Publications by authors named "Lynette M Sholl"

212 Publications

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

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

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

PD-L1 as a biomarker of response to immune-checkpoint inhibitors.

Nat Rev Clin Oncol 2021 06 12;18(6):345-362. Epub 2021 Feb 12.

Center for Thoracic Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Immune-checkpoint inhibitors targeting PD-1 or PD-L1 have already substantially improved the outcomes of patients with many types of cancer, although only 20-40% of patients derive benefit from these new therapies. PD-L1, quantified using immunohistochemistry assays, is currently the most widely validated, used and accepted biomarker to guide the selection of patients to receive anti-PD-1 or anti-PD-L1 antibodies. However, many challenges remain in the clinical use of these assays, including the necessity of using different companion diagnostic assays for specific agents, high levels of inter-assay variability in terms of both performance and cut-off points, and a lack of prospective comparisons of how PD-L1 disease diagnosed using each assay relates to clinical outcomes. In this Review, we describe the current role of PD-L1 immunohistochemistry assays used to inform the selection of patients to receive anti-PD-1 or anti-PD-L1 antibodies, we discuss the various technical and clinical challenges associated with these assays, including regulatory issues, and we provide some perspective on how to optimize PD-L1 as a selection biomarker for the future treatment of patients with solid tumours.
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http://dx.doi.org/10.1038/s41571-021-00473-5DOI Listing
June 2021

Correlation of methylthioadenosine phosphorylase (MTAP) protein expression with MTAP and CDKN2A copy number in malignant pleural mesothelioma.

Histopathology 2021 Jun 14;78(7):1032-1042. Epub 2021 Apr 14.

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

Aims: Methylthioadenosine phosphorylase (MTAP) immunohistochemical expression is a specific marker of CDKN2A deletion in malignant mesothelioma. However, the relationship of MTAP expression with MTAP copy number remains unexplored.

Methods And Results: Forty malignant pleural mesotheliomas were characterised by targeted next-generation sequencing (29), single-nucleotide polymorphism microarray (seven), or both (four). MTAP and CDKN2A copy numbers were correlated with MTAP expression. Twenty-seven (68%) tumours showed CDKN2A deletion (14 heterozygous; 13 homozygous), of which 20 (74%) showed MTAP codeletion (15 heterozygous; five homozygous). No tumours showed MTAP deletion without CDKN2A codeletion. Loss of MTAP expression was seen in 16 (40%) tumours, and was 75% sensitive and 95% specific for MTAP deletion, and 59% sensitive and 100% specific for CDKN2A deletion. Nine of 40 (23%) tumours showed heterogeneous MTAP staining, and the percentage of tumour cells with MTAP loss correlated with molecular detection of MTAP deletion.

Conclusions: MTAP is frequently codeleted with CDKN2A in pleural mesothelioma. However, homozygous deletion of both genes occurs in a minority of tumours (5/40; 13%); CDKN2A deletion often co-occurs with heterozygous MTAP deletion or neutral MTAP copy number; and MTAP expression correlates inconsistently with heterozygous MTAP deletion. Correspondingly, MTAP immunohistochemistry is a highly specific but only moderately sensitive assay for CDKN2A deletion.
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http://dx.doi.org/10.1111/his.14324DOI Listing
June 2021

Pathologic Assessment of Lung Squamous Cell Carcinoma After Neoadjuvant Immunotherapy.

J Thorac Oncol 2021 01;16(1):e9-e10

Department of Translational Molecular Pathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

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http://dx.doi.org/10.1016/j.jtho.2020.11.009DOI Listing
January 2021

Clinicopathological and molecular characteristics of prostate cancer diagnosed in young men aged up to 45 years.

Histopathology 2021 May 16;78(6):857-870. Epub 2021 Mar 16.

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

Aims: To characterise and compare the poorly understood clinicopathological and molecular characteristics of prostatic adenocarcinoma (PCa) in very young patients.

