Publications by authors named "Neal I Lindeman"

107 Publications

How SARS-CoV-2 Transformed the Clinical Laboratory: Challenges and Lessons Learned.

J Appl Lab Med 2021 Apr 6. Epub 2021 Apr 6.

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

The COVID-19 pandemic has made a devastating impact on global health and continues to challenge healthcare infrastructure and delivery. The clinical laboratories were no exception as they are responsible for diagnostic testing that dictates many clinical, infection control and public health decisions. Information technology and laboratory management tools are critical assets for maintaining and adapting operations in response to crises and when utilized effectively, promote the integration between the clinical laboratory specialties (e.g., chemistry, hematology, microbiology, and molecular pathology). During the COVID-19 pandemic, our systems and processes were strained due to high testing volumes, demand for rapid turnaround times, supply chain constraints, and constantly evolving testing algorithms and result interpretations as our knowledge of the virus and of diagnostics increased over time. In this report, we describe those challenges and subsequent adaptations made by each clinical laboratory section. We hope these details help provide potential solutions and approaches for other hospitals facing COVID-19 surges or other future pandemics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jalm/jfab034DOI Listing
April 2021

Matched Targeted Therapy for Pediatric Patients with Relapsed, Refractory or High-risk Leukemias: A Report from the LEAP Consortium.

Cancer Discov 2021 Feb 9. Epub 2021 Feb 9.

Department of Pediatric Oncology, Dana-Farber Cancer Institute

Despite a remarkable increase in the genomic profiling of cancer, integration of genomic discoveries into clinical care has lagged behind. We report the feasibility of rapid identification of targetable mutations in 153 pediatric patients with relapsed/refractory or high-risk leukemias enrolled on a prospective clinical trial conducted by the LEAP Consortium. Eighteen percent of patients had a high confidence, Tier 1 or 2, recommendation. We describe clinical responses in the 14% of patients with relapsed/refractory leukemia who received the matched targeted therapy. Further, in order to inform future targeted therapy for patients, we validated variants of uncertain significance (VUS), performed ex vivo drug sensitivity testing in patient leukemia samples, and identified new combinations of targeted therapies in cell lines and patient-derived xenograft models. These data and our collaborative approach should inform the design of future precision medicine trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-20-0564DOI Listing
February 2021

Practical Considerations Relating to Routine Clinical Biomarker Testing for Non-small Cell Lung Cancer: Focus on Testing for Fusions.

Front Med (Lausanne) 2020 21;7:562480. Epub 2021 Jan 21.

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

For patients with advanced non-small cell lung cancer, genomic profiling of tumors to identify potentially targetable alterations and thereby inform treatment selection is now part of standard care. While molecular analyses are primarily focused on actionable biomarkers associated with regulatory agency-approved therapies, there are a number of emerging biomarkers linked to investigational agents in advanced stages of clinical development will become approved agents. A particularly timely example is the reported data and US Food and Drug Administration approval of highly specific small molecule inhibitors of the proto-oncogene tyrosine-protein kinase receptor RET indicate that testing for tumor gene fusions in patients with NSCLC has become clinically important. As the number of biomarkers to be tested in NSCLC grows, it becomes increasingly important to optimize and prioritize the use of biopsy tissue, in order to both continue to allow accurate histopathological diagnosis and also to support concurrent genomic profiling to identify perhaps relatively uncommon genetic events. In order to provide practical expert consensus guidance to optimize processes facilitating genomic testing in NSCLC and to overcome barriers to access and implementation, a multidisciplinary advisory board was held in New York, on January 30, 2019. The panel comprised physicians involved in sample procurement (interventional radiologists and a thoracic surgeon), surgical pathologists specializing in the lung, molecular pathologists, and thoracic oncologists. Particular consideration was given to the key barriers faced by these experts in establishing institutional genomic screening programs for NSCLC. Potential solutions have been devised in the form of consensus opinions that might be used to help resolve such issues.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmed.2020.562480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859651PMC
January 2021

An Overview of Characteristics of Clinical Next-Generation Sequencing-Based Testing for Hematologic Malignancies.

Arch Pathol Lab Med 2021 Jan 15. Epub 2021 Jan 15.

the Departments of Pathology and Laboratory Medicine & Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill (Merker).

Context.—: With the increasing integration of molecular alterations into the evaluation of hematologic malignancies (HM), somatic mutation profiling by next-generation sequencing (NGS) has become a common clinical testing strategy. Limited data are available about the characteristics of these assays.

Objective.—: To describe assay characteristics, specimen requirements, and reporting practices for NGS-based HM testing using College of American Pathologists proficiency testing survey data.

Design.—: The College of American Pathologists NGS Hematologic Malignancies Survey (NGSHM) results from 78 laboratories were used to determine laboratory practices in NGS-based HM testing.

Results.—: The majority of laboratories performed tumor-only (88.5% [69 of 78]), targeted sequencing of cancer genes or mutation hotspots (98.7% [77 of 78]); greater than 90% performed testing on fresh bone marrow and peripheral blood. The majority of laboratories reported a 5% lower limit of detection for single-nucleotide variants (73.1% [57 of 78]) and small insertions and deletions (50.6% [39 of 77]). A majority of laboratories used benchtop sequencers and custom enrichment approaches.

Conclusions.—: This manuscript summarizes the characteristics of clinical NGS-based testing for the detection of somatic variants in HM. These data may be broadly useful to inform laboratory practice and quality management systems, regulation, and oversight of NGS testing, and precision medicine efforts using a data-driven approach.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5858/arpa.2019-0661-CPDOI Listing
January 2021

Novel Pathogenic Germline Variant of the Adenomatous Polyposis Coli (APC) Gene, p.S2627Gfs*12 Identified in a Mild Phenotype of APC-Associated Polyposis: A Case Report.

Am J Case Rep 2020 Dec 11;21:e927293. Epub 2020 Dec 11.

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

BACKGROUND The diagnoses of adenomatous polyposis coli (APC)-associated polyposis conditions are typically based on suggestive personal features and/or family history, and the identification of a pathogenic variant in the APC gene. However, with large-scale genome sequencing, it is now possible to identify pathogenic variants before or even without the presentation of the expected clinical features. This case describes a novel pathogenic APC variant. CASE REPORT We report the unexpected identification of a rare, pathogenic germline APC variant, p.S2627Gfs*12 in an 80-year-old man with a diagnosis of renal cell carcinoma, without any family history of APC-associated polyposis or personal history of colorectal cancer. After the identification of the APC variant, a review of the patient's medical records showed a personal history of 15 adenomatous polyps over a decade ago, with no follow-up genetic testing at the time. CONCLUSIONS This novel APC variant has not been characterized to date. The presence of the APC-p.S2627Gfs*12 variant in this patient led to the recommendation of additional cascade genetic testing and surveillance measures for any family members who tested positive for this variant. This report highlights the broad spectrum of the APC-associated polyposis features, and a mild phenotype associated with the pathogenic APC p.S2627Gfs*12 variant.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12659/AJCR.927293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737709PMC
December 2020

Genomic Characterization of Metastatic Breast Cancer.

