Cadherin-5: a biomarker for metastatic breast cancer with optimum efficacy in oestrogen receptor-positive breast cancers with vascular invasion

Understanding the molecular pathways that contribute to the development of metastatic breast cancer invasion and metastasis to brain is needed to improve the clinical utility of novel agents, and to predict the success of targeted personalized therapy based on tumor-specific mutations. Little is known about the clinical significance of HER2/ERK1/2/MMP-9 signaling pathway in breast cancer. We performed Global exon array to study the expression of ERK1/2/MMP-9 signaling pathway in metastatic breast cancer to brain, compared its expression in primary breast cancer and breast cancers metastatic to other organs, and validated the findings by RT-PCR. Immunohistochemistry was performed to study the expression and localization of ERK1/2/MMP-9 proteins in primary and metastatic breast cancer tissues and breast cancer cell lines. We performed matrigel invasion, transendothelial migration and membrane potential assays in established lines of normal breast cells.

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The financial impact of trastuzumab in metastatic breast cancer: The experience of the Institut Curie

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.663 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 663-663

Author(s):

M. A. Doz ◽

C. D. Le Tourneau ◽

M. S. Guilhaume ◽

V. Dieras ◽

A. Vincent-Salomon ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Single Agent ◽

Metastatic Breast ◽

Financial Impact ◽

Her2 Overexpression ◽

Breast Cancers ◽

Financing System ◽

High Level ◽

The Cost

663 Purpose: To estimate, in term of public health on the scale of a region, the cost of trastuzumab and to point out the financial impact of this new targeted therapy in the adjuvant setting. Methods: To understand the consequences of the spending on of trastuzumab at a macroeconomic level in the French hospital financing system, we decided to focus on an establishment in particular, and to analyze the increasing spending of trastuzumab at a micro-economic level, to provide a cost analysis of patients treated with trastuzumab for HER2-overexpressing metastatic breast cancer. We retrospectively reviewed 137 medical reports of patients who received trastuzumab either in combination with chemotherapy or as a single agent and in maintenance therapy. Median age of the patients was 52 years (range 32- to 79+). Eighty five percent had 3+ HER2 overexpression and fifteen percent had 2+ HER2 (FISH amplified). Results: Median survival from first treatment with trastuzumab was 38.5 months (range 0,04–53,06+). The cost of the first year treatment is in average €43,435.58 per patient, for the second year €36,419.01 and for the third year €37,198.94. Drugs cost represents 78% of the hospital stays cost for a patient and 2.9% of the budget of Institut Curie. Conclusions: This retrospective analysis showed the very high level of expenses of trastuzumab to treat metastatic breast cancers. With the adjuvant use of trastuzumab, it is expected that these expenses are going to increase exponentially. No significant financial relationships to disclose.

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Phase I/II Study of the Antibody-Drug Conjugate Glembatumumab Vedotin in Patients With Locally Advanced or Metastatic Breast Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2013.52.5683 ◽

2014 ◽

Vol 32 (32) ◽

pp. 3619-3625 ◽

Cited By ~ 54

Author(s):

Johanna Bendell ◽

Mansoor Saleh ◽

April A.N. Rose ◽

Peter M. Siegel ◽

Lowell Hart ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Phase Ii ◽

Transmembrane Protein ◽

Locally Advanced ◽

Metastatic Breast ◽

Breast Cancers ◽

Antibody Drug Conjugate ◽

Drug Conjugate ◽

Antibody Drug

Purpose Glycoprotein NMB (gpNMB), a novel transmembrane protein overexpressed in 40% to 60% of breast cancers, promotes metastases in animal models and is a prognostic marker of a poor outcome in patients. The antibody-drug conjugate glembatumumab vedotin consists of a fully human anti-gpNMB monoclonal antibody, conjugated via a cleavable linker to monomethyl auristatin E. Glembatumumab vedotin is generally well tolerated, with observed objective responses in advanced melanoma. This is, to our knowledge, the first study of glembatumumab vedotin in breast cancer. Patients and Methods Eligible patients had advanced/metastatic breast cancer with at least two prior chemotherapy regimens, including taxane, anthracycline, and capecitabine. A standard 3+3 dose escalation was followed by a phase II expansion. Immunohistochemistry for gpNMB was performed retrospectively for patients with available tumor tissue. Results Forty-two patients were enrolled. Dose-limiting toxicity (DLT) consisted of worsening neuropathy at 1.34 mg/kg. After excluding patients with baseline neuropathy more than grade 1, no DLT occurred through 1.88 mg/kg (the phase II dose). The phase II primary activity end point was met (12-week progression-free survival [PFS12] = 9 of 27 patients; 33%). Sixteen of 19 (84%) patients tested had gpNMB-positive tumors. At the phase II dose, median PFS was 9.1 weeks for all patients, 17.9 weeks for patients with triple-negative breast cancer (TNBC), and 18.0 weeks for patients with gpNMB-positive tumors. Two patients had confirmed partial responses; both had gpNMB-positive tumors and one had TNBC. Conclusion Glembatumumab vedotin has an acceptable safety profile. Preliminary evidence of activity in treatment-resistant metastatic breast cancer requires confirmation, such as the phase II randomized trial (EMERGE) that also examines the relationship between activity and gpNMB distribution/intensity.

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Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial

The Lancet Oncology ◽

10.1016/s1470-2045(16)00106-6 ◽

2016 ◽

Vol 17 (6) ◽

pp. 811-821 ◽

Cited By ~ 140

Author(s):

Ian E Krop ◽

Ingrid A Mayer ◽

Vinod Ganju ◽

Maura Dickler ◽

Stephen Johnston ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Aromatase Inhibitor ◽

Oestrogen Receptor ◽

Metastatic Breast ◽

Phase 2 ◽

Double Blind ◽

Double Blind Placebo ◽

Phase 2 Trial

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A Review of Trastuzumab-Based Therapy in Patients with HER2-positive Metastatic Breast Cancer

Clinical Medicine Therapeutics ◽

10.4137/cmt.s35 ◽

2009 ◽

Vol 1 ◽

pp. CMT.S35

Author(s):

David N. Church ◽

Chris G.A. Price

Keyword(s):

Breast Cancer ◽

Monoclonal Antibody ◽

Metastatic Breast Cancer ◽

Poor Prognosis ◽

Chemotherapy Regimen ◽

Metastatic Breast ◽

Preclinical Studies ◽

Breast Cancers ◽

Her2 Receptor ◽

Her2 Positive

The ERBB2 or HER2 receptor is overexpressed in 25% of breast cancers and is associated with poor prognosis. Trastuzumab, a monoclonal antibody targeting HER2 has been demonstrated to improve survival when combined with chemotherapy for the treatment of HER2 overexpressing metastatic breast cancer (MBC). Further studies have endeavoured to clarify the optimum chemotherapy regimen in combination with trastuzumab for MBC and its use together with novel biological agents. This review summarises these data together with preclinical studies exploring the mechanism of trastuzumab action and causes of drug resistance. The frequent incidence of brain metastases in patients on trastuzumab is highlighted, and data on the continuation of trastuzumab following CNS and non-CNS progression reviewed.

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Safety and antitumor activity of 3-weekly anti-EpCAM antibody adecatumumab (MT201) in combination with docetaxel for patients with metastatic breast cancer: Results of a multicenter phase Ib trial

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.1009 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 1009-1009

Author(s):

M. Sebastian ◽

C. Hanusch ◽

M. Schmidt ◽

N. Marschner ◽

D. Oruzio ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Response Rate ◽

Single Agent ◽

Metastatic Breast ◽

Progression Free Survival ◽

Breast Cancers ◽

Epcam Expression ◽

Secondary Objective ◽

Grade 3

1009 Background: The fully human IgG1 antibody adecatumumab (MT201) binds to the epithelial cell adhesion molecule (EpCAM), which is expressed in over 90% of breast cancers and has been associated with poor prognosis. Data from a previous phase II study in metastatic breast cancer (MBC) indicated that single agent MT201 could prolong progression-free survival in a subset of patients with high EpCAM expression. This study tested safety and tolerability of MT201 treatment in combination with standard docetaxel. Methods: Relapsed or primary refractory, EpCAM-positive MBC patients were treated with docetaxel (100 mg/m2 q21d) in combination with MT201 (dose levels 180 mg/m2, and 550 mg/m2 q21d). A loading dose of 100 mg/m2 and 300 mg/m2, respectively, was administered on day 1 and 7. Patients were grouped into high- and low-level EpCAM expression. Primary objectives were safety and tolerability; anti-tumor activity according to RECIST was a secondary objective. Results: A total of 22 patients with a median of 3 prior chemotherapy lines were enrolled. Most frequent grade 3/4 adverse events (AE) in all patients were leucopenia (90%), neutropenia (77%), lymphopenia (68%), and diarrhea (23%). No evidence for aggravation of grade 3/4 toxicities typically associated with docetaxel was found. The dose level 550 mg/m2 q21d has been determined as MTD in combination with 100 mg/m2 q21d docetaxel. The overall response rate (CR/PR; RECIST) and clinical benefit rate (CR/PR and SD>24wks) in all evaluable patients was 24% and 41%, respectively. Patients with high EpCAM expression showed a response rate of 43%, whereas patients with low EpCAM expression had a response rate of 10%. Median time-to-progression (TTP) in all evaluable patients was 165 days. Conclusions: Combining MT201 with docetaxel for the treatment of MBC appears to be safe and feasible. The DLT of this combination were short and manageable episodes of grade 3 diarrhea. The response rate and TTP observed in this heavily pre-treated population is encouraging and warrant further development of MT201/chemotherapy combinations in patients with tumors of high EpCAM target level. [Table: see text]

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Genomic evaluation of tumor mutational burden-high (TMB-H) versus TMB-low (TMB-L) metastatic breast cancer to reveal unique mutational features.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.1091 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 1091-1091

Author(s):

Sarah Sammons ◽

Andrew Elliott ◽

Jeremy Meyer Force ◽

Nicholas C. DeVito ◽

Paul Kelly Marcom ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Solid Tumors ◽

Immune Checkpoint ◽

Metastatic Breast ◽

Breast Cancers ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition ◽

Mutational Burden ◽

Tumor Mutational Burden

1091 Background: Tumor mutational burden (TMB) has emerged as an imperfect biomarker of immune checkpoint inhibition (ICI) outcomes in solid tumors. Despite the approval for pembrolizumab in all TMB-high (TMB-H) solid tumors, the optimal clinical approach to TMB-H or hypermutated advanced/metastatic breast cancer (MBC) is unknown with sparse prospective data. We hypothesize that TMB-H MBC will have unique genomic alterations compared to TMB-low (TMB-L) breast cancer that could inform novel therapeutic approaches. Methods: Tumor samples (N = 5621) obtained from patients with MBC were analyzed by next-generation sequencing (NGS) of DNA (592-gene panel or whole exome sequencing) and RNA (whole transcriptome sequencing) at Caris Life Sciences (Phoenix, AZ). TMB was calculated based on recommendations from the Friends of Cancer Research TMB Harmonization Project (Merino et al., 2020), with the TMB-H threshold set to ≥ 10 muts/Mb. IHC was performed for PD-L1 (Ventana SP142 ≥1% immune cells). Deficient mismatch repair (dMMR)/high microsatellite instability (MSI-H) was tested by IHC and NGS, respectively. Results: TMB-H was identified in 8.2% (n = 461) of MBC samples, with similar frequencies observed across molecular subtypes (7.8-8.6%, p = 0.85): HR+/HER2- (n = 3087) 7.8%, HR+/HER2+ (n = 266) 8.3%, HR-/HER2+ (n = 179) 7.8%, TNBC (n = 1476) 8.6%. The frequency of TMB-H was significantly increased in lobular (16%) versus ductal (5%) MBC (p < 0.01). TMB-H samples were enriched in genitourinary (42%), soft tissue (20%), and gastrointestinal non-liver (16%) biopsy specimens. Compared to TMB-L tumors, TMB-H tumors exhibited significantly higher mutation rates for TP53 (60 v 52%), PIK3CA (55 vs 31%), ARID1A (34 vs 11%), CDH1 (27 vs 11%), NF1 (22 vs 9%), RB1 (14 vs 5%), KMT2C (12 vs 7%), PTEN (12 vs 7%), ERBB2 (7 vs 2.9%), and PALB2 (3.3 vs 1%) genes (p < 0.05 each). Copy number alteration and fusion rates did not differ between TMB-H and TMB-L breast cancers. PI3K/AKT/MTOR, TP53, Histone/Chromatin remodeling, DNA damage repair (DDR), RAS, and cell cycle pathway alterations were detected in > 25% TMB-H MBCs (p < 0.05 each). dMMR/MSI-High (7.2 vs 0.3%, p < 0.01) and PD-L1 positivity (36 vs 28%, p < 0.05) frequencies were significantly increased in TMB-H tumors. DNA signature analyses including APOBEC and homologous recombination repair deficiency, as well as gene expression profiling to assess immune-related signatures and tumor microenvironment are underway. Conclusions: TMB-H breast cancers contain a unique genomic profile enriched with targetable mutations such as PIK3CA, ARID1A, NF1, PTEN, ERBB2, and PALB2. Concurrent predictive biomarkers of response to immune checkpoint inhibition such as MSI-H and PDL-1 positivity are also more prevalent in TMB-H MBC. These findings suggest novel combination strategies within TMB-H MBC could be explored.

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