tbuckley/cabot-search huggingface dataset:
Early change in 18-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) to predict response to preoperative systemic therapy (PST) in HER2-negative primary operable breast cancer: Translational breast cancer research consortium (TBCRC008).
Authors: Roisin M. Connolly, Jeffrey P Leal, Matthew P. Goetz, Zhe Zhang, Xian C Zhou, Joyce Mhlanga, Stacie Jeter, Bridget Walsh, Penny Powers, Jane Zorzi, John T. Carpenter, Anna Maria Storniolo, Stanley P. Watkins, John H. Fetting, Robert Stephen Miller, Kostandinos Sideras, Nagi Khouri, Edward Gabrielson, Richard L. Wahl, Vered Stearns
Journal: Journal of Clinical Oncology (2012)

10509 Background: PST allows for improved surgical outcomes and response assessment without compromising long term outcomes. PST is an attractive model for assessing surrogate markers of response to therapy. We hypothesized that changes in tumor standardized uptake values corrected for lean body mass (SUL) max on FDG- PET by cycle 1 day 15 (C1D15) of therapy would predict pathological complete response (pCR) to PST in women with stage 2-3, grade 2-3, HER2-negative breast cancer. Methods: TBCRC008 is a multicenter placebo-controlled trial that investigates pCR following 12 weeks of preoperative carboplatin and albumin-bound paclitaxel with or without vorinostat. FDG-PET followed by tumor biopsies were performed at baseline and C1D15. We correlated % reduction in SULmax on FDG-PET (PERCIST 1.0; Wahl RL, J Nuc Med 2009) with pCR (no invasive cancer in breast/axilla). We compared % reduction in SULmax between responders (pCR) and non responders (no pCR) using nonparametric Wilcoxon rank sum test. We explored association of % reduction in SULmax at pre-specified cutoff with response using Fisher’s exact test and logistic regression. We correlated baseline, C1D15, and % change in Ki67 at C1D15 with pCR. Results: Accrual is complete. Of 62 women enrolled (10/2009-11/2011), 40 have completed study PST and surgery (median age 47.5 [range 30-68], ER-positive 67%). Overall pCR was 26%. In an intent to treat analysis (n=39), we observed a significant difference in median % reduction in SULmax between responders vs not (66.6% vs 32.4%, p &lt;0.001). We observed a higher proportion of reduction in SULmax ≥ 60% in responders vs not (80% vs 3.5%, p &lt;0.001). The differences in baseline, C1D15 and % change in Ki67 were not significant between responders and non-responders. Conclusions: Change in SULmax on FDG-PET 15 days after initiating PST was significantly greater in patients with pCR versus no pCR. Future studies will determine whether altering therapy based on early changes in SULmax will improve pCR. Unblinded data from all participants will be presented at the meeting.
Phase II trial of cabazitaxel in patients with advanced or metastatic transitional cell carcinoma of the urothelial tract who have progressed within less than 12 months after cisplatin-based chemotherapy: A Spanish Oncology Genitourinary Group (SOGUG) study.
Authors: Jose Angel Arranz Arija, Miguel Angel Climent Duran, Albert Font Pous, Mirta Garcia Alonso, Enrique Gallardo Diaz, Xavier Garcia del Muro, Aranzazu Gonzalez del Alba, Nuria Lainez Milagro, Martin Lázaro Quintela, Marta F. López-Brea, M Pilar Lopez Criado, Raquel Luque Caro, Cristina Martin Lorente, Maria Jose Mendez Vidal, Alvaro Pinto Marin, M.I. Saez, Carmen Santander Lobera, Sergio Vazquez Estévez, Juan Virizuela Echaburu, Ignacio Duran
Journal: Journal of Clinical Oncology (2012)

