Showing papers by "Juliann Chmielecki published in 2015"
TL;DR: Analysis of tumor genomic profiles from 38,028 patients is reported to identify 221 cases with METex14 mutations, including 126 distinct sequence variants, and identify a unique subset of patients likely to derive benefit from MET inhibitors.
Abstract: Focal amplification and activating point mutation of the MET gene are well-characterized oncogenic drivers that confer susceptibility to targeted MET inhibitors. Recurrent somatic splice site alterations at MET exon 14 ( MET ex14) that result in exon skipping and MET activation have been characterized, but their full diversity and prevalence across tumor types are unknown. Here, we report analysis of tumor genomic profiles from 38,028 patients to identify 221 cases with MET ex14 mutations (0.6%), including 126 distinct sequence variants. MET ex14 mutations are detected most frequently in lung adenocarcinoma (3%), but also frequently in other lung neoplasms (2.3%), brain glioma (0.4%), and tumors of unknown primary origin (0.4%). Further in vitro studies demonstrate sensitivity to MET inhibitors in cells harboring MET ex14 alterations. We also report three new patient cases with MET ex14 alterations in lung or histiocytic sarcoma tumors that showed durable response to two different MET-targeted therapies. The diversity of MET ex14 mutations indicates that diagnostic testing via comprehensive genomic profiling is necessary for detection in a clinical setting.
Significance: Here we report the identification of diverse exon 14 splice site alterations in MET that result in constitutive activity of this receptor and oncogenic transformation in vitro . Patients whose tumors harbored these alterations derived meaningful clinical benefit from MET inhibitors. Collectively, these data support the role of MET ex14 alterations as drivers of tumorigenesis, and identify a unique subset of patients likely to derive benefit from MET inhibitors. Cancer Discov; 5(8); 850–9. ©2015 AACR .
See related commentary by Ma, [p. 802][1] .
See related article by Paik et al., [p. 842][2] .
This article is highlighted in the In This Issue feature, [p. 783][3]
[1]: /lookup/volpage/5/802?iss=8
[2]: /lookup/volpage/5/842?iss=8
[3]: /lookup/volpage/5/783?iss=8
585 citations
TL;DR: This study presents the first unbiased view of the genomic basis of MPM, with whole-exome sequencing on DNA from 22 MPMs and matched blood samples and identified 517 somatic mutations across 490 mutated genes.
Abstract: This is the first unbiased view of the molecular basis of mesothelioma, revealing frequent genetic alterations that will offer a valuable foundation for biologic studies.
266 citations
TL;DR: Almost all CUP samples harbored at least 1 clinically relevant GA with potential to influence and personalize therapy and the ACUP tumors were more frequently driven by GAs in the highly druggable RTK/Ras/mitogen-activated protein kinase (MAPK) signaling pathway than the non-ACUP tumors.
Abstract: Importance For carcinoma of unknown primary site (CUP), determining the primary tumor site may be uninformative and often does not improve outcome. Objective To discover opportunities for targeted therapies in patients with CUP not currently searched for in routine practice. Design, Setting, and Participants Comprehensive genomic profiling on 200 CUP formalin-fixed paraffin-embedded specimens (mean, 756× coverage) using the hybrid-capture–based FoundationOne assay at academic and community oncology clinics. Main Outcomes and Measures Presence of targetable genomic alterations (GAs) in CUP and responses to targeted therapies. Results There were 125 adenocarcinomas of unknown primary site (ACUPs) and 75 carcinomas of unknown primary site without features of adenocarcinoma (non-ACUPs). At least 1 GA was found in 192 (96%) of CUP specimens, with a mean (SD) of 4.2 (2.8) GAs per tumor. The most frequent GAs were in TP53 (110 [55%]), KRAS (40 [20%]), CDKN2A (37 [19%]), MYC (23 [12%]), ARID1A (21 [11%]), MCL1 (19 [10%]), PIK3CA (17 [9%]), ERBB2 (16 [8%]), PTEN (14 [7%]), EGFR (12 [6%]) , SMAD4 (13 [7%]), STK11 (13 [7%]), SMARCA4 (12 [6%]), RB1 (12 [6%]), RICTOR (12 [6%]), MLL2 (12 [6%]), BRAF (11 [6%]), and BRCA2 (11 [6%]). One or more potentially targetable GAs were identified in 169 of 200 (85%) CUP