Statistical analysis was performed using the non-parametric Mann-Whitney test and the chi-square test. Proportions are specified as percentage with 95% confidence limits in parentheses. Results: Lung CA HIV+ case pts were predominantly male (62%), black race (100%), adenocarcinoma histology (77%), stage 4 disease (62%), and had a median age of 48 years. Of case pts with available data, mean CD4 count was 307 (range 37-617) and mean HIV VL was 29,400 (range 0-100,000). PD-L1 expression on tumor cells was positive in 23% (8%, 50%) of cases and 46% (23%, 71%) of controls. B7-H3 expression on tumor cells was positive in 92% (67%, 99%) of cases and 69% (42%, 87%) of controls. PD-1 expression on TIL was positive in 69% (42%, 87%) of cases and 54% (29%, 77%) of controls. PD-L1 expression on TIL was positive in 31% (13%, 58%) of cases and 69% (42%, 87%) of controls (p = 0.05). B7-H3 percent expression on tumor cells was significantly higher in cases vs controls (median 90% vs 20%, p = 0.005), but there were no significant differences in percent expression of PD-L1 on tumor cells, PD-1 on TIL or PD-L1 on TIL. Conclusions: HIV+ lung CA pts had significantly higher B7-H3 tumor percent expression compared to HIV-uninfected controls, with similar rates of PD-L1 tumor percent expression, PD-1 TIL percent expression and PD-L1 TIL percent expression. These results support inclusion of HIV+ lung CA pts in future immunotherapy trials.
Phase I trial combining ipilimumab + high dose stereotactic radiation: Results and serum immune correlates.
Authors: Chad Tang, James William Welsh, Patricia de Groot, Erminia Massarelli, Joe Y. Chang, Kenneth R. Hess, Michael A. Curran, Maria E. Cabanillas, Vivek Subbiah, Siqing Fu, Apostolia Maria Tsimberidou, Daniel D. Karp, Daniel Richard Gomez, Ritsuko Komaki, Padmanee Sharma, Aung Naing, David S. Hong
Journal: Journal of Clinical Oncology (2016)

3022 Background: Preclinical models suggest systemic disease control with ipilimumab (IPI) and radiation. Here we conducted a phase I trial of IPI and high dose stereotactic body radiation therapy (SBRT) to determine the MTD and early efficacy signals. Methods: IPI 3mg/kg was administered q3 wks for 4 cycles. SBRT was sequenced concomitant (C1D2) or sequentially (C2D7) with IPI in 5 groups: concurrent liver 50 Gy in 4 fractions(Gp1), sequential liver 50 Gy(Gp2), concurrent lung 50 Gy(Gp3), sequential lung 50 Gy(Gp4), and sequential lung/liver 60 Gy in 10 fractions(Gp5). MTD for each group was determined using a 3+3 dose de-escalation design. Blood was collected for correlative analyses by the MDACC Immunotherapy Platform. Expression of multiple immune markers was assessed among 3 T cell populations via flow cytometry: total CD8+ [CD3+CD8+], CD4+ T effectors [CD4 Teffs : CD3+CD4+FOXP3-], and CD4+ T regulatory cells [CD4 Treg : CD3+CD4+FOXP3+CD127-/lo]). Significance was assessed via the Wilcoxon rank-sum test. Results: 35 pts initiated IPI, of which 31 completed SBRT. The most common histologies were: 8 NSCLC, 3 sarcoma, 3 colorectal, and 3 RCC. 2 DLTs were observed: a patient in Gp1 experienced gr3 pancreatitis and lipase elevation and a patient in Gp2 experienced gr3 bilirubin and AST increase. 13 pts (37%) experienced gr3+ AEs, with 2 pts taken off protocol due to toxicity. The most common gr3 AEs were colitis (n = 5, 14%) and rash (n = 3, 10%). The majority of AEs was self-limiting and required only outpatient supportive care. Response outside of the SBRT field was assessed in 31 pts with follow up imaging. 3 PRs were observed and 7/31 pts (23%) exhibited clinical benefit (CB = CR, PR, or SD ≥ 6 months). 4 of 4 pts who achieved CB exhibited an increased ratio of CD8:CD4 T cells after SBRT over pretreatment reference as compared to 1/7 in patients who did not achieve CB (P < 0.05). Patients treated with liver SBRT showed an increase in the proportion of CD8+ T cells expressing ICOS, GITR, and LAG3 compared to lung SBRT (all P < 0.05). Conclusions: The combination of SBRT and IPI (3mg/Kg) was safe with preliminary signs of efficacy. Correlative studies suggest differences in early systemic immune activation. Clinical trial information: NCT02239900.
