Publications by authors named "Jo-Anne Vergilio"

63 Publications

Precision medicine treatment in acute myeloid leukemia using prospective genomic profiling: feasibility and preliminary efficacy of the Beat AML Master Trial.

Nat Med 2020 12 26;26(12):1852-1858. Epub 2020 Oct 26.

The Ohio State University, Columbus, OH, USA.

Acute myeloid leukemia (AML) is the most common diagnosed leukemia. In older adults, AML confers an adverse outcome. AML originates from a dominant mutation, then acquires collaborative transformative mutations leading to myeloid transformation and clinical/biological heterogeneity. Currently, AML treatment is initiated rapidly, precluding the ability to consider the mutational profile of a patient's leukemia for treatment decisions. Untreated patients with AML ≥ 60 years were prospectively enrolled on the ongoing Beat AML trial (ClinicalTrials.gov NCT03013998 ), which aims to provide cytogenetic and mutational data within 7 days (d) from sample receipt and before treatment selection, followed by treatment assignment to a sub-study based on the dominant clone. A total of 487 patients with suspected AML were enrolled; 395 were eligible. Median age was 72 years (range 60-92 years; 38% ≥75 years); 374 patients (94.7%) had genetic and cytogenetic analysis completed within 7 d and were centrally assigned to a Beat AML sub-study; 224 (56.7%) were enrolled on a Beat AML sub-study. The remaining 171 patients elected standard of care (SOC) (103), investigational therapy (28) or palliative care (40); 9 died before treatment assignment. Demographic, laboratory and molecular characteristics were not significantly different between patients on the Beat AML sub-studies and those receiving SOC (induction with cytarabine + daunorubicin (7 + 3 or equivalent) or hypomethylation agent). Thirty-day mortality was less frequent and overall survival was significantly longer for patients enrolled on the Beat AML sub-studies versus those who elected SOC. A precision medicine therapy strategy in AML is feasible within 7 d, allowing patients and physicians to rapidly incorporate genomic data into treatment decisions without increasing early death or adversely impacting overall survival.
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http://dx.doi.org/10.1038/s41591-020-1089-8DOI Listing
December 2020

Molecular profiling of mesonephric and mesonephric-like carcinomas of cervical, endometrial and ovarian origin.

Gynecol Oncol Rep 2020 Nov 26;34:100652. Epub 2020 Sep 26.

Foundation Medicine Inc., Cambridge, MA, United States.

Mesonephric carcinoma is a rare cancer that most often arises within the cervix, and less frequently, in the ovary and endometrium. A retrospective search of our CLIA-certified and CAP-accredited reference molecular laboratory database (Foundation Medicine, Inc.) identified 20 mesonephric or mesonephric-like, cervical (n = 10), endometrial (n = 5), ovarian (n = 4) or peri-bladder (n = 1) carcinomas that had undergone comprehensive genomic profiling via next generation sequencing. Activating mutations were present in 90%, 18 of 20 cases, including G12V (n = 7), G12D (n = 6), G12A (n = 3) and G12C (n = 2). Other recurrent alterations were identified in (25%), (20%), (15%), (10%), (10%) and (10%). One wild-type case had a mutation as the sole alteration, while the second wild-type case had an exon 20 insertion D770_N771insSVD alteration. All tumors were negative for HPV DNA, microsatellite instability, high tumor mutational burden and homologous recombination deficiency. A circulating tumor DNA (ctDNA) liquid biopsy from peripheral blood, which was performed 6 years after original solid tumor resection in one patient with suspected lung metastasis, revealed concordance of alteration, gains of chromosomes 1q, 2, 10, 12 and 20, plus new alterations in the liquid biopsy compared to the original sample. G12 mutation is major driver of mesonephric and mesonephric-like carcinomas, with less frequent contribution by ARID1A and PIK3CA pathways in tumors of non-cervical origin. ctDNA liquid biopsy may be useful in detecting mutations in recurrent or metastatic patients, who may potentially be eligible for trials against emerging targeted therapies.
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http://dx.doi.org/10.1016/j.gore.2020.100652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529833PMC
November 2020

Pan-Cancer Landscape Analysis Reveals Recurrent - Gene Fusion in Aggressive Histologic Subtypes of Thymoma.

JCO Precis Oncol 2020 26;4. Epub 2020 Feb 26.

Foundation Medicine, Cambridge, MA.

Purpose: Thymomas are epithelial neoplasms that represent the most common thymic tumors in adults. These tumors have been shown to harbor a relatively low mutational burden. As a result, there is a lack of genetic alterations that may be used prognostically or targeted therapeutically for this disease. Here, we describe a recurrent gene rearrangement in type B2 + B3 thymomas.

Patients And Methods: A single index case of thymoma was evaluated by an RNA-based solid fusion assay. Separately, tissues from 255,008 unique advanced cancers, including 242 thymomas, were sequenced by hybrid capture-based next-generation DNA sequencing/comprehensive genomic profiling of 186 to 406 genes, including lysine methyltransferase 2A () rearrangements, and a portion were evaluated for RNA of 265 genes. We characterized molecular and clinicopathologic features of the pertinent fusion-positive patient cases.

Results: We identified 11 patients with thymomas harboring a gene fusion of and mastermind-like transcriptional coactivator 2 (). Fusion breakpoints were identified between exon 8, 9, 10, or 11 of and exon 2 of . Fifty-five percent were men, with a median age of 48 years at surgery (range, 29-69 years). Concurrent genomic alterations were infrequent. The 11 thymomas were of B2 or B3 type histology, with 1 case showing foci of thymic carcinoma. The frequency of - fusion was 4% of all thymomas (10 of 242) and 6% of thymomas of B2 or B3 histology (10 of 169).

Conclusion: - represents the first recurrent fusion described in type B thymoma. The fusion seems to be specific to type B2 and B3 thymomas, the most aggressive histologic subtypes. The identification of this fusion offers insights into the biology of thymoma and may have clinical relevance for patients with disease refractory to conventional therapeutic modalities.
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http://dx.doi.org/10.1200/PO.19.00288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446345PMC
February 2020

Identifying Opportunities and Challenges for Patients With Sarcoma as a Result of Comprehensive Genomic Profiling of Sarcoma Specimens.

JCO Precis Oncol 2020 18;4. Epub 2020 Mar 18.

The Ohio State University, Columbus, OH.

Purpose: Comprehensive genomic profiling (CGP) of sarcomas is rapidly being integrated into routine clinical care to help refine diagnosis and prognosis and determine treatment. However, little is known about barriers to successful CGP or its clinical utility in sarcoma. We set out to determine whether CGP alters physician treatment decision-making, and whether sarcoma subtypes influence the frequency of successful technical performance of CGP.

Methods: A single-institution study evaluated profiling outcomes of 392 samples from patients with sarcoma, using a commercially available CGP panel. Of this group, 34 patients were evaluated prospectively (Decision Impact Trial) to evaluate the utility of CGP in physician decision-making. All cases were retrospectively analyzed to identify causes of CGP failure.