specimens. Mutations or amplifications of ERBB2 were more frequent in ACUPs (13 [10%]) than in non-ACUPs (3 [4%]). Alterations of EGFR (10 [8%] vs 2 [3%]) and BRAF (8 [6%] vs 3 [4%]) were more common in ACUPs than in non-ACUPs. Strikingly, clinically relevant alterations in the receptor tyrosine kinase (RTK)/Ras signaling pathway including alterations in ALK , ARAF , BRAF , EGFR , FGFR1 , FGFR2 , KIT , KRAS , MAP2K1 , MET , NF1 , NF2 , NRAS , RAF1 , RET , and ROS1 were found in 90 (72%) ACUPs but in only 29 (39%) non-ACUPs ( P .001). Conclusions and Relevance Almost all CUP samples harbored at least 1 clinically relevant GA with potential to influence and personalize therapy. The ACUP tumors were more frequently driven by GAs in the highly druggable RTK/Ras/mitogen-activated protein kinase (MAPK) signaling pathway than the non-ACUP tumors. Comprehensive genomic profiling can identify novel treatment paradigms to address the limited options and poor prognoses of patients with CUP.
192 citations
TL;DR: It is demonstrated that mutations affecting CTNNB1 or APC occur more frequently in desmoids than previously recognized, and designation of wild‐type genotype is largely determined by sensitivity of detection methods.
Abstract: CTNNB1 mutations or APC abnormalities have been observed in ∼85% of desmoids examined by Sanger sequencing and are associated with Wnt/β-catenin activation. We sought to identify molecular aberrations in "wild-type" tumors (those without CTNNB1 or APC alteration) and to determine their prognostic relevance. CTNNB1 was examined by Sanger sequencing in 117 desmoids; a mutation was observed in 101 (86%) and 16 were wild type. Wild-type status did not associate with tumor recurrence. Moreover, in unsupervised clustering based on U133A-derived gene expression profiles, wild-type and mutated tumors clustered together. Whole-exome sequencing of eight of the wild-type desmoids revealed that three had a CTNNB1 mutation that had been undetected by Sanger sequencing. The mutation was found in a mean 16% of reads (vs. 37% for mutations identified by Sanger). Of the other five wild-type tumors sequenced, two had APC loss, two had chromosome 6 loss, and one had mutation of BMI1. The finding of low-frequency CTNNB1 mutation or APC loss in wild-type desmoids was validated in the remaining eight wild-type desmoids; directed miSeq identified low-frequency CTNNB1 mutation in four and comparative genomic hybridization identified APC loss in one. These results demonstrate that mutations affecting CTNNB1 or APC occur more frequently in desmoids than previously recognized (111 of 117; 95%), and designation of wild-type genotype is largely determined by sensitivity of detection methods. Even true CTNNB1 wild-type tumors (determined by next-generation sequencing) may have genomic alterations associated with Wnt activation (chromosome 6 loss/BMI1 mutation), supporting Wnt/β-catenin activation as the common pathway governing desmoid initiation.
123 citations
TL;DR: This is the first report of RET rearrangement co-existing with activated EGFR mutations in EGFR-mutated patients who had progressed on either first- or second generation EGFR TKI.
84 citations
TL;DR: Comprehensive genomic profiling highlights the promise of identifying clinically relevant genomic alterations in both ESCC and EAC and suggests new avenues for molecularly directed therapies in esophageal cancer.
Abstract: Background.
Esophageal squamous cell carcinomas (ESCCs) and esophageal adenocarcinomas (EACs) account for >95% of esophageal malignancies and represent a major global health burden. ESCC is the dominant histology globally but represents a minority of U.S. cases, with EAC accounting for the majority of U.S. cases. The patient outcomes for advanced ESCC and EAC are poor, and new therapeutic options are needed. Using a sensitive sequencing assay, we compared the genomic profiles of ESCC and EAC with attention to identification of therapeutically relevant genomic alterations.
78 citations
TL;DR: This case represents the first report of clinical response to targeted therapy in a tumor harboring a DCTN1-ALK fusion protein, and can identify clinical relevant genomic alterations that both direct treatment targeted therapy and help discriminate between similar diagnostic entities.