Methods And Results: We compared the clinicopathological and molecular characteristics of PCa diagnosed in 90 patients aged ≤45 years with those of PCa diagnosed in 200 patients of typical screening age (i.e. 60-65 years). Patients diagnosed at a younger age had a higher frequency of a family history of PCa and lower prostate-specific antigen (PSA) levels than those diagnosed at regular screening age. There were no statistically significant differences in clinical stage or pathological characteristics of the core biopsy specimens between the groups. Young patients had a higher frequency of Grade Group 1 disease at radical prostatectomy. A subset of 13 aggressive PCa cases from young patients underwent successful DNA-based next-generation sequencing. In all, 46.2% (6/13) had TMPRSS2 rearrangements and 23.1% (3/13) had relevant pathogenic variants in DNA damage repair genes, including a mismatch repair-deficient case with biallelic inactivation of MLH1. No statistically significant differences were observed in PCa-specific recurrence/progression between the younger and older patients, including after adjustment for clinical stage, PSA level, and Grade Group.

Conclusions: In this study, the clinicopathological and molecular features of PCa diagnosed in young patients were comparable to those of PCa diagnosed in patients of screening age. Early-onset PCa cases were not enriched in any of the known molecular PCa subtypes in this small series.
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http://dx.doi.org/10.1111/his.14315DOI Listing
May 2021

Temporal and spatial heterogeneity of host response to SARS-CoV-2 pulmonary infection.

Nat Commun 2020 12 9;11(1):6319. Epub 2020 Dec 9.

Department of Pathology, Brigham and Woman's Hospital, Boston, MA, 02115, USA.

The relationship of SARS-CoV-2 pulmonary infection and severity of disease is not fully understood. Here we show analysis of autopsy specimens from 24 patients who succumbed to SARS-CoV-2 infection using a combination of different RNA and protein analytical platforms to characterize inter-patient and intra-patient heterogeneity of pulmonary virus infection. There is a spectrum of high and low virus cases associated with duration of disease. High viral cases have high activation of interferon pathway genes and a predominant M1-like macrophage infiltrate. Low viral cases are more heterogeneous likely reflecting inherent patient differences in the evolution of host response, but there is consistent indication of pulmonary epithelial cell recovery based on napsin A immunohistochemistry and RNA expression of surfactant and mucin genes. Using a digital spatial profiling platform, we find the virus corresponds to distinct spatial expression of interferon response genes demonstrating the intra-pulmonary heterogeneity of SARS-CoV-2 infection.
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http://dx.doi.org/10.1038/s41467-020-20139-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725958PMC
December 2020

Expanding the utility of cytology preparations in cancer biomarker testing.

Cancer Cytopathol 2021 05 29;129(5):337-340. Epub 2020 Oct 29.

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

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http://dx.doi.org/10.1002/cncy.22380DOI Listing
May 2021

Overcoming MET-Dependent Resistance to Selective RET Inhibition in Patients with RET Fusion-Positive Lung Cancer by Combining Selpercatinib with Crizotinib.

Clin Cancer Res 2021 01 20;27(1):34-42. Epub 2020 Oct 20.

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

Purpose: The proto-oncogene encodes a receptor tyrosine kinase that is activated by gene fusion in 1%-2% of non-small cell lung cancers (NSCLC) and rarely in other cancer types. Selpercatinib is a highly selective RET kinase inhibitor that has recently been approved by the FDA in lung and thyroid cancers with activating gene fusions and mutations. Molecular mechanisms of acquired resistance to selpercatinib are poorly understood.

Patients And Methods: We studied patients treated on the first-in-human clinical trial of selpercatinib (NCT03157129) who were found to have amplification associated with resistance to selpercatinib. We validated activation as a targetable mediator of resistance to RET-directed therapy, and combined selpercatinib with the MET/ALK/ROS1 inhibitor crizotinib in a series of single patient protocols (SPP).

Results: amplification was identified in posttreatment biopsies in 4 patients with fusion-positive NSCLC treated with selpercatinib. In at least one case, amplification was clearly evident prior to therapy with selpercatinib. We demonstrate that increased MET expression in fusion-positive tumor cells causes resistance to selpercatinib, and this can be overcome by combining selpercatinib with crizotinib. Using SPPs, selpercatinib with crizotinib were given together generating anecdotal evidence of clinical activity and tolerability, with one response lasting 10 months.

Conclusions: Through the use of SPPs, we were able to offer combination therapy targeting -amplified resistance identified on the first-in-human study of selpercatinib. These data suggest that MET dependence is a recurring and potentially targetable mechanism of resistance to selective RET inhibition in advanced NSCLC.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009613PMC
January 2021

, a DNA damage response gene, is required for Notch-mediated induction of squamous cell differentiation.

