tbuckley/cabot-search huggingface dataset:
Tumor relevant germline findings in targeted tumor sequencing using matched normal DNA of 1,570 unselected cases.
Authors: Kasmintan A Schrader, Donavan T. Cheng, Joseph Vijai, Meera Prasad, Michael Walsh, Ahmet Zehir, Tinu Thomas, Ryma Benayed, Zsofia Kinga Stadler, Asad Ashraf, Maria E. Arcila, David B. Solit, David Michael Hyman, Liying Zhang, David Klimstra, Marc Ladanyi, Kenneth Offit, Michael F. Berger, Mark E. Robson
Journal: Journal of Clinical Oncology (2015)

1509 Background: Tumor Sequencing (TS) can reveal presumed pathogenic germline variants (PPGV) that may be tumor-relevant (TR) and associated with tumorigenesis. Identification of PPGV may have significant implications for the individual and family. Methods: To estimate the burden of TR-PPGV identified in tumor-normal massively parallel sequencing, we analyzed 1,570 cases, unselected for cancer type or family history, that had undergone TS with matched normal DNA using a 341 gene panel employed at MSKCC (MSK-IMPACT). Subjects had provided IRB approved consent and anonymized analysis of the normal DNA samples was conducted under an IRB approved waiver. Results: Tumor phenotype was assessed for known genotype-phenotype correlations in cases harboring sequence PPGV in cancer-related genes of accepted clinical utility (ACMG gene list). Of 100 PPGV (98 cases, 2 cases had 2 PPGV each), 43 cases had expected tumor phenotypes. While 94 PPGV were retained in the tumor in 93 cases, in 24 cases we observed LOH/aberrant sequence of the other allele, suggesting possible involvement in pathogenesis. Eight out of 24 such cases were in tumors that do not typically trigger genetic evaluation for each corresponding syndrome; BRCA1 (n = 2) in stomach adenocarcinomas; BRCA2 (n = 2) in a neuroendocrine tumor and a pleomorphic sarcoma, RET (n = 1) in a colon cancer, SDHC (n=1) in a breast cancer and MUTYH (n = 2) in a breast cancer and Hurthle cell thyroid cancer. Conclusions: TR-PPGV can be estimated to occur in the matched normal DNA of up to 6% (93/1570) of unselected individuals undergoing TS. Correlation of the PPGV and tumor phenotype was seen in 44% (43/98) of cases, however 14% (8/56) of cases that had PPGV with non-conforming genotype-phenotypes showed evidence supportive of a role of the PPGV in tumorigenesis. These data indicate that phenotypes beyond those linked to known cancer syndromes may benefit from evaluation for TR-PPGV, which may also identify potentially aberrant pathways amenable to targeted therapeutic strategies.
Phase II study of everolimus (E) in refractory testicular germ cell tumors (TGCTs).
Authors: Michal Mego, Daniela Svetlovska, Vera Miskovska, Jana Obertova, Peter Zuzak, Patrik Palacka, Jan Rajec, Zuzana Sycova-Mila, Michal Chovanec, Maria Reckova, Katarina Rejlekova, Dalibor Ondrus, Stanislav Spanik, Jozef Mardiak
Journal: Journal of Clinical Oncology (2015)

