tbuckley/cabot-search huggingface dataset:
Trimodality treatment for locally advanced esophageal malignancies.
Authors: Tarita Thomas, Maya Mathew, Nimra Elahi, Stephen Murata
Journal: Journal of Clinical Oncology (2016)

174 Background: This study sought to review a single-institution experience with the management of patients with locally advanced esophageal adenocarcinoma, focusing on outcome and patterns of failure and factors affecting failure. Methods: A retrospective review of patients with locally advanced esophageal malignancies who were treated at our institution from 2002 to 2014. All patients underwent concurrent chemoradiation and surgery. Radiotherapy was delivered using 3-dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiotherapy (IMRT). Locoregional failure-free survival (LRFFS), distal metastasis free survival (DMFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Different factors which can affect the failure pattern were compared. Results: A total of 46 patients were analyzed. Median age was 66 years (range, 44 to 80 years). Forty three patients (93%) were men. All patients had adenocarcinoma (46% with moderately differentiated &amp; 54% with poorly differentiated histology) involving the distal third of the esophagus. Ninety three percent were treated with 3DCRT while 7% received IMRT with a median dose of 50.4 Gy. 72 % of the tumors were downgraded after the neoadjuvant therapy, with 43 % complete response. With a median follow-up time of 22 months (range, 1 to 116 months), locoregional failure was observed in 10 patients (21%) and distant metastasis in 18 patients (39%). Among the 32 patients who died 16 patients died of disease progression and 6 patients died of post-operative complications. BMI (Body mass index) at the time of diagnosis, time elapsed between chemoradiation and surgery, history of weight loss at presentation and insertion of the J tube before neoadjuvant therapy did not affect the outcomes as per our study. Conclusions: Thoughneoadjuvant chemoradiation followed by surgery produces good pathological response to locally advanced esophageal malignancies, those results are not extrapolated to survival rates with most of the patients dying of distant metastasis. Further multi-institutional studies are required to assess other factors which are affecting the survival of esophageal cancer patients.
Effect of platelet inhibition on the risk of development of metastatic disease in colorectal cancer.
Authors: D. Pulte, S. B. Chalasani, M. Bryan, L. F. Pliner
Journal: Journal of Clinical Oncology (2011)

470 Background: Platelet inhibition has been shown to decrease the risk of metastatic disease in numerous animal models. The use of aspirin to decrease the risk of colorectal cancer (CRC) has been documented in several large studies. However, to date, no studies of whether the use of aspirin or other platelet inhibiting agent (PIA) will reduce the risk of recurrence in patients who develop CRC have been performed. Methods: In this study, we reviewed the charts of all patients treated at the University of Medicine and Dentistry of New Jersey at Newark for stage II or III colon or rectal cancer. Data extracted included use of PIA, stage, treatment, recurrence, time of last contact, and patient characteristics. Patients were defined as having taken a PIA if any evidence of use could be documented. Statistical significance of differences observed was determined using a Fisher's exact test. Results: 111 charts were initially identified. Use of PIA could not be determined for 6, six had metastatic disease at presentation, and one was stage I, leaving 98 patients for analysis. Of these, 35 had evidence of having used PIA, including 20 patients who were taking aspirin. Forty patients without history of use of a PIA had no metastatic disease, compared to 23 patients who developed metastatic disease. For patients taking PIA, 6 developed metastatic disease (Table). Conclusions: Our results suggest that PIA may help decrease the likelihood of the development of metastatic disease in patients who are diagnosed with stage II or III CRC. The study was limited by the number of patients available, which was not large enough to allow consideration of all possible confounders. Further study of the effects of PIA in a translational and clinical setting including a larger, prospective trial of PIA in stage II/III CRC may lead to further insight into this question. [Table: see text] No significant financial relationships to disclose.
Prognostic relevance of a novel AJCC staging classification for neuroendocrine tumors of the pancreas.
Authors: J. R. Strosberg, A. Cheema, J. Weber, L. K. Kvols
Journal: Journal of Clinical Oncology (2011)

