Publications by authors named "Soo Ryum Yang"

19 Publications

  • Page 1 of 1

Brief Report: Molecular characterization of peritoneal mesotheliomas.

J Thorac Oncol 2021 Oct 11. Epub 2021 Oct 11.

Thoracic Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, and Weill Cornell Medical College, New York, NY.

Background: Malignant peritoneal mesothelioma (MPeM) is clinically distinct and less studied than malignant pleural mesothelioma. We report the genomic and immunophenotypic features of a prospectively collected MPeM cohort.

Methods: Next-generation sequencing (NGS) was performed on MPeM tumors. Genomic near-haploidization (GNH) was assessed. WT1, BAP1, mesothelin, VISTA, and PD-L1 were examined by immunohistochemistry (IHC) when tissue was available. Overall survival (OS) was stratified by selected genomic and IHC features.

Results: Fifty consented patients with MPeM (45 epithelioid, 5 non-epithelioid) demonstrated common alterations in BAP1 (60%; 30/50), NF2 (24%; 12/50) SETD2 (22%; 11/50), and TP53 (16%; 8/50). Seventy-six percent (38/50) of specimens were evaluable for allele-specific copy number analysis; 8% (3/38) had GNH. IHC positivity rates were 93% (37/40) for mesothelin, 96% (46/48) for WT1, 50% (19/38) for PD-L1 and 89% (34/38) for VISTA. BAP1 loss by IHC was observed in 76% (29/38), including five wildtype on NGS. Combining NGS and IHC for BAP1, OS was worse with alteration/loss compared to wildtype/retained in all patients (n=37 vs. 13, 43.8 vs. 117.3 months; p=0.04) Three of thirty patients had a pathogenic germline variant: POT1 I78T, MUTYH R109Y, BAP1 E402*.

Conclusion: MPeM has a distinct biology and genomic composition. CDKN2A/B alterations were rare in MPeM while BAP1, NF2, TP53, SETD2, LATS2 were common. BAP1 alteration/loss was associated with shorter survival when all patients were included. A notable minority of specimens had GNH associated with NF2, TP53, and SETDB1 mutations. Pathogenic germline mutations were found in 3 of 30 patients.
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http://dx.doi.org/10.1016/j.jtho.2021.09.012DOI Listing
October 2021

Response to Immune Checkpoint Inhibition as Monotherapy or in Combination With Chemotherapy in Metastatic -Rearranged Lung Cancers.

JTO Clin Res Rep 2021 Jul 18;2(7):100187. Epub 2021 May 18.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Introduction: fusions are oncogenic drivers in 1% to 3% of NSCLCs. The activity of immune checkpoint inhibitor (ICI) monotherapy or in combination with chemotherapy (chemotherapy with ICI [chemo-ICI]) in these tumors and their immunophenotype have not been systematically described.

Methods: In this multi-institutional retrospective study, tumor programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB) were evaluated in patients with rearranged NSCLC. Time-to-treatment discontinuation (TTD) and objective response rate (ORR) (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) were calculated for patients treated with ICI or chemo-ICI in the metastatic setting.

Results: A total of 184 patients were identified. Among 146 assessable cases, PD-L1 expression was less than 1% in 60 (41%), 1% to 49% in 35 (24%), and greater than or equal to 50% in 51 tumors (35%). Of 100 (92%) TMB-assessable tumors, 92 had less than 10 mutations per megabase. TMB was significantly lower for rearranged tumors (n = 97) compared with tumors with (n = 1250) or alterations (n = 1653) and all other NSCLC tumors (n = 2753) evaluated with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (median TMB = 2.6 versus 3.5, 7.0, and 6.1 mutations per megabase, < 0.001). Among patients treated with ICI, median TTD was 2.1 months (95% confidence interval [CI]: 1.0-4.2 mo; n = 28) and ORR 13% (2 of 16 RECIST-assessable; 95% CI: 2%-38%). Among patients treated with chemo-ICI, median TTD was 10 months (95% CI: 4.7-14.1 mo; n = 11) and ORR 83% (5 of 6 RECIST-assessable; 95% CI: 36%-100%). There was no difference in PD-L1 expression ( = 0.91) or TMB ( = 0.83) between responders and nonresponders.

