tbuckley/cabot-search huggingface dataset:
Is there a role for immunotherapy (IO) and tyrosine kinase inhibitors (TKI) for older adults with metastatic renal cell carcinoma (mRCC)?
Authors: Nazli Dizman, Paulo Gustavo Bergerot, Cristiane Decat Bergerot, Joann Hsu, Jacob Adashek, William Dale, Sumanta K. Pal
Journal: Journal of Clinical Oncology (2018)

e22052 Background: Little is currently known about the impact of newer IO or TKI in older adults, the most rapidly-growing cohort with cancer. In the CheckMate025 trial comparing nivolumab and everolimus in patients (pts) with mRCC, overall survival (OS) benefit was seen with nivolumab in pts age 65+. we sought to determine if the same trend might be observed in cohort comprised of pts receiving IO or vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKIs). Methods: We reviewed the medical records of all mRCC pts who had been treated at the City of Hope Comprehensive Cancer Center between 2009 and 2017. Those treated with single agent VEGF-TKI or IO were included and divided into those 65+ and those <65. OS was compared between these two age groups. Results: In total, 293 (211:82 M:F) pts were analyzed. Mean age of pts was 62 (range, 25-87); 164 (56%) were <65 and 129 (44%) were 65+ years old. Overall, 258 (88%) pts were being treated with VEGF-TKI while 35 (12%) were on IO. Following stratification, 112 (43%) VEGF-TKI pts were 65+ and 17 (49%) IO pts. For pts on VEGF-TKIs, progression free survival (PFS) was 10.5 months for pts <65 and 6.5 months for pts 65+ (p=0.012). Amongst IO pts, progression-free survival (PFS) was 4.4 months for <65 and 5.3 months for pts 65+, respectively (p=0.775). OS for pts <65 vs pts 65+ was 16.8 months vs 21.9 months for pts on IO and 52.4 months vs 35.8 months for pts on VEGF-TKI (p= 0.426, p=0.066 respectively). An exploratory analysis showed no PFS or OS differences between pts 65+ treated with VEGF-TKI and IO. Conclusions: Clinical outcome with VEGF-TKIs appears to be inferior in pts 65+. In contrast, we found no difference in efficacy of IO in older adults versus younger ones, although the sample size was limited. Larger, prospective studies should investigate the relative benefit of these systemic therapy approaches in older adults with mRCC
Meta-analysis of phase II trials in metastatic uveal melanoma (MUM) to determine progression-free (PFS) and overall survival (OS) benchmarks for future phase II trials: An irci-ocular melanoma initiative.
Authors: Leila Khoja, Eshetu G. Atenafu, Anthony M. Joshua
Journal: Journal of Clinical Oncology (2016)

9567 Background: Multiple phase II trials in MUM have reported a range of survival outcomes with limited meaningful benefit. We conducted a meta-analysis to establish benchmarks of PFS and OS for future phase II trials Methods: Individual patient data was obtained from 29 trials with a total of 970 patients (pts). Trials were identified from a literature search and were conducted from 1988 to 2015. Univariable (UA) and multivariable (MA) prognostic factor analyses were performed. 6-month PFS and 1-year OS were determined controlling for identified prognostic factors Results: Data from 677 pts enrolled onto 19 trials were available at the time of analysis. Therapy consisted of immunotherapy, kinase inhibitors, chemotherapy and liver directed therapy; the table below details patient characteristics. Superior 6 month PFS (UA) was associated with LDH ≤ ULN (OR 2.05 p < 0.01) and ALP ≤ ULN (OR 2.56 p < 0.01) but each millimeter increase in diameter of the largest liver lesion (DLL) (OR 0.99 p = 0.007) decreased PFS. LDH ≤ ULN (OR 2.14 p < 0.01) and ALP ≤ ULN (OR 1.97 p = 0.015) were significant by MA. Predictive