Clin Cancer Res 2021 Feb 8;27(4):1105-1118. Epub 2020 Dec 8.

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

Purpose: In contrast to recurrence after initial diagnosis of stage I-III breast cancer [recurrent metastatic breast cancer (rMBC)], metastatic breast cancer (dnMBC) represents a unique setting to elucidate metastatic drivers in the absence of treatment selection. We present the genomic landscape of dnMBC and association with overall survival (OS).

Experimental Design: Targeted DNA sequencing (OncoPanel) was prospectively performed on either primary or metastatic tumors from 926 patients (212 dnMBC and 714 rMBC). Single-nucleotide variants, copy-number variations, and tumor mutational burden (TMB) in treatment-naïve dnMBC primary tumors were compared with primary tumors in patients who ultimately developed rMBC, and correlated with OS across all dnMBC.

Results: When comparing primary tumors by subtype, amplification was enriched in triple-negative dnMBC versus rMBC (21.1% vs. 0%, = 0.0005, = 0.111). Mutations in , and were more prevalent, and and less prevalent, in primary HR/HER2 tumors of dnMBC versus rMBC, though not significant after multiple comparison adjustment. Alterations associated with shorter OS in dnMBC included TP53 (wild-type: 79.7 months; altered: 44.2 months; = 0.008, = 0.107), MYC (79.7 vs. 23.3 months; = 0.0003, = 0.011), and cell-cycle (122.7 vs. 54.9 months; = 0.034, = 0.245) pathway genes. High TMB correlated with better OS in triple-negative dnMBC ( = 0.041).

Conclusions: Genomic differences between treatment-naïve dnMBC and primary tumors of patients who developed rMBC may provide insight into mechanisms underlying metastatic potential and differential therapeutic sensitivity in dnMBC. Alterations associated with poor OS in dnMBC highlight the need for novel approaches to overcome potential intrinsic resistance to current treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-1720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887078PMC
February 2021

Identifying Activating Mutations in HER2-Negative Breast Cancer: Clinical Impact of Institute-Wide Genomic Testing and Enrollment in Matched Therapy Trials.

JCO Precis Oncol 2019 15;3. Epub 2019 Nov 15.

Dana-Farber Cancer Institute, Boston, MA.

Purpose: The yield of comprehensive genomic profiling in recruiting patients to molecular-based trials designed for small subgroups has not been fully evaluated. We evaluated the likelihood of enrollment in a clinical trial that required the identification of a specific genomic change based on our institute-wide genomic tumor profiling.

Patients And Methods: Using genomic profiling from archived tissue samples derived from patients with metastatic breast cancer treated between 2011 and 2017, we assessed the impact of systematic genomic characterization on enrollment in an ongoing phase II trial (ClinicalTrials.gov identifier: NCT01670877). Our primary aim was to describe the proportion of patients with a qualifying mutation identified by our institutional genomic panel (OncoMap or OncoPanel) who enrolled in the trial. Secondary objectives included median time from testing result to trial registration, description of the spectrum of mutations, and survival. Associations were calculated using Fisher's exact test.

Results: We identified a total of 1,045 patients with metastatic breast cancer without amplification who had available genomic testing results. Of these, 42 patients were found to have mutation and 19 patients (1.8%) were eligible for the trial on the basis of the presence of an activating mutation, 18 of which were identified by OncoPanel testing. Fifty-eight percent of potentially eligible patients were approached, and 33.3% of eligible patients enrolled in the trial guided exclusively by OncoPanel testing.

Conclusion: More than one half of eligible patients were approached for trial participation and, significantly, one third of those were enrolled in NCT01670877. Our data illustrate the ability to enroll patients in trials of rare subsets in routine clinical practice and highlight the need for these broadly based approaches to effectively support the success of these studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/PO.19.00087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446367PMC
November 2019

Pathomic Fusion: An Integrated Framework for Fusing Histopathology and Genomic Features for Cancer Diagnosis and Prognosis.

IEEE Trans Med Imaging 2020 Sep 3;PP. Epub 2020 Sep 3.

Cancer diagnosis, prognosis, and therapeutic response predictions are based on morphological information from histology slides and molecular profiles from genomic data. However, most deep learning-based objective outcome prediction and grading paradigms are based on histology or genomics alone and do not make use of the complementary information in an intuitive manner. In this work, we propose Pathomic Fusion, an interpretable strategy for end-to-end multimodal fusion of histology image and genomic (mutations, CNV, RNASeq) features for survival outcome prediction. Our approach models pairwise feature interactions across modalities by taking the Kronecker product of unimodal feature representations, and controls the expressiveness of each representation via a gatingbased attention mechanism. Following supervised learning, we are able to interpret and saliently localize features across each modality, and understand how feature importance shifts when conditioning on multimodal input. We validate our approach using glioma and clear cell renal cell carcinoma datasets from the Cancer Genome Atlas (TCGA), which contains paired wholeslide image, genotype, and transcriptome data with ground truth survival and histologic grade labels. In a 15-fold cross-validation, our results demonstrate that the proposed multimodal fusion paradigm improves prognostic determinations from ground truth grading and molecular subtyping, as well as unimodal deep networks trained on histology and genomic data alone. The proposed method establishes insight and theory on how to train deep networks on multimodal biomedical data in an intuitive manner, which will be useful for other problems in medicine that seek to combine heterogeneous data streams for understanding diseases and predicting response and resistance to treatment. Code and trained models are made available at: https://github.com/mahmoodlab/PathomicFusion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1109/TMI.2020.3021387DOI Listing
September 2020

Intestinal metaplasia of the urinary tract harbors potentially oncogenic genetic variants.

Mod Pathol 2021 02 28;34(2):457-468. Epub 2020 Aug 28.

