tbuckley/cabot-search huggingface dataset:
A phase 1 trial of ruxolitinib, lenalidomide, and methylprednisolone for relapsed/refractory multiple myeloma patients.
Authors: James R. Berenson, Jennifer To, Tanya M. Spektor, Carley Turner, Regina A. Swift, Benjamin M Eades, Gary Schwartz, Shahrooz Eshaghian, Laura Stampleman, Robert A. Moss, Stephen Lim, Robert A. Vescio
Journal: Journal of Clinical Oncology (2018)

8005 Background: Preclinical studies from our laboratory have demonstrated that ruxolitinib (RUX) in combination with lenalidomide (LEN) and dexamethasone shows marked anti-myeloma effects both in vitro and in vivo. Furthermore, MUC1 is responsible for LEN resistance in MM cells, and RUX blocks its expression in MM cells. Thus, RUX may restore sensitivity to LEN. Therefore, a phase 1 trial was conducted to determine the safety and efficacy of RUX in combination with LEN and methylprednisolone (MP) for relapsed/refractory (RR)MM patients (pts) who had previously been treated with LEN/steroids and a PI and showed progressive disease at study entry. Methods: A traditional 3+3 dose escalation design was used to enroll subjects in four cohorts with planned total enrollment to be 28 pts. Subjects received RUX twice daily continuously, LEN daily on d1-21 of a 28-d cycle and MP orally every other day. In DL0, pts received RUX 5 mg, LEN 5 mg, and MP 40 mg. In DL+1 and +2, both doses of LEN and MP remained unchanged and RUX was escalated to 10 and 15 mg, respectively. DL+3 escalated LEN to 10 mg with MP unchanged and RUX at 15 mg. Results: As of February 1, 2018, 28 pts had been enrolled, and 21 were evaluable. The median age was 66 years (range, 63-81), and 29 (55%) were male. Pts received a median of 6 prior treatments (range, 2-11). No DLTs occurred, and DL+3 was expanded. Among evaluable pts, the CBR and ORR were 48% and 33%, respectively (1 CR, 6 PR and 3 MR), and 7 and 4 showed SD and PD. G3 AEs included transient thrombocytopenia (14.3%), anemia (9.5%) and gastrointestinal bleeding (9.5%). SAEs included a humeral fracture (4.8%), a cerebral vascular accident from a pt with atrial fibrillation who discontinued his anticoagulation (4.8%), renal insufficiency (4.8%), sepsis (4.8%), and neutropenic sepsis (4.8%). Conclusions: This Ph 1 trial demonstrates for the first time that a JAK inhibitor, RUX, can overcome refractoriness to LEN and steroids for RRMM pts. These promising results are leading to other clinical trials with immunomodulatory agents and steroids with RUX as well as expansion of the current clinical trial to 49 pts, and may represent a new therapeutic approach for treating MM. Clinical trial information: NCT03110822.
Role of time to switch from ipilimumab to anti-PD1 in anti-PD1 efficacy within the French national cohort, MelBase.
Authors: Clara Allayous, Stéphane Dalle, Marie Thérèse Leccia, Francois Aubin, Laurent Mortier, Marie- Beylot-Barry, Philippe Saiag, Sophie Dalac-Rat, Jean Philippe Lacour, Eve Maubec, Vincent Descamps, Bernard Guillot, Thierry Lesimple, Julie De Quatrebarbes, Jean-Philippe Arnault, Pierre-Emmanuel Stoebner, Raphael Porcher, Alice Ballon, Bastien Oriano, Celeste Lebbe
Journal: Journal of Clinical Oncology (2017)