177 Background: The AJCC Cancer Staging Manual (7th edition, 2010) has introduced a novel TNM staging classification for pancreatic neuroendocrine tumors that is derived from the staging system for exocrine pancreatic adenocarcinomas. This classification has not yet been validated. Methods: Patients with pancreatic neuroendocrine tumors treated at the H. Lee Moffitt Cancer Center between 1999 and 2010 were assigned a stage (I-IV) based on the new AJCC classification. Overall survival from time of initial diagnosis was measured and statistical significance calculated using the log-rank test. The prognostic relevance of the AJCC staging classification was compared to the relevance of a staging classification proposed recently by the European Neuroendocrine Tumor Society (ENETS). Results: 425 patients with histologically proven pancreatic neuroendocrine tumors were identified. Both the novel AJCC classification and the ENETS classification were highly prognostic for survival (p&lt;0.00001; Table). Conclusions: The novel AJCC 7th edition TNM classification for pancreatic neuroendocrine tumors is highly prognostic for overall survival and should be adopted in clinical practice. [Table: see text] No significant financial relationships to disclose.
Molecular profiles of gastric cancer: The UCSD experience.
Authors: Devon Marcus McGee, John P. Shen, Paul Timothy Fanta, Andrew M. Lowy
Journal: Journal of Clinical Oncology (2013)

29 Background: Gastric cancer is the 2 nd leading cause of cancer mortality globally. A small number of studies reported that low TS and ERCC1 mRNA levels are associated with improved survival, and may be important as prognostic factors. Methods: Intratumoral gene expression levels were assessed using laser-captured micro-dissection and quantitative Real-Time PCR on formalin fixed paraffin embedded tumor samples from 22 gastric adenocarcinomas. A retrospective chart review was performed to measure clinical parameters. Primary objectives were to determine the range of expression of TS, ERCC1, and HER2, and to investigate if these biomarkers are predictive of survival. Results: TS, ERCC1, and HER2 median expression levels using RT-PCR were 3.56, 1.54, and 0.085, respectively. Median OS was 62 months. Subjects with low TS trended towards improved survival (92 months vs. 34 months, p: 0.17), as did subjects with low ERCC1 (92 months vs. 55 months, p: 0.44). There was no association between HER2 expression and OS. All subjects had HER2 levels below 0.55. With regard to treatment, 90.9% of patients received platinum-based chemotherapy and 4.5% received HER2-guided therapy. Conclusions: Our results are consistent with prior reports that associate low TS and low ERCC1 with improved OS, and may imply prognostic significance. Although these trends did not reach statistical significance, they are consistent with prior studies. Further molecular studies are needed to better assess the utility of these markers as prognostic indicators. There was no clear trend between HER2 levels and OS, most likely because all subjects had low HER2 levels. However, as accurate determination of HER2 expression is becoming increasingly important in the management of gastric cancer patients, further research into the degree of concordance between RT-PCR assessment and FISH assessment of HER2 gene amplication is warranted. Overall, more molecular studies are needed to better stratify this disease into subtypes, and identify new drug targets for chemo-resistant subtypes.
RacGAP1 expression, increasing tumor malignant potential, as a predictive biomarker for lymph node metastasis and poor prognosis in colorectal cancer.
Authors: Hiroki Imaoka, Yuji Toiyama, Susumu Saigusa, Koichiro Mori, Tomofumi Noguchi, Shozo Ide, Ryo Uratani, Satoshi Oki, Hiroyuki Fujikawa, Junichiro Hiro, Minako Kobayashi, Koji Tanaka, Masaki Ohi, Toshimitsu Araki, Yasuhiro Inoue, Yasuhiko Mohri, Masato Kusunoki
Journal: Journal of Clinical Oncology (2015)

