Insights of Clinical Significance From 109 695 Solid Tumor Tissue-Based Comprehensive Genomic Profiles.

BACKGROUND: FoundationOneCDx is approved in the US and Japan as a companion diagnostic test to identify patients with cancer who may benefit from treatment with 30 drug therapies in the US and 23 in Japan. Tumor profiling with FoundationOneCDx also detects genomic findings with evidence of clinical significance that may inform clinical care decisions beyond companion diagnostic claims. This observational study reports the breadth and impact of clinical decision insights from FoundationOneCDx solid tumor profiles. MATERIALS AND METHODS: Consecutive test result reports for patients with solid tumor diagnoses (n = 109 695) were retrospectively analyzed for clinically significant predictive, prognostic, and diagnostic genomic alterations and signatures, determined in accordance with professional guidelines. Interventional clinical trials with targeted therapies or immune checkpoint inhibitors were matched to tumor profiles based on evidence that the genomic finding may be an actionable, investigational, or hypothetical target in the patient's tumor type. RESULTS: In 14 predefined cancer types (80.7% of analyzed solid tumors), predictive, prognostic, and diagnostic markers were reported in 47.6%, 13.2%, and 4.5% of samples, respectively, accounting for a total of 51.2% of tumor profiles. Pan-cancer predictive markers of tumor mutational burden (TMB) of 10 or more mutations per megabase, high microsatellite instability (MSI), or NTRK1/2/3 fusions were observed in 15.6%, 2.0%, and 0.1% of solid tumors, respectively. Most solid tumor profiles (89.2%) had genomic results that could theoretically inform decisions on the selection of immunotherapy and targeted therapy clinical trials. CONCLUSION: For this real-world population of patients with FoundationOneCDx solid tumor profiles in the routine course of clinical care, clinically significant findings were reported for approximately half of patients with genomic results.

Tumor Fraction Correlates With Detection of Actionable Variants Across > 23,000 Circulating Tumor DNA Samples.

PURPOSE: Profiling of circulating tumor DNA (ctDNA) is increasingly adopted in the management of solid tumors, concurrent with increased availability of more comprehensive ctDNA panels. However, variable ctDNA shed can result in variable assay sensitivity. We studied the relationship between ctDNA tumor fraction (TF) and detection of actionable alterations across cancer types. METHODS: A total of 23,482 liquid biopsies (LBx) submitted between September 2020 and October 2021 were sequenced using a hybrid capture panel that reports genomic alterations (GAs) and genomic biomarkers across 324 cancer-related genes. The primary end points were the prevalence of targetable GAs by cancer type and detection in relationship to ctDNA TF. Sensitivity of detection in LBx was assessed in 1,289 patients with available tissue results. RESULTS: 94% (n = 22,130) of LBx had detectable ctDNA, with a median TF of 2.2%. LBx profiling detected GAs in National Comprehensive Cancer Network category 1 genes in 37% of lung, 30% of prostate, 36% of breast, and 51% of colon cancer cases. Potential germline GAs flagged on clinical reports were detected in genes including BRCA1/2, PALB2, CHEK2, and ATM. Polyclonal mutations in genes associated with resistance such as AR, ESR1, RB1, and NF1 were detected. The sensitivity of LBx to detect driver alterations identified in tissue biopsy from the same patient ranged from 58% to 86% but was consistently at or near 100% in cases with TF ≥ 10%. CONCLUSION: Elevated ctDNA shed is associated with both high sensitivity and negative predictive value for detection of actionable GAs. The presence of elevated TF suggests adequate tumor profiling and may reduce the value of subsequent reflex to confirmatory tissue testing in patients with negative LBx results.

Characterization of Clinical Cases of Malignant PEComa via Comprehensive Genomic Profiling of DNA and RNA.