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

In the urinary tract, there is an uncertain relationship between intestinal metaplasia (IM), primary adenocarcinoma, and urothelial carcinoma. Although IM is usually found adjacent to concurrent urothelial carcinoma or adenocarcinoma, small retrospective series have shown that most bladder biopsies with only IM do not subsequently develop cancer. However, IM with dysplasia does seem to be associated with a higher risk of concurrent malignancy or progressing to cancer. Since the molecular landscape of these lesions has remained largely unexplored, there are significant uncertainties about the oncogenic potential of IM in the bladder and urethra. This study investigated the presence of potentially oncogenic genetic variants in cases of IM with and without dysplasia. Twenty-three (23) cases of IM (3 urethra, 20 bladder) were sequenced using a solid tumor next-generation sequencing panel. Of these, five contained IM with high-grade dysplasia (including a case with paired IM-adenocarcinoma and another with paired IM-urothelial carcinoma) and 18 lacked dysplasia. Oncogenic genetic variants were found in all cases of IM with high-grade dysplasia and in five non-dysplastic IM cases, including mutations and copy number variants commonly seen in primary adenocarcinoma of the bladder and urothelial carcinoma. This study demonstrates that IM can harbor potentially oncogenic genetic variants, suggesting that it might represent a cancer precursor or a marker of increased cancer risk in a subset of cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41379-020-00655-zDOI Listing
February 2021

Targeted Informatics for Optimal Detection, Characterization, and Quantification of FLT3 Internal Tandem Duplications Across Multiple Next-Generation Sequencing Platforms.

J Mol Diagn 2020 09 27;22(9):1162-1178. Epub 2020 Jun 27.

Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Assessment of internal tandem duplications in FLT3 (FLT3-ITDs) and their allelic ratio (AR) is recommended by clinical guidelines for diagnostic workup of acute myeloid leukemia and traditionally performed through capillary electrophoresis (CE). Although significant progress has been made integrating FLT3-ITD detection within contemporary next-generation sequencing (NGS) panels, AR estimation is not routinely part of clinical NGS practice because of inherent biases and challenges. In this study, data from multiple NGS platforms-anchored multiplex PCR (AMP), amplicon [TruSeq Custom Amplicon (TSCA)], and hybrid-capture-were analyzed through a custom algorithm, including platform-specific measures of AR. Sensitivity and specificity of NGS for FLT3-ITD status relative to CE were 100% (42/42) and 99.4% (1076/1083), respectively, by AMP on an unselected cohort and 98.1% (53/54) and 100% (48/48), respectively, by TSCA on a selected cohort. Primer analysis identified criteria for ITDs to escape detection by TSCA, estimated to occur in approximately 9% of unselected ITDs. Allelic fractions under AMP or TSCA were highly correlated to CE, with linear regression slopes near 1 for ITDs not duplicating primers, and systematically underestimated for ITDs duplicating a primer. Bias was alleviated in AMP through simple adjustments. This article provides an approach for targeted computational FLT3-ITD analysis for NGS data from multiple platforms; AMP was found capable of near perfect sensitivity and specificity with relatively accurate estimates of ARs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jmoldx.2020.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479488PMC
September 2020

Tumor Mutational Burden and Alterations as Molecular Correlates of Response to PD-1/L1 Blockade in Metastatic Triple-Negative Breast Cancer.

Clin Cancer Res 2020 06 4;26(11):2565-2572. Epub 2020 Feb 4.

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

Purpose: Few patients with metastatic triple-negative breast cancer (mTNBC) benefit from immune checkpoint inhibitors (ICI). On the basis of immunotherapy response correlates in other cancers, we evaluated whether high tumor mutational burden (TMB) ≥10 nonsynonymous mutations/megabase and alterations, defined as nonsynonymous mutations or 1 or 2 copy deletions, were associated with clinical benefit to anti-PD-1/L1 therapy in mTNBC.

Experimental Design: We identified patients with mTNBC, who consented to targeted DNA sequencing and were treated with ICIs on clinical trials between April 2014 and January 2019 at Dana-Farber Cancer Institute (Boston, MA). Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were correlated with tumor genomic features.

Results: Sixty-two women received anti-PD-1/L1 inhibitors alone (23%) or combined with targeted therapy (19%) or chemotherapy (58%). High TMB (18%) was associated with significantly longer PFS (12.5 vs. 3.7 months; = 0.04), while alterations (29%) were associated with significantly lower ORR (6% vs. 48%; = 0.01), shorter PFS (2.3 vs. 6.1 months; = 0.01), and shorter OS (9.7 vs. 20.5 months; = 0.02). Multivariate analyses confirmed that these associations were independent of performance status, prior lines of therapy, therapy regimen, and visceral metastases. The survival associations were additionally independent of PD-L1 in patients with known PD-L1 and were not found in mTNBC cohorts treated with chemotherapy ( = 90) and non-ICI regimens ( = 169).

Conclusions: Among patients with mTNBC treated with anti-PD-1/L1 therapies, high TMB and alterations were associated with longer and shorter survival, respectively. These observations warrant validation in larger datasets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-3507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269810PMC
June 2020

Proficiency Testing of Standardized Samples Shows High Interlaboratory Agreement for Clinical Next Generation Sequencing-Based Hematologic Malignancy Assays With Survey Material-Specific Differences in Variant Frequencies.

Arch Pathol Lab Med 2020 Jan 27. Epub 2020 Jan 27.

From the Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts (Drs Keegan, Lindeman, and Kim); the Departments of Pathology and Microbiology, University of Nebraska Medical Center, Omaha (Dr Bridge); Biostatistics (Mr Long) and Proficiency Testing (Ms Vasalos), ollege of American Pathologists, Northfield, Illinois; the UNC Lineberger Comprehensive Cancer Center (Dr Merker) and the Department of Pathology and Laboratory Medicine (Dr Montgomery), University of North Carolina, Chapel Hill; the Office of the Director, The Joint Pathology Center, Silver Spring, Maryland (Dr Moncur); the Department of Pathology, PierianDx, St Louis, Missouri (Dr Nagarajan); the Department of Pathology and Laboratory Medicine, Strong Memorial Hospital, University of Rochester Medical Center, Rochester, New York (Dr Rothberg); the Department of Hematopathology, MD Anderson Cancer Center, Houston, Texas (Dr Routbort); and the Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland (Dr Xian).

Context.—: As laboratories increasingly turn from single-analyte testing in hematologic malignancies to next-generation sequencing-based panel testing, there is a corresponding need for proficiency testing to ensure adequate performance of these next-generation sequencing assays for optimal patient care.

Objective.—: To report the performance of laboratories on proficiency testing from the first 4 College of American Pathologists Next-Generation Sequencing Hematologic Malignancy surveys.

Design.—: College of American Pathologists proficiency testing results for 36 different engineered variants and/or allele fractions as well as a sample with no pathogenic variants were analyzed for accuracy and associated assay performance characteristics.

Results.—: The overall sensitivity observed for all variants was 93.5% (2190 of 2341) with 99.8% specificity (22 800 of 22 840). The false-negative rate was 6.5% (151 of 2341), and the largest single cause of these errors was difficulty in identifying variants in the sequence of that is rich in cytosines and guanines. False-positive results (0.18%; 40 of 22 840) were most likely the result of preanalytic or postanalytic errors. Interestingly, the variant allele fractions were almost uniformly lower than the engineered fraction (as measured by digital polymerase chain reaction). Extensive troubleshooting identified a multifactorial cause for the low variant allele fractions, a result of an interaction between the linearized nature of the plasmid and the Illumina TruSeq chemistry.

