Publications by authors named "Lynette Sholl"

248 Publications

Association of Clonal Hematopoiesis with Chronic Obstructive Pulmonary Disease.

Blood 2021 Sep 10. Epub 2021 Sep 10.

University of Virginia, Charlottesville, Virginia, United States.

Chronic obstructive pulmonary disease (COPD) is associated with age and smoking, but other determinants of the disease are incompletely understood. Clonal hematopoiesis of indeterminate potential (CHIP) is a common, age-related state in which somatic mutations in clonal blood populations induce aberrant inflammatory responses. Patients with CHIP have an elevated risk for cardiovascular disease, but the association with COPD remains unclear. We analyzed whole-genome and exome sequencing data to detect CHIP in 48,835 subjects, of whom 8,444 had moderate-to-very-severe COPD, from four separate cohorts with COPD phenotyping and smoking history. We measured emphysema in murine models in which Tet2 was deleted in hematopoietic cells. In COPDGene, individuals with CHIP had a risk of moderate-to-severe and severe or very severe COPD 1.6 and 2.2 times greater than non-carriers, respectively (adjusted 95% confidence intervals [CI], 1.1 to 2.2 and 1.5 to 3.2). These findings were consistent observed in three additional cohorts and meta-analyses of all subjects. CHIP was also associated with decreased FEV1% predicted in COPDGene (mean between group difference -5.7%; adjusted 95% CI, -8.8 to -2.6), a finding replicated in additional cohorts. Smoke exposure was associated with a small but significant increased risk of having CHIP (OR 1.03 per ten pack-years, 95% CI 1.01-1.05) in the meta-analysis of all subjects. Inactivation of Tet2 in mouse hematopoietic cells exacerbated emphysema development and inflammation in cigarette smoke exposure models. Somatic mutations in blood cells are associated with the development and severity of COPD, independent of age and cumulative smoke exposure.
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http://dx.doi.org/10.1182/blood.2021013531DOI Listing
September 2021

Molecular assessment of testicular adult granulosa cell tumor demonstrates significant differences when compared to ovarian counterparts.

Mod Pathol 2021 Nov 29. Epub 2021 Nov 29.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Testicular adult granulosa cell tumor (AGCT) is a rare type of sex-cord stromal tumor that affects patients of a wide age range and has the potential for late metastasis. In the testis, the diagnosis of AGCTs often requires the exclusion of other more common types of sex-cord stromal tumors. Immunohistochemistry is of limited utility, being used mostly to confirm sex-cord lineage and to exclude other entities when morphology is not typical. Unlike ovarian AGCTs, which are molecularly homogeneous and harbor a specific activating FOXL2 mutation (c.7558C > T p.C134W) in >90% of cases, the molecular characteristics of testicular AGCTs remain largely unknown. In the current study, we analyzed 13 testicular AGCTs diagnosed at multiple institutions using massively parallel DNA sequencing to evaluate single nucleotide variants, copy number alterations, and structural variants. In all, 10/13 cases were sequenced successfully. Notably, the FOXL2 c.7558C > T (p.C134W) mutation was identified in only a single case (1/10, 10%). The remaining cases were molecularly heterogeneous, with largely nonrecurrent genetic variants. Putative driver events in individual cases included a well-characterized gain-of-function NRAS mutation, as well as inactivation of ATM and TP53, among others. The only highly recurrent finding was single copy loss of 22q (7/10 cases, 70%). Comparatively, the frequencies of FOXL2 c.7558C > T (p.C134W) and 22q loss in 12 metastatic ovarian AGCTs identified in our database were 92% (11/12) and 42% (5/12), respectively. The results of the present study suggest that testicular AGCTs are different from their ovarian counterparts in that they appear to be molecularly heterogeneous and only rarely harbor FOXL2 mutations.
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http://dx.doi.org/10.1038/s41379-021-00977-6DOI Listing
November 2021

Neurotrophin Receptor Kinase: Updated Perspectives, Laboratory Considerations, and Clinical Implications.

J Mol Diagn 2021 Nov 24. Epub 2021 Nov 24.

Emerging and Evolving Biomarker Content Committee, a working group of the Training and Education Committee, Association for Molecular Pathology, Rockville, Maryland; Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address:

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http://dx.doi.org/10.1016/j.jmoldx.2021.11.002DOI Listing
November 2021

The 2021 WHO Classification of Lung Tumors: Impact of advances since 2015.

J Thorac Oncol 2021 Nov 19. Epub 2021 Nov 19.

Memorial Sloan Kettering Cancer Center, New York, NY, USA.

The 2021 World Health Organisation (WHO) Classification of Thoracic Tumours was published earlier this year, with classification of lung tumors being one of the chapters. The principles remain those of using morphology first, supported by immunohistochemistry and then molecular techniques. In 2015, there was particular emphasis on using immunohistochemistry to make classification more accurate. In 2021, there is greater emphasis throughout the book on advances in molecular pathology across all tumor types. Major features within this edition are 1) broader emphasis on genetic testing than in the 2015 WHO Classification, 2) a chapter entirely dedicated to the classification of small diagnostic samples, 3) continued recommendation to document percentages of histological patterns in invasive non-mucinous adenocarcinomas, with utilization of these features to apply a formal grading system, as well as using only invasive size for T-factor size determination in part lepidic non-mucinous lung adenocarcinomas as recommended by the 8 Edition TNM Classification, 4) recognition of spread through airspaces (STAS) as a histological feature with prognostic significance, 5) moving lymphoepithelial carcinoma to squamous cell carcinomas, 6) update on evolving concepts in lung neuroendocrine neoplasm classification, 7) recognition of bronchiolar adenoma/ciliated muconodular papillary tumor (BA/CMPT) as a new entity within the adenoma subgroup, 8) recognition of thoracic SMARCA4-deficient undifferentiated tumor, and 9) inclusion of essential and desirable diagnostic criteria for each tumor.
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http://dx.doi.org/10.1016/j.jtho.2021.11.003DOI Listing
November 2021

Diminished Efficacy of Programmed Death-(Ligand)1 Inhibition in STK11- and KEAP1-Mutant Lung Adenocarcinoma Is Affected by KRAS Mutation Status.

J Thorac Oncol 2021 Nov 2. Epub 2021 Nov 2.

Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.

Introduction: STK11 and KEAP1 mutations (STK11 mutant [STK11] and KEAP1) are among the most often mutated genes in lung adenocarcinoma (LUAD). Although STK11 has been associated with resistance to programmed death-(ligand)1 (PD-[L]1) inhibition in KRAS LUAD, its impact on immunotherapy efficacy in KRAS wild-type (KRAS) LUAD is currently unknown. Whether KEAP1 differentially affects outcomes to PD-(L)1 inhibition in KRAS and KRAS LUAD is also unknown.

