FoundationOne CDx testing accurately determines whole arm 1p19q codeletion status in gliomas

Abstract BACKGROUND Molecular profiling of gliomas is vital to ensure diagnostic accuracy, inform prognosis, and identify clinical trial options for primary and recurrent tumors. The aim of this study was to determine the accuracy of reporting whole arm 1p19q codeletion status from the FoundationOne platform. METHODS Testing was performed on glioma samples as part of clinical care and analyzed up to 395 cancer-associated genes (including IDH1/2). Whole arm 1p19q codeletion status was predicted from the same assay using a custom research-use only algorithm, which was validated using 463 glioma samples with available FISH data. For 519 patients with available outcomes data, progression-free and overall survival were assessed based on whole arm 1p19q codeletion status derived from sequencing data. RESULTS Concordance between 1p19q status based on FISH and our algorithm was 96.7% (449/463) with a positive predictive value (PPV) of 100% and a positive percent agreement (PPA) of 91.0%. All discordant samples were positive for codeletion by FISH and harbored genomic alterations inconsistent with oligodendrogliomas. Median overall survival was 168 months for the IDH1/2 mutant, codeleted group, and 122 months for IDH1/2 mutant-only (HR: 0.42; p<0.05). CONCLUSIONS 1p19q codeletion status derived from FoundationOne testing is highly concordant with FISH results. Genomic profiling may be a reliable substitute for traditional FISH testing while also providing IDH1/2 status.

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ACTR-47. PHASE-III TRIAL OF STANDARD CHEMOTHERAPY VS. CHEMOTHERAPY GUIDED BY CANCER STEM CELL TEST IN RECURRENT GLIOBLASTOMA (NCT03632135)

Neuro-Oncology ◽

10.1093/neuonc/noz175.089 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi24-vi24

Author(s):

Tulika Ranjan ◽

Dawit Aregawi ◽

Christine Lu-Emerson ◽

Jason Schroeder ◽

Mark Anderson ◽

...

Keyword(s):

Clinical Trial ◽

Overall Survival ◽

Median Overall Survival ◽

Tumor Response ◽

Chemotherapeutic Agents ◽

Response To Therapy ◽

Phase Iii ◽

Recurrence Time ◽

Cell Kill ◽

Recurrent Gbm

Abstract Stupp treatment protocol for patients with glioblastoma (GBM) has improved the median overall survival to 14.6 months. However, no investigations have defined effective strategies against recurrence and the prognosis of recurrent GBM patients remains poor. Personalized medicine with assay-guided treatment targeting chemotherapy resistant cancer stem cells (CSCs) alongside the bulk tumor cells is a new paradigm in cancer treatment that may result in improved patient’s outcome. We are using ChemoID, a CLIA and CAP certified CSC cytotoxicity assay for predicting response to chemotherapeutic agents. Our prospective analysis of 61 GBM patients demonstrated that ChemoID-guided treatment significantly improved tumor response. For every 5% increase in cell kill of CSCs by assay-guided chemotherapy, 12-month patient response (non-recurrence of cancer) increased 2.5-fold, OR=2.3 (p=0.01). We also found that median recurrence time was 20-months versus 3-months for patients with a positive (>40% cell kill) CSC test versus negative, whereas median recurrence time was 13-months versus 4-months for patients with a positive (>55% cell kill) bulk test versus negative. We are conducting a multi-institutional phase-III clinical trial (NCT03632135) to determine the clinical validity of the ChemoID assay as a predictor of clinical response in recurrent GBM. The study has been designed as a parallel group controlled clinical trial and the participants are randomized to either standard of care chemotherapy chosen by the physician or ChemoID-guided therapy. Response to therapy will be measured by MRI imaging using RANO criteria. Primary endpoint of median overall survival (OS) and secondary endpoints of OS at 6, 9, and 12 months, median progression free survival (PFS), PFS at 4, 6, 9, and 12 months, objective tumor response, time to recurrence, and quality of life will be measured. Trial is open and currently 22 subjects have been enrolled. Interim analysis of the trial will be conducted in approximately 12 months.

