tbuckley/cabot-search huggingface dataset:
Impact of microsatellite instability status and sidedness of the primary tumor on immunophenotype of colorectal cancer.
Authors: Chen Yang, Ladan Fazlollahi, Robyn D Gartrell, Douglas Marks, Thomas Enzler, Thomas D Hart, Camden L Esancy, Helen Remotti, Yan Lu, Yvonne Saenger
Journal: Journal of Clinical Oncology (2018)

e15664 Background: Colorectal cancer (CRC) is a heterogeneous disease. Distinct features of tumors including sidedness and microsatellite instability status, high (MSI-H) or stable (MSS) have been highlighted. MSI-H confers a favorable prognosis and is predictive of response to checkpoint blockade therapy. While left sided CRC may have a superior prognosis to right sided CRC, the biologic basis for this difference is unknown. We hypothesize that improved prognosis in MSI-H and left sided CRC is due to a favorable immune tumor microenvironment (TME). Methods: 24 patients with stage II/III primary CRC were identified at Columbia University Medical Center, having known anatomic location and MSI status. Quantitative multiplex immunofluorescence (qmIF) was performed on 5µm FFPE slides for DAPI, CD3 (T cell), CD8 (cytotoxic T cell (CTL)), CD68 (macrophages), PDL1 (immunosuppression), and pancytokeratin (tumor). Multiplex images were acquired using Vectra and analyzed using inForm to evaluate for density and nearest neighbor analysis. Results: Preliminary analysis for 11 patients shows no significant difference in density of immune cell subsets comparing sidedness or MSI status, however there is a trend towards increased T cells in MSI-H. There was no difference in PDL1 expression between MSI-H and MSS tumors. PDL1 expression, however, is significantly decreased in left sided tumors (p = 0.044). Nearest neighbor analysis finds that CD3+ T cells are significantly closer to CD68+ macrophages in MSI-H tumors (p = 0.012) and significantly closer to PDL1-tumor cells in left-sided tumors (p = 0.044). Analysis is ongoing on the complete cohort. Conclusions: QmIF offers a novel, quantitative approach to evaluating the TME in stage II/III CRC. Interestingly, T cells are closer to macrophages in MSI- H tumors and closer to PDL1- tumor cells in left sided tumors. Spatial localization may reflect differences in interactions between these cell types impacting anti-tumor immunity and warrants further investigation. Complete qmIF analysis from the entire CRC cohort will be presented at the meeting.
Partial splenic embolization in chemotherapy-induced thrombocytopenia: A retrospective analysis with long term follow-up.
Authors: Letizia Procaccio, Marta Schirripa, Francesca Bergamo, Vincenzo Dadduzio, Silvia Finotto, Alice Menichetti, Stamatia Ziampiri, Riccardo Carandina, Fotios Loupakis, Sara Lonardi, Vittorina Zagonel, Camillo Aliberti
Journal: Journal of Clinical Oncology (2017)

e21654 Background: Chemotherapy-induced thrombocytopenia (CIT) may result in a chemotherapy (CT) dose delay or reduction, thus affecting dose density and intensity. Historically, partial splenic embolization (PSE) has been performed to improve hematologic parameters related to hypersplenism. In this study we reviewed our institutional experience with PSE for gastrointestinal cancer (GI) experiencing CIT. Methods: A retrospective analysis of GI cancer patients with splenomegaly undergoing PSE was performed. Mean PLT (platelet) count was collected at the following time points: before CT start; at nadir pre-PSE; 1 week before PSE (pre-PSE); 4 weeks after PSE (post-PSE); and at the nadir after CT reintroduction post PSE. Time to CT restart after PSE, time to recurrent CIT, periprocedural lab values and adverse events were recorded. Wilcoxon test was adopted to exploratively compare PLT count before and after PSE. Results: 11 patients underwent PSE, 5 with colorectal, 3 with pancreatic and 3 with biliary cancer, 73% had metastatic disease. Baseline PLT count before initiation of CT was 146 x109/L (range, 81-255 x 109/L). PLT count at nadir pre-PSE was 60 x109/L (range, 44-82 x 109/L), and pre-PSE PLT count was 78 x109/L (range, 62-99 x 109/L). Post-PSE PLT count improved significantly ( 132 x 109/L; range, 67-172 x109/L) compared with nadir pre-PSE (p = 0.003). The mean hospital stay was 1 day. Post-procedure abdominal pain occurred in 3 patients. All patients resumed CT and mean time to CT re-start after PSE was 43 days (range, 4-193 d). All patients exhibited recurrent thrombocytopenia. PLT count at nadir after PSE was 54 x 109/L (range, 28-78 x 109/L) and occurred at a mean of 169 days after PSE (range, 37-664 d) No differences were observed when comparing CIT at nadir pre and post PSE (p = 0.447). All patients experienced CT dose delay and 82% of them experienced dose reduction after PSE. Conclusions: Our findings underline that PSE is safe and effective to achieve short-term improvement of CIT and resumption of CT in GI patients. However, PSE does not sustain long-term adequate PLT count. Further studies may help guide patient selection by identifying characteristics that allow a sustained improvement in CIT.
Rates of peripheral neuropathy (PN) in patients (Pts) with relapsed and refractory multiple myeloma (RRMM) treated with carfilzomib vs comparators in pivotal phase III trials.
Authors: Ruben Niesvizky, Vania Hungria, Joy Ho, Aleksandr Suvorov, Darrell White, Dina Ben-Yehuda, Lifen Zhou, Karim S. Iskander, Laura Rosinol
Journal: Journal of Clinical Oncology (2017)