TCT-726 Early intravenous beta-blockers in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction A patient-pooled meta-analysis of randomised clinical trials
Authors: Peter Damman, Niels Hoedemaker, Niels van Royen, Valentin Fuster, Fikret Er, Natig Gassanov, Borja Ibanez, Arnoud van 't Hof
Journal: Journal of the American College of Cardiology (2018)
Expression of VHL and SRC in metastatic renal cell carcinoma (mRCC).
Authors: Jia Luo, Jennifer Podolak, Catherine Degnin, Yiyi Chen, Kyle William Robinson, Marina Pukay, Amy Schilling, Cara Poage, George V. Thomas, Christopher W. Ryan
Journal: Journal of Clinical Oncology (2016)

e16133 Background: SRC is overexpressed in many cancers and promotes growth, angiogenesis and metastasis. We previously reported that RCC expressing higher SRC by immunohistochemistry (IHC) is associated with worse overall survival (OS), and SRC and VHL levels are positively correlated in RCC. We hypothesized that RCC tumors expressing high SRC and VHL (hSRC/hVHL) represent a more aggressive phenotype that is less responsive to therapies given that the presence of VHL suggests an intact VHL/HIF axis. We analysed SRC and VHL expression as well as tumor VHL mutational status in a prospective cohort of mRCC patients (pts). Methods: Pts with mRCC with archival tumor tissue provided written informed consent. Primary and metastatic samples were evaluated for VHL and SRC protein expression by IHC and scored based on intensity and percent staining. The median was used as a cutoff to define high versus low staining for both VHL and SRC. Association was determined using Spearman correlation coefficient. VHL and SRC staining status was analyzed for correlation with OS and time to treatment failure (TTF), defined from initiation of first line systemic therapy to discontinuation from any cause. DNA was extracted from paraffin embedded tumors, PCR amplified and VHL sequenced. Results: 45 nephrectomy and 22 metastatic specimens were available from 54 consented pts. 46 pts (87% clear cell) received systemic therapy (38 VEGF-TKI; 5 mTOR-I; 3 IL-2). 44% harbored hSRC/hVHL. VHL and SRC expression were positively correlated (ρ < 0.0001). On log-rank analysis, hSRC/hVHL was associated with longer TTF (HR 0.43 [0.19, 0.95], ρ = 0.0368) and non-significantly with OS (HR 0.42 [0.15, 1.18], ρ = 0.0889). In multivariate analysis controlling for Heng score and treatment type, hSRC/hVHL was not an independent predictor of TTF. There was no correlation between VHL mutation status and VHL staining. WT-VHL compared to mut-VHLwas marginally associated with longer TTF (median 15.7m vs 5.8m; ρ = 0.0919). Conclusions: hSRC/hVHL was associated with better clinical outcome, but was not an independent predictor when controlled for by Heng score and treatment type. VHL expression by IHC did not correlate with VHL mutation status. The role of SRC and its relation to VHL warrants further investigation.
Improving care delivery for patients with rare cancers: A phase II trial of durvalumab in combination with tremilumimab in subjects with advanced rare tumors in a large community health care system.