Conclusions.—: Laboratories demonstrated an overall accuracy of 99.2% (24 990 of 25 181) with 99.8% specificity and 93.5% sensitivity when examining 36 clinically relevant somatic single-nucleotide variants with a variant allele fraction of 10% or greater. The data also highlight an issue with artificial linearized plasmids as survey material for next-generation sequencing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5858/arpa.2019-0352-CPDOI Listing
January 2020

A model combining clinical and genomic factors to predict response to PD-1/PD-L1 blockade in advanced urothelial carcinoma.

Br J Cancer 2020 02 20;122(4):555-563. Epub 2019 Dec 20.

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

Background: In metastatic urothelial carcinoma (mUC), predictive biomarkers that correlate with response to immune checkpoint inhibitors (ICIs) are lacking. Here, we interrogated genomic and clinical features associated with response to ICIs in mUC.

Methods: Sixty two mUC patients treated with ICI who had targeted tumour sequencing were studied. We examined associations between candidate biomarkers and clinical benefit (CB, any objective reduction in tumour size) versus no clinical benefit (NCB, no change or objective increase in tumour size). Both univariable and multivariable analyses for associations were conducted. A comparator cohort of 39 mUC patients treated with taxanes was analysed by using the same methodology.

Results: Nine clinical and seven genomic factors correlated with clinical outcomes in univariable analysis in the ICI cohort. Among the 16 factors, neutrophil-to-lymphocyte ratio (NLR) ≥5 (OR = 0.12, 95% CI, 0.01-1.15), visceral metastasis (OR = 0.05, 95% CI, 0.01-0.43) and single-nucleotide variant (SNV) count < 10 (OR = 0.04, 95% CI, 0.006-0.27) were identified as independent predictors of NCB to ICI in multivariable analysis (c-statistic = 0.90). None of the 16 variables were associated with clinical benefit in the taxane cohort.

Conclusions: This three-factor model includes genomic (SNV count >9) and clinical (NLR <5, lack of visceral metastasis) variables predictive for benefit to ICI but not taxane therapy for mUC. External validation of these hypothesis-generating results is warranted to enable use in routine clinical care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41416-019-0686-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028947PMC
February 2020

Morphologic, Immunohistochemical, and Molecular Distinction Between Fibroepithelioma of Pinkus and "Fenestrated" Basal Cell Carcinoma.

Am J Dermatopathol 2020 Jul;42(7):513-520

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

Fibroepithelioma of Pinkus (FEP) is a rare cutaneous neoplasm with a characteristic fenestrated architecture and a prominent spindle cell stromal component and which invariably pursues an indolent course. The classification of FEP has been much debated since its first description in 1953, with some arguing that it represents a variant of a basal cell carcinoma (BCC) while others view it as a variant of a trichoblastoma. Multiple previous immunohistochemical studies aiming to clarify this issue have yielded conflicting results. To date, there have been no molecular studies of FEP. We identified 16 cases of fenestrated follicular neoplasms and classified them as BCC or FEP based solely on histomorphologic criteria. CK20 immunohistochemistry supported this classification scheme, with FEP showing significantly more CK20-positive Merkel cells than BCC. We then analyzed a subset of these tumors by a targeted next-generation DNA sequencing platform. All the BCC cases harbored pathogenic PTCH1 mutations, confirming the diagnosis. By contrast, none of the FEP cases harbored a PTCH1 mutation or indeed any mutation known to be causally linked to the development of BCC. Our results suggest that FEP can be distinguished from BCC on morphologic, immunohistochemical, and molecular genetic grounds. We argue that FEP is better considered a benign follicular neoplasm and support its classification as a variant of trichoblastoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/DAD.0000000000001563DOI Listing
July 2020

Phase II Study of Avelumab in Patients With Mismatch Repair Deficient and Mismatch Repair Proficient Recurrent/Persistent Endometrial Cancer.

J Clin Oncol 2019 10 28;37(30):2786-2794. Epub 2019 Aug 28.

Dana-Farber Cancer Institute, Boston, MA.

Purpose: Despite the tissue-agnostic approval of pembrolizumab in mismatch repair deficient (MMRD) solid tumors, important unanswered questions remain about the role of immune checkpoint blockade in mismatch repair-proficient (MMRP) and -deficient endometrial cancer (EC).

Methods: This phase II study evaluated the PD-L1 inhibitor avelumab in two cohorts of patients with EC: (1) MMRD/ (polymerase ε) cohort, as defined by immunohistochemical (IHC) loss of expression of one or more mismatch repair (MMR) proteins and/or documented mutation in the exonuclease domain of ; and (2) MMRP cohort with normal IHC expression of all MMR proteins. Coprimary end points were objective response (OR) and progression-free survival at 6 months (PFS6). Avelumab 10 mg/kg intravenously was administered every 2 weeks until progression or unacceptable toxicity.

Results: Thirty-three patients were enrolled. No patient with -mutated tumor was enrolled in the MMRD cohort, and all MMRP tumors were not -mutated. The MMRP cohort was closed at the first stage because of futility: Only one of 16 patients exhibited both OR and PFS6 responses. The MMRD cohort met the predefined primary end point of four ORs after accrual of only 17 patients; of 15 patients who initiated avelumab, four exhibited OR (one complete response, three partial responses; OR rate, 26.7%; 95% CI, 7.8% to 55.1%) and six (including all four ORs) PFS6 responses (PFS6, 40.0%; 95% CI, 16.3% to 66.7%), four of which are ongoing as of data cutoff date. Responses were observed in the absence of PD-L1 expression. IHC captured all cases of MMRD subsequently determined by polymerase chain reaction or genomically via targeted sequencing.

Conclusion: Avelumab exhibited promising activity in MMRD EC regardless of PD-L1 status. IHC for MMR assessment is a useful tool for patient selection. The activity of avelumab in MMRP/non-mutated ECs was low.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.19.01021DOI Listing
October 2019

Utility of Histologic and Histochemical Screening for 16S Ribosomal RNA Gene Sequencing of Formalin-Fixed, Paraffin-Embedded Tissue for Bacterial Endocarditis.

Am J Clin Pathol 2019 09;152(4):431-437

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

Objectives: 16S ribosomal RNA (rRNA) sequencing is a powerful but expensive tool for the identification of bacteria in culture-negative endocarditis. Histologic criteria to screen formalin-fixed, paraffin-embedded (FFPE) specimens for testing are evaluated.

