Publications by authors named "Hatim Husain"

36 Publications

Utility of Circulating Tumor DNA in Identifying Somatic Mutations and Tracking Tumor Evolution in Patients with Non-small Cell Lung Cancer.

Chest 2021 Apr 17. Epub 2021 Apr 17.

City of Hope Comprehensive Cancer Center, Duarte, CA 91010. Electronic address:

Background: The utility of circulating tumor DNA (ctDNA) in detecting mutations and monitoring treatment response has not been well studied beyond a few actionable biomarkers in non-small cell lung cancer (NSCLC).

Research Question: How does the utility of circulating tumor DNA (ctDNA) compare to that of solid tumor biopsy in non-small cell lung cancer (NSCLC) patients?

Methods: We retrospectively evaluated 370 adult NSCLC patients treated at the City of Hope between November 2015 and August 2019 to assess the utility of ctDNA in mutation identification, survival, concordance with matched tissue samples in thirty-two genes, and tumor evolution.

Results: A total of 1688 somatic mutations were detected in 473 ctDNA samples from 370 NSCLC patients. Of the 473 samples, 177 had at least one actionable mutation with currently available FDA-approved NSCLC therapies. MET and CDK6 amplifications co-occurred with BRAF amplifications (false discovery rates [FDR] < 0.01), and gene-level mutations were mutually exclusive in KRAS and EGFR (FDR = 0.0009). Low cumulative percent ctDNA levels were associated with longer progression-free survival (hazard ratio [HR] 0.56, 95% CI: 0.37-0.85, p = 0.006). Overall survival was shorter in BRAF (HR 2.35, 95% CI: 1.24-4.6, p = 0.009, PIK3CA (HR 2.77, 95% CI: 1.56-4.9, P< 0.001 and KRAS-positive patients (HR 2.32, 95% CI: 1.30-4.1, P= 0.004). Gene-level concordance was 93.8% while the positive concordance rate was 41.6%. More mutations in targetable genes were found in ctDNA than in tissue biopsies. Treatment response and tumor evolution over time were detected in repeated ctDNA samples.

Interpretation: Although ctDNA exhibited similar utility to tissue biopsies, more mutations in targetable genes were missed in tissue biopsies. Therefore, the evaluation of ctDNA in conjunction with tissue biopsies may help to detect additional targetable mutations to improve clinical outcomes in advanced NSCLC.
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http://dx.doi.org/10.1016/j.chest.2021.04.016DOI Listing
April 2021

RNA Based Approaches to Profile Oncogenic Pathways From Low Quantity Samples to Drive Precision Oncology Strategies.

Front Genet 2020 5;11:598118. Epub 2021 Feb 5.

University of California, San Diego, La Jolla, CA, United States.

Precision treatment of cancer requires knowledge on active tumor driving signal transduction pathways to select the optimal effective targeted treatment. Currently only a subset of patients derive clinical benefit from mutation based targeted treatment, due to intrinsic and acquired drug resistance mechanisms. Phenotypic assays to identify the tumor driving pathway based on protein analysis are difficult to multiplex on routine pathology samples. In contrast, the transcriptome contains information on signaling pathway activity and can complement genomic analyses. Here we present the validation and clinical application of a new knowledge-based mRNA-based diagnostic assay platform (OncoSignal) for measuring activity of relevant signaling pathways simultaneously and quantitatively with high resolution in tissue samples and circulating tumor cells, specifically with very small specimen quantities. The approach uses mRNA levels of a pathway's direct target genes, selected based on literature for multiple proof points, and used as evidence that a pathway is functionally activated. Using these validated target genes, a Bayesian network model has been built and calibrated on mRNA measurements of samples with known pathway status, which is used next to calculate a pathway activity score on individual test samples. Translation to RT-qPCR assays enables broad clinical diagnostic applications, including small analytes. A large number of cancer samples have been analyzed across a variety of cancer histologies and benchmarked across normal controls. Assays have been used to characterize cell types in the cancer cell microenvironment, including immune cells in which activated and immunotolerant states can be distinguished. Results support the expectation that the assays provide information on cancer driving signaling pathways which is difficult to derive from next generation DNA sequencing analysis. Current clinical oncology applications have been complementary to genomic mutation analysis to improve precision medicine: (1) prediction of response and resistance to various therapies, especially targeted therapy and immunotherapy; (2) assessment and monitoring of therapy efficacy; (3) prediction of invasive cancer cell behavior and prognosis; (4) measurement of circulating tumor cells. Preclinical oncology applications lie in a better understanding of cancer behavior across cancer types, and in development of a pathophysiology-based cancer classification for development of novel therapies and precision medicine.
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http://dx.doi.org/10.3389/fgene.2020.598118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893109PMC
February 2021

Applications of cell-free circulating tumor DNA detection in EGFR mutant lung cancer.

J Thorac Dis 2020 May;12(5):2877-2882

University of California San Diego, La Jolla, CA, USA.

Analyses of cell-free tumor DNA (ctDNA) have provided a non-invasive strategy for cancer diagnosis, the identification of molecular aberrations for treatment identification, and evaluation of tumor response. Sensitive and specific ctDNA sequencing strategies have allowed for implementation into clinical practice for the initial genotyping of patients and resistance monitoring. The specific need for EGFR mutation detection for the management of lung cancer patients has been an early imperative and has set the stage for non-invasive molecular profiling across other oncogenic drivers. Ongoing efforts are demonstrating the utility of ctDNA analyses in the initial genotyping of patients, the monitoring resistance clones, and the initial evaluation of response.
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http://dx.doi.org/10.21037/jtd.2020.01.66DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330324PMC
May 2020

Assessing tumor heterogeneity using ctDNA to predict and monitor therapeutic response in metastatic breast cancer.