factors of superior 1 year OS by UA were LDH ≤ ULN (OR 2.88 p < 0.001) and ALP ≤ ULN (OR 2.45 p < 0.001). Male sex (OR 0.65 p = 0.008), older age (OR 0.99 p = 0.07), ECOG ≥ 1 (OR 0.45 p < 0.001) and larger DLL (0.98 p < 0.001) predicted inferior OS. Significant prognostic factors by MA were LDH ≤ ULN (OR 2.95 p < 0.001), ALP ≤ ULN (OR 2.07 p = 0.012), and larger DLL (OR 0.98 p < 0.001). Using pooled data controlled for prognostic factors the 6-month PFS rate was 25% and the 1-year OS rate was 40%. Conclusions: Key prognostic factors were identified and benchmarks of PFS and OS were explored. Analysis of the complete dataset (n~900) will be presented and the final results will guide the design of future trials in this rare disease. Characteristic Categories Number (%) Sex M/F 352/325 (52/48) ECOG 0/ ≥ 1 399/157 (72/28) LDH ≤ ULN/ > UNL 257/309 (45/55) ALP ≤ ULN/ > UNL 348/150 (70/30) Line of therapy 0/1/ ≥ 2 33/399/85 (6/77/17) Liver involvement (%) < 20/ ≥ 20 62/76 (45/55) Extrahepatic disease No/yes 391/214 (65/35) Age Median (Range) 61 (19-90) DLL (mm) Median (Range) 35 (0-225)
Genetic landscape of extreme responders with anaplastic oligodendroglioma: NRG Oncology/RTOG 9402.
Authors: Matthias Holdhoff, J. Gregory Cairncross, Robert B. Jenkins, Chetan Bettegowda, Ming Zhang, Thomas M. Kollmeyer, Srinivasan T. Yegnasubramanian, Stuart A. Grossman, Bert Vogelstein, Nickolas Papadopoulos, Kenneth W. Kinzler, Maria Werner-Wasik, Luis Souhami, Jean-Paul Bahary, Young Kwok, Alan C. Hartford, Peixin Zhang, Arnab Chakravarti, Minesh P. Mehta
Journal: Journal of Clinical Oncology (2016)

2054 Background: The randomized multicenter RTOG 9402 trial showed a significant survival benefit in patients with 1p/19q co-deleted anaplastic oligodendrogliomas (AO) who received both radiation (RT) and chemotherapy (PCV regimen) versus RT alone. Interestingly, substantial separation of the survival curves was only seen after 7.3 years. We aimed to determine whether there are specific genetic alterations that can distinguish co-deleted AO patients who benefit from the addition of PCV from those who do not. Methods: Whole exome sequencing on matched tumor and normal DNA was performed on all available short-term (STS) and long-term survivors (LTS) who received RT+PCV. The hTERTand risk allele (G) of rs55705857 status of both cohorts of patients were also analyzed. Results: Seven STS (5 with survival of < 7.3y, 2 with later progression) and 8 LTS (7 with survival of ≥ 7.3y without progression) had sufficient material for whole exome sequencing. Several specimens could not be included due to limited quantities or degradation of the material. Among the specimens studied, there was no significant difference between the groups regarding age, performance status and extent of resection. The average number of somatic mutations for STS vs. LTS was 4 vs. 7. Most common mutations identified were IDH1 (in 57% STS and in 88% LTS), CIC (29% and 75%, respectively) and FUBP1 (71% and 50%, respectively). The hTERT promoter was mutated in 71% STS and in all LTS. Risk allele (G) of rs55705857 was identified in all patients (GA in 43% and 25%, respectively). Intriguingly, mutations of ESX1were found only in the LTS (38%) and not the STS group. Conclusions: Our results did not identify a distinct genetic signature that correlates with improved benefit from chemotherapy with PCV in patients with newly diagnosed 1p/19q co-deleted AO; however, differences in alterations of ESX1 warrant further investigation.
Non-invasive clinical visualization of tumor infiltrating lymphocytes in patients with metastatic melanoma undergoing immune checkpoint inhibitor therapy: A pilot study.
