BRCA1 Promoter Hypermethylation is Associated with Good Prognosis and Chemosensitivity in Triple-Negative Breast Cancer

The aberrant hypermethylation of BRCA1 promoter CpG islands induces the decreased expression of BRCA1 (Breast Cancer 1) protein. It can be detected in sporadic breast cancer without BRCA1 pathogenic variants, particularly in triple-negative breast cancers (TNBC). We investigated BRCA1 hypermethylation status (by methylation-specific polymerase chain reaction (MS-PCR) and MassARRAY® assays), and BRCA1 protein expression using immunohistochemistry (IHC), and their clinicopathological significance in 248 chemotherapy-naïve TNBC samples. Fifty-five tumors (22%) exhibited BRCA1 promoter hypermethylation, with a high concordance rate between MS-PCR and MassARRAY® results. Promoter hypermethylation was associated with reduced IHC BRCA1 protein expression (p = 0.005), and expression of Programmed death-ligand 1 protein (PD-L1) by tumor and immune cells (p = 0.03 and 0.011, respectively). A trend was found between promoter hypermethylation and basal marker staining (p = 0.058), and between BRCA1 expression and a basal-like phenotype. In multivariate analysis, relapse-free survival was significantly associated with N stage, adjuvant chemotherapy, and histological subtype. Overall survival was significantly associated with T and N stage, histology, and adjuvant chemotherapy. In addition, patients with tumors harboring BRCA1 promoter hypermethylation derived the most benefit from adjuvant chemotherapy. In conclusion, BRCA1 promoter hypermethylation is associated with TNBC sensitivity to adjuvant chemotherapy, basal-like features and PD-L1 expression. BRCA1 IHC expression is not a good surrogate marker for promoter hypermethylation and is not independently associated with prognosis. Association between promoter hypermethylation and sensitivity to Poly(ADP-ribose) polymerase PARP inhibitors needs to be evaluated in a specific series of patients.

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Association of BRCA1 promoter methylation in triple-negative breast cancer (TNBC) with resistance to standard anthracyline-based adjuvant chemotherapy.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.15_suppl.1123 ◽

2011 ◽

Vol 29 (15_suppl) ◽

pp. 1123-1123 ◽

Cited By ~ 3

Author(s):

P. Sharma ◽

B. F. Kimler ◽

Y. A. Park ◽

S. R. Stecklein ◽

Q. J. Khan ◽

...

Keyword(s):

Breast Cancer ◽

Adjuvant Chemotherapy ◽

Triple Negative Breast Cancer ◽

Promoter Methylation ◽

Triple Negative ◽

Brca1 Promoter ◽

Brca1 Promoter Methylation

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BRCA1 and TOP2A gene amplification and protein expression in four molecular subtypes of breast cancer

Archives of Biological Sciences ◽

10.2298/abs1302511m ◽

2013 ◽

Vol 65 (2) ◽

pp. 511-518 ◽

Cited By ~ 1

Author(s):

Olivera Mitrovic ◽

Mileva Micic ◽

V. Cokic ◽

Vesna Koko ◽

Dragoslava Djikic ◽

...

Keyword(s):

Breast Cancer ◽

Protein Expression ◽

Significant Positive Correlation ◽

Triple Negative ◽

Molecular Subtypes ◽

Protein Overexpression ◽

Brca1 Protein ◽

Luminal B ◽

Top2a Gene ◽

Top2a Amplification

We studied TOP2A amplification (using FISH methods), and TOP2A and BRCA1 protein overexpression (immunohistochemistry) in four molecular subtypes of breast cancer. Of 53 patients, 32 showed TOP2A and 38 showed BRCA1 overexpression. The highest percentage of TOP2A amplification (47.8%) and deletion (13%) was detected in Luminal B subtypes. Of 11 Luminal B tumors with TOP2A amplification, 9 (81.8%) overexpressed TOP2A. BRCA1 protein overexpression showed significant positive correlation with TOP2A protein expression. BRCA1 and TOP2A proteins exhibited similar patterns of expression in Luminal B and triple-negative breast cancer, suggesting the same prognosis in those patients.

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BRCA1 promoter hypermethylation, 53BP1 protein expression and PARP-1 activity as biomarkers of DNA repair deficit in breast cancer

BMC Cancer ◽

10.1186/1471-2407-13-523 ◽

2013 ◽

Vol 13 (1) ◽

Cited By ~ 31

Author(s):

William Jacot ◽

Simon Thezenas ◽

Romain Senal ◽

Cathy Viglianti ◽

Anne-Claire Laberenne ◽

...