e15567 Background: TGCTs represent a highly curable disease, however, a small proportion of patients develop disease recurrence. Loss of the tumor suppressor gene PTEN (phosphatase and tensin homolog) marks the transition from intratubular germ cell neoplasias to invasive GCTs and correlated with disease progression. PTEN inactivation is associated with dysregulation of PI3K/Akt pathway and increased mTOR signalling. We hypothesize that dysregulation of PI3K/Akt pathway due to PTEN inactivation in GCTs suggests that these patients would have greater benefit from mTOR inhibition. This study aimed to determine of efficacy and toxicity of everolimus in refractory testicular germ cell tumors (TGCTs) Methods: From December 2011 to February 2015, 15 refractory GCTs (14 testicular, 1 primary retroperitoneal) patients were enrolled to the phase II study (clinical trial registry number NCT01466231). All patients were pretreated with at least 3 cisplatin based therapy, 3 patients (21.3%) were absolute cisplatin refractory and 8 patients (57.1%) had visceral non-pulmonary metastases at start of treatment. Everolimus was administered at a dose of 10 mg daily until progression or unacceptable toxicity. The primary endpoint was objective response rate according to RECIST. Results: Median age of patients was 35 years (range 23-52 years). No objective response was observed, 3 patients (21.4%) achieved minor response for 4.9+, 6.3 and 9.5 months including one cisplatin absolute refractory patient and additional 2 patients (14.3%) achieved prolonged disease stabilization for 8.5 and 22.2 months. In median follow-up of 4.9 months (range 1-38 months), 13 patients (92.9%) experienced disease progression and 10 patients (71.4%) died. Median progression-free survival was 1.7 months (range 1.1 - 5.3 months) and median overall survival was 6.0 months (range 2.2 – 11.8 months). Treatment was tolerated well, 2 patients experienced grade 3-4 toxicity (pneumonitis and renal failure). Conclusions: Study failed to achieve its primary endpoint and our data suggest limited efficacy of everolimus in unselected heavily pretreated refractory TGCTs, however prolonged disease stabilization could be achieved in selected patients. Clinical trial information: NCT01466231.
A prospective study on contraceptives used by reproductive-aged patients with breast cancer and the assessment of information.
Authors: Asmaa Lakhdissi, Narjiss Berrada, Khadija Bellahammou, Othman Akkar, El Kabous Mustapha, Sarra Akla, Sihame Ougellit, Hind Mrabti, Hassan Errihani
Journal: Journal of Clinical Oncology (2017)

173 Background: For reproductive-aged breast cancer (BC) patients, contraception is needed during and after treatment. Few data are available concerning the methods used in the real life and the comprehension of patients. The main objective of our study was to describe the contraceptive practice and to identify the need of information for these patients. Methods: We conducted a survey in young BC patients treated at the National Institute of Oncology Rabat–Morocco. We analyzed the contraceptive methods used. Then, we assessed the level of information and counseling about contraception for this population. The SPSS 10.0 software was used for statistical analysis. Results: 72 patients respond to the survey. The mean age was 41.4 ± 6.3 years. 79.2% had localized disease. 97.2 % were under treatment. The sexual activity was maintained in 69.4%. The contraceptive methods used before the diagnosis and after the announcement are summarized in the Table. 52 pts were informed that the hormonal contraception were not recommended. 86.5% had this information from doctors. 67.3% were informed at the moment of announcement of diagnosis, 17.6% at the consultation of surgery, 29.4% before starting chemotherapy, 35.3% during chemotherapy and 17.6% at the end of treatment. After information about the contraceptive methods, 50 % used a masculine condom, 15.7% had a copper IUD, 18.6% used external ejaculation, 14.3% on patient had a tubal ligation and 14.3% didn’t use a contraception method. 66% patients of patients had not asked about contraceptive methods. The reasons: abstinence: 31.3%, the disease is more important than the contraception: 14.6%. Conclusions: Our study found that there is a lack of information concerning contraception for young BC patients. A contraceptive counseling is highly needed to decrease the risk of pregnancy during treatment. [Table: see text]
GEFCAPI 04: A phase III trial comparing a treatment oriented by a molecular analysis with CancerTYPE ID test to cisplatin-gemcitabine in patients with carcinoma of an unknown primary (CUP).
Authors: Geraldine Martineau, Agnes Laplanche, Agnes W Van de Wouw, Gedske Daugaard, Carmen Balana, Nicolas Penel, Loic Chaigneau, Djelila Allouache, Bruno Chauffert, Stephane Culine, Marine Gross-Goupil, Yacine Merrouche, Cristian Moldovan, Elodie Vauleon, Isabelle Borget, Fanny Wunder, Catherine A. Schnabel, Karim Fizazi
Journal: Journal of Clinical Oncology (2014)

