tbuckley/cabot-search huggingface dataset:
Phase I/II multicenter, randomized, open-label trial of the c-Met inhibitor MSC2156119J and gefitinib versus chemotherapy as second-line treatment in patients with MET-positive (MET+), locally advanced, or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor mutation (EGFRm+) and progression on gefitinib.
Authors: Yi-Long Wu, James Chih-Hsin Yang, Keunchil Park, Lianzhe Xu, Friedhelm Bladt, Andreas Johne, Peiqi Li, Hongxia Zheng, Giorgio Massimini
Journal: Journal of Clinical Oncology (2014)

TPS8121 Background: Resistance to EGFR tyrosine kinase inhibitors (eg, gefitinib) in EGFRm+ NSCLC patients (pts) is mainly caused by a secondary mutation in the EGFR (ie, T790M) or by activation of the c-Met/HGF signaling pathway (eg, protein overexpression and/or amplification). MSC2156119J, a highly selective small-molecule c-Met inhibitor, displayed promising antitumor activity in pts with advanced solid tumors in a Phase I trial (Falchook et al. J Clin Oncol 2013:31(Suppl):2506). This Phase Ib/II, multicenter, open-label trial investigates the antitumor activity of MSC2156119J + gefitinib in pts with MET+ advanced EGFRm+ NSCLC (NCT01982955). Methods: Primary objectives are determination of the recommended phase II dose (RP2D) for the combination (Phase Ib), and progression-free survival (PFS) per investigator read (Phase II). Secondary objectives include safety, pharmacokinetics, and antitumor activity of MSC2156119J (PFS per independent read, overall survival, objective response, and disease control). Adults with advanced NSCLC with activating EGFR mutation, ECOG status 0–1, and resistance on 1st-line gefitinib (Phase II only) are recruited in mainland China, South Korea, Taiwan, and other Asian countries. Patients must have confirmed MET+ status, defined as either strong or moderate protein overexpression by immunohistochemistry, or MET gene amplification by in situ hybridization. Main exclusion criteria: life expectancy <3 mo, or prior EGFR targeting therapy other than gefitinib (Phase II only). For the Phase Ib part (3+3 design), 15–18 pts are planned to receive 300 or 500 mg MSC2156119J p.o. + 250 mg gefitinib p.o./d (21-d cycle); for the Phase II part, up to 200 pts are planned to be enrolled into 2 predefined subgroups according to their T790M mutation status and subsequently randomized 1:1 to RP2D MSC2156119J p.o. + 250 mg gefitinib p.o./d or 500 mg/m2 pemetrexed i.v. + 75 mg/m2 cisplatin i.v. on day 1 (max. of six 21-d cycles). Enrollment for Phase Ib began on Dec 23, 2013. Clinical trial information: NCT01982955.
Selecting subjects for a therapeutic target in colorectal cancer (CRC): Using a clinical database to enrich for patients harboring the BRAF<sup>V600E</sup> mutation
Authors: J. Tie, O. M. Sieber, P. Gibbs, L. Lipton, R. N. Jorissen, R. Langland, S. Kosmider, D. McKay, K. B. Nolop, J. Desai
Journal: Journal of Clinical Oncology (2009)

11003 Introduction: The BRAF V600E mutation (BRAF) causes constitutive activation of the RAS-induced MAPK pathway and is found in 10% of colon cancers. B-RAF inhibitors are in early clinical development, but their development in CRC will be challenging unless subsets of patients (pts) with higher rates of BRAF can be defined. The mutation rate in rectal tumors, the concordance between primary and metastases, and the prognostic/predictive significance of BRAF are current gaps in knowledge. Methods: 481 primary tumors and 80 matched primary-metastasis (prim-met) pairs were analysed from a pre-defined cohort of pts with CRC based on age (≥ 70 vs &lt; 70 years), gender, tumor site (right-R, left-L and rectum), stage (A to C vs D) and ≥ 2 years follow-up. BRAF was assessed by routine sequencing of exon 15 and by a mutant-specific PCR assay. KRAS (KRAS-codon 12 and 13) and MSI (Bethesda markers) status were also examined. Results: Overall prevalence of BRAF was 11%. BRAF (see table ) was independently associated with increasing age, female gender and R-sided cancer, but not with stage. Mutations were rare in rectal cancers. BRAF was associated with inferior overall survival in stage D pts (log-rank, p = 0.0003; HR 0.38, 95% CI, 0.10–0.51). Survival analysis will be further stratified by treatment received. No difference in outcome was seen in preliminary analysis of earlier stage cancers. Mutation frequencies in the prim-met pairs were 38% (30/80) and 1.3% (1/80) for KRAS and BRAF, respectively. Overall concordance was 88% (70/80) for KRAS and 100% (80/80) for BRAF status. Conclusions: The development of selective B-Raf inhibitors in CRC is potentially more attractive due to the ability to define patient subsets with a higher prevalence of BRAF mutations. Analysis of the primary tumor reliably predicts the status of metastatic disease in the same patient. The association between BRAFand poor outcome will need to be considered when interpreting the result of studies targeting this mutation. [Table: see text] [Table: see text]
Role of lymph node dissection for intrahepatic cholangiocarcinoma.