Methods: Clinicopathologic and genomic data were collected from September 2013 to September 2020 from patients with advanced LUAD at the Dana-Farber Cancer Institute/Massachusetts General Hospital cohort and the Memorial Sloan Kettering Cancer Center/MD Anderson Cancer Center cohort. Clinical outcomes to PD-(L)1 inhibition were analyzed according to KRAS, STK11, and KEAP1 mutation status in two independent cohorts. The Cancer Genome Atlas transcriptomic data were interrogated to identify differences in tumor gene expression and tumor immune cell subsets, respectively, according to KRAS/STK11 and KRAS/KEAP1 comutation status.

Results: In the combined cohort (Dana-Farber Cancer Institute/Massachusetts General Hospital + Memorial Sloan Kettering Cancer Center/MD Anderson Cancer Center) of 1261 patients (median age = 61 y [range: 22-92], 708 women [56.1%], 1065 smokers [84.4%]), KRAS mutations were detected in 536 cases (42.5%), and deleterious STK11 and KEAP1 mutations were found in 20.6% (260 of 1261) and 19.2% (231 of 1202) of assessable cases, respectively. In each independent cohort and in the combined cohort, STK11 and KEAP1 mutations were associated with significantly worse progression-free (STK11 hazard ratio [HR] = 2.04, p < 0.0001; KEAP1 HR = 2.05, p < 0.0001) and overall (STK11 HR = 2.09, p < 0.0001; KEAP1 HR = 2.24, p < 0.0001) survival to immunotherapy uniquely among KRAS but not KRAS LUADs. Gene expression ontology and immune cell enrichment analyses revealed that the presence of STK11 or KEAP1 mutations results in distinct immunophenotypes in KRAS, but not in KRAS, lung cancers.

Conclusions: STK11 and KEAP1 mutations confer worse outcomes to immunotherapy among patients with KRAS but not among KRAS LUAD. Tumors harboring concurrent KRAS/STK11 and KRAS/KEAP1 mutations display distinct immune profiles in terms of gene expression and immune cell infiltration.
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http://dx.doi.org/10.1016/j.jtho.2021.10.013DOI Listing
November 2021

The 2021 WHO Classification of Tumors of the Thymus and Mediastinum: What Is New in Thymic Epithelial, Germ Cell, and Mesenchymal Tumors?

J Thorac Oncol 2021 Oct 22. Epub 2021 Oct 22.

Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany.

This overview of the fifth edition of the WHO classification of thymic epithelial tumors (including thymomas, thymic carcinomas, and thymic neuroendocrine tumors [NETs]), mediastinal germ cell tumors, and mesenchymal neoplasms aims to (1) list established and new tumor entities and subtypes and (2) focus on diagnostic, molecular, and conceptual advances since publication of the fourth edition in 2015. Diagnostic advances are best exemplified by the immunohistochemical characterization of adenocarcinomas and the recognition of genetic translocations in metaplastic thymomas, rare B2 and B3 thymomas, and hyalinizing clear cell carcinomas. Advancements at the molecular and tumor biological levels of utmost oncological relevance are the findings that thymomas and most thymic carcinomas lack currently targetable mutations, have an extraordinarily low tumor mutational burden, but typically have a programmed death-ligand 1 phenotype. Finally, data underpinning a conceptual advance are illustrated for the future classification of thymic NETs that may fit into the classification scheme of extrathoracic NETs. Endowed with updated clinical information and state-of-the-art positron emission tomography and computed tomography images, the fifth edition of the WHO classification of thymic epithelial tumors, germ cell tumors, and mesenchymal neoplasms with its wealth of new diagnostic and molecular insights will be a valuable source for pathologists, radiologists, surgeons, and oncologists alike. Therapeutic perspectives and research challenges will be addressed as well.
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http://dx.doi.org/10.1016/j.jtho.2021.10.010DOI Listing
October 2021

Atypical uterine polyps show morphologic and molecular overlap with mullerian adenosarcoma but follow a benign clinical course.

Mod Pathol 2021 Oct 21. Epub 2021 Oct 21.

Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.

A subset of clinically benign uterine polyps shows atypical morphologic features worrisome for, but not diagnostic of, Mullerian adenosarcoma. We report clinicopathologic data for 63 polyps from 58 women with atypical morphologic features including abnormal architecture, abnormal periglandular stroma, stromal atypia, and mitoses >2 per 10 hpf. Four (11%) of 36 women with follow-up tissue sampling had residual/recurrent atypical polyp. Twelve (27%) of 44 women underwent hysterectomy subsequent to a diagnosis of atypical polyp. No patient developed adenosarcoma over median follow-up of 150 months. Twenty-one primary atypical polyps underwent molecular profiling. Five (24%) harbored chr 12q13-15 gain or amplification, 9/20 (45%) harbored chr 6q25.1 gain, and 7/21 (33%) had no significant copy number alterations. Gains of chr 1q, chr 8p12, and chr 10q11.21-23, amplifications of chr 12q24.12-13, chr 15p24.1-26.1, and chr 18q21.33, and loss of chr 7 and chr 11q21 were each seen in a single polyp. Mean tumor mutational burden was 3.1 (range, 0.76-8.365) mutations/Mb. Pathogenic point mutations were identified in 12/20 (60%) primary atypical polyps. We propose the term "atypical uterine polyps" for these lesions, which show biologic overlap with early Mullerian adenosarcoma but lack molecular alterations characteristic of clinically aggressive adenosarcoma and appear to follow a benign clinical course. Conservative management with close clinical follow-up and repeat sampling can be considered for these lesions, when clinically appropriate.
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http://dx.doi.org/10.1038/s41379-021-00946-zDOI Listing
October 2021

Biomarkers of response to checkpoint inhibitors beyond PD-L1 in lung cancer.

Authors:
Lynette M Sholl

Mod Pathol 2021 Oct 4. Epub 2021 Oct 4.

Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA.