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Clinical outcomes of patients enrolled in clinical trial compared with patients outside clinical trial in advanced gastric cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.21 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 21-21

Author(s):

Jaejoon Han ◽

Jin Won Kim ◽

Se Hyun Kim ◽

Jeong-Ok Lee ◽

Yu Jung Kim ◽

...

Keyword(s):

Gastric Cancer ◽

Clinical Trial ◽

Overall Survival ◽

Clinical Trials ◽

Metastatic Disease ◽

Median Overall Survival ◽

Phase 1 ◽

Second Line ◽

First Line ◽

Better Than

21 Background: Participation in clinical trials gives patients with cancer a chance to receive potential benefits, such as experimental treatment, meticulous follow-up and toxicity managements. We aimed to assess the evidence that such an effect exists in patients with gastric cancer. Methods: Clinical characteristics and overall survival of patients with metastatic or recurrent gastric cancer who received fluoropyrimidine and platinum combination palliative chemotherapy within or outside clinical trials at tertiary referral hospital from January 2010 to December 2012 were retrospectively analyzed. Results: Of the 244 patients, 84 patients (34%) were enrolled in clinical trials. During the study period, 20 patients in four phase 3 trials, 54 patients in eight phase 2 trials and ten patients in two phase 1 trials were participated in clinical trials. Twenty patients (8%) at first-line and 64 patients (38%) at second-line or later were enrolled in clinical trials. Younger age (P = 0.014), metastatic disease (P = 0.015) and HER2 IHC status (P = 0.005) were correlated with participation in clinical trials. The median overall survival of patients who participated in clinical trials at first-line was better than those who did not participated in clinical trials, although it was not statistically significant (16 months and 11 months, respectively, P = 0.407). Number of participation in clinical trials was not associated with survival outcome (1 versus ≥ 2 trials: 15 months and 18 months, respectively, P = 0.545). Second-line chemotherapy was administered in 167 patients. The median overall survival of patients who participated in clinical trials at second-line or later was also better than those who did not participated in clinical trials, however, it was not statistically significant (9 months and 6 months, respectively, P = 0.101). Conclusions: Younger patients, metastatic disease, positive HER2 IHC status, and clinical setting of second-line or later were associated with more participation in clinical trials. The median overall survival was numerically longer in patients who were enrolled in the clinical trials although it was not statistically significant.

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Efficacy and Safety of Blinatumomab in Asian Adults with Relapsed/Refractory B-Precursor ALL

Blood ◽

10.1182/blood-2019-124582 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5069-5069

Author(s):

Yukio Kobayashi ◽

Iekuni Oh ◽

Toshihiro Miyamoto ◽

Won-Sik Lee ◽

Hiroatsu Iida ◽

...

Keyword(s):