9551 Background: With increasing armamentarium in advanced melanoma management, the impact of various strategies remains to be determined including the importance of time to switch from one treatment to another. We report the impact of time to IPI/APD non-planned switch on APD efficacy in real life patients within MelBase (MB). Methods: MB is a French multicentric biobank dedicated to the prospective follow-up (FU) of unresectable stage III or IV melanoma with 1102 patients included since March 2013. Data were collected (Sept.2016) and analyzed (demography, overall survival (OS), progression-free survival (PFS), response rate, multivariate analysis, safety). Results: 71 patients were treated with IPI/APD sequence. 72% received 4 IPI injections. The median time to switch was 1.7 months (0.36-3). The characteristics at the initiation of APD are: mean age 64 yrs, PS 0-1 80%, elevated LDH 34%, BRAF WT 90%, brain metastasis 25%, ≥ 3 metastatic organ sites (MOS) 49%, median FU 11.9 months, OS 20 months (95%CI:12.6-NR), PFS 3.5 months (95%CI:2.9-6.2). The best overall response was 25%, disease control rate was 54% with a low toxicity profile (17% grade 3/4). In a multivariable analysis, longer time to switch was significantly associated with better OS (adjusted HR 0.38 per 1 more month, 95%CI:0.14-0.93), as well as ECOG 0-1 (aHR 3.11, 95%CI:0.99-9.72) and LDH &lt; ULN (aHR 3.32, 95%CI:1.26-8.75). In addition, the association of time to switch with OS vary significantly according to the number of MOS ( &lt; 3 MOS aHR 0.25, 95%CI:0.10-0.62; ≥3 MOS aHR 0.99 95%CI:0.41-2.39) and AJCC stage (M0/1a/1b aHR 0.06, 95%CI:0.01-0.43 ; M1c aHR 0.77, 95%CI:0.39-1.54). Conclusions: In patients who failed IPI treatment, longer survival after APD was associated to time to switch only in patients with favorable baseline factors. Such results are probably more related to the slow kinetics of the disease than to the delay itself. Our results are different from Blank et al.(ESMO 2016) who tested a planned switch, immediately after 2 IPI perfusions, and showed overall response rate close to IPI+APD association. We are currently conducting a similar study on the reverse sequence (APD/IPI) and the role on IPI efficacy.
Absolute lymphocyte count (ALC) during and after chemoradiation (CRT) for squamous cell carcinoma of the head and neck (SCCHN): Effect of the regimen and potential therapeutic implications.
Authors: Marit Uglane, Shalin Shah, Arif Shaikh, Nicholas Campbell, Mihir Bhayani, Everett E. Vokes, Ranjeev Nanda, Vathsala T. Raghavan, Bruce Brockstein
Journal: Journal of Clinical Oncology (2018)

6042 Background: Radiation (RT) or (CRT) is a component of treatment (tx) for locoregionally advanced (LA) SCCHN. ALC and lymphocyte subsets are known to decrease as a result of RT for SCCHN. The changes in and variables affecting ALC during or after RT/CRT are not well described. Methods: We retrospectively reviewed the ALC of 298 consecutive patients (pts) treated with IMRT based therapy for LASCCHN from 7/2003-7/2015. ALC was categorized using a prespecified algorithm at day 0 of RT, weeks (wk) 1,2,3,4,5,6,7,8,9, months (mo) 3, 6, 12 and years (yr) 2,3,4,5. Chemotherapy (CT) was categorized as induction (IC) yes/no and CRT as one of 4 groups: none/weekly cisplatin/ FHX (5FU, hydroxyurea, taxol)/”other”, and RT was recorded as unilateral or bilateral neck tx. Regression analysis was used to assess survival as a function of ALC. VZV (shingles) infection was noted and recorded. Results: ALC nadir for the entire group occurred at week 9 at a mean level of 0.4 (CTCAE 4.03 grade 3, normal range 1.0 - 4.0 103/uL ) for CRT patients and 0.76 for RT only patients (p = 0.016). At yr 1, ALC ranged from 0.83-1.04 (p = 0.2) amongst 4 groups. By year 5, ALC had only recovered to 69% of baseline with no significant differences between groups. The use of IC did not affect nadir ALC. Pts receiving bilateral neck RT vs. unilateral had significantly lower mean ALC nadirs from wk 3-9 (wk 9: 0.38 vs. 0.88 p < 0.001) but not after 3 mo. ALC nadir had no effect on relapse or survival parameters. 19 pts had documented cases of shingles (VZV) occurring at a median time of 10 mo. There was no effect on nadir ALC by p16 status for oropharynx pts. Conclusions: Pts undergoing RT or CRT for SCCHN have a quick and severe ALC nadir which never recovers to normal. CRT compared with RT decreased the severity of the nadir but not recovery. IC does not impact ALC, but bilateral neck RT leads to a deeper nadir than unilateral. ALC nadir does not affect survival. VZV could be a related adverse event as it follows CRT in at least 6% of patients at a median of 10 mo. The severe and sustained ALC nadir may also have important effects on the timing of the use of checkpoint inhibitor therapy during RT or CRT.
Systemic and tissue microRNAs changes in early phase of breast cancer development.
Authors: Natascia Marino, Rana German, Xi Rao, Xiaoling Xuei, Anna Maria Storniolo
Journal: Journal of Clinical Oncology (2018)