Results: CGP successfully interrogated 75.3% (n = 295 of 392) of patients with sarcoma. Bone sarcomas had lower passing rates at 65.3% (n = 32 of 49) compared with soft tissue sarcomas at 76.7% (n = 263 of 343; = .0008). Biopsy location also correlated with profiling efficiency. Bone biopsy specimens had a 52.8% (n = 19 of 36) passing rate versus lung (61.1%; n = 33 of 54) and abdomen (80.1%; n = 109 of 136) specimens. CGP altered physician treatment selection in 25% of evaluable patients (n = 7 of 28) and was associated with improved progression-free survival.

Conclusion: To our knowledge, this is the largest technical evaluation of the performance of CGP in sarcoma. CGP was effectively performed in the vast majority of sarcoma samples and altered physician treatment selection. Tumor location and tissue subtype were key determinants of profiling success and associated with preanalytic variables that affect DNA and RNA quality. These results support standardized biopsy collection protocols to improve profiling outcomes.
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http://dx.doi.org/10.1200/PO.19.00227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446311PMC
March 2020

Targetable BRAF and RAF1 Alterations in Advanced Pediatric Cancers.

Oncologist 2021 Jan 25;26(1):e153-e163. Epub 2020 Sep 25.

Foundation Medicine Inc., Morrisville, North, Carolina, USA.

RAF family protein kinases signal through the MAPK pathway to orchestrate cellular proliferation, survival, and transformation. Identifying BRAF alterations in pediatric cancers is critically important as therapeutic agents targeting BRAF or MEK may be incorporated into the clinical management of these patients. In this study, we performed comprehensive genomic profiling on 3,633 pediatric cancer samples and identified a cohort of 221 (6.1%) cases with known or novel alterations in BRAF or RAF1 detected in extracranial solid tumors, brain tumors, or hematological malignancies. Eighty percent (176/221) of these tumors had a known-activating short variant (98, 55.7%), fusion (72, 40.9%), or insertion/deletion (6, 3.4%). Among BRAF altered cancers, the most common tumor types were brain tumors (74.4%), solid tumors (10.8%), hematological malignancies (9.1%), sarcomas (3.4%), and extracranial embryonal tumors (2.3%). RAF1 fusions containing intact RAF1 kinase domain (encoded by exons 10-17) were identified in seven tumors, including two novel fusions TMF1-RAF1 and SOX6-RAF1. Additionally, we highlight a subset of patients with brain tumor with positive clinical response to BRAF inhibitors, demonstrating the rationale for incorporating precision medicine into pediatric oncology. IMPLICATIONS FOR PRACTICE: Precision medicine has not yet gained a strong foothold in pediatric cancers. This study describes the landscape of BRAF and RAF1 genomic alterations across a diverse spectrum of pediatric cancers, primarily brain tumors, but also encompassing melanoma, sarcoma, several types of hematologic malignancy, and others. Given the availability of multiple U.S. Food and Drug Administration-approved BRAF inhibitors, identification of these alterations may assist with treatment decision making, as described here in three cases of pediatric cancer.
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http://dx.doi.org/10.1002/ONCO.13519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794197PMC
January 2021

A pan-cancer analysis of PD-L1 immunohistochemistry and gene amplification, tumor mutation burden and microsatellite instability in 48,782 cases.

Mod Pathol 2021 02 3;34(2):252-263. Epub 2020 Sep 3.

Foundation Medicine, Inc., Morrisville, NC, USA.

PD-L1 immunohistochemistry (IHC) currently has the most Food and Drug Administration (FDA) approvals as a companion diagnostic (CDx) for immunotherapies in specific tumor types; however, multiple other immunotherapy biomarkers exist. We performed this study to examine and report the prevalence of PD-L1 expression in a wide variety of tumor types and examine its relationship to microsatellite instability (MSI), tumor mutational burden (TMB), and CD274 (PD-L1) gene amplification. We performed a retrospective analysis of all cases in which both PD-L1 IHC (using the DAKO 22C3 IHC assay with either tumor proportion score (TPS) or combined positive score (CPS); or the VENTANA SP142 assay with infiltrating immune cell score (IC)) and comprehensive genomic profiling (CGP) were tested at Foundation Medicine between January 2016 and November 2019. Of note, PD-L1 positivity is defined per the CDx indication and tumor proportion score (TPS ≥ 1) for indications without a CDx claim; and TMB positivity is defined as ≥10 mutations/Mb. A total of 48,782 cases were tested for PD-L1 IHC and CGP. Immune cell expression of PD-L1 was more frequently identified than tumor cell expression of PD-L1. We saw a high correlation between PD-L1 expression and CD274 gene amplification (p < 0.0001), MSI and TMB (p < 0.0001), and PD-L1 and TMB (p < 0.0001). In addition, the combination of PD-L1 and TMB identified four unique disease subsets PD-L1/TMB, PD-L1/TMB, PD-L1/TMB, and PD-L1/TMB with varying prevalence dependent on tumor type. Lastly, 50.3% (24527/48782) of the overall cohort was positive for at least one of the CDx or exploratory biomarkers described above. This is the largest pan-cancer analysis of relevant biomarkers associated with response to checkpoint inhibitors to date, including more than 48,000 cases. Additional clinical trials with treatment outcome data in individual tumor types are needed to determine whether the double positive PD-L1/TMB disease subset would respond best to immunotherapy.
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http://dx.doi.org/10.1038/s41379-020-00664-yDOI Listing
February 2021

Biomarkers in Breast Cancer: An Integrated Analysis of Comprehensive Genomic Profiling and PD-L1 Immunohistochemistry Biomarkers in 312 Patients with Breast Cancer.

Oncologist 2020 11 14;25(11):943-953. Epub 2020 Sep 14.

Foundation Medicine, Inc., Morrisville, North Carolina, USA.

Background: We examined the current biomarker landscape in breast cancer when programmed death-ligand 1 (PD-L1) testing is integrated with comprehensive genomic profiling (CGP).

Material And Methods: We analyzed data from samples of 312 consecutive patients with breast carcinoma tested with both CGP and PD-L1 (SP142) immunohistochemistry (IHC) during routine clinical care. These samples were stratified into hormone receptor positive (HR+)/human epidermal growth factor receptor negative (HER2-; n = 159), HER2-positive (n = 32), and triple-negative breast cancer (TNBC) cohorts (n = 121).

Results: We found that in the TNBC cohort, 43% (52/121) were immunocyte PD-L1-positive, and in the HR+/HER2- cohort, 30% (48/159) had PIK3CA companion diagnostics mutations, and hence were potentially eligible for atezolizumab plus nab-paclitaxel or alpelisib plus fulvestrant, respectively. Of the remaining 212 patients, 10.4% (22/212) had a BRCA1/2 mutation, which, if confirmed by germline testing, would allow olaparib plus talazoparib therapy. Of the remaining 190 patients, 169 (88.9%) were positive for another therapy-associated marker or a marker that would potentially qualify the patient for a clinical trial. In addition, we examined the relationship between immunocyte PD-L1 positivity and different tumor mutation burden (TMB) cutoffs and found that when a TMB cutoff of ≥9 mutations per Mb was applied (cutoff determined based on prior publication), 11.6% (14/121) patients were TMB ≥9 mutations/Mb and of these, TMB ≥9 mutations per Mb, 71.4% (10/14) were also positive for PD-L1 IHC.