Conclusions: Most rearranged NSCLCs have low PD-L1 expression and TMB. The activity of ICI in these tumors is modest. In contrast, chemo-ICI can achieve meaningful activity.
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http://dx.doi.org/10.1016/j.jtocrr.2021.100187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474494PMC
July 2021

Uterine mesenchymal tumors harboring fusions and response to ALK-targeted therapy.

Gynecol Oncol Rep 2021 Aug 1;37:100852. Epub 2021 Sep 1.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.

Inflammatory myofibroblastic tumor (IMT) of the uterus is a rare but aggressive malignancy that is often misdiagnosed. Approximately 50% of uterine IMTs (UMT) harbor rearrangements involving the gene on chromosome 2p23 with subsequent overexpression of the ALK protein. Molecular characterization and wider availability of immunohistochemistry (IHC) and next generation sequencing (NGS) have improved clinical recognition and accurate diagnosis of UMT. The discovery of fusions as a genomic driver led to the FDA approval of ALK inhibitors in ALK-altered lung cancers, but there are limited data to date on the spectrum of ALK fusions or patterns of response and resistance to ALK inhibitors in ALK-altered UMT. In this report we describe the genomic and histopathological characteristics and the response to ALK-targeted therapy in four patients with UMT. In all four patients, clinical activity of ALK inhibition was observed, with durable responses lasting 12 months or more. Moreover, three patients derived benefit from a second-generation ALK inhibitor after progression of disease or intolerance to the first-generation inhibitor crizotinib. Our report advocates for consideration of expanding the current National Comprehensive Cancer Network (NCCN) guidelines to include later-generation ALK inhibitors for the treatment of ALK-rearranged UMTs.
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http://dx.doi.org/10.1016/j.gore.2021.100852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427213PMC
August 2021

Enhanced specificity of clinical high-sensitivity tumor mutation profiling in cell-free DNA via paired normal sequencing using MSK-ACCESS.

Nat Commun 2021 06 18;12(1):3770. Epub 2021 Jun 18.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Circulating cell-free DNA from blood plasma of cancer patients can be used to non-invasively interrogate somatic tumor alterations. Here we develop MSK-ACCESS (Memorial Sloan Kettering - Analysis of Circulating cfDNA to Examine Somatic Status), an NGS assay for detection of very low frequency somatic alterations in 129 genes. Analytical validation demonstrated 92% sensitivity in de-novo mutation calling down to 0.5% allele frequency and 99% for a priori mutation profiling. To evaluate the performance of MSK-ACCESS, we report results from 681 prospective blood samples that underwent clinical analysis to guide patient management. Somatic alterations are detected in 73% of the samples, 56% of which have clinically actionable alterations. The utilization of matched normal sequencing allows retention of somatic alterations while removing over 10,000 germline and clonal hematopoiesis variants. Our experience illustrates the importance of analyzing matched normal samples when interpreting cfDNA results and highlights the importance of cfDNA as a genomic profiling source for cancer patients.
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http://dx.doi.org/10.1038/s41467-021-24109-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213710PMC
June 2021

Clinicopathologic Features and Response to Therapy of Fusion-Driven Lung Cancers: The eNRGy1 Global Multicenter Registry.

J Clin Oncol 2021 Sep 2;39(25):2791-2802. Epub 2021 Jun 2.

Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY.

Purpose: Although fusions are oncogenic drivers across multiple tumor types including lung cancers, these are difficult to study because of their rarity. The global eNRGy1 registry was thus established to characterize fusion-positive lung cancers in the largest and most diverse series to date.

Methods: From June 2018 to February 2020, a consortium of 22 centers from nine countries in Europe, Asia, and the United States contributed data from patients with pathologically confirmed fusion-positive lung cancers. Profiling included DNA-based and/or RNA-based next-generation sequencing and fluorescence in situ hybridization. Anonymized clinical, pathologic, molecular, and response (RECIST v1.1) data were centrally curated and analyzed.

