tbuckley/cabot-search huggingface dataset:
Role of pazopanib (PZ) in modulating hormone resistance in advanced breast cancer (ABC).
Authors: Melanie Catherine Majure, Michelle E. Melisko, Ariel R. Karwat, Amy Jo Chien, Andrei Goga, Mark M. Moasser, John W. Park, Amy N. DeLuca, Hope S. Rugo
Journal: Journal of Clinical Oncology (2015)

529 Background: Hormone resistance develops in nearly all patients (pts) with hormone receptor positive (HR+) ABC. Preclinical data suggests that higher levels of vascular endothelial growth factor (VEGF) are associated with hormone resistance. We conducted a phase II trial to evaluate the clinical benefit (CB) from adding PZ, a VEGF receptor tyrosine kinase inhibitor (TKI) to a nonsteroidal aromatase inhibitor (NSAI) in pts with ABC progressing on NSAIs. Methods: Eligibility included postmenopausal women with HR+ ABC and evidence of progressive disease after at least one month of NSAI therapy. Treatment was PZ 800 mg/day plus either letrozole or anastrozole. The primary endpoint was CB rate (CBR) at 12 weeks (wks). Secondary endpoints were progression free survival (PFS) and safety. A CBR of 20% was considered a clinically meaningful comparison to the expected CBR of < 5% with continued therapy after progression on an NSAI. Using a 2 stage design, stable disease in at least one of the first 13 pts allowed continued enrollment to a planned 27. Results: Thirty pts were enrolled; 27 are evaluable for study endpoints. The median age was 58 years. Pts were heavily pre-treated with a mean of 2.6 lines of prior hormone therapy (range 1-6) and 1.6 lines of chemotherapy (range 0-8). Eight pts (30%) stopped treatment due to toxicity including hypertension (HTN), fever, transaminitis, and pulmonary embolism; 6 pts progressed prior to wk 12. The CBR at 12 wks was 44.4% (11 SD, 1 PR), and at 24 wks was 22.2% (4 SD, 2 PR). Median PFS for pts with CB at 12 wks was 30 wks (95% CI 20-40); 6 pts had PFS > 6 months (26, 32, 32, 36, 48, and 78 wks). Three pts remain on study at 20, 32 and 78 wks. The most common adverse events (AE) were nausea (52%), fatigue (41%), arthralgia (26%), back pain (26%), and HTN (26%). Grade 3/4 AE included HTN (11%), transaminitis (11%), and headache (7%). Conclusions: The addition of PZ to a NSAI resulted in a CBR of 44% at 12 wks, and 22.2% at 24 wks in pts with heavily pre-treated hormone resistant ABC, suggesting that the antiangiogenic TKI PZ can modulate resistance to hormone therapy. Expected toxicities resulted in early discontinuation in 30% of pts, which limited drug exposure. Evaluation of biomarkers and immune signatures is ongoing. Clinical trial information: NCT01466972.
Patient-specific mathematical modeling as a precision-medicine approach to evaluating therapeutic gains of a novel chemoprotection treatment in newly diagnosed glioblastoma.
