tbuckley/cabot-search huggingface dataset:
Comprehensive genomic profiling of 298 lung cancers of varying histologies harboring <i>MET</i> exon 14 alterations.
Authors: Sai-Hong Ignatius Ou, Garrett Michael Frampton, James Suh, Zachary Rockow Chalmers, Mark Rosenweig, Jonathan Wade Goldman, Patrick M. Forde, Kurt Leuenberger, Nir Peled, Gregory Kalemkerian, Jeffrey S. Ross, Philip J. Stephens, Vincent A. Miller, Siraj Mahamed Ali, Alexa Betzig Schrock
Journal: Journal of Clinical Oncology (2016)

9021 Background: MET exon 14 skipping (METex14) has recently been described a potential driver alteration in lung cancer targetable by MET tyrosine kinase inhibitors (TKIs) (PMID: 25971938, 26729443). However, a large series of lung cancer cases harboring METex14 alterations has not been reported. Methods: Hybrid-capture based comprehensive genomic profiling (CGP) was performed on 11,205 FFPE lung cancer specimens during the course of clinical care. Results: METex14 alterations were identified in 298 (2.7%) lung carcinoma samples including: sarcomatoid (7.7%), adenosquamous (7.2%), histology not otherwise specified (NOS) (3.0%), adenocarcinoma (2.9%), squamous cell (2.1%), large cell (0.8%), and small cell (0.2%). Acinar features were present in 24% of the METex14 samples. The median age of METex14 patients was 73 years (range: 43-95) and 60% were female. No obvious difference in these patient characteristics was observed among METex14 patients with varying histologies. Six cases (2%) of ubiquitination-impaired MET Y1003 mutation were identified among the 298 METex14 cases. Base substitution at the splice donor site (49%) was the most common METex14 alteration. Concurrent MET amplification (METamp) of ≥ 6 copies and ≥ 10 copies was identified in 15% and 8% of METex14 samples, respectively. Concurrent MDM2, CDK4, or EGFR amplification was observed in 35%, 21%, and 6.4% of METex14 patients, respectively, and concurrent KRAS mutation was observed in 3% of cases. There was one case each of EGFR G719A, BRAF G466V, and EML4-ALK co-existing with METex14. There was no notable difference in available characteristics or response to MET TKIs between METamp and non-METamp METex14patients, and multiple responses to MET TKIs were observed in both subsets, including one post-crizotinib initially inoperable tumor that became resectable and pathologic assessment revealed only extensive fibrosis. Conclusions: METex14 alterations were found in 2.7% of all lung cancer samples examined. Hybrid-capture-based CGP to identify METex14 alterations should be performed on non-small cell lung cancer patients regardless of age, gender, or histology to ensure that these patients can benefit from treatment with MET TKIs.
Insulin growth factor-2 binding protein 3 (IGF2BP3) to promote lung tumorigenesis viaregulation of p53 stability.
Authors: Wei Zhao, Dan Lu, Jun Zhang
Journal: Journal of Clinical Oncology (2016)

e23013 Background: Insulin-like growth factor II mRNA-binding protein 3 (IGF2BP3), initially identified as an RNA-binding protein, is highly expressed in embryonic tissues and a variety of cancers. Previously, our group reported that IGF2BP3 may serve as a potential diagnostic marker for lung cancer. However, little is known about the function of IGF2BP3 in lung cancer development. Methods: In this study, the mRNA and protein expression level of IGF2BP3 was examined via real-time PCR and immunohistochemistry in a cohort of carcinomatous and nonneoplastic pulmonary tissues. A series of in vivo and in vitro assays was performed to elucidate the contribution of IGF2BP3 in lung cancer occurrence and metastasis. Results: Here, Bioinformatics analysis indicates that IGF2BP3 DNA copy number is amplified in lung cancer tissues. IGF2BP3 expression was increased in lung cancer tissues compared to normal tissues both in mRNA and protein levels. Overexpression of IGF2BP3 in lung cancer cells promoted cell proliferation, anchorage-dependent and independent tumor growth in vitro and in vivo. Additionally, ectopic IGF2BP3 expression promoted tumor migration and invasion. In contrast, silencing IGF2BP3 in lung cancer cells inhibited proliferation, migration and invasion. Mechanically, our data demonstrated that silencing IGF2BP3 expression in lung cancer cells increased the half-life and protein level of p53 and induced G0/G1 arrest. Conclusions: Collectively, our data demonstrate that IGF2BP3 drives tumorigenesis by induction of p53 instability in lung cancer.
Discontinuation of anti-PD-1 mAb after complete response in advanced melanoma pts.
Authors: Philippe Saiag, Raphael AitMehdi, Astrid Blom, Christine Longvert, Jean-François Emile, Blandine Boru, Magali Fort
Journal: Journal of Clinical Oncology (2018)