Methods: Sixty-eight cases of infective endocarditis and controls were histologically reviewed and analyzed by 16S rRNA gene sequencing.

Results: Sequencing identified a specific pathogenic organism in 33 (49%) of 68 cases with acute inflammation and in 0 of 10 controls (P = .004). Visualization of organisms by Gram or Grocott methenamine silver stains had the strongest association with positive sequencing, while antibiotic treatment effect and acid decalcification decreased sensitivity. Molecular identifications were concordant with blood culture results in 90% of the cases, and a positive sequencing result was obtained in approximately half of the cases with negative valve cultures.

Conclusions: Histologic screening criteria are extremely helpful for identifying cases likely to be positive by molecular testing and can provide significant cost savings in filtering out low-yield specimens.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ajcp/aqz055DOI Listing
September 2019

Targeted Cancer Next-Generation Sequencing as a Primary Screening Tool for Microsatellite Instability and Lynch Syndrome in Upper Gastrointestinal Tract Cancers.

Cancer Epidemiol Biomarkers Prev 2019 07 26;28(7):1246-1251. Epub 2019 Apr 26.

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

Background: No consensus guideline has been established for microsatellite instability testing in upper gastrointestinal tract cancers. This study aims to determine whether targeted cancer next-generation sequencing can accurately detect microsatellite instability in upper gastrointestinal tract cancers and screen for patients with Lynch syndrome.

Methods: In a cohort of 645 upper gastrointestinal tract cancers, targeted next-generation sequencing assessed microsatellite instability by identifying characteristic insertion and deletion mutations. Sequencing classification was compared with mismatch repair protein IHC. Cancers with microsatellite instability by sequencing were analyzed using a testing protocol to identify patients with Lynch syndrome.

Results: Sequencing identified microsatellite instability in 3.6% (23/645) of upper gastrointestinal tract cancers, including 28% (8/29) of small intestinal and 9% (9/97) of gastric carcinomas. In 20 cancers classified as having microsatellite instability, 19 demonstrated loss of expression of MLH1, PMS2, MSH2, or MSH6, and one cancer was indeterminate by IHC. In contrast, 52 control cancers demonstrated retained expression of all mismatch repair proteins. Using targeted sequencing as the initial screening test, 1.1% (7/645) of patients were identified to have pathogenic germline variants confirming a diagnosis of Lynch syndrome.

Conclusions: Targeted cancer next-generation sequencing is an accurate first-line test to detect microsatellite instability in upper gastrointestinal tract cancers.

Impact: This study provides a proof of concept for the use of targeted next-generation sequencing to detect microsatellite instability and screen for Lynch syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-18-1250DOI Listing
July 2019

Performance Comparison of Different Analytic Methods in Proficiency Testing for Mutations in the , , and Genes: A Study of the College of American Pathologists Molecular Oncology Committee.

Arch Pathol Lab Med 2019 10 10;143(10):1203-1211. Epub 2019 Apr 10.

From the Office of the Director, The Joint Pathology Center, Silver Spring, Maryland (Dr Moncur); the Department of Pathology, St Joseph Mercy Hospital, Ypsilanti, Michigan (Dr Bartley); the Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha (Dr Bridge); the Department of Pathology, University Health Network, University of Toronto, Toronto, Ontario, Canada (Dr Kamel-Reid); the Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston (Dr Lazar); the Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts (Drs Lindeman and Kim); Biostatistics (Mr Long) and Proficiency Testing (Ms Vasalos), College of American Pathologists, Northfield, Illinois; the Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill (Dr Merker); the Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York (Dr Rai); the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut (Dr Rimm); and the Department of Pathology and Laboratory Medicine, Strong Memorial Hospital, University of Rochester Medical Center and Pathology and Laboratory Medicine, Molecular Diagnostic Laboratory, Rochester, New York (Dr Rothberg). Dr Moncur is employed by the US Army. The identification of specific products or scientific instrumentation is considered an integral part of the scientific endeavor and does not constitute endorsement or implied endorsement on the part of the authors, the Department of Defense, or any component agency. The views expressed in this article are those of the authors and do not reflect the official policy of the Department of Army/Navy/Air Force, Department of Defense, or US government. The other authors have no relevant financial interest in the products or companies described in this article.

Context.—: The performance of laboratory testing has recently come under increased scrutiny as part of important and ongoing debates on regulation and reimbursement. To address this critical issue, this study compares the performance of assay methods, using either commercial kits or assays designed and implemented by single laboratories ("home brews"), including next-generation sequencing methods, on proficiency testing provided by the College of American Pathologists Molecular Oncology Committee.

Objective.—: To compare the performance of different assay methods on College of American Pathologists proficiency testing for variant analysis of 3 common oncology analytes: , , and .

Design.—: There were 6897 total responses across 35 different proficiency testing samples interrogating 13 different variants as well as wild-type sequences for , , and . Performance was analyzed by test method, kit manufacturer, variants tested, and preanalytic and postanalytic practices.

Results.—: Of 26 reported commercial kits, 23 achieved greater than 95% accuracy. Laboratory-developed tests with no kit specified demonstrated 96.8% or greater accuracy across all 3 analytes (1123 [96.8%] acceptable of 1160 total responses for ; 848 [97.5%] acceptable of 870 total responses for ; 942 [97.0%] acceptable of 971 total responses for ). Next-generation sequencing platforms (summed across all analytes and 2 platforms) demonstrated 99.4% accuracy for these analytes (165 [99.4%] acceptable of 166 total next-generation sequencing responses). Slight differences in performance were noted among select commercial assays, dependent upon the particular design and specificity of the assay. Wide differences were noted in the lower limits of neoplastic cellularity laboratories accepted for testing.

Conclusions.—: These data demonstrate the high degree of accuracy and comparable performance across all laboratories, regardless of methodology. However, care must be taken in understanding the diagnostic specificity and reported analytic sensitivity of individual methods.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5858/arpa.2018-0396-CPDOI Listing
October 2019

-mutated clear cell cervical cancer associated with in-utero diethylstilbestrol exposure.

Gynecol Oncol Rep 2019 May 29;28:15-17. Epub 2019 Jan 29.

Division of Gynecologic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

We report an extraordinary case of a woman, exposed to diethylstilbestrol in utero, who developed clear cell adenocarcinoma of the cervix with a concurrent polymerase-Ɛ () somatic mutation. The tumor exhibited the classic phenotypic characteristics of -mutated tumors originating from other organs (e.g. the uterus or the colon) including increased tumor infiltrating lymphocytes and high PD-L1 expression and has remained in remission since completion of primary therapy for >4 years. This case highlights the importance of next generation sequencing in unraveling the biology of rare tumors and supports that the presence of a mutation and the associated ultramutated state confers a unique phenotype of higher immunogenicity and possibly improved prognosis in a tissue-agnostic manner, i.e. regardless of the type of cancer where the mutation is present.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.gore.2019.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357694PMC
May 2019

Utility of a Simple and Robust Flow Cytometry Assay for Rapid Clonality Testing in Mature Peripheral T-Cell Lymphomas.

