tbuckley/cabot-search huggingface dataset:
Discovery and prevalence of cancer-susceptibility germline mutations (Mts) in patients (Pts) with advanced renal cell carcinoma (aRCC).
Authors: Maria Isabel Carlo, Semanti Mukherjee, Yelena Kemel, Liying Zhang, Diana Mandelker, Joseph Vijai, Devyn Taylor Coskey, Nisha Pradhan, David Michael Hyman, A. Ari Hakimi, Jonathan Coleman, Chung-Han Lee, Darren R. Feldman, Martin Henner Voss, Kenneth Offit, Mark E. Robson, Robert J. Motzer
Journal: Journal of Clinical Oncology (2017)

4524 Background: About 5% of RCC is thought to be familial, but recent studies suggest this may be an underestimate (Int. J. Cancer;100:476). We studied the prevalence of germline cancer-susceptibility mts in pts with aRCC. Methods: Pts with aRCC (stage III or IV), unselected for suspicion of an inherited cancer syndrome, were offered germline testing for 76 cancer-associated genes between 10/2015 and 12/2016. Germline sequencing was done as part of MSK-IMPACT, a matched tumor-normal next-generation sequencing platform. Results: 203/213 pts accepted testing (median age 55, range 13-55) of whom 73% had clear cell RCC (ccRCC), 92% had metastases, 20% were early onset (≤46 yrs at diagnosis), 9% had a family history of RCC, 6% multifocal RCC at diagnosis, and 15% ≥2 primary malignancies. Pathogenic/likely pathogenic mts were found in 35 pts (17%): 12 (6%) with mts in genes associated with familial RCC; 10 (5%) mts in high/moderate penetrance genes not linked to RCC (Table).13 (6%) had mts in genes of low/uncertain penetrance or for autosomal recessive disease. Mts were present in 15% of ccRCC and 19% of non-ccRCC. Mts were not more common in pts with early onset, family history, multifocal RCC, or ≥2 malignancies (p&gt;0.1 for each by Fisher’s exact test). Notably, 4/12 pts with mts in familial RCC genes did not meet the American College of Medical Genetics (ACMG) criteria for testing (1 each VHL, BAP1, SDHA, FH). Prevalence of CHEK2 mts was compared to population databases (ExAC); CHEK2 conferred a relative risk of 10.9 (p&lt; 0. 002; CI=3.9-24.7) for RCC. Conclusions: 17% of aRCC pts had a germline mutation in a cancer-associated gene of which 33% of the high penetrance RCC germline mts were not identified using standard clinical criteria, providing rationale for broad testing. Once the increased risk is confirmed, CHEK2 should be included in RCC genetic testing. [Table: see text]
Genetics of blood lipids among ~300,000 multi-ethnic participants of the Million Veteran Program
Authors: Derek Klarin, Scott M. Damrauer, Kelly Cho, Yan V. Sun, Tanya M. Teslovich, Jacqueline Honerlaw, David R. Gagnon, Scott L. DuVall, Jin Li, Gina M. Peloso, Mark Chaffin, Aeron M. Small, Jie Huang, Hua Tang, Julie A. Lynch, Yuk-Lam Ho, Dajiang J. Liu, Connor A. Emdin, Alexander H. Li, Jennifer E. Huffman, Jennifer S. Lee, Pradeep Natarajan, Rajiv Chowdhury, Danish Saleheen, Marijana Vujkovic, Aris Baras, Saiju Pyarajan, Emanuele Di Angelantonio, Benjamin M. Neale, Aliya Naheed, Amit V. Khera, John Danesh, Kyong-Mi Chang, Gonçalo Abecasis, Cristen Willer, Frederick E. Dewey, David J. Carey, John Concato, J. Michael Gaziano, Christopher J. O’Donnell, Philip S. Tsao, Sekar Kathiresan, Daniel J. Rader, Peter W. F. Wilson, Themistocles L. Assimes
Journal: Nature Genetics (2018)
A phase 1b/2a, multi-center, open-label study to evaluate the safety and efficacy of combination treatment with MEDI0457 (INO-3112) and durvalumab (MEDI4736) in patients with recurrent/metastatic human papilloma virus–associated head and neck squamous cell cancer.