Abstract: Recurrent, metastatic mesenchymal myxoid tumors of the gynecologic tract present a management challenge as there is minimal evidence to guide systemic therapy Such tumors also present a diagnostic dilemma, as myxoid features are observed in leiomyosarcomas, inflammatory myofibroblastic tumors (IMT), and mesenchymal myxoid tumors Comprehensive genomic profiling was performed in the course of clinical care on a case of a recurrent, metastatic myxoid uterine malignancy (initially diagnosed as smooth muscle tumor of uncertain malignant potential (STUMP)), to guide identify targeted therapeutic options To our knowledge, this case represents the first report of clinical response to targeted therapy in a tumor harboring a DCTN1-ALK fusion protein Hybridization capture of 315 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer was applied to >50 ng of DNA extracted from this sample and sequenced to high, uniform coverage Therapy was given in the context of a phase I clinical trial ClinicalTrialsgov Identifier: (
NCT01548144
) Immunostains showed diffuse positivity for ALK1 expression and comprehensive genomic profiling identified an in frame DCTN1-ALK gene fusion The diagnosis of STUMP was revised to that of an IMT with myxoid features The patient was enrolled in a clinical trial and treated with an anaplastic lymphoma kinase (ALK) inhibitor (crizotinib/Xalkori®) and a multikinase VEGF inhibitor (pazopanib/Votrient®) The patient experienced an ongoing partial response (6+ months) by response evaluation criteria in solid tumors (RECIST) 11 criteria For myxoid tumors of the gynecologic tract, comprehensive genomic profiling can identify clinical relevant genomic alterations that both direct treatment targeted therapy and help discriminate between similar diagnostic entities
77 citations
TL;DR: Standard slide-based tests for overexpression or amplification of ERBB2 would fail to detect the majority of activating mutations that occur overwhelmingly in the absence of copy number changes, suggesting comprehensive genomic profiling of a more diverse set of tumor types may identify 3.5 times the number of patients who may benefit from ER BB2-targeted therapy.
Abstract: Background.
Targeted ERBB2/HER2 inhibitors are approved by the U.S. Food and Drug Administration for the treatment of breast, gastric, and esophageal cancers that overexpress or amplify HER2/ERBB2, as measured by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively. Activating mutations in ERBB2 have also been reported and are predicted to confer sensitivity to these targeted agents. Testing for these mutations is not performed routinely, and FISH and IHC are not applied outside of these approved indications.
70 citations
TL;DR: Comprehensive genomic profiling of GC identifies clinically relevant GAs that suggest benefit from targeted therapy including MET-amplified GC and ERBB2 base substitutions.
Abstract: Background. Gastric cancer (GC) is a major global cancer burden and the second most common cause of global cancer-related deaths. The addition of anti-ERBB2 (HER2) targeted therapy to chemotherapy improves survival for ERBB2-amplifiedadvancedGCpatients;however,themajority of GC patients do not harbor this alteration and thus cannot benefit from targeted therapy under current practice paradigms. Materials and Methods. Prospective comprehensive genomic profiling of 116 predominantly locally advanced or metastatic (90.0%) gastric cancer cases was performed to identify genomic alterations(GAs)associatedwithapotentialresponsetotargeted therapiesapprovedbytheU.S.FoodandDrug Administrationor targeted therapy-based clinical trials. Results. Overall, 78% of GC cases harbored one clinically relevant GAormore,withthemostfrequentalterationsbeingfoundinTP53 (50%), ARID1A (24%), KRAS (16%), CDH1 (15%), CDKN2A (14%), CCND1 (9.5%), ERBB2 (8.5%), PIK3CA (8.6%), MLL2 (6.9%), FGFR2 (6.0%), and MET (6.0%). Receptor tyrosine kinase genomic alterations were detected in 20.6% of cases, primarily ERBB2, FGFR2, andMETamplification,withERBB2alterationsevenlysplitbetween amplifications and base substitutions. Rare BRAF mutations (2.6%) were also observed. One MET-amplified GC patient responded for 5 months to crizotinib, a multitargeted ALK/ROS1/MET inhibitor. Conclusion. ComprehensivegenomicprofilingofGCidentifies clinically relevant GAs that suggest benefit from targeted therapy including MET-amplified GC and ERBB2 base substitutions. The Oncologist 2015;20:1–9 ImplicationsforPractice:Despitedescriptionofmanypotentiallyclinicallyrelevantgenomicalterationsinretrospectiveresearch studies, these alterations are not regularly assessed in a comprehensive manner in clinical practice.This study demonstratesthe feasibility of prospective comprehensive genomic profiling (CGP) for advanced gastric carcinoma. We demonstrated a high frequency of genomic alterations associated with potential benefit from targeted therapies. CGP in this setting may inform therapeutic options beyond standard of care testing by identifying genomic alterations such as point mutations in the kinase domain of ERBB2 and MET amplification. Genotype-directed management is highlighted by the response of a MET-amplified gastric carcinoma patient to crizotinib.
61 citations
TL;DR: Comprehensive genomic profiling uncovered a high frequency of GA in IBC with 96 % of cases harboring at least 1 CRGA and the clinical benefit of selected targeted therapies in individual IBC cases suggests that a further study of CGP in I BC is warranted.
Abstract: Inflammatory breast cancer (IBC) is a distinct clinicopathologic entity that carries a worse prognosis relative to non-IBC breast cancer even when matched for standard biomarkers (ER/PR/HER2). The objective of this study was to identify opportunities for benefit from targeted therapy, which are not currently identifiable in the standard workup for advanced breast cancer. Comprehensive genomic profiling on 53 IBC formalin-fixed paraffin-embedded specimens (mean, 800× + coverage) using the hybrid capture-based FoundationOne assay. Academic and community oncology clinics. From a series of 2208 clinical cases of advanced/refractory invasive breast cancers, 53 cases with IBC were identified. The presence of clinically relevant genomic alterations (CRGA) in IBC and responses to targeted therapies. CRGA were defined as genomic alterations (GA) associated with on label targeted therapies and targeted therapies in mechanism-driven clinical trials. For the 44 IBCs with available biomarker data, 19 (39 %) were ER−/PR−/HER2− (triple-negative breast cancer, TNBC). For patients in which the clinical HER2 status was known, 11 (25 %) were HER2+ with complete (100 %) concordance with ERBB2 (HER2) amplification detected by the CGP assay. The 53 sequenced IBC cases harbored a total of 266 GA with an average of 5.0 GA/tumor (range 1–15). At least one alteration associated with an FDA approved therapy or clinical trial was identified in 51/53 (96 %) of cases with an average of 2.6 CRGA/case. The most frequently altered genes were TP53 (62 %), MYC (32 %), PIK3CA (28 %), ERBB2 (26 %), FGFR1 (17 %), BRCA2 (15 %), and PTEN (15 %). In the TNBC subset of IBC, 8/19 (42 %) showed MYC amplification (median copy number 8X, range 7–20) as compared to 9/32 (28 %) in non-TNBC IBC (median copy number 7X, range 6–21). Comprehensive genomic profiling uncovered a high frequency of GA in IBC with 96 % of cases harboring at least 1 CRGA. The clinical benefit of selected targeted therapies in individual IBC cases suggests that a further study of CGP in IBC is warranted.
60 citations
TL;DR: This work queried whether comprehensive genomic profiling of IHCCA, EHCCa and GBCA would reveal clinically relevant genomic alterations (CRGA) that could lead to targeted therapies and found patient characteristics were similar for all three tumor types.
Abstract: 231 Background: Intrahepatic cholangiocarcinoma (IHCCA), extrahepatic cholangiocarcinoma (EHCCA) and gallbladder carcinomas (GBCA) typically present at an advanced stage and systemic chemotherapy provides only modest benefit in most cases. We queried whether comprehensive genomic profiling (GCP) of IHCCA, EHCCA and GBCA would reveal clinically relevant genomic alterations (CRGA) that could lead to targeted therapies. Methods: DNA was extracted from 40µ of FFPE sections from 412 IHCCA, 57 EHCCA and 85 GBCA. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of >600X for 3,230 exons of 182 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. The CGP assay included base substitutions, INDELs, copy number alterations and fusions/rearrangements. CRGA were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: Patient characteristics were similar for all three tumor types. IH...