Immunotherapy, including use of checkpoint inhibitors against PD-1, PD-L1, and CTLA-4, forms the backbone of oncologic management for the majority of non-small cell lung carcinoma patients. However, response to these therapies varies widely, from patients who have complete resolution of metastatic disease and long-term remission, to those who rapidly progress and succumb to their cancer despite use of the newest checkpoint inhibitors. While PD-L1 protein expression by immunohistochemistry serves as the principle predictive biomarker for immunotherapy response, neither the sensitivity nor the specificity of this approach is optimal, and clinical PD-L1 testing is plagued by concerns around result reproducibility and confusion born from the proliferation of different companion diagnostic assays. At the same time, insights into tumor and host immune-specific factors that inform both prognosis and response prediction are beginning to define better immunotherapy biomarkers. Beyond immune checkpoint expression status, common themes in analyses of immunotherapy response prediction include cancer neoantigen production, the state of the antigen presentation pathway in both tumor and antigen presenting cells, the admixture of effector and suppressor immune cells in the tumor microenvironment, and the genomic drivers and comutations that can influence the all of these variables. This review will address the state of PD-L1 testing in lung cancer, the role for tumor mutation burden as a predictive biomarker, the evolving status of human leukocyte antigen/major histocompatibility complex expression as a marker of antigen presentation, approaches to tumor immune cell quantitation including by multiplex immunofluorescence, and the importance of tumor genomic profiling to ascertain oncogenic driver (EGFR, ALK, KRAS, MET, etc.) and co-mutation (STK11, KEAP1, SMARCA4) status.
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http://dx.doi.org/10.1038/s41379-021-00932-5DOI Listing
October 2021

Genomic Evolution in a Patient With Lung Adenocarcinoma With a Germline T790M Mutation.

JTO Clin Res Rep 2021 Apr 30;2(4):100146. Epub 2021 Jan 30.

Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.

Introduction: A subset of lung adenocarcinomas (ADs) has been found to have somatic activating mutations in the tyrosine kinase domain of the gene, associated with response to EGFR tyrosine kinase inhibitor therapy. Rare germline mutations within this domain, including T790M, have been associated with genetic susceptibility to lung ADs. Using high-throughput sequencing, we elucidate the genomic evolution in tissues from a patient with lung AD carrying a germline T790M mutation.

Methods: We performed microdissection, targeted panel, and whole-exome sequencing to molecularly characterize multiple foci of atypical adenomatous hyperplasia (AAH), in situ and invasive components of AD, normal lung tissue, and whole blood from the patient. Normal lung tissue was analyzed for potential acquired somatic genome alterations ("field effect").

Results: All lesions harbored a secondary somatic mutation, either L858R or L861Q, in addition to the germline T790M mutation. Clear overlap was observed between the somatic profiles of in situ and invasive AD components, confirming clonal relatedness. AAH lesions shared few to no somatic alterations with the AD, suggesting clonal independence. No robust evidence of field effect was identified in the normal lung tissue.

Conclusions: Somatic mutations are early events in the pathogenesis of lung ADs arising in the context of germline T790M. Synchronous AAH lesions seem to be independent. Stepwise genomic evolution is observed in association with invasiveness of the neoplastic cell population.
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http://dx.doi.org/10.1016/j.jtocrr.2021.100146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474413PMC
April 2021

-Mutant Pulmonary Langerhans Cell Histiocytosis Mimicking Recurrence of Early-Stage -Mutant Lung Adenocarcinoma.

JTO Clin Res Rep 2021 Feb 3;2(2):100127. Epub 2020 Dec 3.

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

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http://dx.doi.org/10.1016/j.jtocrr.2020.100127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474365PMC
February 2021

A Novel Protective Role for Matrix Metalloproteinase-8 in the Pulmonary Vasculature.

Am J Respir Crit Care Med 2021 Sep 22. Epub 2021 Sep 22.

Brigham and Women's Hospital, 1861, Pulmonary and Critical Care Medicine, Boston, Massachusetts, United States;

Mechanical signaling through cell-matrix interactions plays a major role in progressive vascular remodeling in pulmonary arterial hypertension (PAH). Matrix metalloproteinase-8 (MMP-8) is an interstitial collagenase involved in regulating inflammation and fibrosis of the lung and systemic vasculature, but its role in PAH pathogenesis remains unexplored. To evaluate MMP-8 as a modulator of pathogenic mechanical signaling in PAH. MMP-8 levels were measured in plasma from pulmonary hypertension (PH) patients and controls by ELISA. MMP-8 vascular expression was examined in lung tissue from PAH patients and rodent models of PH. MMP-8 and MMP-8 mice were exposed to normobaric hypoxia or normoxia for 4-8 weeks. PH severity was evaluated by right ventricular systolic pressure (RVSP), echocardiography, pulmonary artery (PA) morphometry and immunostaining. Proliferation, migration, matrix component expression, and mechanical signaling were assessed in MMP-8 and MMP-8 pulmonary artery smooth muscle cells (PASMCs). MMP-8 expression was significantly increased in plasma and PAs of PH patients compared to controls and induced in the pulmonary vasculature in rodent PH models. Hypoxia-exposed MMP-8 mice had significant mortality, increased RVSP, severe RV dysfunction, and exaggerated vascular remodeling compared to MMP-8 mice. MMP-8 PASMCs demonstrated exaggerated proliferation and migration mediated by altered matrix protein expression, elevated integrin-β3 levels, and induction of focal adhesion kinase (FAK) and downstream Yes-associated protein/Transcriptional coactivator with PDZ-binding motif (YAP/TAZ) activity. MMP-8 is a novel protective factor upregulated in the pulmonary vasculature during PAH pathogenesis. MMP-8 opposes pathologic mechanobiological feedback by altering matrix composition and disrupting integrin-β3/FAK and YAP/TAZ-dependent mechanical signaling in PASMCs.
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http://dx.doi.org/10.1164/rccm.202108-1863OCDOI Listing
September 2021

In Response to "Reexamining the molecular findings in specialized stromal tumors of the prostate".

Mod Pathol 2021 Nov 8;34(11):2082-2083. Epub 2021 Sep 8.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1038/s41379-021-00916-5DOI Listing
November 2021

Ectopic Anterior Mediastinal Pancreas: An Unusual Case of New Onset Hemoptysis.

Ann Thorac Surg 2021 Jul 27. Epub 2021 Jul 27.

Brigham and Women's Hospital, Department of Pathology, Boston, MA.

Ectopic pancreas within the anterior mediastinum is a rare congenital anomaly. We present a case of a solid anterior mediastinal mass that presented with hemoptysis and ground glass parenchymal changes in the right upper lobe. Robotic surgical resection was completed, and final pathology was consistent with benign pancreatic tissue. The patient fully recovered with no recurrence of hemoptysis. Ectopic pancreas, although uncommon, should be included in the differential for solid and cystic anterior mediastinal masses, and surgical resection is often curative and effectively manages symptoms.
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http://dx.doi.org/10.1016/j.athoracsur.2021.07.012DOI Listing
July 2021

Liquid Biopsy for Advanced NSCLC: A Consensus Statement From the International Association for the Study of Lung Cancer.

J Thorac Oncol 2021 10 8;16(10):1647-1662. Epub 2021 Jul 8.

