tbuckley/cabot-search huggingface dataset:
Clinical and genomic alternations predictive of response to sunitinib in patients with advanced renal cell carcinoma.
Authors: Chung-Han Lee, Robert J. Motzer, Andreas Hoetker, Oguz Akin, Ana M. Molina, Theresa Margaret Gold, Sujata Patil, Manickam Janakiraman, Banumathy Gowrishankar, Jane Houldsworth
Journal: Journal of Clinical Oncology (2016)

e16109 Background: Sunitinib is a 1st-line therapy for clear cell Renal Cell Carcinoma (ccRCC); however, 20-30% of tumors show primary resistant disease with progression as the best response. This study identifies the genetic changes that are associated with sunitinib clinical response. Methods: Whole genome comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) analysis at 16 select variant positions were performed on pretreatment tumor derived DNA from 76 sunitinib treated patients. Differential copy number alterations (CNAs) were identified using Fisher’s exact test with p-values < 0.05 and a 15% minimum threshold difference. Identified CNAs and SNPs were multivariately tested with MSKCC risk stratification for independent association with PFS and OS. Results: Univariate analysis of CNAs showed gains of 22q and 6p were associated with worse PFS, while loss of 4q and 8p trended toward improved PFS. Univariate analysis of variant sites in Casp8, NR1I2, VEGFA, and IL-8 were also associated with PFS. Integration of clinical features through MSKCC risk stratification demonstrate that only SNPs in Casp8, NR1I2, and VEGFA were independently associated with PFS and OS across the entire cohort. Subgroup analysis of intermediate risk patients demonstrated that patients could further be stratified within the clinical intermediate risk group based on SNPs in VEGFA and IL-8. Conclusions: aCGH and SNP analysis of sunitinib treated ccRCC patients identified multiple genomic features and alterations associated with clinical response. Several SNPs were independent of clinical risk stratification and may provide insight into mechanisms of sunitinib resistance. Genetic Characteristics Univariately Associated with Clinical Response Genetic Characteristics Independently Associated with OS Genetic Characteristics to Further Stratify MSKCC Intermediate Risk Patients CNAs CNAs CNAs Gain 22q (p = 0.06) None None Gain 6p21.2 (p < 0.001) Loss 4q13.1-q13.3 (P = 0.07) Loss 8p21.1 (P = 0.06) SNPs SNPs SNPs Casp8 (P = 0.016) Casp8 (P = 0.01) VEGFA (P = 0.004) NR1L2 (P < 0.001) NR1L2 (P = 0.03) IL-8 (P = 0.04) VEGFA (P = 0.001) VEGFA (P = 0.0007) IL-8 (P = 0.009)
Nutritional parameters for nutritional intervention as predictive factors in patients with metastatic esophageal squamous cell cancer.