Conclusion: Our integrated PD-L1 and CGP methodology identified 32% of the tested patients as potentially eligible for at least one of the two new Food and Drug Administration approved therapies, atezolizumab or alpelisib, and an additional 61.2% (191/312) had other biomarker-guided potential therapeutic options.

Implications For Practice: This integrated programmed death-ligand 1 immunohistochemistry and comprehensive genomic profiling methodology identified 32% of the tested patients as eligible for at least one of the two new Food and Drug Administration-approved therapies, atezolizumab or alpelisib, and an additional 61.2% (191/312) had other biomarker-guided potential therapeutic options. These findings suggest new research opportunities to evaluate the predictive utility of other commonly seen PIK3CA mutations in hormone receptor-positive breast cancers and to standardize tumor mutation burden cutoffs to evaluate its potentially predictive role in triple-negative breast cancer.
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http://dx.doi.org/10.1634/theoncologist.2020-0449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648336PMC
November 2020

Pan-sarcoma genomic analysis of KMT2A rearrangements reveals distinct subtypes defined by YAP1-KMT2A-YAP1 and VIM-KMT2A fusions.

Mod Pathol 2020 11 27;33(11):2307-2317. Epub 2020 May 27.

Foundation Medicine, Inc., 150 Second Street, Cambridge, MA, 02141, USA.

Sarcomas are driven by diverse pathogenic mechanisms, including gene rearrangements in a subset of cases. Rare soft tissue sarcomas containing KMT2A fusions have recently been reported, characterized by a predilection for young adults, sclerosing epithelioid fibrosarcoma-like morphology, and an often aggressive course. Nonetheless, clinicopathologic and molecular descriptions of KMT2A-rearranged sarcomas remain limited. In this study, we identified by targeted next-generation RNA sequencing an index patient with KMT2A fusion-positive soft tissue sarcoma. In addition, we systematically searched for KMT2A structural variants in a comprehensive genomic profiling database of 14,680 sarcomas interrogated by targeted next-generation DNA and/or RNA sequencing. We characterized the clinicopathologic and molecular features of KMT2A fusion-positive sarcomas, including KMT2A breakpoints, rearrangement partners, and concurrent genetic alterations. Collectively, we identified a cohort of 34 sarcomas with KMT2A fusions (0.2%), and YAP1 was the predominant partner (n = 16 [47%]). Notably, a complex rearrangement with YAP1 consistent with YAP1-KMT2A-YAP1 fusion was detected in most cases, with preservation of KMT2A CxxC-binding domain in the YAP1-KMT2A-YAP1 fusion and concurrent deletions of corresponding exons in KMT2A. The tumors often affected younger adults (age 20-66 [median 40] years) and histologically showed variably monomorphic epithelioid-to-spindle shaped cells embedded in a dense collagenous stroma. Ultrastructural evidence of fibroblastic differentiation was noted in one tumor examined. Our cohort also included two sarcomas with VIM-KMT2A fusions, each harboring concurrent mutations in CTNNB1, SMARCB1, and ARID1A and characterized histologically by sheets of spindle-to-round blue cells. The remaining 16 KMT2A-rearranged sarcomas in our cohort exhibited diverse histologic subtypes, each with unique novel fusion partners. In summary, KMT2A-fusion-positive sarcomas most commonly exhibit sclerosing epithelioid fibrosarcoma-like morphology and complex YAP1-KMT2A-YAP1 fusions. Cases also include rare spindle-to-round cell sarcomas with VIM-KMT2A fusions and tumors of diverse histologic subtypes with unique KMT2A fusions to non-YAP1 non-VIM partners.
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http://dx.doi.org/10.1038/s41379-020-0582-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581494PMC
November 2020

Genomic profiling of BCOR-rearranged uterine sarcomas reveals novel gene fusion partners, frequent CDK4 amplification and CDKN2A loss.

Gynecol Oncol 2020 05 7;157(2):357-366. Epub 2020 Mar 7.

Foundation Medicine Inc., Cambridge, MA, United States of America.

Objective: Genomic alterations of BCOR via ZC3H7B-BCOR fusion or BCOR internal tandem duplication (ITD) define a subset of endometrial stromal sarcoma (ESS). The goals of this study were to: 1) determine the molecular landscape of BCOR-rearranged ESS, 2) to identify novel BCOR fusion gene partners in ESS and their associated clinicopathological characteristics, and 3) to potentially unravel targetable genomic alterations in BCOR-mutated ESS.

Methods: A retrospective database search of a CLIA-certified molecular laboratory was performed for uterine sarcomas that contained BCOR rearrangements or BCOR ITD. The cases were previously assayed by comprehensive genomic profiling via both DNA- and RNA-based targeted next generation sequencing during the course of clinical care. Clinicopathological and genomic data was centrally re-reviewed.

Results: We identify largest cohort of BCOR-rearranged ESS to date (n = 40), which included 31 cases with canonical ZC3H7B-BCOR fusion as well as 8 cases with novel BCOR gene rearrangement partners, such as BCOR-L3MBTL2, EP300-BCOR, BCOR-NUTM2G, BCOR-RALGPS1, BCOR-MAP7D2, RGAG1-BCOR, ING3-BCOR, BCOR-NUGGC, KMT2D-BCOR, CREBBP-BCOR and 1 case with BCOR internal rearrangement. Re-review of cases with novel rearrangements demonstrated sarcomas with spindle, epithelioid or small round cell components and frequent myxoid stromal change. Comprehensive genomic profiling revealed high frequency of CDK4 and MDM2 amplification in 38% and 45% of BCOR-rearranged cases, respectively, and homozygous deletion of CDKN2A, which encodes an inhibitor of CDK4 in 28% of cases. Notably, CDK4 and MDM2 amplification was absent in all cases from 15 different ESS cases harboring BCOR ITD.

Conclusions: Alterations of CDK4 pathway members, for which targeted therapy is clinically available (i.e. palbociclib), via CDK4 amplification or CDKN2A loss, contributes to the pathogenesis of BCOR-rearranged uterine sarcomas, which may have therapeutic implications.
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http://dx.doi.org/10.1016/j.ygyno.2020.02.024DOI Listing
May 2020

Comprehensive Assessment of Immuno-oncology Biomarkers in Adenocarcinoma, Urothelial Carcinoma, and Squamous-cell Carcinoma of the Bladder.

Eur Urol 2020 04 17;77(4):548-556. Epub 2020 Jan 17.

Foundation Medicine, Cambridge, MA, USA; Upstate Medical University, Syracuse, NY, USA.

Background: In patients with rare histologies of bladder cancer, including adenocarcinoma of the bladder (ACB) and squamous-cell carcinoma (SCC), there are limited standard therapy options, defining an unmet medical need.

Objective: In this comparative comprehensive genomic profiling (CGP) study, genomic alterations (GAs), and immuno-oncology (IO) biomarkers have been analyzed.

