tbuckley/cabot-search huggingface dataset:
An updated analysis of new oncologic drug approvals at FDA by expedited program.
Authors: Dianne Pulte, Bindu Kanapuru, Michael Shea, Ann T. Farrell, Gideon Michael Blumenthal, Jeff Allen, Richard Pazdur
Journal: Journal of Clinical Oncology (2018)

e18747 Background: The effects of special regulatory pathways to expedite development and approval of new treatments for serious and life threatening diseases such as cancer on pre-marketing review time has not been fully characterized. Here, we update new drug approval times at the FDA, with an analysis of drugs approved under special regulatory pathways. Methods: Data on initial approvals for oncologic drugs at the FDA including information on submission date, goal date for a decision, approval date, and whether the compound was eligible for any special programs were extracted from publically available databases including review summaries. We analyzed approval times under special programs designed to facilitate development or review of promising treatment options including priority review, accelerated approval, and breakthrough designation. Results: A total of 101 new oncologic drugs were approved in 2003-2017, including 68 in July, 2010-September, 2017. Although median approval times did not change significantly between the periods examined, the range of approval times decreased. Drugs granted priority review had shorter review times compared to those not accepted into these programs. Review times for accelerated approval were shorter than those for regular approvals, although the difference was less marked than for priority versus non-priority reviews. Drugs with breakthrough designation had the shortest time to review completion. Conclusions: Review times have not changed significantly in the past decade, but the range has decreased, indicating a more consistent process. Review times were shorter for drugs granted priority review, accelerated approval, or breakthrough designation. Table: Median (range) review days for drugs approved by the FDA Overall All dates Jul, 2010-Sep, 2017 2003-Jun, 2010 Jul, 2010-Sep, 2017 Priority review Approval Accelerated Break-through* 184 (75-1016) 182 (78-1016) 193 (75-456) Y 177 (75-390) 179 (75-394) 158 (75-315) N 292 (147-456) 198 (81-456) 242 (133-456) *Program started in 2012
Concurrent genomic alterations in lung adenocarcinoma with a <i>MET</i> exon 14 skipping mutation.
Authors: Julia Rotow, Wei Wu, Collin M. Blakely, Richard B. Lanman, Victoria M. Raymond, Frederic J. Kaye, Phillipe Gui, James Fraser, Alexander Wolff, Eric Andrew Collisson, Caroline Elizabeth McCoach, Trever Grant Bivona
Journal: Journal of Clinical Oncology (2018)

9083 Background: METex14 oncogenic driver mutations are present in 2-4% of lung adenocarcinoma. While second-site MET mutations have been reported at MET TKI resistance, the factors influencing response to MET TKI therapy are not yet fully characterized. The landscape of co-occurring genetic alterations, which correlates with treatment response in EGFR-mutant NSCLC, is incompletely understood in METex14 NSCLC. Methods: Targeted exome sequencing of cell-free DNA (cfDNA) obtained via the clinical Guardant360 assay for co-occurring alterations (somatic variants, copy-number alterations) in 68 cancer-associated genes within 70 samples from 65 patients with advanced stage METex14 NSCLC. Synonymous mutations and those with predicted neutral or unknown functional impact were excluded. Results: 81.4% of METex14-positive samples contained concurrent genomic alterations, with a mean of an additional 2.6 (range 0-20) alterations/sample. Mutations or amplifications in TP53 (44.6% of patients), CDK4 (13.8%), EGFR (12.3%), and NF1 (12.3%) were most common. Pathway analysis identified receptor tyrosine kinases (40%), cell cycle mediators (29.2%), and the MAPK pathway (26.2%) as frequently altered. Alterations in the MAPK pathway have not yet been implicated in TKI resistance in METex14 NSCLC. We identified two patients with newly acquired MAPK pathway alterations (KRAS amplification, KRAS G12D mutation) at MET TKI resistance. Conclusions: The cfDNA from patients with METex14 NSCLC frequently contains additional oncogenic co-alterations. Among downstream MET signaling mediators there is a high rate of concurrent MAPK pathway alterations in METex14 NSCLC, as well as newly acquired MAPK pathway alterations at resistance to MET TKI therapy. The MAPK pathway is a potential therapeutic target to enhance treatment responses in METex14 NSCLC.
Abstract 19631: Application of Machine Learning Methods for Prediction of Outcomes After Cardiac Transplantation: Insights From the UNOS Database
Authors: Benjamin Vaccaro, Nihar R Desai, Pooja Rao, Rohit Ghosh, Prashant Warier, Daniel L Jacoby, Lavanya Bellumkonda, Jeffrey M Testani, Michael E Chen, Tariq Ahmad
Journal: Circulation (2016)

