tbuckley/cabot-search huggingface dataset:
Definitive chemoradiation with carboplatin and paclitaxel in locally advanced esophageal carcinoma: A retrospective analysis at the Brazilian National Cancer Institute (INCA).
Authors: Kelly Borges Araujo, Mariana Bruno Siqueira, João Paulo Fogacci de Farias, Roberto Almeida Gil
Journal: Journal of Clinical Oncology (2016)

e15549 Background: Esophageal cancer is the 6th cause of cancer deaths worldwide. For patients with unresectable disease or unfit for surgery, definitive chemoradiation with cisplatin, 5-fluoracil (5-FU) and radiotherapy at a dose of 50.4Gy is considered as the standard of care. More recently, several reports have shown the efficacy of chemoradiation with carboplatin plus paclitaxel, which has been associated with a better toxicity profile. Methods: A retrospective analysis of patients with locally advanced esophageal carcinoma (squamous and adenocarcinoma) was performed. Eligible patients presented with unresectable or medically inoperable disease were treated with weekly paclitaxel 50 mg/m2 and carboplatin AUC2 concomitant with radiotherapy. All patients were treated at the Brazilian National Cancer Institute (INCA) between January 2012 and December 2013. Data on clinical and pathological characteristics, toxicity profile were reviewed. Results: A total of 46 patients were analyzed, mostly males (78%), with an ECOG PS of 0 or 1 (80%), and a median age of 62 years (45-76). The most common histological subtype was squamous cell carcinoma (83%), and 61% presented at clinical tumor stage T3N0. Seventy percent of patients received 5 or more cycles of chemotherapy and 89% received radiation doses between 45Gy and 50.4Gy. Four patients underwent surgery after chemoradiation, two of which had complete pathological response. The most serious hematological and non-hematological toxicities (grade 3) were anemia (2%) and fatigue (13%). There were no grade 4 adverse events or treatment related deaths. Median overall survival was 13.4 months (CI 95%, 7.69 to 19.25) and median disease-free survival was 9.5 months (CI 95% 8.15 to 10.9). Conclusions: Definitive treatment with chemoradiation using carboplatin and paclitaxel could be an option for patients who are not surgical candidates. This regimen was associated with low and acceptable toxicity rates and a durable locoregional control. These results are comparable with previous retrospective studies, however, further investigation with prospective randomized studies is warranted.
Fine-mapping and functional studies highlight potential causal variants for rheumatoid arthritis and type 1 diabetes
Authors: Harm-Jan Westra, Marta Martínez-Bonet, Suna Onengut-Gumuscu, Annette Lee, Yang Luo, Nikola Teslovich, Jane Worthington, Javier Martin, Tom Huizinga, Lars Klareskog, Solbritt Rantapaa-Dahlqvist, Wei-Min Chen, Aaron Quinlan, John A. Todd, Steve Eyre, Peter A. Nigrovic, Peter K. Gregersen, Stephen S. Rich, Soumya Raychaudhuri
Journal: Nature Genetics (2018)
NSABP FR-2: Phase II study of durvalumab following neoadjuvant chemoRT in stage II-IV rectal cancer.
