tbuckley/cabot-search huggingface dataset:
Rapid functional assay to elucidate the oncogenic activity of unknown mutations (variants of unknown significance).
Authors: Yoram Altschuler, Revital Sharivkin, Yakov Fellig, Keith Mostov, Nir Peled, Gabi Tarcic
Journal: Journal of Clinical Oncology (2015)

e22125 Background: Two major limitation for performing precision medicine based on next generation sequencing is the lack of ability to differentiate between passenger mutations and those with oncogenic activity that have not been previously documented (VOUS: variants of unknown significance). The later account for the majority of drivers within the tumor and account for much of the resistance mechanisms reducing clinical utility. We have developed a diagnostic platform to differentiate between the passenger and VOUS in the form of a rapid cell based assay that emulates the patient tumor and monitors gene by gene oncogenic activity. Methods: Oncogenes (EGFR, KRAS, BRAF or PI3K) in the form of wild type, driver mutations and mutations with VOUS were either synthetically produced or amplified from patient tissues were cloned into expression vectors. Next, the genes were co-transfected with a reporter genes (ERK2, STAT3, RelA, P38 and AKT1 all fused to green fluorescent gene) into cells. The reporters translocate to the nucleus in response to upstream signaling by the tested genes. Following expression, cells are fixed, microscopy image acquisition and analyzed to define amount of reporter within the nucleus vs. the cytoplasm (N:C ratio). Driver mutations N:C ratio is differentiated compared to that of wild type form. Results: Two VOUS clinical scenarios have been studied. 1. ERBB2 (A771_Y772insYVMA, G776C) together with BRAF as a VOUS. Expression of this BRAF mutant in our assay shows oncogenic activity similar or higher to that of the known V600E mutant. Also this mutation responded to Regorafenib. 2. EGFR triple mutations (VOUS). Here we measured differential activation of 5 sub pathways. Our assay shows no activation of the P38 pathway, activation of AKT and NFkB and high activation of the ERK and JNK pathways. Incubation with Erlotinib showed minimal effect while treatment with Afatinib reduced mutation activity significantly. Conclusions: The platform shows the oncogenic activity of VOUS and ability to predict response to targeted therapy. The platform is expected to close the gap between NGS and the treating oncologist by identifying VOUS oncogenic activity and predicting response to therapy.
A single-center retrospective review of outcomes associated with sunitinib alternative schedule compared to traditional schedule.
Authors: Bradley J. Atkinson, Sarathi Kalra, Xuemei Wang, Nizar M. Tannir, Eric Jonasch
Journal: Journal of Clinical Oncology (2013)

381 Background: Sunitinib is a front-line therapy for metastatic renal cell cancer (mRCC). Recommended dose is 50 mg daily; 28 days (d) on/14 d off (traditional schedule; TS). Sunitinib is associated with several adverse events (AEs). An ideal treatment modification algorithm is not known. We sought to identify (1) common AEs, (2) alternative schedules (AS) that maintained dose intensity while decreasing AEs, and (3) the impact of AS on outcomes. Methods: Single-center retrospective review of mRCC pts performed from January 26, 2006 to March 1, 2011. Pts &gt; 18 years of age with mRCC who received first-line antiangiogenic therapy with sunitinib were eligible. A subset of pts were switched at first intolerable AE from TS to a 14 d/7 d, or further adjusted to 7 d /3 d, or other AS. Control group underwent standard dose reduction. Pt characteristics including demographics, disease status, laboratory data, AEs, AS, and treatment outcomes were analyzed. Results: 186 eligible pts were identified. At baseline, 87% received sunitinib 50 mg and 88% were on TS. 99 pts (53%) continued TS and 87 pts (47%) were switched to AS. Baseline characteristics were similar. Median age was 61 yrs; by MSKCC criteria 5% were good, 50% intermediate, and 45% poor prognosis. Pts had median 2 visceral mets and 42% had primary tumor in place. AEs included fatigue (47%), diarrhea (24%), and hand-foot syndrome (26%). Median time to AS was 126 d with 14 d/7 d the most common (82%). Median time on treatment was 14.9 months (mo) (95% CI:10.2 – 17.0 mo) in AS pts vs. 4.2 mo (95% CI: 3.6 – 5.7 mo), respectively (p &lt; 0.0001). Median OS was 32.9 mo (95% CI:28.3-54.1 mo) vs. 18.5 mo (95% CI: 10.3-21.5 mo), respectively (p = 0.0001). ECOG PS &gt; 2 (HR 3.9), elevated LDH (HR 2.04), and &gt; 2 mets (HR 1.79) were associated with decreased OS. MSKCC intermediate vs. poor (HR 0.57) and AS (HR 0.54) were associated with improved OS by multivariate regression analysis (p &lt; 0.05). Conclusions: In our cohort study, AS sunitinib significantly prolonged outcomes and was predictive of OS. Prospective investigations of alternate dosing schemas are warranted.