Division of Hematology/Oncology, UC Davis Comprehensive Cancer Center, Sacramento, California. Electronic address:

Although precision medicine has had a mixed impact on the clinical management of patients with advanced-stage cancer overall, for NSCLC, and more specifically for lung adenocarcinoma, the advances have been dramatic, largely owing to the genomic complexity and growing number of druggable oncogene drivers. Furthermore, although tumor tissue is historically the "accepted standard" biospecimen for these molecular analyses, there are considerable innate limitations. Thus, liquid biopsy represents a practical alternative source for investigating tumor-derived somatic alterations. Although data are most robust in NSCLC, patients with other cancer types may also benefit from this minimally invasive approach to facilitate selection of targeted therapies. The liquid biopsy approach includes a variety of methodologies for circulating analytes. From a clinical point of view, plasma circulating tumor DNA is the most extensively studied and widely adopted alternative to tissue tumor genotyping in solid tumors, including NSCLC, first entering clinical practice for detection of EGFR mutations in NSCLC. Since the publication of the first International Association for the Study of Lung Cancer (IASLC) liquid biopsy statement in 2018, several additional advances have been made in this field, leading to changes in the therapeutic decision-making algorithm for advanced NSCLC and prompting this 2021 update. In view of the novel and impressive technological advances made in the past few years, the growing clinical application of plasma-based, next-generation sequencing, and the recent Food and Drug and Administration approval in the United States of two different assays for circulating tumor DNA analysis, IASLC revisited the role of liquid biopsy in therapeutic decision-making in a recent workshop in October 2020 and the question of "plasma first" versus "tissue first" approach toward molecular testing for advanced NSCLC. Moreover, evidence-based recommendations from IASLC provide an international perspective on when to order which test and how to interpret the results. Here, we present updates and additional considerations to the previous statement article as a consensus from a multidisciplinary and international team of experts selected by IASLC.
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http://dx.doi.org/10.1016/j.jtho.2021.06.017DOI Listing
October 2021

Acquired Resistance to KRAS Inhibition in Cancer.

N Engl J Med 2021 06;384(25):2382-2393

From Dana-Farber Cancer Institute (M.M.A., S.L., J.D., J.O.J., K.E.L., H.F., K.M.H., B.M.W., P.A.J., A.J.A.), Massachusetts General Hospital (R.S.H., Y.P.H.), and Brigham and Women's Hospital (L.M.S., A.J.A.), Boston, and Broad Institute of MIT and Harvard (S.L., X.Y., N.S.P., D.E.R., K.M.H., A.J.A.) and Foundation Medicine (J.L., A.B.S.), Cambridge - all in Massachusetts; Henry Ford Cancer Institute, Detroit (I.I.R.); Memorial Sloan Kettering Cancer Center, New York (K.C.A., G.J.R., P.L.); Chao Family Comprehensive Cancer Center, University of California, Irvine, School of Medicine, Orange (V.W.Z., S.S.Z., S.-H.I.O.), Boundless Bio, La Jolla (J.W., J.C.), and Mirati Therapeutics, San Diego (L.D.E., L.W., J.D.L., P.O., J.G.C.) - all in California; Sarah Cannon Research Institute, Tennessee Oncology/OneOncology, Nashville (M.L.J.); the University of Colorado, Aurora (T.P.); and Resolution Bioscience, Kirkland, WA (L.P.L., K.G., M.L.).

Background: Clinical trials of the KRAS inhibitors adagrasib and sotorasib have shown promising activity in cancers harboring KRAS glycine-to-cysteine amino acid substitutions at codon 12 (KRAS). The mechanisms of acquired resistance to these therapies are currently unknown.

Methods: Among patients with -mutant cancers treated with adagrasib monotherapy, we performed genomic and histologic analyses that compared pretreatment samples with those obtained after the development of resistance. Cell-based experiments were conducted to study mutations that confer resistance to KRAS inhibitors.

Results: A total of 38 patients were included in this study: 27 with non-small-cell lung cancer, 10 with colorectal cancer, and 1 with appendiceal cancer. Putative mechanisms of resistance to adagrasib were detected in 17 patients (45% of the cohort), of whom 7 (18% of the cohort) had multiple coincident mechanisms. Acquired alterations included G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and high-level amplification of the allele. Acquired bypass mechanisms of resistance included amplification; activating mutations in , , , and ; oncogenic fusions involving , , , , and ; and loss-of-function mutations in and . In two of nine patients with lung adenocarcinoma for whom paired tissue-biopsy samples were available, histologic transformation to squamous-cell carcinoma was observed without identification of any other resistance mechanisms. Using an in vitro deep mutational scanning screen, we systematically defined the landscape of mutations that confer resistance to KRAS inhibitors.

Conclusions: Diverse genomic and histologic mechanisms impart resistance to covalent KRAS inhibitors, and new therapeutic strategies are required to delay and overcome this drug resistance in patients with cancer. (Funded by Mirati Therapeutics and others; ClinicalTrials.gov number, NCT03785249.).
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http://dx.doi.org/10.1056/NEJMoa2105281DOI Listing
June 2021

mTORC1 is a mechanosensor that regulates surfactant function and lung compliance during ventilator-induced lung injury.

JCI Insight 2021 Jul 22;6(14). Epub 2021 Jul 22.

Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, and.

The acute respiratory distress syndrome (ARDS) is a highly lethal condition that impairs lung function and causes respiratory failure. Mechanical ventilation (MV) maintains gas exchange in patients with ARDS but exposes lung cells to physical forces that exacerbate injury. Our data demonstrate that mTOR complex 1 (mTORC1) is a mechanosensor in lung epithelial cells and that activation of this pathway during MV impairs lung function. We found that mTORC1 is activated in lung epithelial cells following volutrauma and atelectrauma in mice and humanized in vitro models of the lung microenvironment. mTORC1 is also activated in lung tissue of mechanically ventilated patients with ARDS. Deletion of Tsc2, a negative regulator of mTORC1, in epithelial cells impairs lung compliance during MV. Conversely, treatment with rapamycin at the time MV is initiated improves lung compliance without altering lung inflammation or barrier permeability. mTORC1 inhibition mitigates physiologic lung injury by preventing surfactant dysfunction during MV. Our data demonstrate that, in contrast to canonical mTORC1 activation under favorable growth conditions, activation of mTORC1 during MV exacerbates lung injury and inhibition of this pathway may be a novel therapeutic target to mitigate ventilator-induced lung injury during ARDS.
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http://dx.doi.org/10.1172/jci.insight.137708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410036PMC
July 2021

Comparative molecular analysis of testicular Leydig cell tumors demonstrates distinct subsets of neoplasms with aggressive histopathologic features.

Mod Pathol 2021 Oct 8;34(10):1935-1946. Epub 2021 Jun 8.

