Abstract LB-225: RNA molecular signatures as predictive biomarkers of response to monotherapy pembrolizumab in patients with metastatic triple-negative breast cancer: KEYNOTE-086

Abstract Purpose of Review Immunotherapy is emerging as an effective treatment option for metastatic triple-negative breast cancer. In this review, we summarize clinical data of immunotherapy in triple-negative breast cancer and comment on future directions in the field. Recent Findings IMpassion130 was a phase III trial that demonstrated progression-free survival benefit, and potentially overall survival benefit, of first-line chemotherapy (nab-paclitaxel) plus anti-programmed death ligand 1 (PD-L1) atezolizumab, among PD-L1-positive metastatic triple-negative breast cancers. Studies are ongoing to evaluate other combination therapies with immune checkpoint blockade in TNBC, and to evaluate efficacy in PD-L1-negative tumors and in later lines of therapy. Summary Immunotherapy is now a standard option in the treatment of triple-negative breast cancer. Ongoing trials may expand the degree of clinical benefit. Further work is ongoing to identify novel predictive biomarkers, which in the future may enable a personalized approach of combination immunotherapy.

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BRCA Mutational Status is a Promising Predictive Biomarker for Platinum- based Chemotherapy in Triple-Negative Breast Cancer

Current Drug Targets ◽

10.2174/1389450121666200203162541 ◽

2020 ◽

Vol 21 (10) ◽

pp. 962-973 ◽

Cited By ~ 3

Author(s):

Amal Tazzite ◽

Hassan Jouhadi ◽

Abdellatif Benider ◽

Sellama Nadifi

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Checkpoint Inhibitors ◽

Susceptibility Gene ◽

Predictive Biomarkers ◽

Predictive Biomarker ◽

Breast Cancer Susceptibility Gene ◽

Mutational Status ◽

Platinum Based Chemotherapy

Triple-negative breast cancer (TNBC) can be distinguished from other breast malignancies by the lack of expression of estrogen receptors (ER), progesterone receptors (PR) as well as human epidermal growth factor receptor 2 (HER2). TNBC is associated with adverse clinical outcomes and high risk of metastasis. Currently, several clinical and translational reports are focusing on developing targeted therapies for this aggressive cancer. In addition to approved targeted drugs such as poly(ADP-ribose) polymerase inhibitors (PARPi) and immune-checkpoint inhibitors, platinum-based chemotherapy is still a cornerstone therapeutic option in TNBC. However, despite the observed improved outcomes with platinum- based chemotherapy in TNBC, there is still a large proportion of patients who do not respond to this treatment, hence, the need for predictive biomarkers to stratify TNBC patients and therefore, avoiding unwanted toxicities of these agents. With the emergence of genetic testing, several recent studies suggested mutations in breast cancer susceptibility gene (BRCA) in TNBC patients as important predictors of outcomes. These mutations alter the homologous recombination repair (HRR) mechanisms leading to genomic instability. Consequently, sensitivity to platinum-based treatments in this subpopulation of TNBC patients may be explained by cell death enhanced by deoxyribonucleic acid (DNA) damage induced by these potent anticancer drugs. Through this paper, we review several recent studies on this topic to better understand the mechanisms and discuss the potential of BRCA mutational status as a predictive biomarker of platinum-based chemotherapy in TNBC.

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Evaluation of predictive biomarkers for AR therapy and to identify the LAR subtype of TNBC.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.595 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 595-595

Author(s):

Sahil Seth ◽

James Crespo ◽

Lei Huo ◽

Alastair Mark Thompson ◽

Elizabeth A. Mittendorf ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Trial ◽

Androgen Receptor ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Predictive Biomarkers ◽

