Targeted Therapy Protocols Research Articles

179P Developing the AI program for TNBC subtyping

Triple-negative breast cancer (TNBC) is a heterogeneous disease with poor prognosis and can be classified into different molecular subtypes. There is a need to develop a computer-aided diagnosis system with artificial intelligence (AI) techniques to increase the accuracy of evaluating suspicious breast lesions and identifying subtypes. A multi-gene analysis panel consisting of 14 genes and 2 reference genes was designed from the TCGA, and cBioportal datasets, which were determined in accordance with in silico analyses in 488 TNBC patients (TCGA:123, cBioportal:365). In the AI part of the study, a convolutional neural network model with 1,838,915 parameters was trained to classify Ultrasound (US) images as “normal, benign, malignant.” In the model, the images of the patients were trained with 1000 epochs. Expression levels of related genes in paraffin-embedded tumors and normal tissues of 38 patients with TNBC were investigated by the RT-PCR method. When the gene expression differences of the tumor and normal tissues of the patients were compared, AR (p=0.013), ER (p=0.025), PGR (p=0.007), FOXA1 (p=0.0154), CXCL11 (p=0.0037), IDO1 (p=0.0005), ADH1B (p=0.018), ADIPOQ (p<0.0001) and CHAD (p=0.0017) genes were found to have a statistically significant difference in expression compared to normal tissue. While no significant expression difference was detected in FOXC1 (p=0.3914), CXCL13 (p=0.2138), LAMP3 (p=0.2576), FGFR2 (p=0.077) and DHRS2 (p=0.715) genes. As a result, it was found that 68.5% of the patients showed a single subtype-specific expression profile (10 BLIA, 3 BLIS, 1 MES, and 12 LAR subtypes), and 31.5% of the patients showed an expression profile of more than one subtype. A random forest model was chosen among the trained models, and in the first stage, 81% accuracy was obtained in the subtyping of TNBC and 83% in the classification of US images. It sheds light on the heterogeneous structure and the role of molecular subtyping in the tumorigenesis of TNBC patients and may contribute to routine clinical practice and the regulation of targeted therapy protocols.

PD-L1 expression on immune cells, but not on tumor cells, is a favorable prognostic factor for patients with intrahepatic cholangiocarcinoma.

Cholangiocarcinoma, the second most common liver malignancy, after hepatocarcinoma is highly aggressive and usually diagnosed in advanced cases. In the era of personalized medicine, targeted therapy protocols are limited for cholangiocarcinoma and the only potential curative treatment, surgical resection, is seldom applicable.This retrospective study included all cases with pathology-confirmed intrahepatic cholangiocarcinoma admitted in a tertiary healthcare facility during a 10-year timeframe. Clinical information, laboratory values, imaging studies, and survival data were retrieved, and PD-L1 immunostaining was performed on representative pathology slides, for each case. From the total of 136 included cases (49 surgical resections and 87 liver biopsies), 38.97% showed PD-L1 positivity on tumoral cells, 34.8% on tumor infiltrating immune cells, 10.11% on epithelial cells within the peritumoral area and 15.95% on immune cells from the peritumoral area. Overall survival was significantly higher in the first two scenarios. However, after adjusting for age, tumor number, tumor size, and tumor differentiation in a multivariate analysis, only PD-L1 positivity on tumor infiltrating immune cells remained a favorable prognostic for survival. High immune cell counts also correlated with increased overall survival.Our study demonstrated that PD-1/PD-L1 checkpoint pathway in the microenvironment of intrahepatic cholangiocarcinoma bears prognostic significance. PD-L1 expression on immune cells, in both resection and biopsy specimens, might be a strong independent predictor for a favorable outcome.

Utilisation of semiconductor sequencing for detection of actionable fusions in solid tumours.

