tbuckley/cabot-search huggingface dataset:
A propensity-matched analysis comparing hepatic recurrence after curative gastrectomy followed by adjuvant HIPEC to surgery alone for advanced gastric cancer.
Authors: Satoshi Murata, Sachiko Kaida, Hirokazu Kodama, Hiroshi Yamamoto, Tsuyoshi Yamaguchi, Reiko Ohtake, Masaji Tani
Journal: Journal of Clinical Oncology (2016)

4056 Background: Prevention of recurrence after curative (R0) surgery is one of the most important subjects to be resolved for gastrointestinal (GI) cancers. We have previously shown that hyperthermic intraperitoneal chemotherapy (HIPEC) following R0 gastrectomy is effective for preventing peritoneal recurrence. However, little is known about the preventive effect of HIPEC for GI cancers on hepatic recurrence. The aim of this study was to compare hepatic or peritoneal recurrence-free survival between patients with or without adjuvant HIPEC after R0 gastrectomy for an advanced gastric cancer (GC). Methods: Patients with advanced GC who underwent gastrectomy with a curative intent in the Shiga University of Medical Science hospital between 1998 and 2012 were included in this single center, retrospective, propensity score-matched cohort study. Cox proportional hazards regression models were used to evaluate the association between adjuvant HIPEC and hepatic or peritoneal recurrence-free survival. The Kaplan-Meier method was used to calculate the survival rate. P values < 0.05 were considered statistically significant. HIPEC was performed using CDDP and MMC, or combined with 5-FU in 5 L of perfusate of saline maintained at 42–43°C for 30 min. Results: A total of 186 patients with an advanced GC, in which the pathological depth of invasion was beyond the muscularis propria, were included in the study. There was no significant difference in clinicopathological factors between the matched cohorts (with or without HIPEC). There were significant differences in the hepatic recurrence-free survival (hazard ratio [HR] for with HIPEC versus without HIPEC: 0.10, 95%CI: 0.012 to 0.83, P: 0.033) and peritoneal recurrence-free survival (HR: 0.20, 95%CI: 0.068 to 0.61, P: 0.005). The 3- and 5-year overall survival rate was 94.0% and 86.8% in patients with HIPEC and 59.1% and 53.4% in patients without HIPEC (log-rank: P < 0.0001). Conclusions: Adjuvant HIPEC performed with R0 gastric surgery showed a preventive effect on hepatic recurrence, as well as peritoneal recurrence and survival benefits for patients with advanced GC compared with R0 surgery alone.
Alternative signalling mechanisms to mediate Braf-Inhibitor resistance in isogenic primary and metastatic melanoma.
Authors: Alanna Maguire, Naomi Walsh, Norma O'Donovan, Thamir Mahgoub, John Crown
Journal: Journal of Clinical Oncology (2016)

e21045 Background: Activating Braf oncogenic mutations occur in up to 60% of malignant melanomas. Braf inhibitors such as Vemurafenib/Dabrafenib have demonstrated clinical benefit but responses are frequently confounded by de novo or acquired resistance. Identification of novel targets that circumvent Braf-I resistance mechanisms will inform alternative effective long-term treatment strategies. Methods: Braf-I resistant isogenic primary (WM115) and metastatic (WM266-4) cutaneous melanoma cell lines were generated by continuous exposure to Vemurafenib (2.5 and 5 µm respectively). To identify kinase inhibitors (KIs) capable of overcoming Braf-I resistance, a drug screen of 160 KIs was performed. Results: Primary and metastatic resistant cells were found to be 13- and 24-fold more resistant than respective parental cells (IC50res vs IC50par : 3.34 µm vs 0.25 and 9.6 µm vs 0.4 µm, respectively). The drug screen identified 10 novel kinase targets that reduced WM266-4res cell proliferation by ≥ 20% at 1 mm compared to parental; including PKR, TPL2, EGFR, CDK1/2/5, PDGF and JNK. WM266-4res cells were exquisitely sensitive to pharmacological inhibition of PKR (21.3 ± 0.6 vs 50 ± 28% (% proliferation at 1 mm compared to WM266-4par)) but less sensitive to TPL2 inhibition (84 ± 23% vs 70 ± 28%). In contrast, WM115res cells were highly sensitive to TPL2 KI (19 ± 4% vs 72 ± 24%) compared to WM115par but no difference in sensitivity was observed to PKR (68 ± 13% vs 63 ± 14%). Both resistant cell lines were refractory to MAPK inhibition (MEK1/2 (PD98059), JNK1/2/3 (SP600125), p38 (SB203580)). Western blot analysis revealed constitutive activation of the ERK pathway in both resistant cell lines; however de novo expression of EGFR occurred only in the WM115res cells. Conclusions: These results provide new insights into alternative mechanisms of Braf-I resistance identified through a high-throughput functional KI screen. Further investigation of the targets identified may facilitate the development of novel therapeutic strategies to overcome resistance.
