Types Of Advanced Cancer Research Articles

Methods of measurement for tumor mutational burden in tumor tissue

Immunotherapies based on immune checkpoint inhibitors are emerging as an innovative treatment for different types of advanced cancers. While the utility of immune checkpoint inhibitors has been clearly demonstrated, the response rate is highly variable across individuals. Due to the cost and toxicity of these immunotherapies, a critical challenge in this field is the identification of predictive biomarkers to discriminate which patients may respond to immunotherapy. Recently, a high tumor mutational burden (TMB) has been identified as a genetic signature that is associated with a favorable outcome for immune checkpoint inhibitor therapy. The TMB is defined as the total number of nonsynonymous mutations per coding area of a tumor genome. Initially, it was determined using whole exome sequencing, but due to the high costs and long turnaround time of this method, targeted panel sequencing is currently being explored to measure TMB. In the near future, TMB evaluation may play an important role in immuno-oncology, but its implementation in a routine setting involves robust analytical and clinical validation. Standardization is also needed in order to make informed decisions about patients. This review presents the methodologies employed for determining TMB and discusses the factors that may have an impact on its measurement.

378P - Circulating cell-free DNA molecular profiling among east Asian patients reveals activating MET alterations are common in diverse advanced cancer types

378P - Circulating cell-free DNA molecular profiling among east Asian patients reveals activating MET alterations are common in diverse advanced cancer types

Liver Toxicity with Cancer Checkpoint Inhibitor Therapy.

Immune checkpoint inhibition targeted against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) has shown clinically significant survival benefit when used to treat multiple types of advanced cancer. These drugs have gained approval by the US Food and Drug Administration and their indications continue to increase. Checkpoint inhibitor therapy is associated with a unique side-effect profile characterized as immune-related adverse events (irAEs), which can result in significant morbidity and rarely mortality. Hepatotoxicity from checkpoint inhibitors is a less common irAE and often mild, while its incidence and severity vary based on the class and dose of checkpoint inhibitor, monotherapy versus combination therapy, and the type of cancer. Histological assessment of suspected irAEs is nonspecific and can show a variety of features. Hepatic irAEs can require discontinuation of checkpoint inhibitor therapy and treatment with immunosuppressive agents.

Clinical utility of 188Rhenium-hydroxyethylidene-1,1-diphosphonate as a bone pain palliative in multiple malignancies

188Rhenium-hydroxyethylidene-1,1-diphosphonate (188Re-HEDP) is a clinically established radiopharmaceutical for bone pain palliation of patients with metastatic bone cancer. Herein, the effectiveness of 188Re-HEDP for the palliation of painful bone metastases was investigated in an uncontrolled initial trial in 48 patients with different types of advanced cancers. A group of 48 patients with painful bone metastases of lung, prostate, breast, renal, and bladder cancer was treated with 2.96–4.44 GBq of 188Re-HEDP. The overall response rate in this group of patients was 89.5%, and their mean visual analog scale score showed a reduction from 9.1 to 5.3 (P < 0.003) after 1 week posttherapy. The patients did not report serious adverse effects either during intravenous administration or within 24 h postadministration of 188Re-HEDP. Flare reaction was observed in 54.2% of patients between day 1 and day 3. There was no correlation between flare reaction and response to therapy (P < 0.05). Although bone marrow suppression was observed in patients receiving higher doses of 188Re-HEDP, it did not result in any significant clinical problems. The present study confirmed the clinical utility and cost-effectiveness of 188Re-HEDP for palliation of painful bone metastases from various types of cancer in developing countries.

Medical Care Costs for Recurrent versus De Novo Stage IV Cancer by Age at Diagnosis.