Oncogenic fusions represent compelling druggable targets in solid tumours highlighted by the recent site agnostic FDA approval of larotrectinib for NTRK rearrangements. However screening for fusions in routinely processed tissue samples is constrained due to degradation of nucleic acid as a result of formalin fixation., To investigate the clinical utility of semiconductor sequencing optimised for detection of actionable fusion transcripts in formalin fixed samples, we have undertaken an analysis of test trending data generated by a clinically validated next generation sequencing platform designed to capture 867 of the most clinically relevant druggable driver-partner oncogenic fusions. Here we show across a real-life cohort of 1112 patients with solid tumours that actionable fusions occur at high frequency (7.4%) with linkage to a wide range of targeted therapy protocols including seven fusion-drug matches with FDA/EMA approval and/or NCCN/ESMO recommendations and 80 clinical trials. The more prevalent actionable fusions identified were independent of tumour type in keeping with signalling via evolutionary conserved RAS/RAF/MEK/ERK, PI3K/AKT/MTOR, PLCy/PKC and JAK/STAT pathways. Taken together our data indicates that semiconductor sequencing for detection of actionable fusions can be integrated into routine diagnostic pathology workflows enabling the identification of personalised treatment options that have potential to improve clinical cancer management across many tumour types.

Utilisation of semiconductor sequencing for the detection of predictive biomarkers in glioblastoma.

The standard treatment for glioblastoma involves a combination of surgery, radiation and chemotherapy but have limited impact on survival. The exponential increase in targeted agents directed at pivotal oncogenic pathways now provide new therapeutic opportunities for this tumour type. However, lack of comprehensive precision oncology testing at diagnosis means such therapeutic opportunities are potentially overlooked. To investigate the role of semiconductor sequencing for detection of predictive biomarkers in routine glioblastoma samples we have undertaken analysis of test trending data generated by a clinically validated next generation sequencing platform designed to capture actionable genomic variants distributed across 505 genes. Analysis was performed across a cohort of 55 glioblastoma patients. Analysis of trending data has revealed a complex and rich actionable mutational landscape in which 166 actionable mutations were detected across 36 genes linked to 17 off label targeted therapy protocols and 111 clinical trials. The majority of patients harboured three or more actionable mutations affecting key cancer related regulatory networks including the PI3K/AKT/MTOR and RAS/RAF/MEK/MAPK signalling pathways, DNA-damage repair pathways and cell cycle checkpoints. Linkage with immunotherapy and PARP inhibitors was identified in 44% of glioblastoma patients as a consequence of alterations in DNA-damage repair genes. Taken together our data indicates that precision oncology testing utilising semiconductor sequencing can be used to identify a broad therapeutic armamentarium of targeted therapies and immunotherapies that can be potentially employed for the improved clinical management of glioblastoma patients.

Abstract 16: Presentation and Management of Egyptian Female Breast Cancer In Alexandria, Egypt: An Implementation Study

Abstract Purpose: Exploration of the population profile and management of female breast cancer in a representative sample from Alexandria, Egypt, to identify system inefficiencies and barriers preventing full implementation of international guidelines, negatively impacting the outcome. Methods: The study surveyed 7125 records from three major public oncology services at Main University Hospital, Gamal Abd-elnasser Hospital and Ayadi Almostakbel Oncology Center, between 2007 and 2016. Results: 73.4% (5236 records) of the records contained usable information. The median age was 54 years, with positive family history in 31.5%. The median duration of complaint before diagnosis was 3.1 months (IQR 1.6-7.5). 55.2% were early stage, 37.6% were locally advanced and 7.2% were stage IV. Breast surgery was performed for 4976 cases. Axillary surgery was done for 4945 cases. Most cases were hormone receptor positive. 15.3% were HER2 positive. The median duration to start chemotherapy was 1.03 months (IQR 0.7-1.6). Adjuvant chemotherapy was given to 3667 and neoadjuvant chemotherapy was given to 333. Anthracycline-based combination chemotherapy, with or without Taxanes was the commonest. 86% received hormonal treatment. 180/317 trastuzumab-eligible patients received trastuzumab. 69.5% started radiotherapy &amp;gt; 6 months from presentation. Conventionally and hypofractionated regimens were used in 46.6% and 53.5%, respectively. 1109 developed relapse (local in 155, distant in 130 and 794 had both). In non-metastatic cases, median overall and disease free survivals were 149.1 and 77.1 months respectively. In metastatic cases, the median progression free survival was 19.6 months. Conclusion: The study revealed defects in the record system, delayed diagnosis and treatment, and inadherence to targeted therapy protocols in a significant part of eligible patients. Suggested implementation strategies include promotion of national or hospital based registries, information, education and communication with target populations and health carers, establishing a patient navigation system and monitoring outcomes of the interventions. Citation Format: Yousri Rostom, Salah Abdelmonem, Marwa Shaker, Nayera Mahmoud, Nevine Labib, Abdelsalam A. Ismail, Maher Soliman. Presentation and Management of Egyptian Female Breast Cancer In Alexandria, Egypt: An Implementation Study [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 16.