Authors: Hiromichi Shirasu, Takahiro Tsushima, Mitsuhiro Furuta, Masahiro Kawahira, Takeshi Kawakami, Yukio Yoshida, Sadayuki Kawai, Satoshi Hamauchi, Akiko Todaka, Nozomu Machida, Tomoya Yokota, Kentaro Yamazaki, Akira Fukutomi, Yusuke Onozawa, Hirofumi Yasui
Journal: Journal of Clinical Oncology (2018)

e22185 Background: Proper nutritional support affects the treatment outcome in cancer. However, the role of nutritional intervention (NI) in patients (pts) with metastatic esophageal squamous cell cancer (mESCC) and whether any nutritional parameter predicts the value of NI remain unclear. Methods: We retrospectively assessed the data of successive pts with mESCC who received chemotherapy as initial treatment at Shizuoka Cancer Center (April 2008–December 2016). We selected pts with the ECOG performance status (PS) 0–2, no sign for curative resection or definitive chemoradiotherapy, adequate organ function, and no advanced malignancies. We evaluated pts’ nutritional statuses by the nutritional risk index (NRI), body mass index, sarcopenia, and dysphagia score (DS). Besides, we classified NI into three levels: none, moderate (dietary advice or oral supplements), and major (enteral feeding or intravenous hyperalimentation). Results: The features of 189 pts in the study cohort were as follows: median age (range), 67 (33−86) y; male/female, 170/19; PS 0/1/2, 99/81/9; number of metastatic sites 1/2/3/4, 98/60/27/4; smoking history, 27/162; previous esophagectomy, 152/37; NRI ≥83.5/ < 83.5, 165/24; C-reactive protein (CRP) < 1.0/≥1.0 mg/dL, 120/69; and low DS (score 0–1)/high DS (score 2–4), 99/90. The multivariate analysis for the OS revealed an independent correlation of five factors with poor survival: PS, 2; metastatic sites, > 2; CRP, ≥1.0 mg/dL; and nutritional parameters, NRI < 83.5 and high DS. In all pts, the median OS was 11.3 months (M), which based on NI was 12.3, 12.7, and 8.2 M in no, moderate, and major NI groups, respectively. The median OS in pts with NRI < 83.5 and high DS was 4.6 and 7.0 M, respectively. No difference was observed in the OS based on NI in pts with NRI < 83.5 (the median OS who received no, moderate, and major NI were 4.8, 4.5, and 5.0 M, respectively). Conversely, in the high DS group, the median OS of those who received no, moderate, and major NI were 5.1, 6.8, and 8.2 M, respectively. Conclusions: Although the role of NI is unclear in the entire population, high DS is the nutritional parameter that predicts the positive effect of NI on the survival of pts with mESCC.
Safety and feasibility of enhanced recovery after surgery program in older patients undergoing gynecologic oncological surgery.
Authors: Alexandre de Nonneville, Camille Jauffret, Cecile Braticevic, Maud Cecile, Marion Faucher, Camille Pouliquen, Gilles Houvenaeghel, Eric Lambaudie
Journal: Journal of Clinical Oncology (2018)

e18559 Background: Enhanced Recovery Programs (ERP) includes multimodal approaches of perioperative patient’s clinical pathways designed to achieve early recovery after surgery and a decreased length of hospital stay (LOS). By quickly allowing patients to recover their environment, older patients are those who could benefit the most from ERP. This study is the first to date to assess feasibility and safety of ERP in older patients undergoing gynecologic oncological surgery. Methods: Data were prospectively collected between December 2015 and September 2017 at the Institut Paoli-Calmettes, a French comprehensive cancer center. All the included patients were referred for hysterectomy and/or pelvic or para-aortic lymphadenectomy for gynecological cancer. The primary objective was to achieve similar LOS in patients ≥ 70 years old than among younger without increasing the proportion of complications and readmission rates. A binary (LOS < or ≥ 2 days) logistic regression was built, including age, Charlson score, BMI, ASA score, oncological indication, surgical procedures and surgical approaches. G8 score was estimate for all the ≥ 70 years old patients. Results: Of a total of 329 patients, 75 were ≥ 70 years old and 254 were < 70. Except a disparity in oncological indications with a higher proportion of endometrial cancer in the ≥ 70 years old group (56% vs. 27%; p < 0.01), there were no differences in patient’s characteristics and surgical procedures. Age ≥ 70 years was associated with a longer LOS (means, 3.88 vs. 3.11 days; p = 0.024) only in univariate analysis. Considering the logistic regression, age was no longer associated with LOS. Total hysterectomy with pelvic lymphadenectomy and ASA score ≥ 3 were independently associated with longer LOS while mini-invasive techniques were associated with a shorter LOS. Morbidities and readmissions occurred respectively in 23% and 8% of the total population without any difference between the two groups. In the ≥ 70 years old population, G8 score was not predictive of LOS, morbidities or readmissions. Conclusions: Our study shows that ERP in patients over 70 years of age undergoing gynecologic oncological surgery is as safe and feasible as in younger patients.