Design, Setting, And Participants: Within the Foundation Medicine database, 143 cases with centrally reviewed pure ACB, 2142 with pure urothelial carcinoma (UC), and 83 with pure SCC were subjected to CGP. All patients developed advanced disease following a primary diagnosis of bladder cancer.

Intervention: CGP using a hybrid capture-based assay and immunohistochemistry (IHC).

Outcome Measurements And Statistical Analysis: Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA, and microsatellite instability (MSI) was determined on 114 loci. Programmed cell-death ligand-1 (PD-L1) expression was determined by IHC (Ventana SP-142 assay), with >1% tumor cells (TCs) or tumor-infiltrating lymphocytes (TILs) scoring positive.

Results And Limitations: Pure ACB patients were younger and more often female than pure UC and pure SCC patients. UC and SCC had a significantly higher median TMB than ACB (p < 0.001). Rare CD274 (PD-L1) amplification cases were more frequently seen in SCC than in UC (5% vs 1%), and were not seen in ACB. MSI high status was very uncommon in all tumor types (0-1%). The frequencies of PD-L1 expression in both TCs and TILs was higher in UC and SCC (both 30%) than in ACB (18%). The results are limited by their retrospective nature and lack of clinical data annotation.

Conclusions: Deep sequencing revealed significant differences in IO biomarkers among the three major subtypes of bladder carcinomas. UC and SCC revealed higher frequencies of PD-L1 expression and higher TMB than ACB, and SCC has the highest frequency of CD274 amplification. The presence of pure SCC features should not disqualify patients for inclusion in IO trials.

Patient Summary: Tumor samples from patients diagnosed with advanced pure adenocarcinoma of the bladder (ACB) or pure squamous-cell carcinoma (SCC) have been analyzed in terms of frequency of putative immunotherapy biomarkers. The results indicated that pure SCC of the bladder was characterized by genomic features that portend similar response possibilities to immunotherapy compared with the classical pure urothelial carcinoma. Conversely, for pure ACB there might be different therapeutic opportunities, such as targeted therapies against peculiar genomic alterations in selected patients.
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http://dx.doi.org/10.1016/j.eururo.2020.01.003DOI Listing
April 2020

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

Mod Pathol 2019 11 12;32(11):1675-1687. Epub 2019 Jun 12.

Foundation Medicine Inc., Cambridge, Massachusetts, USA.

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.
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http://dx.doi.org/10.1038/s41379-019-0303-zDOI Listing
November 2019

Genomic Features of Metastatic Testicular Sex Cord Stromal Tumors.

Eur Urol Focus 2019 09 27;5(5):748-755. Epub 2019 May 27.

Upstate Medical University, Syracuse, NY, USA.

Background: Metastatic testicular sex cord stromal tumors of the testis (MSCSTs) comprise an extremely uncommon form of genitourinary malignancy.

Objective: To perform comprehensive genomic profiling (CGP) to enable the search for potential therapy targets.

Design, Setting, And Participants: Ten patients with testicular Leydig cell tumors (LCTs), six with Sertoli cell tumors (SCTs), and three with undifferentiated sex cord stromal tumors (USCSTs) and a comparison group of 366 patients with ovarian sex cord stromal tumors (SCSTs) underwent hybrid-capture-based CGP to evaluate all classes of genomic alterations (GAs). The tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA, and microsatellite instability (MSI) was determined on 114 loci.

Intervention: CGP on tumor samples.

Outcome Measurements And Statistical Analysis: Descriptive analyses and differences between histological subgroups were reported.

Results And Limitations: In these patients, all of whom had metastatic disease at the time of sequencing, the primary testis tumor was sequenced in six (32%) patients and a metastatic site in 13 (68%) patients. The overall frequencies of GAs were similar in LCTs, SCTs, and USCSTs, ranging from 3.0 to 3.5 GAs/tumor. The most frequent untargetable GAs included CTNNB1 and CDKN2A/B, both ranging from 20% to 33% of cases. Targetable GAs were uncommon in all MSCST subgroups, but several tumors showed potential for cell-cycle inhibitors (CDK4 in LCTs), mTOR inhibitors (RICTOR, NF2, and PTEN in all three tumor types), hedgehog inhibitors (PTCH1 in LCTs), and poly(ADP-ribose) polymerase inhibitors (BAP1 in SCTs). No MSI-high status was identified. The TMB was also low in all MSCST groups, and tumors featuring a TMB of ≥10 mutations/Mb were not identified. GA findings from ovarian SCSTs largely recapitulated those from MSCSTs. A lack of clinical outcome correlation is a limitation of the present analyses.

Conclusions: Rare cases of testicular MSCSTs have GAs linked to potential targeted therapy benefits on CGP. In contrast, the lack of MSI-high status and an overall low TMB indicate a likely lack of benefit for immunotherapies.

Patient Summary: Genomic profiling can guide clinical research and disclose therapeutic opportunities for patients with rare testicular cancers for which standard therapies are lacking.
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http://dx.doi.org/10.1016/j.euf.2019.05.012DOI Listing
September 2019

Comprehensive Genomic Profiling Reveals Diverse but Actionable Molecular Portfolios across Hematologic Malignancies: Implications for Next Generation Clinical Trials.

Cancers (Basel) 2018 Dec 21;11(1). Epub 2018 Dec 21.

Department of Medicine, Division of Hematology/Oncology and Center for Personalized Cancer Therapy, University of California San Diego, 3855 Health Science Drive #0987, La Jolla, CA 92093, USA.

: The translation of genomic discoveries to the clinic is the cornerstone of precision medicine. However, incorporating next generation sequencing (NGS) of hematologic malignancies into clinical management remains limited. : We describe 235 patients who underwent integrated NGS profiling (406 genes) and analyze the alterations and their potential actionability. : Overall, 227 patients (96.5%) had adequate tissue. Most common diagnoses included myelodysplastic syndrome (22.9%), chronic lymphocytic leukemia (17.2%), non-Hodgkin lymphoma (13.2%), acute myeloid leukemia (11%), myeloproliferative neoplasm (9.2%), acute lymphoblastic leukemia (8.8%), and multiple myeloma (7.5%). Most patients ( = 197/227 (87%)) harbored ≥1 genomic alteration(s); 170/227 (75%), ≥1 potentially actionable alteration(s) targetable by an FDA-approved (mostly off-label) or an investigational agent. Altogether, 546 distinct alterations were seen, most commonly involving (10.8%), (4.6%), and (4.2%). The median tumor mutational burden (TMB) was low (1.7 alterations/megabase); 12% of patients had intermediate or high TMB (higher TMB correlates with favorable response to anti-PD1/PDL1 inhibition in solid tumors). In conclusion, 96.5% of patients with hematologic malignancies have adequate tissue for comprehensive genomic profiling. Most patients had unique molecular signatures, and 75% had alterations that may be pharmacologically tractable with gene- or immune-targeted agents.
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http://dx.doi.org/10.3390/cancers11010011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356731PMC
December 2018

Comparative Genomic Profiling of Refractory and Metastatic Penile and Nonpenile Cutaneous Squamous Cell Carcinoma: Implications for Selection of Systemic Therapy.

J Urol 2019 03;201(3):541-548

Upstate Medical University , Syracuse , New York.