Authors: Sandra K. Johnston, Jennifer E. Adair, Carly Bridge, Laura Guyman, Andrea Hawkins-Daarud, Russell Rockne, Anne Baldock, Jason K. Rockhill, Maciej M. Mrugala, Brian C. Beard, Hans-Peter Kiem, Kristin Swanson
Journal: Journal of Clinical Oncology (2013)

e13041 Background: Glioblastoma (GBM) is the most common and lethal of all brain tumors (median overall survival (OS)14.6 months), yet the incidence is low posing difficulty in creating statistically powered clinical trials, delaying advances in treatment. A patient-specific mathematical model for disease progression coupled with clinical imaging data may provide a tool for quantifying each individual tumor’s response relative to its inherent growth kinetics rather than a universal approach, and, potentially, predicting treatment efficacy. Methods: An exploratory analysis with a patient-specific mathematical model of GBM was used to evaluate therapeutic effect of a novel treatment for newly diagnosed GBM compared to standard care treatment. A cohort of 3 patients from a novel-chemoprotective stem cell gene therapy treatment study (CSCGT) received RT only, followed by dose-intense BCNU and infusion of autologous gene-modified hematopoietic stem cells. Patients then received TMZ combined with O 6 -benzylguanine (O 6 BG). Tumor volumes were calculated using T1 weighted gadolinium -enhanced and T2-weighted pretreatment MRI images to estimate patient-specific net rates of proliferation and invasion for predicting untreated tumor growth. Control patients were selected based on matching model-based rates of net proliferation and invasion and standard prognostic variables (age, performance, extent of resection). Deflection of tumor growth, days gained (DG), was determined by finding the time point on the untreated growth curve that corresponded to the post-treatment tumor size and calculating the amount of time treatment gained for the patient. DG per mg of TMZ dosed is used to compare treatment effects of TMZ with differing dose regimens. Results: CSCGT patients experienced higher DG per mg of TMZ dosed compared to their matched controls treated with standard care regimens. Conclusions: Patient-specific mathematical modeling can be used to evaluate treatment gains in small clinical trial design. The addition of O 6 BG to TMZ in the post RT milieu can provide greater treatment gains per mg of TMZ dose than TMZ alone. Clinical trial information: NCT 00669669.
Prognostic effect of single versus multiple somatic mutations in non-small cell lung cancer (NSCLC).
Authors: Kevin Jao, Pascale Tomasini, Suzanne Kamel-Reid, Ming Sound Tsao, Gregorz J Korpanty, Celine Mascaux, Geoffrey Liu, Natasha B. Leighl, Ronald Feld, Penelope Ann Bradbury, Marguerite Ennis, Frances A. Shepherd
Journal: Journal of Clinical Oncology (2015)

7521 Background: Somatic mutations are becoming increasingly important biomarkers for treatment selection and outcome in patients with NSCLC. Methods: Tissue from 200 patients with NSCLC at the Princess Margaret Cancer Centre, were analyzed by next-generation genomic sequencing using Mi-SEQ or Sequenom multiplex platforms. TP53 analysis was added for DNA sequenced by Sequenom. Mutation status was correlated with clinical and demographic data retrieved from patient records. Results: Somatic mutations were identified in 139 patients (70%): single (n = 67) and multiple ( ≥ 2, n = 72). The most common mutations were TP53 (n = 70, 30%), KRAS (n = 48, 21%) and EGFR (n = 45, 20%). Multiple mutations were significantly associated with younger age (p = 0.02), but not with sex, histology, stage, ethnicity or smoking status. Multiple mutations occurred most frequently with TP53 (n = 53, 32%), EGFR (n = 35, 21%) and KRAS (n = 25, 20%). Among multiple mutations, the most common co-mutations were KRAS-TP53 (25%) and EGFR-TP53 (19%); 10% of patients had 2 EGFR mutations. On univariate analysis, there was a trend for multiple mutations to be associated with poorer overall survival (OS) (HR 1.65, CI 0.95-2.87, p = 0.07) in the entire group, and significantly shorter OS in adenocarcinoma (n = 116) (HR 2.12, CI 1.47-2.01, p = 0.028). In the subgroup of 94 surgically resected stage I-III patients, multiple mutations (n = 49) were associated with shorter relapse-free survival (median 1.7 v 3.2 yrs, HR 1.92, CI 1.17-3.14, p = 0.008) and OS (median 5.8 v 7.8 yrs, HR 2.29, CI 1.06-4.94, p = 0.026). No OS difference was seen in advanced stage III/IV patients with single (n = 21) v multiple mutations (n = 23) (HR 0.93 CI 0.4-2.2, p = 0.88). No significant OS difference was seen in adenocarcinoma patients with KRAS mutation alone (n = 21) v KRAS with other mutations (n = 24) (HR 1.53, CI 0.61-3.86, p = 0.366). Conclusions: Multiple mutations are associated with poorer outcomes in resected NSCLC. The differences are both statistically significant and clinically relevant. Larger datasets are required to validate whether mutational status is an independent prognostic factor or predictive of a differential benefit from adjuvant chemotherapy in early stage NSCLC.