Copper: An Intracellular Achilles' Heel Allowing the Targeting of Epigenetics, Kinase Pathways, and Cell Metabolism in Cancer Therapeutics.

Copper is an essential transition metal frequently increased in cancer known to strongly influence essential cellular processes. Targeted therapy protocols utilizing both novel and repurposed drug agents initially demonstrate strong efficacy, before failing in advanced cancers as drug resistance develops and relapse occurs. Overcoming this limitation involves the development of strategies and protocols aimed at a wider targeting of the underlying molecular changes. Receptor Tyrosine Kinase signaling pathways, epigenetic mechanisms and cell metabolism are among the most common therapeutic targets, with molecular investigations increasingly demonstrating the strong influence each mechanism exerts on the others. Interestingly, all these mechanisms can be influenced by intracellular copper. We propose that copper chelating agents, already in clinical trial for multiple cancers, may simultaneously target these mechanisms across a wide variety of cancers, serving as an excellent candidate for targeted combination therapy. This review summarizes the known links between these mechanisms, copper, and copper chelation therapy.

Druggable fusion gene landscape in solid tumors.

e13517 Background: Kinases activated by gene fusions represent an important class of oncogenes in solid tumors highlighted by the unique site agnostic FDA approval of larotrectinib for NTRK gene rearrangements. However, the frequency and types of druggable fusions in solid tumors are not well characterized from the clinical perspective. Methods: Oncofocus is a clinically validated precision oncology platform that includes analysis of 399 druggable driver-partner oncogenic fusion genes linked to 140 unique targeted therapy protocols. A retrospective analysis of Oncofocus trending data in a real-life cohort of 1111 patients has been used to determine the actionable fusion gene landscape in solid tumors. Results: Eighty nine actionable fusion genes were identified in 1111 samples of solid tumors linked to 73 targeted therapy protocols. Seven of the samples harbored multiple fusion genes. Eighty two of the 1111 samples tested had at least one actionable fusion gene representing a frequency of 7.38%. The highest frequency of actionable fusions were observed in glioblastoma (23%), head and neck (12%), kidney (11%) and prostate (10%) cancers. Four of the seven samples with multiple actionable fusions were found in glioblastoma. Pancreatic, lung and endometrial cancers and cancer of unknown primary (CUPs) had an actionable fusion gene frequency ranging from 7-9%. TBL1XR1-PIK3CA, MET-MET, WHSC1L1-FGFR1 and EGFR VIII fusions were identified as the most common druggable fusions. All actionable fusion genes were found to interact with one or more of the following pathways RAS/RAF/MEK/ERK, PI3K/AKT/MTOR, PLCy/PKC and JAK/STAT. Although a targeted agent for TRK fusions now has FDA approval, this rearrangement appears to be a rare event. In contrast, inhibitors targeting the TBL1XR1-PIK3CA, MET-MET, WHSC1L1-FGFR1 fusions and linked downstream signalling pathways appear to offer much broader clinical utility. Conclusions: Druggable fusions were identified at an unexpectedly high frequency and should therefore be included as part of routine comprehensive precision oncology testing. Notably, many of the actionable fusions are not tumor type specific reinforcing the “site agnostic” approach to profiling and supporting the concept of “molecular basket” clinical trials. Precision oncology trending data also provides actionable mutational landscapes which can be used to refine precision oncology testing, patient selection for targeted therapy protocols and enhancement of clinical trial design.