555 Background: Rac GTPase activating protein (RacGAP) 1 plays a key role in controlling various cellular phenomena including cytokinesis, transformation and migration. Recently, the clinical significance of RacGAP1 expression has been reported in several malignancies. However, direct association between the RacGAP1 expression and colorectal cancer (CRC) has not been fully investigated. The aim of this study is to elucidate the function and clinical significance of RacGAP1 expression in CRC. Methods: The intrinsic functions of RacGAP1 in CRC cells were analyzed using small interfering RNA (siRNA). We analyzed RacGAP1 mRNA expression in surgical specimens from 193 CRC patients (Cohort 1) by real-time polymerase chain reaction. Then, we validated RacGAP1 protein expression using formalin-fixed paraffin-embedded samples from 298 CRC patients (Cohort 2) by immunohistochemistry. Finally, we evaluated the association between RacGAP1 mRNA and protein expression and clinicopathological data. Results: Reduced RacGAP1 expression by siRNA in CRC cell lines showed significantly decreased cellular proliferation, migration, and invasion. In Cohort 1, RacGAP1 expression in CRC was significantly higher than in adjacent normal mucosa, and increased according to TNM stage progression. High RacGAP1 expression in tumors was significantly associated with progression and prognosis. In Cohort 2, RacGAP1 protein was overexpressed mainly in the nuclei of CRC cells; however, its expression was scarcely observed in normal colorectal mucosa. RacGAP1 protein expression was significantly higher in CRC patients with higher T stage, vessel invasion, and lymph node and distant metastasis. Increased expression of RacGAP1 protein was significantly associated with poor disease-free and overall survival. Multivariate analyses revealed that high RacGAP1 expression was an independent predictive marker for lymph node metastasis, recurrence, and poor prognosis in CRC. Conclusions: Our data provide novel evidence for the biological and clinical significance of RacGAP1 as a potential biomarker for identifying patients with lymph node metastasis and poor prognosis in CRC.
High-intensity focused ultrasound (HIFU) as salvage therapy for radio-recurrent prostate cancer: Predictors of disease response.
Authors: Shawn Dason, Christopher Brian Allard, Jen Hoogenes, William Orovan, Bobby Shayegan
Journal: Journal of Clinical Oncology (2016)

135 Background: Some patients with localized radio-recurrent prostate cancer (PCa) may have long-term recurrence-free (RFS) survival with salvage high-intensity focused ultrasound (HIFU). In this study, we describe our previously unreported oncologic outcomes and predictors of disease response after salvage HIFU. Methods: Participants were prospectively enrolled in this study from January 2005 to December 2014 if they had localized radio-recurrent prostate cancer. Participants had to meet both biochemical (PSA nadir+ 2ng/ml) and histologic (positive biopsy) definitions of recurrence. Study exclusion criteria included the receipt of prior salvage therapy, presence of metastastatic disease, and receipt of ADT in the 6-months prior to enrollment. Participants were treated with a single session of whole-gland HIFU ablation with the Ablatherm device (EDAP, France). The primary endpoint of this study was RFS, defined as a composite endpoint of PSA progression (PSA nadir + 2 ng/ml), receipt of any further salvage therapy, receipt of ADT, clinical progression, or death. Kaplan-Meier survival analysis was used to determine the primary end-point and stratifications were used to determine the significance of 6 pre-specified predictors of improved RFS (undetectable PSA nadir, low TRUS biopsy grade, &gt;3 TRUS biopsy cores positive, pre-HIFU PSA&lt;4ng/ml, receipt of prior ADT and presence of pre-HIFU palpable disease). Survival analysis was performed on participants with a minimum of 1-year follow-up. Results: Twenty-four participants were eligible for study inclusion with a median follow-up of 31.0 months. Median PSA at study entry was 4.02 ng/ml. Median time to PSA nadir was 3 months after treatment and median post-HIFU PSA nadir was 0.04 ng/ml. 2-year and 5-year RFS were 66.3% and 51.6% respectively. An undetectable PSA nadir was the only significant predictor of improved RFS (HR 0.07, 95% CI 0.02-0.29, log-rank P&lt;0.001). No participants developed a rectourethral fistula. Conclusions: Salvage HIFU allows for disease control in select patients with localized radio-recurrent prostate cancer. An undetectable PSA nadir serves as an early predictor of disease response.
Insulin-like growth factor (IGF) and epidermal growth factor (EGF) receptors as therapeutic targets in metastatic renal cell carcinoma.
Authors: J. E. Elkahwaji, R. J. Hauke
Journal: Journal of Clinical Oncology (2010)

