151 results on '"Douglas I Lin"'
Search Results
2. Automated clear cell renal carcinoma grade classification with prognostic significance.
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Katherine Tian, Christopher A Rubadue, Douglas I Lin, Mitko Veta, Michael E Pyle, Humayun Irshad, and Yujing J Heng
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Medicine ,Science - Abstract
We developed an automated 2-tiered Fuhrman's grading system for clear cell renal cell carcinoma (ccRCC). Whole slide images (WSI) and clinical data were retrieved for 395 The Cancer Genome Atlas (TCGA) ccRCC cases. Pathologist 1 reviewed and selected regions of interests (ROIs). Nuclear segmentation was performed. Quantitative morphological, intensity, and texture features (n = 72) were extracted. Features associated with grade were identified by constructing a Lasso model using data from cases with concordant 2-tiered Fuhrman's grades between TCGA and Pathologist 1 (training set n = 235; held-out test set n = 42). Discordant cases (n = 118) were additionally reviewed by Pathologist 2. Cox proportional hazard model evaluated the prognostic efficacy of the predicted grades in an extended test set which was created by combining the test set and discordant cases (n = 160). The Lasso model consisted of 26 features and predicted grade with 84.6% sensitivity and 81.3% specificity in the test set. In the extended test set, predicted grade was significantly associated with overall survival after adjusting for age and gender (Hazard Ratio 2.05; 95% CI 1.21-3.47); manual grades were not prognostic. Future work can adapt our computational system to predict WHO/ISUP grades, and validating this system on other ccRCC cohorts.
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- 2019
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3. Pan-tumor validation of a NGS fraction-based MSI analysis as a predictor of response to Pembrolizumab
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Douglas I. Lin, Julia C. F. Quintanilha, Natalie Danziger, Lixin Lang, Diane Levitan, Cynthia Hayne, Matthew C. Hiemenz, David L. Smith, Lee A. Albacker, Jeffrey Leibowitz, Douglas A. Mata, Brennan Decker, Sotirios Lakis, Nimesh R. Patel, Ryon P. Graf, Julia A. Elvin, Jeffrey S. Ross, Varun Pattani, Richard S. P. Huang, and Amy K. Wehn
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Microsatellite instability high (MSI-H) and mismatch repair deficient (dMMR) tumor status have been demonstrated to predict patient response to immunotherapies. We developed and validated a next-generation sequencing (NGS)-based companion diagnostic (CDx) to detect MSI-H solid tumors via a comprehensive genomic profiling (CGP) assay, FoundationOne®CDx (F1CDx). To determine MSI status, F1CDx calculates the fraction of unstable microsatellite loci across >2000 loci using a fraction-based (FB) analysis. Across solid tumor types, F1CDx demonstrated a high analytical concordance with both PCR (n = 264) and IHC (n = 279) with an overall percent agreement (OPA) of 97.7% and 97.8%, respectively. As part of a retrospective bridging clinical study from KEYNOTE-158 Cohort K and KEYNOTE-164, patients with MSI-H tumors as determined by F1CDx demonstrated an objective response rate (ORR) of 43.0% to pembrolizumab. In real-world cancer patients from a deidentified clinicogenomic database, F1CDx was at least equivalent in assessing clinical outcome following immunotherapy compared with MMR IHC. Demonstrated analytical and clinical performance of F1CDx led to the pan-tumor FDA approval in 2022 of F1CDx to identify MSI-H solid tumor patients for treatment with pembrolizumab. F1CDx is an accurate, reliable, and FDA-approved method for the identification of MSI-H tumors for treatment with pembrolizumab.
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- 2024
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4. Oncogenic c-terminal cyclin D1 (CCND1) mutations are enriched in endometrioid endometrial adenocarcinomas.
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Jia Xu and Douglas I Lin
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Medicine ,Science - Abstract
Cyclin D1 (CCND1) is a core cell cycle regulator and is frequently overexpressed in human cancers, often via amplification, translocation or post-transcription regulation. Accumulating evidence suggests that mutations of the CCND1 gene that result in nuclear retention and constitutive activation of CDK4/6 kinases are oncogenic drivers in cancer. However, the spectrum of CCND1 mutations across human cancers has not been systematically investigated. Here, we retrospectively mined whole-exome sequencing data from 124 published studies representing up to 29,432 cases from diverse cancer types and sites of origin, including carcinoma, melanoma, sarcoma and lymphoma/leukemia, via online tools to determine the frequency and spectrum of CCND1 mutations in human cancers and their associated clinico-pathological characteristics. Overall, in contrast to gene amplification, which occurred at a frequency of 4.8% (1,419 of 28,769 cases), CCND1 mutations were of very low frequency (0.5%, 151 of 29,432 cases) across all cancers, but were predominantly enriched in uterine endometrioid-type adenocarcinoma (6.5%, 30 of 458 cases) in both primary tumors and in advanced, metastatic endometrial cancer samples. CCND1 mutations in endometrial endometrioid adenocarcinoma occurred most commonly in the c-terminus of cyclin D1, as putative driver mutations, in a region thought to result in oncogenic activation of cyclin D1 via inhibition of Thr-286 phosphorylation and nuclear export, thereby resulting in nuclear retention and protein overexpression. Our findings implicate oncogenic c-terminal mutations of CCND1 in the pathogenesis of a subset of human cancers and provide a key resource to guide future preclinical and clinical investigations.
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- 2018
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5. Precision needle-punch tumor enrichment from paraffin blocks improves the detection of clinically actionable genomic alterations and biomarkers
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Douglas I. Lin, Richard S. P. Huang, Ioannis Ladas, Rachel B. Keller, Nimesh R. Patel, Sotirios Lakis, Brennan Decker, Tyler Janovitz, Douglas A. Mata, Jeffrey S. Ross, Jo-Anne Vergilio, Julia A. Elvin, Roy S. Herbst, Philip C. Mack, and Jonathan K. Killian
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tumor enrichment ,tumor purity ,biomarker ,molecular diagnosis ,FoundationOne®CDx ,tumor microdissection ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
BackgroundWhile many molecular assays can detect mutations at low tumor purity and variant allele frequencies, complex biomarkers such as tumor mutational burden (TMB), microsatellite instability (MSI), and genomic loss of heterozygosity (gLOH) require higher tumor purity for accurate measurement. Scalable, quality-controlled, tissue-conserving methods to increase tumor nuclei percentage (TN%) from tumor specimens are needed for complex biomarkers and hence necessary to maximize patient matching to approved therapies or clinical trial enrollment. We evaluated the clinical utility and performance of precision needle-punch enrichment (NPE) compared with traditional razor blade macroenrichment of tumor specimens on molecular testing success.MethodsPathologist-directed NPE was performed manually on formalin-fixed, paraffin embedded (FFPE) blocks. Quality control of target capture region and quantity of residual tumor in each tissue block was determined via a post-enrichment histologic slide recut. Resultant tumor purity and biomarker status were determined by the computational analysis pipeline component of the FDA-approved next-generation sequencing (NGS) assay, FoundationOne®CDx. Following NPE implementation for real-world clinical samples, assay performance and biomarker (MSI, TMB, gLOH) detection were analyzed.ResultsIn real-world clinical samples, enrichment rate via NPE was increased to ~50% over a 2.5-year period, exceeding the prior use of razor blade macro-enrichment (
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- 2024
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6. Primary Adult Retroperitoneal Sarcoma: A Comprehensive Genomic Profiling Study
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Andrea Necchi, Giuseppe Basile, Filippo Pederzoli, Marco Bandini, Petros Grivas, Gennady Bratslavsky, Philippe E. Spiess, J. Keith Killian, Douglas I. Lin, Erik Williams, Shakti Ramkissoon, Eric A. Severson, Brian M. Alexander, Jeffrey Venstrom, Prasanth Reddy, Kimberley McGregor, Julia A. Elvin, Alexa B. Schrock, Dean V. Pavlick, Dexter X. Jin, Sally E. Trabucco, Natalie Danzinger, and Jeffrey S. Ross
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retroperitoneal sarcoma ,comprehensive genomic profiling ,targeted therapy ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
BackgroundAdult primary retroperitoneal sarcomas (RPSs) are a group of heterogeneous tumors with different histological subtypes. Comprehensive genomic profiling (CGP) analyses have recently provided significant insights into the biology of sarcomas by identifying genomic alterations (GAs) which could benefit from targeted therapies. MethodsRPS were evaluated by CGP using next-generation sequencing of up to 406 cancer-related genes. Tumor mutational burden (TMB) was determined on 0.83 to 1.14 mut/Mb of sequenced DNA. Finally, PD-L1 expression was determined. ResultsOverall, 296 cases of primary RPS were analyzed. Liposarcoma (LPS) subtype had more GA/tumor than leiomyosarcoma (LMS) subtypes, with follicular dendritic cell sarcomas harboring the highest and synovial sarcomas the lowest. TP53 and Rb1 alterations were the highest in LMS, and CDK4/6 and MDM2 in LPS. However, both the TMB and targetable GA rates were low across subtypes. PD-L1 immunostaining was low positive in 21% and high positive in 5% of patients, respectively. ConclusionsCGP analysis revealed that potentially actionable genomic targets were rare in our cohort of RPS. Moreover, RPSs seem less likely to respond to immune checkpoint inhibitors based on putative biomarkers status. Nevertheless, genomic stratification according to histological subtypes led to description of GAs that can inform future clinical trials design.
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- 2021
- Full Text
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7. Variable Genomic Landscapes of Advanced Melanomas with Heavy Pigmentation
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Richard S P Huang, Julie Y Tse, Lukas Harries, Ryon P Graf, Douglas I Lin, Karthikeyan Murugesan, Matthew C Hiemenz, Vamsi Parimi, Tyler Janovitz, Brennan Decker, Eric Severson, Mia A Levy, Shakti H Ramkissoon, Julia A Elvin, Jeffrey S Ross, and Erik A Williams
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Cancer Research ,Oncology ,Pigmentation ,Mutation ,Biomarkers, Tumor ,Humans ,Genomics ,Melanoma ,B7-H1 Antigen - Abstract
Background In the current study, we examined the real-world prevalence of highly pigmented advanced melanomas (HPMel) and the clinicopathologic, genomic, and ICPI biomarker signatures of this class of tumors. Materials and Methods Our case archive of clinical melanoma samples for which the ordering physician requested testing for both PD-L1 immunohistochemistry (IHC) and comprehensive genomic profiling (CGP) was screened for HPMel cases, as well as for non-pigmented or lightly pigmented advanced melanoma cases (LPMel). Results Of the 1268 consecutive melanoma biopsies in our archive that had been submitted for PD-L1 IHC, 13.0% (165/1268) were HPMel and 87.0% (1103/1268) were LPMel. In the HPMel cohort, we saw a significantly lower tumor mutational burden (TMB, median 8.8 mutations/Mb) than in the LPMel group (11.4 mut/Mb), although there was substantial overlap. In examining characteristic secondary genomic alterations (GA), we found that the frequencies of GA in TERTp, CDKN2A, TP53, and PTEN were significantly lower in the HPMel cases than in LPMel. A higher rate of GA in CTNNB1, APC, PRKAR1A, and KIT was identified in the HPMel cohort compared with LPMel. Conclusions In this study, we quantified the failure rates of melanoma samples for PD-L1 testing due to high melanin pigmentation and showed that CGP can be used in these patients to identify biomarkers that can guide treatment decisions for HPMel patients. Using this practical clinical definition for tumor pigmentation, our results indicate that HPMel are frequent at 13% of melanoma samples, and in general appear molecularly less developed, with a lower TMB and less frequent secondary GA of melanoma progression.
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- 2022
8. Integrative analysis of a large real-world cohort of small cell lung cancer identifies distinct genetic subtypes and insights into histological transformation
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Smruthy Sivakumar, Jay A. Moore, Meagan Montesion, Radwa Sharaf, Douglas I. Lin, Caterina I. Colon, Zoe Fleischmann, Ericka M. Ebot, Justin Y. Newberg, Jennifer M. Mills, Priti S. Hegde, Quintin Pan, Afshin Dowlati, Garrett M. Frampton, Julien Sage, and Christine M. Lovly
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Oncology - Abstract
Small cell lung cancer (SCLC) is a recalcitrant neuroendocrine carcinoma with dismal survival outcomes. A major barrier in the field has been the relative paucity of human tumors studied. Here we provide an integrated analysis of 3,600 “real-world” SCLC cases. This large cohort allowed us to identify new recurrent alterations and genetic subtypes, including STK11-mutant tumors (1.7%) and TP53/RB1 wild-type tumors (5.5%), as well as rare cases that were human papillomavirus-positive. In our cohort, gene amplifications on 4q12 are associated with increased overall survival while CCNE1 amplification is associated with decreased overall survival. We also identify more frequent alterations in the PTEN pathway in brain metastases. Finally, profiling cases of SCLC containing oncogenic drivers typically associated with NSCLC demonstrates that SCLC transformation may occur across multiple distinct molecular cohorts of NSCLC. These novel and unsuspected genetic features of SCLC may help personalize treatment approaches for this fatal form of cancer.
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- 2023
9. <scp>POU2AF3</scp> ‐rearranged sarcomas: A novel tumor defined by fusions of <scp>EWSR1</scp> or <scp>FUS</scp> to a gene formerly designated <scp>COLCA2</scp>
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Matthew C. Hiemenz, Jaspreet Kaur, Zheng Kuang, Richard S. P. Huang, Lukas Harries, Dana Metzger, Kelsie Schiavone, Sherri Z. Millis, Douglas I. Lin, Mirna Lechpammer, Brennan Decker, Douglas A. Mata, Abhinav Reddy, Matthew Parke, Eun Y. Lee, Xiaoyan Cui, O. Hans Iwenofu, Darya Buehler, Les Henderson, Erin M. Baldwin, Sosipatros A. Boikos, Shakti H. Ramkissoon, and Steven C. Smith
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Cancer Research ,Genetics - Published
- 2023
10. Predicting EGFR mutational status from pathology images using a real-world dataset
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James J. Pao, Mikayla Biggs, Daniel Duncan, Douglas I. Lin, Richard Davis, Richard S. P. Huang, Donna Ferguson, Tyler Janovitz, Matthew C. Hiemenz, Nathanial R. Eddy, Erik Lehnert, Moran N. Cabili, Garrett M. Frampton, Priti S. Hegde, and Lee A. Albacker
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Multidisciplinary - Abstract
Treatment of non-small cell lung cancer is increasingly biomarker driven with multiple genomic alterations, including those in the epidermal growth factor receptor (EGFR) gene, that benefit from targeted therapies. We developed a set of algorithms to assess EGFR status and morphology using a real-world advanced lung adenocarcinoma cohort of 2099 patients with hematoxylin and eosin (H&E) images exhibiting high morphological diversity and low tumor content relative to public datasets. The best performing EGFR algorithm was attention-based and achieved an area under the curve (AUC) of 0.870, a negative predictive value (NPV) of 0.954 and a positive predictive value (PPV) of 0.410 in a validation cohort reflecting the 15% prevalence of EGFR mutations in lung adenocarcinoma. The attention model outperformed a heuristic-based model focused exclusively on tumor regions, and we show that although the attention model also extracts signal primarily from tumor morphology, it extracts additional signal from non-tumor tissue regions. Further analysis of high-attention regions by pathologists showed associations of predicted EGFR negativity with solid growth patterns and higher peritumoral immune presence. This algorithm highlights the potential of deep learning tools to provide instantaneous rule-out screening for biomarker alterations and may help prioritize the use of scarce tissue for biomarker testing.