Authors: Thomas J. George, Greg Yothers, Samuel A. Jacobs, Gene Grant Finley, Hiral D. Parekh, Timothy David Moore, Bassam Nabih Maalouf, John C. Krauss, Melvin Deutsch, James J. Lee, Carmen Joseph Allegra, Norman Wolmark
Journal: Journal of Clinical Oncology (2020)

TPS264 Background: Clinical improvements for locally advanced rectal cancer have been relatively static over the past few decades. While immunotherapy shows no benefit in microsatellite stable (MSS) colorectal cancer, preclinical models suggest that radiotherapy (RT) can enhance neoantigen presentation, modulate the microenvironment, and improve the likelihood of anti-tumor activity with checkpoint inhibitor use. Using a “window-of-opportunity” study design, this prospective phase II trial will determine the safety and activity of this approach with the anti-PD-L1 agent durvalumab (MEDI4736). Methods: This multi-center phase II trial is currently enrolling patients (pts) with rectal cancer who are undergoing standard NCCN guideline-compliant neoadjuvant chemoradiotherapy (CRT). Eligibility includes pts with MSS stage II-IV rectal cancer with adequate organ function and pre-treatment diagnostic tumor available for profiling with intent to proceed to surgical resection after CRT. Stage IV disease must be limited such that the primary pelvic tumor requires definitive management. Standard ineligibility criteria include active infections, systemic steroid use, or other conditions making immunotherapy use unsafe. Treatment includes durvalumab (750mg IV infusion once every 2 wks) for 4 total doses beginning within 3-7 days after CRT completion. Surgery must be within 8-12 wks of the final CRT dose. Primary endpoint is a demonstrated improvement in Neoadjuvant Rectal Cancer (NAR) score compared to historical controls targeting a 20% relative risk reduction in DFS and 3-4% absolute OS improvement. Secondary endpoints include OS, DFS, toxicity, pCR, cCR, therapy completion, negative surgical margins, sphincter preservation, off-target “abscopal” effects for the subset of stage IV pts, and exploratory assessments of tumor infiltrating lymphocytes, tumor Immunoscore, circulating immunologic profiles, and molecular predictors of response. A safety run-in phase has completed as a precedent to full enrollment. Enrollment now continues to 47 total pts to achieve 41 surgically evaluable pts. Support: AstraZeneca-Medimmune, NSABP Foundation. Clinical trial information: NCT03102047.
Phase II multi-site investigation of neoadjuvant pembrolizumab and adjuvant concurrent radiation and pembrolizumab with or without cisplatin in resected head and neck squamous cell carcinoma.
Authors: Trisha Michel Wise-Draper, Matthew O. Old, Francis P. Worden, Paul E. O'Brien, Ezra E.W. Cohen, Neal Dunlap, Michelle Lynn Mierzwa, Keith Casper, Sarah Palackdharry, Benjamin Hinrichs, Alfredo Molinolo, Vinita Takiar, Jonathan Mark, Alice Tang, Muhammad Kashif Riaz, John Charles Morris, Nooshin Hashemi Sadraei, Changchun Xie, Maura L. Gillison
Journal: Journal of Clinical Oncology (2018)

6017 Background: 2Despite aggressive adjuvant treatment, locally advanced HNSCC patients undergoing primary surgical resection with high risk [HR] features (extracapsular extension of lymph nodes (LN) and/or positive margins) have 3 year disease free survival (DFS) of 47-57%. Pre-clinically, radiation upregulates the immune checkpoint PD-L1 and importantly PD-L1 blockade concurrently with radiation resulted in improved overall survival (OS) in mice bearing HNSCC tumors. Therefore, we initiated a window of opportunity study "Phase II Investigation of Adjuvant Combined Cisplatin and Radiation with Pembrolizumab in Resected HNSCC" (NCT02641093) supported by Merck. Methods: Clinically high risk (T3/4 stage and/or ≥2 + LNs) patients received the PD-1 antibody, pembrolizumab (200 mg I.V. x 1), 1-3 weeks before resection. Adjuvant concurrent pembrolizumab (q3 wks x 6 doses) and radiation (60-66Gy) were administered, along with weekly cisplatin (40mg/m2) for those with HR features. Pre- and post-surgical specimens were archived for H&E, immunohistochemistry, RNAScope and Nanostring. Safety lead-in included first 8 patients of each arm and dose limiting toxicity (DLT) was determined by delay in surgery, radiation and/or cisplatin. Results: Twenty-eight of 80 planned patients have been enrolled with 23 evaluable for efficacy. Characteristics included median age of 52 (range, 27-80), 32% female, T3- 21%, T4- 46% and 64% ≥ N2b. The lead-in safety period is near completion (15/16) without DLT with 9/19 (47%) patients demonstrating a pathological response ( > 10% tumor effect [TE]) and 6/19 (32%) achieving major response ( > 70% TE), one of which had a pathological complete response after 1 dose. Pathological response was associated with robust immune cell infiltration, increased PD-L1 and PD-L2. Two patients (neither attaining pathological response) have recurred. Conclusions: Pathological response was seen after one dose of pembrolizumab in HNSCC. Increased tumor immune cell infiltration predicted pathological response. Adjuvant combination treatment with pembrolizumab has an acceptable safety profile. Clinical trial information: NCT02641093.