Purpose: Metastatic penile squamous cell carcinoma is an aggressive malignancy with limited treatment options. We compared the potential therapy impacting genomic alterations between metastatic penile squamous cell carcinoma and nonpenile metastatic cutaneous squamous cell carcinoma.

Materials And Methods: DNA was extracted from 40 μ of formalin fixed, paraffin embedded samples from 78 cases of metastatic penile squamous cell carcinoma and 338 of metastatic cutaneous squamous cell carcinoma. Comprehensive genomic profiling was performed using a hybrid capture, adaptor ligation based, next generation sequencing assay to a mean coverage depth of greater than 500×. The tumor mutational burden was determined on 1.1 Mbp of sequenced DNA and microsatellite instability was determined on 114 loci.

Results: Potential targeted therapy opportunities in metastatic penile squamous cell carcinoma cases included alterations in the MTOR pathway ( NF1 genomic alterations in 7% and PTEN genomic alterations in 4%) and in the DNA repair pathway ( BRCA2 and ATM genomic alterations in 7% each) and tyrosine kinase ( EGFR genomic alterations in 6%, and FGFR3 and ERBB2 genomic alterations in 4% each). The tumor mutational burden was significantly higher in predominantly ultraviolet light exposed metastatic squamous cell carcinoma than in metastatic penile squamous cell carcinoma, making metastatic squamous cell carcinoma potentially more responsive to immunotherapies than metastatic penile squamous cell carcinoma. Microsatellite high status was extremely rare for metastatic penile and metastatic cutaneous squamous cell carcinoma. CD274 ( PD-L1) amplification was also rare in both tumor types.

Conclusions: Metastatic penile squamous cell carcinoma is a unique subtype of squamous cell carcinoma with distinctive genomic features which contrast with those identified in metastatic cutaneous squamous cell carcinoma of nonpenile ultraviolet light exposed skin. Although not rich in predictors of the response to immunotherapy (the tumor mutational burden and microsatellite instability are low), more than a quarter of metastatic penile squamous cell carcinoma cases may potentially benefit from existing and available therapies targeting MTOR, DNA repair and tyrosine kinase pathways.
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http://dx.doi.org/10.1016/j.juro.2018.09.056DOI Listing
March 2019

Genomic Landscape of Adult and Pediatric -Like B-Lymphoblastic Leukemia Using Parallel DNA and RNA Sequencing.

Oncologist 2019 03 4;24(3):372-374. Epub 2018 Sep 4.

Foundation Medicine, Morrisville, North Carolina, USA.

BCR-ABL1-like B-Acute Lymphoblastic Leukemia (B-ALL) is a subset of B-ALL with a poor prognosis that is found in all age groups. Definitive identification of these patients is difficult in routine clinical practice as gene expression profiling, the gold standard test, is not widely available. Comprehensive genomic profiling performed on 450 patients with extensive fusion profiling revealed a wide range of genomic alterations which were consistent with a classification of BCR-ABL1-like B-ALL in 29% of cases. This manuscript highlights a clinically available alternative method for identifying a large subset of patients with BCR-ABL1-like B-ALL.
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http://dx.doi.org/10.1634/theoncologist.2018-0272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519773PMC
March 2019

Comprehensive Genomic Profiling of Hodgkin Lymphoma Reveals Recurrently Mutated Genes and Increased Mutation Burden.

Oncologist 2019 02 14;24(2):219-228. Epub 2018 Aug 14.

Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Background: The genomic landscape of Hodgkin lymphoma (HL) has been difficult to characterize due to the paucity of neoplastic cells and an abundant microenvironment. Such characterization is needed in order to improve treatment strategies.

Materials And Methods: We performed comprehensive genomic profiling (CGP) using targeted next-generation sequencing on archival formalin-fixed paraffin embedded tumor samples from 63 patients to analyze the landscape of HL.

Results: CGP was successful for 49/63 archival specimens (78%), and revealed aberrations impacting genes including , , and (E571). Of the 34 patients for whom total mutation burden (TMB; mutations/megabase [Mb]) was assessed, 5 (15%) had high TMB (≥20 mutations/Mb), 18 (53%) had intermediate TMB (6-19 mutations/Mb), and 11 (32%) had low TMB (≤5 mutations/Mb). We next tested 13 patients' plasma cell-free DNA with droplet digital polymerase chain reaction for the presence of E571 mutation, which was confirmed in the plasma of 31% of patients. In three patients with serially collected plasma samples, E571K allelic frequency changes corresponded with changes in tumor size on conventional radiographic imaging.

Conclusion: The study demonstrates that comprehensive genomic profiling of archival Hodgkin lymphoma tumor samples is feasible and leads to the identification of genes that are recurrently mutated and that Hodgkin lymphoma has increased mutation burden in the majority of samples analyzed. Furthermore, tracking of E571 mutant allele frequency in a subset of patients may also represent a potential disease-monitoring strategy and warrants further investigation.

Implications For Practice: This study provides the first evidence that comprehensive genomic profiling can be performed to map the genomic landscape of Hodgkin lymphoma and that a subpopulation of patients has mutations in , , , and other genes. It was found that 15% of patients have high mutation burden, which, in cancers such as melanoma, may indicate sensitivity to immune checkpoint inhibitors, and may thus be explored for Hodgkin lymphoma. Lastly, this work demonstrates that changes in the mutant allele frequency of in serially collected plasma cell-free DNA samples correspond with treatment outcomes measured with conventional radiographic imaging.
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http://dx.doi.org/10.1634/theoncologist.2018-0058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369943PMC
February 2019

Genomic Characterization of Testicular Germ Cell Tumors Relapsing After Chemotherapy.

Eur Urol Focus 2020 01 17;6(1):122-130. Epub 2018 Jul 17.

Upstate Medical University, Syracuse, NY, USA; Foundation Medicine Inc., Cambridge, MA, USA.

Background: Although both seminomatous and nonseminomatous testicular germ cell tumors (TGCTs) have favorable outcomes with chemotherapy, a subset is chemorefractory, and novel therapeutic options are needed.

Objective: To molecularly characterize chemotherapy-refractory TGCTs.

Design, Setting, And Participants: Archival tissues from 107 chemotherapy-treated and relapsed TGCT patients (23 seminomas; 84 nonseminomas) underwent hybrid-capture-based genomic profiling to evaluate four classes of genomic alterations (GAs). Tumor mutational burden (TMB) and microsatellite instability (MSI) were also measured.

Intervention: Genomic profiling on tumor samples from chemotherapy-refractory TGCTs.

Outcome Measurements And Statistical Analysis: Descriptive analyses and differences between seminoma and nonseminoma subgroups were reported.

Results And Limitations: The mean GA/tumor was 2.9 for seminomas and 4.0 for nonseminomas (p=0.04). KRAS alterations (mainly amplifications) were the most common GAs at the single-gene level (47.8% of seminomas and 51.2% of nonseminomas). RAS-RAF pathway (56.5% vs 52.3%) and cell-cycle pathway (52.2% vs 56.0%) were the most common GA classes in seminomas and nonseminomas, respectively. Receptor tyrosine kinase pathway and PI3K pathway GAs were more frequent in seminomas (p=0.02). Median TMB was 1.8 mutations/Mb for seminomas and 2.7 mutations/Mb for nonseminomas (p=0.098), and MSI-high status was found in one nonseminoma only (1.2%). A lack of clinical outcome correlation is a limitation of the present analyses.