Clinical Trial ◽

Overall Survival ◽

Research Funding ◽

Median Overall Survival ◽

Efficacy And Safety ◽

Employment Equity ◽

Disease Response ◽

Clinical Trial Research ◽

Asian Patients ◽

Equity Ownership

Introduction: Blinatumomab is a bispecific T-cell engager (BiTE®) targeted immuno-oncology therapy with dual specificity for cluster of differentiation (CD) 19 and CD3 that redirects the patient's CD3-positive cytotoxic T cells to lyse CD19-positive malignant cells. Global studies have evaluated blinatumomab in patients with advanced Philadelphia chromosome-negative relapsed/refractory acute lymphoblastic leukemia (Ph- R/R ALL). In the global phase 3 TOWER study, blinatumomab monotherapy vs standard-of-care chemotherapy resulted in a significantly higher rate of complete remission (CR)/CR with partial hematologic recovery of peripheral blood counts (CRh)/CR with incomplete hematologic recovery of peripheral blood counts (44% vs 25%; P < 0.001) and longer median overall survival (7.7 vs 4.0 months; P = 0.01) (Kantarjian H, et al. NEJM. 2017;376:836-47). There are limited data on the efficacy and safety of blinatumomab in Asian patients, whose immunologic genetic background may differ from other patient populations. Therefore, we conducted a patient-level pooled analysis of the efficacy and safety of blinatumomab in 45 Asian adult patients with Ph- R/R ALL-19 from the blinatumomab arm of TOWER (NCT02013167) and 26 from a phase 1b/2 study in Japanese adults (NCT02412306). Methods: Patients in both studies were ≥ 18 years old and had Ph- R/R ALL, > 5% blasts, Eastern Cooperative Oncology Group performance status 0-2, and no central nervous system pathology. Patients received a maximum of 2 cycles of induction blinatumomab for 4 weeks by continuous intravenous infusion (cycle 1/week 1: 9 μg/day; cycle 1/weeks 2-4: 28 μg/day; subsequent cycles: 28 μg/day) followed by 2 weeks of no blinatumomab (each 6-week cycle). Responders (≤ 5% bone marrow blasts within 2 induction cycles) received blinatumomab 28 μg/day up to a maximum of 5 induction/consolidation cycles. In TOWER, patients who continued morphologic remission received up to 12 months of maintenance therapy. Patients could undergo stem cell transplantation at any time following the first treatment cycle. Results: Of the 45 Asian patients enrolled (26 female; median [range] age, 43 [18-75] years; prior hematopoietic stem cell transplantation, 20 [44.4%]; ≥ 1 prior salvage therapy, 30 [66.7%]), 44 received at least 1 cycle of blinatumomab 9-28 μg/day. Responses in the first 12 weeks of treatment (CR/CRh and minimal residual disease response) are shown in the Table. The Kaplan-Meier (KM) median overall survival time was 11.9 (95% CI: 9.9-17.1) months, and the KM median relapse-free survival time was 8.9 (95% CI: 3.8-10.7) months; median overall survival in the blinatumomab arm of TOWER was 7.7 months. Forty-one (93.2%) patients had grade ≥ 3 treatment-emergent adverse events (TEAEs), and 5 (11.4%) had fatal AEs. Grade ≥ 3 events TEAEs of interest included neurologic events (4.5%), cytokine release syndrome (2.3%), cytopenias (6.8%), and infections (20.5%). Conclusions: The safety and efficacy of blinatumomab in Asian patients were comparable with previous global studies with similar disease response rates and a favorable safety profile with no new safety signals. Disclosures Kobayashi: Astellas Amgen BioPharma: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; SymBio: Consultancy. Iida:Chugai Pharmaceutical Co., Ltd.: Research Funding. Minami:Astellas: Research Funding; Bayer: Honoraria, Other: Clinical trial, Research Funding; Taiho: Honoraria, Other: Clinical trial, Research Funding; Taisho-Toyama: Research Funding; Takeda: Honoraria, Research Funding; CSL Behring: Research Funding; Genomic Health: Honoraria; Daiichi Sankyo: Other: Clinical trial, Research Funding; Sumitomo Dainippon Pharma: Honoraria, Research Funding; Eizai: Honoraria, Research Funding; Janssen: Honoraria; Kowa: Honoraria; Kyowa-Kirin: Honoraria, Research Funding; Nihon Shinyaku: Research Funding; Eli Lilly: Honoraria, Research Funding; Merck Serono: Honoraria, Research Funding; MSD: Honoraria, Other: Clinical trial, Research Funding; Nippon Chemiphar: Honoraria, Research Funding; Ono Yakuhin: Honoraria, Other: Clinical trial, Research Funding; BMS: Honoraria, Other: Clinical trial, Research Funding; Celgene: Honoraria; AstraZeneca: Other: Clinical trial; Boehringer: Honoraria, Research Funding; Otsuka: Honoraria; Pfizer: Honoraria, Other: Clinical trial, Research Funding; Sanofi: Honoraria, Research Funding; Shire Japan: Honoraria; Abbvie: Honoraria; Nihon Medi-Physics: Honoraria; Asahi-Kaseo Pharma: Research Funding; Amgen Inc: Other: Clinical trial; Nihon Kayaku: Research Funding; Shionogi: Research Funding; Novartis: Honoraria, Other: Clinical trial; Chugai: Honoraria, Other: Clinical trial, Research Funding; Yakult: Research Funding; Teijin Pharma: Research Funding. Maeda:Mundipharma Co Ltd.: Honoraria; Kyowa Kirin Co. Ltd.: Honoraria; Astellas Pharma Inc.: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Yoon:Novartis: Consultancy, Honoraria; Yuhan Pharma: Research Funding; MSD: Consultancy; Kyowa Hako Kirin: Research Funding; Genentech, Inc.: Research Funding; Janssen: Consultancy; Amgen: Consultancy, Honoraria. Tran:Amgen: Employment, Equity Ownership. Morris:Amgen: Employment, Equity Ownership. Franklin:Amgen: Employment, Equity Ownership. Chong:Amgen Asia Holding Limited: Employment, Equity Ownership. Kiyoi:Astellas Pharma Inc.: Honoraria, Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Pfizer Japan Inc.: Honoraria; FUJIFILM Corporation: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Daiichi Sankyo Co., Ltd: Research Funding; Perseus Proteomics Inc.: Research Funding.

