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Breast Cancer

Pathways & Targets

AbbVie is exploring a vast array of pathways and proteins implicated in breast cancer cell growth, survival and motility in order to identify possible therapeutic targets. Selected pathways and potential targets include, but are not limited to, poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP).

PARP and DNA Repair

Triple negative breast cancer (TNBC) shares many clinical and pathological similarities with BRCA-deficient breast cancers, including dysfunctional DNA repair mechanisms1. PARP-1 and PARP-2 are attractive therapeutic targets for inhibition because breast cancer cells that are deficient in one or more DNA repair pathways are highly dependent on PARP-mediated base excision repair (BER), which may contribute to resistance to DNA-damaging chemotherapeutic agents.1

Breast Cancer

Breast cancer is diagnosed in nearly 1.7 million women worldwide each year and accounts for over 500 000 deaths, making it not only the most frequently occurring cancer in women globally, but also the leading cause of cancer-related deaths.2

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: estrogen receptor-/progesterone receptor-positive breast cancer (ER/PR+), human epidermal growth factor type 2 receptor-positive breast cancer (HER2+), and triple-negative breast cancer (TNBC), which refers to those tumors that lack expression of ER, PR, or HER2.3,4

Triple-Negative Breast Cancer

TNBC is an aggressive disease of mainly younger women; it accounts for 10% to 20% of all breast cancer cases.4,5 Without a therapeutic target, treatment options for TNBC are limited.6

Mechanism of Disease

TNBC encompasses a heterogeneous group of aggressive subtypes that demonstrate genomic instability. Gene expression profiling has identified 6 TNBC subtypes: 2 basal-like (BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem-like (MSL) and a luminal androgen receptor (LAR) subtype.5 Approximately 65% to 85% of TNBC fall into the basal subtypes.3,4,7

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.8,9 As a result, TNBCs share characteristic similarities with BRCA1/BRCA2-linked breast cancers, including extreme genomic instability and sensitivity to DNA-damaging agents.9 Dysregulated DNA repair mechanisms results in increased dependence on PARP-mediated base excision repair.1 TNBC cells demonstrate increased sensitivity to DNA-damaging agents when PARP-mediated DNA repair is inhibited.10

Overexpression and upregulation of PARP1 in breast cancers is associated with a worse prognosis.11,12 There is a high frequency of PARP1 overexpression in TNBC, suggesting that PARP1 may play a role in promoting disease progression.8,11,12

Diagnosis & Staging

Histologically, TNBC is typically of the ductal type. Women with TNBC frequently present with larger and higher-grade tumors compared with other breast cancer subtypes. TNBC also has a propensity to spread to visceral organs earlier in the disease course.6

The American Joint Committee on Cancer (AJCC) designates staging based on tumor, node, and metastasis (TNM) and this system is used to stage breast cancer.13 Treatment for breast cancer is based on staging categories and tumor characteristics, including triple negative status. Typically, overall performance status and the presence or absence of medical comorbidities are also considered when determining the treatment regimen.13

Challenges in Treatment

TNBC is a heterogeneous group of tumors with differences in tumor biology and treatment response.5

Although patients with TNBC have higher pathological complete response (pCR) rates after neoadjuvant chemotherapy, TNBC patients with residual disease have significantly inferior survival, particularly in the first 3 years.14 There also remains a significant risk of disease recurrence in TNBC, regardless of initial therapeutic response, making it challenging to find an optimal chemotherapy.6

Improved response to neoadjuvant chemotherapy may increase the feasibility of less invasive surgical interventions and the likelihood of breast conservation,15,16 which may be important for young patients with early TNBC.

Unmet Need

Chemotherapy is the mainstay of treatment. Because TNBC lacks ER, PR and HER2, approved targeted therapies are ineffective treatments.6

TNBC represents a significant clinical challenge because of a lack of response to hormonal and receptor-targeted agents coupled with an aggressive disease course. Although initially susceptible to chemotherapy, early complete response (CR) does not correlate with overall survival.6

The risk of relapse for TNBC patients is significantly higher than for women presenting with hormone receptor-positive breast cancer, and recurrence (especially metastatic relapse) often occurs within the first several years after treatment.6,17

AbbVie is committed to helping address these challenges and is actively conducting research in this area to help address this unmet need.


See the role PARP-mediated DNA repair plays in preventing apoptosis.

Related Pathways & Targets


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