TPS11134 Background: Despite advances in tumor imaging and pathology, patients with CUP still account for about 2-3% of all cancer patients in European registries. Two randomized phase II trials: GEFCAPI01 (Culine, J Clin Oncol 2003) and GEFCAPI02 (Gross-Goupil, Eur J Cancer 2012) demonstrated that the combination of cisplatin and gemcitabine has anticancer activity and can be regarded as an acceptable comparator for new treatments. Recently, several groups have shown that molecular analysis can identify a likely primary cancer in up to 80% of patients with CUPs. This trial aims to assess whether the use of a molecular test-oriented systemic treatment improves progression-free survival (PFS) over cisplatin-gemcitabine in patients with CUPs. Methods: GEFCAPI04 is a European randomized, phase III study comparing a diagnostic and therapeutic strategy based on molecular analysis followed by suspected primary cancer tailored specific therapy, to an empiric strategy by cisplatin and gemcitabin (NCT01540058). It was initiated in March 2012. Eligibility criteria include: patients presenting with CUP, confirmed by histo-pathological analysis, diagnostic work-up in keeping with guidelines (Lesimple et al., 2003), good or poor prognosis CUP, CUP not belonging to a subgroup requiring a specific treatment, no previous chemotherapy. Patients are stratified by prognostic factors (performance status and serum LDH level) and center. 223 patients will be randomized 1:1 to cisplatin-gemcitabine (A) or treatment according to the result of the molecular analysis (B). The primary endpoint is PFS based on central independent review. Imaging will be undertaken every 6 weeks, in each arm. A 0.05 level two-sided log-rank test for equality of PFS curves will have 80% power to detect a 3 months difference between PFS medians (5 months in group A and 8 months in Group B, (HR=0.62). Secondary endpoints include: overall survival, objective response rate, tolerance, and economic evaluation. The study is recruiting patients and 30 patients are included. Clinical trial information: NCT01540058.
Predictive importance of ulceration on the efficacy of adjuvant interferon-a (IFN): An individual patient data (IPD) meta-analysis of 15 randomized trials in more than 7,500 melanoma patients (pts).
Authors: Stefan Suciu, Natalie Ives, Alexander M. Eggermont, John M. Kirkwood, Paul Lorigan, Svetomir Markovic, Claus Garbe, Keith Wheatley
Journal: Journal of Clinical Oncology (2014)

9067 Background: Many randomised trials have evaluated the role of adjuvant IFN in high-risk melanoma, some suggesting benefit and others not. To assess the evidence of IFN vs. no IFN, an IPD meta-analysis of these trials was performed. Methods: Standard IPD meta-analysis methods were used to assess event-free (EFS) and overall survival (OS), with odds ratios (OR) and confidence intervals (CI) calculated. Trials were divided by dose of IFN – high (10-20MU/m2), Peg-IFN (3-6µg/Kg), intermediate (5-10MU flat), low (3MU flat) and very low (1MU). Results: IPD was provided for 11 of 15 reported trials of IFN vs. no IFN (for the other 4 trials published data were used). Over 7500 pts were included in the analysis, with over 4700 and 3800 events for EFS and OS. There was benefit for IFN for both EFS (P<0.00001) and OS (P=0.003) (Table). This translated into increased 5-year OS from 46.1% to 49.1%. There was no evidence of differences according to dose, duration of IFN, gender, Breslow thickness or disease stage, but ulceration status impacted the IFN benefit regarding EFS (interaction test: P=0.04) and OS (P=0.002) (Table). For the ulcerated melanoma, IFN increased the OS from 38.1% to 46.0%, at 5 yrs, and from 28.0% to 38.5%, at 10 yrs. Conclusions: This meta-analysis provides evidence that adjuvant IFN significantly reduces the risk of relapse and improves overall survival. This analysis does not identify the optimal dose or duration of IFN. OS benefit was confined to pts with ulcerated tumours. The biological basis of this action is incompletely defined, and being studied in the ongoing study (EORTC 18081 and ECOG-ACRIN Intergroup Trial E1609). Dose* OR (95%CI* or 99%CI**) EFS OS High (N=1196) 0.83 (0.72-0.96) 0.93 (0.80-1.08) Peg-IFN (N=1256) 0.87 (0.76-1.00) 0.96 (0.82-1.11) Intermediate (N=2243) 0.84 (0.74-0.95) 0.91 (0.79-1.04) Low (N=2732) 0.85 (0.77-0.94) 0.86 (0.77-0.96) Very low (N=484) 0.99 (0.80-1.23) 0.96 (0.76-1.21) Overall* 0.86 (0.81-0.91) 0.90 (0.85-0.97) Ulceration** Present (N=1443) 0.79 (0.66-0.94) 0.77 (0.64-0.92) Absent (N=2322) 0.95 (0.82-1.10) 1.02 (0.87-1.20) Unknown (N=2061) 0.88 (0.76-1.01) 0.91 (0.78-1.06)
Distribution of malignant neoplasms in the eastern Rajasthan region of India.
Authors: Bhavesh Amarnath Bang, Raj Govind Sharma, Rahul Kapoor
Journal: Journal of Clinical Oncology (2012)