Authors: Taizo Hibi, Yusuke Takemura, Osamu Itano, Masahiro Shinoda, Minoru Kitago, Yuta Abe, Hiroshi Yagi, Yuko Kitagawa
Journal: Journal of Clinical Oncology (2017)

457 Background: The prognosis of intrahepatic cholangiocarcinoma (ICC) with lymph node metastases is dismal. Recent studies have highlighted the importance of lymph node retrieval from disease staging and therapeutic standpoints. To define the role of lymph node dissection for ICC, this study aimed to evaluate the patterns of lymph node metastases and their prognostic implication. Methods: A retrospective cohort analysis was conducted for 56 consecutive patients who underwent R0/R1 resection for ICC between 1990 and 2015. In principle, lymph nodes in the hepatic hilum and around the pancreas head were systematically removed. For left-sided tumors, lymph nodes in the lesser curvature of the stomach and the root of left gastric artery were also dissected. Clinicopathologic predictors of 3-year survival were identified by Cox multivariate analyses. Lymph node mapping was performed and positive nodes were classified into 3 compartments based on metastatic rates and prognoses. Results: Median tumor size, 4.5 (1.5–16.0) cm; Mass-forming and its dominant type, 42 (75%); R0 resection, 47 (84%). Nineteen (34%) patients had lymph node metastases. After excluding 4 in-hospital deaths, the overall and recurrence-free survival rates at 3 years were 66% and 33%, respectively (median follow-up, 36 months). Cox multivariate analysis revealed lymph node metastases [hazard ratio (HR) 6.3, 95% confidence interval (CI) 1.9-21.7, P = 0.003] and R1 resection (HR 7.8, 95% CI 1.6-38.3, P = 0.01) as independent negative predictors of overall survival. Patients with ≥ 4 positive nodes ( n = 7) had significantly decreased survival compared with those with 1–3 positive nodes ( n = 10, P= 0.005). Metastatic lymph nodes were classified into compartments I (metastatic rates ≥ 10% and longest survival ≥ 3 years), II (5%–10% and 1-year survival ≥ 50%), and III ( &lt; 5% and 1-year survival &lt; 50%). Lymph nodes in the suprapyloric area, celiac trunk, and paraaorta belonged to compartment III and appeared less important to be dissected. Conclusions: Systematic lymph node dissection for ICC based on tumor location provides accurate staging and may prolong survival in patients with limited number of positive nodes. Compartment classification is useful to determine the extent of dissection.
γδ T cells in combination with Newcastle disease virus and dendritic cell therapy as a novel immunotherapeutic approach in treating of advanced lung cancer.