e15113 Background: Renal cell carcinoma (RCC) is associated with mutation or loss of function of the von Hippel-Lindau gene resulting in hypoxia-inducible factor 1-alpha accumulation and production of growth factors involved in proliferation and angiogenesis. Radical nephrectomy remains the primary treatment option for two thirds of RCC patients who present with tumors confined to the kidney. However, approximately one half of patients will develop metastatic RCC. Treatment of RCC has been hampered by its resistance to most chemotherapy and hormonal therapy, although selected patients have long term remission from high dose of interleukin-2. Despite the recent availability of several active targeted agents in this disease, therapy is not curative. As a result, there is continued demand for improving therapy for metastatic disease to enhance both clinical benefits and patients overall survival. The EGF and IGF-1 pathways have been implicated as potential therapeutic targets in RCC. The objective of this study was to investigate the antitumor response to EGF and IGF inhibitors as a novel combination therapy in metastatic RCC. Methods: RCC cells lines (Caki-1 and Caki-2) were cultured in appropriate media supplemented with 10% FBS in a 5% CO2 incubator. Cells were treated for 24, 48, 72h, and 96h with different doses of EGFR (AG1478) and/or IGF-1R (AG1024) inhibitors (0-100 μM) given as single agent or in combination therapy. The epithelial cell proliferation was determined by AlamarBlue proliferation assay. Results: Both AG1478 and AG1024, given as single agent, decreased the epithelial cell proliferation of RCC human malignant cell lines (Caki-1 and Caki-2) (p<0.05). The inhibition occurred in a dose-dependent manner and was more pronounced at higher doses of AG1478 or AG1024 (100 μM), and when both agents were given as combination therapy. Conclusions: These data suggest that both inhibitors exhibit a synergistic antitumor effect when given as combination therapy. This synergistic benefit exhibits an anti-proliferative and pro-apoptotic effects on RCC cell lines in vitro and warrants further investigation as a potential therapeutic approach for metastatic RCC patients. No significant financial relationships to disclose.
Genomic profiling and efficacy of anti-EGFR therapy in appendiceal adenocarcinoma.
Authors: Maria Ignez Freitas Melro Braghiroli, Garrett Michael Nash, Martin Morris, Jaclyn Frances Hechtman, Efsevia Vakiani, Michael F. Berger, David B. Solit, Leonard Saltz, Andrea Cercek
Journal: Journal of Clinical Oncology (2016)

574 Background: Metastatic appendiceal adenocarcinoma (AAC) is a heterogenous disease and the majority of patients present with diffuse metastases in the peritoneal cavity. Cytotoxic and targeted therapies are typically extrapolated from colorectal adenocarcinoma (CRC), however, it is not known whether this is effective or not. Herein we investigated the genetic profiles of these tumors in an effort to identify molecular characteristics and potentially actionable mutations, as well as the response to anti-EGFR therapy in RAS/BRAF wild type (wt) AAC. Methods: We identified patients (pts) with ACC treated at MSKCC who had tumor who had undergone molecular profiling, either by next generation sequencing using our MSK-IMPACT platform, or by MALDI-TOF mass spectroscopy genotyping (Sequenom). MSK-IMPACT tumors and matched normal samples were analyzed either on 410 gene panel. Sequenom (provided an 8 gene panel including KRAS, NRAS, BRAF, and PIK3CA). Via an IRB approved waiver, we collected tumor histology and evaluated pts who were RAS/RAF wt and had been treated with anti-EGFR therapy. Results: We identified a total 97 AAC pts, of whom 60 had Sequenom testing and 37 had IMPACT. Among pts analyzed with IMPACT, 24 had mucinous adenocarcinoma, 3 adenocarcinoma with signet ring, 7 adenocarcinoma ex goblet cell carcinoid, 3 invasive adenocarcinoma. In total 159 alterations were identified with a median 4.2 alterations/patient (range 0-10). Alterations were seen most commonly in KRAS (21/37), GNAS (12/37), TP53 (10/37), SOX9 (5/37), and SMAD4 (4/37). Potentially treatable alterations were present in 15% of patients and included BRAF V600E (1), MTOR (2), ERBB2 (1) and NTRK(2). Of the total 97 pts, 50 (52%) were RAS/BRAF wt. Of those,13 evaluable patients received anti-EGFR therapy with either panitumumab or cetuximab. There were no responders. Conclusions: Mutational sequencing in AAC indicates that 16% have mutations in genes such as BRAFV600E, MTOR, ERBB2 and NTRK with the potential to expand investigational options through increased access to trials of selectively targeted agents. Additionally, in RAS/BRAF wt pts, panitumumab/cetuximab does not appear to have therapeutic efficacy comparable to historic controls in RAS/RAF wt CRC.
High-resolution array CGH of intermediate-risk prostate cancer genomes
Authors: A. Ishkanian, C. Malloff, J. Ho, T. van der Kwast, A. Meng, A. Syed, M. Albert, M. Milosevic, W. Lam, R. E. Bristow
Journal: Journal of Clinical Oncology (2008)