Impact of colorectal cancer (CRC) stage on the incidence of venous thromboembolism (VTE): Analysis of a U.S. veteran population in a single veterans integrated service network (VISN).
Authors: Danielle M. Pastor, Justin T. VanBacker, A. Gregory DiRienzo, Donald T. Pasquale, Laurence S. Kaminsky, Maithao N. Le, Syed Arzoo Mehdi
Journal: Journal of Clinical Oncology (2018)

e15700 Background: The association between VTE and malignancy is well known with cancer patients having significantly higher risk of developing VTE as compared to the general population. However, little is known about the risk of VTE according to the stage of cancer, especially in patients with CRC. This study aims to measure the rate of VTE in CRC patients according to their pathological stage in a Veteran population. Methods: All patients diagnosed and treated for CRC from 1995 through 2011 at the VISN Region 2 hospitals were identified. Data on the incidence of VTE and the stage of their CRC at the time of their VTE diagnosis were gathered. Comorbidities including diabetes, hypertension, vascular disease, arrhythmia, chronic obstructive lung disease, smoking, alcoholism, cirrhosis and second malignancy were identified. Analysis of variance was utilized to compare incidence rates of VTE among the various cancer stages. Results: A study cohort of 1659 Veterans (average age 70 years) was identified. In total, 9% (150) of all patients had developed VTE. The incidence of VTE in stages 0, 1, 2, 3 and 4 CRC were 2.9%, 7.7%, 7.1%, 9.3% and 15.9%, respectively. Both univariate and multivariate analyses demonstrate that the incidence of VTE is significantly associated with advanced CRC stage, with highest risk associated with stage 4 CRC (p < 0.001). The presence of a second malignancy, however, did not independently raise the risk of developing VTE in our Veteran cohort. Conclusions: Our review is one of the largest studies of a single regional network’s experience with VTE in CRC patients with specific focus on the relationship between VTE incidence and cancer stage. We demonstrate that VTE risk increases with increasing stage, with patients diagnosed with stage 4 cancer having twice the risk of developing VTE as compared to patients with locoregional disease and five times the risk as compared to patients with carcinoma in situ. Our data suggest a mechanistic relationship between systemic dissemination of CRC and hypercoagulopathy.
Relationship of ionizing radiation-induced synthetic lethality of PARP inhibition in BRCA1-proficient cancer cells with p53.