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- 2023
11. Genomic landscape of 891 RET fusions detected across diverse solid tumor types
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Vamsi Parimi, Khaled Tolba, Natalie Danziger, Zheng Kuang, Daokun Sun, Douglas I. Lin, Matthew C. Hiemenz, Alexa B. Schrock, Jeffrey S. Ross, Geoffrey R. Oxnard, and Richard S. P. Huang
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Cancer Research ,Oncology - Abstract
In this study, we report the clinicopathologic and genomic profiles of 891 patients with RET fusion driven advanced solid tumors. All patient samples were tested using a tissue-based DNA hybrid capture next generation sequencing (NGS) assay and a subset of the samples were liquid biopsies tested using a liquid-based hybrid capture NGS assay. RET fusions were found in 523 patients with NSCLC and in 368 patients with other solid tumors. The two tumor types with the highest number of RET fusion were lung adenocarcinoma and thyroid papillary carcinoma, and they had a prevalence rate 1.14% (455/39,922) and 9.09% (109/1199), respectively. A total of 61 novel fusions were discovered in this pan-tumor cohort. The concordance of RET fusion detection across tumor types among tissue and liquid-based NGS was 100% (8/8) in patients with greater than 1% composite tumor fraction (cTF). Herein, we present the clinicopathologic and genomic landscape of a large cohort of RET fusion positive tumors and we observed that liquid biopsy-based NGS is highly sensitive for RET fusions at cTF ≥1%.
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- 2023
12. Clinicopathological and genomic characterization of BCORL1-driven high-grade endometrial stromal sarcomas
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Brennan Decker, Richard S.P. Huang, Julia A. Elvin, Jeffrey S. Ross, Douglas I. Lin, Douglas A. Mata, Shakti H. Ramkissoon, Matthew Hiemenz, Mirna Lechpammer, and Natalie Danziger
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Leiomyosarcoma ,Pathology ,medicine.medical_specialty ,Stromal cell ,Endometrial stromal sarcoma ,Histology ,Biology ,medicine.disease ,Pathology and Forensic Medicine ,Gross examination ,medicine ,Atypia ,Nuclear atypia ,Myxoid Leiomyosarcoma - Abstract
BCORL1 is a transcriptional corepressor homologous to BCOR. We describe 12 BCORL1-altered uterine sarcomas with striking resemblance to BCOR-altered endometrial stromal sarcoma (BCOR-ESS), including 5 with BCORL1 rearrangements (JAZF1-BCORL1, EP300-BCORL1, or internal BCORL1 rearrangement), 5 with inactivating BCORL1 mutations (T513fs*22, P600fs*1, R945*, R1196*, or R1265fs*4) and 2 with homozygous BCORL1 deletion. The median patient age was 57.5 years (range 33-79). An association with aggressive clinical behavior was identified. Diagnoses assigned prior to genomic testing varied: 7 tumors were previously diagnosed as ESS, 2 as high-grade uterine sarcomas, 2 as myxoid uterine leiomyosarcomas, and 1 as a uterine spindle cell neoplasm consistent with leiomyosarcoma. Tumors harbored frequent gelatinous, mucomyxoid-like appearance by gross examination and unique histology with morphological overlap with BCOR-ESS. Key microscopic features included (1) a spindle cell appearance, most often with at least focal myxoid stroma, (2) variable amounts of hypocellular fibromyxoid spindle areas with lower grade atypia and/or (3) variable amounts of epithelioid areas with higher grade atypia. Specifically, spindle and epithelioid components were present in 100 and 75% of sarcomas, respectively; myxoid stroma was identified in 83%, collagen plaques or fibrosis in 50%, and high-grade nuclear atypia was present in 42%. Like BCOR-ESS, 50% of BCORL1-altered sarcomas exhibited CDK4 amplification or CDKN2A loss. In contrast, 33% harbored NF1 alterations, while 25% had other alterations in the NF2-mTOR pathway, expanding potential therapeutic targets. In conclusion, inactivating BCORL1 genomic alterations may define a distinct subset of high-grade endometrial stromal sarcomas with biological overlap with BCOR-ESS, both of which may mimic myxoid leiomyosarcomas.
- Published
- 2021
13. Circulating Cell-Free DNA Yield and Circulating-Tumor DNA Quantity from Liquid Biopsies of 12 139 Cancer Patients
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Eric Allan Severson, Ole Gjoerup, Jeffrey M. Venstrom, Lucas Dennis, Douglas I. Lin, Daniel Duncan, Lei Yang, Jonathan Keith Killian, Jeffrey S. Ross, Shakti H. Ramkissoon, Dean Pavlick, Geoff Oxnard, Richard S.P. Huang, Julia A. Elvin, Jinpeng Xiao, Bernard Fendler, Matthew Hiemenz, Cui Guo, Aparna Aiyer, and Dexter X. Jin
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medicine.medical_specialty ,business.industry ,Biochemistry (medical) ,Clinical Biochemistry ,Liquid Biopsy ,Urology ,Cancer ,medicine.disease ,Peripheral blood ,Circulating Cell-Free DNA ,Circulating Tumor DNA ,Patient age ,Circulating tumor DNA ,Neoplasms ,Mutation ,Biomarkers, Tumor ,Humans ,Medicine ,Tumor type ,Stage (cooking) ,Liquid biopsy ,business ,Cell-Free Nucleic Acids ,Retrospective Studies - Abstract
Background The amounts of circulating cell-free DNA (cfDNA) and circulating-tumor DNA (ctDNA) present in peripheral blood liquid biopsies can vary due to preanalytic/analytic variables. In this study, we examined the impact of patient age, sex, stage, and tumor type on cfDNA yield, ctDNA fraction, and estimated ctDNA quantity from a large cohort of clinical liquid biopsy samples. Methods We performed a retrospective analysis of 12 139 consecutive samples received for liquid biopsy (FoundationOne® Liquid) clinical testing. Results Significant differences in both cfDNA yield and estimated ctDNA quantity were observed based on the underlying tumor type that initiated the liquid biopsy analysis and the stage of the patient (P Conclusions In this study, we show that ctDNA quantity varied significantly based on patient age, sex, stage, and tumor type, which could offer an explanation as to why certain liquid biopsy specimens are more likely to fail sequencing or provide clinically meaningful results. In addition, this could affect future clinical decisions on the blood sample volumes required to allow successful liquid biopsy testing.
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- 2021
14. Prevalence of predictive biomarkers in a large cohort of molecularly defined adult-type ovarian granulosa cell tumors
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David M. Gershenson, Barrett C Lawson, Douglas I. Lin, and R. Tyler Hillman
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Adult ,Forkhead Box Protein L2 ,Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Pembrolizumab ,Article ,Loss of heterozygosity ,Interquartile range ,Internal medicine ,Biomarkers, Tumor ,Humans ,Medicine ,Immune Checkpoint Inhibitors ,Aged ,Granulosa Cell Tumor ,Retrospective Studies ,business.industry ,Obstetrics and Gynecology ,Microsatellite instability ,Immunotherapy ,Middle Aged ,medicine.disease ,Cross-Sectional Studies ,Mutation ,Immunohistochemistry ,Female ,Microsatellite Instability ,business ,Ovarian cancer ,Cohort study - Abstract
Objective The objective of this study was to determine the prevalence of predictive biomarkers associated with FDA-approved therapies in molecularly defined adult-type ovarian granulosa cell tumors (aGCTs). Methods We performed a retrospective cross-sectional cohort study of tumor profiles using the inclusion criteria of molecularly defined (FOXL2 c.C402G positive) aGCTs previously sequenced at Foundation Medicine, Inc. The dataset included coding variants for up to 406 genes, microsatellite instability, tumor mutational burden, and genomic loss of heterozygosity (gLOH). PD-L1 expression was determined using the tumor proportion score, as measured using the DAKO 22C3 immunohistochemistry assay. Results 423 tumor profiles met inclusion criteria. The median age at the time of sample submission was 57 years (interquartile range 48–65). The mean tumor mutational burden was 1.8 mutations per megabase (range 0–8.8). No tumors exhibited microsatellite instability, and none were gLOH-High (≥16%). Sixty-seven tumors had PD-L1 expression measurement, and 94% were negative. Potentially actionable variants including MTAP deletion (12/173, 5.8%) and activating PIK3CA mutations (23/423, 5.4%) were identified. TP53-mutated aGCT had a higher tumor mutational burden (mean 2.4 mut/Mb, 95% CI 1.7–3.0 mut/Mb vs mean 1.7 mut/Mb, 95% CI 1.5–1.9 mut/Mb; P = .02) and higher gLOH score (mean 4.4%, 95% CI 2.7–6.1% vs mean 1.4%, 95% CI 1.2–1.6%; P = .002) than TP53 non-mutated tumors. Conclusions No women with molecularly defined aGCT in this large cohort would be eligible for FDA-approved pembrolizumab based on either microsatellite instability or high tumor mutational burden. TP53 mutation identified a subset of this tumor type with distinct molecular features. The development of precision treatment options remains a critical unmet need for this rare disease.
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- 2021
15. Primary Adult Retroperitoneal Sarcoma: A Comprehensive Genomic Profiling Study
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Eric Allan Severson, Filippo Pederzoli, Dexter X. Jin, Marco Bandini, Jeffrey M. Venstrom, Shakti Ramkissoon, Gennady Bratslavsky, Dean V. Pavlick, Erik A. Williams, Alexa B. Schrock, Petros Grivas, Jeffrey S. Ross, Natalie Danzinger, J. Keith Killian, Sally E. Trabucco, Prasanth Reddy, Brian M. Alexander, Giuseppe Basile, Douglas I. Lin, Kimberley McGregor, Andrea Necchi, Philippe E. Spiess, and Julia A. Elvin
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0301 basic medicine ,Genomic profiling ,Follicular dendritic cells ,medicine.medical_treatment ,Liposarcoma ,Biology ,medicine.disease ,Targeted therapy ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Cancer research ,medicine ,biology.protein ,General Earth and Planetary Sciences ,Retroperitoneal sarcoma ,Mdm2 ,Gene ,Immunostaining ,General Environmental Science - Abstract
Background: Adult primary retroperitoneal sarcomas (RPSs) are a group of heterogeneous tumors with different histological subtypes. Comprehensive genomic profiling (CGP) analyses have recently provided significant insights into the biology of sarcomas by identifying genomic alterations (GAs) which could benefit from targeted therapies. Methods: RPS were evaluated by CGP using next-generation sequencing of up to 406 cancer-related genes. Tumor mutational burden (TMB) was determined on 0.83 to 1.14 mut/Mb of sequenced DNA. Finally, PD-L1 expression was determined. Results: Overall, 296 cases of primary RPS were analyzed. Liposarcoma (LPS) subtype had more GA/tumor than leiomyosarcoma (LMS) subtypes, with follicular dendritic cell sarcomas harboring the highest and synovial sarcomas the lowest. TP53 and Rb1 alterations were the highest in LMS, and CDK4/6 and MDM2 in LPS. However, both the TMB and targetable GA rates were low across subtypes. PD-L1 immunostaining was low positive in 21% and high positive in 5% of patients, respectively. Conclusions: CGP analysis revealed that potentially actionable genomic targets were rare in our cohort of RPS. Moreover, RPSs seem less likely to respond to immune checkpoint inhibitors based on putative biomarkers status. Nevertheless, genomic stratification according to histological subtypes led to description of GAs that can inform future clinical trials design.
- Published
- 2021
16. Clinicopathologic and genomic characterization of PD-L1-positive uterine cervical carcinoma
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Matthew Hiemenz, Richard S.P. Huang, Jeffrey S. Ross, James Haberberger, Julia A. Elvin, Daniel L. Duncan, Karthikeyan Murugesan, Douglas I. Lin, Shakti H. Ramkissoon, Natalie Danziger, and Eric Allan Severson
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0301 basic medicine ,APOBEC ,Oncology ,Cervical cancer ,medicine.medical_specialty ,Pathology ,business.industry ,Microsatellite instability ,Pembrolizumab ,medicine.disease ,PD-L1 Positive ,Pathology and Forensic Medicine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Adenocarcinoma ,Immunohistochemistry ,business ,Cervix - Abstract
Positive program death-ligand 1 (PD-L1) immunohistochemistry (IHC) is an approved companion diagnostic guiding the use of immune checkpoint inhibitors in uterine cervical carcinoma (CXC). The clinical and genomic features of PD-L1-positive (PD-L1positive) CXC have not been previously described. We reviewed the clinicopathologic and molecular features of 647 CXC cases that were tested using DAKO 22C3 PD-L1 IHC and comprehensive genomic profiling during the course of clinical care. PD-L1positive cases were defined via a combined positive score of ≥ 1. No differences were found in age, genetic ancestry, and HPV status of the PD-L1positive (n = 548) and PD-L1negative disease subset. The PD-L1 positivity rate varied by histologic subtype of CXC with squamous cell carcinoma (SCC) having a PD-L1 positivity rate of 91% (397/437) and usual-type adenocarcinoma’s PD-L1 positivity rate being 60% (35/58). In addition, the PD-L1 positivity rate varied depending on site of the specimen with 89.1% (261/293) positivity rate observed in cervix specimens compared to 25% (2/8) in brain metastases specimens. No significant difference in tumor mutational burden (TMB), microsatellite instability, and CD274 (encoding PD-L1) amplification was observed between PD-L1positive and PD-L1negative CXC subsets. By combining TMB with PD-L1, an additional 17 patients are eligible for pembrolizumab when compared to PD-L1 testing alone. TERT promoter alterations and APOBEC mutational signature were enriched in the PD-L1positive CXC SCC (p = 0.011, and p = 0.004, respectively). Our study reveals important prevalence data on PD-L1 positivity in CXC non-SCC and suggests that further studies in these histologic subtypes are warranted. In addition, we also provide a key framework to guide both specimen selection and future investigations of predictors of immunotherapy response in cervical cancer patients. Lastly, TERT promoter alterations and APOBEC mutational signature may be a biologically unique subset of PD-L1positive CXC SCC.
