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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.

PARP

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

Related Pathways & Targets

References

  1. Anders CK, Winer EP, Ford JM, Dent R, Silver DP, Sledge GW, Carey LA. Poly(ADP-Ribose) polymerase inhibition: “targeted” therapy for triple-negative breast cancer. Clin Cancer Res. 2010;16:4702-4710.
  2. American Cancer Society. Global Cancer Facts & Figures 3rd Edition. Atlanta: American Cancer Society; 2015.
  3. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61-70.
  4. Bauer KR, Brown M, Cress RD, et al. Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype. Cancer. 2007;109(9):1721-1728.
  5. Lehmann BD, Bauer JA, Chen X, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121:2750-2767.
  6. O'Reilly EA, Gubbins L, Sharma S, et al. The fate of chemoresistance in triple negative breast cancer. BBA Clin. 2015;257-275.
  7. Davis SL, Eckhardt SG, Tentler JJ, Diamond JR. Triple-negative breast cancer: bridging the gap from cancer genomics to predictive biomarkers. Ther Adv Med Oncol. 2014;6:88-100.
  8. Ossovskaya V, Koo IC, Kaldjian EP, Alvares C, Sherman BM. Upregulation of poly (ADP-Ribose) polymerase-1 (PARP1) in triple-negative breast cancer and other primary human tumor types. Genes Cancer. 2010;1:812-821.
  9. Audeh MW. Novel treatment strategies in triple-negative breast cancer: specific role of poly(adenosine diphosphate-ribose) polymerase inhibition. Pharmacogenomics Pers Med. 2014;7:307-316.
  10. Donawho CK, Luo Y, Luo Y, et al. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res. 2007;13:2728-2737.
  11. Goncalves A, Finetti P, Sabatier R, et al. Poly(ADP-ribose) polymerase-1 mRNA expression in human breast cancer: a meta-analysis. Breast Cancer Res Treat. 2011;127:273-281.
  12. Rojo F, Garcia-Parra J, Zazo S, et al. Nuclear PARP-1 protein overexpression is associated with poor overall survival in early breast cancer. Ann Oncol. 2012;23:1156-1164.
  13. National Cancer Institute. General Information About Breast Cancer. Cancer.gov. http://www.cancer.gov/types/breast/hp/breast-treatment-pdq. Accessed March 4, 2016.
  14. Liedtke C, Mazouni C, Hess KR, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 2008;26:1275-1281.
  15. Boughey JC, McCall LM, Ballman KV, et al. Tumor biology correlates with rates of breast-conserving surgery and pathologic complete response after neoadjuvant chemotherapy for breast cancer: findings from the ACOSOG Z1071 (Alliance) prospective multicenter clinical trial. Ann Surg. 2014;260:608-616.
  16. Mathieu MC, Mazouni C, Kesty NC, et al. Breast Cancer Index predicts pathological complete response and eligibility for breast conserving surgery in breast cancer patients treated with neoadjuvant chemotherapy. Ann Oncol. 2012;23:2046-2052.
  17. Dent R, Trudeau M, Pritchard K, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res. 2007;13(15):4429-4434.