Adherence to National Comprehensive Cancer Network Guidelines for BRCA testing among breast cancer patients.
Authors: Nadine M. Tung, Priyanka J. Bobbili, Temitope O. Olufade, Maral DerSarkissian, Rachel Bhak, Julie Reiff, Josefa Maria Briceno, Hong Yu, Rahul Shenolikar, Mei Sheng Duh
Journal: Journal of Clinical Oncology (2018)

e13624 Background: Testing for BRCA mutations can impact treatment decisions for breast cancer (BC) patients (pts) and affect surveillance and prevention strategies for their relatives. This study examined BRCA testing rates in the last 5 years (yrs) among BC pts at an increased risk for mutation who were treated in community medical oncology practices. Methods: A physician panel approach was used to conduct a retrospective medical chart review among community-based US oncologists. BC pts with increased hereditary risk of BC, known family history (FH) of cancer, diagnosed at age ≥18 yrs in ≥ 2013 were included. Proportions of pts tested for BRCA mutations were assessed by each National Comprehensive Cancer Network (NCCN) risk criterion. Results: Charts from 63 physicians, averaging 16 yrs of practice (range 3-35 yrs), were included. They managed an average of 154 BC pts (range 7-1000) in the past yr; 97% were medical oncologists, and 67% had a genetic counselor (GC) in their practice. Data were collected for 411 pts with mean age 52 yrs; 95% were female, 78% were White, and 19% had Ashkenazi Jewish ancestry. Of these, 30% had de novo metastatic BC and 31% had triple negative (TN) BC. Among all pts, 94% were tested for BRCA mutations. Testing rates ranged from 78% in pts with a FH of male BC to 100% in pts with ≥1 blood relative with BRCA mutations, personal history of ovarian cancer, or who were diagnosed at age ≤50 with an additional primary BC. Testing rates were 96%, 95%, 93% and 77% in TNBC, HR+/ HER 2-, HR+/ HER 2+, and HR-/HER 2+ pts respectively. Lower testing rates were observed among Black pts (91%), men (90%), pts with metastatic disease (92%), and pts meeting NCCN criteria based on FH of male BC (78%) and prostate cancer (87%). A higher testing rate was observed in pts treated by physicians with a GC in their practice (95% vs. 91%). Conclusions: Adherence to NCCN BRCA testing guidelines is high in this group of predominantly medical oncologists with extensive experience, with a high proportion having a GC in practice. Testing rates can be improved in pts with risk factors related to male relatives. Any delivery model for genetic testing should maintain this high level of compliance to testing guidelines.
Molecular characterization of immune exclusion in small-cell lung cancer.
Authors: Sope Omowale Olugbile, Riyue Bao, Randy F. Sweis, Thomas A. Hensing, Yusuke Nakamura, Thomas Gajewski, Everett E. Vokes
Journal: Journal of Clinical Oncology (2016)

8565 Background: Small-cell lung cancer (SCLC) is the most aggressive subtype of lung cancer. Treatment options have not significantly changed over the past 3 decades and the 5-year survival has remained around 6%. Results of early phase human trials of immune checkpoint blockers are showing durable responses in about a quarter of patients. However, an immunologic characterization of SCLC is lacking. Based on recent results identifying Wnt/β-catenin pathway as a mechanism for immunotherapy resistance in melanoma, we pursued a similar analysis of immunologic gene signatures and molecular associations in SCLC. Methods: We first analyzed microarray expression data from 23 surgically resected tumors. Samples were classified into T cell-inflamed and non-T cell-inflamed groups using hierarchical clustering based on expression of 150 immune-related genes that show consistent expression across multiple tumor types including melanoma. Positive correlation between T cell transcripts and immune regulatory genes was investigated. Ingenuity pathway analysis was utilized to identify molecular pathways activated in non-T cell-inflamed tumors. Results: 44% of tumors were classified as T cell-inflamed and 56% were non-T cell-inflamed. A positive correlation was observed between CD8A and PD-L1, IDO1, LAG3 and TIM3 (p < 0.001). 200 genes were significantly upregulated in non-T cell inflamed tumors (fold change increase ranged from (2.7 to 37.7; FDR-adjusted p< 0.05). Evidence of activation of 4 pathways was found in the non-inflamed group including CTNNB1 (Wnt/β-catenin), MKNK1, NFE2L2 (which modulates response to oxidative stress) and NR3C1 (glucocorticoid receptor). Gene expression analysis of RNA-sequencing data a second dataset confirmed that the T-cell inflamed gene signature is a property of the tumor rather than normal lung tissue. Conclusions: A large fraction of SCLC tumors show an immunologically active tumor microenvironment which suggests opportunity for immunotherapeutic interventions. Molecular pathways associated with T cell exclusion suggest new opportunities for targeted therapy that might synergize with immunotherapies.