Int J Cancer 2020 03 4;146(5):1359-1368. Epub 2019 Jul 4.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Tumor heterogeneity was associated with treatment outcome of metastatic cancers but few studies have examined whether tumor heterogeneity in circulating tumor DNA (ctDNA) can be used to predict treatment outcome. ctDNA analysis was performed in 37 HER2-positive metastatic breast cancer patients treated with pyrotinib. Patients with high tumor heterogeneity had significantly worse PFS outcomes, with a median PFS of 30.0 weeks vs. 60.0 weeks for patients with low tumor heterogeneity (hazard ratio [HR], 2.9; p = 0.02). Patients with trunk resistance mutations receiving pyrotinib monotherapy had worse outcomes (HR, 4.5; p = 0.03), with a median PFS of 7.8 weeks vs. 27.4 weeks for those with branch resistance mutations or without any resistance mutations in baseline ctDNA. Longitudinal monitoring of 21 patients during treatment showed that the molecular tumor burden index ([mTBI] a measure of the percentage of ctDNA in samples) was positively correlated with tumor size as evaluated by computed tomography (p < 0.0001, Pearson r = 0.52) and detected disease progression 8-16 weeks earlier. Our current findings suggested that ctDNA could be used to assess tumor heterogeneity and predict treatment outcomes. Furthermore, the mTBI is better for assessing therapeutic response than single gene mutations and might supplement the current therapeutic response evaluation system.
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http://dx.doi.org/10.1002/ijc.32536DOI Listing
March 2020

Genome-wide cell-free DNA fragmentation in patients with cancer.

Nature 2019 06 29;570(7761):385-389. Epub 2019 May 29.

Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Cell-free DNA in the blood provides a non-invasive diagnostic avenue for patients with cancer. However, characteristics of the origins and molecular features of cell-free DNA are poorly understood. Here we developed an approach to evaluate fragmentation patterns of cell-free DNA across the genome, and found that profiles of healthy individuals reflected nucleosomal patterns of white blood cells, whereas patients with cancer had altered fragmentation profiles. We used this method to analyse the fragmentation profiles of 236 patients with breast, colorectal, lung, ovarian, pancreatic, gastric or bile duct cancer and 245 healthy individuals. A machine learning model that incorporated genome-wide fragmentation features had sensitivities of detection ranging from 57% to more than 99% among the seven cancer types at 98% specificity, with an overall area under the curve value of 0.94. Fragmentation profiles could be used to identify the tissue of origin of the cancers to a limited number of sites in 75% of cases. Combining our approach with mutation-based cell-free DNA analyses detected 91% of patients with cancer. The results of these analyses highlight important properties of cell-free DNA and provide a proof-of-principle approach for the screening, early detection and monitoring of human cancer.
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http://dx.doi.org/10.1038/s41586-019-1272-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774252PMC
June 2019

Circulating tumor DNA analyses predict progressive disease and indicate trastuzumab-resistant mechanism in advanced gastric cancer.

EBioMedicine 2019 May 25;43:261-269. Epub 2019 Apr 25.

Department of GI Oncology, The Fifth Medical Center, General Hospital of PLA, Beijing 100071, China. Electronic address:

Background: Circulating tumor DNA (ctDNA) isolated from plasma contains genetic mutations that can be representative of those found in primary tumor tissue DNA. These samples can provide insights into tumoral heterogeneity in patients with advanced gastric cancer (AGC). Although trastuzumab has been shown to be effective in first-line therapy for patients with metastatic gastric cancer with overexpression of human epidermal growth factor receptor 2 (HER2), the mechanism of AGC resistance is incompletely understood.

Methods: In this prospective study, we used targeted capture sequencing to analyze 173 serial ctDNA samples from 39 AGC patients. We analyzed cancer cell fractions with PyClone to understand the clonal population structure in cancer, and monitored serial samples during therapy. Serial monitoring of ctDNA using the molecular tumor burden index (mTBI), identified progressive disease before imaging results (mean: 18 weeks).

Findings: We reconstructed the clonal structure of ctDNA during anti-HER2 treatment, and identified 32 expanding mutations potentially related to trastuzumab resistance. Multiple pathways activating in the same patients revealed heterogeneity in trastuzumab resistance mechanisms in AGC. In patients who received chemotherapy, mTBI was validated for the prediction of progressive disease, with a sensitivity of 94% (15/16). A higher mTBI (≥1%) in pretreatment ctDNA was also a risk factor for progression-free survival.

Conclusions: Analysis of ctDNA clones based on sequencing is a promising approach to clinical management, and may lead to improved therapeutic strategies for AGC patients. FUND: This work was supported by grants from the National International Cooperation Grant (to J.X.; Project No. 2014DFB33160).
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http://dx.doi.org/10.1016/j.ebiom.2019.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562020PMC
May 2019

Novel Third-Generation EGFR Tyrosine Kinase Inhibitors and Strategies to Overcome Therapeutic Resistance in Lung Cancer.

Cancer Res 2019 02 4;79(4):689-698. Epub 2019 Feb 4.

University of California San Diego, Moores Cancer Center, La Jolla, California.

EGFR-activating mutations are observed in approximately 15% to 20% of patients with non-small cell lung cancer. Tyrosine kinase inhibitors have provided an illustrative example of the successes in targeting oncogene addiction in cancer and the role of tumor-specific adaptations conferring therapeutic resistance. The compound osimertinib is a third-generation tyrosine kinase inhibitor, which was granted full FDA approval in March 2017 based on targeting EGFR T790M resistance. The compound has received additional FDA approval as first-line therapy with improvement in progression-free survival by suppressing the activating mutation and preventing the rise of the dominant resistance clone. Drug development has been breathtaking in this space with other third-generation compounds at various stages of development: rociletinib (CO-1686), olmutinib (HM61713), nazartinib (EGF816), naquotinib (ASP8273), mavelertinib (PF-0647775), and AC0010. However, therapeutic resistance after the administration of third-generation inhibitors is complex and not fully understood, with significant intertumoral and intratumoral heterogeneity. Repeat tissue and plasma analyses on therapy have revealed insights into multiple mechanisms of resistance, including novel second site EGFR mutations, activated bypass pathways such as MET amplification, HER2 amplification, RAS mutations, BRAF mutations, PIK3CA mutations, and novel fusion events. Strategies to understand and predict patterns of mutagenesis are still in their infancy; however, technologies to understand synthetically lethal dependencies and track cancer evolution through therapy are being explored. The expansion of combinatorial therapies is a direction forward targeting minimal residual disease and bypass pathways early based on projected resistance.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-1281DOI Listing
February 2019

Early Noninvasive Detection of Response to Targeted Therapy in Non-Small Cell Lung Cancer.