Conclusions: In chemotherapy-refractory TGCTs, trials with agents targeting the KRAS pathway may be pursued due to the high frequency of KRAS GAs. Overall, the GAs found in refractory seminomas and nonseminomas differ significantly. Considering the frequency of high TMB or MSI-high status, immunotherapy may benefit a small subset of nonseminomas.

Patient Summary: Testicular cancers that are resistant to or relapse after standard chemotherapy may harbor genomic alterations that are potentially druggable, particularly in the clinical trial setting, and genomic profiling can guide clinical research and disclose therapeutic opportunities for these patients.
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http://dx.doi.org/10.1016/j.euf.2018.07.013DOI Listing
January 2020

Hybrid Capture-Based Comprehensive Genomic Profiling Identifies Lung Cancer Patients with Well-Characterized Sensitizing Epidermal Growth Factor Receptor Point Mutations That Were Not Detected by Standard of Care Testing.

Oncologist 2018 07 14;23(7):776-781. Epub 2018 Mar 14.

Foundation Medicine Inc., Cambridge, Massachusetts, USA.

Background: In our recent study, of cases positive for epidermal growth factor receptor () exon 19 deletions using comprehensive genomic profiling (CGP), 17/77 (22%) patients with prior standard of care (SOC) testing results available were previously negative for exon 19 deletion. Our aim was to compare the detection rates of CGP versus SOC testing for well-characterized sensitizing point mutations (pm) in our 6,832-patient cohort.

Materials And Methods: DNA was extracted from 40 microns of formalin-fixed paraffin-embedded sections from 6,832 consecutive cases of non-small cell lung cancer (NSCLC) of various histologies (2012-2015). CGP was performed using a hybrid capture, adaptor ligation-based next-generation sequencing assay to a mean coverage depth of 576×. Genomic alterations (pm, small indels, copy number changes and rearrangements) involving were recorded for each case and compared with prior testing results if available.

Results: Overall, there were 482 instances of exon 21 L858R (359) and L861Q (20), exon 18 G719X (73) and exon 20 S768I (30) pm, of which 103 unique cases had prior testing results that were available for review. Of these 103 cases, CGP identified 22 patients (21%) with sensitizing pm that were not detected by SOC testing, including 9/75 (12%) patients with L858R, 4/7 (57%) patients with L861Q, 8/20 (40%) patients with G719X, and 4/7 (57%) patients with S768I pm (some patients had multiple pm). In cases with available clinical data, benefit from small molecule inhibitor therapy was observed.

Conclusion: CGP, even when applied to low tumor purity clinical-grade specimens, can detect well-known pm in NSCLC patients that would otherwise not be detected by SOC testing. Taken together with exon 19 deletions, over 20% of patients who are positive for -activating mutations using CGP are previously negative by SOC mutation testing, suggesting that thousands of such patients per year in the U.S. alone could experience improved clinical outcomes when hybrid capture-based CGP is used to inform therapeutic decisions.

Implications For Practice: This study points out that genomic profiling, as based on hybrid capture next-generation sequencing, can identify lung cancer patients with point mutation in epidermal growth factor receptor (EGFR) missed by standard molecular testing who can likely benefit from anti-EGFR targeted therapy. Beyond the specific findings regarding false-negative point mutation testing for EGFR, this study highlights the need for oncologists and pathologists to be cognizant of the performance characteristics of testing deployed and the importance of clinical intuition in questioning the results of laboratory testing.
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http://dx.doi.org/10.1634/theoncologist.2017-0493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058345PMC
July 2018

Targeting HER2 in colorectal cancer: The landscape of amplification and short variant mutations in ERBB2 and ERBB3.

Cancer 2018 04 16;124(7):1358-1373. Epub 2018 Jan 16.

Foundation Medicine Inc, Cambridge, Massachusetts.

Background: In contrast to lung cancer, few precision treatments are available for colorectal cancer (CRC). One rapidly emerging treatment target in CRC is ERBB2 (human epidermal growth factor receptor 2 [HER2]). Oncogenic alterations in HER2, or its dimerization partner HER3, can underlie sensitivity to HER2-targeted therapies.

Methods: In this study, 8887 CRC cases were evaluated by comprehensive genomic profiling for genomic alterations in 315 cancer-related genes, tumor mutational burden, and microsatellite instability. This cohort included both colonic (7599 cases; 85.5%) and rectal (1288 cases; 14.5%) adenocarcinomas.

Results: A total of 569 mCRCs were positive for ERBB2 (429 cases; 4.8%) and/or ERBB3 (148 cases; 1.7%) and featured ERBB amplification, short variant alterations, or a combination of the 2. High tumor mutational burden (≥20 mutations/Mb) was significantly more common in ERBB-mutated samples, and ERBB3-mutated CRCs were significantly more likely to have high microsatellite instability (P<.002). Alterations affecting KRAS (27.3%) were significantly underrepresented in ERBB2-amplified samples compared with wild-type CRC samples (51.8%), and ERBB2- or ERBB3-mutated samples (49.0% and 60.8%, respectively) (P<.01). Other significant differences in mutation frequency were observed for genes in the PI3K/MTOR and mismatch repair pathways.

Conclusions: Although observed less often than in breast or upper gastrointestinal carcinomas, indications for which anti-HER2 therapies are approved, the percentage of CRC with ERBB genomic alterations is significant. Importantly, 32% of ERBB2-positive CRCs harbor short variant alterations that are undetectable by routine immunohistochemistry or fluorescence in situ hybridization testing. The success of anti-HER2 therapies in ongoing clinical trials is a promising development for patients with CRC. Cancer 2018;124:1358-73. © 2018 Foundation Medicine, Inc. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5900732PMC
April 2018

Fusions in a Wide Variety of Tumor Types Respond to Anti-ALK Targeted Therapy.

Oncologist 2017 12 27;22(12):1444-1450. Epub 2017 Oct 27.

Foundation Medicine, Inc., Cambridge, Massachusetts, USA.

Background: Genomic fusions of the anaplastic lymphoma kinase gene () are a well-established therapy target in non-small cell lung cancer (NSCLC). From a survey of 114,200 clinical cases, we determined the prevalence of rearrangements (r) in non-NSCLC tumors and report their responsiveness to therapies targeting ALK.

Materials And Methods: Comprehensive genomic profiling of 114,200 relapsed and metastatic malignancies, including both solid tumors and hematolymphoid cancers, was performed using a hybrid-capture, adaptor ligation-based next-generation sequencing assay.

Results: Of 114,200 clinical samples, 21,522 (18.8%) were NSCLC and 92,678 (81.2%) were other tumor types. Of the 876 (0.8%) cases with fusions (f) or rALK, 675 (77.1%) were NSCLC and 201 (22.9%) were other tumor types. fusions were significantly more frequent in NSCLC (3.1%) than non-NSCLC (0.2%;  < .0001). Patients with non-NSCLC tumors harboring f were significantly younger ( < .0001) and more often female ( < .0001) than patients with f-positive NSCLC. was more often the fusion partner in NSCLC (83.5%) versus non-NSCLC tumors (30.9%;  < .0001).