The actionable genomic mutational landscape in solid tumours.

e13642 Background: The recent exponential increase in targeted agents and immunotherapies provide new therapeutic opportunities for patients with advanced cancers who have failed first line therapy. However, lack of comprehensive precision oncology testing as part of routine pathology assessment means potential therapeutic opportunities are difficult to identify or remain undiscovered for many patients. Methods: To address this unmet clinical need we established Oncofocus, a clinically validated, ISO15189/2012 and CLIA accredited, precision oncology test optimized for analysis of small diagnostic PWET clinical biopsy samples (sample acceptance 94%). Oncofocus detects actionable genetic variants in 505 genes linked to 764 anti-cancer targeted therapy protocols, either on-market FDA and EMA approved, carrying ESMO and NCCN guideline references or currently in clinical trials. Oncofocus trending data was analyzed for a real-life cohort of 1111 patients with the aim of determining the frequency of actionable mutations in this population. This cohort represent patients with advanced stage disease who underwent Oncofocus testing having failed first line treatment protocols. Results: Analysis of trending data revealed a complex mutational landscape in which 90% of solid tumors harbored actionable mutations. The majority of patients harbored one or more actionable mutations (median 2, range 0-13) affecting key cancer related regulatory networks including the PI3K/AKT/MTOR and RAS/RAF/MEK/MAPK signaling pathways, DNA-damage repair pathways and cell cycle checkpoints. Actionable genetic variants across 33 DNA Damage and Repair (DDR) genes were identified in 30% of tumors. Using a defined predictive cut point of &gt; 10% for tumor proportion score, PD-L1 expression levels were significantly raised in 19% of cases. Abrogation of DDR function and elevated PD-L1 levels were identified in 5% of patients, a subpopulation potentially more responsive to immunotherapy. Notably, many of the actionable mutations identified did not show linkage with histological type or site of origin. Conclusions: Our data indicates that comprehensive precision oncology testing should be strongly considered as part of the diagnostic work up for all patients with advanced cancers, independent of tumor type, thereby ensuring capture of all targeted therapy opportunities and accelerating “site agnostic” molecular basket clinical trials. Comprehensive precision oncology testing was performed successfully on routine biopsy samples circumventing the requirement for fresh tissue or large sample specimens.

Infusion Therapy Optimization in Selective Abdominal Surgery

Purpose. Evaluation of the influence of intra-operative targeted infusion therapy managed by the monitoring of stroke volume variability on post-operative results of major surgeries of gastrointestinal organs.Materials and Methods. The prospective study included 80 patients subjected to selective operative interventions of abdominal organs involving entero-enteroanastomosis. In the experimental group (n=39), the infusion therapy was conducted according to the developed targeted therapy protocol, of which the key parameter was stroke volume variability. In the control group (n=41), infusion therapy was conducted based on routine hemodynamic monitoring (average arterial pressure, heart rate, blood loss level with regard to intra-operative situation). In both groups, operative intervention was carried out in identical conditions (combined anesthesia, identical drugs to induce and maintain anesthesia); the only differences included infusion therapy.Results. In the experimental group versus the control group the intra-operative infusion volume was smaller, the number of patients with complications and the total number of complications were reliably lower, and the gastrointestinal tract functional recovery occurred earlier. Conclusion. A targeted infusion therapy based on a stroke volume variability monitoring as the key parameter allows optimizing the infusion load and facilitates reduction of the number of patients with complications and earlier recovery of gastrointestinal tract functions after major operative abdominal interventions.

Pre-radiation chemotherapy improves survival in pediatric diffuse intrinsic pontine gliomas.

The median survival of patients with diffuse intrinsic pontine glioma (DIPG) remains less than 1year. The BSG 98 pre-irradiation chemotherapy protocol showed a significant increase in overall survival. In contrast to current treatment strategies, patients did not have to undergo surgical stereotactic biopsy, which can sometimes lead to complications, to be included in this protocol. We retrospectively reviewed all the cases of DIPG that were treated in our department from September 15, 2004 to September 15, 2014. We compared the group of patients who followed our BSG 98 protocol to those who were treated with new targeted therapy protocols where systematic biopsy was required. Patients in the BSG 98 protocol were treated with BCNU, cisplatin, and methotrexate, followed by radiation at disease progression. Targeted therapy protocols included radiation therapy along with treatment by erlotinib, cilengitide, or an association of nimotuzumab and vinblastine. Sixteen patients were treated with the BSG 98 protocol, and 9 patients were treated with new targeted therapy protocols. Median overall survival was significantly higher in the BSG 98 group compared to the targeted therapy group (16.1months (95% CI, 10.4-19.0) vs 8.8months (95% CI 1.4-12.3); p = 0.0003). An increase in the median progression-free survival was observed (respectively, 8.6 vs 3.0months; p = 0.113). The present study confirms that the BSG 98 protocol is one of the most effective current treatment strategies for DIPG. It may be used as the control arm in randomized trials investigating the use of innovative treatments and may be proposed to families who are averse to biopsy.