e21549 Background: Anti-PD-1 mAb represent a backbone of advanced melanoma therapy, but information on their duration and outcomes after cessation are scarce outside the KEYNOTE-001 pembrolizumab (PEMBRO) trial. We investigated these outcomes and their predictive factors in the real-life situation, where patients are not as highly selected as in registration trials Methods: We searched our prospective database of a skin cancer referral center for all pts with inoperable AJCC stage III-IV melanoma, regardless of BRAF mutational status, who received ≥1 dose of nivolumab (NIVO) or PEMBRO outside KEYNOTE trials as 1st, 2d or 3d-line monotherapy and for whom mAb was discontinued because of CR or toxicity and CR. All pts were evaluated every 12w with CT scans from mAb initiation to the database cutoff (Jan, 18 2018). Before anti-PD-1 cessation, CR had to be confirmed with a second CT-scan performed 12 w later and with a (18)FDG-PET scan. All images were evaluated on a weekly basis during a multi-disciplinary meeting with radiologists using RECIST v1.1. Results: Among 134 pts treated with anti-PD-1 monotherapy, 19 (14%, 15 NIVO & 4 PEMBRO pts) achieved confirmed CR and discontinued mAb. Median duration on mAb was 14.5 m. Median time to partial response and CR was 2.8 and 8.4 months, respectively. All patients are still experiencing CR after a median time off-treatment of 13 months. Some, but not all, previously reported pt characteristics at mAb initiation associated with favorable outcomes, were present in these pts (table). Median N of lines of prior therapy was 0 (range:0-2) Conclusions: Although retrospective, with limited N of pts and off-treatment period, we confirm that CRs are achievable at a frequency similar to KEYNOTE-001 and that anti-PD-1 cessation is possible, with a low probability of early relapse, if any. Pts/melanoma characteristics at baseline Total (N = 19) BRAFV600-mutant 4 (21%) ECOG performance status 0/1 19 (100%) AJCC Stage IV, M1c 10 (53%) N pts with brain mets 3 (16%) N pts with mets other than soft-tissue/lung 11 (61%) N pts with relative lymphocyte count ≥17.5%, N = 18 15 (83%) N pts with relative eosinophils count ≥1.5%, N = 18 9 (50%) Median N of metastatic sites (range) 2 (1-5) LDH level < ULN, N = 18 16 (89%)
Assessing the utility and benefit of granulocyte-colony stimulating factor (G-CSF) in adjuvant therapy for stage III colon cancer.
Authors: Vishal Vashistha, Robert James Pelley, Marc A. Shapiro, Bassam N. Estfan
Journal: Journal of Clinical Oncology (2016)

e15136 Background: The role of granulocyte-colony stimulating factor (G-CSF) agents for patients undergoing oxaliplatin-based adjuvant therapy for stage III colon cancer has not been assessed. We sought to describe indications for prescribing G-CSF and compare outcomes among patients who received G-CSF with those who did not. Methods: A retrospective review of electronic charts at our institution was conducted for patients who received adjuvant oxaliplatin-based regimens for Stage III colon cancer between 2006-2013. We identified indications for G-CSF prescriptions. We further compared disease outcomes, number of cycles with neutropenia, treatment delays, oxaliplatin cycles tolerated, and neuropathy grade at treatment conclusion between patients receiving G-CSF and those who did not. Results: 50 patients were identified of whom 21 (40%) received at least one G-CSF injection. Of those receiving G-CSF, a mean of 5.42 ± 3.35 G-CSF cycles were given. Indications for initial G-CSF prescriptions included grade 3 or 4 neutropenia (61.9% of patients), grade 1 or 2 neutropenia (28.5%), and neutropenic prophylaxis (4.76%). The G-CSF receiving group had an insignificant decreased trend in disease recurrence (31.5% vs. 55.5%, p = 0.11) with no significant improvement in survival (80.1% vs. 67.8%, p = 0.31) or incidence of neutropenic fever (4.76% vs. 0%, p = 0.23). We found no differences in total cycles with neutropenia (3.04 vs. 2.51, p = 0.21), treatment delays (1.33 vs. 0.96, p = 0.16), oxaliplatin cycles tolerated (9.42 vs. 9.44, p = 0.48), or neuropathy grade at treatment conclusion (0.81 vs. 0.79, p = 0.46) between the G-CSF receiving and chemotherapy-alone groups, respectively. Conclusions: G-CSF injections are more often prescribed for severe neutropenia. However, patients receiving G-CSF with adjuvant treatment for stage III colon cancer had no difference in outcomes or treatment delays compared to those who did not. Given the financial cost and potential adverse effects related to G-CSF injections, a higher-powered analysis is necessary to identify specific patients that benefit from G-CSF with oxaliplatin-based treatment as neutropenic severity may not provide clear direction.
Choosing a reduced intensity conditioning, fludarabine melphalan versus fludarabine busulfan: A meta-analysis and systematic review.
Authors: Tania Jain, Mohamad Bassam Sonbol, Belal Firwana, Diana Almader-Douglas, Jeanne Palmer
Journal: Journal of Clinical Oncology (2018)