Authors: Charu Aggarwal, Balazs Halmos, Mercedes Porosnicu, Nabil F. Saba, Ammar Sukari, Sara Jo Grethlein, Ranee Mehra, Douglas Adkins, Mary J. Fidler, Rakesh Kumar, Jie Yang, Shaad Essa Abdullah, Missak Haigentz
Journal: Journal of Clinical Oncology (2018)

TPS6093 Background: Anti–PD-1 immunotherapy has significantly changed outcomes for patients (pts) with recurrent/metastatic (RM) head and neck squamous cell cancer (HNSCC). However, only ≈20% of pts respond, so more effective therapies are needed. MEDI0457 (INO-3112), a plasmid DNA vaccine, comprises 3 plasmids expressing HPV-16 and HPV-18 E6 and E7 proteins along with IL-12. A pilot study in pts with locally advanced HPV-associated HNSCC found MEDI0457 to be safe and well tolerated; it was associated with induction of HPV-16/18 E6/E7–specific humoral and cellular immune responses and showed synergistic activity with anti–PD-1 therapy in immune correlative studies.1 Durvalumab (MEDI4736) is a human IgG1 mAb that blocks programmed death-ligand 1 (PD-L1) binding to PD-1, stimulating anti-tumor immune response. 60-70% of HPV+ HNSCC can be PD-L1 positive.2,3 We hypothesize that MEDI0457 administered with durvalumab may enhance anti-tumor effects against HPV-associated HNSCC and improve outcomes for pts with RM disease. Methods: This phase 1b/2a, open-label, multi-center study is evaluating MEDI0457 plus durvalumab in pts with confirmed HPV-16 or HPV-18–associated RM HNSCC after treatment with ≥1 platinum-based chemotherapy or platinum-ineligible pts in whom an approved treatment failed. Key exclusion criteria are nasopharyngeal cancer and prior immunotherapy. As this is the first study of MEDI0457 combined with durvalumab, a safety analysis run-in phase will assess the first 3-12 pts with a limit of 4 vaccine doses; this will be followed by the planned recommended dosing schedule in ≈50 pts until disease progression or unacceptable toxicity. Primary objectives are safety and objective response rate. Secondary objectives are disease control rate at 16 weeks, overall survival, progression-free survival, and pharmacokinetics and immunogenicity of durvalumab. Recruitment is ongoing (NCT03162224). 1 Aggarwal, et al. SITC 2017 [P125]. 2 Badoual, et al. Cancer Res 2013 [128]. 3 Lyford-Pike, et al. Cancer Res 2013 [1733]. Clinical trial information: NCT03162224.
Mechanism of acquired resistance to sunitinib in RCC
Authors: Manoj Kumar, David Panka, Rupal Bhatt, Rachel Schor-Bardach, Liang Zhang, Michael Atkins, Towia Libermann, Nahum Goldberg, James Mier
Journal: Cancer Research (2008)

1127  As previously shown for sorafenib, the multikinase inhibitor sunitinib induces transient growth arrest in 786-0 human RCC xenografts followed 7-9 days later by the resumption of tumor growth despite the continued administration of the drug. To assess the changes in gene expression induced by treatment and to identify genes whose altered expression may account for the growth arrest and/or the subsequent emergence of drug resistance, RNA was isolated from tumor tissue at various time points before and during treatment and analyzed using Affymetrix HG-U133Aplus 2.0 (human) and various SuperArray (murine) gene chips. The administration of sunitinib resulted in the increased expression of HIF-2α and that of numerous HIF-inducible genes including stanniocalcin, PTH-RH, arginase 2, sphingosine kinase, the metalloprotease MMP-1, and uPAR. This increase in HIF-2α was readily detectable in both growth-arrested and resistant xenografts and in this respect, differed from that induced by sorafenib, which was limited to the period of drug-induced tumor stasis. Likewise, in contrast to the enhanced MMP-1 gene expression induced by sorafenib treatment (which was not observed at the protein level), that induced by sunitinib was readily detectable by Western blot analysis. Like sorafenib, sunitinib treatment resulted in a marked increase in the level of the angiostatic extracellular matrix protein thrombospondin (Tbsp) despite a decrease in Tbsp transcripts. The collagen-derived, angiostatic peptides endostatin and arresten were also increased in 786-0 xenografts as a result of treatment. Several genes associated