PURPOSE: Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal soft tissue neoplasm often linked to mTOR pathway activation via TSC2 mutation. We analyzed a series of 31 consecutive metastatic PEComa (mPEComa) cases using a combined DNA/RNA hybrid capture-based comprehensive genomic profiling (CGP) assay to assess the genomic landscape of mPEComa. PATIENTS AND METHODS: Formalin-fixed, paraffin-embedded (FFPE) blocks or slides were obtained from tumors from 31 unique patients with mPEC-oma. DNA and RNA were extracted and CGP was performed on 405 genes using a targeted next-generation sequencing (NGS) assay in a CLIA-certified lab. RESULTS: All cases had locally advanced or metastatic disease, and 58% of patients were female with a median age of 50 years (range 8-76), and 17 and 14 specimens were from primary and metastatic sites, respectively. One hundred genomic alterations were identified in the cohort, with an average of 3.2 genomic alterations/case including alterations in TSC2 32.3% of cases (10), TSC1 9.6% (3), TFE3 16.1% (5, all fusions), and folliculin (FLCN) 6.4% (2), with all occurring in mutually exclusive fashion. Of TSC2 mutant cases, 70% had biallelic inactivation of this locus, as were 100% of TSC1 mutant cases. Two TSC1/2 wildtype cases harbored truncating mutations in FLCN, both of which were under LOH. Five TFE3 fusion cases were identified including the novel 5' fusion partner ZC3H4. CONCLUSIONS: We describe for the first time mPEComa cases with FLCN mutations under LOH, further characterizing dysregulation of the mTOR pathway as a unifying theme in mPEC-oma. Cumulatively, we demonstrate the feasibility and potential utility of segregating mPEComa by TSC, TFE3, and FLCN status via CGP in clinical care.

Patients with NSCLCs Harboring Internal Inversions or Deletion Rearrangements of the ALK Gene Have Durable Responses to ALK Kinase Inhibitors.

BACKGROUND: ALK fusions are targetable drivers in non-small-cell lung cancer (NSCLC). However, patients with NSCLC harboring ALK rearrangements without a fusion partner identified in DNA have also been shown to respond to ALK inhibitors. We aimed to characterize complex ALK variants that may predict sensitivity to multiple approved ALK inhibitors. METHODS: Comprehensive genomic profiling (CGP) of DNA isolated from formalin-fixed paraffin-embedded (FFPE) tumor tissue or blood-based circulating tumor DNA was performed for 39,159 NSCLC patients during routine clinical care. For a subset of cases, RNA sequencing was performed, and prior ALK test results and clinical treatment information were collected from treating physicians. RESULTS: We queried the Foundation Medicine NSCLC database and identified ALK internal inversions, as well as internal deletions, as the sole ALK rearrangements in 6 (0.02%) and 3 (0.01%) of cases, respectively. In cases with ALK internal inversions, RNA testing identified an EML4-ALK fusion in 2/2 cases evaluated, and 3/3 patients treated with ALK inhibitors had durable responses. A single patient with an ALK internal deletion and clinical data available responded to multiple ALK inhibitors. RNA data available for a subset of non-NSCLC cases suggest that ALK internal deletions removing a portion of the N-terminus are drivers themselves and do not result in ALK fusions. Fluorescence in situ hybridization (FISH) results were inconsistent for both classes of DNA events. CONCLUSION: Rare internal inversions of ALK appear to be indicative of ALK fusions, which can be detected in RNA, and response to ALK inhibitors in patients with NSCLC. In contrast, ALK internal deletions are not associated with ALK fusions in RNA but likely represent targetable drivers themselves. These data suggest that CGP of DNA should be supplemented with immunohistochemistry or RNA-based testing to further resolve these events and match patients to effective therapies.

Treatment of Pediatric Glioblastoma with Combination Olaparib and Temozolomide Demonstrates 2-Year Durable Response.