- Published
- 2021
17. Recurrent urothelial carcinoma-like FGFR3 genomic alterations in malignant Brenner tumors of the ovary
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Jeffrey S. Ross, Jeffrey M. Venstrom, Jonathan Keith Killian, Julia A. Elvin, Shakti H. Ramkissoon, and Douglas I. Lin
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Adult ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,endocrine system diseases ,Serous carcinoma ,Brenner Tumor ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,CDKN2A ,Ovarian carcinoma ,Biomarkers, Tumor ,medicine ,Carcinoma ,Humans ,Receptor, Fibroblast Growth Factor, Type 3 ,Aged ,Ovarian Neoplasms ,business.industry ,Gene Expression Profiling ,Ovary ,Middle Aged ,medicine.disease ,female genital diseases and pregnancy complications ,Cystadenocarcinoma, Serous ,stomatognathic diseases ,Serous fluid ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,Clear cell carcinoma ,Female ,business ,Ovarian cancer ,Carcinoma, Endometrioid ,Clear cell - Abstract
Malignant Brenner tumor is a rare primary ovarian carcinoma subtype that may present diagnostic and therapeutic conundrums. Here, we characterize the genomics of 11 malignant Brenner tumors, which represented 0.1% of 14,153 clinically advanced ovarian carcinomas submitted for genomic profiling during the course of clinical care. At the time of molecular profiling, there was no evidence of a primary urothelial carcinoma of the urinary tract in any case. Cases with transitional-like morphologic features in the setting of variant ovarian serous or endometrioid carcinoma morphology were excluded from the final cohort. Malignant Brenner tumors exhibited CDKN2A/2B loss and oncogenic FGFR1/3 genomic alterations in 55% of cases, respectively; including recurrent FGFR3 S249C or FGFR3-TACC3 fusion in 45% of cases. FGFR3-mutated cases had an associated benign or borderline Brenner tumor pre-cursor components, further confirming the diagnosis and the ovarian site of origin. Malignant Brenner tumors were microsatellite stable, had low tumor mutational burden and exhibited no evidence of homologous recombination deficiency. PIK3CA mutations were enriched with FGFR3 alterations, while FGFR3 wild-type cases featured MDM2 amplification or TP53 mutations. The FGFR3 S249C short variant mutation was absent in 14,142 non-Brenner, ovarian carcinomas subtypes. In contrast to malignant Brenner tumors, FGFR1/2/3 alterations were present in ~5% of non-Brenner, ovarian serous, clear cell and endometrioid carcinoma subtypes, most often as FGFR1 amplification in serous carcinoma or FGFR2 short variant alterations in clear cell or endometrioid carcinomas, respectively. Finally, malignant Brenner tumors had overall distinct genomic signatures compared to FGFR-mutated ovarian serous, endometrioid, and clear cell carcinoma subtypes. This study provides insights into the molecular pathogenesis of malignant Brenner tumors, contrasts the extent of FGFR1/2/3 alterations in ovarian serous, clear cell and endometrioid carcinomas and emphasizes the potential value of novel and FDA-approved, anti-FGFR inhibitors, such as erdafitinib and pemigatinib, in refractory, FGFR3-mutated malignant Brenner tumors.
- Published
- 2021
18. Integrative analysis of a large real-world cohort of small cell lung cancer identifies distinct genetic subtypes and insights into histological transformation
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Smruthy Sivakumar, Jay A. Moore, Meagan Montesion, Radwa Sharaf, Douglas I. Lin, Zoe Fleishmann, Ericka M. Ebot, Justin Newberg, Jennifer M. Mills, Priti S. Hegde, Garrett M. Frampton, Julien Sage, and Christine M. Lovly
- Abstract
Small cell lung cancer (SCLC) is a recalcitrant neuroendocrine carcinoma with dismal survival outcomes. A major barrier in the field has been the relative paucity of human tumors studied. Here we provide an integrated analysis of 3,600 “real-world” SCLC cases. This large cohort allowed us to identify new recurrent alterations and new genetic subtypes, including STK11-mutant tumors (1.7%) and TP53/RB1 wild-type tumors (5.5%), of which 12.7% were human papillomavirus-positive. In our cohort, gene amplifications on 4q12 are associated with increased overall survival while CCNE1 amplification is associated with decreased overall survival. We also identify more frequent alterations in the PTEN pathway in brain metastases. Finally, profiling cases of SCLC containing oncogenic drivers typically associated with NSCLC demonstrates that SCLC transformation may occur across multiple distinct molecular cohorts of NSCLC. These novel and unsuspected genetic features of SCLC may help personalize treatment approaches for this fatal form of cancer.STATEMENT OF SIGNIFICANCEMinimal changes in therapy and survival outcomes have occurred in SCLC for the past four decades. The identification of new genetic subtypes, novel recurrent mutations, and an improved understanding of the mechanisms of transformation to SCLC from NSCLC may guide the development of personalized therapies for subsets of patients with SCLC.
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- 2022
19. A pan-cancer analysis of PD-L1 immunohistochemistry and gene amplification, tumor mutation burden and microsatellite instability in 48,782 cases
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Jonathan Keith Killian, Julie Y. Tse, Shakti H. Ramkissoon, Julia A. Elvin, James Haberberger, Richard S.P. Huang, Priti Hegde, Naomi L Ferguson, Matthew Hiemenz, Clarence Owens, Amanda Hemmerich, Jeffrey S. Ross, Brian M. Alexander, Erik A. Williams, Eric Allan Severson, Claire Edgerly, Jeffrey M. Venstrom, Jo-Anne Vergilio, Daniel L. Duncan, Douglas I. Lin, and Natalie Danziger
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Pathology ,medicine.medical_treatment ,Cell ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Internal medicine ,PD-L1 ,Gene duplication ,medicine ,biology ,business.industry ,Microsatellite instability ,Immunotherapy ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,biology.protein ,Immunohistochemistry ,business ,Companion diagnostic - Abstract
PD-L1 immunohistochemistry (IHC) currently has the most Food and Drug Administration (FDA) approvals as a companion diagnostic (CDx) for immunotherapies in specific tumor types; however, multiple other immunotherapy biomarkers exist. We performed this study to examine and report the prevalence of PD-L1 expression in a wide variety of tumor types and examine its relationship to microsatellite instability (MSI), tumor mutational burden (TMB), and CD274 (PD-L1) gene amplification. We performed a retrospective analysis of all cases in which both PD-L1 IHC (using the DAKO 22C3 IHC assay with either tumor proportion score (TPS) or combined positive score (CPS); or the VENTANA SP142 assay with infiltrating immune cell score (IC)) and comprehensive genomic profiling (CGP) were tested at Foundation Medicine between January 2016 and November 2019. Of note, PD-L1 positivity is defined per the CDx indication and tumor proportion score (TPS ≥ 1) for indications without a CDx claim; and TMB positivity is defined as ≥10 mutations/Mb. A total of 48,782 cases were tested for PD-L1 IHC and CGP. Immune cell expression of PD-L1 was more frequently identified than tumor cell expression of PD-L1. We saw a high correlation between PD-L1 expression and CD274 gene amplification (p
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- 2021
20. Abstract 305: POLE-specific variant classification strategy is critical for identifying patients who may benefit from immunotherapy
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Rachel B. Keller, James Haberberger, Tyler Janovitz, Alexa B. Schrock, Hanna Tukachinsky, Lei Zhong, Douglas A. Mata, Lyle V. Lopez, Zoe Fleischmann, Radwa Sharaf, Ethan S. Sokol, Garrett M. Frampton, Nimesh R. Patel, Douglas I. Lin, Geoff R. Oxnard, Erik A. Williams, Julia A. Elvin, and Brennan Decker
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Cancer Research ,Oncology - Abstract
BACKGROUND: Pathogenic POLE exonuclease domain mutations (pPOLE) undermine mismatch error correction during DNA replication, causing somatic ultramutation and response to immunotherapy. We examined the pan-cancer landscape of POLE mutations and applied a POLE-specific variant classification model. METHODS: Comprehensive genomic profiling was performed during clinical care. Mutational signature calling was performed via decomposition using the 96-feature single-base substitution COSMIC reference signatures. A POLE-specific classification model encompassing mutation position in the exonuclease domain, TMB, presence of POLE signature, absence of other signatures, germline frequency, and other features was applied to identify pPOLE mutations causative of ultramutation. RESULTS: POLE mutation status was evaluated in 458,437 samples (425,520 tissue biopsies (TB) and 32,917 liquid biopsies (LB)). One or more POLE alterations, including pathogenic alterations and variants of unknown significance (VUS), were detected in 3.8% of samples. 19,470 total alterations were identified, 84.8% of which were missense substitutions. Application of the POLE-specific classification model identified 35 unique pathogenic variants, many of which were VUS prior to this study. 749 samples harbored a pPOLE, more than half (56.6%) of which were either p.P286R (n=245) or p.V411L (n=179). pPOLE were found in 1.4% (199/13,688) of endometrial cancers (EC) and 0.5% (270/55,981) of colorectal cancers (CRC) and were rarer in a long tail of other malignancies. The overall pPOLE rate was significantly lower in LB than TB (0.02% vs 0.17%, P CONCLUSIONS: pPOLE were seen in both TB and LB across cancer types. The high rate of passenger mutations underscores the utility of this POLE-specific variant classification model. Because TMB can be underestimated when tumor purity is near the limit of detection for the assay, accurate detection and classification of pPOLE is critical for identifying patients who may benefit from immunotherapy. Citation Format: Rachel B. Keller, James Haberberger, Tyler Janovitz, Alexa B. Schrock, Hanna Tukachinsky, Lei Zhong, Douglas A. Mata, Lyle V. Lopez, Zoe Fleischmann, Radwa Sharaf, Ethan S. Sokol, Garrett M. Frampton, Nimesh R. Patel, Douglas I. Lin, Geoff R. Oxnard, Erik A. Williams, Julia A. Elvin, Brennan Decker. POLE-specific variant classification strategy is critical for identifying patients who may benefit from immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 305.
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- 2023
21. Abstract 931: Comprehensive analysis of 3,600 small cell lung cancer cases reveals rare genetic subtypes and multiple mechanisms of histological transformation
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Smruthy Sivakumar, Jay A. Moore, Meagan Montesion, Douglas I. Lin, Zoe Fleischmann, Ericka M. Ebot, Justin Newberg, Jennifer M. Mills, Priti S. Hegde, Garrett M. Frampton, Julien Sage, and Christine M. Lovly
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Cancer Research ,Oncology - Abstract
Background: Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with limited treatment options and extremely poor survival outcomes. A major barrier in the field has been the relative paucity of human tumors studied and lack of access to longitudinal samples to understand tumor evolution. Methods: Here we provide a comprehensive analysis of 3,600 patients with SCLC who underwent targeted genomic profiling of at least 324 cancer-related genes as part of routine clinical care, including 678 cases with additional clinical and treatment information obtained from a US-based de-identified SCLC clinico-genomic database that originated from approximately 280 US cancer clinics. This large cohort allowed us to examine for new genetic subtypes, ancestry-associated genomic alterations, biopsy site-specific patterns, survival trends and histological transformation of SCLC from non-small cell lung cancer (NSCLC). Results: Consistent with prior studies, SCLCs were predominantly TP53/RB1 altered. Yet, 5.5% of the cases in our cohort were TP53/RB1 wild-type tumors. These tumors often lacked a tobacco mutational signature, exhibited alternate mechanisms of p53/Rb pathway inactivation (e.g., CDKN2A, CCND1, MDM2), and had a high fraction of human papillomavirus-positive cases (12.7%). Another rare subtype of SCLCs included STK11-altered tumors (1.7%), which were observed more frequently in patients of African ancestry, and were associated with a decreased overall survival (OS) compared with the STK11 wild-type cohort. In our cohort, gene amplifications on 4q12 (KDR, KIT, PDGFRA) were associated with increased OS while CCNE1 amplification was associated with decreased OS. Interestingly, alterations in PTEN were more common in brain metastases compared to lung biopsies and liver metastases, suggesting its potentially unique role in brain metastases of SCLCs. Profiling of over 100 putative transformed SCLCs demonstrated that lineage plasticity may occur at variable lengths of time from the original NSCLC diagnosis and include multiple distinct molecular cohorts of NSCLC, beyond EGFR-mutant NSCLC (e.g., kinase fusion+ tumors: RET, ALK, ROS1, NTRK1). Conclusion: Our work underscores the existence of genetic subtypes in SCLC, including rare subtypes with potential clinical utility. Findings from this study provide an improved understanding of genetic subtypes in SCLC and better inform mechanisms of transformation to SCLC from NSCLC, that may further guide the development of personalized therapies for subsets of patients with this fatal tumor. Citation Format: Smruthy Sivakumar, Jay A. Moore, Meagan Montesion, Douglas I. Lin, Zoe Fleischmann, Ericka M. Ebot, Justin Newberg, Jennifer M. Mills, Priti S. Hegde, Garrett M. Frampton, Julien Sage, Christine M. Lovly. Comprehensive analysis of 3,600 small cell lung cancer cases reveals rare genetic subtypes and multiple mechanisms of histological transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 931.