To address the knowledge gap regarding medical care costs for advanced cancer patients, we compared costs for recurrent versus de novo stage IV breast, colorectal, and lung cancer patients. Virtual Data Warehouse (VDW) information from three Kaiser Permanente regions: Colorado, Northwest, and Washington. We identified patients aged ≥21 with de novo or recurrent breast (ndenovo =352; nrecurrent =765), colorectal (nde novo =1,072; nrecurrent =542), and lung (nde novo =4,041; nrecurrent =340) cancers diagnosed 2000-2012. We estimated average total monthly and annual costs in the 12months preceding, month of, and 12months following the index de novo/recurrence date, stratified by age at diagnosis (<65, ≥65). Generalized linear repeated-measures models controlled for demographics and comorbidity. In the pre-index period, monthly costs were higher for recurrent than for de novo breast (<65: +$2,431; ≥65: +$1,360), colorectal (<65: +$3,219; ≥65: +$2,247), and lung cancer (<65: +$3,086; ≥65: +$2,260) patients. Conversely, during the index and post-index periods, costs were higher for de novo patients. Average total annual pre-index costs were five- to ninefold higher for recurrent versus de novo patients <65. Cost differences by type of advanced cancer and by age suggest heterogeneous patterns of care that merit further investigation.

Abstract 586: Sera levels of the immunomodulatory protein the progesterone induced blocking factor (PIBF) are not useful in determining which patients with non-small cell lung cancer will respond to progesterone receptor modulators, e.g., mifepristone

Abstract Human leukemia cancer cell line studies have demonstrated the presence of a 34 kDa intracytoplasmic splice variant of the parent 90 kDa nuclear protein associated with the centrosome that has significant immunosuppressive activity, especially, but not limited to natural killer (NK) cells. One mechanism of suppressing NK cell cytotoxicity is by stabilizing perforin granules. The 34 kDa intracytoplasmic isoform has been shown to be present only in rapidly growing cells, e.g., embryonic, mesenchymal, trophoblast, and cancer cells. During the luteal phase in ovulating women, and throughout pregnancy, there is a rise in the serum level of this immunomodulatory protein. Thus, it is called the progesterone induced blocking factor (PIBF). Interestingly, the abortafacient, mifepristone, has been shown to suppress the 34 kDa intracytoplasmic concentration of PIBF in cancer cell lines, but it does not lower serum PIBF. Based on the demonstration of significant increase in quality and length of life in controlled animal studies, and anecdotal experience in compassionate use treatment of human patients with a variety of advanced cancer types, the FDA has granted an investigator initiated salvage study of 40 patients with advanced non-small cell lung cancer (NSCLC) who have failed a minimum of two rounds of chemo or immunotherapy to be treated with single agent oral mifepristone (www.clinicaltrials.gov). The first 2 patients are doing extremely well (2 years and 1 year so far) with a high quality life without significant disease progression. Sera PIBF levels were obtained on these patients every 2 months using an experimental ELISA assay. For patient 1, a man with stage IV NSCLC with brain metastasis, his PIBF levels (ng/ml) were all in the range of normal males and women in the follicular phase (27, 38, 53, 59, 52, 46, 39, 45, 44, and 49). For patient 2, who is a female positive for the PD-L1 marker, and who progressed despite 3 rounds of chemotherapy and 1 round of nivolumab, her levels were 10, 30, 12, 21, 23, 50, 64, and 30. Thus, these results suggest that measuring serum PIBF levels in patients with very advanced NSCLC has little value in determining which patients will respond to the progesterone receptor modulator mifepristone, or be able to monitor their response to progesterone receptor modulator therapy. Citation Format: Jerome H. Check, Diane Check, Maya Srivastava, Ann DiAntonio. Sera levels of the immunomodulatory protein the progesterone induced blocking factor (PIBF) are not useful in determining which patients with non-small cell lung cancer will respond to progesterone receptor modulators, e.g., mifepristone [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 586.

Extracellular vesicles exposing tissue factor for the prediction of venous thromboembolism in patients with cancer: A prospective cohort study