Cisplatin/5-FU (CF) +/- panitumumab (P) for patients (pts) with non-resectable, advanced, or metastatic esophageal squamous cell cancer (ESCC): An open-label, randomized AIO/TTD/BDGO/EORTC phase III trial (POWER).
Authors: Markus H. Moehler, Peter C. Thuss-Patience, Baruch Brenner, Federico Longo, Johannes Meiler, Thomas Jens Ettrich, Ralf Hofheinz, Salah-Eddin Al-Batran, Arndt Vogel, Lothar Mueller, Manfred P. Lutz, Kersten Borchert, Richard Greil, Maria Alsina, Aysun Karatas, Eric Van Cutsem, Ralph Keller, Julian Larcher-Senn, Sylvie Lorenzen
Journal: Journal of Clinical Oncology (2017)

4011 Background: Most ESCC pts have advanced disease at time of diagnosis. Chemotherapy (CTX) is used to improve quality of life (QoL) and overall survival (OS), but still with limited impact. Prior studies suggested increased efficacy of EGFR antibodies (AB) combined with CF (Lorenzen, Ann Oncol 2009). Methods: This open-label, randomized (1:1), multicenter, multinational phase III included pts with non-resectable, advanced or metastatic ESCC (RECIST1.1), not radiochemotherapy (RCTX) eligible and ECOG 0-1. Previous CTX in metastatic setting, concurrent RCTX and exposure to EGFR-AB were excluded. Pts received CF (C 100 mg/m² d1 + F 1000 mg/m²/d, d1-4) or CFP (9 mg/kg d1) q3 weeks until disease progression. Due to more Gr3-4 SAEs in the first 60 Pts with CFP, C was reduced to 80mg/m²d1 Tumor assessment was performed q9 weeks. Primary objective was OS: superiority of CFP (9 months [mo]) over CF (6 mo) with 300 pts (90% power). Results: Between 6.2012-5.2015, 146/155 pts were randomized. After interim analysis for futility, the trial was stopped. 60(83%) of CFP and 55(79%) of CF pts had any AE, mostly diarrhea, hypokalemia, hypomagnesaemia, rash, and hand-foot syndrome. Main Gr≥3 AEs were low neutrophils 21/ 24% and anemia 13/16 % for CFP vs CF, respectively. Gr 3-4 skin reactions and rash were higher in CFP (10%) vs CF (0%). Overall, 51/72 (71%) of CFP and 36/70 (51%) of CF had SAE. Main SAE were dysphagia, acute kidney injury, diarrhea, fevers and febrile neutropenia in 6/6%, 7/4%, 7/3%, 3/6% and 6/1% for CFP vs CF, respectively. For all CFP vs CF pts, median OS was 9.4 vs. 10.2 mo (hazard ratio (HR) 1.17, 95%CI 0.79-1.75; P=0.43). For 56 pts treated with cisplatin 100mg/m²d1, OS was 9.4 vs. 12.9 mo (HR 1.83, 95 % CI 0.98-3.42; P=0.06). After C was reduced (80mg/m²), OS (85 pts) favored CFP vs CF, with 9.8 vs. 8.3 mo (HR 0.84, 95%CI 0.49-1.43; P=0.51). Median PFS for all CFP vs CF pts, was 5.3 vs. 5.8 mo. (HR 1.21, 95%CI 0.85-1.73; P=0.29) respectively. Conclusions: Addition of Panitumumab to CF provided no additional benefit to chemotherapy alone as first-line treatment of ESCC. Biomarker program is going on for further analyses. Clinical trial information: NCT1627379.
Sex hormones as regulators of levels of growth factors in tissues of multiple primary tumors of female reproductive organs.