For pediatric patients with high-grade gliomas, standard-of-care treatment includes surgery, chemotherapy, and radiation therapy; however, most patients ultimately succumb to their disease. With advances in genomic characterization of pediatric high-grade gliomas, the use of targeted therapies in combination with current treatment modalities offer the potential to improve survival in this patient population. In this report, we present the case of a 3-year-old girl with glioblastoma who continues to experience an exceptional and durable response (>2 years) to the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib. Our patient presented with persistent and progressive seizure activity that upon workup was the result of a large heterogeneously enhancing, mixed cystic and solid mass in the left frontal-parietal-temporal region. Histopathologic analysis of resected tumor tissue confirmed the diagnosis of glioblastoma, and comprehensive genomic profiling demonstrated absence of any BRAF or H3F3A mutations. Genomic profiling, however, did reveal a probable germline heterozygous BRCA2 Lys3326Ter (K3226*) nonsense variant. After debulking surgery, the patient received standard-of-care treatment with radiation and temozolomide. Nine months later the PARP inhibitor olaparib was administered in combination with temozolomide for 16 cycles. This regimen was well tolerated by the patient and serial imaging showed reduction in tumor size. Since completion of the regimen, the patient remains neurologically intact with no evidence of tumor recurrence. To our knowledge, this represents the first case of a pediatric glioblastoma that maintains a durable response to a therapeutic strategy that included the PARP inhibitor olaparib and more generally highlights the potential clinical utility of incorporating these agents into the treatment of pediatric high-grade gliomas. KEY POINTS: Germline mutations detected in pediatric gliomas may represent a cancer predisposition syndrome. Integrating molecular testing into routine clinical care for pediatric patients with glioma is critical to identify therapeutic targets and patients with a cancer predisposition syndrome. Patients with glioma with defects in DNA repair pathway components (e.g., BRCA1/2) may show increased responsiveness to poly (ADP-ribose) polymerase (PARP) inhibitors. Combining PARP inhibitors with temozolomide (standard-of-care treatment) revealed no adverse events or toxicities over the course of 18 months.

MET Genomic Alterations in Head and Neck Squamous Cell Carcinoma (HNSCC): Rapid Response to Crizotinib in a Patient with HNSCC with a Novel MET R1004G Mutation.

Identification of effective targeted therapies for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) remains an unmet medical need. A patient with platinum-refractory recurrent oral cavity HNSCC underwent comprehensive genomic profiling (CGP) that identified an activating MET mutation (R1004). The patient was treated with the oral MET tyrosine kinase inhibitor crizotinib with rapid response to treatment.Based on this index case, we determined the frequency of MET alterations in 1,637 HNSCC samples, which had been analyzed with hybrid capture-based CGP performed in the routine course of clinical care. The specimens were sequenced to a median depth of >500× for all coding exons from 182 (version 1, n = 24), 236 (version 2, n = 326), or 315 (version 3, n = 1,287) cancer-related genes, plus select introns from 14 (version 1), 19 (version 2), or 28 (version 3) genes frequently rearranged in cancer. We identified 13 HNSCC cases (0.79%) with MET alterations (4 point mutation events and 9 focal amplification events). MET-mutant or amplified tumors represent a small but potentially actionable molecular subset of HNSCC. KEY POINTS: This case report is believed to be the first reported pan-cancer case of a patient harboring a MET mutation at R1004 demonstrating a clinical response to crizotinib, in addition to the first documented case of head and neck squamous cell carcinoma (HNSCC) with any MET alteration responding to crizotinib.The positive response to MET inhibition in this patient highlights the significance of comprehensive genomic profiling in advanced metastatic HNSCC to identify actionable targetable molecular alterations as current treatment options are limited.

SMARCA4 inactivation defines a subset of undifferentiated uterine sarcomas with rhabdoid and small cell features and germline mutation association.