with fatty acid metabolism or transport were upregulated in response to treatment, including stearoyl CoA desaturase and the LDL receptor. The expression of metastasis-associated gene metastasin (calvasculin, S100A4) was markedly upregulated at both the mRNA and protein level by sunitinib treatment. The expression of the gene encoding the water channel aquaporin-1 (AQP1) was markedly suppressed during the period of sunitinib-induced growth arrest and equally up-regulated with the development of resistance. The expression of AQP1 has been shown to correlate with microvessel density in ovarian carcinoma and the gene may play a similar pro-angiogenic role in RCC. These gene expression studies have identified several candidates that might account for the development of resistance to VEGF receptor blockade, some of which can be inhibited with pharmaceutical agents currently available. Xenograft studies involving pharmaceutical agents that block the effects of these candidate genes and parallel studies with tumor cells engineered to express various siRNAs corresponding to the candidate genes are currently underway to clarify which of the “resistance-associated” genes actually mediate resistance to sunitinib.
Intra-tumoral tertiary lymphoid structures are associated with a low risk of early recurrence of hepatocellular carcinoma
Authors: Julien Calderaro, Florent Petitprez, Etienne Becht, Alexis Laurent, Théo Z. Hirsch, Benoit Rousseau, Alain Luciani, Giuliana Amaddeo, Jonathan Derman, Cécile Charpy, Jessica Zucman-Rossi, Wolf Herman Fridman, Catherine Sautès-Fridman
Journal: Journal of Hepatology (2018)
A phase II study of ramucirumab for advanced, pre-treated biliary cancers.
Authors: Jonathan Mizrahi, Milind M. Javle, Lianchun Xiao, Gauri R. Varadhachary, Kanwal Pratap Singh Raghav, Robert A. Wolff, Rachna T. Shroff
Journal: Journal of Clinical Oncology (2018)

4081 Background: Biliary cancers (BC) have no clear second-line therapy in advanced disease after progression on standard of care gemcitabine and cisplatin. Angiogenesis has been shown to be a potential target for BC, and ramucirumab, FDA-approved for treatment of advanced gastric, lung and colon cancer, is a novel monoclonal antibody that targets VEGFR2 to inhibit tumor-induced angiogenesis. Methods: We conducted a single arm, phase 2 single center study. Eligibility criteria included patients (pts) with advanced BC, ECOG PS 0 or 1, who had received at least 1 prior regimen containing gemcitabine. Pts were treated with IV ramucirumab at a dose of 8 mg/kg every 2 weeks, and restaging imaging was performed every 8 weeks until progression. The primary endpoint was progression free survival (PFS). Secondary endpoints included overall response rate (ORR), disease control rate (DCR), overall survival (OS) and toxicity (tox) of ramucirumab. Exploratory endpoints included correlating baseline gene expression profile and pre- and post-therapy CT imaging features with tumor response. Results: 43 of a planned 50 pts were enrolled, 42 receiving treatment. The cohort had a median age of 59.9 yrs (range 42-77), ECOG PS 0/1 (16/26), male/female (20/22), intrahepatic cholangiocarcinoma/extrahepatic/gallbladder (23/9/10), median prior therapies = 1 (range 1 to 5). Pts received a median number of 6 cycles. There were 9 (21%) grade 3 tox including anorexia, dehydration, hypertension, hyponatremia, proteinuria and vomiting. No grade 4 tox were observed, and no pts were taken off study due to tox. 5 pts required dose reductions. After a median follow-up of 3.44 months, the median PFS and OS were 2.73 months (95% CI: 1.91-8.03) and 6.31 months (95% CI: 4.7 – not reached). Of 34 pts evaluable for response, ORR = 0% and DCR = 44%, with 6 pts on treatment for > 24 weeks. Analysis of the correlative endpoints is ongoing. Conclusions: Ramucirumab as a single agent was well-tolerated and resulted in a PFS similar to that achieved with more toxic chemotherapy regimens used in the refractory setting. Furthermore, a minority of ramucirumab-treated patients (13%) experienced prolonged PFS > 24 weeks, warranting further investigation of this agent in refractory BC. Clinical trial information: NCT02520141.