Authors: Oleg Ivanovich Kit, Elena Mikhaylovna Frantsiyants, Tatiana Moiseenko, Marina I. Vereskunova, Meri Viktorovich Adamyan, Natalya S. Saforian, Viktor Viktorovich Gurnak, Maria G. Ilchenko
Journal: Journal of Clinical Oncology (2017)

e23180 Background: Sex hormones are known to be able to influence the synthesis of growth factors in breast and uterine tumors; however, their relationship in multiple primary tumors is poorly studied. The purpose of the study was to analyze correlations between sex steroids and growth factors in tissues of solitary and synchronous breast cancer and uterine myoma. Methods: Levels of estrogens (E1, E2, E3), 2OHE1 and 16α-OHE1, Р4, VEGА and EGF were measured by ELISA in tissues of breast cancer (BC, n = 37), uterine myoma (n = 27) and in synchronous BC and uterine myoma (n = 36). Results: Strong positive correlations were observed in synchronous BC and uterine myoma: E3 with VEGF (r 1 = 83, r 2 = 79; p 1,2 &lt; 0.05) and EGF (r 1 = 78, r 2 = 82; p 1,2 &lt; 0.05), Е1 with VEGF ( r 1 = 81, r 2 = 77; p 1,2 &lt; 0.05) and EGF (r 1 = 76, r 2 = 80; p 1,2 &lt; 0.05), 16-OHE1 with VEGF and EGF (r 1 = 80, r 2 = 77; p 1,2 &lt; 0.05 and r 1 = 79 r 2 = 80; p 1,2 &lt; 0.05). We found strong negative correlations of Е3 and VEGF (r 1 = 80, r 2 = 77; p 1,2 &lt; 0.05) and EGF (r 1 = 79 r 2 = 80; p 1,2 &lt; 0.05), Р4 and VEGF (r 1 = - 81, r 2 = -79; p 1,2 &lt; 0.05) and EGF (r 1 = - 77, r 2 = -80; p 1,2 &lt; 0.05). Solitary breast tumors showed moderate positive correlations of E2 and E1 with VEGF (r 1 = 56, r 2 = 63; p 1,2 &lt; 0.05) and EGF (r 1 = 61, r 2 = 65; p 1,2 &lt; 0.05) and a moderate negative correlation between VEGF and EGF and Р4 (r 1 = - 61, r 2 = -59; p 1,2 &lt; 0,05). A strong negative correlation of EGF with Е1 and 16-OHE1 (r 1 = -79, r 2 = -76; р 1,2 &lt; 0.05) was registered in uterine myoma. Conclusions: Tissues of synchronous primary breast tumors and uterine myoma had similar correlations between levels of growth factors and sex hormones. Solitary breast tumors and uterine myoma showed correlations typical of the tumor type. Thus, expression of growth factors in multiple primary tumors, but not in solitary ones, is subject to a clearly determined regulatory role of sex steroids and their metabolites.
Trends in the choice of first line treatment for hormone - responsive (HR+), human epidermal growth factor receptor - 2 negative (HER2-) metastatic breast cancer (MBC) patients (pts): Results of a multicentric Italian observational study.
Authors: Alessia D'Alonzo, Claudia Bighin, Fabio Puglisi, Michelino DeLaurentiis, Andrea Fontana, Palma Pugliese, Grazia Arpino, Francesca Poggio, Marina Vaglica, Chiara Dellepiane, Eva Blondeaux, Benedetta Conte, Francesco Cognetti, Ornella Garrone, Simona Pastorino, Marcello Ceppi, Lucia Del Mastro
Journal: Journal of Clinical Oncology (2018)

e13053 Background: Most of HR+ MBC pts receive both hormonal therapy (HT) and chemotherapy (CT) during the course of their disease. According to international guidelines, HT should be preferred over CT in the first-line setting, restricting CT only to pts not responsive to HT or at risk of visceral crisis. Observational studies indicate that nearly 50% of this pts receive CT as first - line treatment. We aimed to evaluate if this behaviour does change in recent years. Methods: All consecutive MBC pts receiving a first-line treatment at 13 centers of GIM group (Gruppo Italiano Mammella) from 2000 to 2017 were registered. For the purpose of this analysis, we selected only HR+ MBC. The choice between first - line HT or CT was performed by the treating physician on the basis of pts and disease characteristics. The type of first line treatment (HT or CT) was analyzed according to four different cohorts: 2000 - 2005; 2006 - 2010; 2011 - 2013; 2014 - 2017. Results: 1709 pts with MBC were included in the GIM registry, among which 830 had HR+ tumors (306 Luminal A, 458 Luminal B, 66 with Ki67 unknown). Overall, 352 (42,4%) and 478 (57,6%) pts received CT and HT as first line treatment, respectively. HT was the first line treatment in 53%; 54%; 61% and 60% of pts in the 2000 - 2005, 2006 - 2010, 2011 - 2013, 2014 - 2017 cohorts, respectively (p for trend:0.114). Among premenopausal pts, only 40% (n = 80) received HT as first-line treatment for their MBC. Conclusions: Despite our results suggest an increase in the use of HT as first line treatment in HR+ MBC, the percentage of pts receiving CT is still above that expected from adherence to the guidelines. In premenopausal patients, CT remains the preferred option in the first-line setting.