Conclusion: rearrangements can be identified in a wide variety of epithelial and mesenchymal malignancies beyond NSCLC. Anti-ALK therapies can be effective in non-NSCLC tumors driven by f, and further study of therapies targeting in clinical trials involving a wider variety of cancer types appears warranted.

Implications For Practice: Rearrangements involving the gene have been detected in dozens of cancer types using next-generation sequencing. Patients whose tumors harbor rearrangements or fusions respond to treatment with crizotinib and alectinib, including tumors not normally associated with mutations, such as non-Langerhans cell histiocytosis or renal cell carcinoma. Comprehensive genomic profiling using next-generation sequencing can detect targetable fusions irrespective of tumor type or fusions partner.
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http://dx.doi.org/10.1634/theoncologist.2016-0488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728036PMC
December 2017

General paucity of genomic alteration and low tumor mutation burden in refractory and metastatic hepatoblastoma: comprehensive genomic profiling study.

Hum Pathol 2017 12 24;70:84-91. Epub 2017 Oct 24.

Albany Medical College, Albany, NY 12208, USA; Foundation Medicine, Inc. Cambridge, MA 02141, USA.

Hepatoblastoma (HBL) is a hepatic malignancy of infants and young children, which is often cured by combinations of surgery and chemotherapy. Management of refractory and metastatic HBL is challenging. Comprehensive genomic profiling was performed on 31 refractory and metastatic HBL using a hybrid-capture, adaptor ligation-based next-generation sequencing assay. Tumor mutation burden (TMB) was calculated from a minimum of 1.11 Mb of sequenced DNA and reported as mutations/Mb. The results were analyzed for all classes of genomic alterations (GA). Activating CTNNB1 mutation was the most frequent GA seen in 19 (61%) of cases. All 3 (100%) mixed epithelial and mesenchymal HBL harbored CTNNB1 mutation. The small cell undifferentiated subtype showed SMARCB1 loss in both cases. There was no significant further correlation of GA with histologic subtype. In addition to the potential targeting of CTNNB1, other rarely identified possible targetable GA included ERBB4 (6%) and FBXW7, SRC and BRCA2 (each at 3%). The mean TMB was 3.5 mut/Mb, the median was 1.7 mut/Mb. There were 2 HBL with ≥10 mut/Mb. No alterations in TP53 were identified, and alterations in the DNA repair pathways were rare. Refractory and metastatic HBL is characterized by a general paucity of GA and is dominated by frequent CTNNB1 mutation and overall low TMB. Although potentially targetable GA are seen on occasion in HBL and a small number of cases have high TMB with potential to respond to immune checkpoint inhibitors, advanced HBL will remain a treatment challenge.
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http://dx.doi.org/10.1016/j.humpath.2017.10.007DOI Listing
December 2017

Comprehensive Genomic Profiling of 282 Pediatric Low- and High-Grade Gliomas Reveals Genomic Drivers, Tumor Mutational Burden, and Hypermutation Signatures.

Oncologist 2017 12 14;22(12):1478-1490. Epub 2017 Sep 14.

Foundation Medicine, Inc., Morrisville, North Carolina and Cambridge, Massachusetts, USA

Background: Pediatric brain tumors are the leading cause of death for children with cancer in the U.S. Incorporating next-generation sequencing data for both pediatric low-grade (pLGGs) and high-grade gliomas (pHGGs) can inform diagnostic, prognostic, and therapeutic decision-making.

Materials And Methods: We performed comprehensive genomic profiling on 282 pediatric gliomas (157 pHGGs, 125 pLGGs), sequencing 315 cancer-related genes and calculating the tumor mutational burden (TMB; mutations per megabase [Mb]).

Results: In pLGGs, we detected genomic alterations (GA) in 95.2% (119/125) of tumors. was most frequently altered (48%; 60/125), and missense (17.6%; 22/125), loss of function (8.8%; 11/125), and (5.6%; 7/125) mutations were also detected. Rearrangements were identified in 35% of pLGGs, including , , , , and fusions. Among pHGGs, GA were identified in 96.8% (152/157). The genes most frequently mutated were (49%; 77/157), (37.6%; 59/157), (24.2%; 38/157), (22.2%; 35/157), and (21.7%; 34/157). Interestingly, most mutations (81.4%; 35/43) were the variant K28M. Midline tumor analysis revealed mutations (40%; 40/100) consisted solely of the K28M variant. Pediatric high-grade gliomas harbored oncogenic , , , and fusions. Six percent (9/157) of pHGGs were hypermutated (TMB >20 mutations per Mb; range 43-581 mutations per Mb), harboring mutations deleterious for DNA repair in , and genes (78% of cases).

Conclusion: Comprehensive genomic profiling of pediatric gliomas provides objective data that promote diagnostic accuracy and enhance clinical decision-making. Additionally, TMB could be a biomarker to identify pediatric glioblastoma (GBM) patients who may benefit from immunotherapy.

Implications For Practice: By providing objective data to support diagnostic, prognostic, and therapeutic decision-making, comprehensive genomic profiling is necessary for advancing care for pediatric neuro-oncology patients. This article presents the largest cohort of pediatric low- and high-grade gliomas profiled by next-generation sequencing. Reportable alterations were detected in 95% of patients, including diagnostically relevant lesions as well as novel oncogenic fusions and mutations. Additionally, tumor mutational burden (TMB) is reported, which identifies a subpopulation of hypermutated glioblastomas that harbor deleterious mutations in DNA repair genes. This provides support for TMB as a potential biomarker to identify patients who may preferentially benefit from immune checkpoint inhibitors.
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http://dx.doi.org/10.1634/theoncologist.2017-0242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728033PMC
December 2017

Comprehensive Genomic Profiling of Esthesioneuroblastoma Reveals Additional Treatment Options.

Oncologist 2017 07 11;22(7):834-842. Epub 2017 May 11.

Foundation Medicine, Inc., Cambridge, Massachusetts, USA.

Background: Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, is a rare malignant neoplasm of the olfactory mucosa. Despite surgical resection combined with radiotherapy and adjuvant chemotherapy, ENB often relapses with rapid progression. Current multimodality, nontargeted therapy for relapsed ENB is of limited clinical benefit.

Materials And Methods: We queried whether comprehensive genomic profiling (CGP) of relapsed or refractory ENB can uncover genomic alterations (GA) that could identify potential targeted therapies for these patients. CGP was performed on formalin-fixed, paraffin-embedded sections from 41 consecutive clinical cases of ENBs using a hybrid-capture, adaptor ligation based next-generation sequencing assay to a mean coverage depth of 593X. The results were analyzed for base substitutions, insertions and deletions, select rearrangements, and copy number changes (amplifications and homozygous deletions).