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- 2023
22. Single and multi-hit PIK3CA short variant (SV) genomic alterations (GA) in clinically advanced prostate cancer (CAPC): A genomic landscape study
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Carla Miguel, Gennady Bratslavsky, Joseph M Jacob, Petros Grivas, Philippe E. Spiess, Andrea Necchi, Dean C. Pavlick, Richard S.P. Huang, Douglas I. Lin, Natalie Danziger, Ethan Sokol, Smruthy Sivakumar, Ryon Graf, Neil Vasan, and Jeffrey S. Ross
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Cancer Research ,Oncology - Abstract
258 Background: Tumors harboring 2 or more PIK3CA Short variants (SV) (“Multi-hit”) have been described in breast cancer as linked to enhanced clinical outcome from anti-PIK3CA targeted therapies including alpelisib and investigational agents in clinical trials. The landscape and clinical implications of multi-hit PIK3CA alterations in other tumors, including in CAPC, are underexplored. Methods: 19,978 CAPC samples underwent hybrid capture based comprehensive genomic profiling (CGP) to evaluate all classes of GA and determine tumor mutational burden (TMB), microsatellite instability (MSI), genomic ancestry, signature and loss of heterozygosity (gLOH). Tumor cell PD-L1 expression was determined by IHC (Dako 22C3). Results: 18,741 (93.8%) CAPC were PIK3CA wild type (WT), 1,155 (5.8%) featured a single PIK3CA SV and 82 (0.4%) featured multi-hit PIK3CA SVs. The median ages of CAPC patients with single hit (69.1 yrs) or multi-hit (68.7 yrs) PIK3CA SV were older than the PIK3CA WT (67.6 yrs) CAPC (p
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- 2023
23. CDH1-mutated clinically advanced urothelial bladder cancer (UBC): A genomic landscape and real-world clinical outcome study (RWCOS)
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Andrea Necchi, Roger Li, Kyle M. Rose, Facundo Davaro, Elizabeth Davaro, Philippe E. Spiess, Petros Grivas, Gennady Bratslavsky, Joseph M Jacob, Alina Basnet, Dean C. Pavlick, Richard S.P. Huang, Douglas I. Lin, Natalie Danziger, Julia C. F. C. F. Quintanilha, Jeffrey S. Ross, and Ryon Graf
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Cancer Research ,Oncology - Abstract
564 Background: CDH1 mutated UBCs are characterized by plasmacytoid histology and are associated with an aggressive clinical course at the time of diagnosis. Methods: Cohort 1: 6,676 clinically advanced UBC patients (pts) underwent comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA), microsatellite instability (MSI), tumor mutational burden (TMB), and genomic loss of heterozygosity (gLOH, high ≥16%). Predominant genetic ancestry was determined using a SNP-based approach and classified as one of the 5 categories: African (AFR), European (EUR), Central and South American (AMR), South Asian (SAS), or East Asian (EAS). Cohort 2: 586 UBC pts underwent a RWCOS using the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine urothelial clinico-genomic database (FH-FMI CGDB). The de-identified data originated from approximately 280 US cancer clinics (~800 sites of care) Jan 2011-Apr 2022. Differences in real-world progression-free survival (rwPFS) and overall survival (rwOS) were evaluated by Cox proportional hazard models. Results: Cohort 1: 217 (3.3%) of UBC had a CDH1 short variant (SV) mutation with 65.2% featuring plasmacytoid histology. When compared with CDH1 wild-type (WT) UBC, the CDH1-mutated UBC had similar age, gender, and genetic ancestry. The CDH1-mutated UBC featured a higher frequency of MSI (2.7% vs 0.8%; p=.002), mean TMB (14.8 vs 9.9 mut/Mb p
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- 2023
24. Extracellular domain ERBB2 (ERBB2 ECD+) mutations in urothelial bladder cancer (UBC)
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Michael Basin, Joseph M Jacob, Gennady Bratslavsky, Petros Grivas, Philippe E. Spiess, Roger Li, Andrea Necchi, Dean C. Pavlick, Richard S.P. Huang, Douglas I. Lin, Natalie Danziger, Ethan Sokol, Smruthy Sivakumar, and Jeffrey S. Ross
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Cancer Research ,Oncology - Abstract
566 Background: Given the recent approval in lung cancer for the first anti-HER2 targeted therapy directed against activating kinase domain exon 20 ERBB2 insertion mutations, considerable interest has arisen in targeting additional locations in the ERBB2 gene in other tumor types. Methods: 5,485 UBC samples were sequenced using a hybrid capture-based comprehensive genomic profiling (CGP) assay to assess all classes of genomic alterations (GA), tumor mutational burden (TMB), microsatellite instability (MSI), genomic loss of heterozygosity (gLOH), trinucleotide signatures and predominant genetic ancestry. Statistical comparisons utilized the Bonferroni correction. Results: 548 (10.0%) of UBC featured ERBB2 gene amplification (amp) and 219 (4.0%) featured an ERBB2 ECD+ sequence mutation (74% S310F and 26% S310Y). ERBB2 ECD+ mutations and ERBB2 amplification were mutually exclusive. 16.4% of ERBB2 ECD+ UBC had more than one E RBB2 sequence mutation. Central pathology review of the 219 ERBB2 ECD+ UBC revealed that 63 (28.8%) featured a micropapillary histologic appearance (MPUC). ERBB2 ECD+ UBC featured more patients with European ancestry than both ERBB2 WT (90.9% vs 84.2%; p=.03) and ERBB2 amp (90.9% vs 83.2%; p=.04). ECD mut+ UBC also featured lower association with African ancestry than ERBB2 amp (2.7% vs 7.8%; p=.04) and lower frequency of gLOH > 16% (9.3% vs 19.1%; p=.04). MSI-High status was similar and rare in all 3 groups (range 0 to 0.9%). ERBB2 ECD+ UBC had a higher frequency of APOBEC signature than ERBB2 amp (82.9% vs 72.4%; p=.03). TMB > 10 mut/mb was higher in ERBB2 amp (49.2% vs 31.4%; p
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- 2023
25. Penile squamous cell carcinoma (PSCC) with elevated tumor mutational burden (TMB): A genomic landscape study
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Philippe E. Spiess, Roger Li, Petros Grivas, Andrea Necchi, Dean C. Pavlick, Richard S.P. Huang, Douglas I. Lin, Natalie Danziger, Jeffrey S. Ross, Joseph M Jacob, and Gennady Bratslavsky
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Cancer Research ,Oncology - Abstract
4 Background: TMB has emerged as a major biomarker of efficacy in immune checkpoint inhibitor (ICPI) therapies in the neoadjuvant, adjuvant and metastatic disease setting in a wide variety of malignancies, but not in PSCC. Methods: 397 clinically advanced (local major recurrence and/or metastatic disease) PSCC underwent hybrid capture-based comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on up to 114 loci. Trinucleotide mutation signatures were evaluated (Alexandrov, et al. 2013). Genome-wide loss of heterozygosity (gLOH) was determined using validated pipelines and excluding whole-arm and whole-chromosome events. TMB was categorized into three cohorts: 20 muts/Mb (very high). Tumor cell PD-L1 expression was determined by IHC (Dako 22C3) and defined as tumor proportion score (TPS) >1. The presence of HPV16/18 was determined by next generation sequencing (NGS). Statistical comparisons were corrected for multiple comparisons using the Bonferonni method. Results: There were 339 (85.4%) TMB low, 40 (10.1%) TMB 10-19 and 18 (4.5%) TMB very high PSCC cases in this study. The mean age of PSCC with very high TMB at 70.1 yrs was older than for TMB low at 63.4 yrs (p=.08). There were no significant differences in genomic ancestry among the 3 groups. The TMB 10-19 and TMB very high tended to feature an APOBEC genomic mutational signature more than the TMB low PSCC cases (74 and 76% vs 44%). MSI high status was absent in the TMB low PSCC, but was present in 7.5% of the TMB 10-19 and 11.8% of the TMB very high cases. gLOH levels above 16% were similar in all 3 groups and ranged from 6.2 to 9.4%. GA associated with differences in TMB status in the PSCC cases included higher PIK3CA GA in TMB 10-19 (40.0%) vs TMB low (18.3%; p=.035) and TMB very high (66.7%) vs TMB low (p=.0002). CDKN2A GA were higher in TMB low (45.7%) than in the combined TMB 10-19 + very high (25.9%; p=.049). GA in KMT2D were higher in the combined TMB 10-19 + very high (29.3%) than the TMB low PSCC (7.7%; p=0002). FGFR3 GA were similar in all 3 groups. PD-L1 expression was not significantly different among the 3 groups with TMB low (78.3%), TMB 10-19 (64.2%) and TMB very high (54.5%). HPV identification was more frequent as TMB increased: 28.3% for the TMB low, 50.0% for the TMB high and 58.8% for the TMB very high groups. Conclusions: The evaluation of PSCC by CGP based on TMB levels revels significant differences in biomarkers for the near 15% of cases that have TMB >10 muts/Mb. Further study of TMB as a biomarker in ICPI-based clinical trials for advanced PSCC appear warranted.
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- 2023
26. Landscape of genomic alterations (GA) in urothelial bladder carcinoma (UBC) in patients of East Asian and South Asian ancestry
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Taylor Peak, Philippe E. Spiess, Roger Li, Petros Grivas, Andrea Necchi, Dean C. Pavlick, Richard S.P. Huang, Douglas I. Lin, Natalie Danziger, Joseph M Jacob, Gennady Bratslavsky, and Jeffrey S. Ross
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Cancer Research ,Oncology - Abstract
567 Background: UBC is the 10th most common cancer worldwide, with more than 550,00 new cases annually (WHO, International Agency for Research on Cancer, 2020). Rates vary by regions of the world, explained in part by the fact that different genetic ancestries demonstrate varying germline genetics, environmental exposures, and social risk factors. Methods: 8,728 UBC samples underwent hybrid capture-based comprehensive genomic profiling (CGP) to determine all classes of genomic alterations (GA), microsatellite instability (MSI) status, tumor mutational burden (TMB), and genomic trinucleotide signature. Predominant genetic ancestry was determined using a SNP-based approach using an algorithm trained on the 1000 Genomes data (Connelly et al. AACR 2018). Ancestry was classified as one of the five following categories: African (AFR), European (EUR), Central and South American (AMR), South Asian (SAS), or East Asian (EAS). Results: Of the cohort, 7,447 (85.3%) were EUR, 541 (6.2%) were AFR, 461 (5.3%) were of AMR, 74 (0.85%) were SAS, and 205 (2.3%) were EAS. Age, gender, genomic signature distributions, and MSI status (range 0.9%-1.5%) were similar in all cohorts. The frequency of TMB >10 mutations/Megabase was similar in all cohorts (range 30.7%-39.1%) as was the median TMB (6.3 mutations/Megabase for all). At 67.6%, TP53 was the most frequent GA in SAS cohort. When compared with the non-SAS cohort, TERT GA were lower in the SAS cohort (58.1% vs 72.6%; p=0.06) as were GA in FGFR3 (9.5% vs 18.5%, p=0.25). In the EAS cohort, at 59.0%, GA in TP53 were the most common. TERT mutations were significantly lower in EAS compared to the non-EAS cohort (54.1% vs 72.9%; p
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- 2023
27. Microsatellite instability (MSI), mismatch repair (MMR), and tumor mutational burden (TMB) as predictive biomarkers for immune checkpoint inhibitor (ICI) effectiveness in real-world patients with metastatic colorectal cancer (mCRC)
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Haley Ellis, Samuel J Klempner, Julia C. F. C. F. Quintanilha, Parvathi Myer, Douglas I. Lin, Nicole Panarelli, Virginia Fisher, Gerald Li, Richard S.P. Huang, Jeffrey S. Ross, Geoffrey R. Oxnard, and Ryon Graf
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Cancer Research ,Oncology - Abstract
46 Background: The KEYNOTE-177 randomized controlled trial demonstrated that mCRC patients with MSI high (MSI-H) and/or deficient MMR (dMMR) have better outcomes on first-line ICI than chemotherapy. This study aimed to evaluate MSI by next-generation sequencing (NGS) as a predictive biomarker of ICI effectiveness in real-world settings, and compare MSI (NGS), dMMR (immunohistochemistry, IHC), and TMB (10 mut/Mb cutoff) in predicting ICI outcomes. Methods: A prospectively declared statistical analysis plan compared the effectiveness of first-line treatment ICI versus chemotherapy in patients with MSI-H mCRC, and compared the predictive power of ICI outcomes associated with biomarkers in any line of therapy (LOT). Patient data was obtained by the US-based de-identified Flatiron Health-Foundation Medicine real-world mCRC clinico-genomic database (FH-FMI CGDB), originating from ~280 US cancer clinics between Jan/2011 and Dec/2021. Differences in progression-free survival (PFS) and overall survival (OS) were evaluated by Cox proportional hazard models, adjusted for a risk score generated from prognostic clinical features. The likelihood ratio test evaluated the superiority of a biomarker in anticipating outcomes. Results: Patients with MSI-H mCRC had more favorable outcomes receiving first-line ICI (n=49) than chemotherapy (n=89) for PFS (median 24.87 vs. 5.65 months, hazard ratio (HR): 0.31, 95% confidence interval (CI) 0.18-0.52, p 10, three with mutations in MMR genes, and 5 with BRAF mutation, consistent with MSI biology). When MSI (NGS) is added to dMMR (IHC) evaluation, there is an improvement in the prediction of TTNT (p = 0.0013), PFS (p = 0.0202), and OS (p = 0.0717), but adding MMR status to MSI did not improve explanatory power. Conclusions: MSI (NGS) robustly identifies mCRC patients with favorable outcomes on first-line ICI vs. chemotherapy, and is a nominally better predictor of ICI outcomes when compared with dMMR (IHC) alone. dMMR (IHC), MSI (NGS), and TMB have similar predictive power for ICI benefit. [Table: see text]
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- 2023
28. Mixed Endometrioid Adenocarcinoma and Müllerian Adenosarcoma of the Uterus and Ovary
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Teri A. Longacre, W. Glenn McCluggage, Douglas I. Lin, Anna Måsbäc, Christopher N. Otis, Soufiane El Hallani, Rupali Arora, Vinita Parkash, Claudia Mateoiu, Marisa R. Nucci, and Carlos Parra-Herran
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Adult ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Biopsy ,Atypical hyperplasia ,Pathology and Forensic Medicine ,Diagnosis, Differential ,03 medical and health sciences ,0302 clinical medicine ,Carcinosarcoma ,Predictive Value of Tests ,Biomarkers, Tumor ,medicine ,Carcinoma ,Humans ,Uterine Neoplasm ,Aged ,Neoplasm Staging ,Aged, 80 and over ,Ovarian Neoplasms ,Adenosarcoma ,business.industry ,Middle Aged ,medicine.disease ,Endometrial hyperplasia ,Europe ,030104 developmental biology ,030220 oncology & carcinogenesis ,North America ,Uterine Neoplasms ,Adenocarcinoma ,Female ,Surgery ,Sarcoma ,Neoplasm Grading ,Anatomy ,business ,Carcinoma, Endometrioid - Abstract
Mullerian adenosarcoma is a biphasic neoplasm composed of benign or atypical Müllerian epithelium and a malignant mesenchymal component that is usually, but not always, of low grade. Focal architectural or cytologic atypia of the epithelial component resembling atypical hyperplasia may uncommonly be present and foci of adenocarcinoma have been rarely reported. Whether the coexistence of these 2 tumor components is a result of independent primaries (collision tumor), adenocarcinoma arising from the epithelial component of the adenosarcoma, an unusual form of carcinosarcoma or some other mechanism is uncertain. To establish the diagnostic criteria and clinical significance of the coexistence of adenocarcinoma in close association with Müllerian adenosarcoma, we conducted a multi-institutional study of these rare tumors. Twenty-six patients were identified with "mixed" adenosarcoma and adenocarcinoma; they ranged in age from 43 to 87 years (median: 66 y). Tumors occurred in the uterine corpus (n=22), ovary (n=2), and the pelvis (n=2). All but 6 had International Federation of Gynecology and Obstetrics (FIGO) stage I disease. All extrauterine tumors were associated with endometriosis. The tumor size ranged from 2 to 25 cm (median: 7.9 cm). The sarcomatous component was of low grade in 18 and high grade in 8 (the majority demonstrating rhabdomyoblastic differentiation); 9 had stromal overgrowth. Twenty-five carcinomas were endometrioid in type (23 FIGO grade 1; 3 FIGO grade 2) and 1 carcinoma was dedifferentiated with FIGO grade 1 endometrioid adenocarcinoma component; 33% of the uterine neoplasms were associated with adjacent endometrial hyperplasia. Next-generation sequencing in 2 tumors identified similar molecular abnormalities in the sarcomatous and carcinomatous components supporting a clonal relationship. Of 10 patients with available follow-up (median: 18 mo), 8 had no evidence of disease and 2 died of recurrent sarcoma at 7 and 8 months. Endometrioid adenocarcinomas that arise in close spatial association with Müllerian adenosarcoma appear to be clonally related to the sarcoma. Unlike carcinosarcomas, these tumors are usually early stage at presentation. The prognosis appears to be driven by the sarcomatous component. These tumors should be distinguished from carcinosarcomas, dedifferentiated endometrial carcinomas, and corded and hyalinized endometrioid carcinomas.