Authors: Svetomir Markovic, Filippo Galli, Vera J. Suman, Wendy Kay Nevala, Andrew M Paulsen, Joseph C Hung, Denise N Gansen, Lori A Erickson, Paolo Marchetti, Gregory A. Wiseman, Alberto Signore
Journal: Journal of Clinical Oncology (2017)

3034 Background: Unique to modern immune therapy for cancer is that early in the course of treatment, patients frequently exhibit transient tumor enlargement (pseudo-progression, pPROG) due to tumor infiltration by lymphocytes (TIL). Currently, pPROG cannot be reliably distinguished from true tumor progression (PROG). There is a need for biomarker techniques to discriminate pPROG (effect of therapy) and PROG (therapy failure). Nuclear medicine offers radiopharmaceuticals capable of imaging immune cells; images can be fused to evaluate functional and anatomic characteristics of tumors, and potentially discriminate pPROG from PROG. Methods: In our study of metastatic melanoma patients, SPECT/CT imaging with 99m Tc-interleukin-2 ( 99m Tc-IL2) was performed to visualize TIL. Images were collected before/after 12 weeks of ipilimumab (IPI) or pembrolizomab (PEMBRO) therapy. The 99m Tc-IL2 tracer was synthesized by conjugating succinimidyl-6-hydrazinopyridine-3-carboxylate (HYNIC-NHS) with commercial interleukin-2 (Aldesleukin). HYNIC-IL2 was incubated with tricine, 99m TcO 4 - (370-740 MBq) and SnCl 2 . After labelling 99m Tc-IL2 was purified by reverse-phase chromatography and diluted in 5% glucose with 0.1% human albumin before injection. Five patients were enrolled in this study. Two patients failed to complete the 12 week 99m Tc-IL2 scan due to discontinuation of IPI after: 1) grade 3 colitis and 2) patient refusal for adverse events attributed to IPI. No adverse events attributable to the tracer infusion were reported. Results: Metastatic lesions could be visualized by the tracer. Some lesions decreased in size, while others increased. A positive correlation was found between size and 99m Tc-IL2 uptake, before and after therapy, suggesting the potential discrimination of tumor PROG (no 99m Tc-IL2 uptake) from pPROG (high 99m Tc-IL2 uptake). Immunohistochemical staining for TIL of 99m Tc-IL2 positive and negative lesions are illustrated. Conclusions: The results demonstrate feasibility of 99m Tc-IL2 imaging as a clinically useful tool capable of discriminating tumor PROG from pPROG. A clinical validation study is in progress. Clinical trial information: NCT01789827.
Changes in stage at diagnosis of screenable cancers after the Affordable Care Act.
Authors: Xuesong Han, Chun Chieh Lin, Ahmedin Jemal
Journal: Journal of Clinical Oncology (2017)

6521 Background: Extensive evidence links inadequate insurance with later stage at cancer diagnosis, particularly for cancers that can be detected by screening. The Affordable Care Act (ACA) implemented in 2014 has substantially increased insurance coverage for Americans 18-64 years old. This study aims to examine any changes in stage at diagnosis after the ACA for the following cancers for which screening is recommended for individuals at risk: female breast cancer, colorectal cancer, cervical cancer, prostate cancer, and lung cancer. Methods: We used National Cancer Data Base, a nationally hospital-based cancer registry capturing 70% new cancer cases in the US each year, to identify nonelderly cancer patients with screening-appropriate age who were diagnosed during 2013-2014. The percentage of stage I disease was calculated for each cancer type before (2013 Q1-Q3) and after (2014 Q2-Q4) the ACA. 2013 Q4-2014 Q1 was excluded as a washout/phase-in period. Prevalence ratios (PR) and 95% confidence intervals (CI) were calculated using log-binomial models controlling for age, race/ethnicity and sex if applicable. Results: 121,855 female breast cancer patients aged 40-64 years, 39,568 colorectal cancer patients aged 50-64 years, 11,265 cervical cancer patients aged 21-64 years, 59,626 prostate cancer patients aged 50-64 years, and 41,504 lung cancer patients aged 55-64 years were identified. After the implementation of the ACA, the percentage of stage I disease increased statistically significantly for female breast cancer (47.8% vs. 48.9%; PR = 1.02 [95%CI 1.01-1.03]), colorectal cancer (22.8% vs. 23.7%; PR = 1.04 [95%CI 1-1.08]), and lung cancer (16.6% vs. 17.7%; PR = 1.06 [95% CI 1.02-1.11]). A shift to stage I disease was also observed for cervical cancer (47.2% vs. 48.7%; PR = 1.02 [95% CI 0.98-1.06]) although not statistically significant. In contrast, the percentage of stage I decreased for prostate cancer (18.5% vs. 17.2%; PR = 0.93 [95%CI 0.9-0.96]) in 2014. Conclusions: The implementation of the ACA is associated with a shift to early stage at diagnosis for all screenable cancers except prostate cancer, which may reflect the recent US Preventive Services Task Force recommendations against routine prostate cancer screening.
