tbuckley/cabot-search huggingface dataset:
Cost-effectiveness of aromatase inhibitors versus selective estrogen-receptor modulators for breast cancer prevention in postmenopausal women.
Authors: Amy Grace Groom, Chris Skedgel, Daniel Rayson, Tallal Younis
Journal: Journal of Clinical Oncology (2014)

1565 Background: The selective estrogen-receptor modulators (SERMs) tamoxifen (TAM) and raloxifene (RAL), and more recently the aromatase inhibitor (AI) exemestane (EXE) have all been shown to reduce the risk of breast cancer (BC) in post menopausal (PM) women at high risk. As significant differences in adverse effect profiles and costs exist amongst these agents, determining the preferred strategy for clinical use requires consideration of both the risk-benefit profile and overall cost-effectiveness (CE) of each strategy. Prior studies have examined the CE of SERMs in this setting but similar evaluations of AIs have not yet been performed. Methods: We examined the probabilities of various BC prevention strategies, including 1) SERMs (TAM or RAL) relative to placebo and 2) AI relative to SERMs and placebo, meeting the $100,000 per quality-adjusted life year (QALY) gains threshold. A Markov model was constructed for a hypothetical cohort of PM women with varying elevated risks of developing BC and treatment related adverse events. Costs, utilities and probabilities were derived from the literature and relevant BC prevention trials including NSABP-P1, STAR and MAP 3. The analysis took a third-party payer perspective and reports costs in 2013 CDN dollars. Results: Substantial variability in the relative CE of each strategy was observed when probabilistic sensitivity analysis was performed and thus cost effectiveness acceptability frontiers (CEAFs) were used to compare the relative CE of each strategy. Both SERMs were associated with incremental gains in QALYs as well as incremental costs compared to no treatment but AI was most often the preferred BC prevention strategy at a willingness-to-pay threshold of $100,000/QALY. Conclusions: The use of EXE for BC prevention is associated with incremental QALY gains and is a cost-effective strategy in PM women at high risk of BC. The strategy of choice is dependent upon BC risk as well as the risk of adverse effects and the willingness-to-pay for a QALY gain.
Multiplexed mass spectometic quantitation of HER1-3, cMET, and IGF1R in FFPE tumor samples: Implications for targeted therapy and resistance.
Authors: Todd A. Hembrough, Wei-Li Liao, Sheeno Thyparambil, Marlene Darfler, David Krizman, Jon Burrows
Journal: Journal of Clinical Oncology (2012)

e21068 Background: The human EGF receptor family (HER’s) consists of two clinically validated drug targets (EGFR and HER2), and two receptors (HER3 and HER4) which are the subject of intensive preclinical and early clinical investigation. Although drugs inhibiting both EGFR and HER2 show significant antitumor activity in the clinic, the acquisition of resistance is a hallmark of these and other targeted therapies. In the case of both targets, one of the emerging resistance mechanisms is the co-expression of other receptor tyrosine kinases, including members of the EGFR superfamily, cMet and IGF1R. As an example, it was recently shown that HER2 co-expression mediates resistance in cetuximab treated head and neck cancer. Similarly, much attention has been paid to HER3 both as a bona fide drug target and a resistance mechanism. Methods: Using trypsin digestion mapping of recombinant proteins, we identified unique peptide sequences from each of these receptors, and built quantitative mass spectrometric (MS) assays which could be multiplexed into a single MS analysis of 1ug of tumor protein. Assays were preclinically validated on 10 formalin fixed cell lines, and FFPE human NSCLC primary tumor xenografts. Results: The validated multiplex assay was used to measure expression levels of HER1-3, cMET and IGF1R in two cohorts of clinical tumor tissue which had been treated with HER family antagonists. One, a set of gefitinib treated NSCLC tumors (N=15) , and a second, a cohort of advanced breast cancer tissues which had adjuvant treatment with trastuzumab(N=18). Here we present expression patterns for each of the RTKs studied, with the intent to begin to define the relationship between RTK expression and response to either gefitinib or trastuzumab treatment. Conclusions: It is important to not only understand primary mechanisms of tumor growth, but also mechanisms of resistance in patients undergoing targeted therapies. Our Liquid Tissue-SRM promises to be a platform which can deliver extremely high sensitivity, absolute specificity as well as multiplexing capabilities to assess critical oncology targets.
Overall survival (OS) benefit with sipuleucel-T by baseline PSA: An exploratory analysis from the phase III IMPACT trial.
Authors: Gerald Chodak, Paul F. Schellhammer, James Boyd Whitmore, Robert Brownell Sims, Philip W. Kantoff
Journal: Journal of Clinical Oncology (2012)