Results: Although the typified never smoking (57%), mucinous adenocarcinoma (57%), and nonmetastatic (71%) phenotype predominated in 110 patients with fusion-positive lung cancer, further diversity, including in smoking history (43%) and histology (43% nonmucinous and 6% nonadenocarcinoma), was elucidated. RNA-based testing identified most fusions (74%). Molecularly, six (of 18) novel 5' partners, 20 unique epidermal growth factor domain-inclusive chimeric events, and heterogeneous 5'/3' breakpoints were found. Platinum-doublet and taxane-based (post-platinum-doublet) chemotherapy achieved low objective response rates (ORRs 13% and 14%, respectively) and modest progression-free survival medians (PFS 5.8 and 4.0 months, respectively). Consistent with a low programmed death ligand-1 expressing (28%) and low tumor mutational burden (median: 0.9 mutations/megabase) immunophenotype, the activity of chemoimmunotherapy and single-agent immunotherapy was poor (ORR 0%/PFS 3.3 months and ORR 20%/PFS 3.6 months, respectively). Afatinib achieved an ORR of 25%, not contingent on fusion type, and a 2.8-month median PFS.

Conclusion: fusion-positive lung cancers were molecularly, pathologically, and clinically more heterogeneous than previously recognized. The activity of cytotoxic, immune, and targeted therapies was disappointing. Further research examining -rearranged tumor biology is needed to develop new therapeutic strategies.
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http://dx.doi.org/10.1200/JCO.20.03307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407651PMC
September 2021

Invasive Mucinous Adenocarcinomas With Spatially Separate Lung Lesions: Analysis of Clonal Relationship by Comparative Molecular Profiling.

J Thorac Oncol 2021 07 8;16(7):1188-1199. Epub 2021 Apr 8.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address:

Introduction: Pulmonary invasive mucinous adenocarcinomas (IMAs) often present with spatially separate lung lesions. Clonal relationship between such lesions, particularly those involving contralateral lobes, is not well established. Here, we used comparative genomic profiling to address this question.

Methods: Patients with genomic analysis performed on two IMAs located in different lung regions were identified. Molecular assays included DNA-based next-generation sequencing (NGS) for 410 to 468 genes (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets), RNA-based NGS for 62 genes (Memorial Sloan Kettering-Fusion), or non-NGS assays.

Results: Comparative genomic profiling was performed on two separate IMAs in 24 patients, of whom 19 had contralateral lesions. Tumors from all but one patient shared matching driver alterations, including KRAS (n = 19), NRG1 (n = 2), ERBB2 (n = 1) or BRAF (n = 1). In addition, in patients with paired tumors profiled by NGS (n = 12), shared driver alterations were accompanied by up to 4 (average 2.6) other identical mutations, further supporting the clonal relationship between the tumors. Only in a single patient separate IMAs harbored entirely nonoverlapping mutation profiles, supporting clonally unrelated, distinct primary tumors. Notably, in a subset of patients (n = 3), molecular testing confirmed a clonal relationship between the original resected IMAs and subsequent contralateral IMA presenting after an extremely long latency (8.1-11.7 y).

Conclusions: Comparative molecular profiling supports that nearly all separate pulmonary IMA lesions represent intrapulmonary spread arising from a single tumor and documents a subset with a remarkably protracted course of intrapulmonary progression. This study reinforces the unique biology and clinical behavior of IMAs while further highlighting the value of genomic testing for clarifying the clonal relationship between multiple lung carcinomas.
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http://dx.doi.org/10.1016/j.jtho.2021.03.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240964PMC
July 2021

Clinical Experience of Cerebrospinal Fluid-Based Liquid Biopsy Demonstrates Superiority of Cell-Free DNA over Cell Pellet Genomic DNA for Molecular Profiling.

J Mol Diagn 2021 06 27;23(6):742-752. Epub 2021 Mar 27.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.