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Testicular Leydig cell tumor (LCT), the most common sex-cord stromal tumor in men, represents a small fraction of all testicular tumors (~1 to 3%). Although most testicular LCTs are indolent and cured by radical orchiectomy, 5-10% have aggressive biology and metastatic potential. In primary LCTs, large size, cytologic atypia, necrosis, increased mitotic activity, and vascular invasion have been associated with clinically aggressive tumors. From a molecular perspective, the characteristics of aggressive LCTs and the differences between aggressive and nonaggressive LCTs remain largely unexplored. This study compares the genomic landscape of aggressive and nonaggressive testicular LCTs. Twenty-six cases were analyzed using next-generation DNA sequencing (NGS) and immunohistochemistry. Cases were classified as aggressive LCT if they met published criteria for malignancy in primary (i.e., testicular) tumors or if they had pathology-proven metastatic disease; otherwise, cases were considered nonaggressive. This multi-institutional series included 18 aggressive LCTs (14 primary/testicular, 4 metastatic) and 8 nonaggressive LCTs. Two cases (2/26, 8%; both aggressive LCTs) failed sequencing and had negative (i.e., uninformative) FH immunohistochemistry results. One additional primary aggressive LCT failed sequencing but had informative FH immunohistochemistry results. Combined NGS and immunohistochemical analysis demonstrated FH inactivation in 5/26 cases (19%). In addition, NGS demonstrated CTNNB1 mutations or biallelic APC inactivation in 9/23 cases (39%), copy number changes without recurrent mutations in 6/23 (26%) cases, and no alterations in 4/23 cases (17%). CTNNB1 mutations were present in both aggressive and nonaggressive LCTs. In contrast, FH inactivation and multiple copy number changes were only identified in aggressive LCTs. In conclusion, three distinct subgroups of aggressive LCTs were characterized by FH inactivation, Wnt pathway activation, and copy number changes without recurrent mutations, respectively. Nuclear translocation of β-catenin and Wnt pathway activation appear to be early driver events that provide an environment conducive for progression to aggressive biology in a subset of LCTs.
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http://dx.doi.org/10.1038/s41379-021-00845-3DOI Listing
October 2021

Diffuse Tracheobronchial Neurofibromatosis and Papillomatosis. Key Diagnostic Aspects and Treatment.

Ann Thorac Surg 2021 Jun 5. Epub 2021 Jun 5.

Thoracic Surgery Division. Brigham and Women´s Hospital. Boston, MA. Electronic address:

Diffuse tracheobronchial neurofibromatosis is a rare condition and its clinical manifestations include obstruction, cough, wheezing and dyspnea. Furthermore, the limited amount of data makes treatment decisions challenging. In addition, airway papillomatosis tends to affect the upper airway and the larynx, in the form of well-delimited lesions leading to obstruction, predominantly in children. Diffuse involvement of the trachea and the bronchial tree, as well as its association with neurofibromatosis, have been rarely reported in adults.
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http://dx.doi.org/10.1016/j.athoracsur.2021.05.028DOI Listing
June 2021

Pseudoendocrine Sarcoma: Clinicopathologic Analysis of 23 Cases of a Distinctive Soft Tissue Neoplasm With Metastatic Potential, Recurrent CTNNB1 Mutations, and a Predilection for Truncal Locations.

Am J Surg Pathol 2021 Jun 3. Epub 2021 Jun 3.

Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA Department of Pathology & Laboratory Medicine, Mount Sinai Hospital Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.

The number of recognized epithelioid soft tissue neoplasms continues to increase and includes epithelioid schwannoma, sclerosing epithelioid fibrosarcoma, and emerging entities such as sarcomas with GLI1 alterations. Here, we describe 23 cases of a previously unrecognized entity, provisionally termed "pseudoendocrine sarcoma." Pseudoendocrine sarcoma is a rare, distinctive tumor of uncertain lineage with a predilection for paravertebral soft tissue in older adults. Fifteen patients (65%) were male and 8 were female. Age at presentation ranged from 29 to 78 years (median: 62 y). Nineteen tumors (83%) occurred in truncal locations, including 15 tumors (65%) in paravertebral soft tissue; other locations included the posterior head (2 tumors), thigh (1), and orbit (1). Tumor size ranged from 2 to 19 cm (median: 6.35 cm). Pseudoendocrine sarcoma is composed of sheets, trabeculae, and nests of epithelioid or ovoid cells with indistinct borders, palely eosinophilic cytoplasm, and highly monomorphic, round nuclei with speckled chromatin. Pseudoglandular architecture was at least focally present in 16 tumors (70%), large extracellular hyaline globules were identified in 12 tumors (52%), and psammomatous calcifications were present in 8 (35%). Metaplastic ossification was identified in 2 tumors, and myxoid stroma was present in 1. Lymphovascular invasion was present in 5 of 18 tumors (28%). Immunohistochemistry demonstrated that most tumors showed nuclear positivity for β-catenin (20/21 tumors; 95%), and some showed at least focal positivity for S-100 (9/22; 41%), desmin (3/8; 38%), or CD34 (2/8; 25%). All tumors were negative for neuroendocrine and epithelial markers, including synaptophysin (21 tumors), chromogranin (19), INSM1 (4), pan-K (16), CAM5.2 (13), AE1/AE3 (6), epithelial membrane antigen (20), and E-cadherin (13). DNA sequencing detected CTNNB1 point mutations in all 6 sequenced tumors: D32H, S33C, S33F, S37A, S37C, and S37F. RNA sequencing was negative for gene fusions in all 6 sequenced tumors. Clinical follow-up was available for 17 patients (74%; range: 4 mo to 20 y; median: 3.5 y), including 14 patients with >1 year of follow-up. Six of 14 patients with long-term follow-up experienced local recurrence (43%, at intervals of 3 to 6 y). One tumor showed a local lymph node metastasis within the primary excision specimen, and 3 patients developed distant lung metastases (21%). No patient died of the disease as yet. Despite its bland morphology and resemblance to the well-differentiated neuroendocrine tumor, pseudoendocrine sarcoma is best considered an intermediate-grade sarcoma, given its pathologic characteristics and clinical behavior.
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http://dx.doi.org/10.1097/PAS.0000000000001751DOI Listing
June 2021

Twists and turns from "tumor in tumor" profiling: surveillance of chronic lymphocytic leukemia (CLL) leads to detection of a lung adenocarcinoma, whose genomic characterization alters the original hematologic diagnosis.