5158 Background: Prostate cancer is the most common cancer in men and the third leading cause of cancer deaths in North American males. Stratification into low, intermediate and high-risk disease reflects relative propensity for local and distant spread. PSA, Gleason score and T category often fail to predict biochemical recurrence in intermediate risk disease. Improving outcome in this subset requires additional molecular, prognostic and predictive factors. Sub-megabase tiling resolution (SMRT) array CGH is one assay capable of identifying novel markers in intermediate-risk disease. These markers may potentially provide a mechanism for predicting disease outcome. Methods: Fresh frozen needle biopsies obtained from 25 intermediate risk patients were selected for study. DNA was extracted from manually microdissected Gleason 6–7 cells. Genomic signatures were generated using SMRT array CGH. In house SeeGH software was used for visual interrogation of all array CGH profiles. Results: SMRT array CGH was performed on 25 intermediate risk fresh frozen needle biopsies. Reproducible array profiles were generated from separate sections of individual biopsies. Adjacent normal tissue DNA showed none of the changes found in Gleason 6–7 tissue. 283 DNA alterations were observed in our cohort, ranging from 4 to 28 with a mean of 12 per sample. The majority of alterations were single copy gains or losses. 81% of all alterations were losses. 20 alterations were found at frequencies of at least 20%. Known deletions included TMPRSS2:ERG and PTEN, and known amplifications included CMYC and 8p23.1–21.1. Six high frequency novel microdeletions were identified: 1q42.12-q42.3 (33.3%), 5q12.3–13.3 (21%), 20q13.32–13.33 (29.2%), 22q11.21 (25%), 22q12.1 (29.2%), and 22q13.31 (33.3%). Conclusions: SMRT array CGH can be used to assay minute amounts of prostate tissue microdissected from individual fresh frozen needle biopsies. This is the first successful application of this assay to intermediate risk prostate cancer. Reproducible genetic signatures were identified in this intermediate risk group. Multiple known regions of alteration and six novel regions of alteration were identified. Future studies require a larger sample set to potentially identify markers of clinical progression and/or treatment response. No significant financial relationships to disclose.
A phase II trial of metformin and fluorouracil (MetFU) for patients (pts) with metastatic colorectal cancer (mCRC) refractory to standard treatment.
Authors: Vanessa Costa Miranda, Luiza Dib Faria, Maria Ignez Freitas Melro Braghiroli, Monica Jacobs, Jorge Sabbaga, Paulo Marcelo Hoff, Rachel Pimenta Riechelmann
Journal: Journal of Clinical Oncology (2014)

601 Background: Pts with mCRC whose disease progressed after 5-FU, oxaliplatin, irinotecan and monoclonal antibodies have an unmet medical need. There is growing evidence suggesting an antitumoral effect of metformin in several tumor types, including CRC. Methods: Our primary objective was to evaluate the efficacy and safety of MetFU in heavily pretreated CRC pts with current progressive disease Last dose of 5-FU was administred at least 4 months prior to enrollment. Efficacy was defined as disease control rate at 8 weeks, using RECIST 1.1. Secondary endpoints were progression free survival, overall survival and tolerability. Single-arm Simon two-stage phase II trial was used. The treatment consisted of metformin 850 mg bid continuously plus 5-FU 425mg/m2 + Leucovorin (LV) 50 mg weekly for 4 weeks until disease progression, unacceptable toxicity or consent withdrawn in pts with mCRC who had progressed to conventional lines of treatment. Results: In the first stage, 22 pts were included: 12 pts (54%) were men, median age was 55 years and 59% were classified as an ECOG 1.14 pts faced treatment adverse events and 4 pts were excluded due to toxicity G3/4 - 2 pts had thrombocytopenia and 2 had limiting fatigue. Median time on treatment was 3.8 months, and 17 pts were evaluable for response: 6 pts (27%) had stable disease at 8 weeks as best response, with a median progression free survival (PFS) of 8.1 months. For the whole cohort, median overall survival was 5.6 months (IC95%: 3.1-8.2) and PFS was 2.0 months (IC95%: 1.8-2.3). Conclusions: Our results suggest that metformin may have antitumor activity when combined with 5-FU/LV in a subgroup of mCRC pts, with acceptable toxicity. It is unlikely that 5-FU alone had activity in these heavily treated pts. Clinical trial information: NCT01941953.