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- 2020
29. CDKN2C-Null Leiomyosarcoma: A Novel, Genomically Distinct Class of TP53/RB1–Wild-Type Tumor With Frequent CIC Genomic Alterations and 1p/19q-Codeletion
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Helen Toma, Julia A. Elvin, Brennan Decker, Ethan Sokol, Kevin Jon Williams, Shakti H. Ramkissoon, Dean Pavlick, Brian M. Alexander, Meagan Montesion, Erik A. Williams, Douglas I. Lin, Jeffrey S. Ross, Nikunj Shah, Jeffrey M. Venstrom, Adrienne J Werth, Lee A. Albacker, and Radwa Sharaf
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0301 basic medicine ,Genetics ,Leiomyosarcoma ,Cancer Research ,Class (set theory) ,Null (mathematics) ,Wild type ,1p/19q Codeletion ,Biology ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,medicine - Abstract
PURPOSE Leiomyosarcoma (LMS) harbors frequent mutations in TP53 and RB1 but few actionable genomic alterations. Here, we searched for recurrent actionable genomic alterations in LMS that occur in the absence of common untreatable oncogenic drivers. METHODS Tissues from 276,645 unique advanced cancers, including 2,570 uterine and soft tissue LMS, were sequenced by hybrid-capture–based next-generation DNA and RNA sequencing/comprehensive genomic profiling of up to 406 genes. We characterized clinicopathologic features of relevant patient cases. RESULTS Overall, 77 LMS exhibited homozygous copy loss of CDKN2C at chromosome 1p32.3 (3.0% of LMS). Genomic alterations (GAs) in TP53, RB1, and ATRX were rare compared with the remainder of the LMS cohort (11.7% v 73.4%, 0% v 54.5%, 2.6% v 24.5%, respectively; all P < .0001). CDKN2C-null LMS patient cases were significantly enriched for GAs in CIC (40.3% v 1.4%) at 19q13.2, CDKN2A (46.8% v 7.0%), and RAD51B (16.9% v 1.7%; all P < .0001). Chromosome arm-level aneuploidy analysis of available LMS patient cases (n = 1,284) found that 81% (58 of 72) of CDKN2C-null LMS exhibited 1p/19q-codeletion, a significant enrichment compared with 5.1% in the remainder of the LMS cohort ( P < .0001). In total, 99% of CDKN2C-null LMS were in women; the median age was 61 years at surgery (range, 36-81 years). Fifty-five patient cases were uterine primary, four were nonuterine, and the remaining 18 were of uncertain primary site. Sixty percent of cases showed at least focal epithelioid variant histology. Most patients had advanced-stage disease, with 62% of confirmed uterine primary LMS at International Federation of Gynecology and Obstetrics stage IVB. We further validated our findings in two publicly available datasets: The Cancer Genome Atlas and the Project GENIE initiative. CONCLUSION CDKN2C-null LMS defines a genomically distinct tumor that may have prognostic and/or therapeutic clinical implications, including possible use of specific cyclin-dependent kinase inhibitors.
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- 2020
30. Vulvar Squamous Cell Carcinoma: Comprehensive Genomic Profiling of HPV+ Versus HPV– Forms Reveals Distinct Sets of Potentially Actionable Molecular Targets
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Jeff M Venstrom, Molly McLaughlin-Drubin, Jonathan Keith Killian, Brian M. Alexander, Radwa Sharaf, Nikunj Shah, Helen Toma, Jeffrey S. Ross, Rachel L. Erlich, Mark C. Mochel, Adrienne J Werth, Amanda Hemmerich, Julia A. Elvin, Dean Pavlick, Kevin Jon Williams, Ethan Sokol, Douglas I. Lin, Julie Y. Tse, Eric Allan Severson, Shakti H. Ramkissoon, Meagan Montesion, Erik A. Williams, and Natalie Danziger
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0301 basic medicine ,Cancer Research ,Genomic profiling ,Vulvar Squamous Cell Carcinoma ,Biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Original Reports ,Molecular targets ,Cancer research ,Basal cell ,Human papillomavirus - Abstract
PURPOSE Vulvar squamous cell carcinoma (vSCC) encompasses two predominant variants: one associated with detectable high-risk strains of human papillomavirus (hrHPV) and a second form often occurring in the context of chronic dermatitis in postmenopausal women. Genomic assessment of a large-scale cohort of patients with aggressive vSCC may identify distinct mutational signatures. MATERIALS AND METHODS Tumor samples from a total of 280 patients with vSCC underwent hybridization capture with analysis of up to 406 cancer-related genes. Human papillomavirus (HPV) sequences were detected by de novo assembly of nonhuman sequencing reads and aligned to the RefSeq database. Immunohistochemistry for programmed death-ligand 1 (PD-L1) was assessed. RESULTS One hundred two of 280 vSCCs (36%) contained hrHPV sequences, predominantly HPV 16 (88%). The HPV-positive (HPV+) group was significantly younger (median age, 59 v 64 years; P = .001). Compared with HPV-negative (HPV–) vSCCs, HPV+ tumors showed more frequent pathogenic alterations in PIK3CA (31% v 16%; P = .004), PTEN (14% v 2%; P < .0001), EP300 (14% v 1%; P < .0001), STK11 (14% v 1%; P < .0001), AR (5% v 0%; P = .006), and FBXW7 (10% v 3%; P = .03). In contrast, HPV– vSCCs showed more alterations in TP53 (83% v 6%; P < .0001), TERTp (71% v 9%; P < .0001), CDKN2A (55% v 2%; P < .0001), CCND1 amplification (22% v 2%; P < .0001), FAT1 (25% v 4%; P < .0001), NOTCH1 (19% v 6%; P = .002), and EGFR amplification (11% v 0%; P < .0001), as well as a higher rate of 9p24.1 ( PDL1/PDL2) amplification (5% v 1%) and PD-L1 immunohistochemistry high-positive tumor staining (33% v 9%; P = .04). CONCLUSION Comprehensive molecular profiles of vSCC vary considerably with hrHPV status and may inform patient selection into clinical trials. Sixty-one percent of HPV+ vSCCs had a pathogenic alteration in the PI3K/mTOR pathway, whereas HPV– vSCCs showed alterations in TP53, TERTp, CDKN2A, CCND1, and EGFR, and biomarkers associated with responsiveness to immunotherapy.
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- 2020
31. Comparative Effectiveness of Immune Checkpoint Inhibitors vs Chemotherapy by Tumor Mutational Burden in Metastatic Castration-Resistant Prostate Cancer
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Ryon P. Graf, Virginia Fisher, Janick Weberpals, Ole Gjoerup, Marni B. Tierno, Richard S. P. Huang, Nicolas Sayegh, Douglas I. Lin, Kira Raskina, Alexa B. Schrock, Eric Severson, James F. Haberberger, Jeffrey S. Ross, James Creeden, Mia A. Levy, Brian M. Alexander, Geoffrey R. Oxnard, and Neeraj Agarwal
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Male ,Prostatic Neoplasms, Castration-Resistant ,Mutation ,Biomarkers, Tumor ,Humans ,General Medicine ,Genomics ,Immune Checkpoint Inhibitors - Abstract
The most useful biomarkers for clinical decision-making identify patients likely to have improved outcomes with one treatment vs another.To evaluate treatment class-specific outcomes of patients receiving immune checkpoint inhibitor (ICI) vs taxane chemotherapy by tumor mutational burden (TMB).This comparative effectiveness analysis of clinical variables and outcomes used prospectively defined biomarker-stratified genomic data from a deidentified clinicogenomic database. Data included men with previously treated metastatic castration-resistant prostate cancer (mCRPC) receiving ICI or single-agent taxane chemotherapy from January 2011 to April 2021 at approximately 280 US academic or community-based cancer clinics (approximately 800 sites of care). Data were analyzed from July to August 2021.Single-agent ICI or single-agent taxanes. Treatments were assigned at discretion of physician and patient without randomization. Imbalances of known factors between treatment groups were adjusted with propensity weighting.Prostate-specific antigen (PSA) response, time to next therapy (TTNT), and overall survival (OS).A total of 741 men (median [IQR], 70 [64-76] years) with mCRPC received comprehensive genomic profiling and were treated with ICI or single-agent taxane therapy. At baseline, the median (IQR) PSA level was 79.4 (19.0-254) ng/mL, 108 men (18.8%) had Eastern Cooperative Oncology Group Performance Status scores of 2 or greater, and 644 men (86.9%) had received prior systemic treatments for mCRPC. A total of 45 patients (6.1%) received ICI therapy and 696 patients (93.9%) received taxane therapy. Among patients with TMB of fewer than 10 mutations per megabase (mt/Mb) receiving ICI, compared with those receiving taxanes, had worse TTNT (median [IQR], 2.4 [1.1-3.2] months vs 4.1 [2.2-6.3] months; hazard ratio [HR], 2.65; 95% CI, 1.78-3.95; P .001). In contrast, for patients with TMB of 10 mt/Mb or greater, use of ICIs, compared with use taxanes, was associated with more favorable TTNT (median [IQR], 8.0 [3.4 to unknown] months vs 2.4 [2.4-7.3] months; HR, 0.37, 95% CI, 0.15-0.87; P = .02) and OS (median 19.9 [8.06 to unknown] months vs 4.2 [2.69 - 6.12] months; HR, 0.23; 95% CI, 0.10-0.57; P = .001). Among all 741 patients, 44 (5.9%) had TMB of 10 mt/Mb or greater, 22 (3.0%) had high microsatellite instability, and 20 (2.7%) had both. Treatment interactions with TMB of 10 mt/Mb or greater (TTNT: HR, 0.10; 95% CI, 0.32-0.31; P .001; OS: HR, 0.25; 95% CI, 0.076-0.81; P = .02) were stronger than high microsatellite instability alone (TTNT: HR, 0.12; 95% CI, 0.03-0.51; P = .004; OS: HR, 0.38; 95% CI, 0.13-1.12; P = .08).In this comparative effectiveness study, ICIs were more effective than taxanes in patients with mCRPC when TMB was 10 mt/Mb or greater but not when TMB was fewer than 10 mt/Mb. The results add validity to the existing TMB cutoff of 10 mt/Mb for ICI use in later lines of therapy, and suggest that ICIs may be a viable alternative to taxane chemotherapy for patients with mCRPC with high TMB.
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- 2022
32. Activating IGF1R hotspot non-frameshift insertions define a novel, potentially targetable molecular subtype of adenoid cystic carcinoma
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Matthew Margolis, Tyler Janovitz, Jason Laird, Douglas A. Mata, Meagan Montesion, Jessica K. Lee, Russell W. Madison, Alexa B. Schrock, Hanna Tukachinsky, Justin M. Allen, Rachel Erlich, Matthew C. Hiemenz, Richard S.P. Huang, Julia Elvin, Jo-Anne Vergilio, Douglas I. Lin, Jeffrey Ross, Geoffrey Oxnard, and Brennan Decker
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Humans ,Antibodies, Monoclonal ,Salivary Gland Neoplasms ,Carcinoma, Adenoid Cystic ,Protein Kinase Inhibitors ,Pathology and Forensic Medicine ,Fibronectins ,Receptor, IGF Type 1 - Abstract
Activation of the tyrosine kinase receptor IGF1R is targetable with existing tyrosine kinase inhibitors (TKIs) and monoclonal antibodies, but mutations in IGF1R have not been systematically characterized. Pan-cancer analysis of 326,911 tumors identified two distinct, activating non-frameshift insertion hotspots in IGF1R, which were significantly enriched in adenoid cystic carcinomas (ACCs). IGF1R alterations from 326,911 subjects were analyzed by variant effect prediction class, position within the gene, and cancer type. 6502 (2.0%) samples harbored one or more alterations in IGF1R. Two regions were enriched for non-frameshift insertions: codons 663-666 at the hinge region of the fibronectin type 3 domain and codons 1034-1049 in the tyrosine kinase domain. Hotspot insertions were highly enriched in ACCs (27.3-fold higher than in the remainder of the pan-cancer dataset; P = 2.3 × 10
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- 2022
33. Genomic profiling of BCOR-rearranged uterine sarcomas reveals novel gene fusion partners, frequent CDK4 amplification and CDKN2A loss
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Amanda Hemmerich, Claire Edgerly, Eric Allan Severson, Meghan Shea, Jeffrey S. Ross, Yamicia D. Connor, Jonathan L. Hecht, Daniel Duncan, Julia A. Elvin, Richard S.P. Huang, Siraj M. Ali, Douglas I. Lin, Shakti H. Ramkissoon, and Jo-Anne Vergilio
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Adult ,Leiomyosarcoma ,0301 basic medicine ,Sarcoma, Endometrial Stromal ,medicine.medical_treatment ,DNA sequencing ,Targeted therapy ,Cohort Studies ,Fusion gene ,03 medical and health sciences ,0302 clinical medicine ,CDKN2A ,Proto-Oncogene Proteins ,Databases, Genetic ,medicine ,Humans ,Gene ,Cyclin-Dependent Kinase Inhibitor p16 ,Retrospective Studies ,Gene Rearrangement ,Endometrial stromal sarcoma ,biology ,business.industry ,Gene Amplification ,Cyclin-Dependent Kinase 4 ,High-Throughput Nucleotide Sequencing ,Obstetrics and Gynecology ,Sarcoma ,Genomics ,Gene rearrangement ,Middle Aged ,medicine.disease ,Repressor Proteins ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Uterine Neoplasms ,Cancer research ,biology.protein ,Mdm2 ,Female ,Microsatellite Instability ,business - Abstract
Objective Genomic alterations of BCOR via ZC3H7B-BCOR fusion or BCOR internal tandem duplication (ITD) define a subset of endometrial stromal sarcoma (ESS). The goals of this study were to: 1) determine the molecular landscape of BCOR-rearranged ESS, 2) to identify novel BCOR fusion gene partners in ESS and their associated clinicopathological characteristics, and 3) to potentially unravel targetable genomic alterations in BCOR-mutated ESS. Methods A retrospective database search of a CLIA-certified molecular laboratory was performed for uterine sarcomas that contained BCOR rearrangements or BCOR ITD. The cases were previously assayed by comprehensive genomic profiling via both DNA- and RNA-based targeted next generation sequencing during the course of clinical care. Clinicopathological and genomic data was centrally re-reviewed. Results We identify largest cohort of BCOR-rearranged ESS to date (n = 40), which included 31 cases with canonical ZC3H7B-BCOR fusion as well as 8 cases with novel BCOR gene rearrangement partners, such as BCOR-L3MBTL2, EP300-BCOR, BCOR-NUTM2G, BCOR-RALGPS1, BCOR-MAP7D2, RGAG1-BCOR, ING3-BCOR, BCOR-NUGGC, KMT2D-BCOR, CREBBP-BCOR and 1 case with BCOR internal rearrangement. Re-review of cases with novel rearrangements demonstrated sarcomas with spindle, epithelioid or small round cell components and frequent myxoid stromal change. Comprehensive genomic profiling revealed high frequency of CDK4 and MDM2 amplification in 38% and 45% of BCOR-rearranged cases, respectively, and homozygous deletion of CDKN2A, which encodes an inhibitor of CDK4 in 28% of cases. Notably, CDK4 and MDM2 amplification was absent in all cases from 15 different ESS cases harboring BCOR ITD. Conclusions Alterations of CDK4 pathway members, for which targeted therapy is clinically available (i.e. palbociclib), via CDK4 amplification or CDKN2A loss, contributes to the pathogenesis of BCOR-rearranged uterine sarcomas, which may have therapeutic implications.