e13548 Background: MicroRNAs (miRs) and their distribution in circulation have been implicated in physiological and pathological processes. Recently, circulating miRs have emerged as potential biomarkers for early detection of cancer. However, their link with breast cancer predisposition remains unclear. In this study we explored the association of miRs with breast cancer susceptibility in terms of systematic (blood circulation) and local (breast tissue) changes. Methods: Plasma and breast tissue specimens, donated by women before a breast cancer diagnosis (labeled pre-cancer), and age-matched healthy controls, were obtained from the Susan G. Komen Tissue Bank at IUSCC. Plasma samples (16 pre-cancer and 16 controls) were processed for miR extraction and RNA sequencing (Illumina NextSeq500). Reads were mapped to miRBase20 to identify known miRs. The analysis of additional samples is underway. Laser microdissection was used to separate breast epithelium, stroma and adipose tissue from frozen tissue biopsies of 7 pre-cancer and 16 matched-healthy women. RNA sequencing followed. Statistics: The differential expression analysis was done using trimmed mean of M-values in the EdgeR. Pvalues for significantly differentially expressed transcripts are estimated by a Fisher’s exact test on the negative binomial distribution. Results: We identified 45 plasma miRs significantly differentially expressed between pre-cancer samples and healthy controls (p< 0.05, fold change > 1.5). Five miRs were also overexpressed in the breast tissue of pre-cancer versus control group in a compartment-specific mode. MiR103A1 and miR548n, which regulate cell proliferation and migration, were overexpressed in the epithelium. The endothelial specific miR, miR126, and the EMT-suppressive miR, miR590, were found specifically upregulated in the stroma. The oncomiR, miR21 showed higher levels in the adipose tissue. Conclusions: Here, we report a miRNA profile of precursors of breast cancer that provides new insights into the pathways and biologic pressures relevant for tumor etiology and progression. This novel information suggests a potential role of these miRNAs in early diagnosis of or as targets for preventative therapy of breast cancer.
Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade
Authors: Joy Hsu, Jonathan J. Hodgins, Malvika Marathe, Chris J. Nicolai, Marie-Claude Bourgeois-Daigneault, Troy N. Trevino, Camillia S. Azimi, Amit K. Scheer, Haley E. Randolph, Thornton W. Thompson, Lily Zhang, Alexandre Iannello, Nikhita Mathur, Karen E. Jardine, Georgia A. Kirn, John C. Bell, Michael W. McBurney, David H. Raulet, Michele Ardolino
Journal: Journal of Clinical Investigation (2018)

Checkpoint blockade immunotherapy targeting the PD-1/PD-L1 inhibitory axis has produced remarkable results in the treatment of several types of cancer. Whereas cytotoxic T cells are known to provide important antitumor effects during checkpoint blockade, certain cancers with low MHC expression are responsive to therapy, suggesting that other immune cell types may also play a role. Here, we employed several mouse models of cancer to investigate the effect of PD-1/PD-L1 blockade on NK cells, a population of cytotoxic innate lymphocytes that also mediate antitumor immunity. We discovered that PD-1 and PD-L1 blockade elicited a strong NK cell response that was indispensable for the full therapeutic effect of immunotherapy. PD-1 was expressed on NK cells within transplantable, spontaneous, and genetically induced mouse tumor models, and PD-L1 expression in cancer cells resulted in reduced NK cell responses and generation of more aggressive tumors in vivo. PD-1 expression was more abundant on NK cells with an activated and more responsive phenotype and did not mark NK cells with an exhausted phenotype. These results demonstrate the importance of the PD-1/PD-L1 axis in inhibiting NK cell responses in vivo and reveal that NK cells, in addition to T cells, mediate the effect of PD-1/PD-L1 blockade immunotherapy.
Effect of <i>SLCO</i> polymorphisms on high-dose methotrexate clearance in pediatric oncology patients.
Authors: Rachael R Schulte, Richard H. Ho
Journal: Journal of Clinical Oncology (2018)