TPS4672 Background: Advanced transitional cell carcinoma of the urothelium (TCCU) on progression after previous cisplatin-based combination is generally an incurable disease. The appropriate management of these patients is still an unmet need. Many drugs have shown modest or no activity in previous phase 2 trials. Population heterogeneity in these studies emerges as one of the key determinants that could explain the variable outcomes. Recently, in a phase III study in this setting, prognostic factors (PF) for overall survival were identified (Bellmunt J et al, JCO 2010). Taxanes are active drugs in 2nd-line metastatic TCCU. Cabazitaxel (C) is a semi-synthetic taxane that is a poor substrate for the multidrug resistance system. C could be a valid alternative in this patient population. Methods: This is an open label phase II study of C in patients (pts) with advanced or metastatic TCCU who have progressed within 12 months after receiving a 1st-line platinum based chemotherapy. There are three treatment arms as patients will be assigned to one of three groups previously defined based on the presence of 0, 1 or 2-3 PFs as defined by Bellmunt et al. The activity of C will be assessed separately in each group and overall. The primary endpoint is response rate (RR) evaluated according to RECIST 1.1, a maximum of 35 pts are needed in each subgroup (maximum number of pts required: 105). Secondary objectives are RR in the whole population, toxicity, progression-free survival and overall survival. In addition, an external validation of the prognostic model proposed by Bellmunt will be conducted, as well as a pharmacogenomic study in order to better define the toxicity profile of the drug and the potential responders.
Identification of driver gene alterations in Chinese female patients with squamous cell carcinomas of the lung.
Authors: Yi Na Wang, Qiong Zhao, Bo Wang, Zhu Zeng, Ling Peng
Journal: Journal of Clinical Oncology (2014)

e19087 Background: Smoking remains the leading risk factor of NSCLC. Activating mutations in EGFR gene have been reported more frequently in never smokers than smokers with NSCLC. Female pts with squamous cell carcinomas of the lung (SQCLC) differ from males in that most females are life-long never/light smokers. However, molecular abnormalities in female pts with SQCLC have not been well-characterized. Methods: We retrospectively screened 38 female and 40 male pts with SQCLC in China from 2009 to 2012 to determine the prevalence of alterations in EGFR, KRAS, ALK, PI3K, PTEN and FGFR1. Mutational analysis of EGFR, PIK3CA, KRAS and PTEN was performed using PCR-based DNA sequencing. FGFR1 amplification and ALKrearrangements were detected by FISH. A Cox regression model was used to assess the association between genomic mutation status and clinical features as well as OS. Results: 10.3% (8/78) pts were detected with EGFR mutation, 6.4% (5/78) with KRAS mutation, 7.7% (6/78) with PI3K mutation and 6.4% (5/78) with FGFR1 abnormality. No one harbored PTEN or ALK alteration. PI3K mutation were less common (P=0.026) in females compared to males. Most of the pts (84.6%, 66/78) were stage IV at their first diagnosis and the median age was 57 year-old. There were significantly more male pts with a history of smoking than females (90% vs. 5.3%; P<0.001). Median survival time of the whole cohort was 14.1 months. There was no statistical difference in OS based on gender. The median OS was 15.0 months in females and 13.6 months in males. Multivariate Cox regression analysis indicated that no variable was the independent risk factor for OS. Conclusions: We demonstrated thatdespite for the significantly low percent of smoking history, targetable alterations in Chinese female pts with SQCLC were similar with those in males. Furthermore, we report for the first time that female pts with SQCLC might be a distinct disease entity with a particularly lower frequency of PI3K mutation. However, the lower frequency of PI3K mutation in Chinese female pts seems to have no influence on their OS. Due to the small sample size of the study, our data need to be confirmed in future studies.
A Direct Test of Selection in Cell Populations Using the Diversity in Gene Expression within Tumors
Authors: Chunyan Li, Yali Hou, Jin Xu, Aiqun Zhang, Zhenzhen Liu, Furong Qi, Zuyu Yang, Ke Chen, Sixue Liu, Huanwei Huang, Qianfei Wang, Jiahong Dong, Chung-I Wu, Xuemei Lu
Journal: Molecular Biology and Evolution (2017)