Results: Clinically relevant GA (CRGA) were defined as GA linked to drugs on the market or under evaluation in clinical trials. A total of 28 ENBs harbored GA, with a mean of 1.5 GA per sample. Approximately half of the ENBs (21, 51%) featured at least one CRGA, with an average of 1 CRGA per sample. The most commonly altered gene was (17%), with GA in , , , and occurring in 7% of samples.

Conclusion: We report comprehensive genomic profiles for 41 ENB tumors. CGP revealed potential new therapeutic targets, including targetable GA in the mTOR, CDK and growth factor signaling pathways, highlighting the clinical value of genomic profiling in ENB.

Implications For Practice: Comprehensive genomic profiling of 41 relapsed or refractory ENBs reveals recurrent alterations or classes of mutation, including amplification of tyrosine kinases encoded on chromosome 5q and mutations affecting genes in the mTOR/PI3K pathway. Approximately half of the ENBs (21, 51%) featured at least one clinically relevant genomic alteration (CRGA), with an average of 1 CRGA per sample. The most commonly altered gene was (17%), and alterations in , , , or were identified in 7% of samples. Responses to treatment with the kinase inhibitors sunitinib, everolimus, and pazopanib are presented in conjunction with tumor genomics.
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http://dx.doi.org/10.1634/theoncologist.2016-0287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5507647PMC
July 2017

Neonatal anemia: Revisiting the enigmatic pyknocyte.

Am J Hematol 2017 Jul 26;92(7):717-721. Epub 2017 May 26.

Department of Pediatrics, Section of Hematology/Oncology/Stem Cell Transplantation, University of Chicago, Comer Children's Hospital, Chicago, Illinois, USA.

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http://dx.doi.org/10.1002/ajh.24731DOI Listing
July 2017

Comprehensive genomic profiling of malignant phyllodes tumors of the breast.

Breast Cancer Res Treat 2017 04 17;162(3):597-602. Epub 2017 Feb 17.

Foundation Medicine, Inc., Cambridge, MA, USA.

Purpose: Malignant phyllodes tumors (MPT) are exceptionally rare, and the genomic drivers of these tumors are still being elucidated. We performed comprehensive genomic profiling (CGP) of MPT to identify genomic alterations that will inform approaches to targeted therapy for patients with MPT, including relapsed, refractory, and metastatic disease.

Methods: DNA was extracted from formalin-fixed, paraffin-embedded samples from 24 consecutive patient cases of MPT. CGP was performed using a hybrid capture, adaptor ligation-based next generation sequencing assay to a high, uniform coverage (mean, 582×). Tumor mutational burden (TMB) was calculated from a minimum of 1.14 Mb of sequenced DNA as previously described and reported as mutations/Mb. The results were analyzed for all classes of genomic alterations, including short variants (SV; base substitutions, small insertions, and deletions), rearrangements, and copy number changes, including amplifications and homozygous deletions.

Results: The 24 cases of MPT included 15 patients with localized and 9 with metastatic disease. The median TMB was 2.7 mut/Mb, and no cases had a TMB > 10 mut/Mb. 20 out of 24 cases were evaluable for microsatellite status, and all were microsatellite stable. The most commonly mutated genes were TP53 (58.3%), TERT-promoter (57.9%), NF1 (45.8%), MED12 (45.8%), CDKN2A/B (33.3%), and MLL2 (33.3%). Targetable kinase fusions including KIAA1549-BRAF or FGFR3-TACC3 were identified in 2/24 (8.3%) tumors.

Conclusions: This study identifies clinically relevant genomic alterations that suggest novel targeted therapy approaches for patients with MPT.
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http://dx.doi.org/10.1007/s10549-017-4156-1DOI Listing
April 2017

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

Cancer Res 2017 01 9;77(2):509-519. Epub 2017 Jan 9.

Foundation Medicine, Cambridge, Massachusetts.

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.
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http://dx.doi.org/10.1158/0008-5472.CAN-16-1106DOI Listing
January 2017

Next-Generation Sequencing Reveals Pathway Activations and New Routes to Targeted Therapies in Cutaneous Metastatic Melanoma.

Am J Dermatopathol 2017 Jan;39(1):1-13

*Professor of Pathology and Dermatology, Albany Medical College, Albany, NY; †Pathology Resident, Unversidade Estadual Paulista, Botucatu, Brazil; ‡Pathology Resident, Albany Medical College, Albany, NY; §Director of Research, Associate Professor, Department of Pathology, Albany, Medical College, Albany, NY; ¶Research and Development, Foundation Medicine, Inc, Cambridge, MA; ‖Chief Medical Officer, Foundation Medicine, Inc, Cambridge, MA; #Chief Scientific Officer, Foundation Medicine, Inc, Cambridge, MA; **Associate Medical Officer, Foundation Medicine, Inc, Cambridge, MA; ††Associate Medical Director, Foundation Medicine, Inc, Cambridge, MA; ‡‡Research Scientist, Foundation Medicine, Inc, Cambridge, MA; §§Chief, Professor of Pathology, Albany, Medical College, Albany, NY; and ¶¶Medical Director, Foundation Medicine, Inc, Cambridge, MA.

Background: Comprehensive genomic profiling of clinical samples by next-generation sequencing (NGS) can identify one or more therapy targets for the treatment of metastatic melanoma (MM) with a single diagnostic test.

Methods: NGS was performed on hybridization-captured, adaptor ligation-based libraries using DNA extracted from 4 formalin-fixed paraffin-embedded sections cut at 10 microns from 30 MM cases. The exons of 182 cancer-related genes were fully sequenced using the Illumina HiSeq 2000 at an average sequencing depth of 1098X and evaluated for genomic alterations (GAs) including point mutations, insertions, deletions, copy number alterations, and select gene fusions/rearrangements. Clinically relevant GAs (CRGAs) were defined as those identifying commercially available targeted therapeutics or therapies in registered clinical trials.

Results: The 30 American Joint Committee on Cancer Stage IV MM included 17 (57%) male and 13 (43%) female patients with a mean age of 59.5 years (range 41-83 years). All MM samples had at least 1 GA, and an average of 2.7 GA/sample (range 1-7) was identified. The mean number of GA did not differ based on age or sex; however, on average, significantly more GAs were identified in amelanotic and poorly differentiated MM. GAs were most commonly identified in BRAF (12 cases, 40%), CDKN2A (6 cases, 20%), NF1 (8 cases, 26.7%), and NRAS (6 cases, 20%). CRGAs were identified in all patients, and represented 77% of the GA (64/83) detected. The median and mean CRGAs per tumor were 2 and 2.1, respectively (range 1-7).

Conclusion: Comprehensive genomic profiling of MM, using a single diagnostic test, uncovers an unexpectedly high number of CRGA that would not be identified by standard of care testing. Moreover, NGS has the potential to influence therapy selection and can direct patients to enter relevant clinical trials evaluating promising targeted therapies.
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http://dx.doi.org/10.1097/DAD.0000000000000729DOI Listing
January 2017

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

Oncology 2016 21;91(6):348-353. Epub 2016 Oct 21.

The University of Texas MD Anderson Cancer Center, Houston, Tex., USA.

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.
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http://dx.doi.org/10.1159/000449204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5130597PMC
January 2017