Cell-free DNA (cfDNA) from cerebrospinal fluid (CSF) offers unique opportunities for genomic profiling of tumors involving the central nervous system but remains uncommonly used in clinical practice. We describe our clinical experience using cfDNA from CSF for routine molecular testing using Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (targeting 468 cancer-related genes). In all, 148 cfDNA samples were assessed, comparing results of cfDNA versus genomic DNA (gDNA; gDNA from cell pellets) derived from the same CSF sample and the primary tumor. Of these, 71.6% (106/148) were successfully sequenced. Somatic alterations (mutations and fusions) were observed in 70.8% (75/106) of the samples; 97.3% (73/75) comprised variants confirming central nervous system involvement by a previously diagnosed tumor, 14.7% (11/75) had additional variants consistent with a therapy-related resistance mechanism, and 2.7% (2/75) had variants that independently diagnosed a new primary. Among samples with paired cfDNA and gDNA sequencing results, cfDNA was more frequently positive for at least one mutation [43.6% (55/126) versus 19.8% (25/126)] and harbored 1.6× more mutations (6.94 versus 4.65; P = 0.005), with higher mean variant allele fractions (41.1% versus 13.0%; P < 0.0001). Among mutation-positive cfDNAs, the corresponding gDNA was frequently negative (44.6%; 25/55) or failed sequencing (17.8%; 9/55). Routine molecular profiling of cfDNA is superior to gDNA from CSF, facilitating the capture of mutations at high variant allele frequency, even in the context of a negative cytology.
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http://dx.doi.org/10.1016/j.jmoldx.2021.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207471PMC
June 2021

Ultrarapid Mutation Screening Followed by Comprehensive Next-Generation Sequencing: A Feasible, Informative Approach for Lung Carcinoma Cytology Specimens With a High Success Rate.

JTO Clin Res Rep 2020 Sep 18;1(3). Epub 2020 Jul 18.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.

Introduction: For patients with advanced NSCLC, cytologic samples may be the only diagnostic specimen available for molecular profiling. Although both rapid and comprehensive assessment are essential in this setting, an integrated multitest approach remains an important strategy in many laboratories, despite the risks and challenges when working with scant samples. In this study, we describe our experience and high success rate in using a multitest approach, focusing on the clinical validation and incorporation of ultrarapid testing using the Idylla system followed by comprehensive next-generation sequencing (NGS).

Methods: Cytology samples received for routine molecular testing were included in this study. The performance characteristics of the Idylla assay were assessed; tissue suitability parameters and interpretation criteria to supplement automated mutation calling were established. The assay performance was monitored for 1 year, comparing the results with those of concurrent NGS testing by MSK-IMPACT (primarily) or MSK-AmpliSeq and MSK-Fusion solid panel in a subset of cases.

Results: Overall, 301 samples were studied; 83 samples were included in validation (60.2% [50 of 83] were positive for mutations). Concordance with the reference method was 96.4% (80 of 83) of the samples with excellent reproducibility. The limit of detection was variable depending on the total tissue input and the specific mutation tested. Unextracted tissue inputs that maintained total cycle of quantification at less than 23 allowed all mutations to be detected if present at greater than 5% variant allele frequency. Mutations could be detected at 1% variant allele frequency with total cycle of quantification of 18. During the clinical implementation phase, 218 NSCLC samples were tested by Idylla (24.3% [53 of 218] were mutation positive). Concurrent NGS testing was requested on 165 samples and successfully performed on 96.4% (159 of 165) of the samples. The Idylla automated results were concordant with those obtained by NGS in 96.2% (153 of 159) of cases and improved to 98.7% (157 of 159) after incorporation of manual review criteria to supplement automated calling, resulting in a diagnostic sensitivity of 95.6% (95% confidence interval: 84.9%-99.5%). In general, 9% (14 of 159) of the cases tested by NGS had mutations not covered by the Idylla assay, primarily insertions in exon 19 and 20 and minor mutations cooccurring with canonical sensitizing mutations.

Conclusions: Comprehensive molecular testing is feasible and has a high success rate in NSCLC cytology samples when using a multitest approach. Testing with the Idylla system enables rapid and accurate determination of the status without compromising subsequent NGS testing.
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http://dx.doi.org/10.1016/j.jtocrr.2020.100077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839984PMC
September 2020

A Performance Comparison of Commonly Used Assays to Detect RET Fusions.