IntroductionThe procoagulant activity of extracellular vesicles (EV) exposing tissue factor (TF) is a promising biomarker for venous thromboembolism (VTE) in cancer patients. We evaluated an in-house EV-TF activity assay (the fibrin generation test) for the prediction of cancer-associated VTE. We also compared the results with the fibrin generation tests to an EV-TF-dependent factor Xa generation assay in samples from pancreatic cancer patients. Materials and methodsData collected in a multinational, prospective cohort study were used. Patients with various types of advanced cancer were enrolled if chemotherapy was scheduled or started in the previous 3 months. Patients were followed for 6 months for the occurrence of VTE. The fibrin generation test was performed at baseline to measure EV-TF procoagulant activity. ResultsThe fibrin generation test was performed in 648 patients with advanced cancer. The mean age was 62 years; 58% had distant metastasis. Forty patients (6.1%) developed VTE. Overall, a high fibrin generation test result was associated with a two-fold increased risk for VTE (HR 2.0; 95%-CI, 1.1–3.6). The association was stronger in patients with pancreatic cancer (HR 4.1; 95%-CI, 0.91–19) than in those with other tumor types (HR 1.5; 95%-CI, 0.72–3.1). Correlation between the FGT and the TF-dependent factor Xa generation assay in patients with pancreatic cancer was poor (Spearman's R = 0.35). ConclusionThis study shows that a high EV-TF procoagulant activity as measured by the fibrin generation test is associated with an increased risk of VTE in cancer patients, in particular in those with pancreatic cancer. Future studies should aim to further improve the feasibility and accuracy of EV-TF activity assays.

Circulating Tumor DNA Analysis in Patients With Cancer: American Society of Clinical Oncology and College of American Pathologists Joint Review.

Purpose Clinical use of analytical tests to assess genomic variants in circulating tumor DNA (ctDNA) is increasing. This joint review from ASCO and the College of American Pathologists summarizes current information about clinical ctDNA assays and provides a framework for future research. Methods An Expert Panel conducted a literature review on the use of ctDNA assays for solid tumors, including pre-analytical variables, analytical validity, interpretation and reporting, and clinical validity and utility. Results The literature search identified 1,338 references. Of those, 390, plus 31 references supplied by the Expert Panel, were selected for full-text review. There were 77 articles selected for inclusion. Conclusion The evidence indicates that testing for ctDNA is optimally performed on plasma collected in cell stabilization or EDTA tubes, with EDTA tubes processed within 6 hours of collection. Some ctDNA assays have demonstrated clinical validity and utility with certain types of advanced cancer; however, there is insufficient evidence of clinical validity and utility for the majority of ctDNA assays in advanced cancer. Evidence shows discordance between the results of ctDNA assays and genotyping tumor specimens and supports tumor tissue genotyping to confirm undetected results from ctDNA tests. There is no evidence of clinical utility and little evidence of clinical validity of ctDNA assays in early-stage cancer, treatment monitoring, or residual disease detection. There is no evidence of clinical validity and clinical utility to suggest that ctDNA assays are useful for cancer screening, outside of a clinical trial. Given the rapid pace of research, re-evaluation of the literature will shortly be required, along with the development of tools and guidance for clinical practice.

Circulating Tumor DNA Analysis in Patients With Cancer: American Society of Clinical Oncology and College of American Pathologists Joint Review.

Clinical use of analytical tests to assess genomic variants in circulating tumor DNA (ctDNA) is increasing. This joint review from the American Society of Clinical Oncology and the College of American Pathologists summarizes current information about clinical ctDNA assays and provides a framework for future research. An Expert Panel conducted a literature review on the use of ctDNA assays for solid tumors, including preanalytical variables, analytical validity, interpretation and reporting, and clinical validity and utility. The literature search identified 1338 references. Of those, 390, plus 31 references supplied by the Expert Panel, were selected for full-text review. There were 77 articles selected for inclusion. The evidence indicates that testing for ctDNA is optimally performed on plasma collected in cell stabilization or EDTA tubes, with EDTA tubes processed within 6 hours of collection. Some ctDNA assays have demonstrated clinical validity and utility with certain types of advanced cancer; however, there is insufficient evidence of clinical validity and utility for the majority of ctDNA assays in advanced cancer. Evidence shows discordance between the results of ctDNA assays and genotyping tumor specimens, and supports tumor tissue genotyping to confirm undetected results from ctDNA tests. There is no evidence of clinical utility and little evidence of clinical validity of ctDNA assays in early-stage cancer, treatment monitoring, or residual disease detection. There is no evidence of clinical validity or clinical utility to suggest that ctDNA assays are useful for cancer screening, outside of a clinical trial. Given the rapid pace of research, reevaluation of the literature will shortly be required, along with the development of tools and guidance for clinical practice.