4648 Background: Sipuleucel-T is an autologous cellular immunotherapy approved for asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer. In the IMPACT trial, sipuleucel-T showed a 22.5% reduction in risk of death vs the control group (hazard ratio [HR]=0.775 [95% CI 0.614, 0.979]; P=0.032). A pre-specified subgroup analysis for baseline prognostic variables showed homogeneous treatment effects consistently favoring sipuleucel-T. In patients (pts) with baseline PSA below vs above the median, there was a trend toward greater treatment effect (HR=0.685 vs. 0.865). In this exploratory analysis, we further sub-divide baseline PSA into quartiles to evaluate potential treatment effect patterns. Methods: The analysis included all randomized pts from IMPACT (n=512). Pts were categorized by baseline PSA quartile (Table), ECOG PS and by median for other baseline prognostic variables (i.e., LDH, PAP, ALP in bone-only disease, and Hgb). Median OS and HR were estimated using Kaplan-Meier and Cox models, respectively. Results: Increasing baseline PSA quartile was associated with markers of advanced disease. HRs suggest a consistent treatment effect in all subsets, although there is inadequate power to show significant results within each quartile. There was a trend toward an increased magnitude of treatment benefit in pts with a lower baseline PSA (Table). Results for other baseline prognostic variables also suggest a trend toward greater benefit in subjects with better prognostic features. However, results for baseline Hgb indicated an opposite trend. Conclusions: Although not adequately powered for significance, the results of this analysis support a consistent OS benefit with sipuleucel-T across PSA quartiles. The greater magnitude of benefit in pts with lower baseline PSA suggests that pts with less advanced disease may benefit more from treatment with sipuleucel-T. [Table: see text]
MicroRNA-218: A potential regulator of lymphatic metastasis in pancreatic ductal adenocarcinoma.
Authors: Hang He, Yang Di, Min Rui Liang, Feng Yang, Lie Yao, Si Jie Hao, Ji Li, Yong Jian Jiang, Chen Jin, De Liang Fu
Journal: Journal of Clinical Oncology (2012)

e14651 Background: Early lymph node metastasis is one of the most important characteristic features of pancreatic ductal adenocarcinoma (PDAC) with a dismal prognosis. MicroRNAs (miRNAs) have been shown to have a role in oncogenesis, invasion, and metastasis via epigenetic posttranscriptional gene regulation. However lymphatic metastasis related miRNAs of pancreatic cancer (PC) has not been well documented. Methods: Through microarray analysis aberrantly expressing miRNAs potentially regulating lymphatic metastasis in PC were gained from PDAC tissue specimens and cell lines. Candidate miRNAs were confirmed in total 40 resected PDAC cases and cell lines by quantitative reverse transcription-PCR (qRT-PCR). In situ hybridization was performed to elucidate the expression features of miRNA-218 in PDAC, precursor lesions, metastatic lymph nodes and cell lines. Results: MiRNA-218 and other five miRNAs were found aberrantly expressing both in PDAC and BxPC-3-LN5 (cell line with high-metastasis characteristics) by microarray analysis. Down-regulated expression of miRNA-218 was validated in PDAC tissue samples (4 fold decrease) compared to adjacent benign tissue (p=0.006) and cell line BxPC-3-LN5 (3 fold decrease) compared to BxPC-3 (p=0.01). Clinicopathological data demonstrated inverse correlation of miRNA-218 expression with lymph node metastasis (p=0.045). Expression of miRNA-218 was down-regulated in IPMN and even decreased in PDAC in a grade-dependent manner. Almost negative expression of miRNA-218 was revealed in metastatic lymph nodes. Conclusions: Down-regulated expression of miRNA-218 in PDAC and its expression features in precursor lesions suggests a tumor suppressor action of miRNA-218 in PDAC. Decreased expression of miRNA-218 may be associated with lymphatic metastasis of PDAC and interpret the high-metastasis ability of BxPC-3-LN5 cell line.
Poorly differentiated clusters as a prognostic marker at the invasive front of colon cancer.
Authors: Tsuyoshi Konishi, Yoshifumi Shimada, Lik Hang Lee, Marcela Santos Cavalcanti, Martin Morris, Meier Hsu, Mithat Gonen, Jesse Joshua Smith, Garrett Michael Nash, Larissa K. F. Temple, Jose G. Guillem, Philip Paty, Julio Garcia-Aguilar, Efsevia Vakiani, Jinru Shia, Martin R. Weiser
Journal: Journal of Clinical Oncology (2017)