Cancer Res 2019 03 20;79(6):1204-1213. Epub 2018 Dec 20.

Division of Hematology and Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, California.

With the advent of precision oncology, there is an urgent need to develop improved methods for rapidly detecting responses to targeted therapies. Here, we have developed an ultrasensitive measure of cell-free tumor load using targeted and whole-genome sequencing approaches to assess responses to tyrosine kinase inhibitors in patients with advanced lung cancer. Analyses of 28 patients treated with anti-EGFR or HER2 therapies revealed a bimodal distribution of cell-free circulating tumor DNA (ctDNA) after therapy initiation, with molecular responders having nearly complete elimination of ctDNA (>98%). Molecular nonresponders displayed limited changes in ctDNA levels posttreatment and experienced significantly shorter progression-free survival (median 1.6 vs. 13.7 months, < 0.0001; HR = 66.6; 95% confidence interval, 13.0-341.7), which was detected on average 4 weeks earlier than CT imaging. ctDNA analyses of patients with radiographic stable or nonmeasurable disease improved prediction of clinical outcome compared with CT imaging. These analyses provide a rapid approach for evaluating therapeutic response to targeted therapies and have important implications for the management of patients with cancer and the development of new therapeutics. Cell-free tumor load provides a novel approach for evaluating longitudinal changes in ctDNA during systemic treatment with tyrosine kinase inhibitors and serves an unmet clinical need for real-time, noninvasive detection of tumor response to targeted therapies before radiographic assessment..
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http://dx.doi.org/10.1158/0008-5472.CAN-18-1082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481620PMC
March 2019

EGFR-Mutant Adenocarcinomas That Transform to Small-Cell Lung Cancer and Other Neuroendocrine Carcinomas: Clinical Outcomes.

J Clin Oncol 2019 02 14;37(4):278-285. Epub 2018 Dec 14.

1 Massachusetts General Hospital, Boston, MA.

Purpose: Approximately 3% to 10% of EGFR (epidermal growth factor receptor) -mutant non-small cell lung cancers (NSCLCs) undergo transformation to small-cell lung cancer (SCLC), but their clinical course is poorly characterized.

Methods: We retrospectively identified patients with EGFR-mutant SCLC and other high-grade neuroendocrine carcinomas seen at our eight institutions. Demographics, disease features, and outcomes were analyzed.

Results: We included 67 patients-38 women and 29 men; EGFR mutations included exon 19 deletion (69%), L858R (25%), and other (6%). At the initial lung cancer diagnosis, 58 patients had NSCLC and nine had de novo SCLC or mixed histology. All but these nine patients received one or more EGFR tyrosine kinase inhibitor before SCLC transformation. Median time to transformation was 17.8 months (95% CI, 14.3 to 26.2 months). After transformation, both platinum-etoposide and taxanes yielded high response rates, but none of 17 patients who received immunotherapy experienced a response. Median overall survival since diagnosis was 31.5 months (95% CI, 24.8 to 41.3 months), whereas median survival since the time of SCLC transformation was 10.9 months (95% CI, 8.0 to 13.7 months). Fifty-nine patients had tissue genotyping at first evidence of SCLC. All maintained their founder EGFR mutation, and 15 of 19 with prior EGFR T790M positivity were T790 wild-type at transformation. Other recurrent mutations included TP53, Rb1, and PIK3CA. Re-emergence of NSCLC clones was identified in some cases. CNS metastases were frequent after transformation.

Conclusion: There is a growing appreciation that EGFR-mutant NSCLCs can undergo SCLC transformation. We demonstrate that this occurs at an average of 17.8 months after diagnosis and cases are often characterized by Rb1, TP53, and PIK3CA mutations. Responses to platinum-etoposide and taxanes are frequent, but checkpoint inhibitors yielded no responses. Additional investigation is needed to better elucidate optimal strategies for this group.
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http://dx.doi.org/10.1200/JCO.18.01585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001776PMC
February 2019

Assessment of Resistance Mechanisms and Clinical Implications in Patients With EGFR T790M-Positive Lung Cancer and Acquired Resistance to Osimertinib.

JAMA Oncol 2018 11;4(11):1527-1534

Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Importance: Osimertinib mesylate is used globally to treat EGFR-mutant non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitor resistance mediated by the EGFR T790M mutation. Acquired resistance to osimertinib is a growing clinical challenge that is poorly understood.

Objective: To understand the molecular mechanisms of acquired resistance to osimertinib and their clinical behavior.

Design, Setting, And Participants: Patients with advanced NSCLC who received osimertinib for T790M-positive acquired resistance to prior EGFR tyrosine kinase inhibitor were identified from a multi-institutional cohort (n = 143) and a confirmatory trial cohort (NCT01802632) (n = 110). Next-generation sequencing of tumor biopsies after osimertinib resistance was performed. Genotyping of plasma cell-free DNA was studied as an orthogonal approach, including serial plasma samples when available. The study and analysis were finalized on November 9, 2017.

Main Outcomes And Measures: Mechanisms of resistance and their association with time to treatment discontinuation on osimertinib.

Results: Of the 143 patients evaluated, 41 (28 [68%] women) had tumor next-generation sequencing after acquired resistance to osimertinib. Among 13 patients (32%) with maintained T790M at the time of resistance, EGFR C797S was seen in 9 patients (22%). Among 28 individuals (68%) with loss of T790M, a range of competing resistance mechanisms was detected, including novel mechanisms such as acquired KRAS mutations and targetable gene fusions. Time to treatment discontinuation was shorter in patients with T790M loss (6.1 vs 15.2 months), suggesting emergence of pre-existing resistant clones; this finding was confirmed in a validation cohort of 110 patients with plasma cell-free DNA genotyping performed after osimertinib resistance. In studies of serial plasma levels of mutant EGFR, loss of T790M at resistance was associated with a smaller decrease in levels of the EGFR driver mutation after 1 to 3 weeks of therapy (100% vs 83% decrease; P = .01).