TL;DR: Pat characteristics were similar for all three tumor types, and IHCCA and GBCa were more common in females and EHCCa was more common males.
Abstract: 4009 Background: Intrahepatic cholangiocarcinoma (IHCCA), extrahepatic cholangiocarcinoma (EHCCA) and gallbladder carcinomas (GBCA) typically present at an advanced stage and chemotherapy provides ...
TL;DR: For neoplasms harboring PDGFRA rearrangements, FIP1L1–PDGFRA is by far the most common fusion detected, reflecting an 800-kb intrachromosomal deletion [del(4)(q12q12)].1
Abstract: Author(s): Chalmers, ZR; Ali, SM; Ohgami, RS; Campregher, PV; Frampton, GM; Yelensky, R; Elvin, JA; Palma, NA; Erlich, R; Vergilio, J-A; Chmielecki, J; Ross, JS; Stephens, PJ; Hermann, R; Miller, VA; Miles, CR
TL;DR: This data indicates that Sarcomas comprise nearly 10% of all cancers (CA) in adolescents and young adults (AYA, age 15-39) and despite high unmet clinical need for better treatments, comprehensive genomic research into these cancers is still lacking.
Abstract: 11020 Background: Sarcomas comprise nearly 10% of all cancers (CA) in adolescents and young adults (AYA, age 15-39). Despite high unmet clinical need for better treatments, comprehensive genomic pr...
TL;DR: Combination therapy of dabrafenib and trametinib with standard cytotoxic chemotherapy resulted in a durable major ongoing response for the patient, illustrating the utility of comprehensive genomic profiling with personalized targeted therapy for aggressive metastatic colorectal adenocarcinomas.
Abstract: The subset of metastatic colorectal adenocarcinomas that harbor BRAF V600E mutations are aggressive tumors with significantly shortened survival and limited treatment options. Here we present a colorectal cancer patient whose disease progressed through standard chemotherapy and who developed liver metastasis. Comprehensive genomic profiling (FoundationOne(®)) identified a BRAF V600E mutation in the liver lesion, as well as other genomic alterations consistent with colorectal cancers. Combination therapy of dabrafenib and trametinib with standard cytotoxic chemotherapy resulted in a durable major ongoing response for the patient. This report illustrates the utility of comprehensive genomic profiling with personalized targeted therapy for aggressive metastatic colorectal adenocarcinomas.
01 Jul 2015
TL;DR: Treatment with trastuzumab with a chemotherapy backbone elicited stable disease/minor response in the patient over a one year course of therapy, reducing tumor burden and significantly improving quality of life.
Abstract: Somatic ERBB2 amplification or activating mutations occur in approximately 2-5% of metastatic colorectal adenocarcinomas and are presumed to be oncogenic drivers, but limited evidence exists to suggest these lesions are sensitive to targeted monotherapy in patients. Here we present the case of a patient with advanced CRC with pulmonary metastases, who had progressed on both standard of care cytotoxic chemotherapy and anti-EGFR targeted therapy. Comprehensive genomic profiling (FoundationOne(®)) identified amplification of ERBB2 and a TP53 mutation in the metastatic lesion. Treatment with trastuzumab with a chemotherapy backbone elicited stable disease/minor response in the patient over a one year course of therapy, reducing tumor burden and significantly improving quality of life. This report demonstrates the application of personalized targeted therapy guided by comprehensive genomic profiling in metastatic colorectal adenocarcinoma.
TL;DR: Whether comprehensive genomic profiling (CGP) could uncover clinically relevant genomic alterations (CRGA) that could lead to targeted therapy selection is queried.
Abstract: 3553 Background: For patients presenting with advanced and metastatic colorectal carcinoma (CRC), standard cytotoxic therapy can provide significant benefit but patients eventually develop progress...
TL;DR: Complete genomic profiling of clinical RCC samples was performed to assess the spectrum of clinically relevant GAs (CRGAs) in advanced RCC with the goal of informing use of existing and novel targeted therapies.