621 Background: Histology at the invasive front of colon cancer can predict malignant potential. However, the optimal histological marker is yet to be established. This study compares the various invasive front histologic markers. Methods: A single-institution prospective database was queried for consecutive patients who underwent curative resection for Stage I-III colon adenocarcinoma from 2007-14. Histologic features were reviewed by a pathologist, including poorly differentiated clusters (PDC), tumor budding (BD), perineural invasion (PN), desmoplastic reaction (DR) and Crohn’s like reaction (CLR) at the invasive front, and WHO grade of the whole tumor. PDC was defined as cancer clusters of ≥ 5 cancer cells that lack a gland-like structure, and was graded into G1 ( &lt; 5), G2 (5-9) and G3 ( ≥ 10) by the highest number of the clusters /HPF. Clinical outcome included recurrence free survival (RFS) and peak hazard function of recurrence and death identified using the kernel-smoothing method. Predictive accuracy was measured with concordance probability estimate (CPE) for proportional hazards regression. Inter-observer agreement was assessed by weighted kappa values on diagnoses rendered by 3 pathologists on 50 randomly selected cases. Results: The study cohort consisted of 851 patients with a median follow up of 36 months. PDC, BD, PN, DR and CLR at the invasive front were significantly associated with RFS. When analyzed by stage, PDC, BD and PN were associated with RFS both in Stage II and Stage III, while the others were prognostic only in Stage III. CPE was the highest in PDC (0.642), indicating the best predictive accuracy, while it was the lowest in WHO grade (0.526). Weighted kappa was also the highest for PDC, indicating the best inter-observer agreement (PDC: 0.824, WHO grade: 0.568). The smoothed graph of the hazard function showed that the risk of recurrence was not only the highest but peaked earlier for PDC G3 (between0 and 12 months) than PDC G2 (between12 and 24 months) and G1 (no evident peak). Conclusions: Of the commonly evaluated histologic markers at the invasive front, PDC grade is the most predictive and reproducible. Further confirmatory investigations are warranted to determine if PDC can replace WHO grade.
Feasibility and Reproducibility of the New NIH Consensus Criteria To Evaluate Response in Chronic GvHD - A Pilot Study.
Authors: S. Mitchell, B. Reeve, E. Cowen, J. Fall-Dickson, L. Gerber, J.P. Guadagnini, M. Robinson, M. Turner, G. Willis, M. Schubert, J. Bolanos-Meade, M. Higman, D. Jacobsohn, K. Thormann, G. Vogelsang, S. Pavletic
Journal: Blood (2005)
KRAS testing practice in Denmark between 2009 and 2013.
Authors: Anne Gulbech Ording, Trine Frøslev, Karen-Lise Garm Spindler, Margaret Elizabeth McCusker, I-Ning (Elaine) Cheng, Henrik Toft Sørensen, Vera Ehrenstein
Journal: Journal of Clinical Oncology (2017)

654 Background: Guidelines for managing patients with metastatic colorectal cancer (mCRC) were updated in Denmark in 2013, and anti-epidermal growth factor receptor (EGFR) inhibitors were promoted from third-line to first-line treatment for KRAS wildtype mCRC patients. As a result, more patients became eligible for EGFR antibody therapy. Weexamined KRAS testing practice among patients with mCRC who received systemic cancer treatment in Denmark during 2009-2013. Methods: We linked data from several population registries with nationwide coverage - the Danish Cancer Registry, the Danish National Patient Registry, and the Danish National Pathology Registry - to identify patients diagnosed with mCRC (primary or recurrent) between 2009 and 2013, their systemic cancer treatment, and their KRAS testing status. We obtained all KRAS test results through 2014 and calculated proportions of KRAS-tested patients by year of mCRC diagnosis. Results: There were 7,245 mCRC patients, among whom 4,272 (59%) had a record of systemic cancer treatment within 6 months of mCRC diagnosis and were included in the analysis. The proportion of men was 57%; median age at mCRC diagnosis was 67 years (range 20-94 years). Overall, 2,099/4,272 (49%) of the treated mCRC patients had a recorded KRAS test result, with similar proportions for patients with primary and recurrent mCRC. Among patients diagnosed with mCRC in 2009, the proportion with a recorded KRAS test result was 374/900 (42%). Corresponding proportions for patients diagnosed in 2010, 2011, 2012, and 2013 were 411/891 (46%), 457/870 (52%), 430/807 (53%), and 427/804 (53%). Conclusions: Among patients in Denmark diagnosed with mCRC who received systemic cancer treatment, the proportion of patients with a KRAS test result recorded in the Danish National Pathology Registry increased from 2009 to 2013. This may have resulted from increased testing or increased recording, or both.
Impact of M1a and M1b staging in patients (pts) with metastatic colorectal cancer.
Authors: Hagen F. Kennecke, Jason Yu, Sharlene Gill, Winson Y. Cheung, Charles Davic Blanke, Rona Cheifetz, Ryan Woods
Journal: Journal of Clinical Oncology (2013)