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PATH-16. COMPREHENSIVE GENOMIC PROFILING ACCURATELY DETERMINES 1p19q CODELETION STATUS IN GLIOMAS

Neuro-Oncology ◽

10.1093/neuonc/noaa215.698 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii167-ii167

Author(s):

Radwa Sharaf ◽

Dean C Pavlick ◽

Garrett M Frampton ◽

Maureen Cooper ◽

Jacqueline Jenkins ◽

...

Keyword(s):

Diagnostic Accuracy ◽

Research Use ◽

Genomic Profiling ◽

Genomic Profile ◽

Wild Type ◽

Mutation Status ◽

1P19q Codeletion ◽

Comprehensive Genomic Profiling ◽

Ffpe Material

Abstract BACKGROUND Genomic profiling of gliomas is vital to ensure diagnostic accuracy, inform prognosis, and identify therapeutic options for primary and recurrent tumors. The integration of genomic biomarkers into brain tumor classification has improved the diagnostic accuracy and led to the development of molecularly stratified clinical trials. DESIGN Comprehensive genomic profiling (CGP) was performed on FFPE material from 310 (162 FoundationOne® and 148 FoundationOne® CDx) samples of brain tumors with available 1p19q FISH results, initially diagnosed by submitting institutions based on histology. Via CGP, we analyzed tumors in up to 395 cancer-associated genes (including IDH1/2) and predicted 1p19q codeletion using a custom research-use only algorithm. Progression-free (PFS) and overall survival (OS) were determined for 519 patients based on computationally predicted 1p19q codeletion status. RESULTS For all samples, regardless of their IDH1/2 mutation status, concordance between 1p19q status based on FISH and our algorithm was 97.1%, (301/310), with a positive predictive value (PPV) of 100% (133/133) and sensitivity of 93.7% (133/142). All discordant samples were called as positive for codeletion by FISH and negative by our CGP-based algorithm. Discordant samples were either IDH1/2 wild-type (2) or IDH1/2, ATRX, and TP53 altered (7), consistent with the genomic profile of diffuse astrocytomas. For IDH1/2-mutated samples, concordance was 96.7% (238/246). In the clinical outcomes dataset, median PFS was 35 months for the codeletion group compared to 13 months for the non-codeletion group (hazard ratio (HR): 0.60; 95% CI: 0.40-0.88; p=0.009). Similarly, median OS was 160 and 34 months respectively for codeleted versus intact (HR: 0.46; 95% CI: 0.28-0.76; p=0.002). CONCLUSIONS 1p19q codeletion status derived from CGP is highly concordant with FISH results suggesting that CGP-derived 1p19q codeletion status may be a reliable substitute for traditional FISH testing. Patients with CGP-derived 1p19q codeletion showed increased PFS and OS compared to non-codeleted counterparts.