Authors: Steven T. Sizemore, Rahman Mohammad, Gina M. Sizemore, Hao Yu, Michael C. Ostrowski, Arnab Chakravarti, Fen Xia
Journal: Journal of Clinical Oncology (2016)

e14115 Background: PARP inhibitors (PARPi) are potentially effective therapeutic agents capable of inducing synthetic lethality in tumors with deficiencies in homologous recombination (HR)-mediated DNA repair such as those carrying BRCA1 mutations. Unfortunately, the majority of tumors lack BRCA mutations, are proficient in HR repair, and are resistant to PARPi. We previously demonstrated that ionizing radiation (IR) initiates cytoplasmic translocation of BRCA1 leading to suppression of HR-mediated DNA repair and subsequent synthetic PARPi lethality in BRCA1 wild-type and HR-proficient tumor cells. In addition, we have identified p53 as a key factor that regulates DNA damage-induced BRCA1 cytoplasmic sequestration following IR. However, the role of p53 in IR-induced PARPi sensitization remains unclear. This study sought to elucidate if p53 function is required for IR to confer PARPi cytotoxicity to HR-proficient cancer cells and more precisely define the patient population that may benefit from this treatment strategy. Methods: Sensitization of cancer cells to PARPi cytotoxicity following IR was determined in vitro and in vivo utilizing breast and glioma tumor cell lines with wtBRCA1 and wtp53, as well as in associated cell lines, in which p53 expression was inhibited. Results: In breast and glioma cell lines with functional HR-repair, IR-induced BRCA1 cytoplasmic sequestration, HR-repair inhibition, and subsequent PARPi sensitization in vitro and in vivo was dependent upon functional p53. Conclusions: p53 status determines the PARPi sensitization by IR in multiple BRCA1 and HR-proficient tumor types and may predict which patients are most likely to benefit from IR + PARPi combination therapy.
Acupuncture RCT in patients with GI cancer cachexia: A pilot study.
Authors: Saunjoo Yoon, Zhiguang Huo, Oliver Grundmann, Joseph J. Williams, Lucio N. Gordan, Thomas J. George
Journal: Journal of Clinical Oncology (2018)

e22209 Background: Cancer cachexia, marked by unintentional weight loss and muscle wasting impairs treatment outcomes and shortens overall survival. Acupuncture (AP) may lessen the progression of cachexia symptoms by reducing inflammation (CRP), and maintaining nutritional absorption (pre-albumin) and appetite. The purpose of this study was to investigate the effects of a targeted AP intervention on GI cancer cachexia. Methods: Patients with GI cancer experiencing at least 5% weight loss over 6 months while undergoing chemotherapy were randomized to a control (non-targeted AP: NTA) or targeted intervention (TI) group in this IRB approved single blind, parallel, RCT. The intervention involved 8 weekly sessions of TI or NTA. Weight (Wt), appetite, and body composition were measured weekly. CRP and pre-albumin were measured at 3 time points. NCT#02148159 Results: Completion rate was 80% (n = 30/38, 15 TI group, 16 male, mean age: 57 yo). The majority (n = 22) were diagnosed with colorectal cancer (CRC) and 8 with non-CRC (gastric and biliary). While overall comparison did not show statistical difference in Wt change between TI and NTA groups (see table), comparison between non-CRC and CRC groups did. The non-CRC TI group demonstrated Wt gain, appetite improvement, less change in CRP and pre-albumin, and improved lean muscle mass compared to non-CRC NTA at the end of the study. Male patients in the TI vs NTA and the non-CRC group vs CRC group had a trend toward weight gain (8.3 and 9.1lbs) respectively over female patients. Table. Differences between TI and NTA groups (comparison of wk 8 and wk 0) Clinical trial information: NCT# 02148159. Conclusions: AP demonstrated both feasibility and efficacy as a clinically relevant supportive care intervention for patients with cachexia. Findings indicate non-CRC group may respond better to TI acupuncture than CRC patients. These encouraging results warrant a larger study of TI acupuncture for managing GI cancer cachexia. Cancer type Weight CRP Pre-albumin LMM Appetite All GI cancer (N = 30; TI: NTA = 15:15) -0.13 (p = 0.97) 10.14 (p = 0.37) -3.5 (p = 0.09) -1.28 (p = 0.27) -8 (p = 0.39) Non CRC (n1= 8: TI: NTA = 4:4) 6.5 (p = 0.45) 2.6 (p = 0.72) -0.075 (p = 0.98) 0.74 (p = 0.66) 40 (p = 0.002) CRC (n2= 22: TI: NTA = 11:11) -2.5 (p = 0.50) 12.9 (p = 0.41) -4.75(p = 0.06) -2.02 (p = 0.17) -26 (p = 0.028)
ERCC-1 as a predictive biomarker for radioresistance in resected pancreatic cancer undergoing perioperative radiotherapy.