Conclusions And Relevance: Acquired resistance to osimertinib mediated by loss of the T790M mutation is associated with early resistance and a range of competing resistance mechanisms. These data provide clinical evidence of the heterogeneity of resistance in advanced NSCLC and a need for clinical trial strategies that can overcome multiple concomitant resistance mechanisms or strategies for preventing such resistance.
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http://dx.doi.org/10.1001/jamaoncol.2018.2969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240476PMC
November 2018

Genomic and Proteomic Alterations in Desmoplastic Small Round Blue-Cell Tumors.

JCO Precis Oncol 2018 1;2. Epub 2018 Jun 1.

, , , and , University of California San Diego, La Jolla, CA; and , Caris Life Sciences, Phoenix, AZ.

Purpose: Desmoplastic small round blue-cell tumors (DSRCTs) are sarcomas that contain the t(11;22) (p13;q12) translocation EWS-WT1 fusion protein. Because this is a rare tumor type, prospective clinical trials in DSRCT are challenging. Patients are treated in a manner similar to those with Ewing sarcoma; however, differences in prognosis and clinical presentation suggest fundamental differences in biology and potentially different therapeutic implications. This study aimed to characterize the molecular characteristics of DSRCT tumors to explore unique therapeutic options for this extremely rare and aggressive cancer type.

Methods: Thirty-five DSRCT tumors were assessed using next-generation sequencing, protein expression (immunohistochemistry), and gene amplification (chromogenic in situ hybridization or fluorescence in situ hybridization). Three patients had tumor mutational load, which was calculated as somatic nonsynonymous missense mutations sequenced with a 592-gene panel. Gene expression data were obtained for an additional seven DSRCT tumors. Molecular alterations were compared with 88 Ewing sarcomas.

Results: The most common alterations that distinguished DSRCTs from Ewing sarcoma included higher androgen receptor (AR), TUBB3, epidermal growth factor receptor, and TOPO2A expression. Independent analysis by RNA sequencing confirmed higher AR expression from an independent data set of EWS-WT1 fusion-positive DSRCTs compared with Ewing sarcoma and a pan-cancer analysis. DSRCTs had somatic mutations that were identified in and , averaged five mutations per megabase, and no programmed death-ligand 1 expression was detected in any DSRCT samples.

Conclusion: The current analysis provides the first comparative analysis, to our knowledge, of molecular aberrations that distinguish DSRCT from Ewing sarcoma. High AR expression seems to be a defining event in these malignancies, and additional investigation of the responsiveness of AR inhibitors in this disease is encouraged.
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http://dx.doi.org/10.1200/PO.17.00170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446341PMC
June 2018

First-Line Treatment in EGFR Mutant Non-Small Cell Lung Cancer: Is There a Best Option?

Front Oncol 2018 10;8:94. Epub 2018 Apr 10.

University of California San Diego, Moores Cancer Center, La Jolla, CA, United States.

First generation or second generation EGFR tyrosine kinase inhibitors are currently the standard of care for the first-line management of non-small cell lung cancer (NSCLC) patients with activating mutations within the kinase domain of the epidermal growth factor receptor gene (1, 2). Resistance to targeted therapy can develop after 9-11 months (3-8). Third generation inhibitors were developed to target the EGFR T790M clone, which is the most common dominant second site resistance mutation after first or second generation inhibitors. Osimertinib received full FDA approval for the second-line treatment of advanced NSCLC based on a phase III study comparing the compound to chemotherapy. Recent data demonstrates an important impact for osimertinib in the front-line space based on results comparing the compound to first-generation erlotinib or gefitinib therapy.
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http://dx.doi.org/10.3389/fonc.2018.00094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932412PMC
April 2018

Systemic Treatment Options for Brain Metastases from Non-Small-Cell Lung Cancer.

Oncology (Williston Park) 2018 04;32(4):156-63

Brain metastases are common in patients with non-small-cell lung cancer (NSCLC). Because of associated poor prognosis and limited specific treatment options, there is a real need for the development of medical therapies and strategies for affected patients. Novel compounds for epidermal growth factor receptor-dependent and anaplastic lymphoma kinase-dependent lung cancer have demonstrated blood-brain barrier permeability and have led to important improvements in central nervous system outcomes. Studies of targeted therapies for oncogene-driven tumors and of immunotherapies in patients with brain metastases have shown promise and, allied with novel radiation techniques, are driving a rapid evolution in treatment and prognosis for NSCLC brain metastases.
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April 2018

in Lung Cancers: Analysis of Patient Cases Reveals Recurrent Mutations, Fusions, Kinase Duplications, and Concurrent Alterations.

JCO Precis Oncol 2018 19;2. Epub 2018 Apr 19.

, Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ.

Purpose: Dabrafenib and trametinib are approved for the management of advanced non-small-cell lung cancers (NSCLCs) that harbor V600E mutations. Small series and pan-cancer analyses have identified non-V600 alterations as therapeutic targets. We sought to examine a large genomic data set to comprehensively characterize non-V600 B alterations in lung cancer.

Patients And Methods: A total of 23,396 patients with lung cancer provided data to assay with comprehensive genomic profiling. Data were reviewed for predicted pathogenic base substitutions, short insertions and deletions, copy number changes, and rearrangements.

Results: Adenocarcinomas represented 65% of the occurrences; NSCLC not otherwise specified (NOS), 15%; squamous cell carcinoma, 12%; and small-cell lung carcinoma, 5%. was altered in 4.5% (1,048 of 23,396) of all tumors; 37.4% (n = 397) were V600E, 38% were non-V600E activating mutations, and 18% were inactivating. Rearrangements were observed at a frequency of 4.3% and consisted of N-terminal deletions (NTDs; 0.75%), kinase domain duplications (KDDs; 0.75%), and fusions (2.8%). The fusions involved three recurrent fusion partners: , and . V600E was associated with co-occurrence of alterations, but other alterations were not and were instead associated with , , and alterations ( < .05). Potential mechanisms of acquired resistance to V600E inhibition are demonstrated.