Although intratumor diversity driven by selection has been the prevailing view in cancer biology, recent population genetic analyses have been unable to reject the neutral interpretation. As the power to reject neutrality in tumors is often low, it will be desirable to have an alternative means to test selection directly. Here, we utilize gene expression data as a surrogate for functional significance in intra- and intertumor comparisons. The expression divergence between samples known to be driven by selection (e.g., between tumor and normal tissues) is always higher than the divergence between normal samples, which should be close to the neutral level of divergence. In contrast, the expression differentiation between regions of the same tumor, being lower than the neutral divergence, is incompatible with the hypothesis of selectively driven divergence. To further test the hypothesis of neutral evolution, we select a hepatocellular carcinoma tumor that has large intratumor SNV and CNV (single nucleotide variation and copy number variation, respectively) diversity. This tumor enables us to calibrate the level of expression divergence against that of genetic divergence. We observe that intratumor divergence in gene expression profile lags far behind genetic divergence, indicating insufficient phenotypic differences for selection to operate. All these expression analyses corroborate that natural selection does not operate effectively within tumors, supporting recent interpretations of within-tumor diversity. As the expected level of genetic diversity, hence the potential for drug resistance, would be much higher under neutrality than under selection, the issue is of both theoretical and clinical significance.
Induction chemotherapy for debulking advanced oropharyngeal squamous cell carcinoma in preparation for transoral robotic surgery.
Authors: Jonathan Peter Giurintano, Faisal Mohamed, Jared Tompkins, Kathryn King, Courtney Shires, Furhan Yunus, Alva Bowen Weir, Moon Jung Fenton, Omar Ghandour, Todd F. Stockstill, Sandeep Samant
Journal: Journal of Clinical Oncology (2014)

e17058 Background: Transoral robotic surgery (TORS) offers patients a minimally invasive approach to oropharyngeal squamous cell carcinoma but is a treatment modality for tumors of limited size. Induction chemotherapy may provide a safe, effective manner for pre-operative tumor debulking, allowing for the use of TORS even in patients who present with advanced disease. The objective of this study is to evaluate the safety and efficacy of induction chemotherapy in the treatment of advanced oropharyngeal carcinoma. Methods: A retrospective chart review was performed on patients who were treated by the head and neck surgery service at the University of Tennessee, Memphis. A total of 14 patients (11 men, 3 women; mean age of 55.6 years) with advanced squamous cell carcinoma of the oropharynx (9 tonsil, 1 base of tongue, 4 tonsil and base of tongue; 2 T4, 6 T3, 3 T2, and 2 T1 stage tumors; 10 N2, 3 N1, and 1 N0 stage tumors; 9 stage IV, 5 stage III tumors) were treated with induction chemotherapy (6, 7 and one patient receiving 3, 2 and one cycles respectively of a taxane, cisplatinum, and fluorouracil) followed by TORS along with simultaneous unilateral or bilateral neck dissection and risk-adapted adjuvant therapy as indicated. Results: While receiving induction chemotherapy, no patients experienced progression of disease, and no patients experienced significant adverse effects. 43% of patients (6/14) demonstrated complete response to chemotherapy at the primary site on post-operative pathological examination, while 50% (7/14) demonstrated partial response. Only one patient failed to demonstrate a response to induction chemotherapy at the primary site. 57% (8/14) demonstrated complete lymph node response to induction chemotherapy, and 29% (4/14) demonstrated partial response. TORS was able to be performed on all patients, with 86% (12/14) of postoperative specimens demonstrating margins free of disease on pathological examination. Conclusions: Induction chemotherapy consisting of a taxane, cisplatinum, and fluorouracil appears to be a safe, feasible method for debulking advanced stage oropharyngeal carcinomas in preparation for minimally invasive surgical excision with TORS.
Quality of life (QoL) analysis from the randomized phase III REAL3 trial of epirubicin, oxaliplatin, and capecitabine (EOC) with or without panitumumab (P) in advanced esophagogastric adenocarcinoma.
Authors: Tom Samuel Waddell, Ian Chau, Clare Peckitt, David Gonzalez, Andrew Wotherspoon, Bijal Patel, Gary William Middleton, Jonathan Wadsley, David Ferry, Wasat Mansoor, Tom David Lewis Crosby, Fareeda Y. Coxon, David Smith, Justin S. Waters, Timothy Iveson, Stephen Falk, Sarah Slater, Alicia Frances Clare Okines, David Cunningham
Journal: Journal of Clinical Oncology (2014)

