tbuckley/cabot-search huggingface dataset:
Personalizing cancer treatment of combined targeting of PI3K/AKT and MAPK pathways in advanced cancer patients harboring simultaneous oncogenic alterations in both signaling pathways.
Authors: Toshio Shimizu, Anthony W. Tolcher, Kyriakos P. Papadopoulos, Muralidhar Beeram, Drew Warren Rasco, Lon S. Smith, Ronald L. Drengler, Shelly Gunn, Leslie Smetzer, Theresa A. Mays, Brianne Kaiser, Michael Jude Wick, Amita Patnaik
Journal: Journal of Clinical Oncology (2012)

e13025 Background: Frequent coactivation of both PI3K/AKT and MAPK pathways has been seen in a number of different tumor types. Preclinical studies also provide a clear rationale for the co-inhibition of these, "semi-parallel" pathways. Methods: We reviewed the records of 1,672 consecutive advanced cancer patients (pts) in our Phase I Clinical Trials Program and investigated the clinical impact of simultaneous blockade of both PI3K/AKT and MAPK pathways in patients with oncogenic alterations in both signaling pathways from 317 pts who received PI3K pathway inhibitor and/or MAPK pathway inhibitor. Results: 163 of 317 pts (51.4%) were tested for comprehensive tumor genomic analysis using DNA array-based CGH/PCR-based DNA sequencing. PI3K pathway genetic alterations (PIK3CA mutation, n=3; PTEN deletion, n=18; AKT amplification, n=10) were detected in 29 of the 163 (17.8%) pts. RAS/RAF pathway genetic alterations (KRAS mutation, n=33; HRAS mutation, n=4; BRAF mutation, n=6) were detected in 43 of the 163 (26.4%) pts. Simultaneous oncogenic alterations in both PI3K/AKT and MAPK pathways were detected in 12 pts (colorectal cancer, n=7; pancreatic cancer, n=2; melanoma, n=2; non-seminomatous germ cell tumor, n=1). Six of 8 (75%) pts treated with personalized treatment based on dual pathways inhibition had tumor regression with prolonged duration of time to treatment failure compared to that of pts treated with single pathway inhibition. A pt with pancreatic cancer harboring simultaneous KRAS mutation and AKT2 amplification treated with combination MEK1/2 inhibitor and AKT inhibitor showed central cavitations of numerous lung metastatic lesions along with a decrease in CA19-9, which may reflect treatment effect. Conclusions: These data could serve as a platform for therapeutic decision making. The strategy of targeting parallel pathways may be especially important in pts with coexisting PI3K/AKT and MAPK pathway genetic alterations. The data also suggest the need to further investigate the role of molecular profiling and matching pts with targeted drugs for personalized treatment.
Independent validation of the 2002 UICC TNM staging system for papillary renal cell carcinoma in a multicenter cohort
Authors: C. Wulfing, E. Herrmann, L. Trojan, A. Schrader, F. Becker, M. Stähler, A. Haferkamp, W. Legal, W. Brenner, A. Hartmann
Journal: Journal of Clinical Oncology (2009)

5092 Background: Papillary renal cell carcinoma (pRCC) is the second most malignant histologic subtype in nephrectomy specimens. To date, the most recognized staging system to stratify renal cancer patients is the 2002 UICC TNM classification system. Its accuracy for predicting patient outcome for pRCC is unknown. Methods: From ten urologic institutions in Germany follow-up data on 675 patients with pRCC were collected. In most cases histologic slides were available and central pathologic review was performed. The Kaplan-Meier method was used to derive the cumulative cancer-specific survival. For multivariate analysis of prognostic factors, a Cox regression analysis was performed. Results: 498 (74.1%) patients had organ-confined tumor stages (≤pT2). Synchronous distant metastases in the entire group occurred in 58 (8.7%) patients and 69 (11.2%) others developed metastatic disease during follow-up. Cancer-specific survival (CSS) was significantly related to TNM stage and histologic grading in univariate as well as in multivariate analysis (all p &lt; 0.0001). 5-year CSS in pT1b tumors (90.0%) was significantly shorter compared to pT1a tumors (98.3%) (p = 0.017). Patients with ≥pT3 were at high risk for metastases (50.6%), while metastatic disease associated with ≤pT2 tumors occurred in 7.8% (p &lt; 0.0001). Once metastatic disease was present, prognosis was poor (5-year CSS: 7.2%). Age was associated with a worse prognosis in the subgroup of ≥pT3 tumors in univariate (p = 0.026), but not in multivariate analysis. Conclusions: The 2002 UICC TNM staging system is applicable for pRCC. Clinical and radiologic follow-ups should be offered in frequent intervals to patients with venous thrombus and/or locally advanced disease. The role of age remains unclear, but should not be underestimated at risk stratification after tumor resection. No significant financial relationships to disclose.
Patient-derived xenografts as models for the identification of predictive biomarkers in esophagogastric cancer.
Authors: Yelena Yuriy Janjigian, Efsevia Vakiani, Tooba Imtiaz, Xiaodong Huang, David H. Ilson, Nabil P. Rizk, Daniel G. Coit, Vivian E. Strong, Elisa de Stanchina
Journal: Journal of Clinical Oncology (2014)