Conclusion: This series characterized the frequent occurrence (4.4%) of alterations in lung cancers. Recurrent alterations in NSCLC adenocarcinoma are comparable to the frequency of other NSCLC oncogenic drivers, such as , and exceed that of or . This work supports a broad profiling approach in lung cancers and suggests that non-V600E BR alterations represent a subgroup of lung cancers in which targeted therapy should be considered.
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http://dx.doi.org/10.1200/PO.17.00172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446447PMC
April 2018

Desmoplastic Small Round Blue Cell Tumor: A Review of Treatment and Potential Therapeutic Genomic Alterations.

Sarcoma 2017 1;2017:1278268. Epub 2017 Nov 1.

Department of Pediatric Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Desmoplastic small round blue cell tumors (DSRCTs) originate from a cell with multilineage potential. A molecular hallmark of DSRCT is the EWS-WT1 reciprocal translocation. Ewing sarcoma and DSRCT are treated similarly due to similar oncogene activation pathways, and DSRCT has been represented in very limited numbers in sarcoma studies. Despite aggressive therapy, median survival ranges from 17 to 25 months, and 5-year survival rates remain around 15%, with higher survival reported among those undergoing removal of at least 90% of tumor in the absence of extraperitoneal metastasis. Almost 100% of these tumors contain t(11;22) (p13;q12) translocation, and it is likely that EWS-WT1 functions as a transcription factor possibly through WT1 targets. While there is no standard protocol for this aggressive disease, treatment usually includes the neoadjuvant HD P6 regimen (high-dose cyclophosphamide, doxorubicin, and vincristine (HD-CAV) alternating with ifosfamide and etoposide (IE) chemotherapy combined with aggressively attempted R0 resection). We aimed to review the molecular characteristics of DSRCTs to explore therapeutic opportunities for this extremely rare and aggressive cancer type.
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http://dx.doi.org/10.1155/2017/1278268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687144PMC
November 2017

Rapid, ultra low coverage copy number profiling of cell-free DNA as a precision oncology screening strategy.

Oncotarget 2017 Oct 22;8(52):89848-89866. Epub 2017 Sep 22.

Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA.

Current cell-free DNA (cfDNA) next generation sequencing (NGS) precision oncology workflows are typically limited to targeted and/or disease-specific applications. In advanced cancer, disease burden and cfDNA tumor content are often elevated, yielding unique precision oncology opportunities. We sought to demonstrate the utility of a pan-cancer, rapid, inexpensive, whole genome NGS of cfDNA approach (PRINCe) as a precision oncology screening strategy via ultra-low coverage (~0.01x) tumor content determination through genome-wide copy number alteration (CNA) profiling. We applied PRINCe to a retrospective cohort of 124 cfDNA samples from 100 patients with advanced cancers, including 76 men with metastatic castration-resistant prostate cancer (mCRPC), enabling cfDNA tumor content approximation and actionable focal CNA detection, while facilitating concordance analyses between cfDNA and tissue-based NGS profiles and assessment of cfDNA alteration associations with mCRPC treatment outcomes. Therapeutically relevant focal CNAs were present in 42 (34%) cfDNA samples, including 36 of 93 (39%) mCRPC patient samples harboring AR amplification. PRINCe identified pre-treatment cfDNA CNA profiles facilitating disease monitoring. Combining PRINCe with routine targeted NGS of cfDNA enabled mutation and CNA assessment with coverages tuned to cfDNA tumor content. In mCRPC, genome-wide PRINCe cfDNA and matched tissue CNA profiles showed high concordance (median Pearson correlation = 0.87), and PRINCe detectable amplifications predicted reduced time on therapy, independent of therapy type (Kaplan-Meier log-rank test, chi-square = 24.9, < 0.0001). Our screening approach enables robust, broadly applicable cfDNA-based precision oncology for patients with advanced cancer through scalable identification of therapeutically relevant CNAs and pre-/post-treatment genomic profiles, enabling cfDNA- or tissue-based precision oncology workflow optimization.
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http://dx.doi.org/10.18632/oncotarget.21163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685714PMC
October 2017

Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers.

Nat Genet 2017 Dec 6;49(12):1693-1704. Epub 2017 Nov 6.

Department of Medicine, University of California, San Francisco, San Francisco, California, USA.

A widespread approach to modern cancer therapy is to identify a single oncogenic driver gene and target its mutant-protein product (for example, EGFR-inhibitor treatment in EGFR-mutant lung cancers). However, genetically driven resistance to targeted therapy limits patient survival. Through genomic analysis of 1,122 EGFR-mutant lung cancer cell-free DNA samples and whole-exome analysis of seven longitudinally collected tumor samples from a patient with EGFR-mutant lung cancer, we identified critical co-occurring oncogenic events present in most advanced-stage EGFR-mutant lung cancers. We defined new pathways limiting EGFR-inhibitor response, including WNT/β-catenin alterations and cell-cycle-gene (CDK4 and CDK6) mutations. Tumor genomic complexity increases with EGFR-inhibitor treatment, and co-occurring alterations in CTNNB1 and PIK3CA exhibit nonredundant functions that cooperatively promote tumor metastasis or limit EGFR-inhibitor response. This study calls for revisiting the prevailing single-gene driver-oncogene view and links clinical outcomes to co-occurring genetic alterations in patients with advanced-stage EGFR-mutant lung cancer.
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http://dx.doi.org/10.1038/ng.3990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709185PMC
December 2017

Cancer DNA in the Circulation: The Liquid Biopsy.

JAMA 2017 10;318(13):1272-1274

The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.

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http://dx.doi.org/10.1001/jama.2017.12131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5819336PMC
October 2017

Direct detection of early-stage cancers using circulating tumor DNA.