Authors: William Jeffery Edenfield, Julie C. Martin, Mark Allen O'Rourke, Elizabeth H. Cull, Ki Y. Chung
Journal: Journal of Clinical Oncology (2018)

e18535 Background: Patients with rare cancers are an underserved population with limited access to clinical trials aside from Phase I trials in the refractory setting. Providing access to immunotherapy is especially challenging for these patients and is available only with compassionate use mechanisms. There is broad evidence for the efficacy of combined immune checkpoint blockade across multiple tumor types and toxicities from this approach have been defined in numerous prior clinical trials. Methods: This study is a Phase II, investigator initiated, single institution trial utilizing durvalumab (1500mg Q4 weeks x 13) and tremilumimab (75mg Q4 weeks x 7, then Q12weeks x 2) in patients with advanced rare solid tumors (incidence < 6/100,000/yr). Phase II dose and safety defined from prior Phase I trials. Patients also consented to tissue and blood storage for biomarker analysis. Results: 23 of planned 50 patients have been enrolled in 13 months. Durable response or prolonged disease stability seen in salivary adenoid cystic and adrenocortical malignancies thus far. Toxicity profile has paralleled prior reports with no new signals identified. There was one death from immune mediated pneumonitis. Most events have been grade I or II and easily manageable. Conclusions: Investigating novel therapies is feasible in patients with rare cancers by utilizing a basket trial mechanism. Using this methodology is straightforward and is well suited to large cancer delivery systems in communities who care for the majority of these patients. Furthermore, efficacy in specific subgroups can support expansion trials in those cohorts. Innovative cancer care delivery trials such as these will be needed to improve the care of patients with rare tumors. Clinical trial information: NCT02938793.
Platinum rechallenge in patients with advanced biliary tract carcinoma (ABTC) after failure of gemcitabine (GEM)-platinum combination: A national AGEO retrospective study.
Authors: Cindy Neuzillet, Bertrand Brieau, Gregory Manuceau, Benoit Rousseau, Laetitia Dahan, Tarek Boussaha, Philippe Vasseur, David Tougeron, Thierry Lecomte, Romain Coriat, Jean Baptiste Bachet, Jean Marc Phelip, Aziz Zaanan, Olivier Bouche, Jérôme Desramé, Anne Thirot-Bidault, Isabelle Trouilloud, Christophe Locher, Christophe Tournigand, Astrid Lièvre
Journal: Journal of Clinical Oncology (2016)

4076 Background: There is no validated option beyond GEM-platinum standard 1st-line (L1) chemotherapy (CT) for ABTC. In ovarian and colon cancers, platinum rechallenge demonstrated benefit in patients who responded to a prior platinum-based CT and with a significant platinum-free interval. We aimed to assess the usefulness of platinum-based CT as 2nd (L2) or 3rd-line (L3) treatment in ABTC. Methods: Patients with ABTC who received platinum-based CT as L2 or L3 were identified from a national retrospective AGEO cohort of ATBC patients receiving L2 CT after failure of GEM-platinum L1 CT at 18 French institutions. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Results: Among 686 patients who received GEM-platinum L1 CT, 231 were given L2 CT; among them, 92 (39.8%) received a platinum-based CT as L2 (n = 70) or L3 (n = 25). Median age was 65 years (range: 25-81); 50 (54.3%) patients were men and 42 were women. The primary tumor was intrahepatic, extrahepatic and gallbladder carcinoma in 44/28/19 patients. L1 CT was GEMOX in 83 (90.2%) patients and GEMCIS in 9. At the time of platinum rechallenge, 82 (92.1%) patients had metastatic disease; ECOG PS was 0-1 in 73.6%; CA19.9 was > 400 IU/ml in 36.2%. Rechallenge regimens were 5FU-cisplatin (n = 53), FOLFOX/XELOX (n = 28), GEMOX/GEMCIS (n = 9), and carboplatin-based CT (n = 5). Overall, median L1 PFS (mPFS) was 7.2 months and median OS (mOS) from L1 was 17.4 months; mPFS and mOS from platinum rechallenge were 4.4 months (L2: 4.8; L3: 3.4) and 7.7 months (L2: 7.7; L3: 7.7), respectively. 82 patients were evaluable according to RECIST criteria; 12 (14.6%) had partial response and 40 stable disease (48.8%) (disease control rate [DCR] 63.4%). PS (0-1 vs 2-3) and CA19.9 (≤ vs > 400 IU/ml) were significantly associated with longer PFS (HR 2.41, p = 0.0016 and HR 1.88, p = 0.0350); PS, CA19.9, and reason for L1 discontinuation (toxicity/other vs progression) were significantly associated with longer OS (HR 2.17, p = 0.0019; HR 1.69, p = 0.0491; HR 1.77, p = 0.0122, respectively). Conclusions: Platinum rechallenge is an interesting option yielding a DCR over 60% in patients with ABTC.