Exploring dysfunctional pathways, mechanisms, and biomarkers in breast
cancer to discover new insights into the progression of the disease.
INCIDENCE & MORTALITY
Breast cancer was diagnosed in about 2.3 million women worldwide during 2020.1
- Breast cancer is the third most commonly diagnosed cancer overall and the leading diagnosed cancer among women.1
More than 680,000 deaths worldwide are attributed to breast cancer each year.1
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
From these three main clinical biomarkers (ER, PR, and HER2), a diagnostic panel can approximate the four intrinsic breast cancer molecular subtypes: luminal types A and B, basal-like, and HER2-enriched:24,25
Triple-Negative Breast Cancer (TNBC)
TNBC encompasses a heterogeneous group of aggressive subtypes that demonstrate genomic instability, and is defined by the absence of estrogen receptors (ER) and progesterone receptors (PR), and the absence of HER2 overexpression.26 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
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
Inhibition of PARP has been shown effective in causing cell death in BRCA-mutant cells while sparing normal cells – this selective killing of BRCA-mutant cells leverages the concept of "synthetic lethality."27 Synthetic lethality occurs when the simultaneous perturbation of two genes results in cellular or organismal death.29 Synthetic lethality also occurs between genes and small molecules (e.g. PARP inhibitors), and can be used to elucidate the mechanism of action of drugs.29 The shutdown of the predominant DNA repair pathways via PARP inhibition, may explain why BRCA1 or BRCA2 mutant cells are sensitive to PARP1 inhibitiors.16
Hormone Receptor-Positive Breast Cancer with HER2-Negativity (HR+ / HER2-) – Luminal A
The most common subtype of breast cancer is hormone receptor-positive (HR+) breast cancer, which accounts for approximately 60%–80% of all cases.30,31 Hormone receptors, which include estrogen receptor (ER) and progesterone receptor (PR), have been used as critical indicators for endocrine therapy and prognosis in breast cancer (BC) since the mid-1970s.31 In a large cohort analysis (N=823,399) the overall ER/PR positivity rates in breast cancer patients was:31
- ER+/PR+ = 67.2%
- ER+/PR– = 12.2%
- ER–/PR+ = 1.6%
- ER–/PR– = 19.0%
From the perspective of intrinsic molecular subtypes, luminal A is the most common breast cancer subtype and is characterized by ER+ and/or PR+ / HER2– status and low-grade tumors.32
From a clinical point of view, those patients with luminal A breast cancer have an excellent prognosis in general, and the benefits of adjuvant endocrine therapy is well established. However, the impact of adjuvant chemotherapy is questionable.33 In addition, survival studies suggest that risk of late mortality persists in women with luminal A tumors.32
Hormone Receptor-Positive Breast Cancer with HER2-Positivity (HR+ / HER2+) – Luminal B
As described in the luminal A section, HR+ is the most common subtype of breast cancer, although the identified intrinsic molecular subtyping of breast cancer also considers HER2-status.30,32 The luminal B subtype accounts for roughly 10% of all breast cancer and is distinguished by ER+ and/or PR+ / HER2+ status.32 Compared with women with luminal A tumors, women with luminal B tumors had roughly a two-fold increased adjusted risk of breast cancer mortality.32
Luminal B breast cancers are characterized by a lower expression of estrogen receptor (ER), a low expression of progesterone receptor (PgR) and a high histologic grade.34,35 Luminal B breast cancer is recognized as having an aggressive clinical behavior.35 The luminal B subtype has shown increased relapse rates in the first 5 years after diagnosis, decreasing over time, and a metastatic dissemination time pattern similar to basal-like and HER2-enriched cancers behavior, with prognosis similar to that of HER2-enriched and basal-like groups.35
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 Although initially susceptible to chemotherapy, early complete response (CR) does not correlate with overall survival.
- Recent advances in immunotherapy and the use of PD-1/PD-L1 inhibitors in combination with chemotherapy provides an additional therapeutic option for TNBC patients whose tumors express PD-L1.28
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.
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
Relevant Biomarker Pathways
Learn how PARP inhibitors may sensitize cells to the effects of DNA-damaging chemotherapy. MORE>
- Global Burden of Disease Cancer Collaboration; Sung H; Ferlay J, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: Cancer J. Clin. 2021;71(3):209-249.