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Treatment patterns following first-line pertuzumab + trastuzumab in patients with HER2+ metastatic breast cancer in the United States.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e18746 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e18746-e18746

Author(s):

Sandhya Mehta ◽

Melissa Pavilack ◽

Jipan Xie ◽

Raluca Ionescu-Ittu ◽

Xiaoyu Nie ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Trial ◽

Overall Survival ◽

Metastatic Breast Cancer ◽

Treatment Duration ◽

Median Overall Survival ◽

Metastatic Breast ◽

First Line ◽

Line Of Therapy

e18746 Background: Limited real-world data exists on the treatment of HER2+ metastatic breast cancer (mBC) following pertuzumab (P)+trastuzumab (T) based regimens in first-line (1L) setting. In the EMILIA trial, T-DM1 had higher median progression-free survival (mPFS) (9.6 months vs. 6.4 months) and median overall survival (mOS) (30.9 months vs. 25.1 months) than lapatinib plus capecitabine in patients previously treated with trastuzumab and a taxane. Real-world treatment effectiveness data following 1L P+T could complement clinical trial data to help inform understanding of unmet needs of HER2+ mBC patients requiring second-line (2L) treatment. Methods: IQVIA Oncology EMR (US) database was analyzed to identify adult patients with confirmed HER2+ mBC who were treated with a 1L P+T based regimen between Jan 2015-Sep 2019. An anti-HER2-based regimen might include hormonal therapy and/or chemotherapy. Eligible patients who had ≥60 days of follow-up since 1L P+T regimen initiation were included in outcomes assessment. Treatment discontinuation was defined as a treatment gap of at least 365 days, initiation of a new line of therapy, or death. Treatment failure was defined as the initiation of a new line of therapy or death. A new line of therapy was defined as the use of another anti-HER2 agent, switching to a different class of chemotherapy, or re-initiation of the same regimen after a gap of at least 365 days. Median duration of anti-HER2 regimen, median time to treatment failure (mTTF) and median overall survival (mOS) were estimated using Kaplan-Meier analysis. Results: A total of 710 patients were treated with a 1L P+T based regimen (median age: 57 years; 47% HR+, 26% HR- and 27% unknown HR status; 80% received a taxane). Median follow-up was 20.3 months. Median treatment duration for 1L P+T regimens was 15.3 months. A total of 302 patients (43%) discontinued 1L P+T treatment during the study, of which 222 patients received 2L therapy with a median follow-up of 9.6 months post 2L initiation. Among patients receiving 2L treatment, 214 (96%) received anti-HER2-based regimens. T-DM1 based regimens were most common (n = 159; 72%), followed by trastuzumab-based regimens (n = 29; 13%), lapatinib-based regimens (n = 13; 6%) and neratinib (n = 13; 6%). Overall, median 2L treatment duration was 5.9 months, mTTF was 8.6 months, and mOS was 25.4 months. For patients receiving T-DM1 as 2L therapy, median duration of T-DM1 treatment was 5.7 months, mTTF was 7.9 months, and mOS was 24.4 months. Conclusions: T-DM1 was the most common 2L treatment following 1L P+T based regimen for HER2+ mBC. Median TTF and mOS for T-DM1 in this study were numerically shorter than mPFS and mOS reported in the EMILIA trial, possibly due to the inclusion of a broader patient population beyond those studied in a clinical trial in the current study. There remains an unmet need of a more effective treatment for HER2+ mBC after 1L treatment.