Keyword(s):

Breast Cancer ◽

Dna Repair ◽

Protein Expression ◽

Promoter Hypermethylation ◽

Brca1 Promoter ◽

Parp 1

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Metabotropic glutamate receptor 1 is associated with unfavorable prognosis in ER-negative and triple-negative breast cancer

Scientific Reports ◽

10.1038/s41598-020-79248-4 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Anna E. M. Bastiaansen ◽

A. Mieke Timmermans ◽

Marcel Smid ◽

Carolien H. M. van Deurzen ◽

Esther S. P. Hulsenboom ◽

...

Keyword(s):

Breast Cancer ◽

Protein Expression ◽

Glutamate Receptor ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Metabotropic Glutamate Receptor ◽

Metabotropic Glutamate ◽

Metabotropic Glutamate Receptor 1 ◽

Novel Target ◽

Cancer Tissues

AbstractNew therapies are an urgent medical need in all breast cancer subgroups. Metabotropic glutamate receptor 1 (mGluR1) is suggested as a potential new molecular target. We examined the prevalence mGluR1 expression in different clinically relevant breast cancer subgroups and determined its association with prognosis. In this retrospective cohort, 394 consecutive primary breast cancer tissues were incorporated into a tissue microarray and immunohistochemically stained for mGluR1. The prevalence of mGluR1 protein expression in different breast cancer subgroups was evaluated and correlated with metastasis-free survival (MFS) and overall survival (OS). In total, 56% (n = 219) breast cancer tissues had mGluR1 expression. In estrogen receptor (ER)-negative tumors, 31% (n = 18/58) had mGluR1 expression that was significantly associated with MFS (HR 5.00, 95% CI 1.03–24.35, p = 0.046) in multivariate analysis, independently from other prognostic factors. Of the 44 triple-negative breast cancer (TNBC), 25% (n = 11) expressed mGluR1. mGluR1 expression in TNBC was significantly associated with shorter MFS (HR 8.60, 95% CI 1.06–20.39, p = 0.044) and with poor OS (HR 16.07, 95% CI 1.16–223.10, p = 0.039). In conclusion, mGluR1 is frequently expressed in breast cancer. In ER-negative breast cancer and in TNBC mGluR1 protein expression is an unfavorable prognostic marker. This study provides rationale to explore mGluR1 as a novel target for breast cancer treatment, especially for the more aggressive TNBC.

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Loss of BRCA1 expression and morphological features associated with BRCA1 promoter methylation status in triple-negative breast cancer

Journal of Human Genetics ◽

10.1038/s10038-021-00911-3 ◽

2021 ◽

Author(s):

Arisa Morizono ◽

Masahiko Tanabe ◽

Masako Ikemura ◽

Takeshi Sasaki ◽

Tetsuo Ushiku ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Promoter Methylation ◽

Triple Negative ◽

Methylation Status ◽

Morphological Features ◽

Brca1 Expression ◽

Brca1 Promoter ◽

Promoter Methylation Status ◽

Brca1 Promoter Methylation

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Staging Investigations in Asymptomatic Early Breast Cancer Patients at the Cancer Centre of Southeastern Ontario

Current Oncology ◽

10.3390/curroncol28030203 ◽

2021 ◽

Vol 28 (3) ◽

pp. 2190-2198

Author(s):