Inflammatory arthritis: An under-recognized immune-relate adverse effect.
Authors: Meghan Mooradian, Justine Vanessa Cohen, Anita Giobbie-Hurder, Riley Fadden, Krista M. Rubin, Keith Flaherty, Don P. Lawrence, Ryan J. Sullivan
Journal: Journal of Clinical Oncology (2017)

e14565 Background: Checkpoint inhibition (CPI) has significant and durable effectiveness against a broadening range of cancers and currently is FDA approved for more than 10 different malignancies. With increasing use of CPI, there is a need to understand the range and extent of immune-related adverse effects (irAE). Though certain irAEs, such as colitis and pneumonitis have been well studied, CPI- induced arthritis (CA) has not been widely recognized nor well characterized with data on the subject largely comprised of case reports and small case series. Methods: We retrospectively reviewed 125 patients (pts) with advanced melanoma treated with CPI to define the incidence and clinical features of CA. We identified 20 pts who developed CA during the course of CPI treatment. Cases were included only if active rheumatic signs or symptoms developed after receiving therapy. Demographic data (gender, age), type of CPI, number of CPI cycles, treatment of CA and other irAE manifestations were extracted from the medical chart. Results: 16% of patients treated with CPI developed CA. Among the 20 pts, the average age at CA onset was 70.3 (43, 84) with 75% of pts male. 80% had received anti-PD-1 monotherapy, 15% combination anti-PD-1 + anti-CTLA-4 and 5% monotherapy with CTLA-4 inhibition. The average number of infusions prior to symptom onset was 13.5 (1-48) after a median time point of 6.6mths on therapy. Basic rheumatologic testing (RF, CCP, ANA) was only positive in 10% of cases. 20% of pts were treated with non-steroidal anti-inflammatory drugs alone, whereas 40% required corticosteroids (systemic or injection). The remaining 40% necessitated treatment with disease modifying anti-rheumatic drugs. Conclusions: CA is a debilitating irAE with a higher incidence (16%) than most other irAEs and a negative impact on the quality of life of pts affected. Based on our retrospective review, this irAE tends to delayed in onset and often requires systemic immune suppressants for effective treatment. We posit that this is an under recognized and undertreated irAE. Further work is needed to better define the clinical factors that may affect or predict its development.
Reply to Massimo Valerio, Mark Emberton, and Hashim U. Ahmed's Letter to the Editor re: Henk G. van der Poel, Roderick C.N. van den Bergh, Erik Briers, et al. Focal Therapy in Primary Localised Prostate Cancer: The European Association of Urology Position in 2018. Eur Urol 2018;74:84–91
Authors: Henk G. van der Poel, Roderick C.N. van den Bergh, Erik Briers, Philip Cornford, Alex Govorov, Ann M. Henry, Thomas B. Lam, Malcolm D. Mason, Olivier Rouvière, Maria De Santis, Thomas Wiegel, Peter-Paul M. Willemse, Hendrik van Poppel, Nicolas Mottet
Journal: European Urology (2018)
Efficacy and genetic analysis for a phase II multicenter trial of HF10, a replication-competent HSV-1 oncolytic immunotherapy, and ipilimumab combination treatment in patients with stage IIIb-IV unresectable or metastatic melanoma.
