The management of breast cancer is largely shaped by the identification of cellular phenotypes and potential molecular targets and is categorized into three basic therapeutic groups.^3,4

• Estrogen receptor-/progesterone receptor-positive breast cancer (ER/PR+)
• Human epidermal growth factor type 2 receptor-positive breast cancer (HER2+)
• Triple-negative breast cancer (TNBC), referring to those tumors that lack expression of ER, PR, or HER2

TNBC is a highly heterogeneous and aggressive disease affecting mainly younger women.^4-6

• It accounts for 10% to 20% of all breast cancer cases.
• Treatment options are limited due to the lack of a therapeutic target.

Approximately 5% to 10% of breast cancers are hereditary.^7,8

Triple-Negative Breast Cancer (TNBC)

TNBC encompasses a heterogeneous group of aggressive subtypes that demonstrate genomic instability. Gene expression profiling has identified 6 TNBC subtypes.⁵

• 2 basal-like (BL1 and BL2) subtypes; Approximately 65% to 85% of TNBC fall into the basal subtypes.^3,4,9
• Immunomodulatory (IM) subtype
• Mesenchymal (M) subtype
• Mesenchymal stem-like (MSL) subtype
• Luminal androgen receptor (LAR) subtype

The BL1 and BL2 TNBC subtypes show higher expression of cell cycle checkpoint, PI3K-signalling, and DNA damage-response genes.^3,5

Over 70% of TNBCs show mutation or deletion of the TP53 gene, and many display high PARP1 expression levels.^10,11 As a result, TNBCs share characteristic similarities with BRCA1/BRCA2-related breast cancers, including:

• Extreme genomic instability and sensitivity to DNA-damaging agents.¹¹
• Dysregulated DNA repair mechanisms, which results in increased dependence on PARP-mediated base excision repair.¹²

BRCA1- and BRCA2-related Breast Cancer

BRCA1 and BRCA2 are tumor suppressor genes that encode factors that inhibit cell growth.¹³ These factors are also involved in other important cellular processes, including¹³:

• Cell cycle control
• Gene transcription regulation
• DNA damage repair
• Apoptosis

Most hereditary breast cancers have germline mutations of the BRCA1 and/or BRCA2 genes.^14,15 BRCA-related hereditary breast cancer is characterized by a more aggressive phenotype.¹⁴

• BRCA1-related hereditary breast cancer is more frequently high grade and triple negative than sporadic tumors.¹⁵
• BRCA mutation carriers have a very high risk of developing breast cancer by age 70 (47% to 66%).¹⁴
• More than 80% of hereditary BRCA1-related breast cancers are also TNBC.¹⁶

Factors associated with a BRCA1 or BRCA2 mutation in individuals unselected for a family history include¹⁴:

• < 30 to 40 years of age: ~6% to 18%
• <40 to 50 years of age: ~6%
• Any age: 2%
• Ashkenazi Jewish ancestry: ~10%
• Triple-negative histology: 9% to 28%
• Male: 4% to 14%

PARP1 and Breast Cancer

Overexpression and upregulation of PARP1 in breast cancers is associated with a worse prognosis.^17,18

• There is a high frequency of PARP1 overexpression in breast cancer, suggesting that PARP1 may play a role in promoting disease progression.^10,17,18

The American Joint Committee on Cancer (AJCC) stages invasive (infiltrating) carcinoma of the breast and ductal carcinoma in situ of the breast based on history, physical examination, imaging studies if performed, and relevant biopsies.¹⁹

• When biomarker analysis is not available: Anatomic Staging based solely on anatomic extent of cancer as defined by the tumor, node, and metastasis (TNM) categories
• When biomarkers are available: Clinical and Pathological Prognostic Staging
  • Clinical Prognostic Stage is determined by TNM tumor grade and HER2 and ER/PR status.
  • Pathological Prognostic Stage is based on all clinical information, biomarker data, and findings from surgery and resected tissue.

Treatment for breast cancer is based on staging categories and tumor characteristics, including triple negative status.¹⁴

• Typically, overall performance status and the presence or absence of medical comorbidities are also considered when determining the treatment regimen.
• There is general agreement that women with a higher lifetime risk of breast cancer, such as that conferred by a BRCA mutation, should undergo earlier and more frequent screening, with additional imaging modalities considered.

Management approaches for advanced stage IV disease is based on HR/HER status.

• Women with ER/PR+ breast cancer are candidates for endocrine therapy.
• Women with HER2+ breast cancer may benefit from HER2-targeted therapy.
• Treatment options are limited for patients without a therapeutic target (TNBC).⁶ Chemotherapy remains the foundation of treatment for these patients, but only about one-third of patients with TNBC achieve a pathologic complete response from anthracycline/taxane therapy.²¹

5-year survival in patients who present with breast cancer with distant metastases is ~27%.²

• A recent meta-analysis found that BRCA1-mutation carriers had a 30% higher risk of dying than BRCA1-negative or sporadic cases.¹⁵
• Additional treatment options are needed to improve survival in patients with metastatic breast cancer, particularly high-risk patients who carry BRCA mutations.

Chemotherapy is the foundation of treatment for TNBC.¹⁶

• Because TNBC lacks ER, PR, and HER2, approved targeted therapies are ineffective treatments.⁶
• Although initially susceptible to chemotherapy, early complete response (CR) does not correlate with overall survival.

Addressing dysregulated DNA repair mechanisms in breast cancer tumor cells may provide new treatment opportunities for patients with metastatic breast cancer. ¹⁶

• Because PARP is essential for the recognition and repair of DNA damage, inhibition of PARP is hypothesized to potentiate the cytotoxicity of DNA-damaging agents.
• TNBC cells demonstrate increased sensitivity to DNA-damaging agents when PARP-mediated DNA repair is inhibited.²²

AbbVie is committed to helping address these challenges and is actively conducting research in this area to help address the needs of patients with advanced breast cancer.