Objectives: It has been hypothesized that applying advanced analytic methodologies to large patient datasets can revolutionize patient care but the relative performance and comparative effectiveness of various statistical approaches remains unclear. Methods: The United Network for Organ Sharing (UNOS) database was queried to identify initial adult heart transplants performed in the United States from 1987-2014 (N=50,453). We assessed prediction of 1 year survival using all donor and recipient variables except those with >20% missingness using traditional logistic regression and a comprehensive number of machine learning methodologies (ridge regression, regression with LASSO, support vector machines, naive Bayesian, tree-augmented Bayesian, neural network, random forest, and stochastic gradient boosting). We tested the predictive accuracy of these methods across UNOS regions for the following time periods [Period 1 (1987-1996); Period 2 (1996-2005); Period 3 (2006-2014)]. Results: The most powerful univari...
Analysis of 1261 metastatic cancer patients evaluated by comprehensive molecular profiling (CMP) including next-gen sequencing (NGS) from a single institution.
Authors: Jason Claud Chandler, Ari M. Vanderwalde, Bradley G. Somer, Gregory A. Vidal, Lee Steven Schwartzberg
Journal: Journal of Clinical Oncology (2016)

11570 Background: The availability of CMP has increased rapidly, and may be useful in clinical trial matching and making clinical treatment decisions. We sought to standardize the approach to CMP across all providers at a single institution, using an external vendor, and defining tumor types and point of entry into CMP. Methods: We obtained tumor CMP for first line metastatic cancer patients starting in mid 2014. Multi-platform testing included immunohistochemistry, in-situ hybridization, and NGS, with panels ranging from 44 hot spot genes to 592-gene whole exome coverage. We report only on presumed pathogenic mutations, and did not include variants of unknown significance. We opened multiple basket trials for specific molecular targets including PIK3CA, BRAF, FGFR and HER-2-Neu. Results: Results were obtained from 1261 tumor samples. There was not enough tissue for NGS in 7% of submitted samples. The distribution of tumor’s tested is shown below in table. Regarding the individual patient mutational burden by NGS, 399 had 0, 391 had 1, 289 had 2, 179 had 3-5, and 3 had > 5 presumed pathogenic mutation. Across all tumors types a PIK3CA mutations was identified in 11% and a BRAF in 6%. In endometrial cancer, there were 27% PIK3CA and 29% PTEN mutations, while pancreatic had CDKN2A mutations in 25%. 33% of all tumors overexpressed c-MET by IHC. PDL-1 was positive (>5% by IHC) in 16% and varied with tumor type: 14% in esophageal, 16% in kidney, 21% in lung, 34% in melanomas and 36% in sarcoma. Conclusions: CMP for patients with advanced cancer can yield actionable information for both standard of care practice as well as prospective identification for clinical trials requiring specific molecular alterations. Tumor TP53 KRAS APC PIK3CA BRAF CDKN2A PTEN Lung - 27% 61% 26% 2% 4% 3% 9% 2% Colon - 18% 64% 48% 77% 16% 9% 0% 3% Breast - 13% 48% 1% 1% 24% 0% 0% 3% Ovary - 9% 54% 8% 1% 4% 1% 3% 1% Melanoma - 5% 19% 0% 2% 0% 55% 10% 2% Endometrial - 4% 41% 16% 0% 38% 0% 0% 41% CUP - 3% 54% 11% 6% 11% 9% 8% 6% Pancreatic - 3% 56% 72% 3% 6% 0% 33% 0% Other - 19% 35% 4% 4% 9% 1% 3% 7% Total 51% 21% 16% 11% 6% 5% 4%
Survival of metastatic metaplastic breast cancer patients receiving chemotherapy.
Authors: Sparsha Kukunoor, Anna Lee, Evelyn Oluwatoyin Taiwo, David Schreiber, Carol A. Luhrs
Journal: Journal of Clinical Oncology (2018)