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Mutational landscape of ovarian cancers (OC) identified by prospective clinical sequencing in a nationwide cancer network.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e17067 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e17067-e17067

Author(s):

Julian Schink ◽

Ricardo H. Alvarez ◽

Julia Andrea Elvin ◽

Amber Moran ◽

Rebecca Rollins ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Clinical Care ◽

Large Series ◽

Tumor Board ◽

Precision Oncology ◽

Tumor Type ◽

Genomic Profiling ◽

Cancer Network ◽

Matched Treatment

e17067 Background: Tumor genomic profiling is a critical component of precision oncology allowing the detection of genomic alterations (GA) that have the potential to be targeted therapeutically. We present an analysis of comprehensive genomic profiling (CGP) of a large series of OC assayed in a nationwide cancer network. Methods: 449 Pts with advanced OC underwent CGP with hybrid capture of up to 406 cancer-related genes on tumor tissue or for 62 genes on circulating tumor DNA ordered during clinical care for treatment decision-making between 01-2013 to 05-2018. Clinically relevant (CR) GA were defined as associated with targeted therapies or mechanism-driven clinical trials. Treatment histories for the 449 patients were obtained with IRB-approved retrospective review. Results: Median age was 56 years (range, 23-83), 71% were Caucasian. GA were identified in 94% (420/449) of OC, of which 283 (63%) had a clinically relevant genomic alteration (CRGA). 24.0% in HRD ( BRCA1/2, ATM, PALB2, BRIP1). CRGA in other potentially targetable pathways were identified: 48.0% MEK pathway ( KRAS, NRAS, HRAS, BRAF, RAF1, GNAS, NF1, NF2) CRGA, 33.5% PI3K/AKT/mTOR pathway ( PIK3CA, AKT1/2/3, PIK3R1, PTEN, MTOR, STK11, FBXW7), and 10.6% in ERBB ( ERBB2, ERBB3, ERBB4, EGFR). All OC tested were microsatellite stable and only one patient had a tumor mutational burden > 20 muts/Mb. 21% (59/283) of OC patients were ordered a genomically-matched treatment, 58% (37/64) were agents that were FDA approved in a different tumor type, and 17% (11/64) through referral to a matched mechanism driven clinical trial. With access to the clinical trial TAPUR, the frequency of matched treatment through clinical trials increased over time from 2013 to 2018. For the off label non-study population the median PFS was 19 weeks, and the median OS was 34 weeks. Conclusions: In a large series of OC assayed with CGP, 21% of pts received matched treatment, which was predominantly targeted therapy. The comprehensive sensitive and unbiased nature of CGP, coupled with a multidisciplinary molecular tumor board and staff dedicated to genomic interpretation, assisted in achieving a high frequency of patients’ participation in clinical trials and gene-directed treatment.

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The value of defining molecular resistance in patients with progressive EGFR and ALK-driven lung cancer in a public system.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3126 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3126-3126

Author(s):

Carly C. Barron ◽

Tracy Stockley ◽

Jennifer H. Law ◽

Muqdas Shabir ◽

Roxanne Fernandes ◽

...

Keyword(s):