4059 Background: Individual EG cancer subtypes have heterogeneous tumor characteristics and clinical outcome, making EG adenocarcinoma a complex disease to treat. Cytotoxic agents are applied to all disease subtypes with only modest success. Emergence of HER2 and MET as therapeutic targets underscores the importance of tumor profiling to allow optimal treatment planning. Preclinical models that recapitulate tumor biology may aid in discovery of new biomarkers and therapeutic targets. The purpose of this study is to establish PDXs accompanied by annotated molecular and clinical data for identification of predictive biomarkers and testing of targeted therapies. Methods: Fresh specimens obtained under aseptic conditions, mixed with matrigel and inoculated into 8 wks old NOD scid gamma mice subcutaneously (SQ) into flanks or orthotopically (OT) into the gastric wall. PDXs are kept in an in vivo microenvironment to retain a degree of the polyclonality of the tumors from which they were derived. Once established, tumor material is collected for molecular analysis, histology, and primary cultures. Results: To date 90 tumor samples have been implanted SQ, 20 of which were also implanted OT. To date, 22 PDXs have been established and 12 additional tumors (5 SQ, 7 OT) are being monitored for engraftment. Tumor engraftment rate was 46% for OT and 26% for SQ implants. The table below summarizes the results including molecular tumor characteristics. The established PDXs include HER2+ trastuzumab refractory models, MET+ models, and a signet ring gastric cancer model with germ line CDH1mutation. Conclusions: The established EG PDXs provide a platform to further validate differences in tumor biology and guide rational design of clinical trials. Comprehensive molecular profiling and therapeutic experiments with PDXs are underway. Tumor characteristic Established PDX n=22 N (%) Esophagus/GE junction 8 (36) Diffuse/signet ring 2 (9) Distal stomach/intestinal 12 (54) Primary tumor 13 (59) Metastasis 9 (41) HER2-positive 3 (19) MET-positive 13 (81) CDH1 germ-line mutation 1 (4)
Immunoproteomic Identification of Graft-Versus-Leukemia Targets in Patients with Chronic Lymphocytic Leukemia.
Authors: Ovidiu Marina, Melinda Biernacki, Ann Cai, Wandi Zhang, Jonathan S. Duke-Cohan, Vladimir Brusic, Fenglong Liu, Edwin Alyea, Christine M. Canning, Robert Soiffer, Jerome Ritz, Catherine J. Wu
Journal: Blood (2007)
Impact of current treatment status on QOL in cancer survivors.
Authors: Eon Sook Lee, Charles S. Cleeland, Qiuling Shi, Sanghui Chu
Journal: Journal of Clinical Oncology (2014)