TCT-484 Electrosurgical Laceration of Alfieri Stitch (ELASTIC) to Facilitate Transcatheter Mitral Valve Replacement: First-in-Human Report
Authors: Jaffar Khan, Robert Lederman, Saurabh Sanon, Bradley Leshnower, Altayyeb Yousef, Patrick Gleason, Stamatios Lerakis, Toby Rogers, Adam Greenbaum, Vasilis Babaliaros
Journal: Journal of the American College of Cardiology (2018)
Association of circulating tumor DNA (ctDNA) detection in metastatic renal cell carcinoma (mRCC) with tumor burden.
Authors: Manuel Caitano Maia, Paulo Gustavo Bergerot, Nazli Dizman, JoAnn Hsu, Jeremy Jones, Toni K. Choueiri, Guru Sonpavde, Richard B. Lanman, Kimberly Banks, Sumanta K. Pal
Journal: Journal of Clinical Oncology (2017)

4582 Background: In a series of 224 pts with advanced RCC, we have previously reported ctDNA detection in 79% of pts (Pal SK et al ASCO GU 2017). Clinical factors associated with detection are unknown. Methods: Data was obtained from pts with radiographically confirmed stage IV RCC who received ctDNA profiling as a part of routine clinical care using a CLIAA-certified platform evaluating 73 genes. Detailed clinical annotation was performed, including assessment of Heng risk score, previous and current treatments and calculation of tumor burden using scan data most proximal to ctDNA assessment. Tumor burden was equated to the sum of longest diameter (SLD) of all measurable lesions. Results: 32 pts were assessed (M:F 19:13) with a median age of 62 (range, 34-84). 25 pts, 4 pts and 3 pts had clear cell, sarcomatoid and papillary histology, respectively. Heng risk was good, intermediate and poor in 13, 18 and 1 pt, respectively. Pts received a median of 2 lines of prior tx. Specifically, 4 pts were not on active therapy (tx), 16 pts were receiving VEGF-directed tx, 6 pts were receiving checkpoint inhibitors (CPIs) and 6 pts were receiving combined VEGF/CPI tx. ctDNA was detected in 16 pts (50%) with a median of 2 genomic alterations (GAs) per pt. No associations were found between Heng risk, histology or tx type and presence/absence of ctDNA. However, pts with detectable ctDNA had a higher SLD compared to pts with no detectable ctDNA (99.6 vs 50.0 mm; P = 0.041). Furthermore, when evaluated as a continuous variable, number of GAs was correlated with SLD (P = 0.023). TP53 and VHL alterations were the most frequent GAs in this series, each occurring in 25% of the cohort. All 3 pts with brain metastases had ctDNA detected. Conclusions: With the caveat of a limited sample size, it appears that SLD (a surrogate for tumor burden) is higher in mRCC pts with detectable ctDNA, and increasing SLD may be associated with a higher number of GAs. Further validation of these findings may help identify appropriate pts for ctDNA assessment and maximize yield in clinical practice.
Association of autologous AdHER2 dendritic cell vaccination with antitumor activity and number of circulating tumor cells.