Elife 2020 09 16;9. Epub 2020 Sep 16.

Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, United States.

Notch signaling regulates squamous cell proliferation and differentiation and is frequently disrupted in squamous cell carcinomas, in which Notch is tumor suppressive. Here, we show that conditional activation of Notch in squamous cells activates a context-specific gene expression program through lineage-specific regulatory elements. Among direct Notch target genes are multiple DNA damage response genes, including , which we show is required for Notch-induced differentiation of squamous carcinoma cells and TERT-immortalized keratinocytes. is epistatic to , a gene that encodes the PP2A B55α subunit, which we show interacts with IER5 in cells and in purified systems. Thus, Notch and DNA-damage response pathways converge in squamous cells on common genes that promote differentiation, which may serve to eliminate damaged cells from the proliferative pool. We further propose that crosstalk involving Notch and PP2A enables tuning and integration of Notch signaling with other pathways that regulate squamous differentiation.
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http://dx.doi.org/10.7554/eLife.58081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529455PMC
September 2020

Engaging Patients in Precision Oncology: Development and Usability of a Web-Based Patient-Facing Genomic Sequencing Report.

JCO Precis Oncol 2020 14;4. Epub 2020 Apr 14.

Department of Population Sciences, City of Hope Comprehensive Cancer Center, Duarte, CA.

Purpose: Evidence-based somatic and germline sequencing has transformed cancer care and improves patient outcomes. However, patients' low genetic literacy and misunderstanding of their own genomic results poses a threat to the realization of precision oncology. To optimize patient genomic comprehension, we developed a Web-based, patient-directed, genomic sequencing education and return-of-results tool, HOPE-Genomics.

Methods: The HOPE-Genomics prototype included somatic and germline sequencing results, embedded multimedia genomic education, and interactive features (eg, request for genetic counseling). Between January and April 2018, we elicited feedback on tool usability and comprehensiveness through participant surveys, 4 focus groups of patients with cancer and their family members, and 3 provider focus groups (comprising 8 patients, 5 family members, and 19 providers).

Results: We identified themes in patient/family tool-related responses, including the desire to view a patient-friendly report, a desire to receive multiple types of genomic information (eg, prognostic and uncertain), high acceptability of report content, and interest in tool-enabled access to genetic counseling. Major themes from the clinician focus groups included believing the tool could help patients formulate questions and facilitate patients' communication of results to family members. However, there were diverse responses from all participants in terms of tool implementation (ie, timing and nature of report release). Some participants preferred report release before meeting with the provider, and others preferred it during the appointment. Additionally, some clinicians were concerned about providing prognostic and treatment information through the tool.

Conclusion: There was high acceptability and interest from patients, family members, and providers in a patient-directed genomics report. Future work will determine whether direct-to-patient reporting of genomic results improves patient knowledge, care engagement, and compliance with genomically guided interventions.
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http://dx.doi.org/10.1200/PO.19.00195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446413PMC
April 2020

Strategies for the successful implementation of plasma-based NSCLC genotyping in clinical practice.

Nat Rev Clin Oncol 2021 01 11;18(1):56-62. Epub 2020 Sep 11.

UC Davis Comprehensive Cancer Center, Sacramento, CA, USA.

Upfront tumour genotyping is now considered an essential step in guiding treatment decision-making in the management of patients with advanced-stage non-small-cell lung cancer (NSCLC) in light of the ever-expanding toolbox of targeted therapies and immune-checkpoint inhibitors. However, genotyping of tumour biopsy samples is not feasible for all patients and, therefore, genomic analysis of circulating tumour DNA (ctDNA) has emerged as a compelling non-invasive option. Current guidelines universally recommend genotyping and support the use of ctDNA testing in certain settings, although they often omit the detail necessary for integrating these tests into clinical care on an individual basis. In this Perspective, we describe the rationale, promise and challenges associated with ctDNA-based NSCLC genotyping and suggest a framework for the implementation of these assays into routine clinical practice. We also offer considerations for the interpretation of ctDNA genotyping results, which, particularly when using next-generation sequencing panels, can be nuanced. Through the addition of this new approach to clinical practice, we propose that oncologists might finally be able to utilize effective genotyping in nearly all patients with advanced-stage NSCLC.
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http://dx.doi.org/10.1038/s41571-020-0423-xDOI Listing
January 2021
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