Correlation of imaging and plasma-based biomarkers to predict response to bevacizumab in epithelial ovarian cancer (EOC): A GOG 218 ancillary data analysis.
Authors: Megan Buechel, Danielle Enserro, Robert Allen Burger, Mark F. Brady, Katrina Wade, Angeles Alvarez Secord, Andrew B. Nixon, Seyedehnafiseh Mirniaharikandehei, Hong Liu, Bin Zheng, Heidi Gray, Krishnansu Sujata Tewari, David M. O'Malley, Robert S. Mannel, Kathleen N. Moore, Michael J. Birrer
Journal: Journal of Clinical Oncology (2018)

5507 Background: Increasing measures of adiposity can correlate with poor oncologic outcomes and lack of response to antiangiogenic therapies. Limited data exists on the impact of subcutaneous fat and visceral fat density(SFD/ VFD) on oncologic outcomes. IL-6 has been suggested as a predictive serum biomarker for overall survival (OS) with use of bevacizumab (bev) in EOC. Methods: 1249 patients(pts) (67%) from GOG 218 with imaging measurements were included in the OS analysis. Predictive analyses for bev responsiveness used pts who received chemotherapy (CT) + placebo and placebo maintenance and CT + bev and bev maintenance (851 pts). Of these, 522 pts (61%) had IL-6 measurements. SFD and VFD were calculated utilizing Hounsfield units (HU). Proportional hazards models were used to assess the association between BMI, SFD, and VFD with OS. Spearman correlation was used to assess the relationship between IL-6 and VFD. Results: Demographic characteristics for pts included in this analysis did not differ from the entire cohort. Increased SFD and VFD showed an increased HR for death (HR per 1-SD increase 1.12, 95% CI:1.05-1.19 p = 0.0009 and 1.13, 95% CI: 1.05-1.20 p = 0.0006 respectively). OS curves for high SFD and VFD show the most separation within quartiles (difference of ~10 months between the 2nd and 4th quartiles). In the predictive analysis, VFD showed a significantly different effect in the two treatment groups (p = 0.025). High VFD showed an increased hazard for death in the placebo group (HR per 1-SD increase 1.22, 95% CI: 1.09-1.37). However, in the bev group there was no effect seen (HR per 1-SD increase: 1.01, 95% CI: 0.90-1.14). OS curves show median OS of 45 vs 47 months in the VFD low groups and 36 vs 42 months in the VFD High groups on placebo versus bev respectively. There was no correlation between IL-6 and high VFD (r = 0.02, p = 0.57). Conclusions: High SFD and VFD may be prognostic biomarkers for EOC. High VFD may be a predictive biomarker for use of bev. Pts with high VFD improved their OS curve to the low VFD group with the addition of bev. A similar association was seen with IL-6; however, high IL-6 and high VFD occur in different populations. Further biomarker study is warranted.
Polymorphisms in the PRTOR gene in relation to gastric adenocarcinoma susceptibility in an Eastern Chinese population.