YKL-40/c-Met Expression in Rectal Cancer Biopsies Predicts Tumor Regression following Neoadjuvant Chemoradiotherapy: A Multi-Institutional Study

BackgroundNeoadjuvant chemo-radiotherapy (CRT) followed by surgical resection is the standard treatment for locally advanced rectal cancer, although complete tumor pathological regression is achieved in only up to 30% of cases. A clinicopathological and molecular predictive stratification of patients with advanced rectal cancer is still lacking. Here, c-Met and YKL-40 have been studied as putative predictors of CRT response in rectal cancer, due to their reported involvement in chemoradioresistance in various solid tumors.Material and MethodsA multicentric study was designed to assess the role of c-Met and YKL-40 expression in predicting chemoradioresistance and to correlate clinical and pathological features with CRT response. Immunohistochemistry and fluorescent in situ hybridization for c-Met were performed on 81 rectal cancer biopsies from patients with locally advanced rectal adenocarcinoma. All patients underwent standard (50.4 gy in 28 fractions + concurrent capecitabine 825 mg/m2) neoadjuvant CRT or the XELOXART protocol. CRT response was documented on surgical resection specimens and recorded as tumor regression grade (TRG) according to the Mandard criteria.ResultsA significant correlation between c-Met and YKL-40 expression was observed (R = 0.43). The expressions of c-Met and YKL-40 were both significantly associated with a lack of complete response (86% and 87% of c-Met and YKL-40 positive cases, p< 0.01 and p = 0.006, respectively). Thirty of the 32 biopsies co-expressing both markers had partial or absent tumor response (TRG 2-5), strengthening their positive predictive value (94%). The exclusive predictive role of YKL-40 and c-Met was confirmed using a multivariate analysis (p = 0.004 and p = 0.007 for YKL-40 and c-Met, respectively). TRG was the sole morphological parameter associated with poor outcome.Conclusionc-Met and YKL-40 expression is a reliable predictor of partial/absent response to neoadjuvant CRT in rectal cancer. Targeted therapy protocols could take advantage of prior evaluations of c-MET and YKL-40 expression levels to increase therapeutic efficacy.

MP47-20 IDENTIFICATION OF ACTIONABLE TARGETS IN CHROMOPHOBE RENAL CELL CARCINOMA DETECTED BY MULTIPLATFORM MOLECULAR ANALYSIS

