abiraterone-acetate and Triple-Negative-Breast-Neoplasms

A subgroup of androgen receptor-expressing tumors represents approximately 30 % of all triple negative tumors. The androgen receptor and its signaling pathways have a central biological role in this tumor entity. These triple negative androgen receptor-positive tumors occur in older patients and do not appear to have a better prognosis compared to other triple negative tumors. In addition to androgen receptor-expression, these tumors are genomically characterized by a high frequency of PIK3CA activating mutation. Three clinical trials reported efficacy data for anti-androgens (bicalutamide, abiraterone acetate and enzalutamide) based on strong preclinical rationale. These trials report clinical benefit rates in about one in five patients. These encouraging but still limited results make a case for the identification of predictive response factors and therapeutic combinations to improve response rates. This review will provide an update on the biological and clinical knowledge of this tumoral subgroup that opens the way to non-cytotoxic anti-androgen therapies.

Topics: Abiraterone Acetate; Age Factors; Aged; Androgen Antagonists; Anilides; Benzamides; Class I Phosphatidylinositol 3-Kinases; Clinical Trials as Topic; Drug Screening Assays, Antitumor; Female; Forecasting; Humans; Mutation; Nitriles; Phenylthiohydantoin; Prognosis; Rare Diseases; Receptors, Androgen; Signal Transduction; Tosyl Compounds; Triple Negative Breast Neoplasms

Triple-negative (TN) breast cancer are characterized by lack of estrogen receptor (OR) and progesterone receptor (PR) expression, and the absence of overexpression of human epidermal growth factor receptor 2 (HER2). It is a heterogeneous group of tumors with a more pejorative prognosis than other subtypes of breast cancer. Androgen receptors (AR) are nuclear receptors whose expression varies from 80 to 85% of primary breast cancers and 60 to 75% of metastatic cancers. Among the TN breast cancers, the luminal androgen receptor (LAR) subtype expresses AR more frequently, up to 53% of the cases. AR are associated with lower tumor size, histological grade, Ki67, and lymph node involvement. The results of recent clinical trials evaluating anti-androgen therapies in locally advanced or metastatic TN breast cancer are promising. Many new therapies are tested, including enzalutamide or abiraterone acetate, and numerous therapeutic combinations including PI3K/AKT/mTOR inhibitors or CDK inhibitors. These therapies would allow an alternative treatment of patients with TN breast cancer for which there is often a therapeutic impasse.

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Agents; Benzamides; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Ki-67 Antigen; Lymphatic Metastasis; Neoplasm Proteins; Nitriles; Phenylthiohydantoin; Prognosis; Programmed Cell Death 1 Receptor; Receptors, Androgen; Steroid 17-alpha-Hydroxylase; TOR Serine-Threonine Kinases; Triple Negative Breast Neoplasms; Tumor Burden

Breast cancer (BC) is traditionally viewed as an oestrogen-dependent disease in which the androgen receptor (AR) is inhibitory, counteracting the oncogenic activity of oestrogen receptor α (ERα (ESR1)). Most probably as a result of this crosstalk, the AR has prognostic value in ER-positive disease, with AR positivity reported to correlate with a better prognosis. Activation of the AR pathway has been previously used as a therapeutic strategy to treat BC, but its usage declined following the introduction of the anti-oestrogen tamoxifen. More recently, it has been demonstrated that a subset of triple-negative BCs (molecular apocrine) are dependent upon androgen signalling for growth and therapies that inhibit androgen signalling, currently used for the treatment of prostate cancer, e.g. the antiandrogen bicalutamide and the CYP17 inhibitor abiraterone acetate are undergoing clinical trials to investigate their efficacy in this BC subtype. This review summarises the current knowledge of AR activity in BC.

Topics: Abiraterone Acetate; Androgen Antagonists; Androgens; Androstadienes; Anilides; Estrogen Antagonists; Female; Humans; Nitriles; Receptors, Androgen; Receptors, Estrogen; Signal Transduction; Steroid 17-alpha-Hydroxylase; Tamoxifen; Tosyl Compounds; Triple Negative Breast Neoplasms

Several expression array studies identified molecular apocrine breast cancer (BC) as a subtype that expresses androgen receptor (AR) but not estrogen receptor α. We carried out a multicentre single-arm phase II trial in women with AR-positive, estrogen, progesterone receptor and HER2-negative (triple-negative) metastatic or inoperable locally advanced BC to assess the efficacy and safety of abiraterone acetate (AA) plus prednisone.. Patients with a metastatic or locally advanced, centrally reviewed, triple-negative and AR-positive (≥10% by immunohistochemistry, IHC) BC were eligible. Any number of previous lines of chemotherapy was allowed. AA (1000 mg) was administered once a day with prednisone (5 mg) twice a day until disease progression or intolerance. The primary end point was clinical benefit rate (CBR) at 6 months defined as the proportion of patients presenting a complete response (CR), partial response (PR) or stable disease (SD) ≥6 months. Secondary end points were objective response rate (ORR), progression-free survival (PFS) and safety.. One hundred and forty-six patients from 27 centres consented for IHC central review. Of the 138 patients with sufficient tissue available, 53 (37.6%) were AR-positive and triple-negative, and 34 of them were included from July 2013 to December 2014. Thirty patients were eligible and evaluable for the primary end point. The 6-month CBR was 20.0% [95% confidence interval (CI) 7.7%-38.6%], including 1 CR and 5 SD ≥6 months, 5 of them still being under treatment at the time of analysis (6.4+, 9.2+, 14.5+, 17.6+, 23.4+ months). The ORR was 6.7% (95% CI 0.8%-22.1%). The median PFS was 2.8 months (95% CI 1.7%-5.4%). Fatigue, hypertension, hypokalaemia and nausea were the most common drug-related adverse events; the majority of them being grade 1 or 2.. AA plus prednisone treatment is beneficial for some patients with molecular apocrine tumours and five patients are still on treatment.. NCT01842321.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Prednisone; Receptor, ErbB-2; Receptors, Androgen; Receptors, Progesterone; Treatment Outcome; Triple Negative Breast Neoplasms

Our aim was to identify predictive factors of abiraterone acetate efficacy and putative new druggable targets in androgen receptor (AR)-positive triple-negative breast cancer (TNBC) treated in the UCBG 2012-1 trial.. Classic IHC apocrine markers including AR, FOXA1, GGT1, and GCDFP15, from patients' tumors allowed identifying abiraterone acetate-responders and nonresponders. All responders had clear apocrine features. Transcriptome analysis revealed that 31 genes were differentially expressed in the two subgroups, 9 of them being linked to proliferation and DNA damage repair. One of the most significant differences was the overexpression, in nonresponders, of. This study suggests that apocrine features can be helpful in the identification of abiraterone acetate-responders. We identified Chk1 as a putative drug target in AR-positive TNBCs.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Animals; Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Cell Cycle; Cell Line, Tumor; Cell Survival; Checkpoint Kinase 1; Disease Models, Animal; Female; High-Throughput Nucleotide Sequencing; Humans; Immunohistochemistry; Mice; Middle Aged; Neoplasm Grading; Neoplasm Staging; Protein Kinase Inhibitors; Receptors, Androgen; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays