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

Identified as the second leading cause of cancer-related deaths among American women after lung cancer, breast cancer of all types has been the focus of numerous research studies. Even though triple-negative breast cancer (TNBC) represents 15–20% of the number of breast cancer cases worldwide, its existing therapeutic options are fairly limited. Due to the pivotal role of the presence/absence of specific receptors to luminal A, luminal B, HER-2+, and TNBC in the molecular classification of breast cancer, the lack of these receptors has accounted for the aforementioned limitation. Thereupon, in an attempt to participate in the ongoing research endeavors to overcome such a limitation, the conducted study adopts a combination strategy as a therapeutic paradigm for TNBC, which has proven notable results with respect to both: improving patient outcomes and survivability rates. The study hinges upon an investigation of a promising NPs platform for CD44 mediated theranostic that can be combined with JAK/STAT inhibitors for the treatment of TNBC. The ability of momelotinib (MMB), which is a JAK/STAT inhibitor, to sensitize the TNBC to apoptosis inducer (CFM-4.16) has been evaluated in MDA-MB-231 and MDA-MB-468. MMB + CFM-4.16 combination with a combination index (CI) ≤0.5, has been selected for in vitro and in vivo studies. MMB has been combined with CD44 directed polymeric nanoparticles (PNPs) loaded with CFM-4.16, namely CD44-T-PNPs, which selectively delivered the payload to CD44 overexpressing TNBC with a significant decrease in cell viability associated with a high dose reduction index (DRI). The mechanism underlying their synergism is based on the simultaneous downregulation of P-STAT3 and the up-regulation of CARP-1, which has induced ROS-dependent apoptosis leading to caspase 3/7 elevation, cell shrinkage, DNA damage, and suppressed migration. CD44-T-PNPs showed a remarkable cellular internalization, demonstrated by uptake of a Rhodamine B dye in vitro and S0456 (NIR dye) in vivo. S0456 was conjugated to PNPs to form CD44-T-PNPs/S0456 that simultaneously delivered CFM-4.16 and S0456 parenterally with selective tumor targeting, prolonged circulation, minimized off-target distribution.

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Immunotherapy in Triple-Negative Breast Cancer: Present and Future

Current Breast Cancer Reports ◽

10.1007/s12609-019-00345-z ◽

2019 ◽

Vol 11 (4) ◽

pp. 259-271 ◽

Cited By ~ 5

Author(s):

Isaac Kim ◽

Katherine Sanchez ◽

Heather L. McArthur ◽

David Page

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Survival Benefit ◽

Triple Negative ◽

Predictive Biomarkers ◽

Progression Free Survival ◽

Immune Checkpoint Blockade ◽

Phase Iii ◽

Breast Cancers ◽

Effective Treatment Option

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

10.1158/1538-7445.am2019-lb-225 ◽

2019 ◽

Cited By ~ 1

Author(s):

Sherene Loi ◽

Peter Schmid ◽

Javier Cortés ◽

David W. Cescon ◽

Eric P. Winer ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Predictive Biomarkers ◽

Molecular Signatures

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High dose neo-adjuvant chemotherapy in triple-negative breast cancer with evidence of homologous recombination deficiency (HRD)

Annals of Oncology ◽

10.1093/annonc/mdz240.013 ◽

2019 ◽

Vol 30 ◽

pp. v61-v62

Author(s):

S.B. Vliek ◽

E. Van Werkhoven ◽

I. Mandjes ◽

T. Westphal ◽

E.H. Lips ◽

...

Keyword(s):

Breast Cancer ◽

Adjuvant Chemotherapy ◽

Homologous Recombination ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

High Dose ◽

Homologous Recombination Deficiency ◽

Neo Adjuvant Chemotherapy

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Inhibiting fatty acid synthase in operable triple negative breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.584 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 584-584

Author(s):

Sagar D. Sardesai ◽

Alexandra Thomas ◽

Christopher Gallagher ◽

Filipa Lynce ◽

Yvonne Lynn Ottaviano ◽

...

Keyword(s):

Breast Cancer ◽

Fatty Acid ◽

Triple Negative Breast Cancer ◽

Fatty Acid Synthase ◽

Triple Negative ◽

Population Change ◽

Early Stage ◽

Pathologic Complete Response ◽

Breast Cancer Cell Lines ◽

High Dose

584 Background: Fatty acid synthase (FASN) is overexpressed in 70% of newly diagnosed triple negative breast cancer (TNBC) and is associated with poor prognosis. In vitro, FASN overexpression induces drug resistance to DNA damaging agents. Proton pump inhibitors (PPI) selectively inhibit FASN activity and induce apoptosis in breast cancer cell lines with minimal effect on non-malignant cells. We report the results of a single arm phase II study of high dose omeprazole (OMP) in combination with anthracycline- taxane (AC-T) based neoadjuvant chemotherapy. Methods: Patients (pts) with operable TNBC independent of baseline FASN expression; and no prior PPI use within 12 months were enrolled. Pts began OMP 80 mg PO BID for 4-7 days prior to AC-T; carboplatin was allowed per physician discretion. OMP was continued until surgery. Paired biopsy samples were obtained before and after OMP monotherapy. The primary endpoint was pathologic complete response (pCR), defined as no residual invasive disease in breast or axilla, in pts with baseline FASN expression (FASN+) assessed using immunohistochemistry. Relevant secondary endpoints included pCR in the intent to treat population, change in FASN expression, enzyme activity and downstream target gene expression after OMP monotherapy; safety and limited OMP pharmacokinetics. We targeted a pCR rate of 60% in FASN+ pts (null pCR ~ 40%) with 80% power and alpha of 0.10. Results: A total of 42 pts were recruited from 5 US sites. Median age was 51y (28-72). Most pts had >cT2 (33, 79%) and ≥N1 (22, 52%) disease. 14 (33%) were African American. FASN expression prior to AC-T was identified in 28 (85%) samples available for analysis. The pCR rate was 71.4% (95% CI 51.3 to 86.8) in FASN+ pts and 71.8 %( 95% CI 55.1 to 85.0) in all enrolled pts. Fifteen pts (36%) received carboplatin with AC-T; pCR in this subset was 73%. Peak OMP concentration was significantly higher than IC50 observed during preclinical testing; FASN positivity significantly decreased with OMP monotherapy from 0.53(SD 0.25) at baseline to 0.38(SD 0.30; p = 0.02). OMP was well tolerated with no known grade (G) 3 or 4 toxicities. Chemotherapy toxicity was similar to prior studies using AC-T with G3 or 4 neutropenia (19%), febrile neutropenia (7%) and peripheral neuropathy (7%) being the most common. Conclusions: Consistent with previous studies, FASN is frequently expressed in early stage TNBC. OMP can be safely administered in doses that inhibit FASN. The addition of high dose OMP to neoadjuvant AC-T yields a promising pCR rate without adding toxicity. Funded by the Breast Cancer Research Foundation. Clinical trial information: NCT02595372 .

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High-dose chemotherapy for triple negative breast cancer

Annals of Oncology ◽

10.1093/annonc/mdl306 ◽

2007 ◽

Vol 18 (1) ◽

pp. 202-203 ◽

Cited By ~ 31

Author(s):

U. De Giorgi ◽

G. Rosti ◽

L. Frassineti ◽

B. Kopf ◽

N. Giovannini ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

High Dose Chemotherapy ◽

High Dose

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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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