tbuckley/cabot-search huggingface dataset:
Effect of reproductive factors and lifestyle on the onset of breast cancer in female BRCA 1 and 2 mutation carriers.
Authors: Christian F. Singer, Viktoria Rieder, Mohamed Salama, Lena Gloeckner, Daniela Muhr, Andreas Berger, Muy-Kheng Maria Tea, Georg Pfeiler, Christine Rappaport-Fuerhauser, Daphne Gschwantler-Kaulich, Sigrid Weingartshofer
Journal: Journal of Clinical Oncology (2014)

1545 Background: We have recently demonstrated that the onset of breast cancer (BC) in BRCA 1 and 2 mutation carriers is influenced by their birth year, thus indicating a risk-modifying role for reproductive and life style factors. We now examined possible associations between potential risk factors, birth cohorts, and the onset of BC in BRCA1 and 2 mutation carriers. Methods: 130 female BRCA1 and 67 BRCA2 mutation carriers who had been identified at the Vienna University Hospital between 1995 and 2013, and who had developed BC were included in the analysis. Individual reproductive and life style factors were identified by questionnaires. Cox regression analysis and log-Rank testing were used to estimate the effect of potential risk factors on the onset of BC. Results: BRCA mutation carriers who had never been pregnant developed BC at a younger age than those who had been pregnant at least once (36.4 vs 40.9; p=0.001). Similarly, women who had used oral contraceptives, or had smoked, developed BC earlier than never users (39.3 vs. 44.9 years; p=0,0001, and 39.0 vs. 41.4 years; p=0,05, respectively). In Multivariate analysis oral contraceptive use (HR:1.7; p=0.006), and date of birth ≥1965 (HR:4.5; p=0.001) were associated with an earlier BC-onset. Conversely, the more full-term pregnancies a woman had experienced, the longer her BC-onset was delayed (HR:0.2; p=0.04). Mutation carriers born ≥1965 developed BC at a median age of 42 years whereas the median age at diagnosis for women born <1965 was 58 years (p<0.0001 log Rank test). These women were also more likely to have experienced multiple pregnancies and to have breastfed, but were less likely to have used oral contraceptives or to have smoked. Conclusions: We here demonstrate that in BRCA1 and 2 mutation carriers the birth-cohort-associated differences in the onset of BC are profound and largely influenced by reproductive factors such as the number of pregnancies and the use of oral contraceptives.
Gene set enrichment analysis to evaluate expression of autoantigens in lung cancer
Authors: K. Johnson, A. Berger, T. Watkins, C. Cheadle, L. Casciola-Rosen, S. M. Levine
Journal: Journal of Clinical Oncology (2009)

e22048 Background: There is a well-established association between certain autoimmune diseases and the development of specific malignancies. It has been demonstrated that myositis-specific autoantigens are expressed at higher levels in tumors associated with myositis compared to normal tissue, suggesting that immune responses to antigens expressed in nascent tumors may contribute to the autoimmune process. Whether this observation is a general feature of autoantigen expression in tumor tissue, and whether the relative expression of these antigens is enriched in relation to the rest of the tumor transcriptome is currently unknown. Methods: Tumor tissue from ten lung cancer biopsies (adenocarcinoma (4), carcinoid (4), and squamous cell carcinoma (2)) and normal lung from the same patients were obtained. Total RNA was extracted and hybridized to Illumina Sentrix BeadChips. Hiearchical clustering was used to visualize the expression levels of 146 known autoantigens. Gene Set Enrichment Analysis was performed using 20 disease-specific autoantigen gene sets and 1892 gene sets from the Molecular Signatures Database. Protein levels of selected autoantigens were assessed by immunoblotting detergent tissue lysates. Results: Single-linkage hierarchical clustering analysis reveals groups of autoantigens that are differentially expressed between normal lung tissue, carcinoid tumors, and adenocarcinomas. Adenocarcinoma tumor samples were significantly enriched for myositis (nominal p-value &lt;0.001, false discovery rate (FDR) q-value 0.009) and SLE autoantigens (p-value 0.004, FDR 0.029). Scleroderma autoantigens were enriched in carcinoid tumors (p-value 0.003, FDR 0.053). Increased protein expression of the autoantigens Mi-2 and topoisomerase-1 in carcinoid tumors was confirmed by immunoblotting. Conclusions: This study reveals that autoantigens targeted in several autoimmune diseases are both transcribed and expressed at high levels in malignancies known to associate with those disorders. While autoantigens comprise only a small fraction of the total transcriptome, they are disproportionately expressed in tumors known to associate with autoimmunity, supporting the hyporthesis that autoimmunity to these proteins may arise via nascent anti-tumor responses. No significant financial relationships to disclose.