You have accessJournal of UrologyKidney Cancer: Basic Research II1 Apr 2015MP47-20 IDENTIFICATION OF ACTIONABLE TARGETS IN CHROMOPHOBE RENAL CELL CARCINOMA DETECTED BY MULTIPLATFORM MOLECULAR ANALYSIS Philip Abbosh, Sherri Millis, Nancy Doll, Adam Hauben, Sandeep Reddy, Daniel Geynisman, and Robert Uzzo Philip AbboshPhilip Abbosh More articles by this author , Sherri MillisSherri Millis More articles by this author , Nancy DollNancy Doll More articles by this author , Adam HaubenAdam Hauben More articles by this author , Sandeep ReddySandeep Reddy More articles by this author , Daniel GeynismanDaniel Geynisman More articles by this author , and Robert UzzoRobert Uzzo More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.1540AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Chromophobe renal cell carcinoma (chRCC) is a rare kidney cancer subtype that infrequently metastasizes or recurs after definitive local therapy. Limited biomarker data exists to prognosticate outcome or predict response to therapy. We explored the utility of a CLIA-certified biomarker panel which uses immunohistochemistry (IHC) and targeted next generation sequencing (tNGS) to assess presence of druggable targets with the intent of developing targeted therapy protocols in patients with (chRCC). Because of the non-aggressive nature of small chRCCs, we excluded T1a tumors. METHODS Cases were identified from 65,000+ tumors submitted for commercial testing at Caris Life Sciences. All tissues were internally reviewed by a dedicated genitourinary pathologist to confirm diagnosis. Markers were analyzed on tumor tissue removed during partial or radical nephrectomy. IHC was performed on 19 proteins. FISH was performed on EGFR, HER2, and TOP2A. tNGS was performed on 47 genes. RESULTS Twelve patients with chRCC underwent biomarker panel testing. Five patients had metastatic disease. Median age was 54 years old; 50% of patients were male. One patient had a T1b tumor, two patients had T2 tumors, 8 patients had T3 tumors, and one had a T4 tumor. Thymidylate synthase (TS), ribonucleotide reductase M1 (RRM1), and O-6-methylguanine-DNA methyltransferase (MGMT) expression was absent in 12/12, 11/12 and 11/12 tumors, respectively. PTEN expression was absent in 7/12 of tumors. cKIT and PDGFR was expressed in 6/9 and 0/4 tumors, respectively. Lastly, point mutations in APC and TP53 were detected in 1/7 and 3/7 tumors, respectively. No mutations were identified in the other 45 genes tested and no changes in copy number were identified. CONCLUSIONS Biomarker analysis showed that advanced chRCC might be amenable to chemotherapy with 5-fluorouracil, gemcitabine, or temozolamide because of absent TS, RRM1, and MGMT expression, respectively. Such rationale has been used successfully in targeted treatment of other cancers. In addition, sunitinib or imatinib but not sorafenib might be preferred tyrosine kinase inhibitors, as cKIT but not PDGFR was detected. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e559 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Philip Abbosh More articles by this author Sherri Millis More articles by this author Nancy Doll More articles by this author Adam Hauben More articles by this author Sandeep Reddy More articles by this author Daniel Geynisman More articles by this author Robert Uzzo More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Identification of actionable targets in chromophobe renal cell carcinoma detected by multiplatform molecular analysis.

451 Background: Chromophobe renal cell carcinoma (chRCC) is a rare kidney cancer subtype that infrequently metastasizes or recurs after definitive local therapy. Limited biomarker data exists to prognosticate outcome or predict response to therapy. We explored the utility of multiplatform tumor profiling, which uses immunohistochemistry (IHC) and targeted next generation sequencing (tNGS) to identify druggable targets, with the intent of developing targeted therapy protocols in patients with (chRCC). Because of the non-aggressive nature of small chRCCs, we excluded T1a tumors. Methods: Cases were identified from 65,000+ tumors submitted for commercial testing at Caris Life Sciences. All tissues were internally reviewed by a dedicated genitourinary pathologist to confirm diagnosis. Markers were analyzed on tumor tissue removed during partial or radical nephrectomy. IHC was performed on 19 proteins. FISH was performed on EGFR, HER2, and TOP2A. tNGS was performed on 47 genes. Results: Twelve patients with chRCC were profiled. Five patients had metastatic disease. Median age was 54 years old; 50% of patients were male. One patient had a T1b tumor, two patients had T2 tumors, 8 patients had T3 tumors, and one had a T4 tumor. Thymidylate synthase (TS), ribonucleotide reductase M1 (RRM1), and O-6-methylguanine-DNA methyltransferase (MGMT) expression was absent in 12/12, 11/12 and 11/12 tumors, respectively. PTEN expression was absent in 7/12 of tumors. cKIT and PDGFR was expressed in 6/9 and 0/4 tumors, respectively. Lastly, point mutations in APC and TP53 were detected in 1/7 and 3/7 tumors, respectively. No mutations were identified in the other 45 genes tested and no changes in copy number were identified. Conclusions: Biomarker analysis showed that advanced chRCC might be amenable to chemotherapy with 5-fluorouracil, gemcitabine, or temozolamide because of absent TS, RRM1, and MGMT expression, respectively. Such rationale has been used successfully in targeted treatment of other cancers. In addition, sunitinib or imatinib but not sorafenib might be preferred tyrosine kinase inhibitors, as cKIT but not PDGFR was detected.

Wnt-/-β-catenin pathway signaling in human hepatocellular carcinoma.