e12014 Background: Cancer is not a notifiable disease in India. Cancer data in India is derived mainly from Population &amp; Hospital based cancer registries which pursue active data collection. Rajasthan, which is the largest state of India, has no established Cancer registry. Therefore, cancer data from this region is limited. This study was done to put the Cancer data from Eastern Rajasthan region in proper perspective Methods: A retrospective analysis of histopathology records of 5 years was done by studying the proportion &amp; site wise distribution of malignancy cases which were reported at major hospitals &amp; pathology centers in the region. Approximately 200,000 histopathology &amp; cytology reports were analyzed &amp; 34,486 new cancer cases were identified. Cases were classified according to the WHO International Classification of Disease (ICD) coding. Results: Of the 34,486 new cases of cancer that were recorded in five years, 58.58% were (20202) males and 41.42% (14284) females, with the male to female ratio being 1.41:1. Organ wise, Lung (13.25%), Larynx (5.35%), Oropharynx (5.09%), Brain (4.84%), Tongue (4.62%) and Prostate (4 %) were the most common sites involved in males, whereas Breast (25.6%), Cervix (10.26%), Ovary (5.4%), Brain (3.68%), Esophagus (3.4%), Lung (3.01%) &amp; Gall Bladder (2.35%) were common sites of malignancy in females. System wise distribution of cancers revealed that Head &amp; Neck (24.93%), Pulmonary (13.25%), Gastrointestinal (12.01%), Hematological (10.6%) &amp; Genitourinary tract (10.5%) were the most common systems involved in males, where as, in females, Breast cancer was the most common (25.6%) followed by Genitourinary tract (20.27%), Gastrointestinal cancers (11.2%) and Head and Neck cancers (8.11%). Conclusions: A high frequency of tobacco related cancers i.e. Lung cancer and Head &amp; Neck cancer in males, and screening detectable cancers (Breast &amp; Cervix) in females was observed. Frequency of Lung cancer in females was noted to be high in comparison to previous studies from the region. An unusually high frequency of Gall Bladder Cancers especially among the female population in this region is also a cause of concern.
Thalidomide increases thrombin generation in multiple myeloma patients
Authors: D. Candelaria, B. Armijo, R. Montgomery, F. Lee, S. Moll, D. Garcia, J. Liebmann, E. Libby
Journal: Journal of Clinical Oncology (2006)

7602 Background: Numerous reports have demonstrated that the clinical use of thalidomide (THAL) carries a risk for deep venous thrombosis. Only limited investigations into the causative mechanisms for this complication have been conducted. Thrombin generation is a global measurement of hyper or hypocoagulability that has not been used to examine the hypercoagulable state caused by THAL. The aim of this study was to determine if THAL affects thrombin generation in patients with multiple myeloma (MM). Methods: MM patients on and off THAL were recruited. Patients were considered to be “on THAL” if they had been taking the medication for at least three months and “off THAL” if they had not been taking the medication for at least three months. Coagulation tubes of blood containing 3.2% sodium citrate were drawn from each patient. Platelet poor plasma was prepared from these specimens using standard technique. The samples were snap frozen at -70 C and stored until analysis. Thrombin generation was measured using the Calibrated Automated Thrombogram as described by Hemker(Pathophysiol Haemo Thromb 2003;33:4–15) using a microplate fluorometer, the Fluoroskan Ascent from Thermo Electron and the Thrombinoscope software package. The endogenous thrombin potential or ETP (area under the thrombin generation curve) and peak thrombin generation (the maximum release of thrombin per unit of time) were the variables of interest for this study. Results: Twenty seven patients were recruited. Five were excluded from analysis because they were on warfarin or enoxaparin. The normal ETP in females is 1803 ± 241 nM*min and in males is 1745 ± 259 nM *min. Normal peak thrombin generation in females is 318.5 ± 52.9 nM and in males is 293.4 ± 48.5 nM. The t-test was used to compare subjects to normal values.Peak thrombin generation was significantly increased in the 9 subjects taking THAL, 374 ± 10.6 nM (p&lt;0.001) and in the 13 subjects not taking THAL, 352 ± 14.7 nM (p=0.009) when compared to normal values. The ETP was not significantly increased 1818 ± 10.7 nM*min (p=0.69) in subjects not taking THAL. However, ETP was increased in subjects taking THAL, 1939± 90 nM*min and showed a trend toward statistical significance (p=0.10). Conclusions: Thalidomide therapy increases thrombin generation significantly in patients with MM. [Table: see text]
Tissue-Specific Signaling Networks Rewired by Major Somatic Mutations in Human Cancer Revealed by Proteome-Wide Discovery
Authors: Junfei Zhao, Feixiong Cheng, Zhongming Zhao
Journal: Cancer Research (2017)