Authors: Jan Nesselhut, Dagmar Marx, Michael Herrmann, Nicole Cillien, Raymond Y. Chang, Thomas Nesselhut
Journal: Journal of Clinical Oncology (2014)

3062 Background: γδ T cells represent a minority white cell in blood, which expand dramatically in acute infections. γδ T cells recognize antigens usually in a non-MHC-restricted fashion. A number of trials have shown that epithelial tumors were susceptible to γδ T cell lysis. A combination of γδ T cells with other cell based immune therapies such as Newcastle disease virus (NDV) or dendritic cell therapy (DC) may enhance their therapeutic efficacy. Methods: Peripheral blood mononuclear cells (PBMC) were isolated from 200 ml whole blood for treatment of n=6 patients with advanced metastatic lung cancer. γδ T cells were expanded ex vivo with an amino –bisphosphonate (5 mM Zometa) and IL-2 (100 U/ml). After 10 to 12 days,γδ T cells were harvested by MACS techniques. Purity and activity were analyzed by flow cytometry. γδ T cells was administered to patients intravenously at monthly intervals. Additionally, patients receive a treatment with NDV and DC one day prior to the γδ T cell application. Results: The mean percentage of γδ T cells within the isolated PBMC was 2.3%. After in-vitro expansion the mean percentage increased to 70% with expansion rates up to 268 fold. Further purification by MACS leads to a mean percentage of 92% (highest 99.6%). The mean number of infused γδ T cells was 3.82 x 108 for each treatment. Patients are 2-12 months under treatment to date. 2 patients had disease stabilization and are still alive (8 and 11 months). Another patient with bilateral SCLC and liver metastases showed a complete remission of the lung lesions and a remission of the liver metastases after two treatment cycles and is still alive (12 months). Conclusions: γδ T cells can be efficiently expanded and purified. A combination of DC based therapy, NDV and treatment with γδ T cells may improve the clinical outcome for advanced lung cancer patients .
Prognostic factors for disease-free survival of ethnic Chinese patients with ocularmelanoma.
Authors: Xi Nan Sheng, Si Ming Li, Zhihong Chi, Lu Si, Chuan Liang Cui, Li Li Mao, Xuan Wang, Bin Lian, Bi Xia Tang, Jun Guo
Journal: Journal of Clinical Oncology (2014)

e20016 Background: Ocluar melanoma is worthy of unique concerns because of its noticeable differences with cutaneous melanoma. The knowledge on clinical outcome in Asian patients is also limit. There is no standard recommendation in surgery for primary ocular melanoma and adjuvant treatment after surgery. The aim of this study is to evaluate the prognostic factors for disease-free survival (DFS) after surgery in Chinese ocular melanoma. Methods: Clinical data from January 2006 to April 2013 including age at diagnosis, gender, anatomic location (uveal or conjunctival), stage (I, II, III), type of surgery, adjuvant therapy, and DFS of patients with ocular melanoma were retrieved from Beijing Cancer Hospital’s database. Univariate and multivariate analyses of factors associated with DFS were respectively performed by Kaplan-Meier method and Cox proportional hazard model. Results: A total of 95 patients (61 males, 34 females) with ocular melanoma were evaluated. 53.7% had uveal melanoma and46.3% had conjunctival melanoma. Stages I, II and III disease were present in 33.7%, 52.6%, and 13.7%, respectively. The 3-year DFS rate and the median DFS time of all 95 patients were 47.5% and 35 months, respectively. Three-year DFS rate of patients with diseases of stage I, II, III were 57.9%, 48.2%, 8.5%, respectively. Patients who received high-dose interferon-α2b (HDI) as adjuvant therapy had significantly higher 3-year DFS ratesthan those who did not receive adjuvant therapy or received chemotherapy. Multivariate analysis indicated that the anatomic location, stage, and adjuvant therapy were significant predictive factors for DFS. Conclusions: The clinical stage, anatomic location and adjuvant therapy are independent prognostic factors for DFS in Chinese ocular melanoma patients.