- National Cancer Institute. Surveillance, Epidemiology, and End Results Program. https://seer.cancer.gov/statfacts/html/breast.html. Accessed September 2021.
- Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61-70.
- 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.
- 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.
- O'Reilly EA, Gubbins L, Sharma S, et al. The fate of chemoresistance in triple negative breast cancer. BBA Clin. 2015;257-275.
- American Cancer Society website. Breast cancer. https://www.cancer.org/cancer/breast-cancer/risk-and-prevention/breast-cancer-risk-factors-you-cannot-change.html. Accessed July 2020
- National Cancer Institute. Breast Cancer Treatment (PDQ®)-Health Professional Version. https://www.cancer.gov/types/breast/hp/breast-treatment-pdq. Accessed July 2020.
- 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.
- 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.
- 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.
- 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.
- Zhu Y, et al. BRCA mutations and survival in breast cancer: an updated systematic review and meta-analysis. Oncotarget. 2016;7(43):70113-70127.
- Bayraktar S, et al. BRCA mutation genetic testing implications in the United States. Breast. 2017;31:224-232.
- Baretta Z, et al. Effect of BRCA germline mutations on breast cancer prognosis: A systematic review and meta-analysis. Medicine (Baltimore). 2016;95(40):e4975
- Andreopoulou E, et al. Therapeutic advances and new directions for triple-negative breast cancer. Breast Care (Basel). 2017 Mar;12(1):21-28.
- 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.
- 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.
- Hortobagyi GN, Connolly JL, D'Orsi CJ, et al. Breast. In: AJCC Cancer Staging Manual, 8th ed. Chicago, IL: The American College of Surgeons (ACS). Updated March 13, 2018. Available at: https://cancerstaging.org/references-tools/deskreferences/Pages/Breast-Cancer-Staging.aspx. Accessed July 2019.
- Carlson RW, Allred DC, Anderson BO, et al. Breast cancer. Clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2009;7(2):122-192.
- Jiang T, Shi W, Wali VB, et al. Predictors of chemosensitivity in triple negative breast cancer: an integrated genomic analysis. PLoS Med. 2016 Dec 13;13(12):e1002193.
- 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.
- Farmer H, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434:917-921.
- Gretchen GL, et al. Epidemiology of Triple Negative Breast Cancers. Breast Dis. 2010;32(0):5-24.
- Haque R, et al. Impact of Breast Cancer Subtypes and Treatment on Survival: An Analysis Spanning Two Decades. Cancer Epidemiol Biomarkers Prev. 2012;21(10):1848-1855.
- Hubalek M, et al. Biological Subtypes of Triple-Negative Breast Cancer. Breast Care 2017;12:8-14.
- Turk AA, Wisinski KB. PARP Inhibitors in Breast Cancer: Bringing Synthetic Lethality to the Bedside. Cancer. 2018 Jun 15;124(12):2498-2506.
- Marra A, et. al. Recent Advances in Triple Negative Breast Cancer: The Immunotherapy Era. BMC Med. 2019 May 9;17(1):90.
- Nijman SMB. Synthetic lethality: General principles, utility and detection using genetic screens in human cells. FEBS Lett. 2011 Jan 3; 585(1): 1-6.
- Matutino A, et al. Hormone receptor-positive, HER2-negative metastatic breast cancer: redrawing the lines. Curr Oncol. 2018 Jun;25(S1):S131-S141.
- Li Y, et al. Clinicopathological Characteristics and Breast Cancer–Specific Survival of Patients With Single Hormone Receptor-Positive Breast Cancer. JAMA Network Open. 2020;3(1):e1918160.
- Haque R, et al. Impact of Breast Cancer Subtypes and Treatment on Survival: An Analysis Spanning Two Decades. Cancer Epidemiol Biomarkers Prev 2012;21(10):1848-1855.
- Herr D, et al. Does chemotherapy improve survival in patients with nodal positive luminal A breast cancer? A retrospective Multicenter Study. PLoS One. 2019; 14(7): e0218434.
- Li ZH, et al. Luminal B breast cancer: patterns of recurrence and clinical outcome. Oncotarget. 2016 Oct 4; 7(40): 65024-65033.
- Ades F, et al. Luminal B Breast Cancer: Molecular Characterization, Clinical Management, and Future Perspectives. J Clin Oncol. 2014;2(25):2794-2803.