Effects of immediate compared with delayed gefitinib after front-line chemotherapy in Chinese with advanced non-small cell lung cancer
Authors: J. Z. Wang, T. T. An, L. Yang, H. Bai, J. Zhao, J. C. Duan, P. P. Li, M. N. Wu, H. Sun, P. Yang, J. Z. Wang
Journal: Journal of Clinical Oncology (2009)

8069 Background: To compare therapeutic effects of immediate vs. delayed gefitinib used for advanced non-small cell lung cancer (NSCLC) patients who obtained disease control (DC) after front-line chemotherapy in Chinese population. Methods: The study included 121 Chinese with advanced NSCLC treated with standard chemotherapy and obtained DC followed by either immediate gefitinib (66 cases) or delayed gefitinib, i.e. when tumors progressed (55 cases). The disease control rate (DCR), median progression-free survival time (PFS), median overall survival time (OS) of the two groups were analyzed. The impact of EGFR mutation status on the treatments was also evaluated. Results: The median PFS of patients treated in the immediate treatment setting was significantly longer than that of patients without gefitinib treatment (15.23 months versus 8.13 months,P&lt;0.001). However, the overall median PFS was similar in patients treated with either immediate or delayed settings (15.23 months and 16.23 months respectively, P=0.450). There was no significant difference in OS between the two groups. Although patients whose tumors had EGFR mutation showed a longer median PFS compared to those without the mutation in both treatment groups, similar overall PFS was observed between the groups for patients with EGFR mutation (18.75 months and 18.30 months for maintenance and second-line groups, respectively). Conclusions: Immediate gefitinib use may improve PFS for Chinese patients with advanced NSCLC after front-line chemotherapy. However, similar PFS may be achieved by delayed use of gefitinib. No significant financial relationships to disclose.
A prospective phase II study of induction erlotinib therapy in stage IIIA-N2 non-small cell lung cancer.
Authors: Wenzhao Zhong, Xuening Yang, Riqiang Liao, Qiang Nie, Jian Su, Zhihong Chen, Xuchao Zhang, Shejuan An, Qing Zhou, Jinji Yang, Yi Long Wu
Journal: Journal of Clinical Oncology (2012)

7039 Background: Stage IIIA NSCLC represents a heterogeneous group of patients with ipsilateral mediastinal (N2) lymph nodes involvement. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) provide dramatic responses in patients with non-small cell lung cancer (NSCLC) carrying EGFR mutations. The purpose of this study is to evaluate the role of induction EGFR-TKI therapy in IIIA-N2 NSCLC. Methods: Patients with resectable NSCLC of stage IIIA-N2 were assigned to either induction erlotinib arm or induction gemcitabine/carboplatin(GC) arm based on the EGFR mutations analysis (NCT00600587) . Study Design: Phase II, factorial Assignment, Safety/Efficacy; Primary outcome measures: Response to Induction Therapy; Estimated enrollment: 5 cases with partial response in the erlotinib arm. Results: From January 2008 till June 2011, 24 patients with IIIA-N2 NSCLC diagnosed by mediastinoscopy or PET/CT have been enrolled. Twelve cases with EGFR mutation were assigned to the erlotinib arm (30-42 days), while 12 cases harboring wild-type EGFR received the GC regimen (3 cycles). The primary end point of the response rates were 58% (7/12) for the erlotinib arm and 33% (4/12) for the GC arm (P=0.49). The pathological N2 complete response rates were 17% for the erlotinib arm and 25% for the GC arm (P=0.64). In the erlotinib arm, the most common failure model after initial therapy was distant metastases (9/10), especially brain metastases (3/9). The median progression free survival time was 7 months for the erlotinib arm and 9 months for the GC arm (P=0.27). The median overall survival was 27 months for the erlotinib arm and 23 months for the GC arm (P=0.52). In addition, four cases in the erlotinib arm got partial response to the 2nd EGFR-TKI therapy after progression to erlotinib induction therapy and the following thoracotomy. Conclusions: Induction erlotinib therapy in IIIA-N2 NSCLC with EGFR activating mutation is a promising strategy. Distance metastases were major failure model. A multicenter, randomized, phase II study evaluating efficacy and safety of erlotinib vs GC as neoadjuvant therapy for stage IIIA-N2 NSCLC patients with EGFR mutations (NCT01407822) is currently recruiting participants.