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- 2020
34. Germline mutations of SMARCA4 in small cell carcinoma of the ovary, hypercalcemic type and in SMARCA4-deficient undifferentiated uterine sarcoma: Clinical features of a single family and comparison of large cohorts
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Kimberly R. DeLeonardis, Katharine M. Esselen, Douglas I. Lin, Yamicia D. Connor, Diana Miao, John L. Dalrymple, Brooke E. Howitt, Michele R. Hacker, Meghan Shea, and Cynthia Hayne
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Adult ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Ovary ,medicine.disease_cause ,Small-cell carcinoma ,Article ,Germline ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,Internal medicine ,Humans ,Medicine ,Carcinoma, Small Cell ,Germ-Line Mutation ,Retrospective Studies ,Genetic testing ,Ovarian Neoplasms ,Mutation ,Chemotherapy ,medicine.diagnostic_test ,business.industry ,DNA Helicases ,Nuclear Proteins ,Obstetrics and Gynecology ,Cell Differentiation ,Sarcoma ,Middle Aged ,Prognosis ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Uterine Neoplasms ,Hypercalcemia ,SMARCA4 ,Female ,business ,Transcription Factors - Abstract
Objective Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) and SMARCA4-deficient undifferentiated uterine sarcoma (SMARCA4-DUS) are rare and aggressive tumors, primarily affecting pre- and perimenopausal women. Inactivating SMARCA4 mutations are thought to be the driving molecular events in the majority of these tumors. Here, we report the clinical course of a family with germline SMARCA4 mutation and compare large cohorts of these rare tumor types. Methods We extracted clinico-pathological medical record data for the family with germline SMARCA4 mutation. Clinico-genomic data from SCCOHT and SMARCA4-DUS cohorts were retrospectively extracted from the archives of a large CLIA-certified reference molecular laboratory. Results We identified a single family with an inherited germline SMARCA4 mutation, in which two different family members developed either SCCOHT or SMARCA4-DUS, both of whom died within one year of diagnosis, despite aggressive surgical, chemotherapy and immunotherapy treatment. Retrospective comparative analysis of large SCCOHT (n = 48) and SMARCA4-DUS (n = 17) cohorts revealed that SCCOHT patients were younger (median age: 28.5 vs. 49.0) and more likely to have germline SMARCA4 alterations (37.5% vs. 11.8%) than SMARCA4-DUS patients. Conclusions Growing understanding of the role SMARCA4 plays in the pathogenesis of these rare cancers may inform recommended genetic testing and counseling in families with these tumor types.
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- 2020
35. Urothelial cancer harboursEGFRandHER2amplifications and exon 20 insertions
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Jeffrey S. Ross, Prasanth Reddy, John V. Heymach, Vincent A. Miller, Alexa B. Schrock, Brian M. Alexander, Siraj M. Ali, Russell Madison, Andrea Necchi, Yasir Elamin, Douglas I. Lin, Sumanta K. Pal, Sumati Gupta, and Jon Chung
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0301 basic medicine ,business.industry ,Urology ,Hybrid capture ,Poziotinib ,03 medical and health sciences ,ERBB2 Amplification ,Exon ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Cancer research ,Medicine ,Urothelial cancer ,Non small cell ,business ,Gene ,Urothelial carcinoma - Abstract
Objective To review the genomic landscape of advanced urothelial carcinoma (UC) to assess the frequencies of EGFR and ERBB2 (HER2) alterations. Materials and methods Tumour specimens from 3753 patients with advanced UC were assayed with hybrid capture-based comprehensive genomic profiling of 180-395 genes. Tumour mutational burden (TMB) was assessed on 0.8 or 1.1 Mb of DNA, and is reported as mutations per megabase. Results In 3753 cases of UC, EGFR alterations were detected in 4.1% (154) and were most commonly amplifications (64%; 99/154), while exon 20 insertions (EGFRexon20ins ) were the second most common alteration (18%; 27/154). Alterations in ERBB2 were observed in 15% (552/3753) of cases and, similarly, ERBB2 amplification was the most commonly observed alteration (278/552; 50%); ERBB2exon20ins occurred in 3.6% (20/552) of cases. EGFRexon20ins and ERBB2exon20ins occurred in younger patients (median age 62 vs 69 years, P = 2.6E-2 and 60 vs 68 years, P = 7.8E-4), and these cases had significantly lower TMB (median 3.6 vs 7.2, P = 2.7E-4 and 2.5 vs 10, P = 1.2E-7) and less frequent TP53 alterations (3.7% vs 83%, P = 4.3E-14 and 20% vs 68%, P = 9.8E-4) compared to cases with other EGFR or ERBB2 alterations. Conclusion EGFR and ERBB2 alterations occur in 4% and 15% of UC, respectively. EGFRexon20ins and ERBB2exon20ins were present in 0.7% and 0.5% of UC overall and collectively define a small, but distinct, subset of UC with infrequent co-occurrence of other drivers and low TMB. Given recent promising clinical studies of inhibitors with activity against exon 20 insertions in non-small cell lung cancer, consideration should be given to developing a trial inclusive of patients with UC harbouring these alterations.
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- 2020
36. Characterization of Clinical Cases of Malignant PEComa via Comprehensive Genomic Profiling of DNA and RNA
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Evgeny Yakirevich, Garrett M. Frampton, Claire Edgerly, Russell Madison, Arjun Vasant Balar, Shridar Ganesan, Jeffrey S. Ross, Alexa B. Schrock, Saranya Akumalla, Douglas I. Lin, Vincent A. Miller, Margaret Rosenzweig, Rachel L. Erlich, and Siraj M. Ali
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Cancer Research ,RNA ,Locus (genetics) ,TFE3 ,General Medicine ,Biology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,030212 general & internal medicine ,TSC1 ,Folliculin ,Gene ,PI3K/AKT/mTOR pathway ,DNA - Abstract
Purpose: Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal soft tissue neoplasm often linked to mTOR pathway activation via TSC2 mutation. We analyzed a series of 31 consecutive metastatic PEComa (mPEComa) cases using a combined DNA/RNA hybrid capture-based comprehensive genomic profiling (CGP) assay to assess the genomic landscape of mPEComa. Patients and Methods: Formalin-fixed, paraffin-embedded (FFPE) blocks or slides were obtained from tumors from 31 unique patients with mPEComa. DNA and RNA were extracted and CGP was performed on 405 genes using a targeted next-generation sequencing (NGS) assay in a CLIA-certified lab. Results: All cases had locally advanced or metastatic disease, and 58% of patients were female with a median age of 50 years (range 8–76), and 17 and 14 specimens were from primary and metastatic sites, respectively. One hundred genomic alterations were identified in the cohort, with an average of 3.2 genomic alterations/case including alterations in TSC2 32.3% of cases (10), TSC1 9.6% (3), TFE3 16.1% (5, all fusions), and folliculin (FLCN) 6.4% (2), with all occurring in mutually exclusive fashion. Of TSC2 mutant cases, 70% had biallelic inactivation of this locus, as were 100% of TSC1 mutant cases. Two TSC1/2 wildtype cases harbored truncating mutations in FLCN, both of which were under LOH. Five TFE3 fusion cases were identified including the novel 5′ fusion partner ZC3H4. Conclusions: We describe for the first time mPEComa cases with FLCN mutations under LOH, further characterizing dysregulation of the mTOR pathway as a unifying theme in mPEComa. Cumulatively, we demonstrate the feasibility and potential utility of segregating mPEComa by TSC, TFE3, and FLCN status via CGP in clinical care.
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- 2020
37. HPV51-associated Leiomyosarcoma: A Novel Class of TP53/RB1-Wildtype Tumor With Predilection for the Female Lower Reproductive Tract
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Erik A. Williams, Meagan Montesion, Vadim Lincoln, Julie Y. Tse, Matthew C. Hiemenz, Douglas A. Mata, Bhamini B. Shah, Adebowale Shoroye, Brian M. Alexander, Adrienne J. Werth, Kathleen Foley-Peres, Riza R. Milante, Jeffrey S. Ross, Shakti H. Ramkissoon, Kevin Jon Williams, Laura J. Adhikari, Rosemary E. Zuna, Philip E. LeBoit, Douglas I. Lin, and Julia A. Elvin
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Leiomyosarcoma ,Retinoblastoma Binding Proteins ,Ubiquitin-Protein Ligases ,Papillomavirus Infections ,Humans ,Surgery ,Female ,Anatomy ,Middle Aged ,Tumor Suppressor Protein p53 ,Papillomaviridae ,In Situ Hybridization ,Pathology and Forensic Medicine - Abstract
Inactivating mutations in tumor suppressor genes TP53 and RB1 are considered central drivers in leiomyosarcomas (LMSs). In high-risk human papillomavirus (HPV)-related tumors, a similar functional outcome is achieved through oncoproteins E6 and E7, which inactivate the p53 and RB1 proteins, respectively. Here, we hypothesized that HPV infection could provide an alternative mechanism for tumorigenesis in a subset of TP53/RB1-wildtype LMS. We evaluated tumor samples from 2585 consecutive unique patients carrying a diagnosis of gynecologic or soft tissue LMS. Tumor DNA and available RNA were analyzed by hybrid-capture-based next-generation sequencing/comprehensive genomic profiling of 406 genes and transcripts (FoundationOneHeme). Of the initial 2585 cases, we excluded 16 based on the presence of molecular alterations that are considered defining for sarcomas other than LMS. In the remaining 2569 cases, we searched for LMS that were TP53/RB1-wildtype (n=486 of 2569; 18.9%). We also searched LMS tumors for HPV sequences that we then classified into genotypes by de novo assembly of nonhuman sequencing reads followed by alignment to the RefSeq database. Among TP53/RB1-wildtype LMS, we identified 18 unique cases harboring HPV sequences. Surprisingly, most (n=11) were HPV51-positive, and these 11 represented all HPV51-positive tumors in our entire LMS database (n=11 of 2569; 0.4%). The absence of genomic alterations in TP53 or RB1 in HPV51-positive LMS represented a marked difference from HPV51-negative LMS (n=2558; 0% vs. 72% [P0.00001], 0% vs. 53% [P=0.0002]). In addition, compared with HPV51-negative LMS, HPV51-positive LMS were significantly enriched for genomic alterations in ATRX (55% vs. 24%, P=0.027) and TSC1 (18% vs. 0.6%, P=0.0047). All HPV51-positive LMS were in women; median age was 54 years at surgery (range: 23 to 74 y). All known primary sites were from the gynecologic tract or adjacent anogenital area, including 5 cases of vaginal primary site. Histology was heterogeneous, with evaluable cases showing predominant epithelioid (n=5) and spindle (n=5) morphology. In situ hybridization confirmed the presence of high-risk HPV E6/E7 mRNA in tumor cells in three of three evaluable cases harboring HPV51 genomic sequences. Overall, in our pan-LMS analysis, HPV reads were identified in a subset of TP53/RB1-wildtype LMS. For all HPV51-associated LMS, the striking absence of any detectable TP53 or RB1 mutations and predilection for the female lower reproductive tract supports our hypothesis that high-risk HPV can be an alternative tumorigenic mechanism in this distinct class of LMS.
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- 2022
38. Comparative Effectiveness of Immune Checkpoint Inhibitors vs Chemotherapy in Patients With Metastatic Colorectal Cancer With Measures of Microsatellite Instability, Mismatch Repair, or Tumor Mutational Burden
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Julia C. F. Quintanilha, Ryon P. Graf, Virginia A. Fisher, Geoffrey R. Oxnard, Haley Ellis, Nicole Panarelli, Douglas I. Lin, Gerald Li, Richard S. P. Huang, Jeffrey S. Ross, Parvathi A. Myer, and Samuel J. Klempner
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General Medicine - Abstract
ImportanceThe KEYNOTE-177 trial demonstrated that patients with metastatic colorectal cancer (MCRC) with high microsatellite instability (MSI-H) and/or mismatch repair deficiency (DMMR) have better outcomes when receiving first-line immune checkpoint inhibitors (ICIs) compared with chemotherapy. Data on performance of ICIs in patients with MCRC in standard practice settings remain limited, and direct MMR vs MSI outcome association comparisons are lacking.ObjectiveTo validate MSI (determined by next-generation sequencing [NGS]) as a biomarker of ICI effectiveness among patients with MCRC in standard practice settings and examine the association of MSI assessed by NGS, DMMR by immunohistochemistry, and tumor mutational burden (cutoff, 10 mutations/megabase) with ICI outcomes.Design, Setting, and ParticipantsThis comparative effectiveness research study of outcomes in prospectively defined biomarker subgroups used data from a deidentified clinicogenomic database and included patients who received Foundation Medicine testing (FoundationOne or FoundationOne CDx) during routine clinical care at approximately 280 US academic or community-based cancer clinics between March 2014 and December 2021. The population included 1 cohort of patients with MSI-H MCRC who received first-line ICIs or chemotherapy and a second cohort who received ICIs in any line of therapy (LOT) for biomarker examination.ExposuresICI therapy or chemotherapy assigned at physician discretion without randomization.Main Outcomes and MeasuresThe main outcomes were time to next treatment (TTNT), progression-free survival (PFS), and overall survival (OS). Hazard ratios were adjusted for known prognostic imbalances. Comparisons of explanatory power used the likelihood ratio test.ResultsA total of 138 patients (median age, 67.0 years [IQR, 56.2-74.0 years]; 73 [52.9%] female) with MSI-H MCRC received first-line ICIs or chemotherapy. A total of 182 patients (median age, 64.5 years [IQR, 55.2-72.0]; 98 [53.8%] female) received ICIs in any LOT. Patients receiving first-line ICIs vs chemotherapy had longer TTNT (median, not reached [NR] vs 7.23 months [IQR, 6.21-9.72 months]; adjusted hazard ratio [AHR], 0.17; 95% CI, 0.08-0.35; P P P = .02). MSI added to DMMR better anticipated TTNT and PFS in patients receiving ICIs than DMMR alone. The same was not observed when DMMR evaluation was added to MSI.Conclusions and RelevanceIn this comparative effectiveness research study, MSI assessed by NGS robustly identified patients with favorable outcomes on first-line ICIs vs chemotherapy and appeared to better anticipate ICI outcomes compared with DMMR.
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- 2023
39. Endometrioid Tubal Intraepithelial Neoplasia (E-TIN) of the Fallopian Tube: A Case Series
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Leslie A. Garrett, Jonathan L. Hecht, and Douglas I. Lin
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,animal structures ,endocrine system diseases ,Serous carcinoma ,Endometrium ,Pathology and Forensic Medicine ,Diagnosis, Differential ,03 medical and health sciences ,0302 clinical medicine ,Carcinoma ,Fallopian Tube Neoplasms ,Humans ,Medicine ,neoplasms ,Fallopian Tubes ,beta Catenin ,Aged ,Intraepithelial neoplasia ,urogenital system ,business.industry ,PAX2 Transcription Factor ,Obstetrics and Gynecology ,Serous Tubal Intraepithelial Carcinoma ,Middle Aged ,Hyperplasia ,medicine.disease ,female genital diseases and pregnancy complications ,Endometrial Neoplasms ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,Tumor Suppressor Protein p53 ,Differential diagnosis ,business ,Carcinoma, Endometrioid ,Precancerous Conditions ,Carcinoma in Situ ,Fallopian tube - Abstract
Although serous tubal intraepithelial carcinoma has been well described in the distal fallopian tube as precancers of pelvic high-grade serous carcinoma, endometrioid precancers have drawn less attention. Recently, endometrioid precursor lesions have been identified and reported to have a specific immunophenotype (PAX2-, ALDH1+, diffuse nuclear beta-catenin), as well as an association with both uterine and ovarian endometrioid carcinomas. These have been referred to as endometrioid (or type II) secretory cell outgrowths. A subset of endometrioid secretory cell outgrowths show architectural complexity resembling hyperplasia of the endometrium and have been referred to as endometrioid tubal intraepithelial neoplasia. We report 4 cases of endometrioid tubal intraepithelial neoplasia with clinical correlation and morphologic differential diagnosis.
