A. Martinez-Cardús (Badalona, Spain)

Badalona·Applied Research Group in Oncology (B·ARGO)

Author Of 2 Presentations

 On-Demand ePoster Display

33P - Epigenetics biomarkers ID1, HOXB2 and ATOH8 could predict response to chemotherapy and prognosis in early breast cancer

Abstract

Background

Epigenetic alterations play an important role in the development of breast cancer and could differ between the different subtypes as well act as prognostic and/or predictive factor of response to chemotherapy. The potential reversibility of these alterations justifies the growing interest in their research as possible therapeutic targets in the context of precision medicine. Our aim is to perform a DNA methylation screening to identify potential biomarkers of prognosis and treatment response in breast cancer.

Methods

We retrospectively analyzed 138 breast cancer patients treated with neoadjuvant chemotherapy based on anthracyclines and taxanes. Patients were classified in breast cancer subtypes according to clinical and pathological characteristics. In the epigenetic analysis, a \"discovery\" cohort was selected from the BRCA cohort from TCGA. 28 cases with available methylation data were chosen, and 3 candidate genes (ID1, HOXB2 and ATOH8) were selected using bioinformatics tools. These biomarkers were validated in our \"validation cohort\" by pyrosequencing techniques. Results were correlated with clinical-pathological characteristics, response rate and survival.

Results

After pyrosequencing analyses, ID1 methylation was different (p< 0.001) among breast cancer subtypes; its hypomethylation was associated with triple negative subtype. Hypomethylation of HOXB2 was mostly detected in luminal tumors and was associated with a lower response rate (p=0.025) and worse survival. The combination of both hipermethylated ID1 and hypomethylated HOXB2, defined a subgroup of luminal patients with worse prognosis. Hypomethylation of ATOH8 was correlated with triple negative tumors (p=0.01), but it was related to a higher rate of pathological complete responses (p=0.016) and a trend to a greater disease-free survival in this subgroup.

Conclusions

Epigenetic platforms could be a useful tool to select predictive and prognostic markers in cancer. Although a validation in a larger and prospective cohort is required, ID1, HOXB2 and ATOH8 are suggested as epigenetic biomarkers for predicting response to chemotherapy and prognosis in breast cancer.

Legal entity responsible for the study

The authors.

Funding

Celgene.

Disclosure

V. Quiroga Garcia: Honoraria (self): Roche; Honoraria (self): Pfizer; Research grant/Funding (institution): Celgene; Travel/Accommodation/Expenses: Novartis; Travel/Accommodation/Expenses: Roche. B. Cirauqui Cirauqui: Advisory/Consultancy: BMS; Advisory/Consultancy: Roche; Advisory/Consultancy: Merck; Speaker Bureau/Expert testimony: BMS; Speaker Bureau/Expert testimony: Roche; Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: BMS; Travel/Accommodation/Expenses: Merck; Travel/Accommodation/Expenses: MSD. M. Romeo Marin: Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): GSK; Research grant/Funding (institution): Clovis. All other authors have declared no conflicts of interest.

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120P - Prognostic significance of SAMHD1 expression in breast cancer

Abstract

Background

SAMHD1 is a triphosphohydrolase that catalyzes the degradation of deoxynucleoside triphosphates, and its function is tightly linked to cell cycle progression and proliferation, and potential inhibition of the innate inmune response. We explored the potential rol of SAMHD1 expression in metastatic breast cancer (MBC).

Methods

SAMHD1 effect on proliferation, efficacy of diferent chemotherapy agents was evaluated in vitro, using breast cancer cell lines modified to express or not SAMHD1. In patients, a cohort of capecitabine-treated MBC (n=46) patients were retrospectively selected to evaluate SAMHD1 expression by immunohistochemistry (anti-SAMHD1 polyclonal antibody 12586-1-AP, Proteintech) on tissue microarrays from primary tumour or metastasis.Median time to progresion (TTP) to capecitabine in MBC cohort was 13 months and median overal survival (OS) was 28.8 months. SAMHD1 positivity was defined as cellular positivity ≥1%. SAMHD1 gene was also sequenced from tumor biopsies in a subgroup of patients with none (n=10) or high (n=10) expression of the protein, to identify somatic mutations. Statistical analysis was performed using Chi-square test for qualitative covariables, Kaplan-Meier survival curves and log Rank function, considering a p < 0.05 as statistically significant.

Results

SAMHD1 knock-out cells showed higher sensitivity to carboplatin-induced cell death. In patients, SAMHD1 positivity was strongly associated with ki67 >15% (p<0.000). and high grade of proliferation (p=0.004). SAMHD1 positivity was associated with patients diagnosed with MBC and those who presented early relapse (DFS) ≤ 5 years (p=0.005). In multivariate analysis for DFS including ki67, histological Grade, and SAMHD1; SAMHD1 and ki 67 were the most important factors, being SAMHD1 the most significant. Interestingly, a higher proportion of gene mutations was found in sequences from SAMHD1 null patients. SAMHD1 positivity was also associated with worst OS from BC diagnosis (p=0.001), and with worst OS from the diagnosis of metastatic disease (Chi-Square test; p=0.05).

Conclusions

SAMHD1 expression may represent a new strong prognostic factor in breast. Thus, modulation of SAMHD1 function may constitute a promising target for the improvement of multiple cancer therapies.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

M. Margeli Vila: Research grant/Funding (self): Pfizer; Research grant/Funding (self): Novartis; Research grant/Funding (self): Roche; Advisory/Consultancy: Novartis; Advisory/Consultancy: Eisai. V. Quiroga: Speaker Bureau/Expert testimony: Pfizer; Speaker Bureau/Expert testimony: Novartis. M. Romeo: Research grant/Funding (self): Pfizer; Research grant/Funding (self): AstraZeneca; Research grant/Funding (self): GSK; Research grant/Funding (institution): Clovis. B. Cirauqui: Advisory/Consultancy: BMS; Advisory/Consultancy: Roche; Advisory/Consultancy: Merck. All other authors have declared no conflicts of interest.

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