Clin Cancer Res 2021 03 3;27(5):1316-1328. Epub 2020 Dec 3.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: Selpercatinib and pralsetinib induce deep and durable responses in patients with advanced fusion-positive lung and thyroid cancer. fusion testing strategies with rapid and reliable results are critical given recent FDA approval. Here, we assess various clinical assays in a large pan-cancer cohort.

Experimental Design: Tumors underwent DNA-based next-generation sequencing (NGS) with reflex to RNA-based NGS if no mitogenic driver or if a structural variant of unknown significance (SVUS) were present. Canonical DNA-level fusions and RNA-confirmed fusions were considered true fusions. Break-apart FISH and IHC performance were assessed in subgroups.

Results: A total of 171 of 41,869 patients with DNA NGS harbored structural variants, including 139 canonical fusions and 32 SVUS. Twelve of 32 (37.5%) SVUS were transcribed into RNA-level fusions, resulting in 151 oncogenic fusions. The most common fusion-positive tumor types were lung (65.6%) and thyroid (23.2%). The most common partners were (45%), (29.1%), and (13.3%). DNA NGS showed 100% (46/46) sensitivity and 99.6% (4,459/4,479) specificity. FISH showed 91.7% (44/48) sensitivity, with lower sensitivity for - (66.7%, 8/12). A total of 87.5% (7/8) of SVUS negative for RNA-level fusions demonstrated rearrangement by FISH. The sensitivity of IHC varied by fusion partner: sensitivity was highest (100%, 31/31), followed by (88.9%, 16/18) and (50%, 6/12). Specificity of RET IHC was 82% (73/89).

Conclusions: Although DNA sequencing has high sensitivity and specificity, RNA sequencing of SVUS is necessary. Both FISH and IHC demonstrated lower sensitivity for - fusions.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285056PMC
March 2021

Genetic and epigenetic landscape of IDH-wildtype glioblastomas with FGFR3-TACC3 fusions.

Acta Neuropathol Commun 2020 11 9;8(1):186. Epub 2020 Nov 9.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.

A subset of glioblastomas (GBMs) harbors potentially druggable oncogenic FGFR3-TACC3 (F3T3) fusions. However, their associated molecular and clinical features are poorly understood. Here we analyze the frequency of F3T3-fusion positivity, its associated genetic and methylation profiles, and its impact on survival in 906 IDH-wildtype GBM patients. We establish an F3T3 prevalence of 4.1% and delineate its associations with cancer signaling pathway alterations. F3T3-positive GBMs had lower tumor mutational and copy-number alteration burdens than F3T3-wildtype GBMs. Although F3T3 fusions were predominantly mutually exclusive with other oncogenic RTK pathway alterations, they did rarely co-occur with EGFR amplification. They were less likely to harbor TP53 alterations. By methylation profiling, they were more likely to be assigned the mesenchymal or RTK II subclass. Despite being older at diagnosis and having similar frequencies of MGMT promoter hypermethylation, patients with F3T3-positive GBMs lived about 8 months longer than those with F3T3-wildtype tumors. While consistent with IDH-wildtype GBM, F3T3-positive GBMs exhibit distinct biological features, underscoring the importance of pursuing molecular studies prior to clinical trial enrollment and targeted treatment.
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http://dx.doi.org/10.1186/s40478-020-01058-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653727PMC
November 2020

Precision medicine in non-small cell lung cancer: Current applications and future directions.

Semin Cancer Biol 2020 Jul 27. Epub 2020 Jul 27.

University Hospital of Cologne, Department of Pathology, Germany. Electronic address:

Advances in biomarkers, targeted therapies, and immuno-oncology have transformed the clinical management of patients with advanced NSCLC. For oncogene-driven tumors, there are highly effective targeted therapies against EGFR, ALK, ROS1, BRAF, TRK, RET, and MET. In addition, investigational therapies for KRAS, NRG1, and HER2 have shown promising results and may become standard-of-care in the near future. In parallel, immune-checkpoint therapy has emerged as an indispensable treatment modality, especially for patients lacking actionable oncogenic drivers. While PD-L1 expression has shown modest predictive utility, biomarkers for immune-checkpoint inhibition in NSCLC have remained elusive and represent an area of active investigation. Given the growing importance of biomarkers, optimal utilization of small tissue biopsies and alternative genotyping methods using circulating cell-free DNA have become increasingly integrated into clinical practice. In this review, we will summarize the current landscape and emerging trends in precision medicine for patients with advanced NSCLC with a special focus on predictive biomarker testing.
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http://dx.doi.org/10.1016/j.semcancer.2020.07.009DOI Listing
July 2020

RAS/MAPK Pathway Driver Alterations Are Significantly Associated With Oncogenic KIT Mutations in Germ-cell Tumors.