Authors: Jesus Rodriguez-Pascual, Rafael Alvarez-Gallego, Lisardo Ugidos, Elena Garralda, Cesar Munoz, Estela Vega, Yolanda Quijano, Emilio De Vicente, Ovidio Hernando, Carmen Rubio, Juan Carlos Plaza, Fernando Lopez-Rios, Juliana Sierra Marticorena, Ana Reymundo, Jose M Cardenas, Antonio Cubillo
Journal: Journal of Clinical Oncology (2016)

e15714 Background: Excission Repair Cross-Complementing 1 (ERCC-1) has been shown to increase the resistance to platinum in some cancers. ERCC-1 expression was investigated as a predictor of response to radiotherapy in patients (pt) with resected pancreatic cancer (RPC) undergoing pre or postoperative radiotherapy. Methods: A retrospective, non-interventional study was conducted using data from the medical records of eligible RPC pt. Patients treated as part of clinical research trials were included. ERCC-1 expression was determined by immunohistochemistry (IHQ) in primary or metastasis specimen. Results: Between January 1st 2007 and January 1st 2015, a total of 77 RPC pt were identified (median age 66 years old, 38 [49%] male, 73 [95%] ECOG 0-1). 31 pt received perioperative chemo-radiotherapy and 46 received adjuvant or neoadjuvant chemotherapy alone. Median follow-up for patients was 31 months. ERCC-1 expression did not predict overall Relapse-Free Survival (RFS) or overall survival (OS) in the entire cohort or in the chemotherapy alone subgroup. In chemo-radiotherapy subgroup, 13 ERCC-1 negative pt presented longer RFS in comparison to 18 ERCC-1 positive pt (ERCC-1 negative 15,6 months [CI% 9,8-21,2] vs. ERCC-1 positive 3,8 months [CI% 2,4-5,3] log rank 18,419, p = 0,0001). Conclusions: Relapse-Free Survival for RPC pt treated with radiotherapy was longer in ERCC-1 negative patients compared with ERCC-1 positive patients. Prospective randomized studies are mandatory to confirm ERCC-1 expression clinical usefulness.
Regional socio-demographic determinants of breast cancer incidence in the United States.
Authors: Hermann T Simo, Abhinav Tiwari, Mohammad S Khan, Zaid A Ammari, Aubin Sandio, Chinonso B Agubosim, Andrew J Wodarcyk, Reham Bakhsh, William Barnett
Journal: Journal of Clinical Oncology (2018)

e13550 Background: Epidemiological studies on breast cancer incidence have focused on age, race and poverty level as major factors impacting the incidence, but few have looked at body mass index (BMI), smoking rate, median income, insurance coverage rate. We wanted to investigate the correlation between the following socio-demographic factors (BMI, smoking rate, median income, insurance coverage rate) and breast cancer incidence. Using regional variations in these socio-demographic factors, we plan to examine correlation patterns with U.S breast cancer incidence geographical variations between 1999-2012. Methods: From 1999 to 2012, data for median income and insurance coverage rate per state were obtained from the United States census bureau, data for BMI per state were obtained from the Robert Wood Johnson Foundation, data for smoking rate per state were obtained from the Institute for Health Metrics and Evaluation, data for breast cancer incidence were obtained from the Centers for Disease Control and Prevention to construct the dataset. All 50 states were grouped into 7 regional subdivisions (West, Southern Rockies, Northern Rockies, South Central, North Central, Southeast and Northeast). A multiple regression analysis was performed using R 3.4 for data analysis. Results: We found regional difference in our analysis. For instance, the incidence rate is declining in the West, while slightly rising in the Southern Rockies, South Central, and South West regions. Furthermore, the incidence increased with an increase in BMI only in the West. It increased as smoking rates increased in the South Central, the Northern and Southern Rockies, but the opposite effect was noticed in the Northeast and West. Breast cancer incidence rate increased as the insurance rate increased; but decreased as income increased in all regions. Conclusions: Regional differences exist in the correlation coefficient between Breast cancer incidence and the selected socio-demographic factors, suggestive of their various level of influence on its incidence. One of the way to decrease breast cancer incidence will be to concomitantly decrease smoking rate, increase median income and insurance coverage.