Sci Transl Med 2017 Aug;9(403)

The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Early detection and intervention are likely to be the most effective means for reducing morbidity and mortality of human cancer. However, development of methods for noninvasive detection of early-stage tumors has remained a challenge. We have developed an approach called targeted error correction sequencing (TEC-Seq) that allows ultrasensitive direct evaluation of sequence changes in circulating cell-free DNA using massively parallel sequencing. We have used this approach to examine 58 cancer-related genes encompassing 81 kb. Analysis of plasma from 44 healthy individuals identified genomic changes related to clonal hematopoiesis in 16% of asymptomatic individuals but no alterations in driver genes related to solid cancers. Evaluation of 200 patients with colorectal, breast, lung, or ovarian cancer detected somatic mutations in the plasma of 71, 59, 59, and 68%, respectively, of patients with stage I or II disease. Analyses of mutations in the circulation revealed high concordance with alterations in the tumors of these patients. In patients with resectable colorectal cancers, higher amounts of preoperative circulating tumor DNA were associated with disease recurrence and decreased overall survival. These analyses provide a broadly applicable approach for noninvasive detection of early-stage tumors that may be useful for screening and management of patients with cancer.
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http://dx.doi.org/10.1126/scitranslmed.aan2415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714979PMC
August 2017

Utility of Genomic Assessment of Blood-Derived Circulating Tumor DNA (ctDNA) in Patients with Advanced Lung Adenocarcinoma.

Clin Cancer Res 2017 Sep 24;23(17):5101-5111. Epub 2017 May 24.

Center for Personalized Cancer Therapy and Division of Hematology and Oncology, UCSD Moores Cancer Center, La Jolla, California.

Genomic alterations in blood-derived circulating tumor DNA (ctDNA) from patients with non-small cell lung adenocarcinoma (NSCLC) were ascertained and correlated with clinical characteristics and therapeutic outcomes. Comprehensive plasma ctDNA testing was performed in 88 consecutive patients; 34 also had tissue next-generation sequencing; 29, other forms of genotyping; and 25 (28.4%) had no tissue molecular tests because of inadequate tissue or biopsy contraindications. Seventy-two patients (82%) had ≥1 ctDNA alteration(s); among these, 75% carried alteration(s) potentially actionable by FDA-approved (61.1%) or experimental drug(s) in clinical trials (additional 13.9%). The most frequent alterations were in the (44.3% of patients), (27.3%), (14.8%), (13.6%), and (6.8%) genes. The concordance rate for alterations was 80.8% (100% vs. 61.5%; ≤1 vs. >1 month between ctDNA and tissue tests; = 0.04) for patients with any detectable ctDNA alterations. Twenty-five patients (28.4%) received therapy matching ≥1 ctDNA alteration(s); 72.3% ( = 16/22) of the evaluable matched patients achieved stable disease ≥6 months (SD) or partial response (PR). Five patients with ctDNA-detected T790M were subsequently treated with a third generation EGFR inhibitor; all five achieved SD ≥ 6 months/PR. Patients with ≥1 alteration with ≥5% variant allele fraction (vs. < 5%) had a significantly shorter median survival ( = 0.012). ctDNA analysis detected alterations in the majority of patients, with potentially targetable aberrations found at expected frequencies. Therapy matched to ctDNA alterations demonstrated appreciable therapeutic efficacy, suggesting clinical utility that warrants future prospective studies. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-2497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581668PMC
September 2017

Cell-Free DNA from Ascites and Pleural Effusions: Molecular Insights into Genomic Aberrations and Disease Biology.

Mol Cancer Ther 2017 05;16(5):948-955

Division of Hematology and Oncology, University of California San Diego, San Diego, California.

Collection of cell-free DNA (cfDNA) from the blood of individuals with cancer has permitted noninvasive tumor genome analysis. Detection and characterization of cfDNA in ascites and pleural effusions have not yet been reported. Herein, we analyzed cfDNA in the ascites and pleural effusions from six individuals with metastatic cancer. In all cases, cfDNA copy number variations (CNV) were discovered within the effusate. One individual had a relevant alteration with a high copy amplification in in a never smoker with lung cancer, who showed only and amplification in a prior tissue biopsy. Another subject with metastatic breast cancer had cytology-positive ascites and an activating mutation identified in the tissue, blood, and ascites collectively. This individual had tumor regression after the administration of the mTOR inhibitor everolimus and had evidence of chromotripsis from chromosomal rearrangements noted in the cell-free ascitic fluid. These results indicate that cfDNA from ascites and pleural effusions may provide additional information not detected with tumor and plasma cell-free DNA molecular characterization, and a context for important insights into tumor biology and clonal dynamic change within primary tumor and metastatic deposits. .
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http://dx.doi.org/10.1158/1535-7163.MCT-16-0436DOI Listing
May 2017

Monitoring Daily Dynamics of Early Tumor Response to Targeted Therapy by Detecting Circulating Tumor DNA in Urine.

Clin Cancer Res 2017 Aug 18;23(16):4716-4723. Epub 2017 Apr 18.

University of California San Diego, Moores Cancer Center, La Jolla, California.

Noninvasive drug biomarkers for the early assessment of tumor response can enable adaptive therapeutic decision-making and proof-of-concept studies for investigational drugs. Circulating tumor DNA (ctDNA) is released into the circulation by tumor cell turnover and has been shown to be detectable in urine. We tested the hypothesis that dynamic changes in EGFR activating (exon 19del and L858R) and resistance (T790M) mutation levels detected in urine could inform tumor response within days of therapy for advanced non-small cell lung cancer (NSCLC) patients receiving osimertinib, a second-line third-generation anti-EGFR tyrosine kinase inhibitor. Eight of nine evaluable NSCLC patients had detectable T790M-mutant DNA fragments in pretreatment baseline samples. Daily monitoring of mutations in urine indicated a pattern of intermittent spikes throughout week 1, suggesting apoptosis with an overall decrease in fragment numbers from baselines to day 7 preceding radiographic response assessed at 6 to 12 weeks. These findings suggest drug-induced tumor apoptosis within days of initial dosing. Daily sampling of ctDNA may enable early assessment of patient response and proof-of-concept studies for drug development. The modeling of tumor lysis through the day-to-day kinetics of ctDNA released into the blood and then into the urine is demonstrated in this proof-of-concept study in lung cancer patients receiving anti-EGFR tyrosine kinase inhibitors. This strategy may determine the specific clonal populations of cells which undergo apoptosis within the first week of therapy. This has important implications for developing combinational strategies to address inter- and intralesional heterogeneity and characterizing residual disease after initial drug exposure. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-0454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737735PMC
August 2017

Circulating Tumor DNA for Mutation Detection and Identification of Mechanisms of Resistance in Non-Small Cell Lung Cancer.