Urology 2020 Oct 25;144:111-116. Epub 2020 Jul 25.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address:

Objective: To report the mutational profile and clinical outcomes of a cohort of patients with KIT-mutant seminomas and nonseminomatous germ-cell tumors (SGCT/NSGCTs).

Patients And Methods: Retrospective cohort study of all patients with KIT-mutant GCTs sequenced at Memorial Sloan Kettering between March 2014 and March 2020. Tumors were assessed with MSK-IMPACT, a DNA next-generation sequencing assay for targeted sequencing of up to 468 key cancer genes.

Results: Among 568 patients with GCTs, 8.1% had somatic KIT mutations, including 28 seminomas and 18 mixed/NSGCTs. Exons 17 (67.3%), 11 (22.4%), and 13 (6.1%) were most commonly affected. KIT-mutant cases were enriched for oncogenic RAS/MAPK pathway alterations compared to KIT-wildtype cases (34.8% vs 19.2%, P = .02). Among KIT-mutant cases, concurrent mutations were noted in KRAS (21.7%), RRAS2 (11.8%), CBL (6.5%), NRAS (4.3%), MAP2K1 (2.2%), and RAC1 (2.2%). Mutations in KRAS, RRAS2, and NRAS were mutually exclusive. In all, 73.9% of patients developed metastases and 95.7% received chemotherapy. No patients received KIT-directed tyrosine kinase inhibitors (TKIs). Classification as a NSGCT rather than a SGCT was associated with an increased risk of death (hazard ratio 9.1, 95% confidence interval 1.1-78.4, P = .04) while the presence of a concurrent RAS/MAPK pathway alteration was not (hazard ratio 0.8, 95% confidence interval 0.1-4.3, P = .76).

Conclusion: Mitogenic driver alterations can co-occur with activating KIT mutations, which may explain the lack of efficacy of KIT-directed TKIs in prior trials. Novel KIT-directed TKIs that target exon 17 mutations may benefit chemotherapy-refractory patients with KIT-mutant GCTs without RAS/MAPK alterations. Dual MEK/KIT inhibitor therapy in KIT-mutant GCTs with concurrent RAS/MAPK alterations could also be a plausible therapeutic strategy.
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http://dx.doi.org/10.1016/j.urology.2020.07.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276690PMC
October 2020

Integrated genomic characterization of ERBB2/HER2 alterations in invasive breast carcinoma: a focus on unusual FISH groups.

Mod Pathol 2020 08 11;33(8):1546-1556. Epub 2020 Mar 11.

Department of Pathology, School of Medicine, Stanford University, Stanford, CA, USA.

In patients with invasive breast cancer, fluorescence in situ hybridization (FISH) testing for HER2 typically demonstrates the clear presence or lack of ERBB2 (HER2) amplification (i.e., groups 1 or 5). However, a small subset of patients can present with unusual HER2 FISH patterns (groups 2-4), resulting in diagnostic confusion. To provide clarity, the 2018 CAP/ASCO HER2 testing guideline recommends additional testing using HER2 immunohistochemistry (IHC) for determining the final HER2 status. Despite this effort, the genomic correlates of unusual HER2 FISH groups remain poorly understood. Here, we used droplet digital PCR (ddPCR) and targeted next-generation sequencing (NGS) to characterize the genomic features of both usual and unusual HER2 FISH groups. In this study, 51 clinical samples were selected to represent FISH groups 1-5. Furthermore, group 1 was subdivided into two groups, with groups 1A and 1B corresponding to cases with HER2 signals/cell ≥6.0 and 4-6, respectively. Overall, our findings revealed a wide range of copy number alterations in HER2 across the different FISH groups. As expected, groups 1A and 5 showed the clear presence and lack of HER2 copy number gain, respectively, as measured by ddPCR and NGS. In contrast, group 1B and other uncommon FISH groups (groups 2-4) were characterized by a broader range of HER2 copy levels with only a few select cases showing high-level gain. Notably, these cases with increased HER2 copy levels also showed HER2 overexpression by IHC, thus highlighting the correlation between HER2 copy number and HER2 protein expression. Given the concordance between the genomic and protein results, our findings suggest that HER2 IHC may inform HER2 copy number status in patients with unusual FISH patterns. Hence, our results support the current recommendation for using IHC to resolve HER2 status in FISH groups 2-4.
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http://dx.doi.org/10.1038/s41379-020-0504-5DOI Listing
August 2020

