Publications by authors named "Douglas Lin"

Embryonic-type neuroectodermal tumors (ENTs) arising from testicular germ cell tumors (GCTs) is a relatively common type of somatic transformation in GCTs with poor prognosis and limited therapeutic options, particularly when patients develop disease recurrence or metastasis. Knowledge of key events driving this transformation is limited to the paucity of comprehensive genomic data. We performed a retrospective database search in a CLIA- and CAP-certified laboratory for testicular GCT-derived ENTs that had previously undergone NGS-based comprehensive genomic profiling during the course of clinical care.

View Article and Find Full Text PDF

Real-world success rate of liquid and tissue-based comprehensive genomic profiling (CGP) is unknown. We analyzed real-world pan-tumor cohorts that underwent CGP during clinical care via FoundationOne CDx (F1CDx) and FoundationOne Liquid CDx (F1LCDx) to determine tissue and liquid sample adequacy based on tumor type. Pan-tumor presequencing adequacy was high (>90%) by both tissue-based F1CDx (median: 92.

View Article and Find Full Text PDF

Background: Tumors harboring two or more PIK3CA short variant (SV) ("multi-hit") mutations have been linked to improved outcomes with anti-PIK3CA-targeted therapies in breast cancer. The landscape and clinical implications of multi-hit PIK3CA alterations in clinically advanced prostate cancer (CAPC) remains elusive.

Objective: To evaluate the genomic landscape of single-hit and multi-hit PIK3CA genomic alterations in CAPC.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

Purpose: Although both urachal (U) and nonurachal (NU) bladder adenocarcinomas (adenoCas) share several histologic similarities, they differ in location and sometimes in therapeutic options. We analyzed the differences in genomic alterations (GAs) between these tumor entities, with the aim of identifying potential therapeutic targets for clinical trials.

Materials And Methods: Overall, 133 U and 328 NU adenoCas were analyzed.

View Article and Find Full Text PDF

Targeted anti-HER2 therapy has been recently added to the standard treatment recommendations in endometrial serous carcinoma. Current eligibility requires testing for HER2 overexpression and/or gene amplification by immunohistochemistry and by fluorescence in situ hybridization. However, clinical trials have also demonstrated the efficacy of anti-HER2 drugs against activating ERBB2/HER2 mutations in a variety of solid tumor types, and fam-trastuzumab deruxtecan is now approved by the US Food and Drug Administration for HER2-mutant non-small cell lung cancer.

View Article and Find Full Text PDF
Article Synopsis
  • - The study examines genomic alterations (GA) in patients with urothelial bladder cancer (UBC), focusing on those with ERBB2 mutations and amplifications, and comparing them to patients with wild-type ERBB2.
  • - Findings show that 6.3% of UBC cases have short variant GAs in the ERBB2 extracellular domain, 2.7% in the kinase domain, and 9.1% show ERBB2 amplification, while 81.9% are ERBB2 wild-type.
  • - The analysis indicates that ERBB2-altered cases exhibit higher tumor mutational burden and specific genetic changes compared to wild-type ERBB2 cases, with notable associations found between various genetic markers
View Article and Find Full Text PDF

Background: While 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.

View Article and Find Full Text PDF
Article Synopsis
  • The micropapillary subtype of urothelial carcinoma (MPUC) is a highly aggressive form of bladder cancer, often linked to specific mutations in the ERBB2 gene, particularly in the extracellular domain (ECD).
  • In a study analyzing 5,485 bladder cancer cases, researchers found that 63 out of 219 ERBB2 ECD-mutated cases were MPUC, with notable co-alterations in genes like TERT, TP53, and ARID1A.
  • Key differences in MPUC included lower KMT2D and higher RB1 mutation rates, which may help in developing prognostic and predictive biomarkers for treatment response and tumor behavior.
View Article and Find Full Text PDF
Article Synopsis
  • - The study investigates the relationship between tumor mutational burden (TMB) and treatment outcomes for immune checkpoint inhibitors (ICIs) in patients with penile squamous cell carcinoma (PSCC), exploring its potential as a biomarker in this specific cancer type.
  • - Researchers analyzed 397 PSCC cases to identify genetic alterations and categorized TMB levels into low, high, and very high, examining the implications of these levels for patient survival and treatment effectiveness.
  • - Results showed variations in age and ancestry among patients with different TMB levels, emphasizing the need for further research to clarify how TMB influences the success of ICI therapies in PSCC.
View Article and Find Full Text PDF

Unlabelled: Tumor mutational burden (TMB) is a biomarker that predicts response to immune checkpoint inhibitor therapy. We currently lack a comprehensive understanding of how genomic and clinical factors correlate with TMB. We used a clinicogenomic database to assess independent predictors of TMB levels.