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- 2019
40. Molecular analysis of endometrial serous carcinoma reveals distinct clinicopathologic and genomic subgroups
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Douglas I. Lin, Alexander Fine, Natalie A. Danziger, Richard S.P. Huang, Douglas A. Mata, Brennan Decker, Jonathan K. Killian, Shakti H. Ramkissoon, Mirna Lechpammer, Tyler Janovitz, Jeffrey S. Ross, Ethan S. Sokol, and Julia A. Elvin
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Oncology ,Class I Phosphatidylinositol 3-Kinases ,Mutation ,Biomarkers, Tumor ,Obstetrics and Gynecology ,Humans ,Female ,Microsatellite Instability ,Carcinoma, Endometrioid ,Cystadenocarcinoma, Serous ,Endometrial Neoplasms ,Retrospective Studies - Abstract
Endometrial serous carcinoma (EMSC) is an aggressive variant of uterine cancer with limited therapeutic options. We sought to define distinct clinicopathologic and genomic EMSC subgroups.We retrospectively analyzed 2159 EMSC and 2346 endometrioid-type endometrial carcinomas (EEC) tissue specimens that had undergone comprehensive genomic profiling (CGP) via the FoundationOne CDx assay during routine clinical care. High tumor mutational burden (TMB) was defined as ≥10mut/Mb using the FDA-approved CDx cutoff for pembrolizumab. Microsatellite instability (MSI) was determined on 95 loci. Evidence of homologous recombination deficiency (HRD) was determined via genomic loss of heterozygosity (gLOH), a validated HRD detection method for predicting PARP inhibitor effectiveness in ovarian carcinoma. High gLOH was defined as ≥16%.A genomic analysis of 2159 EMSCs revealed a predominance of TP53 mutations, microsatellite stability, low tumor mutational burden (TMB), and recurrent alterations of PIK3CA, PPP2R1A, ERBB2, CCNE1, FBXW7 and MYC. Evidence of HRD via high gLOH was identified in 22% of EMSCs. BRCA1 and BRCA2 alterations, as well as unique SET (solid, pseudo-endometrioid, and transitional cell-like) variant morphology, were enriched in HRD-EMSC. There was an increased frequency of CCNE1 amplification, a lower prevalence of PIK3CA and PPP2R1A alterations, and no differences in HRD, MSI or TMB biomarker frequencies in patients of predicted African ancestry. EMSC exhibited distinct gene mutation frequencies and MSI, TMB and gLOH biomarker signatures compared to a cohort 2346 EEC.Molecularly defined subgroups provide a framework to test the susceptibility of EMSC to targeted therapies in specific genetic settings (e.g. HRD, PIK3CA, PPP2R1A, ERBB2, MYC, CCNE1).
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- 2021
41. MP40-14 A COMPARATIVE GENOMIC PROFILING STUDY OF DIFFERING CLINICALLY ADVANCED PELVIC SQUAMOUS CELL CARCINOMAS
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Joseph M. Jacob, Andrea Necchi, Jeffrey R. Ross, Natalie Danzinger, Ole Gjoerup, Ethan Sokol, Philippe E. Spiess, Gennady Bratslavsky, DA Matta, Brennan Decker, Douglas I. Lin, and Richard Huang
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Genomic profiling ,medicine.anatomical_structure ,business.industry ,Urology ,Cell ,Cancer research ,Medicine ,business - Published
- 2021
42. Contrasting genomic profiles from metastatic sites, primary tumors, and liquid biopsies of advanced prostate cancer
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Ethan Sokol, Andrea Necchi, Jonathan Keith Killian, Hanna Tukachinsky, Joseph Jacob, Richard S.P. Huang, Petros Grivas, Alexa B. Schrock, Philippe E. Spiess, Jeffrey M. Venstrom, Douglas I. Lin, Jeffrey S. Ross, Gennady Bratslavsky, Ole Gjoerup, Vito Cucchiara, Russell Madison, Shakti H. Ramkissoon, Natalie Danziger, Ryon Graf, Geoffrey R. Oxnard, Brennan Decker, Necchi, A., Cucchiara, V., Grivas, P., Bratslavsky, G., Jacob, J., Spiess, P. E., Sokol, E. S., Killian, J. K., Lin, D., Ramkissoon, S., Huang, R. S. P., Madison, R. W., Venstrom, J. M., Schrock, A. B., Danziger, N., Decker, B., Gjoerup, O., Graf, R. P., Oxnard, G. R., Tukachinsky, H., and Ross, J. S.
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Male ,Cancer Research ,medicine.medical_treatment ,TMPRSS2 ,Somatic evolution in cancer ,Targeted therapy ,Circulating Tumor DNA ,Prostate cancer ,medicine ,Biomarkers, Tumor ,PTEN ,Humans ,Lymph node ,circulating tumor DNA ,biology ,comprehensive genomic profiling ,business.industry ,Liquid Biopsy ,biomarkers ,High-Throughput Nucleotide Sequencing ,Prostatic Neoplasms ,Genomics ,prostate cancer ,targeted therapy ,medicine.disease ,medicine.anatomical_structure ,Oncology ,Tumor progression ,Mutation ,biology.protein ,Cancer research ,Microsatellite Instability ,business ,Erg - Abstract
Background This study assessed the contrasting genomic profiles from the primary tumors (PTs), metastatic (MET) sites, and circulating tumor DNA (ctDNA) of patients with prostate cancer (PC). Methods A total of 1294 PC tissue specimens and 2462 ctDNA specimens underwent hybrid capture-based comprehensive genomic profiling (CGP). Specimens included tissue from PTs; MET biopsies from bone, liver (LIV), lung (LU), brain (BN), lymph node, and soft tissue sites; and ctDNA. Results Differences in alteration frequencies between PT, MET, and ctDNA specimens for selected genes were observed. TMPRSS2:ERG fusion frequencies were similar between PTs and MET sites (35% vs 33%) but varied among MET sites. Genomic alterations (GAs) in AR were lowest in PTs (2%) and highest in MET sites (from 24% in LU to 50% in LIV). BN had the highest genomic alterations/tumor (8) and enrichment for PTEN GAs. The BRCA2 GA frequency varied from 0% in BN to 15% in LIV. ERBB2 amplification was increased in MET sites in comparison with PTs. RB1 GAs were increased in LIV. Biomarkers potentially associated with an anti-PD(L)1 response included CDK12 GAs (16% in LU) and a microsatellite instability-high status (29% in BN). Analyses of ctDNA featured a broad spectrum of GAs similar to those detected across MET sites. Conclusions CGP of PTs, MET sites, and ctDNA in PC exhibited differences most likely associated with tumor progression, clonal evolution, and exposure to systemic therapies; ctDNA can also capture a broad range of potential therapeutic opportunities for patients with PC.
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- 2021
43. Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2)
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Ling Ma, Tanya T. Kwan, Clare L. Scott, Isabelle Ray-Coquard, Ana Oaknin, Alexander Dobrovic, Robert L. Coleman, Iain A. McNeish, Andrea E. Wahner Hendrickson, Lee-may Chen, Alexandra Leary, Stephen Welch, Thomas Harding, Lara Maloney, Carol Aghajanian, Kevin K. Lin, Heidi Giordano, E. Dominy, Ashan Musafer, Gottfried E. Konecny, Scott H. Kaufmann, Diane Provencher, Julia A. Elvin, Oliver Dorigo, Sandra Goble, R Kristeleit, Douglas I. Lin, Anna V. Tinker, Amit M. Oza, Setsuko K. Chambers, David M. O'Malley, Elizabeth M. Swisher, Prafull Ghatage, Lan Thanh Vo, Institut Català de la Salut, [Swisher EM] University of Washington, Seattle, WA, USA. [Kwan TT] Clovis Oncology, Inc., Boulder, CO, USA. [Oza AM] Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. [Tinker AV] BC Cancer—Vancouver, Vancouver, BC, Canada. [Ray-Coquard I] GINECO, Centre Léon Bérard and University Claude Bernard, Lyon, France. [Oaknin A] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Imperial College Healthcare NHS Trust- BRC Funding, Cancer Research UK, and Ovarian Cancer Action
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0301 basic medicine ,Indoles ,endocrine system diseases ,General Physics and Astronomy ,neoplasias::neoplasias por localización::neoplasias de las glándulas endocrinas::neoplasias ováricas [ENFERMEDADES] ,Carcinoma, Ovarian Epithelial ,Other subheadings::Other subheadings::/drug therapy [Other subheadings] ,Poly (ADP-Ribose) Polymerase Inhibitor ,Tumour biomarkers ,chemistry.chemical_compound ,0302 clinical medicine ,Ovarian carcinoma ,Ovarian Epithelial ,80 and over ,Medicine ,Promoter Regions, Genetic ,Cancer ,Aged, 80 and over ,Ovarian Neoplasms ,neoplasias::procesos neoplásicos::recurrencia neoplásica local [ENFERMEDADES] ,Multidisciplinary ,BRCA1 Protein ,Ovaris - Càncer - Tractament ,Cell cycle ,Middle Aged ,BRCA2 Protein ,female genital diseases and pregnancy complications ,Ovarian Cancer ,DNA-Binding Proteins ,Local ,030220 oncology & carcinogenesis ,DNA methylation ,PARP inhibitor ,RAD51C ,Female ,Adult ,Science ,Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] ,Antineoplastic Agents ,Poly(ADP-ribose) Polymerase Inhibitors ,General Biochemistry, Genetics and Molecular Biology ,Article ,Promoter Regions ,03 medical and health sciences ,Rare Diseases ,Genetic ,Clinical Research ,Ovarian cancer ,Neoplasms::Neoplastic Processes::Neoplasm Recurrence, Local [DISEASES] ,Genetics ,Humans ,Rucaparib ,Ovaris - Càncer - Recaiguda ,Aged ,Platinum ,business.industry ,Neoplasms::Neoplasms by Site::Endocrine Gland Neoplasms::Ovarian Neoplasms [DISEASES] ,Carcinoma ,General Chemistry ,DNA Methylation ,030104 developmental biology ,Good Health and Well Being ,Neoplasm Recurrence ,chemistry ,Cancer research ,Neoplasm Recurrence, Local ,business - Abstract
ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1/BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity., The identification of biomarkers of response to PARP inhibitors can enable selection of appropriate ovarian cancer patients for treatment. In this study, the authors report clinical results and exploratory biomarker analyses from the ARIEL2 phase 2 clinical trial on the safety and efficacy of the PARP inhibitor rucaparib in patients with recurrent ovarian cancers
- Published
- 2021
44. Abstract P4-06-07: PIK3CA-mutant breast phyllodes tumors show a uniformly aggressive histology and significant mutual exclusivity with MED12 mutation
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Nhu Ngo, Ethan Sokol, Vincent A. Miller, Nikunj Shah, Dean Pavlick, Jeffrey S. Ross, Erik A. Williams, Jo-Anne Vergilio, Douglas I. Lin, Jonathan Keith Killian, and Julia A. Elvin
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Cancer ,Histology ,Disease ,medicine.disease ,MED12 ,Breast cancer ,CDKN2A ,Internal medicine ,medicine ,Histopathology ,business ,Fibroepithelial neoplasms - Abstract
Introduction: De-regulation of the class I phosphoinositide 3’-kinase (PI3K) pathway has long been known to contribute to the development and progression of many tumors. However, the FDA only recently approved the first selective inhibitor of PIK3CA, the p110-alpha catalytic subunit of PI3K, specifically for use in treatment of a subset of PIK3CA-mutant breast carcinomas. Given the emergence of this therapeutic class of agents, we sought to identify other subsets of breast tumors that may be driven largely by PIK3CA mutations and which therefore could be candidates for these therapies. In breast fibroepithelial neoplasms, mutations in PIK3CA have been occasionally reported in borderline and malignant phyllodes tumors. In contrast, mutations in MED12 are common and recurrent across the entire spectrum of benign and malignant breast fibroepithelial tumors, and are enriched in borderline/malignant phyllodes cases that still have benign fibroadenoma-like areas. In the current study, we sought to define the histologic and molecular features of PIK3CA-mutant phyllodes tumors. Methods: From 2014 to 2019, we analyzed clinical tumor samples using comprehensive genomic profiling by a hybrid capture-based DNA sequencing platform. We searched our case archive to find breast phyllodes tumors with known or likely pathogenic alterations in PIK3CA and other known tumor-related genes. All cases were clinically advanced. We reviewed pathology reports, histopathology, and patient clinical data. Results: We identified 12 (16%) of 76 breast phyllodes tumors in our case archive as PIK3CA-mutant. Median patient age for PIK3CA-mutant phyllodes tumors was 56 years. Cases consisted of 6 primary tumors, 2 local recurrences, and 4 lung metastases. Primary tumor size measured from 38 to 220 mm (median 100 mm; mean 114 mm). Digital slides were available for histology review in 9 cases. Cases showed uniformly malignant histology, with no benign or fibroadenoma-like regions. 3 cases showed malignant heterologous elements. Compared to the rest of our breast phyllodes tumor cohort, PIK3CA-mutant cases showed significantly fewer pathogenic genomic alterations in MED12 (8% vs. 55%, p=0.0037) and TP53 (17% vs. 56%, p=0.0245), as well as a trend to fewer mutations in RB1 (0% vs. 22%, p=0.11). The other most frequently mutated genes in the PIK3CA-mutant group were TERTp (70%), CDKN2A (67%), and NF1 (50%). Conclusions: PIK3CA-mutant phyllodes tumors define a unique subset of tumors characterized by aggressive histologic features and largely lacking the MED12 mutations seen in many fibroepithelial neoplasms. These findings provide compelling rationale for comprehensive genomic profiling of advanced cases of this disease in an effort to inform therapeutic options including clinical trials of PI3K-targeted agents in this setting. Citation Format: Erik A Williams, Ethan S Sokol, Dean C Pavlick, Nikunj Shah, Julia A Elvin, Jo-Anne Vergilio, Jonathan K Killian, Nhu Ngo, Douglas Lin, Vincent A Miller, Jeffrey S Ross. PIK3CA-mutant breast phyllodes tumors show a uniformly aggressive histology and significant mutual exclusivity with MED12 mutation [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-06-07.
- Published
- 2020
45. Comparing histologic evaluation of prostate tissue using nonlinear microscopy and paraffin H&E: a pilot study
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Oscar Carrasco-Zevallos, Tadayuki Yoshitake, Michael G. Giacomelli, James G. Fujimoto, Yubo Wu, Huihui Ye, Douglas I. Lin, Lucas C. Cahill, Seymour Rosen, and Andrew A. Wagner
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Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Time Factors ,Materials science ,Microscope ,H&E stain ,Perineural invasion ,Pilot Projects ,Article ,Workflow ,Pathology and Forensic Medicine ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Predictive Value of Tests ,Prostate ,law ,Microscopy ,medicine ,Humans ,Coloring Agents ,Hematoxylin ,Prostatectomy ,Frozen section procedure ,Intraoperative Care ,Staining and Labeling ,Margins of Excision ,Prostatic Neoplasms ,Reproducibility of Results ,Histology ,Microscopy, Fluorescence, Multiphoton ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Eosine Yellowish-(YS) ,Prostate surgery - Abstract
Rapid histological assessment of large areas of prostate tissue is required for many intraoperative consultation scenarios such as margin evaluation. Nonlinear microscopy (NLM) enables imaging of large (whole mount) specimens without freezing or cryotoming. This study demonstrates rapid histological imaging of unsectioned prostate cancer surgical specimens using nonlinear microscopy and compares features of prostate pathology to standard paraffin embedded H&E histology. Fresh or formalin fixed specimens were stained in 2.5 min with fluorescent nuclear and stromal dyes. Nonlinear microscopy images of unsectioned tissues were generated by nonlinear (two-photon) excitation of the fluorophores, where fluorescence is only emitted from tissue at the microscope focus, avoiding the need for physical sectioning. The images were displayed in real time using a color scale similar to H&E, then tissues were processed for standard paraffin embedded H&E histology. Seventy nonlinear microscopy and corresponding paraffin H&E images of fresh and fixed prostate specimens (15 cancer, 55 benign) from 24 patients were read by genitourinary pathologists to assess if nonlinear microscopy could achieve an equivalent evaluation to paraffin embedded H&E histology. Differences between nonlinear microscopy images and paraffin H&E slides, including cytoplasmic color and stromal density, were observed, however nonlinear microscopy images could be interpreted with minimal training. Nonlinear microscopy enabled visualization of benign, atrophic and hyperplastic glands and stroma, ejaculatory ducts, vasculature and inflammatory changes. Nonlinear microscopy enabled identification of typical and variants of adenocarcinoma, as well as Gleason patterns. Perineural invasion and extraprostatic extension could also be assessed. Nonlinear microscopy images closely resemble paraffin H&E slides and enable rapid assessment of normal prostate architecture, benign conditions, and carcinoma in freshly excised and fixed specimens. Nonlinear microscopy can image large regions of tissue, equivalent to multiple frozen section tissue blocks, within minutes because cryotoming/microtoming are not required, making it a promising technique for intraoperative consultation.