3590 Background: In 2009, pts with M1 colorectal cancer were divided into two subsets for the American Joint Committee on Cancer (AJCC) 7th edition. Pts with metastases (mets) confined to one organ or site at initial diagnosis became stage M1a while multiple sites or peritoneal mets became M1b. The objectives of the study are to evaluate the impact of site of mets and M1a/b staging among pts with M1 colorectal cancer. Methods: All pts referred to the BC Cancer Agency from 1999-2007 with newly diagnosed M1 colon or rectal cancer were included. Demographic, treatment, and outcome data were prospectively collected. The prognostic impact of individual sites of mets was assessed by hazard ratio estimates from univariate Cox models. Multivariable Cox proportional-hazards models were used to determine variables associated with overall survival in the entire cohort and in those undergoing resection of their primary tumor. Results: 2,049 pts with M1 disease were included. Median age was 66 years; 71% had colonic origin; 70% had their primary tumor resected; and 69% received chemotherapy. In univariate analysis, solitary mets were associated with improved survival. In multivariable analysis, M1a/b status still had significant prognostic effect. The effect remained significant in the subgroup analysis of pts with resected primary tumors when histology, T and N stage were included. Conclusions: Pts with solitary mets, including peritoneum, have superior overall survival as compared to those with multiple sites of mets. AJCC 7th edition staging that includes M1a/b provides significant prognostic information and should be considered in clinical practice and trials of pts with M1 disease who otherwise have few prognostic factors. [Table: see text]
Growing a cancer survivorship care plan program.
Authors: Claire Michelle Sutherby (Bennett)
Journal: Journal of Clinical Oncology (2017)

58 Background: More than 15.5 million cancer survivors live in the United States. This number is expected to be over 20 million by 2026. Cancer survivors have increased risk of morbidity; therefore, preventive and on-going medical treatment requires close monitoring and coordination. The Institute of Medicine’s (IOM) 2005 report, Cancer Patient to Cancer Survivor: Lost in Transition, recommended health providers raise awareness of cancer survivors’ needs and establish cancer survivorship as a distinct phase of care. The IOM also recommended patients who complete primary treatment are provided a comprehensive summary and plan that is effectively explained. A survivorship care plan maps out and improves care related to accessibility of past diagnosis and treatment history, surveillance guidelines, and potential long term side effects. In 2012, the Commission on Cancer (CoC) added Standard 3.3 Survivorship Care Planto the program standards. This met the IOM’s objective of addressing potential patients that get “lost” as they transition from care they received during treatment through phases of their life or disease. Methods: The Cancer Committee within a CoC certified organization developed multiple strategies to address the IOM and CoC standards. Strategies included a process to disseminate a comprehensive care summary for cancer patients who are completing primary treatment, adoption of the American Society of Clinical Oncology’s Treatment Summary and Survivorship Care Plan template, and adding a survivorship nurse navigator to the interprofessional treatment team. The survivorship nurse navigator monitors and reviews survivorship care plans with patients, advises when to seek treatment for symptoms, discusses surveillance guidelines, navigates patients through therapies, and educates on prevention and screening. Results: Evaluation for quality of life and compliance with individualized surveillance guidelines is ongoing. Conclusions: The oncology nurse navigator role is uniquely positioned to lead care coordination and improve outcomes through the continuum of care. Providing patients with a summary of their treatment and a plan moving forward may decrease stress related to the transition from active treatment to survivorship.
Phase I Dose-Escalation Study of Taselisib, an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors
Authors: Dejan Juric, Ian Krop, Ramesh K. Ramanathan, Timothy R. Wilson, Joseph A. Ware, Sandra M. Sanabria Bohorquez, Heidi M. Savage, Deepak Sampath, Laurent Salphati, Ray S. Lin, Huan Jin, Hema Parmar, Jerry Y. Hsu, Daniel D. Von Hoff, José Baselga
Journal: Cancer Discovery (2017)