Association of a 2-weeks-on and 1-week-off schedule of sunitinib with decreased toxicity in metastatic renal cell carcinoma.
Authors: Yana George Najjar, Paul Elson, Laura S. Wood, Jorge A. Garcia, Robert Dreicer, Brian I. Rini
Journal: Journal of Clinical Oncology (2013)

e15534 Background: Treatment of metastatic renal cell carcinoma (mRCC) with sunitinib can be associated with toxicity leading to dose reduction. Maintaining adequate sunitinib dosing and avoiding dose interruptions that lower drug levels are essential for optimizing clinical efficacy. Standard sunitinib schedule is 4 weeks of treatment and 2 weeks of rest (schedule 4/2). Empirically in clinical practice, several metastatic RCC patients at The Cleveland Clinic (CCF) have been changed from a 4/2 schedule to a 2 weeks on /1 week off (2/1) schedule after experiencing toxicity in an attempt to maintain daily dose but reduce toxicity. Methods: The medical records of mRCC patients who were changed to a 2/1 schedule of sunitinib at CCF were retrospectively reviewed. Patient toxicity on each schedule was recorded during routine clinic visits and graded according to the Common Toxicity Criteria, version 4.0. Results: 21 patients were identified: 71% male, 78% clear cell histology, and 29% prior systemic therapy. All but one had prior nephrectomy. 95% of patients on the 4/2 schedule had grade 3 or 4 toxicity which led to the schedule change to 2/1. No grade 4 toxicities were observed on the 2/1 schedule, and 33% of patients experienced grade 3 toxicity (p = 0.0001 for comparison of worst grade toxicity on 4/2 versus 2/1). Two of the most common toxicities, fatigue and hand-foot syndrome (HFS), were significantly less frequent on the 2/1 schedule than on the 4/2 schedule (fatigue 52% all grade/33% grade 3 on 4/2 versus 33%/14% on 2/1; HFS 33%/29% on 4/2 versus 14%/0% on 2/1; p =.04 for both). Median overall treatment duration on the 4/2 schedule was 13.5 months (range 1.1-60.6 months) and median overall treatment duration on the 2/1 schedule was 24.4 months (range 1.3 to 67.6+ months). Conclusions: Treatment with sunitinib on a 2/1 schedule is associated with significantly decreased toxicity in patients who initially experience grade 3 or greater toxicity on the 4/2 schedule and can extend treatment duration considerably. Prospective clinical trials are required to define the optimal schedule of sunitinib to balance efficacy and toxicity.
Heart dose exposure as prognostic marker after radiotherapy for resectable stage IIIA/B non-small-cell lung cancer: secondary analysis of a randomized trial
Authors: M. Guberina, W. Eberhardt, M. Stuschke, T. Gauler, F. Heinzelmann, D. Cheufou, M. Kimmich, G. Friedel, H. Schmidberger, K. Darwiche, V. Jendrossek, M. Schuler, G. Stamatis, C. Pöttgen
Journal: Annals of Oncology (2017)
Retrospective assessment of quality of cancer care in last 6 months of life.