First Comprehensive Companion Diagnostic OK'd.

The FDA has approved F1CDx, a comprehensive companion diagnostic test that can detect genetic alterations and two genomic signatures in any type of solid tumor. Patients with five common types of advanced cancer can be matched to one of 17 targeted therapies with this single test.

Silencing LDHA inhibits proliferation, induces apoptosis and increases chemosensitivity to temozolomide in glioma cells.

Glioblastoma multiforme (GBM) is a prevalent and aggressive disease, and the development of a novel therapy to better treat advanced GBM is urgently required. Lactate dehydrogenase A (LDHA), which functions as a key enzyme in transforming pyruvate into lactate, has attracted more attention in recent years due to its critical role in various types of advanced cancer. Previous data derived from the Oncomine database have shown that the expression of LDHA is higher in GBM tissues than that in corresponding normal control tissues. However, the association of LDHA levels with glioma clinical grades and the possible mechanisms of LDHA in GBM progression have not been investigated. The present study showed that there is a significant positive correlation between LDHA expression levels and tumor clinical stages. The knockdown of LDHA inhibited cell growth by inhibiting cell cycle progression and inducing apoptosis in glioma cell lines. Upon investigating the molecular mechanism, LDHA knockdown via siRNA treatment was associated with decreased cyclin D1 expression, increased cleavage of PARP, and altered B-cell lymphoma 2 and B-cell lymphoma 2-associated protein X expression. In addition, LDHA knockdown led to the marked downregulation of matrix metalloproteinase (MMP)-2, MMP-9, VE-Cadherin and vascular endothelial growth factor expression levels. Furthermore, knock down of LDHA enhanced the chemosensitivity of glioma cells to temozolomide (TMZ), a second-generation alkylating agent with activity against recurrent high-grade glioma. These findings support LDHA as a novel target for developing effective therapeutic strategies to treat GBM.

Serotonin transporter 5-HTTLPR polymorphism and response to citalopram in terminally ill cancer patients: report of twenty-one cases.

The aim of this study was to examine the effects of the SSRI antidepressant drug citalopram on anxiety, depression and mental adjustment to cancer in terminally ill cancer patients, considering also the 5-HTTLPR genetic polymorphism. A group of twenty-one consecutive patients admitted to the hospice of the Casa di Cura Pineta del Carso (Trieste, Italy) with different types of advanced cancer, who were clinically judged to require treatment with an antidepressive drug, was treated with citalopram for two weeks. The response was determined and related to 5-HTTLPR. Citalopram significantly reduced the scores on the depression and anxiety subscales of the Hospital Anxiety and Depression Scale (HADS). When the effects of citalopram were analyzed in relation to the 5-HTTLPR polymorphism, the HADS depression score was significantly decreased only in patients with the "l/l" allelic variant of the serotonin transporter conferring high functional activity, while the score of the Mini-MAC fatalism scale was significantly increased in patients carrying at least one "s" allele. These preliminary findings seem to indicate that two weeks of treatment with citalopram are effective in reducing depressive symptoms in terminally ill cancer patients. Moreover, the effects of citalopram on fatalism as a strategy of mental adaptation to cancer, and on depressive symptoms depend on the allelic variants of the 5-HTTLPR genotype of the patients. These results seem to encourage the examination of a larger patient sample and of different treatment schedules, as well as a more thorough characterization of fatalism as a coping strategy in cancer patients.

SY23-3 - Utility of Therapeutic Drug Monitoring to Individualize Oral Targeted Agents

Oral multikinase inhibitors and mammalian target of rapamycin (mTOR) inhibitors such as everolimus have been widely used to treat patients with various types of advanced cancer. However, these drugs have variable pharmacokinetic characteristics, and a significant number of patients often experience severe adverse events leading to dose reduction/interruption or treatment discontinuation. Therefore, it is important to develop an individualized dosing strategy for oral targeted therapies. Currently, associations between drug exposure and treatment outcomes have been described for several tyrosine kinase inhibitors as well as everolimus in cancer patients. Hence, the use of therapeutic drug monitoring (TDM) is considered one of such strategies to optimize drug exposure. In this symposium, we will focus on the clinical pharmacokinetics of regorafenib and its metabolites and the mTOR inhibitor everolimus, and the utility of TDM to improve treatment outcomes will be discussed.