8041 Background: PN is a dose-limiting toxicity for some anti-MM agents, such as the proteasome inhibitor (PI) bortezomib (V). Carfilzomib (K), a novel irreversible PI associated with low PN, was evaluated in 2 recent phase 3 studies in RRMM pts. Methods: This analysis evaluated PN rates in ASPIRE (K [27 mg/m 2 ]-lenalidomide [R]-dexamethasone[d] [KRd] vs Rd in relapsed MM; Stewart 2015) and ENDEAVOR (Kd [K 56 mg/m 2 ] vs Vd in RRMM; Dimopoulos 2016). We evaluated grade ≥2 PN during treatment, patient-reported outcomes (PROs; QLQ-C30 pain, FACT/GOG-neurotoxicity subscales), and progression-free survival (PFS) in pts with BL history of PN. Results: In ASPIRE, grade ≥2 PN rate was low (8.9% [KRd] vs 8.0% [Rd]; Table). Pain subscale scores were similar between arms. Median PFS was longer with KRd vs Rd for pts with BL grade ≥2 PN. In ENDEAVOR, grade ≥2 PN rate during the study (prespecified key secondary endpoint) was significantly lower with Kd vs Vd (6.0% vs 32.0%; Table). Pts had significantly improved pain and neurotoxicity subscale scores with Kd vs Vd. PFS improved with Kd vs Vd in pts with BL history of grade ≥2 PN (Table). Conclusions: In ENDEAVOR, Kd resulted in less PN vs Vd; in ASPIRE, PN rate was similar for KRd vs Rd. PFS was longer with KRd and Kd vs Rd and Vd, respectively, including in pts with BL grade ≥2 PN. Improved pain and neurotoxicity outcomes with K may be attributed to better disease control and/or lower PN rates. Clinical trial information: NCT01568866, NCT01080391. [Table: see text]
Adjuvant gemcitabine plus docetaxel followed by doxorubicin versus observation for uterus-limited, high-grade leiomyosarcoma: A phase III GOG study.
Authors: Martee Leigh Hensley, Danielle Enserro, Helen Hatcher, P. B. Ottevanger, Anders Krarup-Hansen, Jean-Yves Blay, Cyril Fisher, Katherine M. Moxley, Shashikant B. Lele, Jayanthi Sivasothy Lea, Krishnansu Sujata Tewari, Premal H. Thaker, Oliver Zivanovic, David M. O'Malley, Katina Robison, David S. Miller
Journal: Journal of Clinical Oncology (2018)