A rare subset of aggressive SMARCA4-deficient uterine sarcomas has been recently proposed, with only a limited number of cases having been previously described. Here, we identify 16 additional cases of SMARCA4-deficient uterine sarcoma from the database of a large, CLIA-certified and CAP-accredited, reference molecular laboratory, and we expand on their clinicopathological and genomic features. Median patient's age was 49 years (range 32-70). Most tumors were aggressive with distant metastasis. SMARCA4-deficient uterine sarcoma demonstrated predominantly rhabdoid or large epithelioid cells with abundant cytoplasm, but also had varying degrees of small cell and spindle cell morphology. Tumors were microsatellite stable and exhibited no other or only few co-occurring genomic alterations by comprehensive genomic profiling. We discovered one patient, who developed SMARCA4-deficient uterine sarcoma at the age of 55, had a germline SMARCA4 mutation, whose daughter had previously died of small cell carcinoma of the ovary, hypercalcemic type, at the age of 32. Our data support the notion that SMARCA4 inactivation is the driver oncogenic event of a morphologically and molecularly distinct form of uterine sarcoma. Identification of SMARCA4-deficient uterine sarcomas may be clinically important due to their aggressive behavior, germline association, and emerging targeted therapies.

Effect of a Collaboration Between a Health Plan, Oncology Practice, and Comprehensive Genomic Profiling Company from the Payer Perspective.

BACKGROUND: Comprehensive genomic profiling (CGP) is a next-generation sequencing-based methodology that detects 4 classes of genomic alterations, as well as gene signature biomarkers such as microsatellite instability and tumor mutational burden. In the context of precision oncology, CGP can help to direct treatment to genomically matched therapies. OBJECTIVE: To describe the results of a 3-year observational analysis of patients undergoing testing with CGP assays (either FoundationOne or FoundationOne Heme) at a community oncology practice after a regional health plan implemented a medical policy that enabled coverage of CGP. METHODS: A retrospective analysis of medical records was completed at the oncology practice from November 2013 to January 2017; this date range was chosen to coincide with the regional health plan's medical policy implementation of CGP. The medical policy provided coverage of CGP for patients with advanced solid and hematologic cancers. A medical record review assessed all previous and current molecular test results, matched therapy or clinical trial enrollment, and clinical outcomes (clinical benefit or disease progression). The potential cost diversion, from payer to study sponsor, for patients who enrolled in clinical trials was explored. RESULTS: There were 96 patients in the community oncology practice who received CGP over the 3-year period, 86 of whom had clinically relevant genomic alterations. Of the 86, 15 patients were treated with genomically matched therapy, and 6 patients enrolled in clinical trials based on CGP results. In a subset of 32 patients who previously underwent conventional testing, most (84%) had clinically relevant genomic alterations detected by CGP that conventional testing did not identify, and a portion of these patients subsequently received treatment based on the CGP results. In the separate cost diversion analysis of 20 patients who enrolled in phase 1 clinical trials, an estimated $25,000 per-patient cost-benefit may have been accrued to the payer. CONCLUSIONS: This observational analysis characterized the use of CGP in a large community oncology practice among a group of patients insured by a regional health plan. Clinical trial enrollment was facilitated by CGP use in the community setting and may have contributed to cost diversion from the payer to study sponsors. DISCLOSURES: No separate study-related funding was provided by or to Priority Health, Foundation Medicine, and Cancer and Hematology Centers of West Michigan. Data analysis by Reitsma was conducted as part of an internship funded by Priority Health. Reitsma and Fox are employed by Priority Health. Anhorn, Vanden Borre, Cavanaugh, Chudnovsky, and Erlich are employed by Foundation Medicine.

Detection of an ALK Fusion in Colorectal Carcinoma by Hybrid Capture-Based Assay of Circulating Tumor DNA.

ALK rearrangements have been observed in 0.05%-2.5% of patients with colorectal cancers (CRCs) and are predicted to be oncogenic drivers largely mutually exclusive of KRAS, NRAS, or BRAF alterations. Here we present the case of a patient with metastatic CRC who was treatment naïve at the time of molecular testing. Initial ALK immunohistochemistry (IHC) staining was negative, but parallel genomic profiling of both circulating tumor DNA (ctDNA) and tissue using similar hybrid capture-based assays each identified an identical STRN-ALK fusion. Subsequent ALK IHC staining of the same specimens was positive, suggesting that the initial result was a false negative. This report is the first instance of an ALK fusion in CRC detected using a ctDNA assay. KEY POINTS: Current guidelines for colorectal cancer (CRC) only recommend genomic assessment of KRAS, NRAS, BRAF, and microsatellite instability (MSI) status.ALK rearrangements are rare in CRC, but patients with activating ALK fusions have responded to targeted therapiesALK rearrangements can be detected by genomic profiling of ctDNA from blood or tissue, and this methodology may be informative in cases where immunohistochemistry (IHC) or other standard testing is negative.