The molecular basis of the carcinogenesis of hepatocellular carcinoma (HCC) has not been adequately clarified, which negatively impacts the development of targeted therapy protocols for this overwhelming neoplasia. The aberrant activation of signaling in the HCC is primarily due to the deregulated expression of the components of the Wnt-/-β-catenin. This leads to the activation of β-catenin/T-cell factor-dependent target genes that control cell proliferation, cell cycle, apoptosis, and cell motility. The deregulation of the Wnt pathway is an early event in hepatocarcinogenesis. An aggressive phenotype was associated with HCC, since this pathway is implicated in the proliferation, migration, and invasiveness of cancer cells, regarding the cell's own survival. The disruption of the signaling cascade Wnt-/-β-catenin has shown anticancer properties in HCC's clinical evaluations of therapeutic molecules targeted for blocking the Wnt signaling pathway for the treatment of HCC, and it represents a promising perspective. The key to bringing this strategy in to clinical practice is to identify new molecules that would be effective only in tumor cells with aberrant signaling β-catenin.

Abstract C143: Overcoming melanoma dual resistance to Vemurafenib and adoptive immunotherapy by chromatin remodeling drug.

Abstract BRAFV600E-inhibitors (BRAFi) and modern immune-based therapies have significantly improved the care of melanoma patients. We developed an in vitro model to determine whether tumor resistance mechanisms to this small molecule inhibitor of a driver oncogene and to cytotoxic T lymphocyte (CTL)-delivered apoptotic death signals were exclusive or intersecting. We generated melanoma sublines resistant to BRAFi Vemurafenib and to CTL recognizing the MART-1 melanoma antigen. Vemurafenib-resistant (VemR) sublines were cross-resistant to MART CTL indicating a common apoptotic pathway governing response to both modalities was disrupted. Pretreatment of VemR melanomas with a histone deacetylase inhibitor (HDACi) restored sensitivity to MART CTL apoptosis. These findings suggest that aberrant apoptotic pathways, amenable by a chromatin remodeling drug, regulate tumor resistance mechanisms and identify potential obstacles and solutions for combining these therapies clinically. TModulation of apoptotic machinery by inclusion of HDACi in BRAFV600E targeted therapy protocols as adjuvant will sensitize VemR (also CTL cross-resistant) human melanomas to immunotherapy. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C143. Citation Format: Ali R. Jazirehi, Ramin Nazarian, Antonio Javier Toress-Collado, James S. Economou. Overcoming melanoma dual resistance to Vemurafenib and adoptive immunotherapy by chromatin remodeling drug. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C143.

A snapshot of microarray-generated gene expression signatures associated with ovarian carcinoma

It was hypothesized that analysis of global gene expression in ovarian carcinoma can identify dysregulated genes that can serve as molecular markers and provide further insight into carcinogenesis and provide the basis for development of new diagnostic tools as well as new targeted therapy protocols. By applying bioinformatics tools for screening of biomedical databases, a gene expression profile databank, specific for ovarian carcinoma, was constructed with utilizable data sets published in 28 studies that applied different array technology platforms. The data sets were divided into four compartments: (i) genes associated with carcinogenesis: in 14 studies, 1881 genes were extracted, 75 genes were identified in more than one study, and only 4 genes (PRKCBP1, SPON1, TACSTD1, and PTPRM) were identified in three studies. (ii) Genes associated with histologic subtypes: in four studies, 463 genes could be identified, but none of them was identified in more than a single study. (iii) Genes associated with therapy response: in seven studies, 606 genes were identified from which 38 were differentially regulated in at least two studies, 3 genes (TMSB4X, GRN, and TJP1) in three studies, and 1 gene (IFITM1) in four studies. (iv) Genes associated with prognosis and progression: 254 genes were found in seven studies. From these genes, merely three were identified in at least two different studies. This snapshot of available gene expression data not only provides independently described potential diagnostic and therapeutic targets for ovarian carcinoma but also emphasizes the drawbacks of the current state of global gene expression analyses in ovarian cancer.