mTOR pathway activation in KIT-mutated melanoma with acquired imatinib resistance.
Authors: Lu Si, Xiao wei Xu, Yan Kong, Keith T. Flaherty, Zhi Hong Chi, Chuan Liang Cui, Xi Nan Sheng, Si Ming Li, Bi Xia Tang, Jun Guo
Journal: Journal of Clinical Oncology (2012)

8562 Background: c-Kit mutation is a common genetic abnormality in certain melanoma subtypes, and is a target for treatment. However, the mechanisms of secondary (acquired) resistance and how to treat patients in the second line are unknown. Methods: Tissuesamples were obtained from c-Kit-mutated melanoma patients who failed of imatinib after having PR or SD for at least 6 months pre- and post-imatinib therapy. Somatic mutations in genes in MAP kinase (c-Kit, BRAF, NRAS, etc) and PI3K-AKT-mTOR (AKT1, TSC1, PTEN, etc) pathways were detected by DNA sequencing. The expression of pS6RP, p4E-BP1, pAKT and pERK1/2 were examined by immunohistochemistry (IHC) assays. Results: Four paired samples (formalin-fixed, paraffin-embedded) were analyzed. 1) Laboratory results: No secondary mutations in addition to the c-Kit mutations identified at baseline were identified. However, IHC showed increased pS6RP and p4E-BP1 (two targets of mTOR activation) as well as increased pAKT and pERK1/2 in imatinib-resistant samples, suggested that mTOR signaling pathway was selectively activated in these secondary imatinib-resistant melanomas. 2) Treatment: Everolimus is an orally administered inhibitor of mTOR. The four patients received everolimus (10 mg/day) by continuous daily dosing. The tumor response revealed 1 PR and 3 SD (all &gt;3 months) with grade 1-2 toxicities consisting of myelosupression, hyperglycemia, hypercholesterolemia and hypertriglyceridemia, consistent with previously reported toxicities for everolimus. Conclusions: The case series provides an important clue that activation of the mTOR signal pathway may be one of the mechanisms for secondary imatinib resistance in c-Kit-mutated melanomas. The results also show that everolimus may be effective and safe for melanoma patients who develop resistance to imatinib and could be investigated in combination with c-Kit inhibitors in treatment-naive patients.
Three-arm randomized trial of sodium alginate, orally administered mucoprotective agent, for preventing radiation esophagitis in pts with locally advanced non-small-cell lung cancer (LA-NSCLC) receiving concurrent chemoradiotherapy (CRT): Okayama Lung Cancer Study Group 1401.