Authors: Meng-Yun Wang, Ming Jia, Jing He, Qing-Yi Wei
Journal: Journal of Clinical Oncology (2017)

e15552 Background: RPTOR is an essential scaffold for MTOR complex which is necessary for the MTOR-catalyzed phosphorylation. Methods: In this study of 1,100 gastric cancer (GCa) cases and 1,137 matched cancer-free controls, we investigated associations between eight potentially functional single nucleotide polymorphisms (SNPs) (rs3751934 C &gt; A, rs1062935 T &gt; C, rs12602885 G &gt; A, rs1468032 T &gt; A, rs1468033 A &gt; G, rs2271610 C &gt; G, rs2271612 C &gt; T, and rs2878052 G &gt; A) in RPTOR and gastric cancer risk in an Eastern Chinese Population. Results: In logistic regression analysis, a significantly increased GCa risk was associated with the rs1468032 AA variant genotype (adjusted odds ratio [OR] = 1.32, 95% confidence interval [CI] = 1.09-1.60) under a dominant model, which remained significant after correction by the false-positive reporting probability. This risk was more evident in subgroups of younger subjects, females, never smokers, never drinkers, cancers of non-cardia and stage of Ⅲ+Ⅳ. We then performed SNP-mRNA expression correlation analysis in GTEx database as well as using real-time PCR in adjacent noncancerous tissues. We found that the AA variant genotype was associated with non-significantly decreased expression of RPTOR mRNA level. Conclusions: Our results suggest that the RPTOR rs1468032 A variant may be markers for GCa susceptibility. Larger, independent studies are warranted to validate our findings.
Time to treatment discontinuation (TTD) as a pragmatic endpoint in metastatic non-small cell lung cancer (mNSCLC): A pooled analysis of 8 trials.
Authors: Yutao Gong, Kenneth L. Kehl, Geoffrey R. Oxnard, Sean Khozin, Pallavi Shruti Mishra-Kalyani, Gideon Michael Blumenthal
Journal: Journal of Clinical Oncology (2018)

9064 Background: Progression-free survival (PFS) is an important efficacy endpoint in oncology trials. However, clinical trials increasingly allow treatment beyond objective radiographic progression (TBP) for patients deriving clinical benefit from therapy. Furthermore, treatment discontinuation due to toxicity is increasingly uncommon in trials of targeted therapies. Thus, TTD may represent a practical endpoint for real-world evidence (RWE) studies. Methods: We pooled data from patients (pts) with mNSCLC treated on 13 arms of 8 randomized controlled trials of tyrosine kinase inhibitors (TKI), immune checkpoint inhibitors (ICI), or chemotherapy (Chemo) initiated between 2007-2014; 3 chemo arms with planned discontinuation without maintenance therapy were excluded. We measured the pt-level correlation (corr) between TTD and PFS within each drug category (EGFR TKI; ALK TKI; ICI; or Chemo), and determined rates of disparity between TTD and PFS greater than 3 months. Results: 2369 pts met criteria for analysis. 1868 pts (79%) had a TTD event, and 1638 pts (69%) had a PFS event. Overall, median TTD was 5.7 months, and median PFS was 6.6 months. Pt-level analysis of the difference between PFS and TTD revealed recurring outliers (TABLE), with early TTD seen on chemo (PFS-TTD > 3 months in 10.9% of pts) and late TTD seen on TKI (TTD-PFS > 3 months in 12.1% of pts). Overall, the correlation between TTD and PFS was 0.91, stronger in pts treated with TKI or ICI (0.92) and weaker in pts treated with chemo (0.78; TABLE). Conclusions: Pt-level analysis indicates TTD is strongly correlated with PFS in contemporary trials of pts with mNSCLC, particularly those treated with TKI or ICI. Among pts treated with TKI or ICI, TTD exceeds PFS by > 3 months in several cases. These results indicate a need for further investigation of TTD across cancers and treatments to assess its role as an endpoint in RWE studies. Subgroup N Median PFS Median TTD Corr Early TTD % Late TTD % All 2369 5.7 6.6 0.91 5.2 7.3 EGFR TKI 595 12.1 10.9 0.95 0.7 10.9 ALK TKI 475 12.6 13.3 0.89 3.0 13.5 ICI 581 3.5 3.8 0.88 4.7 7.1 Chemo 718 2.8 4.2 0.78 10.9 0.6