Effect of Vitamin D and Calcium Supplementation on Cancer Incidence in Older Women
Authors: Joan Lappe, Patrice Watson, Dianne Travers-Gustafson, Robert Recker, Cedric Garland, Edward Gorham, Keith Baggerly, Sharon L. McDonnell
Journal: JAMA (2017)

<h3>Importance</h3> Evidence suggests that low vitamin D status may increase the risk of cancer. <h3>Objective</h3> To determine if dietary supplementation with vitamin D<sub>3</sub>and calcium reduces the risk of cancer among older women. <h3>Design, Setting, and Participants</h3> A 4-year, double-blind, placebo-controlled, population-based randomized clinical trial in 31 rural counties (June 24, 2009, to August 26, 2015—the final date of follow-up). A total of 2303 healthy postmenopausal women 55 years or older were randomized, 1156 to the treatment group and 1147 to the placebo group. Duration of treatment was 4 years. <h3>Interventions</h3> The treatment group (vitamin D<sub>3</sub> + calcium group) received 2000 IU/d of vitamin D<sub>3</sub>and 1500 mg/d of calcium; the placebo group received identical placebos. <h3>Main Outcomes and Measures</h3> The primary outcome was the incidence of all-type cancer (excluding nonmelanoma skin cancers), which was evaluated using Kaplan-Meier survival analysis and proportional hazards modeling. <h3>Results</h3> Among 2303 randomized women (mean age, 65.2 years [SD, 7.0]; mean baseline serum 25-hydroxyvitamin D level, 32.8 ng/mL [SD, 10.5]), 2064 (90%) completed the study. At year 1, serum 25-hydroxyvitamin D levels were 43.9 ng/mL in the vitamin D<sub>3</sub> + calcium group and 31.6 ng/mL in the placebo group. A new diagnosis of cancer was confirmed in 109 participants, 45 (3.89%) in the vitamin D<sub>3</sub> + calcium group and 64 (5.58%) in the placebo group (difference, 1.69% [95% CI, −0.06% to 3.46%];<i>P</i> = .06). Kaplan-Meier incidence over 4 years was 0.042 (95% CI, 0.032 to 0.056) in the vitamin D<sub>3</sub> + calcium group and 0.060 (95% CI, 0.048 to 0.076) in the placebo group;<i>P</i> = .06. In unadjusted Cox proportional hazards regression, the hazard ratio was 0.70 (95% CI, 0.47 to 1.02). Adverse events potentially related to the study included renal calculi (16 participants in the vitamin D<sub>3</sub> + calcium group and 10 in the placebo group), and elevated serum calcium levels (6 in the vitamin D<sub>3</sub> + calcium group and 2 in the placebo group). <h3>Conclusions and Relevance</h3> Among healthy postmenopausal older women with a mean baseline serum 25-hydroxyvitamin D level of 32.8 ng/mL, supplementation with vitamin D<sub>3</sub>and calcium compared with placebo did not result in a significantly lower risk of all-type cancer at 4 years. Further research is necessary to assess the possible role of vitamin D in cancer prevention. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT01052051
Limited impact of tamoxifen following dose-intensive L-FAC multimodality therapy of breast cancer
Authors: K. W. Jabboury, A. Wong, K. Sexton, L. Rogers, K. King, C. Reilly, S. Thomas, P. Curtis, O. Mangini, R. Behar
Journal: Journal of Clinical Oncology (2006)

10741 Background: Front-line dose-intensive L-FAC has demonstrated a favorable 5-year relapse free survival pattern (ASCO 2004 #739). Tamoxifen was given for 5 years to ER+ patients after L-FAC completion. We evaluated the impact of adding tamoxifen to L-FAC. By design, this pilot study excluded low-risk patients not candidates for chemotherapy. Methods: 109 breast cancer patients were enrolled (4 excluded due to treatment violations) from 6/1989 to 1/2003: 20 Stage I (S), 52 S-II, 22 S-III, for a total of 94 patients. 11 S-IV patients were excluded from survival analysis. Adverse tumor presentations included: ER- 49, PgR- 60, P53+ 24, non-diploid 39, histological grade III 37, CerbB2+ 33. L-FAC included 72 hour (h) iv infusion 400mg/m 2 /day (d) 5-fluorouracil (F) modulated by iv bolus 200mg/m 2 /d X3 leucovorin (L), concomitantly with 24h iv d1 600–1000mg/m 2 cyclophosphamide (C), 48h iv d2 + d3 60mg/m 2 doxorubicin (A). S-I and S-II were given 6 courses and 8 for S-III. Increasing A + C dose level and/or shortening treatment intervals &lt; 3 weeks with growth factors provided intensification. 40 patients received tamoxifen. Results: At a median follow-up of 74 months (range 9–214), 73 (78%) are alive (1 with relapse). Relapse free survival was: S-I 95%, S-II 81%, S-III 78%. At average course intervals of 18 days, dose intensity A/C mg/m 2 /wk was 24.2 / 335.4 with evidence of WHO grade III/IV stomatitis in 43%, neutropenia 59%, cumulative thrombocytopenia 50%, hand-foot syndrome 32% of patients. Aside from delayed relapse associated with tamoxifen, relapse-free survival &gt;82 months was similar with and without tamoxifen. No relapse was observed after &gt;53 months in ER- tumors despite showing higher frequency of adverse tumor risk factors. Conclusion: The impact of adding tamoxifen appears quite limited in a patient population with adverse tumor presentation treated with dose-intensive L-FAC. No significant financial relationships to disclose.