5505 Background: We conducted a phase III trial to determine whether adjuvant chemotherapy with gemcitabine-docetaxel followed by doxorubicin improves survival compared to observation in women with resected, uterus-confined, high grade LMS. Methods: Women with uterus-confined high grade LMS, confirmed disease-free by post-resection imaging, were randomly assigned to treatment with gemcitabine-docetaxel x 4 cycles, followed by doxorubicin x 4 cycles (CHEMO) or to observation (OBS). All were followed by CT or MR imaging every 4 mos for 3 yrs, then every 6 mos for 2 yrs for recurrence. The primary endpoint was overall survival. Results: The study was opened with international collaboration. 38 of the target accrual of 216 patients (pts) were enrolled, after which the study was closed for National Cancer Institute-defined accrual futility. 20 pts were assigned to CHEMO and 18 to OBS. 3 pts assigned to CHEMO never received treatment. Among the 17 pts treated with at least one cycle of CHEMO grade 3 or 4 toxicities were observed in 47%; among 18 pts assigned to OBS, 1 had grade 3 hypertension. There were 6 deaths, (5 - CHEMO, 1-OBS), all due to disease. Over 48 mos, the restricted mean survival time (RMST) for OS in the CHEMO arm was estimated to be 34.3 mos (95% CI: 25.3 mos – 43.3 mos); RMST for OS in the OBS arm was estimated to be 46.4 mos (95% CI: 43.6 mos – 49.1 mos). There were 8 recurrences in each arm. Over 24 mos, the RMST for RFS in the CHEMO arm was estimated to be 18.1 mos (95% CI: 14.2 mos – 22.0 mos) and the RMST for RFS in the OBS arm was estimated to be 14.6 mos (95% CI: 10.3 mos – 19.0 mos). The difference in RMST comparing the CHEMO arm to the OBS arm was estimated as 3.4 mos (95% CI: -2.4 mos – 9.3 mos). Neither survival outcome comparison is considered statistically robust due to the small sample size and low number of events. Conclusions: Despite international collaboration to answer the critical question of the role of adjuvant chemotherapy in early-stage uterine LMS, this study was closed for accrual futility. While sample size and number of events preclude robust statistical comparison, observed OS and RFS data do not suggest superior outcomes for patients treated with adjuvant chemotherapy. Clinical trial information: NCT01533207.
Gene expression profiling of primary and metastatic renal cell carcinoma tumor initiating cells.
Authors: Anna Malgorzata Czarnecka, Mohammed Imran Khan, Slawomir Lewicki, Magdalena Krol, Robert Zdanowski, Igor Helbrecht, Cezary Szczylik
Journal: Journal of Clinical Oncology (2016)

e16091 Background: Tumor initiating cells represent a minor cell subpopulation that is resistant to therapies and has cancer stem cell characteristics including self-renewal, multiple lineage differentiation, tumor initiation and cancer dissemination potential. Endoglin has been shown as renal cell cancer tumor initiating cells surface marker. Methods: Endoglin expressing subpopulation of cells was isolated from ACHN (metastatic RCC) and CAKI-2 (primary RCC) cell lines under FACSAriaII based protocol. Agilent human GE 4x44K v2 microarrays and GeneSpring GX 13.0 package were used for gene expression analysis. (Sponsored: TEAM/2010-6/8 FNP). Results: In comparison to normal renal proximal tubule cells in endoglin expressing subpopulation of cells from metastatic and primary tumors - 2324 and 1346 genes were overexpressed while 2763 and 1614 genes were down-regulated, respectively. 1411 genes were commonly deregulated in metastatic and primary tumor derived endoglin positive cells. TGF-β, Wnt/β-catenine signalling and Epithelial-Mesenchymal Transition pathway were deregulated in renal cell cancer tumour initiating cells. TGFB1, ERBB2, and TNF are transcriptional regulators in these cells. Gene Set Enrichment Analysis has shownRap1, PI3K-Akt and Hippo signaling pathways as significantly deregulated in endoglin positive renal cell cancer cells. Genes expressed were shown to be primarily located in TP53, cytokine and kinase networks. Conclusions: Tumor initiating cells share deregulated pathways with typical normal stem cells, however rely on distinct signalling networks to maintain stemness and possibly to contribute to the progression of disease and metastasis. Renal cell cancer tumor initiating cells may also represent novel treatment target and their gene expression profile could be used as initial data for new functional and drug design studies.
Comprehensive detection of targetable fusions in lung adenocarcinomas by complementary targeted DNAseq and RNAseq assays.
Authors: Ryma Benayed, Michael David Offin, Kerry A. Mullaney, Purvil Sukhadia, Kelly M. Rios, Patrice Desmeules, Jason C. Chang, David Michael Hyman, Michael F. Berger, Ahmet Zehir, Maria E. Arcila, Mark G. Kris, Alexander E. Drilon, Marc Ladanyi
Journal: Journal of Clinical Oncology (2018)