ISY13-4 - Gene expression and mutation profiling for cancer of unknown primary

Cancer of unknown primary site (CUP) is characterized as a metastatic cancer diagnosed without the primary site. As treatment for specific types of advanced cancer improves, it becomes increasingly that accurate identification of the tissue of origin and subsequent site-specific therapy may result in improved prognosis for patients with CUP. In addition, several tumor growth driving mutations have been identified for which inhibition of the target using molecular targeted drugs results in definite survival benefit for specific group of patients. We have now developed integrative algorithm using the next generation sequencer platform to identify gene expression-based cancer classifiers and detect known oncogenic driver mutations. We identified a molecular signature through genome-wide expression profiles and constructed a cancer classifier with weighted-voting system. Multicenter phase 2 clinical trial using this platform for CUP patients is now under investigation in 18 sites to determine the utility of treatment strategy using NGS. Additionally, targeting of the immune system has shown clinical benefit for several advanced solid tumors. Nevertheless, there is few research to establish the backgrounds of such treatment strategy using immuno-checkpoint inhibitors for CUP. We have now under investigation to evaluate immune-related factors for CUP. Our results suggested that prospective trial to evaluate the benefit of immuno-checkpoint inhibitor for CUP is warranted.

A setback for immune checkpoint therapy?

Cancer Immunotherapy Nivolumab, an immunotherapy drug, has shown unprecedented success at treating patients with certain types of advanced cancer. The U.S. Food and Drug Administration approvals for nivolumab, and other drugs like it, are for patients with advanced cancer that has progressed or relapsed while on chemotherapy. Carbone et al. tested whether nivolumab could be used as a first-line therapy (before chemotherapy) in lung cancer patients that express the nivolumab target, PD1, and unexpectedly found that the drug was not better than chemotherapy. Compared with chemotherapy, nivolumab did not extend the time before the disease progressed, nor did it improve overall survival. These results suggest that pretreatment with chemotherapy may influence the response to nivolumab. N. Engl. J. Med. 376 , 2415 (2017).

Immune checkpoint inhibition-related colitis: Correlation between ulcers and need for infliximab.

e21062 Background: Immune checkpoint inhibition has improved survival of patients with several types of advanced cancer. With these new treatments previously unseen adverse events (AE) have become relevant. Considering the fact that most of these immune related AEs can be reversed when identified early and treated adequately, the need for updated algorithms is crucial. Colitis is one of the most severe AEs upon anti-CTLA-4 (e.g. ipilimumab) monotherapy or combination therapies. Severe colitis with deep ulcerations is associated with life-threatening complications such as perforation. Therefore, early recognition and treatment is warranted. Anti-TNF therapy (infliximab) can resolve colitis fast. We sought to identify endoscopic features that indicate the need for early treatment with infliximab. Methods: We retrospectively analyzed all patients who developed diarrhea upon checkpoint inhibition. Only patients undergoing endoscopy were included. All patients were treated at the NKI between August 2010 and March 2016 for either metastatic melanoma or non-small cell lung cancer. Results: A total of 89 patients underwent an endoscopy due to immune related diarrhea (irDiarrhea). Patients were treated with either monotherapy anti-CTLA-4, anti-PD-(L)1, a combination of both, or the combination of anti-CTLA-4 and radiofrequency ablation. Median age was 58 years (range 30-88) and 54% of patients were female. A colonoscopy was performed in 64 (72%) patients and a sigmoidoscopy in 25 (28%) patients. Ulcers were seen during 29 endoscopies (32%). In 18 endoscopies (20%) there were ≤ 10 ulcers and in 11 endoscopies (12%) &gt; 10. Of all patients that had ulcers at endoscopy 23 (79%) required additional infliximab treatment for corticosteroid refractory colitis, while only 25 (42%) of patients without ulcers required additional infliximab ( p= 0.001). Conclusions: Patients with ulcerative irColitis require twice as often infliximab in addition to corticosteroids. Early treatment with infliximab may be indicated in ulcerative irColitis. Treatment based on endoscopic features makes colonoscopy an important diagnostic tool in irDiarrhea. Prospective analysis of endoscopy-driven management of irColitis is warranted.