Mol Diagn Ther 2017 08;21(4):375-384

University of California San Diego Moores Cancer Center, #3011, San Diego, CA, 92093, USA.

Targeted therapies have changed the treatment landscape of non-small cell lung cancer over the past decade. Analyses of cell free circulating tumor DNA (ctDNA) provide a non-invasive and robust approach for cancer diagnosis and prognosis, real-time monitoring of treatment response, and the identification of appropriate therapeutic targets based on the detection of tumor genetic aberrations. Recent improvements in the sensitivity, specificity, and feasibility of ctDNA detection assays allow the possibility for implementation into clinical practice. This review will focus on key studies using ctDNA analysis in early lung cancer detection, prediction of treatment response, monitoring minimal residual disease and disease relapse, and the identification of resistance mechanisms. We explore how ctDNA can be used as a surrogate for tissue biopsy and an integral biomarker in the clinical management of patients with non-small cell lung cancer.
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http://dx.doi.org/10.1007/s40291-017-0260-5DOI Listing
August 2017

Strategies to Overcome Bypass Mechanisms Mediating Clinical Resistance to EGFR Tyrosine Kinase Inhibition in Lung Cancer.

Mol Cancer Ther 2017 02;16(2):265-272

Division of Hematology and Oncology, Center for Personalized Cancer Therapy, University of California, San Diego, Moores Cancer Center, La Jolla, California.

The vast majority of patients with metastatic lung cancers who initially benefit from EGFR-targeted therapies eventually develop resistance. An increasing understanding of the number and complexity of resistance mechanisms highlights the challenge of treating tumors resistant to EGFR inhibitors. Resistance mechanisms include new, second-site mutations within EGFR (e.g., T790M and C797S), upregulation of MET kinase, upregulation of insulin growth factor receptor (IGFR), HER2 amplification, increased expression of AXL, BIM modulation, NF-κB activation, histologic switch to small-cell cancer, epithelial-to-mesenchymal transition, PDL1 expression with subsequent immune tolerance, and release of cytokines such as TGFβ and IL6. Herein, we review the growing body of knowledge regarding EGFR bypass pathways, and the development of new drugs and combination treatment strategies to overcome resistance. Mol Cancer Ther; 16(2); 265-72. ©2017 AACR.
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http://dx.doi.org/10.1158/1535-7163.MCT-16-0105DOI Listing
February 2017

New Targets in Non-Small Cell Lung Cancer.

Hematol Oncol Clin North Am 2017 02;31(1):113-129

Division of Hematology and Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address:

With the implementation of genomic technologies into clinical practice, we have examples of the predictive benefit of targeted therapy for oncogene-addicted cancer and identified molecular dependencies in non-small cell lung cancer. The clinical success of tyrosine kinase inhibitors against epidermal growth factor receptor and anaplastic lymphoma kinase activation has shifted treatment emphasize the separation of subsets of lung cancer and genotype-directed therapy. Advances have validated oncogenic driver genes and led to the development of targeted agents. This review highlights treatment options, including clinical trials for ROS1 rearrangement, RET fusions, NTRK1 fusions, MET exon skipping, BRAF mutations, and KRAS mutations.
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http://dx.doi.org/10.1016/j.hoc.2016.08.010DOI Listing
February 2017

Use of Liquid Biopsies in Clinical Oncology: Pilot Experience in 168 Patients.

Clin Cancer Res 2016 Nov 16;22(22):5497-5505. Epub 2016 May 16.

Center for Personalized Cancer Therapy and Division of Hematology and Oncology, UCSD Moores Cancer Center, La Jolla, California.

Purpose: There is a growing interest in using circulating tumor DNA (ctDNA) testing in patients with cancer.

Experimental Design: A total of 168 patients with diverse cancers were analyzed. Patients had digital next-generation sequencing (54 cancer-related gene panel including amplifications in ERBB2, EGFR, and MET) performed on their plasma. Type of genomic alterations, potential actionability, concordance with tissue testing, and patient outcome were examined.

Results: Fifty-eight percent of patients (98/168) had ≥1 ctDNA alteration(s). Of the 98 patients with alterations, 71.4% had ≥ 1 alteration potentially actionable by an FDA-approved drug. The median time interval between the tissue biopsy and the blood draw was 2.7 months for patients with ≥ 1 alteration in common compared with 14.4 months (P = 0.006) for the patients in whom no common alterations were identified in the tissue and plasma. Overall concordance rates for tissue and ctDNA were 70.3% for TP53 and EGFR, 88.1% for PIK3CA, and 93.1% for ERBB2 alterations. There was a significant correlation between the cases with ≥ 1 alteration with ctDNA ≥ 5% and shorter survival (median = 4.03 months vs. not reached at median follow-up of 6.1 months; P < 0.001). Finally, 5 of the 12 evaluable patients (42%) matched to a treatment targeting an alteration(s) detected in their ctDNA test achieved stable disease ≥ 6 months/partial remission compared with 2 of 28 patients (7.1%) for the unmatched patients, P = 0.02.

Conclusions: Our initial study demonstrates that ctDNA tests provide information complementary to that in tissue biopsies and may be useful in determining prognosis and treatment. Clin Cancer Res; 22(22); 5497-505. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-16-0318DOI Listing
November 2016

Novel Treatment Strategies for Brain Metastases in Non-small-cell Lung Cancer.

Curr Treat Options Oncol 2016 May;17(5):25

Division of Hematology and Oncology, University of California, San Diego School of Medicine, UCSD Moores Cancer Center, San Diego, CA, USA.