Authors: Brian Cassel, Nevena Skoro, Kathleen Kerr, Lisa Shickle, Patrick J. Coyne, Egidio Del Fabbro
Journal: Journal of Clinical Oncology (2012)

234 Background: National organizations such as the Centers for Medicare and Medicaid Services (CMS) and the National Quality Forum (NQF) have developed metrics that assess the quality of cancer care. These metrics include consensus standards by the NQF for management of symptoms and end-of-life-care. Cancer centers need feasible methods for self-evaluating their performance on such metrics. Methods: Claims for our cancer patients were matched to Social Security Death Index data to determine date of death.3,128 adult cancer patients died between January 2009 and July 2011 and had at least 1 contact with our center in their last six month of life. All inpatient and outpatient claims data generated in the last six months of life at our hospital were analyzed. Results: 32% of patients had an admission in their last 30 days of life, with 15% dying in the hospital. 19% had at least one 30-day readmission in their last six months of life. 6.7% had chemotherapy in the 2 weeks prior to death, and 11.4% in the last month. 27.5% had some contact with the specialist palliative care (SPC) team. Solid tumor patients with SPC earlier than 1 month until death had fewer in-hospital deaths (15.6%) versus those with later or no SPC (19.5%), p=.041. There was no SPC difference for 30-day mortality, or 14- or 30-day chemotherapy metrics. Conclusions: Hospitals can self-evaluate their own performance on NQF endorsed measures, and CMS outcome measures. These data provide additional impetus for earlier integration of specialist palliative care teams. SPC in the last 1-3 weeks of life did not improve most utilization metrics.[Table: see text]
Endometrial metastatic neoplasia: Prognostic factors.
Authors: M. O. Nicoletto, M. Dalla Palma, M. Donach, A. Casetta, C. Saccardi, L. Borgato, P. Fiduccia, S. Mocellin, P. Litta, V. Zagonel, G. B. Nardelli
Journal: Journal of Clinical Oncology (2011)

e15594 Background: We report pathologic characteristics and survival (OS) for women with metastatic or relapsed endometrial cancer (EC). Methods: Patients (pts) diagnosed with EC from Jan/2000 to Apr/2010 were identified in the I.O.V. cancer database. Differences between chemotherapy and other characteristics were examined by Chi-square and Fisher's exact test; survival analyses used Kaplan Meier and Long-Rank test. 47 pts, mean age 63 yrs, range 33-70, had radical hysterectomy, bilateral salpingo-oophorectomy and/or systematic pelvic and para-aortic lymphadenectomy and peritoneal cytology. AJCC staging was: stage I 15 pts, II 8 pts, III 15 pts, IV 8 pts; 1 unstaged; 28 were endometrioid; 19 were other histology. Grade 1, 2, and 3 tumors were seen in 6, 18 and 15 pts respectively; 8 unknown. Receptor status was positive in 15 pts, negative in 4; 28 unknown. 29 pts had radiotherapy and/or brachytherapy adjuvantly, 6 pts as metastatic/relapsed, 12 no therapy. Residuum at relapse was ≤2 cm in 23 pts, >2 cm in 20, and 4 unknown. 7 pts received doxorubicin-cisplatin (doxorubicin 50 mg/m2, cisplatin 50 mg/m2) mean cycles 4 (range 2-6); 17 received taxol-platin (uaxol 175/m2, platin 75/m2) mean 4 cycles (range 2-8) or Jm8-taxol, and 18 taxol-epidoxorubicin-cisplatin (taxol 175 mg/m2, epirubicin 70 mg/m2, cisplatin 50 mg/m2) mean cycles 6 (range 1-9). 24 had extrapelvic metastases; 23 had disease involving adnexa and/or pelvic lymph node (PLN), and para-aortic lymph nodes (PAN). Results: Differences in chemotherapy cycles administered (+/-4) were not significant. Extrapelvic metastases had a 5-yr OS of 50% vs 47% for pelvic+/-lymph node disease. Multivariate analysis shows stage, intra- vs extrapelvic metastases and diameter of relapsed lesion are not significant for 5-yr OS in EC. We found no difference in OS for therapy with taxol-platinum +/- doxorubicin. 5-yr OS of endometrioid cancer is 127 mo vs 38 mo for other histotypes, long-rank test 9.89 p <0.002; OS of Grade 1 and 2 was 127 mo vs 37 mo for grade 3, long-rank test 3.89 p<0.05. Conclusions: We confirm that endometrioid and lower histologic grade has better survival independent of radiotherapy, brachytherapy, chemotherapy or hormone therapy. More intensive therapy combinations do not significantly improve median OS.
