Biomarkers of Targeted Therapy and Immuno-Oncology in Cancers Metastatic to the Breast

Vranić, Semir; Senarathne, Wijendra; Stafford, Phillip; Poorman, Kelsey; Pockaj, Barbara A.; Gatalica, Zoran

doi:10.1097/pai.0000000000000808

Cited by 10 publications

(7 citation statements)

References 56 publications

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“…Genes having ≥ 6 copies were considered amplified. 13,14,[17][18][19] The ArcherDx FusionPlex Assay (ArcherDX, Boulder, CO) was used for the gene fusion assessment. The gene fusions panel (n = 54) is available at: www.carismolecularintelligence.…”

Section: Next-generation Sequencing (Ngs)mentioning

confidence: 99%

Molecular Profiling Reveals Limited Targetable Biomarkers in Neuroendocrine Carcinoma of the Cervix

Cimic

Vranić

Arguello

et al. 2020

Applied Immunohistochemistry &Amp; Molecular Morphology

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Neuroendocrine carcinoma of the cervix (NEC) is a rare and highly aggressive cervical malignancy. Given that no targeted therapy has been approved specifically to NEC, we investigated the presence of novel, potentially targetable biomarkers in a large cohort of NEC. Sixty-two NEC were molecularly profiled for biomarkers of targeted therapies including antibody-drug conjugates [delta-like canonical notch ligand 3 (DLL3), a trophoblast cell surface antigen 2 (TROP-2), and folate receptor 1 (FOLR1)], NTRK1-3 gene fusions, and immune checkpoint inhibitors [programmed death-ligand 1 (PD-L1), tumor mutational burden, and microsatellite instability] using immunohistochemistry and DNA/RNA next-generation sequencing assays. A cohort of squamous cell carcinomas of the cervix (n = 599) was used for comparison for immune-oncology biomarkers. DLL3 expression was observed in 81% of the cases. DLL3 expression was inversely correlated with commonly observed pathogenic mutations in PIK3CA (17%) (P = 0.018) and PTEN (10%) (P = 0.006). Other more frequently seen pathogenic mutations (TP53 17%, KRAS 11%, and CTNNB1 5%) were not associated with DLL3 expression. TROP-2 expression was detected in only 1 case and no case expressed FOLR1. Although NTRK protein expression was observed in 21% of the cases, none of these had an NTRK gene fusion. PD-L1 expression (10%) and high tumor mutational burden (3%) were significantly less frequent in NEC compared with the squamous cell carcinoma cohort (79% and 11%, respectively). None of the NEC exhibited high microsatellite instability status. Despite frequent DLL3 expression in NEC, a potential therapeutic benefit of DLL3targeted drugs remains uncertain given the recent failure of the Rova-T therapeutic trial in small cell lung carcinomas. Small cohorts of NEC enriched in PIK3CA/PTEN/AKT and programmed cell death protein 1/PD-L1 alterations indicate therapeutic roles for their respective inhibitors.

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Section: Next-generation Sequencing (Ngs)mentioning

confidence: 99%

Molecular Profiling Reveals Limited Targetable Biomarkers in Neuroendocrine Carcinoma of the Cervix

Cimic

Vranić

Arguello

et al. 2020

Applied Immunohistochemistry &Amp; Molecular Morphology

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“…The following biomarkers were tested by immunohistochemistry (IHC): steroid receptors (ER, PR, AR, ARv7), HER2, pTRK, PD‐L1, PTEN, and mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) (clones and thresholds for positivity are provided in Table S1). 4,6,7 Both ER and PR were positive in the majority of cases (8+/9 cases each) (Table 1). AR was positive in 7/9 cases (78%) without the presence of the ARv7 splice variant.…”

Section: Figurementioning

confidence: 93%

“…The NGS platform covered exons from 592 genes (SureSelect XT, Agilent, Santa Clara, CA; and the NextSeq instrument, Illumina, San Diego, CA). The tumor mutational burden (TMB) was considered high if ≥11 mutations/megabase were detected 4 (Table 1). Microsatellite instability (MSI) was calculated from NGS data by direct analysis of short tandem repeat tracts in the target regions of sequenced genes 5 .…”

Section: Figurementioning

confidence: 99%

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Novel targetable biomarkers in clear cell carcinoma of the breast uncovered by molecular profiling: A study of nine cases

et al. 2020

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Clear cell differentiation may be occasionally seen in various subtypes of breast cancer, but pure forms of clear cell carcinoma (>90% clear cell morphology) are exceptionally rare. These cancers are characterized by neoplastic cells with an abundant and clear cytoplasm that typically contains glycogen. 1 This type of cancer is considered a distinct cyto-morphological pattern of invasive breast carcinoma of no special type (IBC-NST). 1 The clinical data on clear cell carcinoma are limited and predominantly include small retrospective studies that reported the conflicting results. 2 However, a recent Surveillance, Epidemiology, and End Results (SEER) study revealed that clear cell carcinomas tend to be pathologically high-grade cancers that clinically present at an advanced stage and have poor outcomes. 3 Apart from reports of variable steroid receptor (ER and PR) and HER2 positivity, no studies have systematically explored molecular features and potentially targetable biomarkers in clear cell carcinomas. 2 Herein, we profiled nine pure clear cell carcinomas of the breast using massively parallel DNA and RNA sequencing (NGS), in situ hybridization (ISH), and immunohistochemistry (IHC). All cases were primary mammary clear cell carcinomas that were diagnosed in female patients (mean age: 53.4 years; range: 31-69 years) (Figure 1). Six out of nine cases were periodic acid-Schiff (PAS) positive and PAS-diastase sensitive (glycogen-rich). The NGS platform covered exons from 592 genes (SureSelect XT, Agilent, Santa Clara, CA; and the NextSeq instrument, Illumina, San Diego, CA). The tumor mutational burden (TMB) was considered high if ≥11 mutations/megabase were detected 4 (Table 1). Microsatellite instability (MSI) was calculated from NGS data by direct analysis of short tandem repeat tracts in the target regions of sequenced genes. 5 The ArcherDX FusionPlex Assay (ArcherDX, Boulder, CO) was used for gene fusion assessment (n = 54; Table 1). The following biomarkers were tested by immunohistochemistry (IHC): steroid receptors (ER, PR,

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“…We have previously characterized multiple cancers with a comprehensive molecular profiling approach that uses various molecular techniques for the identification of potentially targetable biomarkers. 9 – 13 Our initial case of metastatic LCT showed an LDLR:TERT gene fusion upon routine genetic profiling for the detection of therapeutic targets. This finding led us to investigate a cohort of additional LCTs.…”

Section: Introductionmentioning

confidence: 98%

TERT Gene Fusions Characterize a Subset of Metastatic Leydig Cell Tumors

Krušlin

Gatalica

Hes

et al. 2021

Clinical Genitourinary Cancer

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Biomarkers of Targeted Therapy and Immuno-Oncology in Cancers Metastatic to the Breast

Abstract: Supplemental Digital Content is available in the text.

Cited by 10 publications

References 56 publications

Molecular Profiling Reveals Limited Targetable Biomarkers in Neuroendocrine Carcinoma of the Cervix

Molecular Profiling Reveals Limited Targetable Biomarkers in Neuroendocrine Carcinoma of the Cervix

Novel targetable biomarkers in clear cell carcinoma of the breast uncovered by molecular profiling: A study of nine cases

TERT Gene Fusions Characterize a Subset of Metastatic Leydig Cell Tumors

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