e22503 Background: High-dose methotrexate (HD MTX) is a critical treatment component for pediatric acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma, and osteosarcoma. While very effective, HD MTX regimens have significant risk of toxicity and require serial drug level monitoring through MTX clearance. There is substantial interpatient variation in HD MTX clearance with important implications: slow clearance increases toxicity while rapid clearance may decrease efficacy. Organic anion transporting polypeptides (OATPs; SLCO) are drug uptake transporters critical to the uptake and disposition of many drugs. OATP1B1, -1B3, and -1A2 transport MTX and have common function-altering polymorphisms. Methods: This is an observational pharmacogenetic:pharmacokinetic correlative study in pediatric oncology patients treated with HD MTX of key polymorphisms in SLCO and other MTX disposition pathway genes. Clinical/demographic data were obtained from the electronic medical record. BioVU, Vanderbilt’s DNA biobank linked to a de-identified medical record, is also being utilized for subject accrual. The primary endpoint is MTX clearance. Secondary endpoints are incidence/severity of MTX toxicities (mucositis, neutropenia, hepatotoxicity) and patient outcomes (survival, relapse). Linear regression and pharmacokinetic modeling will be used for analysis of the primary endpoint; logistic regression modeling will be used for the secondary endpoints. Results: 113 patients have been enrolled to date. Median age at first HD MTX is 9.9 y (range 0.7-27.6y). 66% have ALL. Preliminary analysis shows a trend toward higher 24-hour MTX levels, a surrogate for clearance, in patients with at least one copy of the key variant SLCO1B1 allele rs4149056 (521T > C) compared to wild-type (p = 0.11). Additional analysis is underway to assess the relationship between clearance and SLCO genotype and examine the influence of genetic variation on toxicity and survival. Goal accrual is 200 patients. Conclusions: Our data suggest SLCO polymorphisms are associated with variation in MTX levels in pediatric oncology patients, which may have important implications for differential rates of MTX clearance and MTX-associated toxicities.
Clinical factors predictive for efficacy of treatment with cabazitaxel in metastatic castration resistant prostate cancer (mCRPC) in second and later lines.
Authors: Stefanie Zschaebitz, Sonia Vallet, Stefan Duensing, Boris Hadaschik, Dirk Jäger, Sascha Pahernik, Cathleen Spath, Markus Hohenfellner, Carsten Grüllich
Journal: Journal of Clinical Oncology (2016)

e16511 Background: Several newtreatment options for patients with mCRPC have been approved within the last years - among them cabazitaxel, abiraterone acetate, enzalutamide, and radium-223. No factors predictive for efficacy are known and the optimal treatment sequence has yet to be defined. Methods: We analyzed all patients with mCRPC treated with cabazitaxel at our institution between 2011 and 2016. Data were retrieved retrospectively from the prospective electronical patient chart. Results: 38 patients received cabazitaxel (29 % 2nd line, 37 % 3rd line, 34 % > 3rd line). Treatment was generally well tolerated with an average of 4.76 cycles (range 1-11) and a treatment duration of 2.95 months (range 0-8). In 2 patients treatment was discontinueddue to toxicity. 22 patients were still alive with a median follow-up time of 7 months calculated from end of cabazitaxel treatment (range 0-34). Median progression free survival (PFS) was 4.03 months (95% CI 0.625 – 7.441). Median overall survival (OS) was 12.13 months (95% CI 7.571 – 16.692). There were no differences in OS and PFS regarding treatment line (2nd vs. above) or age at begin of cabazitaxel treatment. Duration of remission on 1st line treatment ( > 6 months (6m) vs. < 6m) was associated with a longer PFS and OS with subsequent cabazitaxel treatment (PFSPFS 1st line > 6m = 8.03 months [95%-CI 4.232-11.834] vs. PFSPFS 1st line < 6m = 2.95 months [95%-CI 1.749-4.153]; p = 0.018 and OSPFS 1st line > 6m = 22.03 months [95%-CI 7.409-36.657] vs. OSPFS 1st line < 6m = 10.07 months [95%-CI 67.271-12.860]; p = 0.063). Conclusions: Results from our patient cohort suggest that patients who progress rapidly following 1st line treatment do not significantly benefit from cabazitaxel as 2nd or later line treatment. Limitations of the study are its retrospective design, single center data and small sample size. These findings should be confirmed within a prospective trial aiming to identify those patients who benefit from cabazitaxel most.
Cell-free circulating tumor DNA (cfDNA) to identify germline (GL) and somatic BRCA alterations (alts) in men with advanced prostate cancer (ProsCA).
Authors: Victoria M. Raymond, Tanisha M. Mojica, Elizabeth V. Harris, Richard B. Lanman, Celestia S. Higano
Journal: Journal of Clinical Oncology (2018)

