Clinical and genomic assessment of PD-L1 SP142 expression in triple-negative breast cancer

Abstract Purpose The SP142 PD-L1 assay is a companion diagnostic for atezolizumab in metastatic triple-negative breast cancer (TNBC). We strove to understand the biological, genomic, and clinical characteristics associated with SP142 PD-L1 positivity in TNBC patients. Methods Using 149 TNBC formalin-fixed paraffin-embedded tumor samples, tissue microarray (TMA) and gene expression microarrays were performed in parallel. The VENTANA SP142 assay was used to identify PD-L1 expression from TMA slides. We next generated a gene signature reflective of SP142 status and evaluated signature distribution according to TNBCtype and PAM50 subtypes. A SP142 gene expression signature was identified and was biologically and clinically evaluated on the TNBCs of TCGA, other cohorts, and on other malignancies treated with immune checkpoint inhibitors (ICI). Results Using SP142, 28.9% of samples were PD-L1 protein positive. The SP142 PD-L1-positive TNBC had higher CD8+ T cell percentage, stromal tumor-infiltrating lymphocyte levels, and higher rate of the immunomodulatory TNBCtype compared to PD-L1-negative samples. The recurrence-free survival was prolonged in PD-L1-positive TNBC. The SP142-guided gene expression signature consisted of 94 immune-related genes. The SP142 signature was associated with a higher pathologic complete response rate and better survival in multiple TNBC cohorts. In the TNBC of TCGA, this signature was correlated with lymphocyte-infiltrating signature scores, but not with tumor mutational burden or total neoantigen count. In other malignancies treated with ICIs, the SP142 genomic signature was associated with improved response and survival. Conclusions We provide multi-faceted evidence that SP142 PDL1-positive TNBC have immuno-genomic features characterized as highly lymphocyte-infiltrated and a relatively favorable survival.

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Abstract PD9-05: A tiered algorithm using mid-therapy ultrasound (US) response assessment and a novel gene expression signature (GES) improves the prediction of pathologic complete response (pCR) to neoadjuvant therapy (NAT) in triple-negative breast cancer (TNBC): Results from the ARTEMIS trial (NCT02276443)

10.1158/1538-7445.sabcs20-pd9-05 ◽

2021 ◽

Author(s):

Sahil Seth ◽

Gaiane M Rauch ◽

Beatriz Adrada ◽

Helen Piwnica-Worms ◽

Lei Hou ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Neoadjuvant Therapy ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Pathologic Complete Response ◽

Gene Expression Signature ◽

Response Assessment ◽

Complete Response ◽

Expression Signature

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Abstract PD1-03: Multivariate analysis of subtype and gene expression signatures predictive of pathologic complete response (pCR) in triple-negative breast cancer (TNBC): CALGB 40603 (Alliance)

10.1158/1538-7445.sabcs16-pd1-03 ◽

2017 ◽

Author(s):

KA Hoadley ◽

T Hyslop ◽

C Fan ◽

DA Berry ◽

O Hahn ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Multivariate Analysis ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Pathologic Complete Response ◽

Complete Response ◽

Gene Expression Signatures

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Interferon-beta represses cancer stem cell properties in triple-negative breast cancer

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1713728114 ◽

2017 ◽

Vol 114 (52) ◽

pp. 13792-13797 ◽

Cited By ~ 39

Author(s):

Mary R. Doherty ◽

HyeonJoo Cheon ◽

Damian J. Junk ◽

Shaveta Vinayak ◽

Vinay Varadan ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Triple Negative Breast Cancer ◽