4067 Background: REAL3 evaluated EOC + P in advanced oesophago-gastric adenocarcinoma. We previously reported that addition of P was associated with increased diarrhoea, skin rash and mucositis without improvement in survival endpoints. This analysis reports QoL outcomes for participants in both arms of the trial. Methods: QoL was assessed via EORTC QLQ-C30 questionnaires requested at baseline (BA), post-cycles 4 (C4) and 8 (C8), and at 3 months follow-up (3M). Functional and symptomatic scores were calculated using recommended EORTC methods. Comparison of differences between study arms was performed using one sample t-test with 2-sided p-values and repeated measures analysis investigated scores over time. A threshold of 0.05 indicated statistical significance. Data in both arms was censored at time of early trial closure (Oct 2011) when all patients crossed to EOC. Results: 553 patients were recruited between June 2008 and October 2011. Excluding duplicates and those censored, the questionnaire response rate at each timepoint was: BA 470/553 (85%); C4 163/418 (39%); C8 72/196 (37%); 3M 35/64 (55%) with similar response rate in both arms. Irrespective of treatment allocation there was a non-significant decrease in global health score during chemotherapy which recovered by 3M. A similar trend was observed for physical, role and social function scales with no difference between arms. Cognitive function scores showed more marked deterioration in patients receiving EOC+P with mean decrease of 15 points between BA and 3M, compared to no change in patients receiving EOC (p=0.026). Chemotherapy was associated with a trend towards improved nausea and vomiting, appetite, and pain scores in both arms. Conversely it worsened scores related to fatigue, dyspnoea and diarrhoea. Diarrhoea was increased by addition of P (p=0.007) with no other significant differences in symptom scores between arms. Conclusions: Chemotherapy did not have a detrimental effect on global QoL and seemed to improve some disease-related symptoms. Increased scores related to diarrhoea with addition of P are in keeping with the known toxicity profile. Clinical trial information: 2007-005976-15.
Effects of delays in the adoption of cancer innovation: Case studies of six landmark medications.
Authors: Jason Shafrin, Jin Joo Shim, Seanna Vine, Caroline Huber, Beata Korytowsky, Manan Shah, David Chan
Journal: Journal of Clinical Oncology (2017)

27 Background: Although new oncology treatments have the potential to improve patient health, these innovations take time to reach to real-world patients. In this study, we estimated how delays in the uptake of novel oncology treatments affect real-world patient survival. Methods: This retrospective cohort study used 1991-2013 data from a cancer-registry linked to health care claims (SEER-Medicare). Our endpoint of interest was patient overall survival. We used variability in the adoption of new cancer treatments across aggregated Metropolitan Statistical Areas (MSAs) (n = 50) as a “natural experiment” that assigned treatments randomly across patients, depending entirely on where they live. This approach recovers the effect of the new treatment on the overall survival of the “marginal patient,” who received treatment solely because she resides in an area with faster uptake. This framework was applied to six case studies: trastuzumab (breast), bevacizumab (colorectal), bevacizumab (lung), erlotinib (lung), bortezomib (myeloma) and lenalidomide (myeloma). Results: Among the 92,496 patients in the study, the difference between adoption rates among eligible patients for MSAs at the 90th percentile and those at the 10th percentile was 20.1 percentage points, with the largest differences being for bevacizumab (colorectal) (51.2% at the 90th percentile MSA vs. 20.9% at the 10th percentile), and smallest for erlotinib (10.3% vs. 2.8%). Median OS among eligible patients gaining access to these landmark therapies increased by 9.6 months. Survival improvements were largest for the lenalidomide case study (33.4 months OS improvement, p &lt; 0.005) followed by erlotinib (21.2 mo., p &lt; 0.001), trastuzumab (19.2 mo., p = 0.016), bevacizumab for lung (7.4 mo., p = 0.002), bevacizumab for colorectal cancer (4.0 mo., p = 0.062), and bortezomib (2.9 mo., p = 0.630). Conclusions: Improving the speed at which landmark treatments are adopted in practice—through physician education and outreach or more generous health insurance access policies—has the potential to improve real-world survival for cancer patients.
Real life experience with check point and kinase inhibitors in Swiss advanced melanoma patients.
Authors: Simone M. Goldinger, Joanna Mangana, Anna L. Frauchiger, Corina Kaufmann, Ulrike Held, Roger Von Moos, Emanuela Romano, Olivier Michielin, Mitchell Paul Levesque, Reinhard Dummer
Journal: Journal of Clinical Oncology (2015)