Opinion Statement: Brain metastases are common in patients with non-small cell lung cancer (NSCLC), and due to associated poor prognosis, this field is an important area of need for the development of innovative medical therapies. Therapies including local approaches through surgical intervention and/or radiation and evolving systemic therapies have led to improvements in the treatment of brain metastases in patients with lung cancer. Strategies that consider applying advanced radiation techniques to minimize toxicity, intervening early with effective systemic therapies to spare radiation/surgery, testing radiosensitization combinations, and developing drug penetrant molecules have and will continue to define new practice patterns. We believe that in carefully considered asymptomatic patients, first-line systemic therapy may be considered before radiation therapy and small-molecule targeted therapy may provide an opportunity to defer radiation therapy for recurrence or progression of disease. The next several years in oncology drug development will see the reporting on of brain penetrant molecules in oncogene-defined non-small cell lung cancer. Ongoing studies will evaluate immunotherapies in patients with brain metastases with associated endpoints. We hope that continued drug development and carefully designed clinical trials may afford an opportunity to improve the lives of patients with brain metastases.
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http://dx.doi.org/10.1007/s11864-016-0400-xDOI Listing
May 2016

Detection rate of actionable mutations in diverse cancers using a biopsy-free (blood) circulating tumor cell DNA assay.

Oncotarget 2016 Mar;7(9):9707-17

Center for Personalized Cancer Therapy and Division of Hematology and Oncology, UCSD Moores Cancer Center, La Jolla, CA, USA.

Analysis of cell-free DNA using next-generation sequencing (NGS) is a powerful tool for the detection/monitoring of alterations present in circulating tumor DNA (ctDNA). Plasma extracted from 171 patients with a variety of cancers was analyzed for ctDNA (54 genes and copy number variants (CNVs) in three genes (EGFR, ERBB2 and MET)). The most represented cancers were lung (23%), breast (23%), and glioblastoma (19%). Ninety-nine patients (58%) had at least one detectable alteration. The most frequent alterations were TP53 (29.8%), followed by EGFR (17.5%), MET (10.5%), PIK3CA (7%), and NOTCH1 (5.8%). In contrast, of 222 healthy volunteers, only one had an aberration (TP53). Ninety patients with non-brain tumors had a discernible aberration (65% of 138 patients; in 70% of non-brain tumor patients with an alteration, the anomaly was potentially actionable). Interestingly, nine of 33 patients (27%) with glioblastoma had an alteration (6/33 (18%) potentially actionable). Overall, sixty-nine patients had potentially actionable alterations (40% of total; 69.7% of patients (69/99) with alterations); 68 patients (40% of total; 69% of patients with alterations), by a Food and Drug Administration (FDA) approved drug. In summary, 65% of diverse cancers (as well as 27% of glioblastomas) had detectable ctDNA aberration(s), with the majority theoretically actionable by an approved agent.
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http://dx.doi.org/10.18632/oncotarget.7110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891078PMC
March 2016

An integrin β₃-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition.

Nat Cell Biol 2014 May 20;16(5):457-68. Epub 2014 Apr 20.

Department of Pathology and Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.

Tumour cells, with stem-like properties, are highly aggressive and often show drug resistance. Here, we reveal that integrin α(v)β₃ serves as a marker of breast, lung and pancreatic carcinomas with stem-like properties that are highly resistant to receptor tyrosine kinase inhibitors such as erlotinib. This was observed in vitro and in mice bearing patient-derived tumour xenografts or in clinical specimens from lung cancer patients who had progressed on erlotinib. Mechanistically, α(v)β₃, in the unliganded state, recruits KRAS and RalB to the tumour cell plasma membrane, leading to the activation of TBK1 and NF-κB. In fact, α(v)β₃ expression and the resulting KRAS-RalB-NF-κB pathway were both necessary and sufficient for tumour initiation, anchorage independence, self-renewal and erlotinib resistance. Pharmacological targeting of this pathway with bortezomib reversed both tumour stemness and erlotinib resistance. These findings not only identify α(v)β₃ as a marker/driver of carcinoma stemness but also reveal a therapeutic strategy to sensitize such tumours to RTK inhibition.
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http://dx.doi.org/10.1038/ncb2953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4105198PMC
May 2014

Nuclear epidermal growth factor receptor and p16 expression in head and neck squamous cell carcinoma.

Laryngoscope 2012 Dec 19;122(12):2762-8. Epub 2012 Oct 19.

Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Objectives/hypothesis: Epidermal growth factor receptor (EGFR) and p16 (a surrogate marker of human papillomavirus [HPV] infection) expression are strong prognostic factors in patients with head and neck squamous cell carcinoma (HNSCC).

Study Design: We examined expression levels of total and nuclear EGFR as well as p16 status based on evidence that nuclear EGFR may have a role in DNA damage repair.

Methods: An HPV-negative (SQ20B) and an HPV-positive (UMSCC47) HNSCC cell line were examined for EGFR and γH2AX expression. A tissue microarray containing 123 cores obtained from 101 HNSCC tumors was analyzed for EGFR expression by automated quantitative analysis and p16 expression by immunohistochemical staining, and these results were correlated with available clinical data.

Results: SQ20B had higher EGFR expression than UMSCC47. Nuclear localization of EGFR on activation with transforming growth factor-α was observed in SQ20B, but not in UMSCC47. SQ20B also had increased γH2AX foci compared to UMSCC47, suggesting that SQ20B has more DNA damage compared to UMSCC47. Total and nuclear EGFR was reliably obtained from 80 of 101 patients. p16 levels were determined in 87 of 101 patients. p16 levels were strongly associated with the oropharyngeal subsite and poorly differentiated histology. Expression of total and nuclear EGFR was higher in p16-negative tumors compared to p16-positive tumors (Wilcoxon rank test, P = .038 and P = .014, respectively).

Conclusions: Further studies are required to determine a mechanistic link between these two prognostic factors and the significance of EGFR localization to nucleus in DNA damage repair pathway activation.
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http://dx.doi.org/10.1002/lary.23647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3574977PMC
December 2012