Authors: Lauren Virginia Wood, Brenda D. Roberson, Piyush K. Agarwal, Andrea B. Apolo, David Stroncek, Louis M. Weiner, John Charles Morris, Masaki Terabe, Min-Jung Lee, Jane B. Trepel, Jay A. Berzofsky
Journal: Journal of Clinical Oncology (2017)

3089 Background: We achieved cure of large established tumors in syngeneic BALB/c mice using an adenoviral vector vaccine expressing rodent HER2 extracellular (EC) and transmembrane (TM) domains mediated by the induction of anti-HER2 antibodies. We report clinical translation utilizing an autologous adenoviral- transduced dendritic cell (DC) vaccine expressing human HER2 EC and TM domains (AdHER2ECTM) in adults with advanced metastatic tumors with 1-3+ HER2 expression. Methods: In this two-part phase I study (NCT01730118) subjects with HER2+ metastatic solid tumors naïve to HER2-targeted therapies (Part 1) or HER2+ treatment-experienced breast cancer (Part 2) received 5 doses of vaccine at Weeks 0, 4, 8, 16 and 24. Part 1 dose escalation involved 3 cohorts of 6 patients utilizing 5x10 6 , 10x10 6 and 20x10 6 viable DCs per dose, respectively. With no DLTs or evidence of cardiac toxicity, dose escalation to 40x10 6 viable DCs per dose was allowed in the Part 1 Expansion Cohort and Part 2 treatment was begun at a starting dose of 20x10 6 viable DCs per vaccine. Adjuvant muscle-invasive bladder cancer patients were allowed to enroll with safety documented out to 12 weeks in &gt; 10 treated patients. Re-staging was assessed using immune-related response criteria (irRC). Remaining study accrual: Part 1 (N = 9), Part 2 (N = 24). Results: A total of 27 cancer patients (7 colon, 6 breast, 5 ovarian, 3 bladder, 6 other) have received &gt; 2 vaccine doses (median 4): 19F, 8M, median age 60 yrs, median 3 prior treatment regimens (range 1-11); HER2 IHC 1+ N = 6, 2+ N = 9, 3+ N = 12. Of metastatic patients receiving 10x10 6 viable DCs per dose or higher, 7 of 19 (37%) had evidence of response by irRC: 1 CR (ongoing at 100 weeks), 1 PR (-71% lasting 44 weeks) and 5 SD (median duration 24 weeks, range 8 to 48 weeks). Two adjuvant bladder cancer patients remain without disease at 100 weeks. Adverse events were limited to local injection site reactions &lt; G2. Of patients with paired baseline samples, 40% (8/20), 83% (5/6) and 100% (2/2) exhibited decreases in circulating tumor cells at 12, 28 and 48 weeks, respectively. Conclusions: AdHER2 DC vaccination is safe and is associated with evidence of clinical benefit and anti-tumor activity. Clinical trial information: NCT01730118.
Real world treatment patterns of first-line combination therapies among patients with metastatic melanoma and BRAF mutation.