12076 Background: While ALK, ROS1, RET fusions, and MET exon 14 (METex14) alterations are routinely detected by hybridization capture-based DNASeq assays such as MSK-IMPACT, a genomic DNA-based approach may not identify all patients with such events. We evaluated the utility of targeted RNAseq for the identification of these alterations in MSK-IMPACT driver-negative lung cancers. Methods: MSK-IMPACT driver-negative tumors (defined in Jordan E et al, 2017, PMID 28336552), underwent further molecular profiling with the MSK-Fusion Solid panel, a custom RNAseq panel based on the Archer FusionPlex technology designed to detect fusions involving 62 cancer genes and METex14 skipping. Low tumor mutation burden (TMB) was assessed as a potential prioritization criterion for targeted RNAseq. Results: Between 01/01/2014 and 12/31/2017, 2502 lung adenocarcinomas were profiled using MSK-IMPACT; 201 (8%) gene fusions and 119 (5%) MET exon 14 alterations were identified (table). Among 276 driver-negative cases, 255 (92%) with available tissue were subjected to targeted RNAseq. A previously undetected alteration was identified in 36 of 255 (14%) cases by the MSK-Fusion Solid panel, 33 of which were actionable (27 in-frame gene fusions, 6 METex14 skipping events; table). Of these 33 patients, 11 were eligible for matched targeted therapies (the rest had early-stage disease or low KPS, or were on alternate therapies, on active observation, or deceased). All 11 patients received targeted therapy, 8 of whom (72%) derived clinical benefit. In the subset of 63/255 MSK-IMPACT driver-negative cases with low TMB (0-5 mt/Mb), 19 (30%) were positive for previously undetected gene fusions. Conclusions: Our results emphasize the importance of complementary targeted DNAseq and RNAseq assays to ensure robust and comprehensive detection of actionable gene fusions and METex14 alterations in clinical samples. Furthermore, we observed enrichment for gene fusions in driver-negative samples with low TMB, supporting the prioritization of such cases for complementary RNAseq analysis. Gene ALK RET ROS1 BRAF NRG1 NTRK1 NTRK2 NTRK3 FGFR1 FGFR2 FGFR3 METex14 DNASeq (n = 2502) 86 44 50 7 3 4 0 0 1 1 5 119 RNASeq (n = 255) 4 3 10 1 5 0 1 2 0 1 0 6
Design and implementation of a novel value framework for oncology clinical pathway decision-making: Chemotherapy comparative index and scale.
Authors: Edward C. Li, Cecilia Tran, She-Chia S Chen, Nancy Pham, Andrew Allan Hertler
Journal: Journal of Clinical Oncology (2018)

e18925 Background: ASCO released a policy statement in 2015 that stressed the synthesis of transparent and robust clinical pathways to abate treatment variability and incentivize the most cost-effective care. The statement was shared at the 2016 AMCP Partnership Forum: Driving Value and Outcomes in Oncology. This multi-stakeholder forum addressed the variation and limitations of the five oncology value frameworks, which lack transparency and robust processes. Objective: In response to the 2016 AMCP Forum, NCH created the Chemotherapy Comparative Index and Scale (NCH Value Index); a value framework designed to enhance transparency within oncology clinical pathway decision-making processes, reflect efficacy, toxicity, and cost of existing treatment options. Methods: NCH Value Index is comprised of three indexes for: Effectiveness, Evidence, and Toxicity. The indexes are then construed into three domains: toxicity (T, lower the better), evidence and efficacy (EE, higher the better), and proximity to the Theoretical Best Regimen (TBR, lower the better). All study regimens are plotted with monthly costs and corresponding scores of T, EE and TBR on a scatter plot, which deduces the best regimen with the above variables. The pilot pathway formed from NCH Value Index was for Urothelial Cancer Subsequent Therapy, which included an analysis of twelve regimens from NCCN Bladder Cancer Guidelines. Regimen data ranged from phase 1 to 3 trials and were derived from published literature. Results: Among the twelve regimens, pembrolizumab has the highest EE and the lowest TBR, followed by gemcitabine. Ifosfamide had the lowest EE, the longest TBR, and a high T score. Based on analysis with NCH Value Index, ifosfamide was removed from the preferred pathway, where pembrolizumab and gemcitabine were added to the Urothelial Cancer pathway. Conclusions: NCH Value Index promotes transparency through a more explicit visualization of literature supporting clinical pathway decisions. The combination of NCH Value Index, practicing oncologists’ expertise, and patient preferences conserves precision medicine and value-based care that will positively impact multiple oncology stakeholders.
Association of hypoxia-induced centrosome amplification with clinical outcomes in triple-negative breast cancer.
Authors: Karuna Mittal, Da Hoon Choi, Angela Ogden, Brian D Melton, Meenakshi Vij Gupta, Michelle D. Reid, Kristin Jonsdottir, Emiel A. Janssen, Mohammad A. Aleskandarany, Ian O. Ellis, Emad A. Rakha, Padmashree C.G. Rida, Ritu Aneja
Journal: Journal of Clinical Oncology (2017)