Cold Spring Harb Mol Case Stud 2021 08 2;7(4). Epub 2021 Aug 2.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

Comprehensive characterization of somatic genomic alterations has led to fundamental shifts in our understanding of tumor biology. In clinical practice, these studies can lead to modifications of diagnosis and/or specific treatment implications, fulfilling the promise of personalized medicine. Herein, we describe a 78-yr-old woman under surveillance for long-standing untreated chronic lymphocytic leukemia (CLL). Molecular studies from a peripheral blood specimen revealed a p.V157F mutation, whereas karyotype and fluorescence in situ hybridization (FISH) identified a 17p deletion, trisomy 12, and no evidence of rearrangement. Positron emission tomography-computed tomography scan identified multistation intra-abdominal lymphadenopathy and a pulmonary nodule, and subsequent pulmonary wedge resection confirmed the presence of a concurrent lung adenocarcinoma. Targeted next-generation sequencing of the lung tumor identified an in-frame exon 19 deletion, two mutations (p.P152Q, p.V157F), and, unexpectedly, a rearrangement. Follow-up immunohistochemistry (IHC) studies demonstrated a cyclin D1-positive lymphoid aggregate within the lung adenocarcinoma. The presence of the p.V157F mutation in the lung resection, detection of an rearrangement, and cyclin D1 positivity by IHC led to revision of the patient's hematologic diagnosis and confirmed the extranodal presence of mantle cell lymphoma within the lung mass, thus representing a "tumor in tumor." Manual review of the sequencing data suggested the rearrangement occurred via an insertional event, whose size precluded detection by original FISH studies. Thus, routine imaging for this patient's known hematologic malignancy led to detection of an unexpected solid tumor, whose subsequent precision medicine studies in the solid tumor redefined the original hematological diagnosis.
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http://dx.doi.org/10.1101/mcs.a006089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327883PMC
August 2021

Rates of invasive disease and outcomes in NSCLC patients with biopsy suggestive of carcinoma in situ.

Lung Cancer 2021 07 26;157:17-20. Epub 2021 May 26.

Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Introduction: Carcinoma in situ is a rare non-invasive histology of non-small cell lung cancer (NSCLC) with excellent survival outcomes with resection. However, management of lung biopsy suggestive of in situ disease remains unclear. To inform decision-making in this scenario, we determined the rate of invasive disease presence upon resection of lesions with an initial biopsy suggestive of purely in situ disease.

Methods: The study included 960 patients diagnosed with NSCLC from 2003 to 2017 in the National Cancer Database whose workup included a lung biopsy suggestive of in situ disease. Among the cohort who proceeded to resection, we identified the rate of invasive disease discovered on surgical pathology along with significant demographic and clinical contributors to invasion risk. Survival outcomes were measured for the observed cohort that did not receive local therapy after biopsy.

Results: Invasive disease was identified at resection in 49.3 % of patients. Lesion size was associated with risk of invasive disease: 35.7 % for ≤1 cm, 45.2 % for 1-2 cm, 55.7 % for 2-3 cm, and 87.5 % for 3-5 cm (p < 0.001). Of patients with squamous histology, 61.5 % had invasive disease versus 46.5 % with adenocarcinoma histology (p = 0.026). On multivariable logistic regression, invasive disease remained associated with tumor size (OR 1.9 per cm, 95 % CI 1.5-2.4, p < 0.001), and squamous histology (OR 1.8, 95 % CI 1.1-3.2, p = 0.028). Overall survival at 3 years was 51.5 % in the observed cohort.

Conclusion: Nearly half of patients with biopsy suggestive of in situ disease had invasive disease at resection. Tumor size and histology are strong predictors of invasive disease and may be used for risk stratification. However, the findings support the practice of definitive therapy whenever feasible.
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http://dx.doi.org/10.1016/j.lungcan.2021.05.028DOI Listing
July 2021

Re-evaluating tumors of purported specialized prostatic stromal origin reveals molecular heterogeneity, including non-recurring gene fusions characteristic of uterine and soft tissue sarcoma subtypes.

Mod Pathol 2021 09 13;34(9):1763-1779. Epub 2021 May 13.

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Tumors of purported specialized prostatic stromal origin comprise prostatic stromal sarcomas (PSS) and stromal tumors of uncertain malignant potential (STUMP). Prior studies have described their clinicopathologic characteristics, but the molecular features remain incompletely understood. Moreover, these neoplasms are morphologically heterogeneous and the lack of specific adjunctive markers of prostatic stromal lineage make precise definition more difficult, leading some to question whether they represent a specific tumor type. In this study, we used next-generation DNA and RNA sequencing to profile 25 primary prostatic mesenchymal neoplasms of possible specialized prostatic stromal origin, including cases originally diagnosed as PSS (11) and STUMP (14). Morphologically, the series comprised 20 cases with solid architecture (11 PSS and 9 STUMP) and 5 cases with phyllodes-like growth pattern (all STUMP). Combined DNA and RNA sequencing results demonstrated that 19/22 (86%) cases that underwent successful sequencing (either DNA or RNA) harbored pathogenic somatic variants. Except for TP53 alterations (6 cases), ATRX mutations (2 cases), and a few copy number variants (-13q, -14q, -16q and +8/8p), the findings were largely nonrecurrent. Eight gene rearrangements were found, and 4 (NAB2-STAT6, JAZF1-SUZ12, TPM3-NTRK1 and BCOR-MAML3) were useful for reclassification of the cases as specific entities. The present study shows that mesenchymal neoplasms of the prostate are morphologically and molecularly heterogeneous and include neoplasms that harbor genetic aberrations seen in specific mesenchymal tumors arising in other anatomic sites, including soft tissue and the uterus. These data suggest that tumors of purported specialized prostatic stromal origin may perhaps not represent a single diagnostic entity or specific disease group and that alternative diagnoses should be carefully considered.
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http://dx.doi.org/10.1038/s41379-021-00818-6DOI Listing
September 2021

SMARCA4 and Other SWItch/Sucrose NonFermentable Family Genomic Alterations in NSCLC: Clinicopathologic Characteristics and Outcomes to Immune Checkpoint Inhibition.

J Thorac Oncol 2021 07;16(7):1176-1187

Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Electronic address:

Introduction: The SWItch/Sucrose Nonfermentable (SWI/SNF) chromatin remodeling complex acts as a regulatory component of transcription, and inactivating mutations (muts) within the complex are implicated in genomic instability, higher tumor mutational burden, and an aggressive cancer phenotype. Whether SMARCA4 and other SWI/SNF alterations are independent prognostic factors or associated with clinical outcomes to immune checkpoint inhibitors (ICIs) in NSCLC remains unclear.

Methods: We collected clinicopathologic and genomic data from patients with NSCLC who underwent targeted next-generation sequencing at the Dana-Farber Cancer Institute. Tumors were characterized on the basis of the presence or absence of muts across a set of six SWI/SNF genes (ARID1A, ARID1B, ARID2, PBRM1, SMARCA4, and SMARCB1).