Comprehensive analysis of driver mutations in Chinese squamous cell lung carcinomas by targeted next-generation sequencing.
Authors: Sheng Yang, Dan Tao, Di Wu, Ningning Zhang, Lin Wang, Yutao Liu, Xiaohong Han, Yuankai Shi
Journal: Journal of Clinical Oncology (2015)

7544 Background: The aim of the study was to analyze the driver mutation profiles in a large cohort of Chinese SqCLCs to identify potential therapeutic targets. Methods: We detected approximately 2,800 COSMIC mutations from 50 oncogenes and tumor suppressor genes on 159 samples by using Ion Torrent semiconductor-based next-generation sequencing.We conducted FISH for fibroblast growth factor receptor 1 (FGFR1) and cyclin D1 (CCND1) amplification on 172 and 246 samples, respectively. In addtion, we analyzed PTEN expression by immunohistochemistry on 172 samples. Results: Somatic mutations were detected in 73.6% (117/159) of patients. The most commonly mutated gene detected in this study was TP53 (89 cases, 56.0%), followed by CDKN2A (14 cases, 8.8%), PI3KCA (14 cases, 8.8%), KRAS (7 cases, 4.4%), and EGFR (5 cases, 3.1%). The incidences of FGFR1 amplification, CCND1 amplification and loss of PTEN expression in this cohort of patients were 16.9% (29/172), 11% (27/246) and 43.6% (75/172), respectively. The frequency of EGFR mutation was significantly higher in female and never smokers, while TP53 mutations were significantly more common in men and smokers. The incidence of FGFR1amplification in current smokers was significantly higher than that in former smokers and never smokers (Ptrend= 0.025). The incidence of FGFR1 and CCND1 amplification significantly increased with increment of total cigarette smoking dosage (Ptrend < 0.001 and Ptrend = 0.006, respectively). Loss of PTEN expression was more frequent in elders (P= 0.047), male gender (P= 0.033), patients with early stage (P= 0.042) and positive pleural invasion (P= 0.030). No significant association was observed between the molecular abnormalities and overall survival. Conclusions: Somatic mutations were detected in nearly three-fourth (73.6%) of Chinese SqCLC patients. FGFR1 amplification, CCND1 amplification and loss of PTEN expression are also frequent alterations in SqCLC. Comprehensive analysis of driver mutations in our study could facilitate the development of targetd therapies and optimize the therapeutic strategies for patients with SqCLC.
BCL2 protein in prediction of relapse in triple-negative breast cancer (TNBC) treated with adjuvant anthracycline-based chemotherapy.