Dalia Kamel ◽

Veronica Youssef ◽

Wilma M. Hopman ◽

Mihaela Mates

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Adjuvant Chemotherapy ◽

Early Breast Cancer ◽

Triple Negative ◽

Metastatic Breast ◽

Receptor Status ◽

Cancer Centre ◽

Radiological Staging

Background: In 2012, the American Society for Clinical Oncology (ASCO) identified five key opportunities in oncology to improve patient care, recommending against imaging tests for the staging of patients with early breast cancer (EBC) at low risk for metastases. Similarly, the European Society of Medical Oncology (ESMO) guideline does not support radiological staging in asymptomatic EBC (aEBC). The purpose of this study was to assess local practice and outcomes of staging investigations (SIs) in aEBC at the Cancer Centre of Southeastern Ontario (CCSEO). Methods: A retrospective electronic and paper chart review was undertaken to identify all aEBC patients treated at our institution between January 2012 and December 2014. Patients with pathological staging of T1-T2 and N0-1 with any receptor status were included. We collected patient demographics, treatment and pathologic tumor characteristics. The use and outcomes of initial and follow-up SIs were recorded. Data were analyzed to determine associations between the use of SIs and clinical characteristics (chi-square tests, independent samples t-tests and Mann–Whitney U tests). Results: From 2012 to 2014, 295 asymptomatic EBC patients were identified. The mean age was 64, 81% were postmenopausal and 76% had breast conserving surgery. Stage distribution was as follows: stage I 42%, stage IIA 37% and stage IIB 21%. Receptor status was as follows: ER+ 84%, HER2+ 13% and triple negative 12%. Adjuvant chemotherapy was received by 36%, Trastuzumab by 10% and endocrine therapy by 76% of patients. Baseline SIs were performed in 168 patients (57%) for a total of 332 tests. Overt metastatic disease was found in five patients (one bone scan and four CT scans). Seventy-one out of the 168 patients (42%) who received initial staging imaging underwent 138 follow-up imaging tests, none of which were diagnostic for metastases. Nine patients with suspicious CT findings underwent biopsies, of which four were malignant (one metastatic breast cancer and three new primaries). Factors significantly associated with SI were as follows: younger age (p = 0.001), premenopausal status (p = 0.01), T2 stage (p < 0.001), N1 stage (p < 0.001), HER2 positive (p < 0.001), triple negative status (p = 0.007) and use of adjuvant chemotherapy (p < 0.001). Conclusions: Over a 3-year period at our institution, more than 50% of aEBC patients underwent a total of 470 initial and follow-up staging tests, yielding a cancer diagnosis (metastatic breast cancer or second primary cancer) in four patients. We, therefore, conclude that routine-staging investigations in aEBC patients have low diagnostic value, supporting current guidelines that recommend against the routine use of SI in this population.

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321 Phase I clinical trial assessing the combination of systemic chemokine modulatory regimen targeting TLR3 with neoadjuvant chemotherapy in triple negative breast cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0321 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A347-A347

Author(s):

Shipra Gandhi ◽

Mateusz Opyrchal ◽

Cayla Ford ◽

Victoria Fitzpatrick ◽

Melissa Grimm ◽

...

Keyword(s):

Breast Cancer ◽

Neoadjuvant Chemotherapy ◽

Phase I ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Early Stage ◽

Standard Dose ◽

Surrogate Marker ◽

Comprehensive Cancer Center ◽

Cancer Center

BackgroundNeoadjuvant chemotherapy (NAC) with taxanes is the standard of care in triple negative breast cancer (TNBC). Intratumoral prevalence of CD8+ cytotoxic T-lymphocytes (CTLs) is associated with an improvement in relapse-free survival (RFS) and overall survival (OS), while regulatory T-cells (Treg) and myeloid derived suppressor cells (MDSC) are associated with poor survival. Higher ratio of CTL/Treg is associated with higher probability of obtaining pathological complete response (pCR), a surrogate marker for RFS. Intratumoral production of CCL5, CXCL9, CXCL10 and CXCL11 is critical for local infiltration with CTLs, while CCL22 is responsible for Treg attraction. Previous studies have shown that CXCL9 expression in the pre-treatment breast tissue is associated with a three-fold higher rate of achieving pCR. Our preclinical data show that Chemokine modulating (CKM) regimen, combining rintatolimod (TLR3 agonist), interferon (IFN)-α2b, and celecoxib (COX-2 inhibitor) increases CTL-attracting, and decreases MDSC-, Treg-favoring chemokines, increasing CTL/Treg ratio in tumor microenvironment, with preferential tumor tissue activation than adjacent healthy tissues. We hypothesize that the combination of CKM with paclitaxel will result in infiltration of TNBC with CTLs, and along with doxorubicin/cyclophosphamide (AC), result in higher pCR, translating into improved RFS and OS.MethodsIn this phase I study NCT04081389, eligibility includes age ≥18 years, confirmed resectable TNBC, radiographically measurable disease ≥1 cm, ECOG PS ≤ 2, adequate organ and marrow function. Patients with autoimmune disease, serious mood disorders, invasive carcinoma within 3 years, history of peptic ulcers or hypersensitivity to NSAIDs will be excluded. We plan to treat three patients with early stage TNBC with paclitaxel 80 mg/m2 IV weekly for 12 weeks, rintatolimod 200 mg IV, celecoxib 200 mg oral twice daily, and accelerated titration of IFN-α2b at doses 0, 5, or 10 million units (MU)/m2 [Dose Levels (DL) 1, 2 and 3 respectively] on days 1–3 (no intra-patient dose escalation) in weeks 1–3. Dose-limiting toxicity (DLT) is defined as grade 3 or higher toxicities within the first 3 weeks. Any DLT will mandate recruitment per the 3+3 model. If no DLT, three patients will be enrolled at DL 4 at 20 MU/m2 IFN- α2b. This will be followed by standard dose-dense AC, and then surgery. The primary endpoint is safety and tolerability of combination and to identify the appropriate DL of CKM and paclitaxel for extended efficacy study. The secondary endpoints include investigation of efficacy (pCR and breast MRI response), along with RFS and OS. Intratumoral biomarkers will be analyzed in an exploratory manner.ResultsN/AConclusionsN/ATrial RegistrationNCT04081389Ethics ApprovalThe study was approved by Roswell Park Comprehensive Cancer Center Institution’s Ethics Board, approval number I-73718.