Authors: Katsuyuki Hotta, Kiichiro Ninomiya, Isao Oze, Akihiro Bessho, Toshi Murakami, Naoyuki Sone, Shingo Harita, Naoyuki Nogami, Shoichi Kuyama, Mitsune Tanimoto, Katsuyuki Kiura
Journal: Journal of Clinical Oncology (2015)

TPS9641 Background: Concurrent CRT is the standard treatment in LA-NSCLC. Our phase 3 trial also showed a favorable efficacy of cisplatin-docetaxel and concurrent thoracic radiotherapy (JCO 2010). However, this intensive therapy can cause G3 or worse severe esophagitis of around 14%~27%, which would deteriorate pt’s QOL and then lead to poor treatment compliance. Unfortunately, various types of supportive therapy including amifostine have failed to demonstrate the prevention of this toxicity. Sodium Alginate, already approved in Japan for gastritis, is highly viscous enough to stay long on the esophageal mucosa, leading to a mucosal protective effect in esophagus. To investigate if the agent indeed has a preventive effect for severe esophagitis in pts receiving concurrent CRT, we started three-arm randomized trial of sodium alginate with two different schedules vs. water. Methods: Pts have to meet the followings: untreated LA-NSCLC; suitable for receiving CRT; PS of 0 or 1; age > 20 yrs. The primary endpoint is set as proportion of ≥ G3 esophagitis by CTCAE ver.4.0. With the stratiﬁcation by institute, PS and esophagus V35 (Technol Cancer Res Treat. 2013), pts will be randomly assigned centrally to one of the followings; sodium alginate initiated concomitantly with CRT (A), sodium alginate initiated soon after developing extremely mild esophagitis during CRT (B), or water administered through CRT (C). Sodium alginate is administered at a dose of 60 ml per day. Assuming the proportion of ≥ G3 esophagitis would be 8% each in arms A and B and 27% in arm C, the required sample size is 200 pts (1-β: .7, α: .05). The secondary endpoint includes QOL, the frequency of additional prescription of analgesics, response and survival. Enrollment began in 2014, and will complete by 2017. UMIN registration number of 000013113 Clinical trial information: 000013113.
10-year outcomes of breast cancer patients with histologically confirmed axillary lymph node metastases and pathologic complete response after primary systemic chemotherapy.
Authors: Sarah Schellhorn Mougalian, Xiudong Lei, Limin Hsu, Gabriel N. Hortobagyi, Henry Mark Kuerer, William Fraser Symmans, Vicente Valero
Journal: Journal of Clinical Oncology (2013)

1017 Background: Pathologic complete response (pCR) of tumors in the breast and axillary lymph nodes (ALN) after primary systemic chemotherapy (PST) is associated with an excellent outcome. A previous analysis showed superior 5-year overall survival (OS) and relapse-free survival (RFS) for patients who achieved an ALN pCR after PST compared to those without a pCR in 5 prospective clinical trials. This study is an expanded analysis of all patients treated with PST at our institution examining the impact of ALN pCR on 10-year OS and RFS. Methods: Patients with clinical stage II/III and pathologically confirmed ALN metastases who underwent PST were categorized into 1 of 2 groups: ALN pCR and ALN residual disease. Additional data were collected, including breast cancer subtype, clinical tumor size, and lymph node staging, pathologic tumor (T) stage, and class of PST. RFS and OS were estimated by the Kaplan-Meier product limit method. Subset analyses were performed on patients with HER2-positive cancer. Results: 1,600 women diagnosed between 1989 and 2007 were identified. Median follow-up was 79 months (5-277); 454 (28.4%) achieved an ALN pCR. ALN pCR was associated with triple-negative and higher grade cancers, lower clinical stage, and lower pathologic breast T stage. 5-year OS and RFS estimates were similar to prior analysis. The 10-year OS was 85% and 58% and the 10-year RFS 83% and 55% (p &lt; 0.001), for patients who achieved an ALN pCR and those with residual ALN disease. For HER2-positive breast cancers, 67.3% of patients who received HER2-targeted therapy achieved an ALN pCR vs. 32.3% without HER2-targeted therapy (p &lt; 0.001). For patients receiving HER2-targeted therapy for HER2-positive breast cancer (n = 153), the 10-year OS was 92% and 52% (p = 0.006), and the 10-year RFS was 89% and 59% (p &lt; 0.001) for those with and without an ALN pCR. Conclusions: ALN pCR is an excellent early surrogate marker for long-term outcome, 10-year RFS and OS. In HER2-positive breast cancers, HER2-targeted therapy is associated with high rates of pCR. Despite the aggressive nature of their disease, patients who achieve ALN pCR with PST have an excellent 10-year prognosis.