Exceptional durable response to everolimus in a patient with biphenotypic breast cancer harboring an STK11 variant.

Metastatic triple-negative breast cancer comprises 12%-17% of breast cancers and carries a poor prognosis relative to other breast cancer subtypes. Treatment options in this disease are largely limited to systemic chemotherapy. A majority of clinical studies assessing efficacy of targeted therapeutics (e.g., the mammalian target of rapamycin [mTOR] inhibitor everolimus) in advanced breast cancer patients have not utilized predictive genomic biomarker-based selection and have reported only modest improvement in the clinical outcome relative to standard of care. However, recent reports have highlighted significant clinical responses of breast malignancies harboring alterations in genes involved in the phosphoinositide 3-kinase (PI3K)/AKT/mTOR signaling pathway to mTOR-inhibitor-involving regimens, underscoring the potential clinical benefit of treating subsets of breast cancer patients with molecularly matched targeted therapies. As the paradigm of cancer treatment shifts from chemotherapeutic regimens to more personalized approaches, the identification of additional reliable biomarkers is essential for identifying patients likely to derive maximum benefit from targeted therapies. Herein, we report a near-complete and ongoing 14-mo response to everolimus therapy of a heavily pretreated patient with biphenotypic, metastatic breast cancer. Genomic profiling of the metastatic triple-negative liver specimen identified a single reportable point mutation, STK11 F354L, that appears to have undergone loss of heterozygosity. No other alterations within the PI3K/mTOR pathway were observed. Published functional biochemical data on this variant are conflicting, and germline data, albeit with unclear zygosity status, are suggestive of a benign polymorphism role. Together with the preclinical data, this case suggests further investigation of this variant is warranted to better understand its role as a potential biomarker for mTOR inhibitor sensitivity in the appropriate clinical context.

Pediatric, Adolescent, and Young Adult Thyroid Carcinoma Harbors Frequent and Diverse Targetable Genomic Alterations, Including Kinase Fusions.

BACKGROUND: Thyroid carcinoma, which is rare in pediatric patients (age 0-18 years) but more common in adolescent and young adult (AYA) patients (age 15-39 years), carries the potential for morbidity and mortality. METHODS: Hybrid-capture-based comprehensive genomic profiling (CGP) was performed prospectively on 512 consecutively submitted thyroid carcinomas, including 58 from pediatric and AYA (PAYA) patients, to identify genomic alterations (GAs), including base substitutions, insertions/deletions, copy number alterations, and rearrangements. This PAYA data series includes 41 patients with papillary thyroid carcinoma (PTC), 3 with anaplastic thyroid carcinoma (ATC), and 14 with medullary thyroid carcinoma (MTC). RESULTS: GAs were detected in 93% (54/58) of PAYA cases, with a mean of 1.4 GAs per case. In addition to BRAF V600E mutations, detected in 46% (19/41) of PAYA PTC cases and in 1 of 3 AYA ATC cases, oncogenic fusions involving RET, NTRK1, NTRK3, and ALK were detected in 37% (15/41) of PAYA PTC and 33% (1/3) of AYA ATC cases. Ninety-three percent (13/14) of MTC patients harbored RET alterations, including 3 novel insertions/deletions in exons 6 and 11. Two of these MTC patients with novel alterations in RET experienced clinical benefit from vandetanib treatment. CONCLUSION: CGP identified diverse clinically relevant GAs in PAYA patients with thyroid carcinoma, including 83% (34/41) of PTC cases harboring activating kinase mutations or activating kinase rearrangements. These genomic observations and index cases exhibiting clinical benefit from targeted therapy suggest that young patients with advanced thyroid carcinoma can benefit from CGP and rationally matched targeted therapy. The Oncologist 2017;22:255-263 IMPLICATIONS FOR PRACTICE: The detection of diverse clinically relevant genomic alterations in the majority of pediatric, adolescent, and young adult patients with thyroid carcinoma in this study suggests that comprehensive genomic profiling may be beneficial for young patients with papillary, anaplastic, or medullary thyroid carcinoma, particularly for advanced or refractory cases for which clinical trials involving molecularly targeted therapies may be appropriate.