9597 Background: Many cancer survivors have been reported to have poor health related quality of life (HRQoL). This could be caused by various symptoms of cancer itself and treatment. For better understanding of cancer treatment and HRQoL, we investigated HRQoL and associating factors according to current treatment status and compared them with general population. Methods: Using national survey data in South Korea (KNHANES IV-V) from 2007 to 2010, we analyzed 14,396 subjects aged over 50years. Cancer survivors were defined as person diagnosed cancer by physician and divided into two groups, with current treatment and no treatment. Euro QOL was measured as HRQoL. Socioeconomic status (age, sex, education, having SSI), number of non-cancer disease, depressive mood, time since diagnosis and health behaviors (smoking, alcohol, physical activity) were collected as risk factors. EQ5D index and EQ_VAS of survivors receiving treatment were compared with no treatment group and general population, respectively. Results: Cancer survivors with treatment (N=191) showed lower EQ_VAS (β=-3.57, P=0.047) when compared to the general population, while group with no treatment (N=464) did not show the difference in multivariate analysis. Depressive mood was a consistent risk factor of poor HRQoL regardless current cancer treatment status (OR= 3.73, 95% CI=1.18-11.78 in cancer treatment, 2.64 95% CI=1.37-5.09 in non-treatment), and same even in non-cancer group (OR=2.37, 95%=2.11-2.65). Except depressive mood, other risk factors influencing poor HRQoL could be attenuated among survivors with treatment. Survivors with no treatment still had a number of non-cancer morbidity and lower income as risk factors for low score of EQ5D index, similar to the non-cancer group. Conclusions: Current cancer treatment is a strong indicator for poor HRQoL in survivors. Cancer survivors had different risk factors for poor HRQoL according to current treatment status. Depressive mood was an important factor for poor HRQoL in both treatment and non-treatment groups. For evaluating HRQoL of cancer survivors even in long term group, the influence of current treatment status should be considered. Attention and management of depressive mood should be part of the care of cancer survivors.
Variability in data selection between local sites and blinded independent central review during a RECIST phase II trial: Association with rate of adjudication.
Authors: Hubert Beaumont, Antoine Iannessi, Saerom Hong, Sebastien Lavialle, Mustapha Chadjaa, Zsuzsanna Monostori
Journal: Journal of Clinical Oncology (2015)

e18555 Background: In clinical trials, the double reading of images local investigator / central review (LI/CR) results in discordant evaluations. Some origins of disagreements have been investigated, as the limited precision of measurements or the mis-conformance to response criteria. However, other causes are less analysed as the variability in selecting target lesions (TL) or images in series. This study describes the LI/CR variability of data selection and its consequences on adjudication rate (AR). Methods: We retrospectively analysed a RECIST 1.1 Randomized Phase II clinical trial of Cabazitaxel versus Topotecan. 179 relapsing adult patients were enrolled if meeting histological/cytological proven locally advanced or metastatic small cell lung cancer. Sixty-six LI sites, one CR and one adjudicator were involved. For each time point of LI/CR, we documented TLs location, non-Target Lesions (nTL) and new lesions (NL). TLs were labelled as equivocal when LI/CR had obvious different perception. Odd ratio measured the association between adjudication for progressive disease and differences in image, TL selection and NL detection. Results: The average number of TL selected by patient differed for LI/CR (p = 0.0012), respectively 2.93 and 3.37. LI/CR selected respectively 29.9% Vs 35.5%, 21.5% Vs 19.2% and 31.6% Vs 31.2% of pulmonary, hepatic and nodal lesions. For 59% of patients, LI/CR evaluated different images at baseline and for 85% they did not select the same TLs. 18% of TLs were equivocal. AR was 36.7% (54/147). Disagreement was on NL (53%), tumoral burden assessment (18%), progressive nTL (11.2%) and 17.8% was a combination of causes. NL declaration were nearly associated with adjudications (p = 0.075). No association was found with small tumoral burden (p = 0.16), equivocal lesion (p = 0.47), different images (p = 0.58) or progressive nTL (p = 0.29). Near inverse association was found when selecting different TLs (p = 0.06). Conclusions: The distribution of direct causes of discordances were drawn. NL detection was the main factor of discordance. We observed a large variability in data selection; however, some of these variabilities had no impact on AR. Clinical trial information: NCT01500720.
Droplet digital PCR monitoring of BRAF and NRAS plasma DNA as biomarkers of treatment response in stage IV melanoma.
Authors: David Polsky, Jyothirmayee S. Tadepalli, Gregory Chang, Nathaniel H. Fleming, Yongzhao Shao, Anna C. Pavlick, Iman Osman, Manohar Furtado, Cynthia Spittle, Paula Stonemetz, Dawne Shelton, George Karlin-Neumann
Journal: Journal of Clinical Oncology (2014)