Lung Cancer ◽

Clinical Trial ◽

Targeted Therapy ◽

Cell Transformation ◽

Molecular Profiling ◽

Resistance Mechanisms ◽

Copy Number Variations ◽

Small Cell ◽

Braf V600e ◽

Genomic Profiling

3126 Background: Repeat molecular profiling, except to detect EGFR T790M, is not routinely performed in Canadian patients with lung cancer progressing on EGFR tyrosine kinase inhibitors (TKIs). We performed genomic profiling on post-progression biopsies in patients with stage IV non-small cell lung cancer (NSCLC) and known EGFR/ ALK aberrations treated with TKIs to identify resistance mechanisms, evaluate options for subsequent treatment, and to assess clinical trial eligibility and costs. Methods: From Feb 2018-Aug 2020, post-progression tumour biopsies from consenting patients at a major cancer centre underwent genomic profiling (ThermoFisher OCA v3.0 including hotspots, fusions, and copy number variations in 161 cancer-associated genes). Outcomes of interest were the identification of resistance mutations, actionable targets, clinical trial eligibility (per clinicaltrials.gov), and costs. Results: Thirty-two patients consented to the study. Most, 84% (n = 27), had successful testing completed while 16% (n = 5) had insufficient tissue. Median age of the cohort was 56 yrs, 59% (n = 16) were female, 74% (n = 20) were never-smokers, 81% (n = 22) had ECOG performance status 0-1, and 67% (n = 18) were Asian. The majority, 81% (n = 22) had EGFR mutated NSCLC, and had progressed on EGFR TKIs (15 with previously identified T790M had progressed on osimertinib), and 19% (n = 5) had ALK fusions. Patients had received a median of 2 prior lines of targeted therapy prior to re-biopsy (IQR 1.5,3). One patient had evidence of small cell transformation and associated TP53 and RB1 mutations, 11% (n = 3) had acquired EGFR C797S mutations, and 11% (n = 3) had acquired ALK resistance point mutations (G1202R n = 2, I1171N n = 1). Genomic profiling identified additional actionable targets in 19% of patients (n = 5: MET exon 14 skip mutation n = 1, MET amplification n = 2, BRAF V600E n = 2). Overall, 33% (n = 9) patients had management-changing resistance mechanisms identified (small cell transformation n = 1, actionable targets n = 5, ALK inhibitor resistance = 3). New clinical trial options based on genomic profiling results were identified for 67% (n = 18) of patients. Incremental costs for repeat genomic profiling were approximately $880 CAD per case. Conclusions: Molecular profiling upon development of resistance to targeted therapy in our cohort revealed actionable resistance mechanisms for over a third of patients and clinical trial options for 67%. These incremental benefits for patients highlight the importance of routine molecular profiling in the setting of acquired TKI resistance in lung cancer.

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Role of CX3CR1 Signaling in Malignant Transformation of Gliomas

Neurosurgery ◽

10.1093/neuros/nyz310_214 ◽

2019 ◽

Vol 66 (Supplement_1) ◽

Author(s):

Sungho Lee ◽

Khatri Latha ◽

Ganesh Rao

Keyword(s):

Overall Survival ◽

Malignant Transformation ◽

Microvessel Density ◽

Median Overall Survival ◽

M2 Macrophage ◽

Low Grade ◽

Loss Of Function ◽

Sequencing Data ◽

Altered Expression

Abstract INTRODUCTION High-grade gliomas (HGGs), including the most common primary brain tumor, glioblastoma (GBM), may arise from malignant transformation of low-grade gliomas (LGGs). While LGGs are often clinically indolent, GBMs have dismal outcomes despite maximal therapy. Accumulating evidence suggests that chemokine signaling directly contributes to malignant progression of LGGs by altering tumor behavior or impacting the immune microenvironment. Here, we examined the role of CX3CR1 signaling in malignant transformation of LGGs. METHODS First, patients with malignantly transformed LGGs were genotyped for the presence of the common loss-of-function CX3CR1 V249I polymorphism, and median overall survival was compared between the genotypes. Second, RNA sequencing data was analyzed for differential gene expression based on genotype. Third, surgical samples were examined for altered expression of M2 macrophage markers and microvessel density between the genotypes. Finally, genetically engineered murine model was leveraged to generate endogenous intracranial gliomas with targeted expression of CX3CL1 and CX3CR1, individually or in combination. RESULTS Heterozygosity (V/I) or homozygosity (I/I) for the loss-of-function CX3CR1 polymorphism is associated with significantly better median overall survival in patients with malignantly transformed LGGs, compared to the wild type genotype (V/V). In addition, HGGs from V/I and I/I genotypes exhibit significantly decreased levels of CCL2, important for the recruitment of M2 macrophages, as well as decreased levels of ANGPT1 and MMP9, which mediate angiogenesis. This correlates with reduced intratumoral accumulation of CD204-positive macrophages and microvessel density in tumors from V/I and I/I patients. Finally, in the RCAS-PDGFB driven model of LGG, co-expression of CX3CL1 and CX3CR1 promotes more malignant tumor phenotype and shorter tumor-free survival in association with increased intratumoral microglia and macrophage infiltration and microvessel density. CONCLUSION Taken together, our results show that CX3CL1-CX3CR1 signaling promotes malignant transformation of LGGs via accumulation of glioma associated macrophages and microglia and increased angiogenesis.

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