Immunologic and genomic characterization of high grade serous ovarian cancer (HGSOC) in patients (pts) treated with pembrolizumab (Pembro) in the phase II INSPIRE trial.
Authors: Ilaria Colombo, Scott Lien, Cindy Yang, Derek L. Clouthier, Luisa Bonilla, Sunu Cyriac, Josee-Lyne Ethier, Yeh Chen Lee, Yada Kanjanapan, Victoria Mandilaras, Neesha C. Dhani, Marcus O. Butler, Amit M. Oza, Judy Quintos, Helen Chow, Trevor John Pugh, Pamela S Ohashi, Lillian L. Siu, Stephanie Lheureux
Journal: Journal of Clinical Oncology (2017)

5581 Background: Checkpoint inhibitors have shown to be effective in different tumors and are under investigation in HGSOC. Methods: INSPIRE (NCT02644369) is a prospective multi-cohort study investigating tumor genomic and immune landscapes in pts treated with Pembro at 200 mg IV Q3W. Patients underwent tumor biopsy pre, on-treatment and at progression for DNA/RNA sequence, immune-profile, and PD-L1 expression by immunohistochemistry (IHC). Serial blood samples for immunophenotyping were collected. Correlative data are available for 6 pts: 3 with shrinkage in target lesion and 3 with progressive disease (PD). Results: At interim analysis as of January 2017, 18 pts with HGSOC have been enrolled and 16 have platinum-resistant disease, with median 3 prior lines of treatment (range 1-7). Of 14 evaluable pts, best response by RECIST 1.1 was stable disease (SD) in 5 (36%) and PD in 9 (64%). Mean Tumor Proportion Score of PD-L1 by IHC (Qualtek) was 6.4% (range 0-30%). Grade 3/4 adverse events possibly related to Pembro were observed in 4/18 (22%) pts; none was fatal and the most common were fatigue and hyponatremia. Preliminary correlative data showed no significant change in CD4, CD8 and myeloid-derived suppressor cells in peripheral blood after Pembro treatment. Mean PD-1 expression on CD4 and CD8 T cells on baseline tumor tissue (measured as product of PD-1+ cells and the per cell expression of PD-1 [% of mean fluorescence intensity]) was significantly higher in pts with tumor shrinkage compared to pts with PD (CD4: 2658 vs 678, p = .02; CD8: 1999 vs 451, p = .048). Genomic analysis of baseline tumor tissue was available for 3 pts with tumor shrinkage and 2 with PD. Mean mutation burden was higher for pts with tumor shrinkage (2.38 vs 1.0 mutations/Mb covered). The pt with the longest SD in our cohort (6 months) had the highest mutation burden (2.72), including somatic POLE (c.6331-6C &gt; G) and germline BRCA2mutations. Conclusions: In HGSOC, pts with higher PD-1 level on tumor CD4 and CD8 T cells and higher mutation burden at baseline may have a better outcome following treatment with Pembro. POLE mutation is rare in HGSOC but may correlate with checkpoint inhibitor activity. Clinical trial information: NCT02644369.
Oncologists rationale for testing PD-L1 expression levels in patients with disease states where PD-L1 testing is not part of the IO product specific indications.