Targeted deep sequencing of cell-free DNA in serous body cavity fluids with malignant, suspicious, and benign cytology.

Cancer Cytopathol 2020 01 21;128(1):43-56. Epub 2019 Nov 21.

Department of Pathology, Stanford University School of Medicine, Stanford, California.

Background: Liquid biopsy using cell-free DNA (cfDNA) presents new opportunities for solid tumor genotyping. While studies have demonstrated the utility of cfDNA from plasma, cfDNA from other body fluids remains underexplored.

Methods: We evaluated the molecular features and clinicopathologic correlates of cfDNA from serous body cavity fluids by performing hybrid capture-based next-generation sequencing (NGS) on cfDNA isolated from residual effusion supernatants. Twenty-one serous effusions from pleural (n = 15), peritoneal (n = 5), and pericardial (n = 1) cavity were analyzed.

Results: The supernatants provided a median cfDNA concentration of 10.3 ng/µL. Notably, all effusions were sequenced successfully to a median depth >1000×, revealing a broad range of genetic alterations including single nucleotide variants, small insertions and deletions, amplifications, and fusions. Specifically, pathogenic alterations were identified in all malignant fluids (13/13), all fluids suspicious for malignancy (2/2), and 1 benign fluid (1/6) from a patient with metastatic cancer. To validate our findings, we examined matching results from 11 patients who underwent additional testing using formalin-fixed, paraffin-embedded (FFPE) specimens. In 8 patients, the paired results between FFPE and supernatant testing were concordant, whereas in the remaining 3 patients, supernatant analysis identified additional variants likely associated with resistance to targeted therapies. Additional comparison between FFPE and supernatant testing showed no difference in DNA concentration (P = .5), depth of coverage (P = .6), or allele frequency of pathogenic mutations (P = .7).

Conclusion: cfDNA isolated from serous body cavity fluids represents a promising source of genomic input for targeted NGS.
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http://dx.doi.org/10.1002/cncy.22205DOI Listing
January 2020

Teaching and learning FNA biopsy: An update for the modern audience.

Cancer Cytopathol 2019 10 21;127(10):615-617. Epub 2019 Aug 21.

Department of Pathology, University of California at San Francisco, San Francisco, California.

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http://dx.doi.org/10.1002/cncy.22169DOI Listing
October 2019

A Structured Tumor-Immune Microenvironment in Triple Negative Breast Cancer Revealed by Multiplexed Ion Beam Imaging.

Cell 2018 09;174(6):1373-1387.e19

Department of Pathology, Stanford University, Stanford CA, 94305, USA. Electronic address:

The immune system is critical in modulating cancer progression, but knowledge of immune composition, phenotype, and interactions with tumor is limited. We used multiplexed ion beam imaging by time-of-flight (MIBI-TOF) to simultaneously quantify in situ expression of 36 proteins covering identity, function, and immune regulation at sub-cellular resolution in 41 triple-negative breast cancer patients. Multi-step processing, including deep-learning-based segmentation, revealed variability in the composition of tumor-immune populations across individuals, reconciled by overall immune infiltration and enriched co-occurrence of immune subpopulations and checkpoint expression. Spatial enrichment analysis showed immune mixed and compartmentalized tumors, coinciding with expression of PD1, PD-L1, and IDO in a cell-type- and location-specific manner. Ordered immune structures along the tumor-immune border were associated with compartmentalization and linked to survival. These data demonstrate organization in the tumor-immune microenvironment that is structured in cellular composition, spatial arrangement, and regulatory-protein expression and provide a framework to apply multiplexed imaging to immune oncology.
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http://dx.doi.org/10.1016/j.cell.2018.08.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132072PMC
September 2018

Comprehensive Genomic Profiling of Malignant Effusions in Patients with Metastatic Lung Adenocarcinoma.