e20064 Background: Metastatic melanoma is an aggressive disease with a median survival in untreated Stage IV patients of only 6–9 months. Recent therapeutic developments in immunotherapy and targeted therapy have shown substantial improvement in response in metastatic melanoma. The current project intends to determine the benefit of the introduction of these new molecules in advanced melanoma across several regions of Switzerland. Methods: This is a retrospective multi-center analysisof 328 Swiss advanced melanoma patients treated with standard chemotherapy, checkpoint inhibitors (anti CTLA-4 or anti PD1 antibodies) and kinase inhibitors (Vemurafenib, Dabrafenib/Trametinib, Encorafenib and Binimetinib) either in first or second line setting from January 2008 until June 2013. Results: Median overall survival (mOS) from date of diagnosis of metastatic melanoma of all patients was 13.4 months. mOS of patients treated either with checkpoint or kinase inhibitors (n = 196, 17.1 months) between 2008-2013 was significantly prolonged (p < 0.001) compared to patients treated with standard chemotherapy within 2008-2009 (n = 88, 9.4 months). There was no significant difference in survival in BRAF mutated and wildtype patients (mOS 14.0 and 15.3 months, respectively, p = 0.84). 284 patients were further analyzed for survival in terms of treatments. One-year-survival was 71% (CI 60-79%) in 100 patients treated with ipilimumab, 55% (CI 45-65%) in 96 patients treated with targeted therapies and 37% (CI 27-48%) in 88 patients treated with standard chemotherapy. Proportion of patients surviving 2 years was 33% for patients treated with ipilimumab, 24% for patients with targeted therapy, and 14% in patients treated with chemotherapy. Conclusions: Treatments with check-point and kinase inhibitors beyond clinical trials significantly improve mOS and are consistent with published prospective data. Survival is independent from BRAF mutation status alone. National melanoma registries and cancer statistics are useful for monitoring outcomes of approved therapies or newly established treatment protocols across multiple institutions and patient populations.
Phase I/II study of exisulind (E) and vinorelbine (V) in elderly patients with advanced non-small cell lung cancer (NSCLC)
Authors: A. M. Traynor, J. J. Merchant, T. Hoang, H. G. Ahuja, P. A. Beatty, R. M. Hansen, G. A. Masters, K. R. Oettel, G. R. Shapiro, J. H. Schiller
Journal: Journal of Clinical Oncology (2004)

7272 Background: Exisulind (E) is an oral selective apoptotic antineoplastic drug that exerts its antitumor effect via the inhibition of tumor-related cGMP phosphodiesterase and activation of protein kinase G. E caused growth inhibition when used alone and with chemotherapy in multiple in vitro and in vivo tumor models. The aim of this study is to define the maximum tolerated dose (Phase I) and efficacy (Phase II) of V + E in elderly patients with IIIB/IV NSCLC. Methods: Patients (pts) were > 69 yrs of age. No prior chemotherapy was allowed. PS 0–1. Pts were entered on 3 dose levels of E (125 mg BID, 125 mg qAM and 250 mg qPM, and 250 mg BID) with V (25 mg/m2) given weekly in a 4 week cycle. Pts with clinical benefit (CR/PR/SD) after 6 cycles of V + E were allowed to continue on E alone Results: 14 pts were enrolled in the phase I portion of the study: 3 on dose level 1, 4 on dose level 2 and 7 on an expanded dose level 3. Median age of this group was 78 yrs (range 72–84). Dose limiting toxicities included grade (Gr) 3 constipation (1 pt) and Gr 3 diarrhea (1 pt), both at dose level 2, and Gr 4 neutropenic fever (1 pt) at dose level 3. The MTD of E was 125 mg BID. One PR was confirmed. 15 pts have been enrolled thus far in the phase II portion of the study (a total accrual of 30 pts is anticipated); median age is 77 yrs (range 71–81). Gr 3/4 treatment-related toxicities include neutropenia (5 pts; 2 with Gr 4), leukopenia (4 pts), anemia (1 pt), fatigue (3 pts), dyspnea (2 pts), and constipation (1 pt). 12 pts are evaluable for response: 2 PRs have been confirmed. The preliminary median survival for pts in the phase II portion of the study to date is 23 weeks (range 1 – 49+ weeks). Conclusions: E does not appear to worsen the toxicity of V in untreated elderly patients with advanced NSCLC. The phase II portion of this study is on-going. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Cell Pathways, Inc.; OSI Pharmaceuticals, Inc.
Microparticles Modulate Formation, Structure, and Properties of Fibrin Clots
Authors: Rosa M. Nabiullina, Dzhigangir A. Faizullin, Chandrasekaran Nagaswami, Yuriy F. Zuev, Ilshat G. Mustafin, Rustem I. Litvinov, John W. Weisel, Laily D. Zubairova
Journal: Blood (2014)