Epithelial To Mesenchymal Transition ◽

Triple Negative ◽

Mammary Epithelial Cells ◽

Gene Expression Signature ◽

Tumor Infiltrating Lymphocytes ◽

Gene Signature ◽

Mesenchymal Transition

Triple-negative breast cancer (TNBC), the deadliest form of this disease, lacks a targeted therapy. TNBC tumors that fail to respond to chemotherapy are characterized by a repressed IFN/signal transducer and activator of transcription (IFN/STAT) gene signature and are often enriched for cancer stem cells (CSCs). We have found that human mammary epithelial cells that undergo an epithelial-to-mesenchymal transition (EMT) following transformation acquire CSC properties. These mesenchymal/CSCs have a significantly repressed IFN/STAT gene expression signature and an enhanced ability to migrate and form tumor spheres. Treatment with IFN-beta (IFN-β) led to a less aggressive epithelial/non–CSC-like state, with repressed expression of mesenchymal proteins (VIMENTIN, SLUG), reduced migration and tumor sphere formation, and reexpression of CD24 (a surface marker for non-CSCs), concomitant with an epithelium-like morphology. The CSC-like properties were correlated with high levels of unphosphorylated IFN-stimulated gene factor 3 (U-ISGF3), which was previously linked to resistance to DNA damage. Inhibiting the expression of IRF9 (the DNA-binding component of U-ISGF3) reduced the migration of mesenchymal/CSCs. Here we report a positive translational role for IFN-β, as gene expression profiling of patient-derived TNBC tumors demonstrates that an IFN-β metagene signature correlates with improved patient survival, an immune response linked with tumor-infiltrating lymphocytes (TILs), and a repressed CSC metagene signature. Taken together, our findings indicate that repressed IFN signaling in TNBCs with CSC-like properties is due to high levels of U-ISGF3 and that treatment with IFN-β reduces CSC properties, suggesting a therapeutic strategy to treat drug-resistant, highly aggressive TNBC tumors.

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Gene Expression Signature Predicting Pathologic Complete Response With Gemcitabine, Epirubicin, and Docetaxel in Primary Breast Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2005.04.7019 ◽

2006 ◽

Vol 24 (12) ◽

pp. 1839-1845 ◽

Cited By ~ 113

Author(s):

Olaf Thuerigen ◽

Andreas Schneeweiss ◽

Grischa Toedt ◽

Patrick Warnat ◽

Meinhard Hahn ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Primary Breast Cancer ◽

Core Biopsy ◽

Pathologic Complete Response ◽

Gene Expression Signature ◽

Complete Response ◽

Support Vector ◽

Her2 Overexpression ◽

Expression Signature

Purpose Primary systemic therapy (PST) with gemcitabine (G), epirubicin (E), and docetaxel (Doc) has resulted in a pathologic complete response (pCR) in 26% of primary breast cancer patients. This study was aimed at the identification of a gene expression signature in diagnostic core biopsy tissue samples that predicts pCR. Patients and Methods Core biopsy samples from patients with operable primary breast cancer, T2-4N0-2M0, enrolled onto two phase I and II trials evaluating GEDoc (n = 48) and GE sequentially followed by Doc (GEsDoc; n = 52) as PST were snap frozen and subjected to RNA expression profiling. A signature predicting pCR was discovered in the training set (GEsDoc) applying a support vector machine algorithm, and performance of this classifier was validated on the independent test set (GEDoc) by receiver operator characteristics analysis. Results We identified a signature consisting of 512 genes, which was enriched in genes involved in transforming growth factor beta and RAS-mediated signaling pathways, that predicts pCR with a sensitivity of 78%, a specificity of 90%, and an overall accuracy of 88% (95% CI, 75% to 95%). Apart from our signature, only HER2 overexpression was an independent predictor of pCR in multivariate analysis. Conclusion In conclusion, our gene expression signature allows prediction of pCR to PST containing G, E, and Doc with unprecedented high overall accuracy and robustness.

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A gene signature predicts response to neoadjuvant chemotherapy in triple-negative breast cancer patients

Bioscience Reports ◽

10.1042/bsr20190414 ◽

2019 ◽

Vol 39 (5) ◽

Cited By ~ 2

Author(s):

Tianzhi Zheng ◽

Zhiyuan Pang ◽

Zhao Zhao

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Neoadjuvant Chemotherapy ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Characteristic Curve ◽

Complete Response ◽

Gene Signature ◽

Differentially Expressed ◽

Breast Cancer Patients

Abstract Triple-negative breast cancer (TNBC) accounts for approximately 15% of all breast cancer cases. TNBC is highly aggressive and associated with poor prognosis. The present study aimed to compare gene expression between TNBC patients with pathological complete response (pCR) and those with not complete response (nCR) to neoadjuvant chemotherapy. Microarray data of 16 TNBC patients received neoadjuvant chemotherapy were identified from the Gene Expression Omnibus database and 10 patients of them had pCR. We found that 250 coding genes and 155 long noncoding RNAs (lncRNAs) were statistically differentially expressed between patients with pCR and nCR. Receiver operator characteristic curve and area under the curve (AUC) were calculated to assess predictive value of differentially expressed genes. A gene signature of three coding genes and two lncRNA was developed: 2.318*TCF3 + 7.349*CREB1 + 0.891*CEP44 + 0.091*NR_023392.1 + 1.424*NR_048561.1 − 106.682. The gene signature was further validated and had an AUC = 0.829. In summary, we profiled gene expression in pCR patients and developed a gene signature, which was effective to predict pCR among TNBC patients received neoadjuvant chemotherapy.

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