Safety and pharmacokinetics of crizotinib in patients (pts) with hepatic impairment (HI) and advanced cancer.

2552 Background: Crizotinib is a kinase inhibitor approved for treating ALK+ and ROS1+ advanced non-small cell lung cancer. Since crizotinib undergoes hepatic metabolism, this phase 1 study evaluated the pharmacokinetics (PK) and safety of crizotinib in pts with liver dysfunction. Methods: Crizotinib-naïve pts with different types of advanced cancer (ALK and ROS1 status unknown), ≥ 18 yr old, and ECOG PS 0–2 were enrolled. Pts were assigned to groups A1 – D based on liver function: normal (A1/A2) = both AST and TB ≤ the upper limit of normal (ULN); mild impairment (B) = AST &gt; ULN and TB ≤ ULN, or TB &gt; 1.0 – 1.5 × ULN; moderate (C1/C2) = TB &gt; 1.5 – 3 × ULN; severe (D) = TB &gt; 3 × ULN. Starting dose was based on HI. Pts in A1 and A2 were matched for weight, age, gender, race and ECOG PS to pts in B and C2, respectively. Study objectives included PK, safety and antitumor activity. Results: 88 pts were enrolled in A1 (n=11), A2 (n=15), B (n=20), C1 (n=10), C2 (n=16) and D (n=16). The geometric means of PK parameters at steady-state (Cycle 2 Day 1) are shown below. 75% of pts experienced treatment-related AEs (TRAEs), 9 (81.8%), 14 (93.3%), 15 (75.0%), 6 (60.0%), 11 (68.8%) and 11 (68.8%) in groups A1, A2, B, C1, C2 and D, respectively. 25% of pts experienced Grade 3/4 TRAEs, 3 (27.3%), 3 (20.0%), 3 (15.0%), 1 (10%), 7 (43.8%), 5 (31.3%) in groups A1, A2, B, C1, C2 and D, respectively. Three (3.4%) pts, all in A2, experienced treatment-related SAEs. Two pts (10%) in B and 1 (6.3%) in C2 required dose reductions for TRAEs. TRAEs associated with permanent discontinuation of treatment occurred in 1 pt in A1, A2, C2 and D. Overall, 3 pts had partial responses with durations of 96, 17 and 17 wks; 25 pts had stable disease. Conclusions: Systemic exposures of crizotinib in pts with mild HI receiving 250 BID and in pts with moderate HI receiving 200 mg BID are comparable with that of pts with normal hepatic function at 250 mg BID. All TRAEs were manageable across the various levels of hepatic function. Clinical trial information: NCT01576406. [Table: see text]

MET aberrations across multiple tumor types: Results of a molecular screening program (MOSCATO 01).

e23110 Background: MET gene, encoding the tyrosine kinase receptor for HGF, has been shown to have an oncogenic role in several tumors. We report here the frequency, distribution and clinical characteristics of the patients (pts) found to have MET alterations in a molecular screening trial. Methods: InMOSCATO clinical trial, pts with locally advanced or metastatic solid cancers had an on-purpose tumor biopsy to perform a comprehensive molecular characterization. Results: Among the 844 adult pts who had a successful molecular portrait, 29 (3.4%) had MET aberrations distributed as follows: 18 had abnormalities at the genomic analysis level while 11 had exclusively expression of phosporylated-MET by immunohistochemistry (IHC) and/or a positive fluorescence in situ hybridization (FISH). Only one of the 74 pediatric pts included had a missense mutation. According to the primary tumor, MET alterations were found in 13/170 successfully biopsied pts with lung cancer, 8/197 with digestive tumors, 3/158 with genito-urinary tumors, 2/83 with gynecologic tumors, 2/111 with head and neck cancers, 1/135 with breast cancer and 1 pt with pediatric glioblastoma. Pathogenic variants (PV) were detected in 3 pts by targeted Next Generation Sequencing (NGS), 2 of these PV were exon 14 donor splice site mutations detected also by whole-exome sequencing (WES) in 2 lung tumors. Missense mutations were identified in 3 pts by RNA-sequencing and in one patient by WES. 8 pts had MET amplification identified by comparative genomic hybridization array (CGH) in 5 cases, by FISH in one case and by both FISH and CGH in 2 cases. One patient displayed both amplification and a missense mutation. Ten pts received an anti-MET targeted therapy. One had PV on NGS and missense mutation on WES, 3 had amplification on CGH or FISH and 6 positive IHC. One patient displaying MET exon 14 donor splice site mutation was treated with crizotinib achieving a rapid and sustained partial response. The other 9 pts were treated with SAR125844, a selective MET tyrosine kinase inhibitor, in TED11449 trial (NCT01391533). Conclusions: In this analysis, we saw that MET aberrations are rare in various types of advanced cancers. In selected patients, targeting MET is of clinical interest. Clinical trial information: NCT01566019.