New perspectives on metastatic patterns in lung cancer: The M. D. Anderson thoracic medical oncology database

7630 Background: We previously reported a retrospective study suggesting that sites of metastatic disease characterize distinct prognostic groups with non-small cell lung cancer (NSCLC) (ASCO 2005 Abstract No: 7197). To confirm these observations, we prospectively evaluated pts with newly diagnosed NSCLC to correlate extent of disease with survival. Methods: We developed a prospective comprehensive database of 2,487 pts registered in the Thoracic Medical Oncology Department from 9/1/2004 - 8/31/2006, with up to 845 days follow-up. 694 were untreated stage IV NSCLC pts with data for ECOG performance status (PS), TNM staging, histology, identification of all metastatic sites, and survival. Results: Bone was the most common metastatic site, affecting 280 pts, 114 having bone only metastases (280/114). Similarly, the following results were found for lung (261/137), brain (143/46), adrenal (112/36), and liver (98/31). PS = 0 (101), PS = 1 (329), PS = 2 (103), PS = 3 (74), PS = 4 (10), PS = unknown (77). As of January 2007, median survival for the group was 8 months. By the Cox regression model, statistically significant effects on overall survival were seen for gender, smoking status, age, performance status, and number of metastases. The following hazard ratios [with 95% CI] of death were seen for males vs. females 1.41 ([1.13, 1.75], p = 0.0025), former smokers vs. non-smokers 1.66 ([1.18, 2.31], p = 0.0032), active smokers vs. non-smokers 1.79 ([1.21, 2.64], p = 0.0036), for one year increase in age 1.02 ([1.00, 1.03], p = 0.0046), for one unit increase in performance status 1.63 ([1.45, 1.82], p &lt; 0.0001) and for one unit increase in number of metastases 1.48 ([1.32, 1.66], p &lt; 0.0001). Pts with one metastatic site had superior survival over pts with more sites. Six of 10 metastatic sites were found to have significant independent effects on overall survival, based on log-rank test. Conclusions: Number and sites of metastases were strong independent determinants of survival in NSCLC. Furthermore, our work suggests marked heterogeneity of metastatic patterns at presentation. Pts with fewer metastatic sites demonstrate better survival. Future targeted therapy protocols should stratify according to metastatic sites to better analyze patterns of failure and outcomes. No significant financial relationships to disclose.

Effective ICP Reduction by Decompressive Craniectomy in Patients with Severe Traumatic Brain Injury Treated by an ICP-Targeted Therapy

Severe traumatic brain injury (TBI) is one of the major causes of death in younger age groups. In Umeå, Sweden, an intracranial pressure (ICP) targeted therapy protocol, the Lund concept, has been used in treatment of severe TBI since 1994. Decompressive craniectomy is used as a protocol-guided treatment step. The primary aim of the investigation was to study the effect of craniectomy on ICP changes over time in patients with severe TBI treated by an ICP-targeted protocol. In this retrospective study, all patients treated for severe TBI during 1998-2001 who fulfilled the following inclusion criteria were studied: GCS <or= 8 at intubation and sedation, first recorded cerebral perfusion pressure (CPP) of >10 mm Hg, arrival within 24 h of trauma, and need of intensive care for >72 h. Craniectomy was performed when the ICP could not be controlled by evacuation of hematomas, sedation, ventriculostomy, or low-dose pentothal infusion. Ninety-three patients met the inclusion criteria. Mean age was 37.6 years. Twenty-one patients underwent craniectomy as a treatment step. We found a significant reduction of the ICP directly after craniectomy, from 36.4 mm Hg (range, 18-80 mm Hg) to 12.6 mm Hg (range, 2-51 mm Hg). During the following 72 h, we observed an increase in ICP during the first 8-12 h after craniectomy, reaching approximately 20 mm Hg, and later levelling out at approximately 25 mm Hg. The reduction of ICP was statistically significant during the 72 h. The outcome as measured by Glasgow Outcome Scale (GOS) did not significantly differ between the craniectomized group (DC) and the non-craniectomized group (NDC). The outcome was favorable (GOS 5-4) in 71% in the craniectomized group, and in 61% in the non-craniectomized group. Craniectomy is a useful tool in achieving a significant reduction of ICP overtime in TBI patients with progressive intracranial hypertension refractory to medical therapy. The procedure seems to have a satisfactory effect on the outcome, as demonstrated by a high rate of favorable outcome and low mortality in the craniectomized group, which did not significantly differ compared with the non-craniectomized group.