Abstract Massive somatic mutations discovered by large cancer genome sequencing projects provide unprecedented opportunities in the development of precision oncology. However, deep understanding of functional consequences of somatic mutations and identifying actionable mutations and the related drug responses currently remain formidable challenges. Dysfunction of protein posttranslational modification plays critical roles in tumorigenesis and drug responses. In this study, we proposed a novel computational oncoproteomics approach, named kinome-wide network module for cancer pharmacogenomics (KNMPx), for identifying actionable mutations that rewired signaling networks and further characterized tumorigenesis and anticancer drug responses. Specifically, we integrated 746,631 missense mutations in 4,997 tumor samples across 16 major cancer types/subtypes from The Cancer Genome Atlas into over 170,000 carefully curated nonredundant phosphorylation sites covering 18,610 proteins. We found 47 mutated proteins (e.g., ERBB2, TP53, and CTNNB1) that had enriched missense mutations at their phosphorylation sites in pan-cancer analysis. In addition, tissue-specific kinase–substrate interaction modules altered by somatic mutations identified by KNMPx were significantly associated with patient survival. We further reported a kinome-wide landscape of pharmacogenomic interactions by incorporating somatic mutation-rewired signaling networks in 1,001 cancer cell lines via KNMPx. Interestingly, we found that cell lines could highly reproduce oncogenic phosphorylation site mutations identified in primary tumors, supporting the confidence in their associations with sensitivity/resistance of inhibitors targeting EGF, MAPK, PI3K, mTOR, and Wnt signaling pathways. In summary, our KNMPx approach is powerful for identifying oncogenic alterations via rewiring phosphorylation-related signaling networks and drug sensitivity/resistance in the era of precision oncology. Cancer Res; 77(11); 2810–21. ©2017 AACR.
Combined modality radioimmunotherapy (RIT) in metastatic prostate (PC) and breast cancer (BC) using paclitaxel (PT) and a MUC-1 monoclonal antibody, m170, linked to yttrium-90 (Y-90): A phase I trial
Authors: C. M. Richman, S. J. Denardo, R. T. O'Donnell, A. Yuan, A. Natarajan, T. Wun, J. M. Tuscano, H. L. Chew, P. N. Lara, G. L. Denardo
Journal: Journal of Clinical Oncology (2004)

2554 Background: While RIT alone is effective in lymphoma, its application to more radioresistant solid tumors will likely require a combined approach similar to the use of radiosensitizing chemotherapy with external beam radiotherapy. Methods: Patients with metastatic hormone-refractory PC or advanced BC were imaged with Indium-111-DOTA-peptide-m170 (In-111-m170). One week later, Y-90-m170 was infused (12mCi/m2 for PC, 22mCi/m2 for BC). Initial cohorts received RIT alone. Subsequent cohorts received RIT followed by PT (75 mg/m2) 48 hours after RIT, a time when most radioactivity is concentrated in tumor and has been eliminated from normal tissues. Cyclosporin A (CSA) was given to prevent development of human antimouse antibody (HAMA). Peripheral blood stem cells (PBSC) were harvested prior to imaging for BC patients. Results: Bone and soft tissue metastases were targeted by In-111-m170 in 15 of the 16 patients imaged, with no unexpected uptake in normal tissue. 13 patients were treated with Y-90-m170. In 3 PC patients treated with RIT alone, no Grade 3/4 toxicity was seen. With RIT plus PT, 2 of 3 PC patients had neutrophils (ANC)<500/uL. In BC, with RIT alone, 1 of 4 patients had ANC <500, and 2 had platelets (pl) <25K. With RIT plus PT, all 3 BC patients had ANC < 500 and 2 of 3 had pl<25K. PBSC were given to 3 BC patients because of neutropenic fever or bleeding. One patient developed + HAMA (6%) in contrast to 71% of patients in a prior trial using m170 without CSA. Conclusions: Y-90-m170 targeted PC and BC. In combination with PT, toxicity was limited to marrow suppression at the dose levels above. Myelosuppression can be ameliorated by PBSC, and the maximum tolerated dose of RIT plus fixed-dose PT with PBSC support has not been reached. CSA was effective in preventing HAMA, suggesting the possibility of repeated “fractionated” therapy that could enhance antitumor response. No significant financial relationships to disclose.