Abstract: 433 Background: Despite the availability of targeted therapy, effective management of advanced RCC is an unmet medical need as treatment is not personalized and is not guided by patient-specific genomic alterations (GAs). To assess the spectrum of clinically relevant GAs (CRGAs) in advanced RCC, comprehensive genomic profiling (CGP) of clinical RCC samples was performed with the goal of informing use of existing and novel targeted therapies. Methods: DNA was extracted from 40 microns of FFPE sections from 443 consecutive patients with relapsed/metastatic RCC. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 646X for 3,230 exons of 182 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. The CGP assay included base substitutions (SUB), INDELs, copy number alterations (CNA) and fusions/rearrangements. CRGA were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: T...
TL;DR: It is hypothesized that, since the majority of ER-positive breast cancers are actually sensitive to endocrine therapy, the most prevalent aberration in this pathway will more likely be associated with endocrine-sensitivity rather than resistance.
Abstract: 532 Background: Aberrations of the PI3K/AKT/mTOR pathway are common in ER-positive breast cancer and may be associated with endocrine-resistance. We hypothesized that, since the majority of ER-posi...
TL;DR: CGP of 99 advanced stage cS CC was undertaken to identify GA associated with targeted therapeutic options relevant to the systemic treatment of cSCC, and CRGA were defined as GAassociated with on-label targeted therapies and targeted therapies in mechanism-driven clinical trials.
Abstract: 5602 Background: High risk HPV initiates neoplasia in cSCC and progression requires additional genomic alterations (GA). Treatment of localized cSCC is effective but the response to systemic therap...
TL;DR: A comprehensive genomic profile-based (CGP) study of UC designed to detect clinically relevant genomic alterations (CRGA) that could inform the selection of established and novel targeted therapies.
Abstract: 4526 Background: Clinically advanced metastatic urothelial carcinoma (UC) is a devastating disease lacking effective systemic therapies. Herein, we present a comprehensive genomic profile-based (CGP) study of UC designed to detect clinically relevant genomic alterations (CRGA) that could inform the selection of established and novel targeted therapies. Methods: DNA was extracted from 295 consecutive cases of relapsed/metastatic UC. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 688X for 236 cancer-related genes. The CGP assay included base substitutions (SUB), INDELs, copy number alterations (CNA) and fusions/rearrangements. CRGA were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: There were 75% male and 25% female patients with a mean age of 66 years. 295/295 (100%) of UC were high grade and advanced stage (III and IV). 294/295 (99.7%) UC had at least 1 GA on CGP with a mean of 6.4 GA...
TL;DR: Comprehensive genomic profiling on 70 patients with ASCC to identify the spectrum of clinically relevant genomic alterations (CRGA), which were defined as GA linked to FDA-approved agents or investigational agents in clinical trials.
Abstract: 3522 Background: Anal squamous cell carcinoma (ASCC) is an HPV-associated rare tumor that has nearly doubled in incidence since 1973, with cisplatin-based chemotherapy as the only treatment shown t...
TL;DR: Characterization of BRAF mutations in glioblastoma and astrocytoma may identify a subgroup of patients with sensitivity to BRAF inhibitors, and this work may help clarify the rationale behind the continued presence of these mutations in patients with GBM.
Abstract: 2074 Background: Although well characterized in pilocytic astrocytoma and pleomorphic xanthroastrocytoma, the prevalence of BRAF alterations in glioblastoma (GBM) and astrocytoma is not well establ
TL;DR: Complete genomic profiling (CGP) of adult granulosa cell tumors (aGCT) identifies clinically relevant genomic alterations (CRGA) and targeted therapy options and demonstrates potential efficacy of an AKT inhibitor in a subset of patients suffering from this otherwise treatment refractory tumor.