Results: Of 2689 patients with NSCLC, 20.6% (N = 555) had SWI/SNF genomic alterations. Compared with SWI/SNF wild-type (wt) NSCLC, patients with SWI/SNF-mutant NSCLCs had a lower prevalence of concurrent targetable driver muts (33.2% versus 22.2%; p < 0.001), a higher tumor mutational burden (median 8.5 versus 12.2 muts/megabase; p < 0.001), and a shorter median overall survival (mOS) from the time of advanced disease diagnosis (25.0 versus 19.3 mo, p = 0.01); the detrimental effect in OS seemed to be largely driven by SMARCA4 muts (mOS: 25.0 for SMARCA4 wt versus 15.6 mo for SMARCA4 mutant; p < 0.001). Among 532 patients who received ICIs, 25.5% (N = 136) harbored SWI/SNF muts. From the start of immunotherapy, there was no difference in objective response rate (ORR = 19.9% versus 25.0%, p = 0.2), median progression-free survival (mPFS = 3.0 versus 3.0 mo, hazard ratio [HR] = 0.96 [95% confidence interval [CI] = 0.77-1.18], p = 0.7), or mOS (13.1 versus 9.5 mo, HR = 0.81 [95% CI: 0.64-1.02], p = 0.07) in SWI/SNF-wt versus SWI/SNF-mutant NSCLC, respectively. Nevertheless, among KRAS-mutant NSCLCs treated with ICIs (N = 176), a concurrent SWI/SNF mut (N = 39) conferred a numerically lower ORR (21.9% versus 12.8%, p = 0.2), a significantly shorter mPFS (4.1 versus 1.8 mo, HR = 0.57 [95% CI: 0.38-0.84], p = 0.005), and a significantly shorter mOS (15.5 versus 8.2 mo, HR = 0.56 [95% CI: 0.36-0.86], p = 0.008). The deleterious effect on immunotherapy outcomes in KRAS-mutant NSCLC was most pronounced in the SMARCA4-mutant subset (N = 17), with a lower ORR (22% versus 0%, p = 0.03), a significantly shorter mPFS (4.1 versus 1.4 mo, HR = 0.25 [95% CI: 0.14-0.42], p < 0.001), and a significantly shorter mOS (15.1 versus 3.0 mo, HR = 0.29 [95% CI: 0.17-0.50], p < 0.001) compared with SMARCA4-wt KRAS-mutant NSCLCs.

Conclusions: Although there were no associations between SWI/SNF mut status and immunotherapy efficacy in the overall NSCLC cohort, the presence of a SMARCA4 alteration may confer a worse outcome to immunotherapy among KRAS-mutant NSCLCs.
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http://dx.doi.org/10.1016/j.jtho.2021.03.024DOI Listing
July 2021

Phase II Clinical Trial of Everolimus in a Pan-Cancer Cohort of Patients with mTOR Pathway Alterations.

Clin Cancer Res 2021 Jul 16;27(14):3845-3853. Epub 2021 Mar 16.

Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Purpose: This was a multicenter, histology-agnostic, single-arm prospective phase II trial of therapeutic activity of everolimus, an oral mTORC1 inhibitor, in patients with advanced solid tumors that harbored / or mutations.

Patients And Methods: Patients with tumors with inactivating / or activating mutations identified in any Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory were eligible. Patients were treated with everolimus 10 mg once daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Whole-exome sequencing was performed to identify co-occurring genomic alterations.

Results: Between November 2015 and October 2018, 30 patients were enrolled at Dana-Farber Cancer Institute and Memorial Sloan Kettering Cancer Center. Tumors harbored (13/30), (15/30), concurrent and (1/30), or (1/30) mutations. The most common treatment-related adverse event of any grade was mucositis (8/30, 27%); 1 patient had fatal pneumonitis. Partial responses were seen in 2 patients [7%; 95% confidence interval (CI), 1%-22%]. Median progression-free survival was 2.3 months (95% CI, 1.8-3.7 months) and median overall survival (OS) was 7.3 months (95% CI, 4.5-12.7 months). There was no clear association between other genomic alterations and response. Of the 2 patients with objective response, 1 had upper tract urothelial carcinoma with biallelic inactivation of and high tumor mutation burden, and the other had uterine carcinoma with biallelic -inactivating mutations and PEComa-like pathologic features.

Conclusions: Everolimus therapy had a disappointing ORR (7%) in this pan-cancer, mutation-selected, basket study..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282751PMC
July 2021

Characterization of genetics in patients with mucosal melanoma treated with immune checkpoint blockade.

Cancer Med 2021 04 15;10(8):2627-2635. Epub 2021 Mar 15.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Mucosal melanoma is a rare form of melanoma which arises from melanocytes in the mucosal membranes and can be effectively treated with immune checkpoint blockade (ICB). However, response rates in mucosal melanoma are lower than those observed for cutaneous melanomas. Targeted sequencing of up to 447 genes (OncoPanel) was performed on tumors from all mucosal melanoma patients seen at the Dana-Farber Cancer Institute from 2011 until March 2019. We identified a total of 46 patients who received ICB with both tumor-genotype and ICB response data available. Within this cohort of patients, 16 (35%) had durable clinical benefit (DCB) to their first line of ICB. The average mutational burden/megabase was 6.23 and did not correlate with tumor response to ICB. Patients with KIT aberrations had a higher DCB rate compared with patients with wildtype KIT (71 vs. 28%), but this was not found to be statistically significant. For comparison, we analyzed tumor genotypes from an additional 50 mucosal melanoma tumors and 189 cutaneous melanoma tumors. The most frequent mutations in mucosal melanoma were in SF3B1 (27%), KIT (18%), and NF1 (17%), a pattern that is distinct from cutaneous melanomas. In addition, there were genetic differences observed based upon the site of origin of the mucosal melanoma. Our findings explore clinical features of response in patients with mucosal melanoma treated with ICB and demonstrate a low mutational burden that does not correlate with response. In addition, the lack of significant association between the genetic aberrations tested and response to ICB indicates the need for further exploration in this patient population.
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http://dx.doi.org/10.1002/cam4.3789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026918PMC
April 2021

Intrinsic Immunogenicity of Small Cell Lung Carcinoma Revealed by Its Cellular Plasticity.

Cancer Discov 2021 Aug 11;11(8):1952-1969. Epub 2021 Mar 11.

Translational Pathology, Bristol Myers Squibb, Trenton, New Jersey.