Derivation of genomic risk models for early relapse in colorectal cancer from microdissected FFPE tumor and from mucosal tissue
Authors: A. C. Hoffmann, Y. Wettergren, E. Odin, G. Carlsson, A. Omori, J. Cooc, K. D. Danenberg, P. V. Danenberg, B. Gustavsson
Journal: Journal of Clinical Oncology (2008)

15126 Background: Whereas cancerous tissue would be expected to contain molecular markers for genomic risk models of cancer, non-cancerous tissue from the same organ might also express prognostic markers if partial progression toward the malignant state has occurred. We investigated whether paraffin-embedded cancerous as well as non-cancerous mucosal tissue show genomic profiles that are linked to early relapse. Methods: Paraffin-embedded tumor tissue samples were obtained from 14 patients with stage III primary colorectal cancer (9 colon, 5 rectal), with a median age of 80 years (Range 52–92), with a medium follow-up time of 489 days. Sections taken from of each paraffin block were microdissected to separate tumor cells and mucosal tissue located at least 10 cm from the tumor. Following isolation, RNA was amplified, labeled, and hybridized to Affymetrix U133 Plus 2.0 GeneChips. Differentially expressed gene lists were determined between relapsed and non-relapsed tumor and mucosal tissue by T-Test and hierarchical clustering. Results: Between the groups of all tumor and all mucosa specimens there were 616 differentially expressed genes at p<0.0005. Using the tumor samples, gene clusters created with supervised analyses based on outcome identified 193 differentially expressed genes between the relapsed and the non-relapsed groups (p=0.005). Interestingly, 276 differentially expressed genes were also identified in mucosa samples (p=0.005). However, Venn diagrams showed only 15 common predictive genes between the two tissue types. Diagnostic gene sets developed with tumor samples failed to properly classify the mucosa samples and vice versa. Conclusions: Gene profiles generated from cancerous and mucosal samples of the same tumors both contain prognostic information. However, the profiles are very dissimilar, suggesting that a) mucosal tissue influences recurrence of tumors by a different mechanism than that in tumors and b) that non-microdissected samples may not give gene profiles characteristic of cancer, but rather of pathologic stromal-tumor interaction. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Response Genetics Inc. Response Genetics Inc. Response Genetics Inc.
Chromosome (Ch17) disorder and Ki67expression: Negative prognostic factors in invasive breast cancer.
Authors: S. Petroni, T. Addati, F. Giotta, M. Centrone, E. Mattioli, M. Caponio, C. Quero, V. Rubini, G. Giannone, A. Millaku, G. Simone
Journal: Journal of Clinical Oncology (2011)

e21073 Background: Ch17 polysomy has been identified in 20-40% of invasive breast cancer, probably related to HER-2 protein expression, but other studies failed to confirm this relation, demonstrating that it’s a rare event. The aim of this study was to evaluate Cep17 alterations in invasive breast cancer related to Ki67, hormonal receptor status and HER-2 expression Methods: 647 cases of ductal invasive breast cancer diagnosed between 2007 and 2009, were collected. Immunostaining of estrogen and progesteron receptors (61%), and Ki67 was performed on 629 cases; receptor positive status and high Ki67 index has been detected in 61% and 60% of tumours, respectively. HER-2 protein overexpression was evidenced on 107/608 samples (17.6%). Amplification was detected by FISH in 120 tumors (18.5%). Results: Alterations of Cep17 were observed in 177/647 cases (26.3%); in this subset the 56.2% of valuable tumors presented with nodal metastasis, HER-2 gene amplification was detected in 25/177 cases (14.1%). HER-2 protein overexpression was evaluated: 35 (20.1%) were scored 3+, 108 (62.1%) 2+ and 31 (17.8%) as 0/1+. None of HER-2 negative cases was amplified whereas 17 cases (9.8%) overexpressed/not amplified were found. The overall agreement was 74.2% (49/66 valuable cases). In 470 eusomic cases HER-2 gene amplification was detected in 95 cases (20.2%). The overall agreement in 434 eusomic cases valuable for HER2-expression and FISH was 96.8%. Conclusions: HER-2 amplification showed a higher incidence in the cases without Cep17 copy number alterations, confirming that HER-2 gene alteration is not necessarily due to Chr17 disorder. In this study, a high number of aneusomic cases resulted overexpressed but not amplified and related to a high proliferation index (p= 0.002), differently by eusomic cancer, This result suggests that the presence of centromere 17 alterations could be associated to non-responsiveness to therapy independently from HER-2 amplification status.