View Article and Find Full Text PDF

The authors present a cohort of 661 young adult glioblastomas diagnosed using 2016 WHO World Health Organization Classification of Tumors of the Central Nervous System, utilizing comprehensive genomic profiling (CGP) to explore their genomic landscape and assess their relationship to currently defined disease entities. This analysis explored variants with evidence of pathogenic function, common copy number variants (CNVs), and several novel fusion events not described in literature. Tumor mutational burden (TMB) mutational signatures, anatomic location, and tumor recurrence are further explored.

View Article and Find Full Text PDF
Article Synopsis
  • PDAC is typically nonimmunogenic, but about 1% of patients exhibit high tumor mutational burden (TMB) or other alterations that could indicate a better response to immune checkpoint inhibitors (ICI).
  • In a study of 21,932 PDAC patients, only 1.3% showed high-TMB, with associated genomic alterations differing based on TMB levels.
  • Patients with high-TMB who received ICI therapy had significantly improved overall survival compared to those with low-TMB, highlighting the potential of high-TMB as a biomarker for ICI therapy efficacy in PDAC.
View Article and Find Full Text PDF

Background: Despite the low rate of urothelial carcinoma of the bladder (UCB) in patients of South Asian (SAS) and East Asian (EAS) descent, they make up a significant portion of the cases worldwide. Nevertheless, these patients are largely under-represented in clinical trials. We queried whether UCB arising in patients with SAS and EAS ancestry would have unique genomic features compared to the global cohort.

View Article and Find Full Text PDF

Unlabelled: 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.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

Gene fusions involving EWSR1 or FUS as the 5' partner have been reported in a diverse array of sarcomas. Here, we characterize the histopathology and genomics of six tumors harboring a gene fusion between EWSR1 or FUS and POU2AF3, an understudied, putative colorectal cancer predisposition gene. Striking morphologic features reminiscent of synovial sarcoma were observed including a biphasic appearance with variable fusiform to epithelioid cytomorphology and staghorn-type vasculature.

View Article and Find Full Text PDF

Objective: Molecular profiling is developing to inform treatment in endometrial cancer. Using real world evidence, we sought to evaluate frontline immune checkpoint inhibitor vs chemotherapy effectiveness in advanced endometrial cancer, stratified by Tumor Mutational Burden (TMB) ≥10 mut/MB and microsatellite instability (MSI).

Methods: Patients with advanced endometrial cancer in the US-based de-identified Flatiron Health-Foundation Medicine Clinico-Genomic Database were included.

View Article and Find Full Text PDF
Article Synopsis
  • The study investigates the clinicopathologic and genomic characteristics of 891 patients with advanced solid tumors driven by RET fusions, utilizing both tissue-based and liquid-based next-generation sequencing (NGS) methods.
  • RET fusions were notably identified in 523 patients with non-small cell lung cancer (NSCLC) and 368 with other solid tumors, with lung adenocarcinoma and thyroid papillary carcinoma showing the highest prevalence rates.
  • The research revealed 61 novel RET fusions and confirmed that liquid biopsies are highly effective for detecting these fusions, particularly in patients with a composite tumor fraction of at least 1%.
View Article and Find Full Text PDF

Importance: The 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.

Objective: To 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.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

Background: Advanced pelvic squamous cell carcinoma (pSCC) is a broad category of cancers affecting different pelvic organs and usually featuring unfavorable clinical outcomes. Thus, we aimed to assess genomic differences among pSCC cases and learn whether pSCC could potentially benefit from targeted therapies and/or immunotherapy.

Materials And Methods: A total of 1917 advanced pSCCs, including penile (penSCC), male urethral (murthSCC), male anal (manSCC), female urethral (furthSCC), vulvar (vulSCC), cervical (crvSCC), female anal (fanSCC), and vaginal (vagSCC), underwent comprehensive genomic profiling (CGP).

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

Importance: The most useful biomarkers for clinical decision-making identify patients likely to have improved outcomes with one treatment vs another.

Objective: To evaluate treatment class-specific outcomes of patients receiving immune checkpoint inhibitor (ICI) vs taxane chemotherapy by tumor mutational burden (TMB).

Design, Setting, And Participants: This comparative effectiveness analysis of clinical variables and outcomes used prospectively defined biomarker-stratified genomic data from a deidentified clinicogenomic database.

View Article and Find Full Text PDF