Genomic Profiling of a Large Set of Diverse Pediatric Cancers Identifies Known and Novel Mutations across Tumor Spectra.

Pediatric cancers are generally characterized by low mutational burden and few recurrently mutated genes. Recent studies suggest that genomic alterations may help guide treatment decisions and clinical trial selection. Here, we describe genomic profiles from 1,215 pediatric tumors representing sarcomas, extracranial embryonal tumors, brain tumors, hematologic malignancies, carcinomas, and gonadal tumors. Comparable published datasets identified similar frequencies of clinically relevant alterations, validating this dataset as biologically relevant. We identified novel ALK fusions in a neuroblastoma (BEND5-ALK) and an astrocytoma (PPP1CB-ALK), novel BRAF fusions in an astrocytoma (BCAS1-BRAF) and a ganglioglioma (TMEM106B-BRAF), and a novel PAX3-GLI2 fusion in a rhabdomyosarcoma. Previously characterized ALK, NTRK1, and PAX3 fusions were observed in unexpected malignancies, challenging the "disease-specific" alterations paradigm. Finally, we identified recurrent variants of unknown significance in MLL3 and PRSS1 predicted to have functional impact. Data from these 1,215 tumors are publicly available for discovery and validation. Cancer Res; 77(2); 509-19. ©2017 AACR.

Significant and durable clinical benefit from trastuzumab in 2 patients with HER2-amplified salivary gland cancer and a review of the literature.

BACKGROUND: Salivary ductal carcinoma and carcinoma ex pleomorphic adenoma (CEPA) are aggressive salivary gland cancers with poor prognosis. The standard of care is resection with or without radiotherapy, and there are no established systemic therapy options. METHODS: We describe 1 patient with metastatic CEPA and 1 patient with metastatic recurrent salivary duct carcinoma whose tumors were evaluated by comprehensive genomic profiling. Testing identified human epidermal growth factor receptor 2 (HER2) amplification in both patients, and an additional activating HER2 mutation in the CEPA case. RESULTS: Both patients were treated with the HER2-targeting monoclonal antibody trastuzumab (herceptin) plus chemotherapy and experienced rapid responses. Subsequently, both patients were given single-agent maintenance trastuzumab and continue to experience durable disease control. CONCLUSION: Given the poor prognosis for salivary gland cancers and the limited treatment options upon recurrence or metastasis, patients should be tested for all classes of HER2 alterations. In cases with HER2 overexpression or activation, targeted therapies, such as trastuzumab are promising. © 2016 Wiley Periodicals, Inc. Head Neck 39: E40-E44, 2017.

Activity of c-Met/ALK Inhibitor Crizotinib and Multi-Kinase VEGF Inhibitor Pazopanib in Metastatic Gastrointestinal Neuroectodermal Tumor Harboring EWSR1-CREB1 Fusion.

Malignant gastrointestinal neuroectodermal tumor (GNET) is an aggressive rare tumor, primarily occurring in young adults with frequent local-regional metastases and recurrence after local control. The tumor is characterized by the presence of EWSR1-ATF1 or EWSR1-CREB1 and immunohistochemical positivity for S-100 protein without melanocytic marker positivity. Due to poor responses to standard sarcoma regimens, GNET has a poor prognosis, and development of effective systemic therapy is desperately needed to treat these patients. Herein, we present a patient with a small bowel GNET who experienced recurrent hepatic and skeletal metastases after a primary resection. Comprehensive genomic profiling (CGP) in the course of clinical care with DNA and RNA sequencing demonstrated the presence of an exon 7 to exon 6 EWSR1-CREB1 fusion in the context of a diploid genome with no other genomic alterations. In a clinical trial, the patient received a combination of 250 mg crizotinib with 600 mg pazopanib quaque die and achieved partial response and durable clinical benefit for over 2.8 years, and with minimal toxicity from therapy. Using a CGP database of over 50,000 samples, we identified 11 additional cases that harbor EWSR1-CREB1 and report clinicopathologic characteristics, as these patients may also benefit from such a regimen.