Underweight as a risk factor for esophageal squamous cellcarcinoma: A nationwide population-based study.
Authors: Yoon Jin Choi, Dong Ho Lee
Journal: Journal of Clinical Oncology (2017)

14 Background: Obesity is a well-known risk factor for the development of esophageal cancer (EC). However, the impact of underweight on esophageal squamous cell carcinoma (ESCC) has not been fully recognized to date. Therefore, we herein sought to determine the risk of EC in subjects with underweight. Methods: We analyzed the clinical data from a total of 264,084 individuals with the age of 40 years or older, who received healthcare checkups arranged by the national insurance program, between 2003 and 2008. Newly diagnosed EC was identified using the claims data during a median follow-up duration of 7.9 years. Results: The mean body mass index (BMI) of patients was 23.80 ± 3.05kg/m2, and 6,784 individuals (2.6%) were classified as being underweight (BMI &lt; 18.5 kg/m2). During the study period, 278 individuals (0.1%) developed EC. It was determined that underweight and obesity—compared with normal weight—were significantly associated with 73% increased risk and 30% decreased risk of EC, respectively. Excess risk of EC in the underweight group was independent of age, gender, smoking, and alcohol consumption. Heavy alcohol use had a synergistically increasing effect for developing EC among those in the underweight group. Conclusions: The mean body mass index (BMI) of patients was 23.80 ± 3.05kg/m2, and 6,784 individuals (2.6%) were classified as being underweight (BMI &lt; 18.5 kg/m2). During the study period, 278 individuals (0.1%) developed EC. It was determined that underweight and obesity—compared with normal weight—were significantly associated with 73% increased risk and 30% decreased risk of EC, respectively. Excess risk of EC in the underweight group was independent of age, gender, smoking, and alcohol consumption. Heavy alcohol use had a synergistically increasing effect for developing EC among those in the underweight group.
Genomic-directed therapy of gastrointestinal cancers by comprehensive genomic profile (CGP): Clinical and genomic characteristics at the John Theurer Cancer Center (JTCC).