Immunohistochemical Analysis ◽

Predictive Biomarker ◽

Molecular Profiling ◽

Molecular Signature

595 Background: Androgen-receptor-like (LAR) triple-negative breast cancer (TNBC) is a subtype identified using Vanderbilt’s molecular signature. LAR subtype has the lowest pCR rate for NACT among all TNBC subtypes (10% vs. 28% for TNBC in general). We launched a clinical trial to determine the effectiveness of enzalutamide and paclitaxel (ZT) in improving this poor chemo. response in the neoadjuvant setting for pts with anthracycline-refractory, androgen receptor (AR)+ TNBC (NCT02689427). However, we do not yet have a robust predictive biomarker to detect an activated AR pathway and have not seen a robust correlation between molecular LAR subtype and AR IHC staining intensity. Methods: Molecular profiling and immunohistochemical analysis of key biomarkers (LAR, Ki67, and vimentin) was performed for all pts enrolled in A Randomized triple negative breast cancer enrolling Trial to Confirm Molecular Profiling Improves Survival (ARTEMIS; NCT02276443). Patients receive 4 cycles of AC, followed by an experimental arm or standard taxane, tailored using nuclear IHC staining. IHC staining of ≥30% AR+ was used as a threshold for selection for enzalutamide combination arm. We evaluated the concordance between LAR-subtype using molecular profiling vs % AR+ cells via IHC. Results: As part of the clinical trial, tumors with ≥30% AR+ cells were classified as LAR. In addition, we used RNA profiling to assign Vanderbilt subtype scores, resulting in classification of 15 tumors as LAR+. We observed a significant correlation (r=0.75) between LAR score and %AR+ cells, with 13 of 15 LAR tumors having ≥30% AR+ cells. Among patients with high % of AR+ tumor cells, 11 received enzalutamide, with 43% (3/7) having responses (pCR or RCB-I). Conclusions: Comparison on numerical scores for Vanderbilt subtype and IHC scores suggests ≥30% AR+ IHC staining as the threshold (ppv=0.65, npv=0.98, Table) to identify the molecular LAR subtype. We observed a trend where response rate was higher in patients with ≥ AR+ IHC scores treated with enzalutamide; however, these results need confirmation in a larger cohort of patients. Clinical trial information: NCT02689427, NCT02276443. [Table: see text]

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Abstract 550: Genomic instability and telomere characteristics as predictive biomarkers of therapeutic response in triple-negative breast cancer

10.1158/1538-7445.am2014-550 ◽

2014 ◽

Author(s):

Mathilde Gay-bellile ◽

Nina Radosevic-Robin ◽

Eleonore Eymard-Pierre ◽

Fabrice Kwiatkowski ◽

Marie-Mélanie Dauplat ◽

...

Keyword(s):

Breast Cancer ◽

Genomic Instability ◽

Triple Negative Breast Cancer ◽

Therapeutic Response ◽

Triple Negative ◽

Predictive Biomarkers

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Estimating the Voi of Pivotal Studies Towards Predictive Biomarkers of High Dose Alkylating Chemotherapy in Triple Negative Breast Cancer

Value in Health ◽

10.1016/j.jval.2014.08.2329 ◽

2014 ◽

Vol 17 (7) ◽

pp. A644

Author(s):

A. Miquel Cases ◽

V.P. Retèl ◽

W.H. van Harten ◽

L.M.G. Steuten

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Predictive Biomarkers ◽

High Dose

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Emerging Predictive Biomarkers of Response to Platinum Therapy in Triple-Negative Breast Cancer

Current Breast Cancer Reports ◽

10.1007/s12609-015-0194-z ◽

2015 ◽

Vol 7 (4) ◽

pp. 224-231

Author(s):

Michal Mego ◽

James M. Reuben

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Predictive Biomarkers

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Carboplatin-Cyclophosphamide or Paclitaxel without or with Bevacizumab as First-Line Treatment for Metastatic Triple-Negative Breast Cancer (BOOG 2013-01)

Breast Care ◽

10.1159/000512200 ◽

2021 ◽

pp. 1-9

Author(s):

Annelot G.J. van Rossum ◽

Ingrid A.M. Mandjes ◽

Erik van Werkhoven ◽

Harm van Tinteren ◽

A. Elise van Leeuwen-Stok ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Growth Factor Receptor ◽

Predictive Biomarkers ◽

Progression Free Survival ◽

First Line ◽

Significant Treatment ◽

Individual Agent ◽

Efficacy Analysis

Background: The addition of bevacizumab to chemotherapy conferred a modest progression-free survival (PFS) benefit in metastatic triple-negative breast cancer (mTNBC). However, no overall survival (OS) benefit has been reported. Also, its combination with carboplatin-cyclophosphamide (CC) has never been investigated. Methods: The Triple-B study is a multicenter, randomized phase IIb trial that aims to prospectively validate predictive biomarkers, including baseline plasma vascular endothelial growth factor receptor-2 (pVEGFR-2), for bevacizumab benefit. mTNBC patients were randomized between CC and paclitaxel (P) without or with bevacizumab (CC ± B or P ± B). Here we report on a preplanned safety and preliminary efficacy analysis after the first 12 patients had been treated with CC+B and on the predictive value of pVEGFR-2. Results: In 58 patients, the median follow-up was 22.1 months. Toxicity was manageable and consistent with what was known for each agent separately. There was a trend toward a prolonged PFS with bevacizumab compared to chemotherapy only (7.0 vs. 5.2 months; adjusted HR = 0.60; 95% CI 0.33–1.08; p = 0.09), but there was no effect on OS. In this small study, pVEGFR-2 concentration did not predict a bevacizumab PFS benefit. Both the intention-to-treat analysis and the per-protocol analysis did not yield a significant treatment-by-biomarker test for interaction (pinteraction = 0.69). Conclusions:CC and CC+B are safe first-line regimens for mTNBC and the side effects are consistent with those known for each individual agent. pVEGFR-2 concentration did not predict a bevacizumab PFS benefit.

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