Phase 1 study to evaluate the safety and tolerability of MEDI4736 (durvalumab, DUR) + tremelimumab (TRE) in patients with advanced solid tumors.
Authors: Margaret K. Callahan, Kunle Odunsi, Mario Sznol, John J. Nemunaitis, Patrick Alexander Ott, Patrick Michael Dillon, Andrew J. Park, Paul Schwarzenberger, Toni Ricciardi, Mary J. Macri, Aileen Ryan, Ralph Rudolph Venhaus, Jedd D. Wolchok
Journal: Journal of Clinical Oncology (2017)

3069 Background: DUR is a human IgG1 monoclonal antibody (mAb) that blocks PD-L1. TRE is a human IgG2 mAb inhibitor of CTLA-4. Blocking these checkpoints can result in antitumor activity in some solid tumors. The targets for DUR and TRE are non-redundant, providing sound rationale for clinical testing of the combination. Methods: This is an ongoing Phase 1, multicenter, open label study (NCT01975831) with a dose escalation (3+3 design) and subsequent expansion phase. Patients (pts) with renal cell carcinoma (RCC), cervical (CC), colorectal (CRC), non-triple-negative breast (NTNBC), ovarian (OC), non-small cell lung, or head and neck cancer are eligible. Primary endpoints are safety/tolerability and identification of maximum tolerated dose (MTD) of the combination. Secondary objectives include tumor response and progression-free/overall survival. Results: As of 16 Dec 2016, 105 pts were treated. DUR 1500 mg every 4 weeks (Q4W) and TRE 75 mg Q4W X 4 was the regimen used for opening the expansion phase. Dose-limiting toxicities were reported in 4 pts: diarrhea, colitis, abnormal liver function tests (abn LFTs), and hyponatremia. The majority of treatment-related AEs (TRAEs) were Grades (Gr) 1 and 2. TRAEs ≥ Gr 3 were reported in 12 pts; the majority were diarrhea/colitis (n = 5) and abn LFTs (n = 4) and responded to established treatment algorithms. There was 1 Gr 5 TRAE: multi organ failure. No new toxicities were identified. The preliminary responses by tumor type with n ≥ 10 pts are shown in the table below. Responses were seen in OC and RCC at the Cohort 2 dose escalation level (DUR 1/TRE 3 mg/kg). There were 4 cases of SD &gt; 24 weeks: CC, n=2; CRC, n=1; OC, n=1. PD-L1 status was not tested. Conclusions: The DUR + TRE combination has a manageable safety profile, with preliminary evidence of clinical activity. These data support continued study of the combination therapy; the study is ongoing. Clinical trial information: NCT01975831. [Table: see text]
Access to biomarker testing in patients with advanced non-small cell lung cancer.