9019 Background: Management of melanoma suffers from a lack of robust biomarkers of disease activity. In this study, we tested the ability of droplet digital PCR (ddPCR) to quantitatively measure levels of circulating BRAF and NRAS mutant DNA in the plasma of metastatic melanoma patients undergoing treatment with BRAF-targeted therapy or immunotherapy. Methods: We analyzed plasma samples from 45 patients with stage IV melanoma prospectively enrolled in the NYU Melanoma Biorepository program. All patients were commercially genotyped for BRAF V600E. SNaPshot assays were used to identify NRAS Q61 mutations in BRAF-WT tumors. Each patient had at least 3 serially collected plasma samples including one drawn prior to treatment, one or more after treatment began and one upon signs of disease progression. ddPCR was used to measure mutant copies/ml of BRAF V600E and NRAS Q61K/L/R DNA in plasma samples. Results: Among 45 patients, 28 patients had BRAF and 8 patients had NRAS tumor mutations. We extracted DNA from 151 plasma samples. Our preliminary results include analysis of 50 plasma samples from 10 BRAF-mutant and 5 NRAS-mutant patients. All BRAF V600E patients received BRAF inhibitor therapy and had partial responses followed by disease progression. Levels of circulating V600E DNA decreased with clinical response and/or increased with disease progression in 8/10 patients. In 3 patients with progressing disease, plasma samples drawn in-between imaging visits showed increasing BRAF mutant copies/ml up to 2 months prior to clinical scans. Among NRAS mutant patients, all were treated with Ipilimumab: 3 patients progressed, 1 had a near complete response, and 1 progressed and was then treated with Nivolumab. Levels of circulating Q61 DNA rose with disease progression and/or fell with clinical response in 5/5 immunotherapy treated patients. Conclusions: Our results indicate that ddPCR is able to measure clinically meaningful changes in the levels of BRAF and NRAS mutant copies/ml in the plasma of stage IV melanoma patients. This analytical platform has the potential for monitoring disease progression and patient response to both targeted and immune-based therapies, and may be a useful adjunct to imaging studies.
Mutations of <i>KIT</i> tyrosine kinase (TK) gene predict relapse in adult patients (pts) with core binding factor acute myeloid leukemia (CBF AML): A Cancer and Leukemia Group B (CALGB) study
Authors: P. Paschka, G. Marcucci, A. S. Ruppert, K. Mrózek, H. Chen, R. A. Kittles, T. Vukosavljevic, D. Perrotti, R. A. Larson, C. D. Bloomfield
Journal: Journal of Clinical Oncology (2006)

2 Background: Multi-course high-dose cytarabine (HDAC) has largely improved the outcome of CBF AML pts with t(8;21)(q22;q22) and inv(16)(p13q22). Yet, ∼50% of pts relapse within 5 years (yrs), indicating the need for markers identifying high-risk pts who require more aggressive and/or novel therapies. KIT mutations (mKIT) of exons 17 (mKIT17) and 8 (mKIT8) are good candidates to be such markers. Previous studies showed that mKIT17 impacted adversely on outcome of t(8;21), but not inv(16), pts. Methods: Sixty-one pts with inv(16) and 49 with t(8;21), assigned to HDAC consolidation on CALGB protocols,were analyzed at diagnosis for mKIT17 and mKIT8 by denaturing high-performance liquid chromatography and direct sequencing. The median follow-up was 5.3 yrs. Results: Among pts with inv(16), 10 had mKIT17 (3 with concurrent mKIT8) and 8 sole mKIT8; among pts with t(8;21), 9 had mKIT17 (2 with mKIT8) and 2 sole mKIT8. In each cytogenetic group, complete remission rates were similar for pts with wild-type KIT (wtKIT) and those with mKIT or mKIT17. In both groups, cumulative incidence of relapse (CIR) was higher for pts with any mKIT [inv(16), P=.050, 5-yr CIR 56% vs 29%; t(8;21), P=.017, 5-yr CIR 70% vs 36%], and also for the subsets of pts with mKIT17 [inv(16), P=.002, 5-yr CIR 80% vs 29%; t(8;21), P=.014, 5-yr CIR 75% vs 36%] compared to wtKIT. Neither mKIT nor mKIT17 significantly affected overall survival (OS). In multivariable analyses (see table ), mKIT [in t(8;21)] and mKIT17 [in inv(16) and t(8;21)] independently predicted worse CIR; worse OS correlated significantly with mKIT only in inv(16) pts. Conclusions: We show for the first time that mKIT17 confer significantly higher relapse rates in inv(16) pts and confirm their adverse impact on t(8;21) pts. Thus, this subset of pts may benefit from more aggressive treatment and/or, since mKIT17 lead to constitutive KIT activation, from therapy that includes TK inhibitors, such as imatinib or PKC412. [Table: see text] No significant financial relationships to disclose.
Real world experience of immuno-oncology agents in metastatic renal cell carcinoma: Results from the IMDC.
Authors: Steven Yip, Connor Wells, Raphael Brandao Moreira, Alex Wong, Sandy Srinivas, Benoit Beuselinck, Camillo Porta, Hao-Wen Sim, D. Scott Ernst, Brian I. Rini, Takeshi Yuasa, Naveen S. Basappa, Ravindran Kanesvaran, Lori Wood, Denis Soulieres, Christina M. Canil, Anil Kapoor, Simon Yuen Fai Fu, Toni K. Choueiri, Daniel Yick Chin Heng
Journal: Journal of Clinical Oncology (2017)