e19017 Background: Of the various reduced intensity conditioning (RIC) regimens, fludarabine combined with reduced intensity dose melphalan (FM) or busulfan (FB) are commonly used prior to allogeneic stem cell transplantation (HCT). Currently, the choice largely depends upon physician preference. We conducted this meta-analysis to determine differences in clinical outcomes with the use of these 2 RIC regimens. Methods: We searched different databases, including PubMed, Embase and Cochrane, to identify randomized control trials or observational studies comparing the 2 RIC regimens. DerSimonian random effects model was used to measure efficacy outcomes. Primary end-points were overall survival (OS) and progressions free survival (PFS) while secondary end-points were non-relapse mortality (NRM) and graft versus host disease (GVHD). Results: Seven studies including 1,955 patients, 1004 in the FB group and 951 in the FM group. Pooled analysis of all studies showed no statistically significant difference in OS between FM and FB (HR 1.19; 95% CI 0.90 – 1.59). In the subgroup analysis including only AML and MDS patients from 3 studies, there was no statistically significant difference in OS (1276 patients, HR 0.87; 95 % CI 0.72-1.05). In the subgroup analysis for the 2 lymphoid studies (230 patients), OS was better with FB (HR 2.09; 95% CI 1.3 – 3.36). There was no statistical significant difference in PFS between FB and FM in the pooled data from 5 studies (HR 0.86; 95% CI 0.70 – 1.06). NRM was higher with FM versus FB in analysis of all studies, subgroup analysis for 3 AML/MDS studies and 2 lymphoid studies (HR 1.94, 95% CI 1.45 – 2.61; HR 1.56, 95% CI 1.12 – 2.19; HR 4.17, 95% CI 2.08 – 8.36, respectively). Rates of grade 2-4 and grade 3-4 acute GVHD was higher in patients who received FM versus FB: HR 1.35; 95% CI 1.07 – 1.69 and HR 1.76; 95% CI 1.40 – 2.19, respectively. Relapse (6 studies) was lower in patients who received FM compared to FB (HR 0.65, 95% CI 0.56 – 0.77). Conclusions: This meta-analysis shows that FB and FM are associated with a similar OS and PFS. Relapse is improved with FM but at the cost of higher NRM. In lymphoid malignancies, FB is associated with better OS attributed to a lower NRM.
High-dose chemotherapy (HDCT) and autologous peripheral-blood stem cell transplant (PBSCT) for relapsed metastatic germ-cell tumors (mGCT): The Indiana University (IU) experience.
Authors: Nabil Adra, Sandra Althouse, Mary J. Brames, Cheryl K Sullivan, Rafat Abonour, Nasser H. Hanna, Costantine Albany, Lawrence H. Einhorn
Journal: Journal of Clinical Oncology (2016)