e23170 Background: Centrosome amplification (CA) which refers to presence of supernumerary or abnormally large centrosomes is believed to drive tumor progression by promoting chromosomal instability and the generation of aggressive tumor clones that are more capable of rapid metastasis. Not much is known about factors that drive CA within solid tumors. We have previously shown the existence of rampant CA in triple-negative breast cancers (TNBCs).We report here thatintratumoral hypoxia, which is one of the major contributors to tumor heterogeneity, induces CA in TNBCs via HIF-1α. Methods: We immunohistochemically labeled 24 TNBC and adjacent normal tissue samples for HIF-1α and derived weighted indices (WIs) for nuclear HIF-1α. Adjacent serial sections from the same tumors were immunofluorescently labeled for the centrosomal marker γ-tubulin and CA was determined. Using public microarray datasets (Kao dataset, n = 327), we investigated whether centrosomal gene expression is enriched in breast tumors characterized by a hypoxia gene expression signature. Finally, to test the role of hypoxia in CA induction we exposed cultured TNBC cells (MDA-MB-231 and MDA-MB-468) to hypoxia and overexpressed (OE) or knocked out (KO) HIF-1α and quantitated CA. Results: A strong positive correlation was found between nuclear HIF-1α WI and CA in TNBC samples (Spearman’s rho p = 0.722, p &lt; 0.001), and higher nuclear HIF-1α was associated with worse overall survival (p = 0.041; HR = 1.03). Furthermore, breast tumors with high expression of hypoxia-associated genes exhibited higher expression of centrosomal genes than breast tumors with low expression of hypoxia-associated genes. TNBC cells cultured in hypoxic conditions exhibited ~1.5 fold higher (p &lt; 0.05) CA compared to cells cultured in normoxic conditions. Interestingly, level of CA decreased when HIF-1α KO TNBC cells were exposed to hypoxia; conversely, CA increased when HIF-1α OE TNBC cells were cultured in normoxic conditions. Conclusions: Thus,intratumoral hypoxia drives CA in TNBC via HIF-1α and contributes to poor outcomes. Determination of CA may help identify TNBC patients who could benefit from centrosome declustering drugs and HIF-1α inhibitors.
Real-life efficacy and safety of nivolumab for non-small cell lung cancer: A 10-months French cohort.
Authors: Jennifer Corny, Christophe Maritaz, Sophie Renet, Stephane Jouveshomme, Vincent Fallet, Claire Gazaniol, Claire-Marie Monnet, Jean Tredaniel, Meryam Jardin
Journal: Journal of Clinical Oncology (2016)

e20633 Background: In France, nivolumab (NVB) is available since April 2015 and is now widely used in previously treated advanced non-small cell lung cancer (NSCLC). The aim of this study was to retrospectively evaluate its efficacy and safety in real life patients. Methods: From April 2015 to January 2016, demographics and tumor characteristics data were extracted from 46 consecutive patients treated by NVB in a French center. Tumor response was assessed by physical examination and computerized tomography scan (CT-scan) using response evaluation criteria in solid tumours (RECIST v1.1) criteria between week 8-12. Results: Thirty one patients (67%) had non squamous NSCLC. At initiation, 12 patients (27%) had PS > 1. Twenty three patients (50%) received NVB as a 2nd line. At first evaluation, response rate was 15% and 17 patients (37%) progressed. Twelve patients (26%) discontinued NVB prematurely ( < 2 months): 2 (4%) because of side effects (diarrhea and asthenia grade III according to Common Terminology Criteria for Adverse Events 4.0) and 10 because of rapid clinical worsening (22%). Of the latter, only one patient could benefit from another chemotherapy but died after 2 injections. Patients with quick worsening seemed to be older (median 67 years vs 63) with non-squamous tumors (75% vs 67%). Global clinical improvement at 1st evaluation was noticed in 16 patients (35%), including 7 patients with progressive disease at first CT-scan (1 was still in progression at 2ndevaluation). A median of 6 doses [1-21] of NVB were administered. At 3 and 6 months, 44% and 31% patients were still under treatment. Among patients with initial PS > 1, 44% were still under treatment after 3 months. Conclusions: NVB was well-tolerated and was associated with clinical improvement in 35% of patients, including PS > 1 patients. Clinical improvement did not always correlate with radiological response. NVB was also associated with a rapid worsening of clinical condition in a substantial number of patients (22% of patients), particularly older, non-squamous NSCLC and with initial PS > 1 patients.