e13126 Background: Metaplastic breast cancer (MBC) is a rare, aggressive variant of breast cancer, usually triple negative disease and chemotherapy refractory. Despite this, the standard of care remains the same as invasive breast cancer. We sought to analyze outcomes of chemotherapy in patients with metastatic MBC. Methods: Patients over 18 years diagnosed with metastatic MBC from 2004-2015 were identified in the National Cancer Database (NCDB). Clinical and demographic details were compared between two groups (chemotherapy vs no chemotherapy). Univariable and multivariable logistic regression was performed to assess for predictors of receiving chemotherapy. The KaplanMeier method was used to assess overall survival (OS) and multivariable Cox regression analysis was used to assess impact of covariates on OS. Results: There were 7,580 patients with MBC of which 417 (5.5%) presented with metastatic disease. Median age was 65 years and median follow up for living patients was 48 months. Patient characteristics of the two groups (chemotherapy vs no chemotherapy) were balanced with the exception that patients who received chemotherapy were more likely to be under 65 years of age (p < 0.001) and patients in the no chemotherapy group were more likely to have received palliative surgery (p < 0.001). Most patients (79.1%) had a Charlson Deyo score of 0 and there was no significant difference between the chemotherapy and no chemotherapy groups (p = 0.038). On logistic regression analyses the only factor predicting receipt of chemotherapy was age less than 65 years (p < 0.009). Patients who received chemotherapy had improved median, 1-year and 2-year overall survival as seen in the table (p = 0.006). On multivariable Cox regression analysis for overall survival, there was no difference in survival between patients under 65 and over 65 years (p 0.229). Conclusions: In this cohort of metastatic MBC studied, chemotherapy had an overall survival benefit for patients in both age groups although chemotherapy was more likely to be given to patients under 65 years despite no difference in co-morbidity score between the two groups. ChemotherapyN = 156 (37.4%) No chemotherapyN = 261 (62.6%) Median OS 12 months 8 months 1-year OS 50.6% 37.8% 2-year OS 34.6% 20.5%
Downstream revenue attributable to lung cancer screening program serving a minority predominant population.
Authors: Arden Plumb, Mary Pasquinelli, Lawrence Eric Feldman
Journal: Journal of Clinical Oncology (2018)