Authors: Miguel Gonzalez Velez, Narjust Duma, Valentina Jaramillo Restrepo, Pablo Lopez-Zertuche, Ricardo Daniel Parrondo, Veronica Mariotti, Sejal Kothadia, Beth Boseski, Andrew Jennis, Martin Gutierrez
Journal: Journal of Clinical Oncology (2017)

803 Background: The routine use of comprehensive genomic profiling (CGP) has led to better genomic characterization, more personalized treatments and higher enrollment in clinical trials for many solid cancers. The aim of this study was to evaluate the clinical and genomic prolife of patients (pts) with gastrointestinal cancers (GIC) with the use of a CGP assay and their potential therapeutic benefit at a large comprehensive cancer center. Methods: We retrospectively analyzed 83 consecutive pts with GIC that had CGP at the JTCC between 01/2014-09/2016. Demographics, CGP results, and clinical characteristics were studied. Clinically relevant genomic alterations (CRGAs) were identified using the FoundationOne assay (Foundation Medicine, Cambridge, MA), and were defined as alterations linked to approved therapies and those under evaluation in genotype-driven clinical trials. Results: 83 pts with GIC were analyzed. 46.9% males and 53.0% females. The median age at diagnosis was 58.5 years. 73 (88%) patients were stage III/IV at diagnosis. Tumors consisted of colorectal (36%), gastric (24%), pancreatic (12%) and cholangiocarcinoma (6%). All the pts were found to have at least one genomic alteration (GA). CRGAs were identified in 63 (76%) of cases, with an average of 2 per pt. The most frequently identified GAs were TP53 43 (29.9%), APC 24 (16.7%), KRAS 31 (21.5%), ARID1A 12 (8.3%), PIK3CA 11 (7.6%), and SMAD4 11 (7.6%). Of the 63 pts with CRGAs, 23 (36%) received one of the therapies suggested by the NGS assay, and 9 (14%) were enrolled in a clinical trial. Conclusions: The use of CGP assay identified a high frequency of CRGAs in GIC pts. The assay provided information for genomic-directed therapy in 36% of the patients. The routine use of CGP in GIC may lead to pts receive more personalized treatments. The potential benefit of selected targeted therapies in individual cases suggests that larger studies of treatment guided by routine CGP in gastrointestinal malignancies are warranted.
Clinical utility of serum miRNAs for the prediction and early detection of recurrence in melanoma patients.
Authors: Nathaniel H. Fleming, Ines Esteves Domingues Pires Da Silva, Eleazar Vega-Saenz de Miera, Bobbi G. Brady, Sung Won Han, Douglas Hanniford, Jinhua Wang, Richard L. Shapiro, Eva Hernando-Monge, Judy Zhong, Iman Osman
Journal: Journal of Clinical Oncology (2014)

9046 Background: The improvement of recurrence risk assessment at the time of primary melanoma diagnosis and the development of better surveillance strategies to monitor recurrence remain critical challenges in melanoma patient care. In the current study, we examine the ability of serum-based miRNAs to 1) improve patient risk stratification and 2) improve early detection of melanoma recurrence. Methods: Sera levels of 12 miRNAs were measured using qRT-PCR (Exiqon) in serum prospectively collected at diagnosis from 201 melanoma patients (median FU of survivors 91 months). A multivariate logistic regression model that includes miRNAs in combination with stage was built using the training cohort and evaluated in an independent validation cohort of 82 patients (median FU of survivors 39 months). Sera levels of the most informative miRNA signature were assessed longitudinally in a subset of patients (n=82) with samples drawn pre- and post-recurrence when applicable (n=225 samples). An L1 penalized regression approach (Lasso) was performed on TCGA melanoma data to predict the biological role of the miRNA signature. Results: A risk score that included four miRNAs (miR-15b, miR-30d, miR-150, and miR-425) in addition to stage significantly separated recurrence-free and overall survival in both the training and validation cohorts (training RFS and OS P<0.001, validation RFS P<0.001, OS P=0.005). The model improved prediction of recurrence over stage alone, increasing AUC from 0.70 to 0.76 (training) and from 0.76 to 0.79 (validation). Normalized serum levels of miR-15b significantly increased over time in recurrent patients (P<0.001), but not in non-recurrent patients (P=0.17). Serum levels of miR-15b increased in the three months prior to evident recurrence, peaking at recurrence diagnosis and falling after treatment. In TCGA data, miR-15b was predicted to be associated with mRNAs such as AURKB and CNPA involved in the cell cycle, mitotic regulation, and DNA replication (P<0.001 for all). Conclusions: The addition of serum-based miRNAs can improve prediction of recurrence at time of primary diagnosis. Our data also revealed that dynamic serum miRNA levels can be useful in informing the timing of imaging studies.
Trends and clinico-sociodemographic determinants of stereotactic body radiotherapy use for localized prostate cancer: A National Cancer Database study.