4505 Background: Patients (pts) with mGCT who relapse after initial chemotherapy (CT) can still be cured with second-line and even third-line regimens. We previously reported series of 184 pts treated with HDCT between 1996-2004 (N Engl J Med 2007;357:340-8). We now report survival outcomes of 364 pts with relapsed mGCT treated with HDCT and PBSCT at IU between 2004-2014. Methods: 364 consecutive pts with mGCT who progressed after cisplatin-based combination CT. 341 pts received 2 consecutive courses of HDCT consisting of 700mg/m2 carboplatin and 750mg/m2etoposide, each for 3 consecutive days, and each followed by PBSCT. 23 pts received only a single course of HDCT due to progressive disease or toxicity. Kaplan-Meier methods were used for progression free survival (PFS) analysis. Results: Median age was 32. At time of starting HDCT, median AFP was 7.5 (range, 1-21,347) and median hCG was 37.1 (range, 0.5-178,140). Of the 364 pts, 230 had complete remission (CR) without relapse during a median follow-up of 29 months. Of the 302 pts who received treatment as second-line therapy, 195 pts were disease-free. 35 of 62 pts who received treatment as third-line or later therapy were disease-free. There were 6 treatment-related deaths. Secondary leukemia developed in 5 pts. Conclusions: This large single-institution study further demonstrates that relapsed mGCT are curable by HDCT plus PBSCT even when used in third-line or later therapy. Variable (N) 2-year PFS p value All pts (364) 57% HDCT - 0.02 -Second-line (302) 59% -Third-line or subsequent (62) 43% Platinum Sensitivity - <0.001 -Sensitive (242) 71% -Refractory (122) 30% Salvage AFP - 0.04 -≤1000 ng/mL (336) 58% ->1000 ng/mL (28) 36% Salvage hCG - <0.001 -≤1000 mIu/mL (274) 65% ->1000 mIu/mL (90) 34% Histology - <0.001 -Seminoma (79) 90% -Nonseminoma (285) 48% Response to initial CT - <0.001 -CR or partial remission (PR) with normal serum markers (289) 64% -Less than CR or PR (75) 29% IGCCCG risk - <0.001 -Good (151) 80% -Intermediate (38) 55% -Poor (175) 38% Primary site - <0.001 -Testicular/retroperitoneal (344) 20% -Mediastinal nonseminoma (20) 20% Brain metastasis - <0.001 -yes (64) 35% -no (300) 61%
Improving bone health in men with prostate cancer on ADT: Results of a randomized phase II trial.
Authors: Shabbir M.H. Alibhai, Henriette Breunis, Narhari Timilshina, Maryam S. Hamidi, George A. Tomlinson, Tharsika Manokumar, Osai Samadi, Joanna Sandoval, Sara Durbano, Angela Cheung, Padraig Richard Warde, Jennifer M. Jones
Journal: Journal of Clinical Oncology (2016)

10099 Background: Androgen deprivation therapy (ADT) is widely used to treat men with PC but is associated with accelerated bone loss and fragility fractures. Although guidelines have recommended several strategies to optimize bone health care for these men, multiple studies have shown important gaps in the quality of bone health care and there are no proven interventions to address these gaps. We conducted a phase II randomized controlled trial (RCT) of two educational interventions to see if either could improve bone health care. Methods: Men with PC starting or continuing on ADT for at least 6 months were randomized 1:1:1 to either (a) a customized bone health pamphlet for the patient and a one-page summary of bone health recommendations for their family physician (BHP+FP); (b) a BHP for the patient and support from a bone health coordinator (BHP+BHC); or (c) usual care (UC). The primary outcome was receipt of a bone mineral density (BMD) test within 6 months. Secondary outcomes included guideline-appropriate use of calcium and vitamin D, lifestyle changes, and bisphosphonate prescriptions for men at high risk of fracture. Analyses used chi-square and logistic regression. The trial is registered at clinicaltrials.gov (NCT02043236). Results: 115 men were recruited (40 men in the BHP+FP arm, 37 men in the BHP+BHC arm, and 38 men in the UC arm). Baseline characteristics were well balanced across groups. The BHP+BHC strategy (78% versus 36%, odds ratio (OR 6.19, 95% confidence interval (CI) 2.19-17.5)) but not the BHP+FP strategy (58%, OR 2.39, 95% CI 0.95-6.04) was associated with an increased odds of BMD ordering compared to UC. Both strategies were associated with numerically higher rates of calcium and vitamin D use but neither intervention was statistically significant (p > 0.20). Too few men were smoking or consuming excess alcohol to allow meaningful between-group comparisons. The BHP+BHC strategy was associated with a greater rate of exercise uptake (p = 0.028) than UC. None of the 5 men at high fracture risk received a bisphosphonate. Conclusions: BHP+BHC is associated with a greater rate of BMD ordering and exercise uptake than UC in men on ADT, but other aspects of bone health do not appear to be improved by either intervention. Clinical trial information: NCT02043236.
Magnitude and duration of immune checkpoint up-regulation and changes in the immune microenvironment post chemo-radiation (CRT) in esophageal cancer.
Authors: Ronan Joseph Kelly, Ali Hussainy Zaidi, Matthew A Smith, Ashten N Omstead, Juliann E Kosovec, Daisuke Matsui, Samantha A Martin, Christina DiCarlo, E. Day Werts, Jan F Silverman, David H. Wang, Blair Anderson Jobe
Journal: Journal of Clinical Oncology (2017)