e18909 Background: The goal of incorporating lung cancer screening programs into health systems is to identify cases of early stage lung cancer and thereby reduce mortality. However, there is limited data on the financial outcome of these programs, particularly programs that serve diverse populations. This study will provide an estimate of the downstream revenue of the screening program at UIH (2015-2017). Downstream revenue from this program captures the profits from screening as well as any required follow-up –additional chest CTs, chemotherapy, radiation, etc. Thirty-eight percent of patients within the program receive insurance through Medicaid/Medicaid Managed Care and 46% have Medicare as their insurance provider. Approximately 70% patients screened are Black/African American. Methods: Compass billing software was queried using the medical record number (MRN) and screening dates for the LDCT screenings between FY14 and FY17. All downstream cases were then filtered using the diagnosis code field to include only those cases related to low-dose computed tomography (LDCT). Using the filtered downstream cases, Trendstar was queried to gather cost and operating margin data. Results: The downstream revenue for screened patients in the program resulted in a net revenue of approximately $515K. This is approximately $770/case in net revenue. The program detected 14 total cases of lung cancer, 8 of which were early stage. Two cases of prostate cancer were also detected. Conclusions: The downstream revenue attributable to the lung cancer screening program at UIH is approximately $770/case. The overall net revenue for the screening program is approximately $515K from 2015-2017. In consideration of the mortality benefit of this program and the higher risk population it serves, a positive downstream revenue of $770/case demonstrates that a lung cancer screening program is viable in a low socioeconomic environment. Further research could evaluate the financial value of this screening program as it continues to expand. It is notable that the LDCT used for screening may incidentally detect additional health problems, and this could provide additional downstream revenue attributable to this screening.
Abstract 15097: Icosapent Ethyl Reduces Potentially Atherogenic Lipid and Inflammatory Markers in High-Risk Statin-Treated Patients With Stage 3 Chronic Kidney Disease and Persistent High Triglycerides
Authors: Krishnaswami Vijayaraghavan, Harold M Szerlip, Christie M Ballantyne, Harold E Bays, Sephy Philip, Ralph T Doyle, Rebecca A Juliano, Craig Granowitz
Journal: Circulation (2017)

Introduction: Patients with chronic kidney disease (CKD) have increased cardiovascular disease (CVD) risk. Atherogenic and inflammatory markers beyond LDL-C likely drive this risk, but data are lac...
Clinical impact of BRCA1 and BRCA2 mRNA expression in ovarian cancer.
Authors: Irina Tsibulak, Giridhar Shivalingaiah, Soeren Wenzel, Susanne Sprung, Sigurd Lax, Christian Marth, Heidi Fiegl, Alain G Zeimet
Journal: Journal of Clinical Oncology (2018)

e17533 Background: Mutations in cancer susceptibility genes BRCA1 and BRCA2 are associated with better survival in ovarian cancer (OC) patients due to a better response to platinum-based chemotherapy and PARP inhibitors. However, the impact of the expression of these genes is not well characterized in OC. Methods: We investigated BRCA1 and 2 mRNA expression in 12 non-neoplastic fallopian tubes and 201 fresh frozen epithelial OCs using real-time PCR. BRCA mutations detection was performed by next generation sequencing. The association between BRCA expression and clinical characteristics (age, FIGO stage, tumor grading, residual tumor) were evaluated using Mann-Whitney-U and Kruskal-Wallis tests. Overall and relapse free survival rates were estimated using Kaplan-Meier plots and Cox-Regression. Optimal cut off points were defined using Youden index. Results: We found higher BRCA1 and 2 mRNA expression in OCs in comparison to controls (p = 0.011, p < 0.001, respectively), and in type II compared to type I tumors (p = 0.034, p = 0.001, respectively). BRCA1 mutated OC tissues exhibited lower BRCA1 (p = 0.014) but higher BRCA2 mRNA expression (p = 0.001). Univariate survival analysis showed that BRCA1 expression below the 90th percentile was associated with favorable overall survival (OS) (p = 0.012) and BRCA2 expression below the 21st percentile with better progression free survival (PFS) and OS (p = 0.004, p = 0.001. respectively). A subgroup analysis revealed the prognostic effects of BRCA1 and BRCA2 expression was confined to the BRCA1 wild-type cancers. Cox-regression survival analysis confirmed the prognostic significance of BRCA1 expression for OS (p = 0.028). Independency of the prognostic value of BRCA2 expression for PFS (p = 0.045) and OS (p = 0.015) was restricted to patients with high grade serous OC. Conclusions: As all patients included in this investigation have been treated with platinum-based chemotherapy, the revealed favorable survival may reflect higher platinum sensitivity due to reduced capacity of DNA damage repair via homologous recombination in tissues with low BRCA1 and BRCA2 expression.
Inherited predisposition to malignant mesothelioma (MM) due to mutations in DNA repair genes.
Authors: Raffit Hassan, Betsy Morrow, Tom Walsh, Ming K Lee, James Gao, Idrees Mian, Javed Khan, Mark Raffeld, Snehal Patel, Liqiang Xi, Jun S. Wei, David Schrump, Mary Hesdorffer, Jingli Zhang, Kathy Calzone, Emerson Padiernos, Christine Alewine, Seth M. Steinberg, Anish Thomas, Mary-Claire King
Journal: Journal of Clinical Oncology (2018)