Authors: Brandon Arvin Virgil Mahal, Yu-Wei Chen, Vinayak Muralidhar, David Yang, Amandeep R. Mahal, James B. Yu, Peter F. Orio, Paul L. Nguyen
Journal: Journal of Clinical Oncology (2017)

e545 Background: Stereotactic body radiotherapy (SBRT) represents an emerging and cautiously guideline-approved definitive therapy option for prostate cancer, though long-term data on efficacy and toxicity is still pending. Herein, we sought to determine contemporary national SBRT trends and clinico-sociodemographic determinants associated with its use in prostate cancer. Methods: The National Cancer Data Base (NCDB) was queried to identify 181,544 patients diagnosed with localized prostate cancer from 2004-2012 who received external beam radiotherapy. Multivariable logistic regression adjusted for sociodemographic and clinical factors was used to identify independent determinants of SBRT use. Results: Rate of SBRT use for localized prostate cancer increased from 0.05% in 2004 to 4.87% in 2012 ( P trend &lt; 0.001). SBRT was more likely to be delivered at academic centers, to patients with Medicare, and to patients who were white, younger, healthier, from wealthier and more educated zipcodes, and who had lower risk disease features (all P&lt; 0.001). Relative to Whites, men from more affluent zipcodes, or men with low stage or grade prostate cancer, Blacks, Hispanics, and men from less affluent zipcodes and men with high stage or grade prostate cancer were less likely to receive SBRT after multivariable adjustment, with adjusted hazard ratios of 0.66, 0.35, 0.33, 0.07, and 0.21, respectively (all P&lt; 0.001). Conclusions: The absolute national rate of SBRT use as definitive therapy for prostate cancer has increased nearly 100-fold over the last decade. Men who are White, younger, healthier, from more affluent zipcodes and with favorable disease characteristics are more likely to receive an emerging form of radiotherapy with unknown long-term efficacy and toxicity.
Empowering breast cancer survivors: Results of a community-based survivorship clinic.
Authors: Heather Thompson Mackey, Stacy Wentworth
Journal: Journal of Clinical Oncology (2017)

29 Background: Based on advances in detection and treatment, survival for breast cancer patients has increased over the past decade with 5-year survival rates approaching 90%. Survivors remain at risk for treatment related side effects, which can profoundly impact their quality of life. The Breast Cancer Survivorship Clinic (BCSC) was established in January 2016 to provide patient-centered care to survivors with the intent to maximize quality of life, empower decision making, and facilitate care coordination in order to pursue a life of wellness and overall health in patients’ lives after cancer. Methods: A Survivorship Nurse Practitioner (SNP) meets newly diagnosed breast cancer patients to introduce survivorship as part of the treatment course for those treated with curative intent. Upon completion of active treatment, survivors are scheduled to see the SNP to review their Survivorship Care Plan (SCP) outlining treatment history, surveillance schedule, side effects of treatment, and recommendations for cancer screening and health maintenance. Survivors are surveyed to assess symptoms and concerns at the end of treatment, as well as assess patient empowerment after meeting with the SNP. Results: Over the first nine months of BCSC, 95 patients have been seen. The most common concerns related to physical side effects include fatigue (57%), hormone changes (39%), and insomnia (39%). Survivors report fear of recurrence (58%), finances (47%), and anxiety (35%) to be among their greatest psychosocial concerns. 86% said they would appreciate reviewing a SCP with the SNP. After meeting with the SNP, 93% felt better or much better able to understand their illness, cope with illness, and keep themselves healthy. After meeting with the SNP, 92% felt more confident in their health and felt as though they can better help themselves. Conclusions: The first months of the BCSC have been a success with excellent reported empowerment via validated survey measure. Continued refinement in program development will ensure the initial successes of the program will continue in order to provide all survivors with late/long-term side effect management, physical/emotional support, and survivorship care planning at the completion of cancer treatments.