Characterization of 298 Patients with Lung Cancer Harboring MET Exon 14 Skipping Alterations.

BACKGROUND: The hepatocyte growth factor receptor gene (MET) exon 14 skipping (METex14) has recently been described a potential driver alteration in lung cancer targetable by mesenchymal-to-epithelial transition factor (MET) tyrosine kinase inhibitors (TKIs). METHODS: Well-validated hybrid capture-based comprehensive genomic profiling was performed at the request of individual treating physicians. RESULTS: Of 11,205 lung cancers profiled by comprehensive genomic profiling, 298 (2.7%) carcinomas harbored alterations predicted to cause METex14, including adenosquamous (8.2%), sarcomatoid (7.7%), histologic subtype not otherwise specified (3.0%), adenocarcinoma (2.9%), squamous cell (2.1%), large cell (0.8%), and SCLC (0.2%). Acinar features were present in 24% of the METex14 samples. Six cases (2%) harbored MET Y1003X mutations affecting binding of the MET-negative regulator, E3 ubiquitin protein ligase. The median age of all patients with METex14 was 73 years (range 43-95) and 60% were female. Concurrent, murine double minute gene (MDM2) amplification, cyclin-dependent kinase 4 gene (CDK4) amplification, and EGFR amplification were observed in 35%, 21%, and 6.4% of patients with METex14, respectively. KRAS mutation was observed in 3% of cases. Concurrent MET amplification (METamp) (median copy number 10) was identified in 15% of METex14 samples. Significant differences in tumor mutational burden and type of the METex14 alterations were observed between the METamp and non-METamp samples. Response to MET TKI was observed in both in patients with METamp and in patients without METamp METex14. CONCLUSION: Diverse targetable METex14 alterations were identified in patients with NSCLC across age groups, including elderly patients, and in all major NSCLC histologic subtypes with an overall frequency of 2.7%. These findings support the use of hybrid capture-based molecular profiling across NSCLC subtypes to identify patients who will potentially benefit from MET TKIs.

Comprehensive Genomic Profiling of Clinically Advanced Medullary Thyroid Carcinoma.

OBJECTIVE: The aim of this study was to determine the genomic alterations of cancer-related genes in advanced medullary thyroid carcinoma during the course of clinical care. METHODS: Hybrid-capture-based comprehensive genomic profiling was performed on 34 consecutive medullary thyroid carcinoma cases to identify all four classes of genomic alterations, and outcome for an index patient was collected. RESULTS: RET was mutated in 88% (30/34) of cases, with RET M918T being responsible for 70% (21/30) of the RET alterations. The other RET alterations were RET E632_L633del, C634R, C620R, C618G/R/S, V804M, and RET amplification. Two of the four RET wild-type patients harbored mutations in KRAS or HRAS (1/34 each). The next most frequent genomic alterations were amplifications of CCND1, FGF3, and FGF19 and alterations in CDKN2A (3/34 each). One case with a RET M918T mutation developed acquired resistance to progressively dose-escalated vandetanib. When the mTOR inhibitor everolimus was added to continued vandetanib treatment, the patient achieved a second 25% reduction of tumor volume (RECIST 1.1) for 8 months. CONCLUSIONS: Comprehensive genomic profiling identified the full breadth of RET alterations in metastatic medullary thyroid carcinoma and possible cooperating oncogenic driver alterations. This approach may refine the use of targeted therapy for these patients.