A phase II study of alternating chemotherapy with CDDP/ 5FU/ folinic acid (FA) and epirubicin (E)/ docetaxel (T) (CF-ET regimen) as first line therapy for patients (pts) with metastatic gastric cancer (MGC)
Authors: H. H. Kirchner, P. Panagiotou, O. Jordan, S. Hamann, M. Sosada
Journal: Journal of Clinical Oncology (2006)

14021 Background: Active single agents in MGC are 5FU, CDDP, Anthracyclines, Taxanes and irinotecan. Combinations consisting of docetaxel, cisplatin, 5FU (TPF) and epirubicin, cisplatin, 5FU (ECF) have been investigated and both have shown activity and improvement of survival. However, the most efficient regimen is not yet defined. Methods: Chemotherapy-naive Patients with histologically confirmed MGC and measurable lesions were enrolled in this study. They received CDDP 35 mg/m 2 iv on day (d) 1, 2, 15 and 16, 5FU 2000 mg/m 2 continuous infusion (ci) d 1, 8, 15 and 22, FA 200 mg/m 2 iv d 1, 8, 15 and 22 and E 60 mg/m 2 d 29 and 43, T 60 mg/m 2 d29 and 43 q d 57. Pts with at least one completed cycle were eligible. Objectives of this study were to evaluate the response rate, toxicity, PFS and OAS of CF-ET. Results: Between 2002 and 2005 34 pts (22 male and 9 female) aged 31 - 77 years (median 61) entered. The total number of treatment cycles was 56, mean 1.8 (1 - 5). 31 pts were eligible. 9 pts had complete response; 11 pts had partial response, 4 pts had stable disease, 7 pts had progressive disease and 3 pts were not evaluable. The overall response rate was 64.5%. The median response duration was 6.1 months (2 - 29.4). The overall survival was 11.4 months (2.6 - 43.6). Grade 3/4 toxicities were leukopenia 41/37.5%, neutropenia 16/82%, thrombocytopenia 23.2/0%, neutropenia related fever was observed in 4 cycles. No severe organ toxicities nor toxic death was seen. Conclusions: The alternating CF-ET regimen showed significant efficacy with prolonged survival. The ET-part of the regimen induced severe but manageable haematological toxicities. The results require further evaluation in a randomized phase III - trial. No significant financial relationships to disclose.
Severe skin rash during vemurafenib treatment: A predictive factor of early positive response in metastatic melanoma?
Authors: Nora Kramkimel, Lilia Sakji, Audrey Thomas-Schoemann, Jean-Louis Golmard, Elodie Regnier-Rosencher, Christine Theodore, Francois Goldwasser, Michel Vidal, Eve Maubec, Laurent Mortier, Marie-Françoise Avril, Nicolas Dupin, Benoit Blanchet
Journal: Journal of Clinical Oncology (2014)

9092 Background: Interindividual variability in pharmacokinetics may influence clinical benefit or toxicity of vemurafenib (VMF) in metastatic melanoma (MM) and identification of predictive factors of response and toxicity are mandatory. Methods: From Nov. 2011 to Dec. 2013, VMF plasma concentration was assayed at different times within the first 65 days of treatment, after informed consent, in 55 patients treated with VMF for MM in 3 French Dermatologic Departments. Baseline clinical and biologic characteristics, average VMF plasma concentration per patient for tumor response analysis and absolute exposure at the day of the toxicity, tumor response (PFS, OS, early response rate evaluated after 2 months of VMF) according to RECIST criteria and toxicities (grade ≥2 rash and renal failure, any grade≥3 adverse events) graded using the NCI 4.0 scale, were tested univariately. Candidate variables with p<0.1 were studied in multivariate analysis. Results: Mean age was 55 years (25-84). 