Authors: Robert Hans Ingemar Andtbacka, Merrick I. Ross, Sanjiv S. Agarwala, Matthew H. Taylor, John T. Vetto, Rogerio Izar Neves, Adil Daud, Hung T. Khong, Richard S. Ungerleider, Maki Tanaka
Journal: Journal of Clinical Oncology (2018)

9541 Background: HF10, a bioselected replication-competent oncolytic virus derived from HSV-1, has been evaluated in combination with ipilimumab (ipi) in a Phase II trial (NCT02272855) in unresectable/unresected Stage IIIB-IV melanoma pts. Herein we report the recent efficacy and gene expression findings correlating with responders. Methods: HF10 injected into single or multiple tumors (1 x 107 TCID50/mL/dose, up to 5mL depending on tumor size and numbers); 4 injections q1wk; then up to 15 injections q3wk. Four ipi IV infusions (3 mg/kg; concurrent with HF10) were administered q3wk. AEs assessed per CTCAE 4.0. Tumor responses were assessed per mWHO and irRC at 12, 18, 24, 36 and 48 wks for patients (pts) continuing on HF10 monotherapy. Primary endpoint was Best Overall Response Rate (BORR) at 24 wks. Evaluation of correlative studies (nCounter PanCancer Immune Profiling Panel) including tumor biopsy was performed at baseline and on Days 85 and 169. Results: 46 pts were enrolled and treated: 59% men, median age 67 yrs (range 28 to 91); disease stage 20% IIIB, 43% IIIC and 37% IV; 57% were treatment naïve and 43% with ≥ 1 prior cancer therapy for unresectable/metastatic melanoma. HF10+ipi combination was well tolerated. HF10 adverse event (AE) profile was similar in combination with ipi as in HF10 monotherapy. 28.3% pts had treatment-related ≥G3 AEs, and the majority of ≥G3 AEs were due to ipi. Of the 44 efficacy evaluable pts, irRC BORR at 24 weeks was 41% (18% irCR and 23% irPR); disease stability rate was 68% (27% irSD). As of Feb 07, 2018, median PFS was 19 months and median overall survival was 26 months. Responding tumors exhibited an activation of the adaptive immune response with increased total tumor infiltrating lymphocytes and CD8+ T-cells, and decreased CD4+ T-cells. Conclusions: The combination HF10 and ipilimumab treatment demonstrated a favorable benefit/risk profile and encouraging antitumor activity in advanced melanoma pts by inducing immune-cell infiltration in the tumor microenvironment. Clinical trial information: NCT02272855.
Safety and preliminary efficacy of talimogene laherparepvec (T-VEC) in combination (combo) with pembrobrolizumab (Pembro) in patients (pts) with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M HNSCC): A multicenter, phase 1b study (MASTERKEY-232).
Authors: Kevin J. Harrington, Anthony Hee Kong, Nicolas Mach, Tamara Rordorf, Jesus Corral Jaime, Vittoria Espeli, Sheryl Treichel, Burak Gumuscu, Jenny J. Kim, Jason Alan Chesney
Journal: Journal of Clinical Oncology (2018)

6036 Background: We evaluated the safety and efficacy of the combo of T-VEC, the first FDA-approved oncolytic immunotherapy that enhances systemic antitumor immune responses, and Pembro, an immune checkpoint inhibitor against programmed death receptor-1 (PD-1), in pts with R/M HNSCC. Methods: Pts were eligible for enrollment if they had histologically confirmed R/M HNSCC unsuitable for curative resection or radiotherapy, and platinum-refractory and injectable disease. T-VEC was injected intralesionally at a dose of up to 8.0 mL of 106 PFU/mL on day 1. After 3 weeks, subsequent doses of up to 8.0 mL of 108 PFU/mL were administered every 3 weeks (Q3W). Pembro was administered intravenously at a dose of 200 mg Q3W. The primary objective was to evaluate safety, as assessed by the incidence of dose limiting toxicity (DLT). Key secondary objectives were objective response rate (ORR), best overall response per immune-related RECIST, and long-term safety. Results: 36 pts were enrolled and treated: 28 (77.8%) had confirmed PD-L1-positive tumor; 5 (13.9%) were HPV-positive and 13 (36.1%) were HPV-negative, with 18 (50%) unknown. One (6.3%) DLT, fatal arterial hemorrhage, was observed among 16 DLT-evaluable pts. Overall, 24/36 (66.7%) pts had grade 3 or higher treatment-emergent adverse events (TEAEs): 5 (13.9%) and 3 (8.3%) pts had TEAEs related to T-VEC and Pembro; 2 (5.6%) and 1 (2.8%) pt discontinued treatment due to T-VEC- and Pembro-related TEAEs, respectively. The most common TEAEs were pyrexia (36.1%), dyspnea (33.3%), and fatigue (25.0%). 24/36 (66.7%) pts had serious AEs. 7 deaths were reported during the study, 1 of which was related to T-VEC (the DLT pt) and none to Pembro. The ORR was 16.7% (6/36 pts; 5 PD-L1-positive; 95% CI, 6.4–32.8), and the disease control rate (objective response/stable disease) was 38.9% (14/36 pts; 11 PD-L1-positive; 95% CI, 23.1–56.5). Conclusions: The combo demonstrated a manageable safety profile. Preliminary ORR showed clinical activity in R/M HNSCC. Further follow-up is ongoing for PFS/OS. Clinical trial information: NCT02626000.