Abstract Taselisib is a potent and selective tumor growth inhibitor through PI3K pathway suppression. Thirty-four patients with locally advanced or metastatic solid tumors were treated (phase I study, modified 3+3 dose escalation; 5 cohorts; 3–16 mg taselisib once-daily capsule). Taselisib pharmacokinetics were dose-proportional; mean half-life was 40 hours. Frequent dose-dependent, treatment-related adverse events included diarrhea, hyperglycemia, decreased appetite, nausea, rash, stomatitis, and vomiting. At 12 and 16 mg dose levels, dose-limiting toxicities (DLT) were observed, with an accumulation of higher-grade adverse events after the cycle 1 DLT assessment window. Pharmacodynamic findings showed pathway inhibition at ≥3 mg in patient tumor samples, consistent with preclinical PIK3CA-mutant tumor xenograft models. Confirmed response rate was 36% for PIK3CA-mutant tumor patients with measurable disease [5/14: 4 breast cancer (3 patients at 12 mg); 1 non–small cell lung cancer], where responses started at 3 mg, and 0% in patients with tumors without known PIK3CA hotspot mutations (0/15). Significance: Preliminary data consistent with preclinical data indicate increased antitumor activity of taselisib in patients with PIK3CA-mutant tumors (in comparison with patients with tumors without known activating PIK3CA hotspot mutations) starting at the lowest dose tested of 3 mg, thereby supporting higher potency for taselisib against PIK3CA-mutant tumors. Cancer Discov; 7(7); 704–15. ©2017 AACR. See related commentary by Rodon and Tabernero, p. 666. This article is highlighted in the In This Issue feature, p. 653
I-SPY 2 low risk registry: An I-SPY 2 trial sub-study for women with clinically advanced, ER+, HER2- breast cancer and molecular good-prognosis gene signature.
Authors: Tufia C. Haddad, Mamta D Shah, William Fraser Symmans, Nola Hylton, Christina Yau, Julia Lyandres, Michelle E. Melisko, Andres Forero, Kathy S. Albain, Henry G. Kaplan, Rebecca Klein Viscusi, I-Spy Trial Investigators, Donald A. Berry, Laura Esserman, Amy Jo Chien
Journal: Journal of Clinical Oncology (2015)

TPS635 Background: With the increased utilization of molecular gene signatures, clinicians have identified a population of breast cancer patients that have clinically advanced disease associated with a low risk molecular profile. This discordance between tumor stage and molecular prognosis results in a dilemma for which consensus and evidence to guide treatment decisions are lacking. The I-SPY 2 Low Risk Registry (LRR) was therefore developed to capture the critical treatment data and clinicopathologic outcomes of these patients. A correlative biomarker study to characterize the biology and heterogeneity amongst these tumors is also planned. The goals of the LRR are to observe treatment patterns, determine tumor chemoendocrine sensitivity, and monitor clinical outcomes of these patients in order to inform the development of future studies aimed to optimize their management and outcomes. Methods: Patients with stage II or III breast cancer are recruited from the ongoing phase 2 neoadjuvant I-SPY 2 TRIAL. I...
Continuing EGFR-TKI in combination with super-selected arterial infusion chemotherapy beyond RECIST PD for patients with advanced EGFR positive mutation non-small cell lung cancer.
Authors: Huiwei Qi, Jie Zhang, Caicun Zhou, Sen Jiang, Dong Yu, Huijuan Ni, Qiong Hu
Journal: Journal of Clinical Oncology (2015)

e19119 Background: Local therapy showed promising results for the patient who had an oligo-metastasis after acquired resistance of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Our study is to evaluate the efficacy and safety of continuing EGFR-TKI treatment in combination with regional interventional chemotherapy beyond RECIST progression disease (PD) of EGFR-TKI in advanced patients with EGFR mutation-positive NSCLC. Methods: Advanced NSCLC patients with EGFR mutation who got a locally progressed in central lung lesion after the treatment of EGFR-TKI were included. Patients received EGFR-TKI continually in combination with super-selected systemic arterial infusion with docetaxel (75 mg/m2) every 21 days until disease progression again or unacceptable side effect. Response to treatment, progression-free survival (PFS) 1 (time to RECIST PD), PFS 2 (time to PD if EGFR-TKI was extended beyond RECIST PD) and treatment-related adverse effects (AEs) were analyzed, and patient-reported outcomes were evaluated based on the QLQ-LC13 scales. Results: A total of 6 patients were recruited. Patients had the median age of 54.17 years (range, 40-68 years). Two patients achieved partial responses and four had stable disease. Median PFS1 was 11.70±8.97 months. Median PFS2 was 5.36±1.47 months. There was one death (none treatment related). OS data are immature. No unexpected side effects were found in our study. Patients reported significantly greater reductions from baseline in the symptoms of cough, hemoptysis, chest pain and dyspnea (P < 0.05 for all comparisons). Conclusions: Continuing EGFR-TKI in combination with super-selected systemic arterial infusion chemotherapy beyond progression for advanced NSCLC patients with EGFR mutation is feasible and warrant further investigation.