92.7% had stage IV MM, 25.5% had brain metastasis and 76% were PS 0-1. 90.7% of tumor had BRAF V600E mutation and 2.5% V600K. VMF was the first line treatment in 66.7%. Early response rate (i.e CR, PR and SD) was 61.5%. Mean PFS was 5.4 months (0.3-17) and mean OS was 9.0 months (0.3-24+). Mean VMF concentration (n=118) was 47.5 ± 20.4 mg/L. Interindividual variability in dose-normalized VMF exposure was 43%. In multivariate analysis, higher average VMF dose was associated with longer PFS (OR: 0.998 [0.997-0.999], p=0.0025). Grade ≥2 rash, observed in 29.6%, (OR: 5.64 [1.004-31.696], p =0.0495) and daily VMF dose regimen (OR: 1.29 [1.032-1.612],p=0.0256) were associated with early 2-month response. BMI (OR: 0.75 [0.592-0.95], p=0.0173) and VMF plasma concentration (OR: 1.061 [1.017-1.108], p =0.0065) were associated with grade ≥2 rash. Conclusions: This is the first study that highlights correlation between grade≥2 rash and early MM response under VMF. Moreover, relationship between PFS and high VMF average dose underlines importance to keep highest VMF dose even after adverse event. Finally, low BMI and high VMF plasma exposure were identified as risk factors for development of grade≥2 rash.
Pulsed dosing of erlotinib for central nervous system (CNS) progression in EGFR-mutant non-small cell lung cancer (NSCLC).
Authors: David Michael Jackman, Stacy L. Mach, Jennifer C. Heng, Michael S. Rabin, David Allen Barbie, Leena Gandhi, J Paul Marcoux, Daniel Botelho Costa
Journal: Journal of Clinical Oncology (2013)

8116 Background: Lung cancer is the most common cause of CNS metastases. Options for CNS progression are limited, particularly with leptomeningeal metastases (LM). High dose EGFR-TKIs have been used in this setting. This is a retrospective series of our experience with pulsed high dose erlotinib for these patients. Methods: Eligible pts with EGFR-mutant NSCLC were identified through our institutions’ databases and had received pulsed high dose erlotinib for CNS progression. Patients had received erlotinib 1000-1500 mg once weekly. The primary endpoint was CNS response; secondary endpoints included toxicity, systemic response, CNS progression-free survival, and overall survival. Results: Between 10/2010 – 10/2012, 10 eligible pts received pulsed dose erlotinib for CNS progression. The median age was 60 yrs; 8/10 were female, 7/10 were never-smokers, with a median of 2 pack-years. All pts had lung adenocarcinoma, and 9/10 had received prior EGFR-TKI. Median duration of prior TKI was 19 months. 6 received prior erlotinib, 1 received prior dacomitinib, and 2 received prior erlotinib followed by dacomitinib. The overall CNS response rate was 10% (1/10); 2 others achieved CNS stability. Median overall survival was 1.7 months (range 0.6 – 7.0). There was no clear correlation between outcomes and underlying EGFR genotype; type, duration, or dose of prior EGFR-TKI; or extent of CNS involvement. Conclusions: While there has been evidence of higher penetration of EGFR-TKI’s into cerebrospinal fluid with pulsed high doses of EGFR-TKI’s, the clinical efficacy of this strategy remains limited. [Table: see text]
Adjuvant stereotactic body radiotherapy (SBRT) for resected primary and metastatic liver cancers.