4060 Background: PD-1 inhibitors in metastatic gastroesophageal cancer have demonstrated response rates of approximately 25%. Unfortunately, the majority of patients do not respond. Therefore, a rationale strategy of combining immunotherapeutic agents with CRT in earlier stage esophageal cancer may prevent metastatic disease in a greater proportion of patients. This study assessed the impact of CRT on the immune microenvironment and the expression patterns of multiple immune checkpoints to optimally design neoadjuvant clinical trials. Methods: To determine the effects of CRT on resected esophageal adenocarcinomas (EAC), we examined the immune microenvironment pre and post CRT using IHC, LCM followed by qRT-PCR, and functional analysis of tumor-infiltrating lymphocytes. Additionally, to assess the duration and dependency of radiation-induced PD-L1 sensitization, esophagojejunostomy were performed on rats to induce gastroduodenoesophageal reflux and EAC formation. First, tumor bearing animals were dosed with single fraction 13 Gy or 16 Gy radiation to determine safety, dose correlation, and PD-L1 sensitization using qRT-PCR post-radiation. Next, longitudinal PD-L1 expression levels within individual tumor bearing animals were determined using serial endoscopic biopsies at baseline, 1, 5 and 9 weeks post 16 Gy radiation. Results: The majority of cancers displayed enhanced interferon γ and activated CD8+ T lymphocytes at the tumor stroma interface. These tumors also demonstrated enhanced upregulation of PD-L1 and multiple other immune checkpoints including – TIM3, GITR, IDO1, LAG3, CD137, OX40 and KIR. The animal model results indicated PD-L1 upregulation is dose dependent and transiently elevated post radiation exposure. Conclusions: Collectively, these findings provide insights into the evolving immune landscape after CRT and have significant implications for future neoadjuvant trial designs that will combine radiotherapy with immune checkpoint inhibitors. Currently, we are conducting a neoadjuvant trial assessing Nivolumab or Nivolumab/Ipilimumab in combination with CRT in stage II/III operable esophageal cancer.
Anti-dementia and anti-hyperlipidemic medication use at end of life in elderly lung cancer patients: Analysis of SEER-Medicare data.
Authors: Min Ji Kim, Zhigang Duan, Hui Zhao, Holly Michelle Holmes, Joanna-Grace Mayo Manzano, Sharon Hermes Giordano, Maria E. Suarez-Almazor
Journal: Journal of Clinical Oncology (2017)

10027 Background: Despite risk for polypharmacy, elderly cancer patients may receive drugs whose time to benefit likely exceeds life expectancy. This study aims to describe use of drugs considered potentially unnecessary, namely anti-hyperlipidemics and anti-dementia drugs, and to identify factors associated with their use in Stage 3 or 4 non-small cell lung cancer (NSCLC) patients approaching end of life. Methods: We identified all patients older than 65 diagnosed with primary Stage 3 or 4 NSCLC between 2006 and 2011 in the Surveillance, Epidemiology and End Results (SEER)-Medicare database. Information on drug prescriptions was extracted from Medicare Part D files. First-time hospice enrollment or death date was used as the final endpoint in analysis. The primary outcome was use of drugs of interest at 4 months before NSCLC diagnosis, 6 months and 3 months before death or hospice. Associations with demographic or other factors were tested using the Pearson χ2 test. Results: Of all 7983 patients, 45.1% were taking statins before diagnosis, while 40.7% and 30.9% were still taking statins at 6 and 3 months before death or hospice. Use of bile acid sequestrants, fibric acid derivatives, and cholesterol absorption inhibitors were found to decrease toward death or hospice. In contrast, anti-dementia drug use did not decrease, with 3.4% before diagnosis and 4.2% and 3.5% at 6 and 3 months before death or hospice. Approximately 30% of anti-dementia medications were newly prescribed at 6 and 3 months before study endpoint. Having a higher number of prescriptions at 3 months before death or hospice was associated with higher rates of drug use both before and after cancer diagnosis. Having a higher Charlson comorbidity index correlated with greater anti-dementia drug use before diagnosis. Demographic, socioeconomic, and treatment factors were not found to be correlated with drug use. Conclusions: A high prevalence of statin use persists while a notable proportion of anti-dementia drugs are newly prescribed toward death or hospice. Our findings suggest an opportunity for clinicians to re-evaluate risks and benefits of potentially unnecessary medications in elderly patients nearing end of life.