Am J Clin Pathol 2019 04;151(5):494-503

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

Objectives: Flow cytometry immunophenotyping is limited by poor resolution of T-cell clones. A newly described antibody was recently used to distinguish normal peripheral blood T cells from malignant T-cell clones. Here, we evaluate this antibody as a new diagnostic tool for detecting T-cell clonality in mature peripheral T-cell lymphomas.

Methods: Immunostaining for the T-cell receptor β chain constant region 1 (TRBC1) along with routine T-cell markers was performed on 51 peripheral blood and two bone marrow samples submitted to the flow cytometry laboratory for suspected T-cell malignancy.

Results: TRBC immunophenotyping identified malignant T-cell clones with 97% sensitivity and 91% specificity. Findings correlated with molecular T-cell clonality testing. In cases with equivocal molecular results, TRBC1 immunophenotyping provided additional diagnostic information.

Conclusions: TRBC1 flow cytometric immunophenotyping is a robust and inexpensive method for identifying T-cell clonality that could easily be incorporated into routine flow cytometric practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ajcp/aqy173DOI Listing
April 2019

Clinicopathologic and genetic characteristics of interval colorectal carcinomas favor origin from missed or incompletely excised precursors.

Mod Pathol 2019 05 19;32(5):666-674. Epub 2018 Nov 19.

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

Interval colorectal cancers may arise from missed or incompletely excised precursors or from a unique rapid progression pathway. We compared the clinicopathologic and molecular profiles of interval and matched non-interval colorectal cancer to determine whether interval colorectal cancers harbor any unique genetic characteristics. Fifty one of 982 colorectal cancer (5.2%) were categorized as interval colorectal cancer, defined as colorectal cancer detected in a diagnostic examination prior to the next recommended colonoscopy and at least 1 year after the last colonoscopy. Clinicopathologic characteristics of interval colorectal cancer were compared to non-interval colorectal cancer matched 1:1 on age, gender, and tumor location. Molecular profile of a subset of interval colorectal cancer (n = 20) and matched (1:2) non-interval colorectal cancer (n = 40) were evaluated using next generation sequencing. Interval colorectal cancer were more likely to occur in the right colon (55% vs. 35%; p = 0.02) and in patients > 70 years of age (55% vs. 34%; p = 0.002). Clinicopathologic features and aberrant DNA mismatch repair protein expression were not significantly different between interval and matched non-interval colorectal cancer. The frequency and spectrum of genetic alterations was also similar in interval and matched non-interval colorectal cancer. Similar findings were seen when analysis was restricted to interval colorectal cancer diagnosed <5 years after last colonoscopy (n = 42). Interval and non-interval colorectal cancers share similar clinicopathologic and genetic profiles when matched for tumor location. Interval colorectal cancers and are more likely to develop from missed or incompletely excised precursors rather than a unique rapid progression pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41379-018-0176-6DOI Listing
May 2019

Proficiency Testing of Standardized Samples Shows Very High Interlaboratory Agreement for Clinical Next-Generation Sequencing-Based Oncology Assays.

Arch Pathol Lab Med 2019 04 30;143(4):463-471. Epub 2018 Oct 30.

From the Departments of Pathology and Laboratory Medicine & Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill (Dr Merker); the Departments of Pathology (Drs Devereaux and Montgomery, and Mr Smail) and Genetics (Dr Montgomery), Stanford University School of Medicine, and the Biomedical Informatics Program (Mr Smail), Stanford University, Stanford, California; the Department of Pathology, Massachusetts General Hospital (Dr Iafrate), and the Department of Pathology, Brigham and Women's Hospital (Drs Kim and Lindeman), Harvard University, Boston; the Departments of Pathology and Clinical Laboratory Genetics, The University Health Network and the University of Toronto, Toronto, Ontario, Canada (Dr Kamel-Reid); the Department of Pathology, Walter Reed National Military Medical Center, Bethesda, Maryland (Dr Moncur); PierianDx, St Louis, Missouri (Dr Nagarajan); the Department of Global Medical Affairs, Roche, Tucson, Arizona (Dr Portier); the Departments of Hematopathology (Dr Routbort) and Pathology, Genomic Medicine, and Translational Molecular Pathology (Dr Lazar), he University of Texas MD Anderson Cancer Center, Houston (Dr Routbort); the Department of Pathology, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia (Dr Surrey); and Proficiency Testing, College of American Pathologists, Northfield, Illinois (Ms Vasalos).

Context.—: Next-generation sequencing-based assays are being increasingly used in the clinical setting for the detection of somatic variants in solid tumors, but limited data are available regarding the interlaboratory performance of these assays.

Objective.—: To examine proficiency testing data from the initial College of American Pathologists (CAP) Next-Generation Sequencing Solid Tumor survey to report on laboratory performance.

Design.—: CAP proficiency testing results from 111 laboratories were analyzed for accuracy and associated assay performance characteristics.

Results.—: The overall accuracy observed for all variants was 98.3%. Rare false-negative results could not be attributed to sequencing platform, selection method, or other assay characteristics. The median and average of the variant allele fractions reported by the laboratories were within 10% of those orthogonally determined by digital polymerase chain reaction for each variant. The median coverage reported at the variant sites ranged from 1922 to 3297.

Conclusions.—: Laboratories demonstrated an overall accuracy of greater than 98% with high specificity when examining 10 clinically relevant somatic single-nucleotide variants with a variant allele fraction of 15% or greater. These initial data suggest excellent performance, but further ongoing studies are needed to evaluate the performance of lower variant allele fractions and additional variant types.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5858/arpa.2018-0336-CPDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6910717PMC
April 2019

MGMT promoter methylation status testing to guide therapy for glioblastoma: refining the approach based on emerging evidence and current challenges.

Neuro Oncol 2019 02;21(2):167-178

Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada.

Glioblastoma (GBM) is the most common primary malignant brain tumor, with a universally poor prognosis. The emergence of molecular biomarkers has had a significant impact on histological typing and diagnosis, as well as predicting patient survival and response to treatment. The methylation status of the O6-methylguanine-DNA methyl-transferase (MGMT) gene promoter is one such molecular biomarker. Despite the strong evidence supporting the role of MGMT methylation status in prognostication, its routine implementation in clinical practice has been challenging. The methods and optimal cutoff definitions for MGMT status determination remain controversial. Variation in detection methods between laboratories presents a major challenge for consensus. Moreover, consideration of other clinical and genetic/epigenetic factors must also be incorporated into treatment decision making. In this review, we distill the available evidence to summarize our position on the optimal use of available assays, and propose strategies for resolving cases with equivocal methylation status and a framework for incorporating this important assay into research and clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/noy132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374759PMC
February 2019

Validation of a targeted next-generation sequencing approach to detect mismatch repair deficiency in colorectal adenocarcinoma.