Authors: Daniel F. Winkelman, Stacy Mecham, Amir Forouzan, Yacoub Faroun
Journal: Journal of Clinical Oncology (2018)

e15164 Background: Immuno-Oncology (IO) agents are currently approved in a range of cancer types. In the majority of cases, the agent’s FDA-approved label does not require PD-L1 testing. The purpose of this research is to understand from the Oncologist’s perspective why PD-L1 tests are performed in treatment situations where there is no FDA testing requirement. Methods: BrandImpact, is a longitudinal panel of 450 Oncologists who continuously report cancer treatment decisions from the point-of-care. A survey was developed specifically for this research to understand why PD-L1 testing is initiated. Market research best practices were followed. The research was conducted from 12/13/17 to 1/16/18, with 99 respondents reporting 604 patient visits in 8 cancer types that do not require testing. Results: The table shown outlines the survey responses received from all Oncologists. The response provided most often (54%) was that the importance of PD-L1 expression is still evolving. The 2nd and 3rd most often provided responses were related to PD-L1’s influence on prescribing either the IO class (46%) or a specific IO agent (42%). PD-L1 testing’s inclusion in national guidelines was the 4th most often provided response (41%). When results were segmented by Academic vs. Community practice settings, Community had a higher rating for influences prescribing decisions (class or product) while the Academic segment had a higher rating for following national or institutional guidelines. Conclusions: Oncologists are performing PD-L1 testing in situations where there is no FDA requirement most often because the science is evolving. They are also utilizing the test results to determine the IO class or agent to use, likely to adhere to guidelines or protocols. Response % Top 3 Relevance PD-L1 expression is evolving for treatment decisions 54% Influences decision to Rx the IO Class 46% Influences decision to Rx the IO agent 42% PD-L1 testing part of national guidelines 41% PD-L1 testing included in my institution protocols 26% Required by FDA indication 24% Automatically tested without order 23% Needed clinical trial acceptance 17% Request by the patient 16%
Polymorphisms of genes encoding for vitamin D binding protein and Wnt5a to predict outcome for mCRC patients treated with first-line FOLFIRI and bevacizumab: Data from FIRE-3 trial.
Authors: Martin D. Berger, Sebastian Stintzing, Volker Heinemann, Dongyun Yang, Yu Sunakawa, Yan Ning, Satoshi Matsusaka, Satoshi Okazaki, Yuji Miyamoto, Mitsukuni Suenaga, Marta Schirripa, Jordan David West, Afsaneh Barzi, Diana L. Hanna, Wu Zhang, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2016)

3581 Background: Vitamin D mainly exerts its inhibitory influence on the development of colon cancer by inhibiting the canonical Wnt signaling pathway, whereas its role in modulating the non-canonical Wnt pathway is less clear. Additionally, there are preliminary data suggesting that vitamin D may inhibit tumor angiogenesis. We hypothesize that SNPs in genes involved in Vitamin D and non-canonical Wnt5a signaling are associated with outcome in metastatic colorectal cancer (mCRC) patients (pts) treated with first-line FOLFIRI and bevacizumab (bev). Methods: 295 pts with mCRC enrolled in the phase III FIRE-3 trial and treated with first-line FOLFIRI and bev were included in this study. Genomic DNA was extracted from formalin fixed paraffin embedded tissue. 10 functional SNPs in 10 genes (GC, CAMK2B, CYP24A1, CYP27B1, VDR, DKK1, CST5, ROR2, Wnt5a, CASR) were analyzed by PCR-based direct sequencing. Results: Baseline characteristics were as follows: female/male = 99/196; median age = 65y; primary tumor site right/left = 74/215;median PFS/OS = 10.2/24.2 months. G alleles carriers of the GC rs4588 SNP encoding for the vitamin D binding protein showed a longer median overall survival (OS) than those with a TT genotype (25.0 vs 15.9 months) in both univariate (HR 2.18, p = 0.002) and multivariate analysis (HR 1.73, p = 0.043). Pts with a CC genotype of the Wnt5a rs1829556 SNP yielded a higher response rate compared to those harboring any T allele (75% vs 56%, p = 0.006) which also translated into better progression-free (PFS) (11.5 vs 10.1 months, HR 1.45, p = 0.016) and OS (29.0 vs 22.1 months, HR 1.56, p = 0.011). These associations remained significant in multivariate analysis. Conclusions: This is the first report demonstrating that the GC rs4588 SNP encoding for the vitamin D binding protein might serve as a prognostic marker in pts with mCRC. Additionally we provide the first evidence that the Wnt5a rs1829556 SNP might be both a prognostic and predictive biomarker for mCRC pts treated with first-line FOLFIRI and bev. Targeting the Wnt5a ligand and the vitamin D binding protein might be a promising approach to improve our treatment options against mCRC.