Authors: Katerina Bouchalova, Marek Svoboda, Gvantsa Kharaishvili, Lenka Radova, Jan Bouchal, Radek Trojanec, Vladimira Koudelakova, Marian Hajduch, Karel Cwiertka, Zdenek Kolar
Journal: Journal of Clinical Oncology (2012)

1087 Background: Preclinical data show an association of BCL2 expression and resistance to anthracyclines. The absence of BCL2 expression in prechemotherapy samples is associated with a higher probability of pathological complete response to neoadjuvant doxorubicin-based chemotherapy. The aim of our research is identification of markers predicting sensitivity to adjuvant treatment in TNBC. Here we focus on BCL2 protein as a putative predictor of sensitivity to adjuvant anthracycline-based chemotherapy. The objective was to determine whether BCL2 expression predicts relapse in TNBC patients treated with anthracycline-based regimens. Methods: The study included 187 patients with TNBC, 178 of whom were treated with adjuvant chemotherapy (164 had anthracyclines). BCL2 analysis was performed using IHC, proportion score and intensity score were counted. The data were analysed with software Statistica and R. Results: High BCL2 expression predicts poor relapse free survival (RFS) in patients treated with adjuvant anthracycline-based regimens (logrank p=.035, hazard ratio, HR 2.37, 95%CI 1.04-5.41). High BCL2 predicts trend to poor overall survival (OS) in patients treated with adjuvant anthracycline-based regimens (logrank p=0.075, HR 2.31, 95%CI 0.90-5.97). In univariate analysis of anthracycline treated patients, stage (RFS p=.0004, OS p=.0005), size (RFS p=.003, OS p=.00009) and nodal status (RFS p=0.018, OS p=.028) were associated with outcome, as well. In multivariate analysis of athracycline treated patients, BCL2, size and nodal status had an independent predictive significance for both RFS (p=.005, p=.056, p=.003) (logrank test, p=0.0004) and OS (p=.014, p=.006, p=.012) (logrank test p=0.0007). Conclusions: This study is the first to prove that high BCL2 expression predicts poor outcome in TNBC treated with adjuvant anthracycline-based chemotherapy. BCL2 expression could facilitate decision making on adjuvant treatment in TNBC patients and its assessment should be included in standard diagnostics. In patients with high BCL2 expression other types of adjuvant treatment should be considered. Grants: IGA NS10286,IGA NS10357-3 and Biomedreg CZ.1.05/2.1.00/01.0030.
Evaluation of biomarker alterations in small cell cervical cancer identifies therapeutic options.
Authors: Jennifer K. Burzawa, Sherri Z. Millis, Sandeep K. Reddy, Igor A. Astsaturov, Robert L. Coleman, Jubilee Brown, Michael M. Frumovitz
Journal: Journal of Clinical Oncology (2015)

5601 Background: Small cell cervical cancer (SCCC) is an extremely rare and aggressive form of cervical cancer, accounting for only 1% of all cervical cancer cases, or ~150 cases/yr. 70% of patients will recur, even when diagnosed with early stage disease and there are few therapeutic options in this setting. We evaluated tumor samples obtained from a large repository to determine prevalent targetable molecular aberrations in these rare tumors. Methods: Seventy-eight SCCC samples were profiled, 53 of those on a commercial multiplatform, including a combination of gene sequencing (Sanger or NGS, up to 47 genes), amplification (CISH or FISH), and protein expression (IHC). Twenty-five samples were analyzed at a cancer center using a 50 gene NGS platform (CMS50). The profiles were compared to ~800 HPV+ cervical cancers (CC), neuroendocrine tumors (NET, all sites), and small cell lung cancers profiled at the same laboratory. Results: TOP2A (85%) and TOPO1 (55%) had high overexpression, while ERCC1 had low expression (11%) in SCCC samples. SCCC tumors had higher protein expression of KIT (26%) than HPV+ non-SCCC (7%, p < 0.05), but similar expression of KIT to small cell lung cancers (37%). HER2 amplification was identified in 4.5% of SCCC and 8% of HPV+ CC. EGFR amplification was not seen in SCCC but was identified in 10% of HPV+ CC. Gene sequencing identified higher mutation rates for TP53 (27%) and KRAS (18%) in SCCC compared to HPV+ CC (12% and 7%, respectively) but lower rates of PIK3CA (17% vs. 28%). Comparatively, small cell lung cancers had mutations in TP53 in 34% of cases and in KRAS in 5% of cases. NGS evaluation of 51 cases also identified 3 GNAS and RB1mutations (6%), 2 CTNNB1 and SMAD4 mutations (4%), and single gene mutations in BRCA1, PTEN, MET, SMARCB1, APC, ATM, HNF1A, and FBXW7 (2% each). Conclusions: Multiplatform tumor profiling identified high expression of TOP2A and TOPO1 in SCCC, which may explain the sensitivity to etoposide and topotecan, while low levels of ERCC1 raise concern for cisplatinum resistance. Potential druggable mutations include AKT1, KRAS, PIK3CA, and TP53. We have identified one patient with a KRAS mutation treated with a MEK inhibitor who had a complete response and remains in remission at 12 months.