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Quantitative estimation of BRCA1 protein expression in breast cancer tissue using the method of flow cytometry

European Journal of Cancer ◽

10.1016/s0959-8049(16)61649-0 ◽

2016 ◽

Vol 61 ◽

pp. S183

Author(s):

E. Shestakova ◽

E. Dudko ◽

A. Grishanina ◽

V. Kirsanov ◽

N. Vichljantzeva ◽

...

Keyword(s):

Breast Cancer ◽

Flow Cytometry ◽

Protein Expression ◽

Quantitative Estimation ◽

Breast Cancer Tissue ◽

Cancer Tissue ◽

Brca1 Protein

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Surgery provides survival benefit over systemic therapy alone for stage IV triple negative breast cancer: A propensity matched analysis of the National Cancer Database.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e13054 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e13054-e13054

Author(s):

Lifen Cao ◽

Jonathan T. Bliggenstorfer ◽

Kavin Sugumar ◽

Christopher W. Towe ◽

Pamela Li ◽

...

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Systemic Therapy ◽

Survival Benefit ◽

Triple Negative ◽

Stage Iv ◽

National Cancer Database ◽

Propensity Matching ◽

N Stage ◽

Metastatic Sites

e13054 Background: Conflicting data exist regarding benefit of surgery of the primary site for stage IV breast cancer, in which systemic therapy is standard of care and patient characteristics may bias treatment decisions. Metastatic triple negative breast cancer (TNBC) is an aggressive subtype with limited therapy options and poor prognosis. Our aim was to assess whether surgery for the primary tumor in stage IV TNBC provides a survival advantage over systemic therapy alone. Methods: The National Cancer Database was queried for patients with de-novo stage IV TNBC who received systemic therapy alone or systemic therapy and surgery of the primary breast site 2004-2016. Patients receiving surgery for metastatic tumor sites or with incomplete follow up data were excluded. 1:1 propensity matching was performed for demographics, comorbidities, clinical T and N stage, and metastatic sites to minimize confounding factors. Survival outcomes were analyzed using a stratified log-rank test and Cox proportional hazard regression analysis. Results: Of 2989 patients, 782 (26.21%) underwent surgery plus systemic therapy and 2207 (73.84%) were treated with systemic therapy alone. The majority of all patients were aged 51-70 with low co-morbidity, and treated in metropolitan areas. Patients treated at academic facilities (OR = 0.67, p = 0.025), with multiple metastatic sites (OR = 0.59, p < 0.001), or advanced clinical N stage (OR = 0.55, p < 0.001) were less likely to undergo surgery. Of those who completed surgery, 58% had unilateral mastectomy, and 63% had axillary lymph node dissection. Propensity matching identified 507 ‘paired’ patients with similar characteristics in the surgery and systemic therapy alone groups. After multivariable adjustment, surgery was associated with superior overall survival compared with systemic therapy alone (HR 0.73, P < 0.001). Older age (HR = 1.47, p < 0.001), greater comorbidity (HR = 1.28, p < 0.001) and multiple metastatic sites (HR = 1.53, p < 0.001) significantly decreased overall survival in the matched cohort. Median survival was shortest in the systemic therapy alone group (12.8 months, 95% CI 11.3-14.5) and longest in those undergoing systemic therapy plus simple mastectomy (18 months, 95% CI 14.3-21.2), though approximately 4 months of median survival was added for all patients undergoing any surgery vs. systemic therapy alone (p = 0.0001). Conclusions: In stage IV TNBC, surgical resection of the primary tumor site in addition to systemic therapy may provide a survival benefit in selected patients. Though in this retrospective study the sequence of treatment was unknown, surgery could be considered for low disease burden as in other malignancies with oligometastatic disease. Additional research is needed to determine if these findings persist in prospective studies and for other hormone-receptor subtypes.

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