8504 Background: Identifying the profile of DNA repair genes predisposing to MM will enable treatment options for patients (pts) and risk assessment for their families. Methods: In this prospective study of the natural history of MM (NCT01950572) we enrolled 239 consecutive pts independent of site of disease, family history of cancer, age at diagnosis, ethnicity, or asbestos exposure. Germline DNA was sequenced for all 239 pts, identifying mutations of all classes in 73 DNA repair genes. Tumor DNA from 12 pts with germline BAP1 mutations was evaluated by whole exome sequencing. Results: Of the 239 pts, 29 (12%) carried a pathogenic germline mutation in a DNA repair gene: BAP1 (N = 17 pts), CHEK2 (N = 5), PALB2 (N = 2), and BRCA2, MLH1, POT1, TP53, and MRE11A (N = 1 each). Pts with mutations were more likely to be female (P = 0.02) and to have been diagnosed with another cancer (P = 0.009). Pts with germline mutations were more likely to have a 1o relative with a diagnosis of MM (P < 0.0001), melanoma (P = 0.003), or breast cancer (P = 0.022). Pleural MM pts with germline mutations had better overall survival than pts without mutations (median 7.9 vs 2.1 years, P = 0.003). There was no difference in history of asbestos exposure between pts with or without mutations (P = 0.64). Tumors from all 12 pts with germline BAP1 mutations carried a second somatic event likely to lead to complete loss of BAP1 function. Five tumors had somatic stop mutations, 2 somatic missense mutations, 4 somatic loss of part or all of the BAP1 locus and 1 copy neutral loss of the wildtype BAP1 allele (LOH). Conclusions: Among unselected MM pts, 7% carried a pathogenic mutation in BAP1 and 5% carried a pathogenic mutation in another DNA repair gene, which have not been previously described in MM. Analysis of more pts is important to evaluate if increased MM risk is conferred by any of these genes. Mutation carriers and their 1o relatives were at increased risk of developing MM, melanoma, or breast cancer. Genetic testing for germline mutations in DNA repair genes should be considered for MM pts since it has implications for both pts and their relatives. Finally, we suggest that, pts with BAP1-null tumors due to both germline and somatic mutations could be sensitive to PARP inhibitors. Clinical trial information: NCT01950572.
Combining BH3-mimetics to target both BCL-2 and MCL1 has potent activity in pre-clinical models of acute myeloid leukemia
Authors: Donia M. Moujalled, Giovanna Pomilio, Corina Ghiurau, Adam Ivey, Jessica Salmon, Sewa Rijal, Sarah Macraild, Lan Zhang, Tse-Chieh Teh, Ing-Soo Tiong, Ping Lan, Maia Chanrion, Audrey Claperon, Francesca Rocchetti, Adrien Zichi, Laurence Kraus-Berthier, Youzhen Wang, Ensar Halilovic, Erick Morris, Frédéric Colland, David Segal, David Huang, Andrew W. Roberts, Ana Leticia Maragno, Guillaume Lessene, Olivier Geneste, Andrew H. Wei
Journal: Leukemia (2018)