Radiation dose and volume to the pancreas and subsequent risk of diabetes mellitus: A report from the Childhood Cancer Survivor study.
Authors: Danielle Novetsky Friedman, Patrick Hilden, Chaya S. Moskowitz, Rebecca M. Howell, Rita Weathers, Susan A Smith, Suzanne L. Wolden, Emily S. Tonorezos, Sogol Mostoufi-Moab, Eric Jessen Chow, Lillian Meacham, John Whitton, Wendy Leisenring, Leslie L. Robison, Gregory T. Armstrong, Kevin C. Oeffinger, Charles A. Sklar
Journal: Journal of Clinical Oncology (2018)

10564 Background: Childhood cancer survivors exposed to abdominal radiotherapy (abdRT) are at increased risk for diabetes mellitus (DM). We examined the association between DM risk and pancreatic radiation dose and dose-volume metrics. Methods: Participants included 4,527 5-year survivors (median age 35 years, range 10–58; median follow-up 21 years, range 2–34) diagnosed 1970–1999 and treated with abdRT, excluding total body irradiation. We estimated maximum radiation dose to the abdomen, whole pancreas, pancreatic head, body and tail, and volume of the pancreas absorbing ≥10, 20, and 30 Gy (V10, V20, V30). Prevalence of DM, defined by DM medication use, was compared to 4,853 siblings and 15,944 survivors without a history of abdRT using a GEE model with a Poisson distribution adjusted for attained age. Results: Survivors exposed to abdRT were 2.9 times more likely than siblings (95% confidence interval [CI] 2.0–4.3) and 1.6 times more likely than survivors not exposed to abdRT (95% CI 1.3–2.1) to have DM. Among those treated with abdRT, the prevalence of DM was 2.9% for survivors aged 31–40 years and 4.7% for those over 40. In multivariable analysis of survivors treated with abdRT, attained age (RR = 1.09, 95% CI 1.06–1.11, p < 0.001); body mass index ( < 18.5: RR = 1.1, 95% CI 0.4–2.7; 18.5–24.9: reference; 25–29.9: RR = 2.7, 95% CI 1.6–4.6; ≥30, RR = 7.7, 95% CI 4.8–12.4, p < 0.001); and pancreatic tail dose (0.1–9.9 Gy: reference; 10–19.9 Gy: RR = 6.3, 95% CI 2.1–18.8; 20–29.9 Gy: RR = 4.7, 95% CI 1.4–16.3; ≥ 30 Gy: RR = 11.4, 95% CI 3.6–36.3, p < 0.001) were associated with increased DM risk. An interaction was noted between age at diagnosis and pancreatic tail dose (p < 0.001), with the largest differences between tail doses found among those diagnosed at age < 10. Radiation to other regions of the pancreas, by dose or volume, as well as exposure to cranial irradiation, alkylating agents, and corticosteroids, were not associated with DM risk. Conclusions: Among survivors treated with abdRT, DM risk is associated with higher pancreatic tail dose, but not with other dosimetric or volumetric factors. Research is needed to identify interventions to decrease cardiometabolic risk in survivors treated with abdRT.