Adjunctive role of preoperative liver magnetic resonance imaging added to computed tomography among resected pancreatic cancer patients.
Authors: Hyoung Woo Kim, Jin-Hyeok Hwang, Jong-chan Lee, Kyu-hyun Paik, Jingu Kang, Jaihwan Kim, Young Soo Park
Journal: Journal of Clinical Oncology (2016)

207 Background: Multi-detector computed tomography using pancreatic protocol (pCT) has been a preferred diagnostic imaging modality before resection of the pancreatic ductal adenocarcinoma (PDAC), because an adjunctive role of liver magnetic resonance imaging (MRI) is still unclear. The current study evaluated whether liver MRI added to pCT can help to select proper surgical candidates, and reduce the risk of early recurrence, eventually result in longer survival in resected PDAC patients. Methods: Among 197 PDAC patients who underwent curative-intended surgery, 167 patients who achieved complete resection with no grossly visible tumor were enrolled retrospectively. All patients had no metastatic lesions on pCT and/or MRI, preoperatively. Among them, 102 patients underwent pCT alone (CT group), and 65 patients liver MRI as well as pCT (MRI group). Results: By adding the liver MRI, hepatic metastases were newly discovered in 3 of 58 patients (5.2%) with no hepatic lesions on pCT and in 17 of 53 patients (32.1%) with indeterminate hepatic lesions on pCT. Among 167 patients who achieved R0/R1 resection, the median overall and disease-free survival were 20.1 vs 29.3 months and 8.5 vs 10.0 months in the CT and the MRI group, respectively (p = 0.011 and = 0.012), during median follow-up of 16.4 months. 80 (78.4%) patients in the CT group and 39 (60.0%) in the MRI group experienced recurrence during follow-up. Cumulative initial hepatic recurrence rate was higher in the CT group than in the MRI group (43.7% vs 18.5% at 1yr and 57.4% vs 26.9% at 2yr, p &lt; 0.001), although the other sites recurrence did not differ in both groups. Conclusions: Liver MRI added to pCT has an incremental value in detecting PDAC hepatic metastases. Furthermore, because PDAC patients who underwent resection after liver MRI as well as pCT expect lower rate of hepatic recurrence and better survival than pCT alone, therefore, liver MRI added to pCT is needed to patients who planned curative resection of PDAC.
Pharmacogenetic prediction of clinical outcome in gastric cancer patients receiving oxaliplatin-based adjuvant chemotherapy.