Authors: Hossein Borghaei, Fred R. Hirsch, Murry Wynes, Arliene Ravelo, Suresh S. Ramalingam, Raluca Ionescu-Ittu, Irina Pivneva, Apar Kishor Ganti
Journal: Journal of Clinical Oncology (2016)

e20655 Background: Access to biomarker testing is critical for selecting appropriate treatment for patients with advanced (stages IIIB and IV) non-small cell lung cancer (aNSCLC). This study assesses rates and patterns of biomarker testing among patients with aNSCLC. Methods: Patients aged ≥65 years diagnosed with aNSCLC between 2007-2011 were identified in the SEER-Medicare database and were followed for ≥4 months post-diagnosis. Patients’ first biopsy within ± 8 weeks of diagnosis was defined as the index date. Biomarker tests included EGFR, FISH, PCR, and non-specific tests (e.g., molecular test). IHC tests, which are mostly used for diagnosis, were excluded. Use of biomarker tests was assessed from the index date until the end of follow-up (end of data availability on 12/31/2013 or end of Medicare Parts A, B and D eligibility) in both the main study sample and a patient subgroup with cancer stages IIIB-T4 or IV and adenocarcinoma, adenosquamous or unknown type of NSCLC histology. Results: The study sample included 9,651 patients observed for a median of 11 months. Median age was 74 years, 65% patients had cancer stage IV and 59% had adenocarcinoma histology. Only 18% of patients in the main study sample and 22% of patients in the subgroup had a biomarker test during the follow-up (Table). Use of biomarker testing increased over time, from 5% of patients in the study sample diagnosed in 2007 to 35% of those diagnosed in 2011. In the subgroup, the increase was from 6% to 45% over the same period. More patients seen by a cancer specialist (CS) had a biomarker test than those not seen by a CS. Among patients tested, >40% of the patients in both the study sample and subgroup had their first biomarker test >8 weeks after biopsy. Conclusions: Among patients with aNSCLC diagnosed in 2007-2011 a substantial proportion did not undergo biomarker testing or had their biomarker test delayed by >8 weeks post-biopsy. Study sample N = 9,651 Subgroup N = 6,193 Patients with a biomarker test during follow-up, % Overall 18% 22% By year of diagnosis 2007 5% 6% 2008 8% 9% 2009 16% 19% 2010 24% 31% 2011 35% 45% By access to cancer specialist (CS) Patients seen by CS 18% 23% Patients not seen by CS 3% 4% Timing of first biomarker test, % ≤8 weeks post-biopsy 55% 58% >8 weeks post-biopsy 45% 42%
In situ, therapeutic vaccination against refractory solid cancers with intratumoral Poly-ICLC: A phase I study.
Authors: Chrisann Kyi, Rachel Lubong Sabado, Yvonne M. Saenger, Marshall R. Posner, Michael Donovan, William Loging, Erlinda Sacris, John P Mandeli, Tin Htwe Thin, Krzysztof Misiukiewicz, Robert G. Maki, Andres M. Salazar, Philip Adam Friedlander, Nina Bhardwaj
Journal: Journal of Clinical Oncology (2016)

3086 Background: Poly-ICLC, a double-stranded RNA complex, can directly activate dendritic cells and trigger NK cells to kill tumor cells. It can be given intramuscularly (IM) to induce systemic inflammation and intratumorally (IT) to induce immune infiltration of tumors. Methods: Patients (7 head and neck cancer (HNSCC), 1 melanoma) with recurrent metastatic disease who had failed prior systemic therapy were enrolled in the study. Patients received 2 cycles of treatment with each cycle consisting of 1mg Poly-ICLC 3x weekly IT for 2 weeks followed by IM boosters biweekly for 6 weeks with 2 week rest period. The 10-week cycle was repeated, followed by a 6-week no-treatment period. Evaluation of immune response was performed by immunohistochemistry (IHC) and RNA Sequencing (RNASeq) on tumor biopsies and blood collected throughout the study. Results: Two subjects completed 2 cycles of treatment; 6 subjects completed 1 cycle or less due to progressive disease. One patient achieved clinical benefit (stable disease, PFS 41 weeks) while the remaining patients had progressive disease. Poly-ICLC was well tolerated with principal side effects, fatigue and inflammation at injection site ( < grade 2). One case of grade 3 tumor necrosis was observed. In the patient with clinical benefit, IHC analysis of tumor showed increased CD4(60x), CD8(10x), PD1(20x) and PDL1(3x) compared to patients with progressive disease whose tumor biopsies showed unchanged/decreased CD4, CD8, PD1, and PDL1 levels over treatment period. Furthermore, RNASeq analysis of the same patient’s tumor and PBMC showed dramatic changes such as upregulation of interferon-stimulated genes, chemokines, and genes associated with T cell activation and antigen presentation indicative of local and systemic immune activation in response to Poly-ICLC treatment. Conclusions: Poly-ICLC was well tolerated in advanced solid cancer patients, and generated local immune response in tumor microenvironment and systemic immune response as evident in the patient achieving clinical benefit. These results warrant further investigation, and are currently being explored in a larger multicenter adaptive phase II clinical trial. Clinical trial information: NCT01984892.