Mod Pathol 2018 12 28;31(12):1882-1890. Epub 2018 Jun 28.

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

Mismatch repair protein deficiency is a hallmark of cancers associated with Lynch syndrome and is a biomarker for response to immunotherapy. With the increasing adoption of cancer next-generation sequencing, there has been a movement to develop screening approaches that take advantage of the unique mutational signatures of mismatch repair-deficient tumors. Here, we develop a sequencing-based metric that distinguishes mismatch repair-deficient from mismatch repair-proficient colorectal adenocarcinomas with comparison to immunohistochemical staining. We find that a single criterion of three or more single base pair insertion or deletion mutations per megabase sequenced, occurring in mononucleotide repeat regions of four or more nucleotides, is sufficient to detect mismatch repair deficiency with 96% sensitivity and 100% specificity in a training set of 241 cancers and 96% sensitivity and 99% specificity in a validation set of 436 additional cancers. Using data from the same cohort, we also find that sequencing information from only three genes-ARID1A, KMT2D, and SOX9-is sufficient to detect mismatch repair-deficient colorectal adenocarcinomas with 76% sensitivity and 98% specificity in the validation set. These findings support the notion that targeted next-generation sequencing already being performed for clinical or research purposes can also be used to accurately detect mismatch repair deficiency in colorectal adenocarcinomas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41379-018-0091-xDOI Listing
December 2018

Durable response in a woman with recurrent low-grade endometrioid endometrial cancer and a germline BRCA2 mutation treated with a PARP inhibitor.

Gynecol Oncol 2018 08 22;150(2):219-226. Epub 2018 Jun 22.

Division of Gynecologic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Electronic address:

A 42-year-old woman with a germline BRCA2 mutation and recurrent low-grade endometrioid endometrial adenocarcinoma experienced clinical and radiographic response to the poly (ADP ribose) polymerase (PARP) inhibitor, olaparib. Molecular and treatment factors are discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ygyno.2018.05.028DOI Listing
August 2018

Phase I Trial of a Tablet Formulation of Pilaralisib, a Pan-Class I PI3K Inhibitor, in Patients with Advanced Solid Tumors.

Oncologist 2018 04 28;23(4):401-e38. Epub 2018 Mar 28.

Early Drug Development Center, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

Lessons Learned: A phase I study of the pan-class I phosphoinositide 3-kinase inhibitor pilaralisib (in capsule formulation) in advanced solid tumors established the maximum tolerated dose as 600 mg once daily.The current study investigated pilaralisib in tablet formulation.Pilaralisib tablets were associated with a favorable safety profile and preliminary antitumor activity.Based on pharmacokinetic data, the recommended phase II dose of pilaralisib tablets was established as 400 mg once daily.

Background: A phase I trial of pilaralisib, an oral pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, established the maximum tolerated dose (MTD) of the capsule formulation in patients with advanced solid tumors as 600 mg once daily. This phase I study investigated pilaralisib in tablet formulation.

Materials And Methods: Patients with advanced solid tumors received pilaralisib tablets (100-600 mg once daily). Primary endpoints were MTD and safety; secondary and exploratory endpoints included pharmacokinetics (PK), pharmacodynamics, and efficacy.

Results: Twenty-two patients were enrolled. No dose-limiting toxicities (DLTs) were reported. The most common treatment-related adverse events were diarrhea (40.9%), fatigue (40.9%), decreased appetite (22.7%), and hyperglycemia (22.7%). Pilaralisib plasma exposure did not appear to increase dose-proportionally. Steady-state exposure was higher with pilaralisib tablet formulation at 400 mg than with pilaralisib capsule formulation at 400 or 600 mg (mean area under the curve [AUC] 2,820,000 ng × h/mL vs. 2,653,000 and 1,930,000 ng × h/mL, respectively). Of 18 evaluable patients, 2 (11.1%) had a partial response (PR).

Conclusion: Pilaralisib tablets were associated with a favorable safety profile and preliminary antitumor activity. MTD was not determined. The recommended phase II dose for pilaralisib tablets, based on PK data, was 400 mg once daily.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1634/theoncologist.2017-0691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896717PMC
April 2018

Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.

J Mol Diagn 2018 03 23;20(2):129-159. Epub 2018 Jan 23.

Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan.

Context: In 2013, an evidence-based guideline was published by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology to set standards for the molecular analysis of lung cancers to guide treatment decisions with targeted inhibitors. New evidence has prompted an evaluation of additional laboratory technologies, targetable genes, patient populations, and tumor types for testing.

Objective: To systematically review and update the 2013 guideline to affirm its validity; to assess the evidence of new genetic discoveries, technologies, and therapies; and to issue an evidence-based update.

Design: The College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology convened an expert panel to develop an evidence-based guideline to help define the key questions and literature search terms, review abstracts and full articles, and draft recommendations.

Results: Eighteen new recommendations were drafted. The panel also updated 3 recommendations from the 2013 guideline.

Conclusions: The 2013 guideline was largely reaffirmed with updated recommendations to allow testing of cytology samples, require improved assay sensitivity, and recommend against the use of immunohistochemistry for EGFR testing. Key new recommendations include ROS1 testing for all adenocarcinoma patients; the inclusion of additional genes (ERBB2, MET, BRAF, KRAS, and RET) for laboratories that perform next-generation sequencing panels; immunohistochemistry as an alternative to fluorescence in situ hybridization for ALK and/or ROS1 testing; use of 5% sensitivity assays for EGFR T790M mutations in patients with secondary resistance to EGFR inhibitors; and the use of cell-free DNA to "rule in" targetable mutations when tissue is limited or hard to obtain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jmoldx.2017.11.004DOI Listing
March 2018

Molecular Testing of Nodules with a Suspicious or Malignant Cytologic Diagnosis in the Setting of Non-Invasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP).