Abstract: Background: Adult granulosa cell tumors account for ∼70% of sex cord stromal tumors of the ovary. Most behave as low-grade malignancies and present as stage I disease. However 20% recur, often after a prolonged time (median time to recurrence 6 years). Current therapeutic options (bleomycin/etoposide/cisplatin (BEP), hormone therapy, bevacizumab) have shown modest efficacy in the setting of advanced or recurrent disease. Prior genomic studies of aGCT identified recurrent FOXL2 mutations as characteristic of this tumor type, however this mutation is not currently amenable to targeted therapy. We present the CGP of 70 advanced/recurrent stage aGCT with identification of CRGAs and include a description of a patient response to CGP-matched targeted therapy. Methods: DNA was extracted from 70 FFPE aGCT clinical specimens. Hybridization captured libraries of 236 (FoundationOne, n = 28) or 315 (FoundationOne, n = 42) genes, plus select introns frequently rearranged in cancer, which were sequenced to high (median 780x), uniform coverage. All classes of genomic alterations (base subs, small in/dels, rearrangements, and copy number alterations) were evaluated and reported. CRGA were defined as GA associated with on-label targeted therapies and targeted therapies in mechanism-driven clinical trials. Results: 70 samples, 10% from primary site tissue and 90% from metastatic sites were included. The patients were women aged 30-80 (median 56.5y) with predominantly advanced stage aGCT. 68 cases (97%) had the FOXL2 402C>G mutation and 61% of cases had at least one additional GA (total n = 165) including 37 different genes (avg 2.4 GA per tumor) of which 27 were CRGA (avg 0.44 per tumor). 40% of aGCT cases featured ≥ 1 CRGA, including 14 (20%) cases with CRGA in the PI3K/Akt/mTOR pathway. The most common CRGAs observed were: MLL2 (10%),PIK3CA (8.6%), CDKN2A/B (8.6%), AKT1 (4.3%), KRAS (4.3%); and NRAS (2.8%). To date, we are aware of one patient with an AKT1 missense mutation in the pleckstrin homology domain (AKT1 Q79K) who showed a durable 6-month partial response to AKT-directed targeted treatment. Conclusions: Almost two-thirds of advanced stage aGCT demonstrate GAs in addition to the pathognomonic FOXL2 mutation. 40% of cases demonstrate other targetable mutations, most commonly in the PI3K/Akt/mTOR pathway which present the opportunity for targeted therapy. This first account of a clinical response to CGP-directed targeted therapy in aGCT demonstrates potential efficacy of an AKT inhibitor in a subset of patients suffering from this otherwise treatment refractory tumor. Patients who have exhausted other SOC therapy for metastatic aGCT may similarly achieve clinical benefit from CGP-directed therapeutic decision- making and this provides support for development of further mutation-matched therapeutic trial designs. Citation Format: Michelle Rowland, Scott McMeekin, Kathleen Moore, Mark Bailey, Siraj M. Ali, Rosemary Zuna, Jo-Anne Vergilio, James Suh, Juliann Chmielecki, Garrett M. Frampton, Doron Lipson, Philip J. Stephens, Vincent A. Miller, Jeffrey S. Ross, Julia A. Elvin. Comprehensive genomic profiling (CGP) of adult granulosa cell tumors (aGCT) identifies clinically relevant genomic alterations (CRGA) and targeted therapy options. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A79.
01 Jan 2015
TL;DR: Next-generation sequencing-based comprehensive genomic profiling was performed on hybridization-captured, adaptor ligation-based libraries to a median coverage depth of.6503 for allcodingexonsof315cancer-relatedgenes plus selectedintrons from28genesfrequentlyrearrangedincancer.
Abstract: Background. Esophageal squamous cell carcinomas (ESCCs) andesophagealadenocarcinomas(EACs)accountfor.95%of esophageal malignancies and represent a major global health burden.ESCCisthedominanthistologygloballybutrepresents aminorityofU.S.cases,withEACaccountingforthemajorityof U.S.cases.ThepatientoutcomesforadvancedESCCandEACare poor,andnewtherapeuticoptionsareneeded.Usingasensitive sequencing assay, we compared the genomic profiles of ESCC and EAC with attention to identification of therapeutically relevantgenomic alterations. Methods. Next-generation sequencing-based comprehensive genomic profiling was performed on hybridization-captured, adaptor ligation-based libraries to a median coverage depth of.6503forallcodingexonsof315cancer-relatedgenesplus selectedintronsfrom28genesfrequentlyrearrangedincancer. Results from a single sample were evaluated for all classes of genomic alterations (GAs) including point mutations, short insertions and deletions, gene amplifications, homozygous deletions, and fusions/rearrangements. Clinically relevant genomic alterations (CRGAs) were defined as alterations linked to approved drugs and those under evaluation in mechanismdriven clinical trials.