Improving outcomes in acute myeloid leukemia (AML) remains a major clinical challenge. Overexpression of pro-survival BCL-2 family members rendering transformed cells resistant to cytotoxic drugs is a common theme in cancer. Targeting BCL-2 with the BH3-mimetic venetoclax is active in AML when combined with low-dose chemotherapy or hypomethylating agents. We now report the pre-clinical anti-leukemic efficacy of a novel BCL-2 inhibitor S55746, which demonstrates synergistic pro-apoptotic activity in combination with the MCL1 inhibitor S63845. Activity of the combination was caspase and BAX/BAK dependent, superior to combination with standard cytotoxic AML drugs and active against a broad spectrum of poor risk genotypes, including primary samples from patients with chemoresistant AML. Co-targeting BCL-2 and MCL1 was more effective against leukemic, compared to normal hematopoietic progenitors, suggesting a therapeutic window of activity. Finally, S55746 combined with S63845 prolonged survival in xenograft models of AML and suppressed patient-derived leukemia but not normal hematopoietic cells in bone marrow of engrafted mice. In conclusion, a dual BH3-mimetic approach is feasible, highly synergistic, and active in diverse models of human AML. This approach has strong clinical potential to rapidly suppress leukemia, with reduced toxicity to normal hematopoietic precursors compared to chemotherapy.
Hyperfractionated reirradiation with cetuximab for recurrent head and neck cancer: The GORTEC 2008-01 multicentric phase II study.
Authors: Mathilde Saint-Ghislain, Yungan Tao, Marc Alfonsi, Pierre Boisselier, Muriel Garcia-Ramirez, Claude Tuchais, Philippe Maingon, Christian Sire, Ali Hasbini, Marie Saliou, Cedrik Lafond, Hao Qiu, Sébastien Guihard, Pascal Garaud, marie-Helene Calais, Juliette Thariat, Laurent Martin, Jean Bourhis
Journal: Journal of Clinical Oncology (2018)

6034 Background: Most head and neck cancer (HNC) patients die of locoregional progression. Surgery is feasible in less than half the patients only and chemotherapy only offers palliation. Locoregional reirradiation of recurrent HNC or second HNC primary may achieve long-term disease control in some patients, at the expense of high rates of late sequelae. We evaluated the feasibility and tolerance of slightly accelerated hyperfractionated reirradiation and cetuximab in recurrent inoperable/unresectable HNC in a prospective GORTEC phase II study. Methods: Patients from 13 GORTEC centers underwent twice-daily reirradiation (1.2 Gy / fraction, 5 days a week, over 5.5 weeks) to 66 Gy. Weekly cetuximab was delivered as 400mg/m2 load dose one week before reirradiation and 250mg/m2 thereafter for 6 weeks. Results: From October 2010 to October 2014, 48 patients with recurrent inoperable/unresectable HNC were enrolled. Of those, 71% were in the oropharynx. Median age was 61 years (range 40-75). The median delay between the first and second irradiation was 5 years (0.5-35) years. Median tumor size was 3.5 cm (range 1.3-7.0). Acute grade 3-4 toxicities were dermatitis (15%), mucositis (49%) and dysphagia (24%). Anaphylaxis with cetuximab was observed in one patient (2%). Radiotherapy was completed in 90 %. The full cetuximab course was completed in 79%. Complete response was observed in 40% of the patients. Objective response was 53%. Median follow-up for living patients was 24 months. In 28 evaluable patients, there were 7, 1, 4 and 2 patients with late grade 3 dermatitis/fibrosis, osteoradionecrosis, xerostomia or dysphagia. There was two grade 4 toxicities, mucositis and laryngeal. There was one late grade 5 toxicity carotid blowout. Median survival was 9 months and two-year overall survival rate was 22%. Tumor size at recurrence was identified as a prognostic factor for survival with a median survival time of 11.9 months ( < 35 mm) vs 7.4 months (≥35 mm). Conclusions: High dose twice-daily HNC reirradiation with cetuximab is feasible in this population. Median survival was similar to those observed in previous studies, with 22% of long survivors, especially in patients with tumor diameter < 35 mm. Clinical trial information: A91168-41.