e24287 Background: cfDNA NGS is a non-invasive tumor profiling method which interrogates circulating tumor and leukocytic DNA, and thus has the potential to identify GL alts. These “secondary findings”, outside the primary cfDNA analysis indication, can inform therapy decisions. GL BRCA1/2 (gBRCA) alts are reported in 6% of men with advanced ProsCA, making them eligible for PARPi. We aimed to determine the prevalence of cfDNA detected putative gBRCA alts in patients (pts) with advanced ProsCA. Methods: Between 11/2016 – 02/2018, men with treatment naïve or progressing advanced ProsCA underwent a clinical cfDNA analysis (Guardant360®) which evaluates SNVs, indels, amplifications, and fusions in up to 73 genes, including BRCA1/2 SNVs and indels. cfDNA results were retrospectively reviewed to identify putative gBRCA alts and correlated with clinical gBRCA and/or somatic tumor testing. Results: 32 cfDNA samples were collected from 29 unique pts. Average age at cfDNA sample collection was 68.5 years (49 – 86y). Putative gBRCA alts were identified in 5 cfDNA samples (15.6%) from 3 pts (10.3%) and clinical GL testing was concordant in all 3 pts. Variant allele frequency (VAF) of putative gBRCA (45-85%) was higher than the maximum VAF of somatic alts identified in the same sample (0.19 – 79.5%). Two additional pts had only somatic BRCA (sBRCA) alts detected at low VAF (0.18, 0.22%), both had negative gBRCA testing. Of the 24 pts (25 samples) with no cfDNA BRCA alts, 21 had additional clinical molecular testing, and none had BRCA alts identified (0/17 - GL testing, 0/3 - somatic tumor testing, and 0/1 - GL and somatic tumor testing). Conclusions: In a single center cohort of men with advanced ProsCA, 10.3% (3/29) of pts who underwent clinical cfDNA analysis were found to have putative gBRCA alts and 6.9% (2/29) had sBRCA alts, of which 100% (5/5) were confirmed with GL testing. Pts negative for cfDNA detected BRCA alts were also negative by other molecular testing. Putative GL alts were observed at a VAF consistent with heterozygosity, indicating that cfDNA VAF can aid in distinguishing gBRCA versus sBRCA. Detection of cfDNA gBRCA/sBRCA alts can aid in identification of ProsCA pts eligible for PARPi.
Effect of definitive concurrent therapy with or without surgery on resectable esophageal cancer survival: An analysis of the National Cancer Data Base.
Authors: Kushal Naik, Yuan Liu, Michael Goodman, Theresa Wicklin Gillespie, Bassel F. El-Rayes, Allan Pickens, Seth Force, Conor Ernst Steuer, Taofeek Kunle Owonikoko, Suresh S. Ramalingam, Dong Moon Shin, Field F. Willingham, Jerome Carl Landry, Felix Fernandez, Nabil F. Saba
Journal: Journal of Clinical Oncology (2016)

4045 Background: Locally advanced resectable esophageal cancers (rEC) are managed either with concurrent chemo-radiation followed by surgery (CRSx) or concurrent chemo-radiation alone (cCR). There is insufficient evidence comparing the overall survival (OS) of these two groups in a large population. Methods: The National Cancer Data Base (NCDB) was queried for rEC cases diagnosed from 2003 to 2011. Patients with previous cancers, cervical rEC, clinical stage T1N0 or metastatic disease were excluded. Only adeno-, squamous or mixed adeno-squamous carcinomas treated with cCR or CRSx were included. cCR was defined as chemotherapy and radiotherapy given within 30 days of each other. CRSx was defined as cCR followed by surgical resection within 90 days of initiation of cCR. The OS in the two groups was compared using Kaplan-Meier methods and extended Cox-proportional hazard models. Results: A total of 14,495 eligible patients were identified; of those, 10,645 (73.4%) received cCR and the rest were treated with CRSx. Univariate survival analysis showed that survival following CRSx was significantly better than that after cCR with a mortality hazard ratio (HR) of 0.48 and a 95% confidence interval (CI) from 0.45 to 0.50 (p < 0.001). The odds of receiving CRSx was higher among patients with having stage III disease, private insurance, living more than 10 miles away or in areas with higher median income or greater proportion of high school-educated residents. Patients over 70 years of age, males, African-Americans, with co-morbidities, squamous cell EC, lesions of upper third of esophagus, or those treated at community programs were most likely to receive cCR alone. After adjusting for age, sex, race, insurance, area-based measures of income and education, treatment facility type, co-morbidities, primary site, grade, histology and stage, the HR for CRSx compared to cCR alone was 0.66 (95% CI: 0.45-0.96, p = 0.03) and the median survival with CRSx was longer (14.3 vs. 34.7 months). Conclusions: Data from the NCDB strongly support the inclusion of surgery after concurrent chemoradiotherapy for patients with locally advanced, resectable esophageal cancer.