Authors: Y. Liu, Y. Ling, B. Liu, Y. Zhang
Journal: Journal of Clinical Oncology (2010)

e14506 Background: Many findings have been reported on the effect of polymorphisms of ERCC1, XRCC1, XPD, and GSTP1 genes on the response to platinum-based chemotherapy in various types of solid tumors. The aim of this study was to determine whether these molecular parameters could be partly responsible for sensitivity to oxaliplatin (OX)-based chemotherapy used as adjuvant treatment in resected gastric cancer. Methods: 126 resected gastric cancer patients received OX/5-fluorouracil chemotherapeutic regimen. Genetic polymorphisms of ERCC1-118, XRCC1-399,XPD-751, and GSTP1-105 were determined by the TaqMan 5′nuclease assay, using DNA from peripheral blood. Relapse-free survival (RFS) and overall survival (OS) were evaluated according to each genotype. Results: In the univariate analysis, ERCC1-118 and XRCC1-399 polymorphisms were significant for RFS (p<0.001 and p=0.001, respectively) and OS (p<0.001). After adjustment for the most relevant clinical variables, only ERCC1-118 retained significance for RFS (p<0.001) and OS (p<0.001) in the multivariate Cox survival analysis. Conclusions: Our data suggested that gastric cancer patients harboring ERCC1-118 C/C genotype and XRCC1-399 A/G or G/G genotypes may better receive oxaliplatin-based adjuvant chemotherapy. Hazard ratios for relapse-free survival and overall survival in patients receiving surgery followed by oxaliplatin-based adjuvant chemotherapy Prognostic factors RFS OS HR 95%CI p value HR 95% CI p value ERCC-118 <0.001 <0.001 C/C 1 1 C/T+T/T 2.501 1.560-4.009 2.478 1.505-4.080 Staging <0.001 <0.001 I + II + III 1 1 IV 3.328 2.120-5.225 3.027 1.846-4.962 Carcinoembryonic antigen 0.001 0.001 ≤ 5 ng/ml 1 1 > 5 ng/ml 2.228 1.373-3.614 2.521 1.496-4.251 Abbreviations: RFS, relapse-free survival; OS, overall survival; HR, hazard ratio. No significant financial relationships to disclose.
Necitumumab in metastatic squamous non-small cell lung cancer (mSqNSCLC): Establishing a value-based cost.
Authors: Daniel A. Goldstein, Qiushi Chen, Turgay Ayer, David H. Howard, Joseph Lipscomb, Suresh S. Ramalingam, Fadlo Raja Khuri, Christopher Flowers
Journal: Journal of Clinical Oncology (2015)

6505 Background: The SQUIRE trial demonstrated that adding necitumumab to chemotherapy for patients with mSqNSCLC produces a median overall survival benefit of 1.6 months (hazard ratio 0.84). The objective of this study was to evaluate the range of drug costs for which adding necitumumab to chemotherapy could be considered cost-effective. Methods: We developed a Markov model to compare the incremental cost-effectiveness of standard chemotherapy with or without necitumumab in the first-line treatment of mSqNSCLC. In the model, patients received gemcitabine and cisplatin for 6 cycles or gemcitabine, cisplatin, and necitumumab for 6 cycles followed by maintenance necitumumab. The clinical inputs were the survival benefits and frequency of adverse events (AEs) described in the SQUIRE trial. Weibull models were fitted to the survival curves in the SQUIRE trial. The cost inputs included drug costs based on the Medicare average sale prices, and costs for drug administration and the management of AEs based on Medicare reimbursement rates (all in 2014 US $). Model robustness was addressed by probabilistic sensitivity analyses (PSA) in which we ran 10,000 Monte Carlo simulations sampling from the distributions for all variables. We performed multiple model simulations each time varying Willingness To Pay (WTP) values to evaluate the incremental cost effectiveness ratio (ICER) across a range of values for the cost of necitumumab. Results: In the base case analysis, the addition of necitumumab produced an incremental survival benefit of 0.15 life years (LY) and 0.11 quality-adjusted life years (QALY). The PSAs established that: when necitumumab cost < $563 per cycle there was 90% confidence that the ICER for adding necitumumab would be < $100,000/QALY; when necitumumab cost $1309 per cycle there was 90% confidence that the ICER would be < $200,000/QALY; and when the cost of necitumumab was > $6,628 per cycle there was > 99% confidence that the ICER would be > $500,000/QALY. Conclusions: These findings provide a value-based range for the cost of necitumumab from $563 to $1309 per cycle. This study provides a framework for establishing value based pricing for new oncology drugs entering the US marketplace.