Significance of the Glasgow Prognostic Score for patients with colorectal liver metastasis

BackgroundSystemic inflammation and nutritional status are strongly associated with tumor progression. Inflammation-based prognostic scores, such as the Glasgow Prognostic Score (GPS), reflect these states and are predictive in patients with several types of advanced cancers. The aim of this study was to evaluate the significance of GPS in patients with colorectal liver metastasis (CRLM). Patients and methodsStudy subjects were 134 patients with CRLM who underwent initial radical liver resection at Hiroshima University Hospital between January 2000 and December 2013. Univariate and multivariate analyses were performed to identify variables associated with overall and recurrence-free survival following liver resection in two groups based on GPS. ResultsThere was no significant relationship between overall survival and GPS. Recurrence-free survival was significantly poorer in patients with GPS 1–2 than in those with GPS 0 (p < 0.01). In multivariate analysis for recurrence-free survival, moderate histologic differentiation, carcinoembryonic antigen level ≥10 ng/mL, and GPS 1–2 were identified as independent prognostic factors. ConclusionWe suggest that GPS is an important predictor of recurrence following liver resection in patients with CRLM, and it should be considered one of the evaluation criteria for liver resection.

Abstract A39: Tumor suppressor protein DAB2IP participates in chromosomal stability maintenance through activating spindle assembly checkpoint and stabilizing kinetorchore-microtubule attachments

Abstract The DAB2IP tumor suppressor protein is a member of the Ras GTPase-activating protein family and is often downregulated by epigenetic silencing in many advanced cancer types. Current literature indicates that DAB2IP plays a crucial role in suppression of the PI3K-Akt pathway and epithelial-mesenchymal transition. Loss of DAB2IP is often detected in advanced prostate cancer (PCa) and is associated with increased androgen receptor signaling and poor patient prognosis. Here we report that loss of DAB2IP is also resulted in chromosomal instability due to defects in kinetochore-microtubule (KT-MT) attachment and the spindle assembly checkpoint (SAC) during mitotic cell cycle transition. Chromosomal instability is one of the key hallmarks of carcinogenesis and has been linked to metastasis, poor prognosis, and therapy resistance in cancer. Our results further indicate that DAB2IP directly interacts with Plk1, and its loss attenuates Plk1 kinase activity and Plk1-dependent BubR1 phosphorylation which is required for BubR1 localization at the kinetochore during mitosis and SAC regulation. Consequently, loss of DAB2IP leads to increased resistance of PCa cells toward microtubule stabilizing drugs (paclitaxel, docetaxel) and Plk1 inhibitor (BI2536). Our findings demonstrate a novel function of DAB2IP in the maintenance of KT-MT structure and proper SAC regulation during mitosis to promote chromosomal stability and genome integrity. Citation Format: Lan Yu, Zeng-Fu Shang, Benjamin P. C. Chen, Debabrata Saha. Tumor suppressor protein DAB2IP participates in chromosomal stability maintenance through activating spindle assembly checkpoint and stabilizing kinetorchore-microtubule attachments [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr A39.