492 Background: Immuno-oncology (IO) checkpoint inhibitors have demonstrated efficacy in metastatic renal cell cancer (mRCC) treatment. Real world data is required to assess outcomes when applied to the general population. Methods: A retrospective analysis was performed using the IMDC database. It included mRCC patients treated with IO agents, including atezolizumab (Atezo), avelumab, ipilimumab, nivolumab (Nivo), and pembrolizumab (Pembro). Some patients were treated with combination therapy with a targeted agent. Patients may have received IO therapy as first-, second-, third-, or fourth-line treatment. Overall survival (OS), treatment duration, and overall response rates (ORR) were calculated. Results: 255 patients with mRCC treated with IO therapy were included. The ORR to IO therapy in those patients who were evaluable was 29% (32% first-, 22% second-, 33% third-, and 32% fourth-line therapy). Patients treated with second-line IO therapy were divided into favorable, intermediate, and poor risk using IMDC criteria; the corresponding median OS rates were not reached, 26.7 mo, and 12.1 mo, respectively (p&lt;0.0001). Conclusions: Response rates to IO therapies appear to remain consistent no matter which line of therapy it is used in. Within second-line treatment, IMDC criteria appear to stratify patients appropriately into favorable, intermediate, and poor risk groups. Survival data are premature and will be updated. In contrast to Nivo clinical trial data, where median treatment duration was 5.5 mo, longer treatment length is observed in real world practice. [Table: see text]
The impact of extrahepatic disease among patients undergoing liver-directed therapy for neuroendocrine liver metastasis: A multi-institutional analysis.
Authors: Aslam Ejaz, Timothy M. Pawlik, Bradley Reames, Shishir Kumar Maithel, George A. Poultsides, Todd W. Bauer, Ryan C. Fields, Matthew J. Weiss, Hugo Marques, Luca Aldrighetti
Journal: Journal of Clinical Oncology (2017)

277 Background: Management of neuroendocrine liver metastasis (NELM) in the presence of synchronous extrahepatic disease (EHD) is controversial. We sought to examine the outcomes of patients undergoing liver-directed therapy for NELM in the presence of EHD using a large multicenter international cohort of patients. Methods: 612 patients who underwent liver-directed therapy were identified from 8 participating institutions. Postoperative outcomes, as well as overall (OS) and progression-free survival (PFS) were compared between patients with (N = 70, 11.4%) and without (N = 542, 88.6%) EHD. Results: Median age of the cohort was 57 years (IQR: 48, 65) with a slight majority of patients being male (N = 326, 53.3%). The majority of primary tumors were located in the pancreas (N = 254, 41.8%) followed by the small bowel (N = 188, 30.9%). At the time of liver-directed surgery, patients underwent surgery alone (N = 471, 77.0%), ablation alone (N = 15, 2.5%), or a combined approach (N = 126, 20.6%). Most patients underwent a non-anatomic wedge resection (N = 404, 66.0%). Patients with EHD had more aggressive high-grade tumors (EHD: 44.4% vs. no EHD: 16.1%; P &lt; 0.001). EHD was most commonly located in the peritoneum (N = 29, 41.4%) and lung (N = 19, 27.1%). Among the 70 patients with EHD, 20.0% (N = 14) underwent concurrent resection for the EHD. After a median follow-up of 51 months, 174 (28.4%) patients died with a median OS of 140.4 months among the entire cohort. Patients with EHD had a shorter median OS versus patients who did not have EHD (EHD: 87 months vs. no EHD: not reached; P = 0.002). Similarly, PFS was shorter among patients with EHD compared with patients without EHD (EHD: 46.8 months vs. no EHD: 68.6 months; P = 0.005). In the cox regression model, the presence of EHD was independently associated with an increased risk of death (HR: 2.56, 95%CI 1.16-5.62; P = 0.02). Conclusions: Patients with NELM and EHD had more aggressive tumors, which conferred over a 2-fold increased risk of death compared with patients who did not have EHD. Surgical treatment of NELM among patients with EHD should be individualized.