Endocr Pathol 2018 Mar;29(1):68-74

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

Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is an indolent thyroid tumor characterized by frequent RAS mutations and an absence of the BRAF V600E mutation commonly seen in classical papillary thyroid carcinoma (cPTC). The ability to differentiate potential NIFTP/follicular variant of papillary thyroid carcinoma (FVPTC) from cPTC at the time of fine-needle aspiration (FNA) can facilitate conservative management of NIFTP. The aim of the current study was to investigate how molecular testing may add to cytologic assessment in the pre-operative differentiation of potential NIFTP/FVPTC and cPTC. We had previously evaluated cytologists' ability to prospectively distinguish potential NIFTP/FVPTC from cPTC in a cohort of 56 consecutive FNAs diagnosed as malignant or suspicious for malignancy. We utilized this cohort to perform molecular analysis. Detected molecular abnormalities were stratified into two groups: (1) those supporting malignancy and (2) those supporting a diagnosis of potential NIFTP/FVPTC. The cytologists' characterization of cases and the detected molecular alterations were correlated with the final histologic diagnoses. Molecular testing was performed in 52 (93%) of the 56 cases. For the 37 cases cytologists favored to be cPTC, 31 (84%) had a molecular result that supported malignancy (28 BRAF V600E mutations, 2 NTRK1 fusions, 1 AGK-BRAF fusion). For the 8 cases that were favored to be NIFTP/FVPTC by cytologists, 7 (88%) had a molecular result that supported conservative management (1 NRAS mutation, 6 wild-type result). Seven cases were designated as cytomorphologically indeterminate for NIFTP/FVPTC or cPTC, of which 6 (86%) had a molecular result that would have aided in the pre-operative assessment of potential NIFTP/FVPTC or cPTC/malignancy. These included 3 BRAF V600E mutations in nodules that were cPTC on resection, an HRAS mutation, and a wild-type result in the 2 nodules that were NIFTP, and a TERT promoter mutation along with an NRAS mutation in a poorly differentiated thyroid carcinoma. For nodules with an FNA diagnosis of suspicious for malignancy or malignant, cytologists can differentiate most cases of potential NIFTP/FVPTC from cPTC. However, molecular testing may be valuable for a subset of cases, especially those that are indeterminate for potential NIFTP/FVPTC versus cPTC based on cytologic features alone.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12022-018-9515-xDOI Listing
March 2018

Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.

J Thorac Oncol 2018 03 25;13(3):323-358. Epub 2018 Jan 25.

Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan.

Context: In 2013, an evidence-based guideline was published by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology to set standards for the molecular analysis of lung cancers to guide treatment decisions with targeted inhibitors. New evidence has prompted an evaluation of additional laboratory technologies, targetable genes, patient populations, and tumor types for testing.

Objective: To systematically review and update the 2013 guideline to affirm its validity; to assess the evidence of new genetic discoveries, technologies, and therapies; and to issue an evidence-based update.

Design: The College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology convened an expert panel to develop an evidence-based guideline to help define the key questions and literature search terms, review abstracts and full articles, and draft recommendations.

Results: Eighteen new recommendations were drafted. The panel also updated 3 recommendations from the 2013 guideline.

Conclusions: The 2013 guideline was largely reaffirmed with updated recommendations to allow testing of cytology samples, require improved assay sensitivity, and recommend against the use of immunohistochemistry for EGFR testing. Key new recommendations include ROS1 testing for all adenocarcinoma patients; the inclusion of additional genes (ERBB2, MET, BRAF, KRAS, and RET) for laboratories that perform next-generation sequencing panels; immunohistochemistry as an alternative to fluorescence in situ hybridization for ALK and/or ROS1 testing; use of 5% sensitivity assays for EGFR T790M mutations in patients with secondary resistance to EGFR inhibitors; and the use of cell-free DNA to "rule in" targetable mutations when tissue is limited or hard to obtain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2017.12.001DOI Listing
March 2018

Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.

Arch Pathol Lab Med 2018 Mar 22;142(3):321-346. Epub 2018 Jan 22.

From the Departments of Pathology (Drs Lindeman and Sholl) and Medicine (Dr Kwiatkowski), Brigham and Women's Hospital, Boston, Massachusetts; the Cancer Center (Dr Bernicker) and the Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas (Dr Cagle); the Department of Pathology, University of Colorado School of Medicine, Denver (Dr Aisner); the Diagnostic and Molecular Pathology Laboratory (Dr Arcila) and the Molecular Diagnostics Service (Dr Ladanyi), Memorial Sloan Kettering Cancer Center, New York, New York; the Department of Pathology & Medicine, Pulmonary, Critical Care and Sleep Medicine, New York, New York (Dr Beasley); the Pathology and Laboratory Quality Center, College of American Pathologists, Northfield, Illinois (Mss Colasacco and Ventura); the Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr Dacic); the Department of Medicine and Pathology, University of Colorado, Denver (Dr Hirsch); the Department of Pathology, University of Aberdeen, Aberdeen, Scotland (Dr Kerr); the Department of Molecular Pathology, Roswell Park Cancer Institute, Buffalo, New York (Dr Nowak); the Clinical and Scientific Affairs Division, Association for Molecular Pathology, Bethesda, Maryland (Dr Temple-Smolkin); the Molecular Therapeutics and Biomarkers Laboratory, Peter Maccallum Cancer Center, Melbourne, Australia (Dr Solomon); the Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands (Dr Thunnissen); the Department of Laboratory Medicine and Pathobiology, Princess Margaret Cancer Center, Toronto, Ontario, Canada (Dr Tsao); Scientific Affairs, International Association for the Study of Lung Cancer, Aurora, Colorado (Dr Wynes); and the Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan (Dr Yatabe). Dr Souter is in private practice in Wellanport, Ontario, Canada.

Context: - In 2013, an evidence-based guideline was published by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology to set standards for the molecular analysis of lung cancers to guide treatment decisions with targeted inhibitors. New evidence has prompted an evaluation of additional laboratory technologies, targetable genes, patient populations, and tumor types for testing.

Objective: - To systematically review and update the 2013 guideline to affirm its validity; to assess the evidence of new genetic discoveries, technologies, and therapies; and to issue an evidence-based update.

Design: - The College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology convened an expert panel to develop an evidence-based guideline to help define the key questions and literature search terms, review abstracts and full articles, and draft recommendations.

Results: - Eighteen new recommendations were drafted. The panel also updated 3 recommendations from the 2013 guideline.

Conclusions: - The 2013 guideline was largely reaffirmed with updated recommendations to allow testing of cytology samples, require improved assay sensitivity, and recommend against the use of immunohistochemistry for EGFR testing. Key new recommendations include ROS1 testing for all adenocarcinoma patients; the inclusion of additional genes ( ERBB2, MET, BRAF, KRAS, and RET) for laboratories that perform next-generation sequencing panels; immunohistochemistry as an alternative to fluorescence in situ hybridization for ALK and/or ROS1 testing; use of 5% sensitivity assays for EGFR T790M mutations in patients with secondary resistance to EGFR inhibitors; and the use of cell-free DNA to "rule in" targetable mutations when tissue is limited or hard to obtain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5858/arpa.2017-0388-CPDOI Listing
March 2018