Effect of concurrent CYP3A4 interacting medications on ibrutinib outcomes in patients with CLL.
Authors: Adam Kittai, Ashray Maniar, Max J Gordon, Michael Churnetski, Xavier Rivera, Hamood Alqahtani, Sheila Hoff, Douglas Rice, Gregory Rice, Daniel Oscar Persky, Michael Y. Choi, Jonathon Brett Cohen, Alexey Valeryevich Danilov
Journal: Journal of Clinical Oncology (2018)

e19514 Background: Concurrent use of strong CYP3A4 inhibitors increases ibrutinib exposure 20-fold. Hence, use of strong CYP3A4 inhibitors/inducers is not recommended, and moderate inhibitors warrant ibrutinib dose reduction. Concurrent use of ibrutinib and CYP3A4 inducers/inhibitors is inevitable in clinical practice, and may result in adverse events. In this multicenter analysis, we investigated whether concurrent use of CYP3A4 interacting drugs impacts outcomes of ibrutinib therapy. Methods: We performed a retrospective analysis of 141 patients who received ibrutinib therapy for CLL at 4 academic centers. Survival time on ibrutinib was estimated in Cox proportional hazards model. Chi-squared test was used to evaluate discontinuation of ibrutinib due to side effects. Results: 141 patients were treated with ibrutinib, 26 (18%) were concurrently prescribed a moderate or strong inducer or inhibitor of CYP3A4. 24 (17%) were on CYP3A4 inhibitors, most often fluconazole (n = 10) and ciprofloxacin (n = 11), and 2 patients used a CYP3A4 inducer (fosphenytoin, etravirine). 11 (8%) were on CYP3A4 inducers or inhibitors for ≥31 days, of which 4 had ibrutinib dose reduced, and 0 stopped ibrutinib due to adverse events. Although not statistically significant, there is a trend towards improved survival for patients who had ibrutinib dose reduced and were on concurrent CYP3A4 interacting medications versus patients whose ibrutinib was not dose reduced (HR 0.27, p = 0.21, CI 0.04-2.07). There was a strong trend towards improved survival (HR 0.29, p = 0.06, CI 0.08-0.97), and time on ibrutinib therapy (HR 0.33, p = 0.08, CI 0.10-1.13) for patients who did not require therapy with moderate or strong CYP3A4 interacting medications. Patients who took ibrutinib concurrently with CYP3A4 interacting medications did not have an increase on the rate of discontinuation of ibrutinib due to adverse events (p = 0.47). Conclusions: In this real world multicenter dataset, concurrent use of CYP3A4 interacting medications resulted in a trend towards shortened survival and time on ibrutinib. Dose reduction of ibrutinib for CYP3A4 interactions may correct for the change in overall survival seen. Additional data is needed to make a conclusive statement.