Authors: Ying Qiu, Zhiyi Li, Jackson Tang, Pavel Atanasov, Syed Mahmood, Kris Grzegorzewski, Lei Chen, Joyce S Chen
Journal: Journal of Clinical Oncology (2017)

e21011 Background: First line (1L) systemic combination (combo) therapies for treatment of metastatic melanoma (MM) include targeted combo therapies such as dabrafenib+trametinib (D+T) or vemurafenib+cobimetinib for patients (pts) with BRAF mutation (BRAF+), or immunotherapy combo ipilimumab+nivolumab (I+N) for pts irrespective of BRAF status. The objective of this study was to describe real world characteristics and treatment patterns among BRAF+ mm pts who were treated with either D+T or I+N as 1L therapy. Methods: This retrospective observational study utilized Flatiron Health’s electronic health record (EHR) data from Jan 2013 to Jul 2016. Pts were aged ≥18 years with a mm diagnosis, and treated with either D+T (N = 86) or I+N (N = 61) as 1L therapy. Prior to therapy initiation, 86/86 of D+T pts were tested BRAF+. 55/61 of I+N pts completed BRAF testing and 19/61 were BRAF+. All analyses focused on BRAF+ pts who were treated with either D+T or I+N as 1L therapy. Baseline characteristics, treatment patterns and data on therapy discontinuation were collected from structured data in patient records and unstructured data in physician notes, and were descriptively assessed. Statistical inferences were not drawn due to sample size limitations. Results: At baseline, 35% of D+T pts vs 32% of I+N pts had brain metastasis, 29% of D+T pts vs 11% of I+N pts had high LDH levels, and 20% of D+T pts vs 42% of I+N pts reported ECOG = 0 status. The median follow-up time was 219 days for the D+T pts vs 150 days for the I+N pts. The 3 and 6 month discontinuation rates were 9% and 24% for the D+T pts vs 21% and 47% for the I+N pts. 13% of D+T pts vs 26% of I+N pts discontinued treatment citing toxicity in physician notes. Among pts with brain metastasis, the 3 and 6 month discontinuation rates were 3% and 20% for D+T pts vs 33% and 50% for I+N pts. Conclusions: Among BRAF+ mm pts who were treated with either D+T or I+N as 1L therapy, D+T pts were more likely to have advanced disease such as brain metastasis and high LDH levels than I+N pts. Compared with 1L D+T pts, 1L I+N pts had higher discontinuation rates due to toxicity, even with a shorter median follow-up time. 1L I+N pts with brain metastasis also had higher discontinuation rates.
Identification of outcome-correlated serum cytokine and chemokine clusters in ovarian clear cell carcinoma.
Authors: Akira Yabuno, Hirokazu Matsushita, Daisuke Shintani, Tetsutaro Hamano, Nao Fujieda, Sho Sato, Tadaaki Nishikawa, Keiichi Fujiwara, Kazuhiro Kakimi, Kosei Hasegawa
Journal: Journal of Clinical Oncology (2018)

5544 Background: With the progress of immune-oncology, the immunological background of epithelial ovarian carcinoma (EOC) is gradually becoming understood. However, most of the studies have been focused on the local tumor-immune microenvironment, and the systemic immunological background in patients with EOC has not been well studied. Serum cytokines and chemokine networks may reflect the complex systemic immunological interactions in cancer patients. Studying groups of cytokines and their networks may help in improving immunotherapy for EOC patients. Methods: A total of 178 cases of EOC were analyzed in this study, including 73 high-grade serous (HGSC), 66 clear cell (CCC) and 39 endometrioid (EMC) subtype cases. Suspension cytokine arrays, which enable measurement of the levels of 27 cytokines and chemokines, were performed with the patients’ sera taken before the primary surgery. Levels of all cytokines were log(x+1) transformed and normalized. Associations between each cytokine and clinocopathological factor were analyzed in all EOC patients using multivariate linear regression models. Cluster analyses were performed for all EOC and each histotype. Results: In the multivariate analyses, eleven of 27 cytokines were correlated with histotypes. In contrast, no correlations were found between each cytokine and FIGO stage. Cluster analysis of all EOC patients revealed distinct cytokine profiles in HGSC and CCC, but not in EMC. Cluster analyses in each histotype revealed 2 cytokine clusters in both HGSC and CCC. Interestingly, 22 of 27 cytokines (81.5%) were commonly clustered in HGSC and CCC. Cluster 1 included IL-2, 6, 8, 15, chemokines and angiogenic factors, whereas Cluster 2 included IL-4, 5, 9, 10, 13, TNFalpha and G-CSF. We classified the tumors into 4 subgroups based on a high or low level for each cluster in both HGSC and CCC, and this cluster-based classification demonstrated significantly different progression-free and overall survivals for CCC patients (p = 0.00097 and p = 0.017). Conclusions: Serum-based cytokine clusters determine the histotypes of EOC and their prognosis in patients with CCC. Further study of cytokine networks may provide new strategies for cancer immunotherapy.