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- 2019
46. MDM2 amplification and immunohistochemical expression in sarcomatoid renal cell carcinoma
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Alexander C. Mackinnon, Shira Ronen, Saul Suster, David Suster, Ondrej Hes, Jess F. Peterson, and Douglas I. Lin
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0301 basic medicine ,Polysomy ,Pathology ,medicine.medical_specialty ,biology ,medicine.diagnostic_test ,business.industry ,Cell ,medicine.disease ,Pathology and Forensic Medicine ,Metastasis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Renal cell carcinoma ,030220 oncology & carcinogenesis ,Gene duplication ,medicine ,biology.protein ,Mdm2 ,Immunohistochemistry ,business ,Fluorescence in situ hybridization - Abstract
Summary The sarcomatoid variant of renal cell carcinoma is a highly aggressive tumor with propensity for metastasis and limited therapeutic options. Metastases of sarcomatoid renal cell carcinoma can sometimes be mistaken for a variety of spindle cell sarcomas, particularly at soft tissue sites in the absence of a history of a kidney tumor. Immunoreactivity for markers associated with certain types of soft tissue sarcomas can, therefore, pose a pitfall for diagnosis under such circumstances. We evaluated the immunohistochemical and molecular features of 49 cases of sarcomatoid renal cell carcinoma with special emphasis on the expression of MDM2 by immunohistochemistry and MDM2 amplification by fluorescence in situ hybridization. Of the 49 sarcomatoid renal cell carcinoma cases evaluated by fluorescence in situ hybridization, 5 (10%) were positive for MDM2 gene amplification and 5 (10%) contained polysomy 12. Immunohistochemical nuclear expression for MDM2 was also observed in 30/49 (61%) cases; of these, 15/19 (78%) were metastatic and 15/30 (50%) were primary. MDM2 expression by immunohistochemistry has been previously reported in conventional clear cell renal cell carcinoma; however, occurrence of this phenomenon has not yet been properly assessed in the sarcomatoid variant of renal cell carcinoma. Our study demonstrates that alterations of the MDM2 pathway are relatively frequent in sarcomatoid renal cell carcinoma, and nuclear positivity for MDM2 by immunohistochemistry, as well as MDM2 amplification by fluorescence in situ hybridization may pose a potential pitfall for diagnosis with dedifferentiated liposarcoma at metastatic sites. A panel approach to immunohistochemical testing is recommended for the diagnosis of these lesions. Also, identification of cases of sarcomatoid renal cell carcinomas harboring MDM2 copy number gain or gene amplification may also have potential therapeutic implications.
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- 2019
47. Landscape of homologous recombination reversion mutations in gynecologic malignancies
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Susan M. Domchek, Kim Anna Reiss, Kate Nathanson, Shannon Bailey, Natalie Danziger, James Thornton, Mark Hartman, Chenming Cui, Lei Yang, Matthew Margolis, Erica Gornstein, Ethan Sokol, Douglas I. Lin, Alexa Betzig Schrock, Douglas A Mata, Christine Vietz, Jeffrey S. Ross, Geoffrey R. Oxnard, Julia Andrea Elvin, and Brennan James Decker
- Subjects
Cancer Research ,Oncology - Abstract
5576 Background: Homologous recombination (HR) reversion mutations (REV) are biomarkers for predicting resistance to platinum and PARP inhibitor therapies. The biologic diversity of REV represents a diagnostic challenge. An automated computational approach was used to detect REV for analysis of genomic features of REV-positive ovarian epithelial, fallopian tube, and peritoneal cancers. Methods: Retrospective study of tissue (n = 23,612) and liquid biopsy (n = 869) samples from patients undergoing hybrid-capture comprehensive genomic profiling during routine clinical care 11/2012-03/2021. A proprietary algorithm tested for seven distinct REV mechanisms in BRCA1, BRCA2, PALB2, RAD51C, or RAD51D. For subjects with multiple samples, the earliest REV-positive sample was used for downstream analyses. Results: Among 23,866 ovarian epithelial, fallopian tube, and peritoneal cancers, 16.4% (n = 3,920) had at least one pathogenic variant (PV) in BRCA1 (10%, n = 2,383), BRCA2 (5.5%, n = 1,320), PALB2 (0.67%, n = 160), RAD51C (0.64%, n = 152), or RAD51D (0.47%, n = 113). 3.9% (154/3,920) of patients with one or more PV had REV. REV were found in tumors with PV in BRCA2 at twice the frequency of BRCA1 (6.0%, [79/1,320] vs 3.0% [71/2,383]; p < 0.001). REV involving RAD51D (1.8%, 2/113), RAD51C (0.7%, 1/152), or PALB2 (0.6%, 1/160) were rarer. A total of 193 REV pairs were identified. The most frequent REV mechanism was an exonic non-frameshift deletion completely encompassing a PV (45%, 87/193). Other recurrent mechanisms included restoration of the reading frame of a frameshift PV (21%, 42/193), replacement of a PV with a benign missense substitution at the same codon (16%, 32/193), and deletion with intronic breakpoints encompassing a PV (15%, 29/193). REV were significantly more prevalent in liquid biopsies than in tissue samples with PV (16% [20/124] vs. 3.5% [134/3,796]; p < 0.001). A range of 1-6 REV pairs were found per sample (liquid: 1-6, tissue: 1-3). Multiple REV per sample was more common in liquid biopsies (35% [7/20] vs. 11% [15/134]; p = 0.011). These differences likely reflect stage of disease and sampling of multiple subclones. Conclusions: BRCA2 PV are most frequently reverted in gynecologic tumors. REV are also common in tumors with BRCA1 PV and can more rarely occur in other HR genes. Liquid biopsy is enriched for detection of polyclonal resistance. Diverse REV mechanisms highlight a need for robust detection to incorporate REV in identifying treatment resistance and guiding downstream therapy selection.
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- 2022
48. Landscape of fibroblast growth factor receptor (FGFR) genomic alterations (GA) in urothelial bladder cancer (UBC)
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Maroun Bou Zerdan, Gennady Bratslavsky, Joseph M Jacob, Richard S.P. Huang, Oleksandr Kravtsov, Vamsi Parimi, Douglas I. Lin, Ryon Graf, Natalie Danziger, Jeffrey S. Ross, Hanan Goldberg, and Alina Basnet
- Subjects
Cancer Research ,Oncology - Abstract
4568 Background: Urothelial bladder carcinomas (UBC) with genomic alterations (GA) in the Fibroblast Growth Factor Receptor ( FGFR) genes have been postulated to be less responsive to immune checkpoint inhibitors (ICI). Immune microenvironment of these tumors could be altered due to suppression of interferon signaling pathways. Here, we present comprehensive genomic profiling (CGP) of FGFR altered UBC to study the underlying immunogenomic mechanisms of response and resistance. Methods: 4,035 UBC underwent hybrid capture based CGP. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined using 114 loci. Programmed death ligand (PD-L1) expression in tumor cells was assessed by IHC (Dako 22C3). Results: 894 (22%) of UBC featured FGFR GA ( FGFR1 3.7%; FGFR2 1.1%; FGFR3 17.4%). Gender and age distribution was similar in all groups. FGFR3 cases had lower GA/tumor and 14.7% GA were fusions. ERBB2 amplification was significantly higher in FGFR1/2 altered UBC compared with FGFR3 altered UBC. MTOR pathway GA were highest in FGFR3 altered UBC. FGFR3 altered UBC featured significantly higher frequencies of biomarkers predicting resistance to ICI including lower TMB, lower PD-L1 expression and higher frequencies of GA in MDM2. FGFR3 driven UBC also features significantly higher frequencies of CDKN2A/B loss and MTAP loss which have also recently been linked to IO drug resistance. Conclusions: UBC harboring FGFR GA have increased frequency of alterations that have been linked to ICI resistance. Further evaluation of FGFR-based biomarkers in UBC clinical trials focused on the assessment of the patient response to ICI appears warranted. [Table: see text]
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- 2022
49. Biomarker associations of immune checkpoint inhibitor versus chemotherapy effectiveness in first-line metastatic endometrial carcinomas: A real-world study
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Alessandro Santin, Ryon Graf, Kunal J. Shah, Andrew David Kelly, Natalie Danziger, Douglas I. Lin, Geoffrey R. Oxnard, and Julia Andrea Elvin
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Cancer Research ,Oncology - Abstract
5596 Background: Limited evidence exists comparing outcomes of single-agent anti-PD1 immune checkpoint inhibitors (ICPI) vs. chemotherapy in the 1st line among metastatic endometrial carcinoma (mEC) patients. dMMR, MSI status, and Tumor Mutational Burden (TMB) have been characterized as predictive biomarkers of ICPI response in many solid tumors, including mEC. We sought to evaluate ICPI vs. chemotherapy effectiveness in 1st line mEC, stratified by TMB ≥ 10 mut/MB and MSI as assessed by next-generation sequencing. Methods: Following a prespecified analysis plan, this study used the nationwide (̃280 US cancer clinics) de-identified, EHR-derived, Flatiron Health-Foundation Medicine mEC clinico-genomic database (FH-FMI CGDB), with tissue CGP between 1/2011 - 6/2021. Cohort inclusion criteria: recurrent mEC patients with stage I-III at original diagnosis, 1st line ICPI or platinum chemotherapy treatment with TMB and MSI assessments available. Adjusted hazard ratios (aHR) from multivariable Cox proportional hazard models were utilized for time to next treatment (TTNT) and overall survival (OS) comparisons between 1L chemotherapy and 1L ICPI from start of 1L treatment stratified by TMB (≥ 10 vs. < 10) and adjusted for ECOG, BMI, and stage at diagnosis. Results: Among the 1st line cohort, patients received either Chemotherapy (n = 139, 87%) or first-line ICPI (n = 20, 13%). While the overlap between the TMB ≥ 10 (n = 46) population and MSI-H (n = 39) populations was high, with 38/46 (83%) of TMB ≥ 10 classified as MSI-H and 38/39 (97%) of MSI-H with a TMB ≥ 10, there were also 8 (17%) TMB ≥ 10 patients who were MSS. TMB ≥ 10 was associated with more favorable TTNT (aHR: 0.11 [0.03 - 0.44]) and OS (aHR: 0.1 [0.01 - 0.82]) on single-agent ICPIs vs. chemotherapy; however, TMB < 10 patients exhibited no observed differences in TTNT (aHR: 1.66 [0.79 - 3.48]) or OS (aHR: 1.79 [0.66 - 4.8]) between treatments. MSI-H pts were associated with more favorable TTNT (aHR: 0.1 [0.02 - 0.39]) and OS (aHR: 0.1 [0.01 - 0.86]) on single-agent ICPIs over chemotherapy; however, MSS pts did not observe differences in TTNT (aHR: 1.5 [0.65 - 3.5]) or OS (aHR: 2.14 [0.63 - 7.26]) between ICPI vs. chemotherapy. Conclusions: Recurrent 1st line mEC patients with TMB ≥ 10 and/or MSI-H exhibit more favorable outcomes on single-agent ICPI than standard chemotherapy in real-world settings. These findings warrant prospective randomized validation. Future studies should assess the utility of a combined biomarker approach across TMB and MSI status to identify the broadest group of patients who might benefit from ICPI.
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- 2022
50. Landscape of Biomarkers in Non-small Cell Lung Cancer Using Comprehensive Genomic Profiling and PD-L1 Immunohistochemistry
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Brian M. Alexander, Charlotte Brown, Douglas I. Lin, Deborah L. McEwan, N. Lynn Ferguson, Pratheesh Sathyan, Shakti H. Ramkissoon, Prasanth Reddy, Jeffrey S. Ross, Samantha Morley, Richard S.P. Huang, Amanda Hemmerich, Erik A. Williams, Jonathan Keith Killian, Garrett M. Frampton, Jeffrey M. Venstrom, Clarence Owens, Oliver Holmes, James Haberberger, Natalie Danziger, Rachel Anhorn, Jo-Anne Vergilio, Michael B. Cohen, Julia A. Elvin, Eric Allan Severson, Claire Edgerly, Kimberly McGregor, and Daniel L. Duncan
- Subjects
Male ,PD-L1 ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Cancer Research ,Lung Neoplasms ,STK11 ,medicine.disease_cause ,B7-H1 Antigen ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,Biomarkers, Tumor ,Humans ,Medicine ,Lung cancer ,non-small cell lung cancer ,Aged ,biology ,comprehensive genomic profiling ,business.industry ,biomarkers ,Cancer ,Genomics ,General Medicine ,Brief Research Report ,medicine.disease ,Immunohistochemistry ,Society Journal Archive ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,biology.protein ,Biomarker (medicine) ,Female ,Immunotherapy ,KRAS ,business ,Companion diagnostic - Abstract
Comprehensive genomic profiling (CGP) and immunohistochemistry (IHC) are important biomarker tools used for patients with non-small cell lung cancer (NSCLC) given the expanding number of standard-of-care therapies that require companion diagnostic testing. We examined 9450 NSCLC real-world patient samples that underwent both CGP and programmed death-ligand 1 (PD-L1) IHC to understand the biomarker landscape in this patient cohort. By assessing National Comprehensive Cancer Network (NCCN)-recommended biomarkers including genomic alterations, tumor mutational burden (≥10 mutations/Mb cut-off), and PD-L1 expression (Tumor Proportion Score (TPS) ≥ 50% cut-off), we show that CGP + PD-L1 IHC yielded potentially actionable results for 70.5% of the 9,450 patients with NSCLC. Among the remaining 29.5% (2,789/9,450) of patients, 86.7% (2,419/2,789) were potentially eligible for another biomarker-associated therapy and/or clinical trial based on their genomic profile. In addition, in the PD-L1TPS≥50% disease subset, BRAF mutations, MET mutations, MET amplifications, and KRAS mutations were significantly enriched; and in the PD-L1TPS, EGFR mutations, ERBB2 mutations, STK11 mutations, and KEAP1 mutations were enriched. These findings highlight the improved clinical utility of combining CGP with IHC to expand the biomarker-guided therapeutic options available for patients with NSCLC, relative to single biomarker testing alone.
- Published
- 2021
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