Small cell lung carcinoma (SCLC) is highly mutated, yet durable response to immune checkpoint blockade (ICB) is rare. SCLC also exhibits cellular plasticity, which could influence its immunobiology. Here we discover that a distinct subset of SCLC uniquely upregulates MHC I, enriching for durable ICB benefit. modeling confirms epigenetic recovery of MHC I in SCLC following loss of neuroendocrine differentiation, which tracks with derepression of STING. Transient EZH2 inhibition expands these nonneuroendocrine cells, which display intrinsic innate immune signaling and basally restored antigen presentation. Consistent with these findings, murine nonneuroendocrine SCLC tumors are rejected in a syngeneic model, with clonal expansion of immunodominant effector CD8 T cells. Therapeutically, EZH2 inhibition followed by STING agonism enhances T-cell recognition and rejection of SCLC in mice. Together, these data identify MHC I as a novel biomarker of SCLC immune responsiveness and suggest novel immunotherapeutic approaches to co-opt SCLC's intrinsic immunogenicity. SIGNIFICANCE: SCLC is poorly immunogenic, displaying modest ICB responsiveness with rare durable activity. In profiling its plasticity, we uncover intrinsically immunogenic MHC I subpopulations of nonneuroendocrine SCLC associated with durable ICB benefit. We also find that combined EZH2 inhibition and STING agonism uncovers this cell state, priming cells for immune rejection..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8338750PMC
August 2021

Predictive 'biomarker piggybacking': an examination of reflexive pan-cancer screening with pan-TRK immunohistochemistry.

Histopathology 2021 Aug 7;79(2):260-264. Epub 2021 Apr 7.

Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.

Aims: Tropomyosin receptor kinase (TRK)-targeted therapies represent an important therapeutic option for patients with advanced solid tumours harbouring neurotrophin receptor kinase (NTRK) gene fusions. However, NTRK fusions are rare in common adult carcinomas, and systematic approaches to screening for these alterations are lacking. Pan-TRK immunohistochemistry (IHC) has been proposed as one method to screen for NTRK fusion-positive tumours. Reflexive testing strategies have been endorsed for several IHC-based biomarkers, and thus offer a convenient and low-cost entry point to incorporate pan-TRK screening.

Methods And Results: In this study, 447 consecutive cases of adult solid tumours undergoing mismatch repair (MMR), human epidermal growth factor receptor 2 (HER2) and/or programmed cell death ligand 1 (PD-L1) testing were prospectively stained with pan-TRK IHC. Four cases (0.9%) were pan-TRK positive, including three (1.3% of 223) colonic adenocarcinomas, two of which were MMR-deficient and one (1.4% of 71) was gastroesophageal carcinoma. None of 108 non-small cell lung carcinomas showed pan-TRK expression. NTRK gene fusion was confirmed by DNA sequencing in one MMR-deficient colonic adenocarcinoma. In one MMR-deficient tumour, an alternative mitogen-activated protein kinase (MAPK) driver was identified. In the oesophageal (squamous cell) carcinoma, RNA sequencing identified relative NTRK2 transcript overexpression in the absence of a fusion. In one MMR-proficient colonic adenocarcinoma, no MAPK drivers were identified; therefore, a falsely negative sequencing result was favored. None of the patients met clinical criteria for TRK-targeted therapy.

Conclusion: The clinical impact of pan-TRK IHC 'piggybacking' on existing reflexive testing strategies in surgical pathology appears negligible. Carcinomas may rarely show high-level pan-TRK expression in the absence of an underlying NTRK fusion event.
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http://dx.doi.org/10.1111/his.14351DOI Listing
August 2021

The International Association for the Study of Lung Cancer Global Survey on Programmed Death-Ligand 1 Testing for NSCLC.

J Thorac Oncol 2021 04 2;16(4):686-696. Epub 2021 Mar 2.

Carolinas Pathology Group, Charlotte, North Carolina.

Introduction: Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) is required to determine the eligibility for pembrolizumab monotherapy in advanced NSCLC worldwide and for several other indications depending on the country. Four assays have been approved/ Communauté Européene-In vitro Diagnostic (CV-IVD)-marked, but PD-L1 IHC seems diversely implemented across regions and laboratories with the application of laboratory-developed tests (LDTs).

Method: To assess the practice of PD-L1 IHC and identify issues and disparities, the International Association for the Study of Lung Cancer Pathology Committee conducted a global survey for pathologists from January to May 2019, comprising multiple questions on preanalytical, analytical, and postanalytical conditions.

Result: A total of 344 pathologists from 64 countries participated with 41% from Europe, 24% from North America, and 18% from Asia. Besides biopsies and resections, cellblocks were used by 75% of the participants and smears by 11%. The clone 22C3 was most often used (69%) followed by SP263 (51%). They were applied as an LDT by 40% and 30% of the users, respectively, and 76% of the participants developed at least one LDT. Half of the participants reported a turnaround time of less than or equal to 2 days, whereas 13% reported that of greater than or equal to 5 days. In addition, quality assurance (QA), formal training for scoring, and standardized reporting were not implemented by 18%, 16%, and 14% of the participants, respectively.

Conclusions: Heterogeneity in PD-L1 testing is marked across regions and laboratories in terms of antibody clones, IHC assays, samples, turnaround times, and QA measures. The lack of QA, formal training, and standardized reporting stated by a considerable minority identifies a need for additional QA measures and training opportunities.
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http://dx.doi.org/10.1016/j.jtho.2020.12.026DOI Listing
April 2021

OncoTree: A Cancer Classification System for Precision Oncology.

JCO Clin Cancer Inform 2021 02;5:221-230

Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Cancer classification is foundational for patient care and oncology research. Systems such as International Classification of Diseases for Oncology (ICD-O), Systematized Nomenclature of Medicine Clinical Terms (SNOMED-CT), and National Cancer Institute Thesaurus (NCIt) provide large sets of cancer classification terminologies but they lack a dynamic modernized cancer classification platform that addresses the fast-evolving needs in clinical reporting of genomic sequencing results and associated oncology research.

Methods: To meet these needs, we have developed OncoTree, an open-source cancer classification system. It is maintained by a cross-institutional committee of oncologists, pathologists, scientists, and engineers, accessible via an open-source Web user interface and an application programming interface.

Results: OncoTree currently includes 868 tumor types across 32 organ sites. OncoTree has been adopted as the tumor classification system for American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE), a large genomic and clinical data-sharing consortium, and for clinical molecular testing efforts at Memorial Sloan Kettering Cancer Center and Dana-Farber Cancer Institute. It is also used by precision oncology tools such as OncoKB and cBioPortal for Cancer Genomics.

Conclusion: OncoTree is a dynamic and flexible community-driven cancer classification platform encompassing rare and common cancers that provides clinically relevant and appropriately granular cancer classification for clinical decision support systems and oncology research.
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http://dx.doi.org/10.1200/CCI.20.00108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240791PMC
February 2021
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