J Mol Diagn 2018 03 19;20(2):184-194. Epub 2017 Dec 19.

Department of Pathology, Stanford University School of Medicine, Stanford, California. Electronic address:

Cytology samples are increasingly used for comprehensive molecular testing. Although fine-needle aspirates are adequate substrates for high-throughput sequencing, the suitability of malignant body fluids remains largely unexplored. We investigated the adequacy and utility of performing targeted next-generation sequencing (NGS) on malignant effusions from patients with metastatic lung adenocarcinoma. Thirty-two effusion samples submitted for hybrid capture-based NGS using a clinically validated solid tumor genotyping panel were examined. All cases showed ≥5% tumor cellularity; however, 28 (88%) provided sufficient DNA for NGS (≥1 ng/μL). The sequencing reads showed satisfactory quality control statistics, and the variant allele frequencies were correlated with tumor cellularity. Furthermore, pathogenic or likely pathogenic genomic alterations were identified in 26 of 28 samples (93%), whereas clinically actionable alterations were present in 18 (64%). Notably, nine patients had additional molecular testing performed on preceding or subsequent biopsy specimens, and the results across multiple samples were compared. In two patients, the NGS-based fluid analysis identified clinically actionable alterations that were not detected by other hotspot testing. In four patients treated with tyrosine kinase inhibitors, malignant fluid sequencing confirmed driver alterations from prior testing and revealed new resistance mechanisms. Hence, given adequate DNA input and tumor cellularity, comprehensive genomic profiling of malignant effusions may be used to establish mutational status at diagnosis and inform treatment resistance during targeted therapy.
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http://dx.doi.org/10.1016/j.jmoldx.2017.10.007DOI Listing
March 2018

Will oncotype DX DCIS testing guide therapy? A single-institution correlation of oncotype DX DCIS results with histopathologic findings and clinical management decisions.

Mod Pathol 2018 04 15;31(4):562-568. Epub 2017 Dec 15.

Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.

Given the increased detection rates of ductal carcinoma in situ (DCIS) and the limited overall survival benefit from adjuvant breast irradiation after breast-conserving surgery, there is interest in identifying subsets of patients who have low rates of ipsilateral breast tumor recurrence such that they might safely forgo radiation. The Oncotype DCIS score is a reverse transcription-PCR (RT-PCR)-based assay that was validated to predict which DCIS cases are most likely to recur. Clinically, these results may be used to assist in selecting which patients with DCIS might safely forgo radiation therapy after breast-conserving surgery; however, little is currently published on how this test is being used in practice. Our study examines traditional histopathologic features used in predicting DCIS risk with Oncotype DCIS results and how these results affect clinical decision-making at our academic institution. Histopathologic features and management decisions for 37 cases with Oncotype DCIS results over the past 4 years were collected. Necrosis, high nuclear grade, biopsy site change, estrogen receptor and progesterone receptor positivity <90% on immunohistochemistry, and Van Nuys Prognostic Index score of 8 or greater were significant predictors of an intermediate-high recurrence score on multivariate regression analysis (P<0.02). Low Oncotype DCIS scores and low nuclear grade were associated with lower rate of radiation therapy (P<0.008). There were seven cases (19%) with Oncotype DCIS results that we considered unexpected in relation to the histopathologic findings (ie, high nuclear grade with comedonecrosis and a low Oncotype score, or hormone receptor discrepancies). Overall, pathologic features correlate with Oncotype DCIS scores but unexpected results do occur, making individual recommendations sometimes challenging.
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http://dx.doi.org/10.1038/modpathol.2017.172DOI Listing
April 2018
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