Authors: Latifa Bazzi, Mary Uan-Sian Feng, Theodore Steven Lawrence, Kyle Clifford Cuneo, Dawn Owen
Journal: Journal of Clinical Oncology (2017)

487 Background: Stereotactic body radiotherapy (SBRT) has been shown to be a safe and effective treatment for hepatobiliary cancers. However, little is known about the efficacy of adjuvant SBRT for resected liver tumors with positive margins. We examined the characteristics and outcomes of patients who received adjuvant SBRT for both primary and metastatic cancers of the liver. Methods: We retrospectively reviewed the charts of patients who had received liver SBRT from 2009-2015 at our institution. During that time frame, 11 patients were identified as having received adjuvant SBRT post resection. Patient data such as age, gender, portal vein thrombosis, cirrhosis, ECOG performance status, prior liver directed therapies, and SBRT dose were collected. Descriptive statistics were used for analysis given the small number of patients in this series. Results: Median age at the time of treatment was 63 years (range 51-79), and the majority of patients (72.7%) were male. Seven tumors (63.6%) were hepatocellular carcinomas, and 4 (36.4%) were adenocarcinomas. Of the tumors with adenocarcinoma histology, 3 were cholangiocarcinomas and one was metastatic colorectal cancer. Ten patients (90.9%) were treated for positive margins, and one was treated for inferior vena cava (IVC) invasion. Seven patients (63.6%) had no other liver-directed treatment prior to adjuvant SBRT. Two patients received systemic therapy prior to SBRT. Median EQD2 was 83.3 Gy (range 60-126), and 81.8% of patients received 5 fractions. There were no grade 3 or above late toxicities from treatment. Median follow-up was 14.1 months (range 5.4-38.1). None of the treated tumors progressed locally. Six patients (54.5%) progressed elsewhere in the liver, and one patient experienced distant metastatic progression. One patient experienced both intrahepatic progression and distant metastatic progression. Conclusions: Adjuvant SBRT appears to be a safe and feasible adjuvant treatment in patients with primary liver resection for either primary liver cancer or metastatic disease who are at high risk of recurrence.
Relationship between genetic markers and quality of life (QOL) in stage III colon cancer (CC) patients (pts) prior to adjuvant treatment (N0147).
Authors: Jeff A. Sloan, Qian Shi, Adam Lee, Robert B. Diasio, Emily S Pavey, Daniel J. Sargent, Richard M. Goldberg, Frank A. Sinicrope, Michelle R. Mahoney, Steven R. Alberts
Journal: Journal of Clinical Oncology (2012)

3617 Background: In metastatic colorectal cancer (CRC), previous studies suggested potential relationships between certain drug metabolizing (DM) genes (DPYD, ERCC2, GSTP1 and TYMS) and QOL prior to receipt of chemotherapy (Sloan, Plenary Session ASCO 2004). The current study is the first to examine relationships between similar DM genes and QOL in stage III CC pts. Methods: 1,583 CC pts on a randomized adjuvant stage III, phase III trial received FOLFOX, FOLFIRI, or either +/- Cetuximab. Genomic DNA and baseline QOL data via linear analogue self assessment (LASA) scales with 4 QOL variables were obtained. 53 DM SNPs were selected for known functional effect within potential regulatory sites. Two-sample t-tests assessed differences in QOL between pts with variants and wild-type status. Differences of at least 10 points on a 0-100 point QOL score were considered clinically significant. Results: 14 relationships between DM genes and QOL were detected at the nominal p &lt; 0.05 level; six of these were related to DPYD, ERCC2, GSTP1 and TYMS. Relationships were also observed at the 0.05 level with polymorphisms of genes DPYS, ERCC1, MGMT, MTHFR, OPRT and UGT1A1 based on unadjusted and adjusted association tests. GSTP1 I105V and OPRT 5’UTR 28 A&gt;G markers differed on fatigue scores (p=0.04, 0.005, respectively). Variants on MTHFR R594Q were associated with higher mental acuity scores (p=0.02). These relationships remained after adjusting for age, gender, race, T stage, PS, disease site, lymph nodes involved, and grade. The robustness of the observed associations varied with the multiple comparison adjustment method. Conclusions: Similar to the earlier study of stage IV CRC, we observed a possible relationship in pts with Stage III CC with regard to DM genes and QOL, although these relationships were more modest than observed in Stage IV pts. These DM genes may be in linkage disequilibrium with other genetic variants that more directly affect behavior and QOL. Further genome wide association studies are needed to clarify these relationships.