Have you considered the unique link between PARP-mediated DNA repair and BRCA-mutated metastatic breast cancer?1,2

PARP proteins play an integral part of the tumor DNA repair process.1,2 BRCA-mutated tumor cells rely more on PARP and, subsequently, may be particularly vulnerable to PARP disruption.1,2 Disrupting PARP may lead to accelerated cancer cell death.1,2

In metastatic breast cancer (mBC), patients with BRCA-mutated disease are different. Identifying these patients early has many potential implications.3

DNA damage and repair occur naturally.

DNA Damage and Repair Occur Naturally

  • DNA is subject to continual damage from both endocellular defects and exocellular forces such as chemotherapy and radiation4
  • DNA damage occurs in different ways, including single-strand breaks (SSBs) and double-strand breaks (DSBs)4
  • Specific repair mechanisms exist to address SSBs and DSBs:
    • PARP enzymes play a fundamental role in SSB repair by helping to recruit other DNA repair proteins4
    • BRCA1/2 proteins are essential for DSB repair through a high-fidelity process called homologous recombination4
  • Unrepaired SSBs become DSBs, which can be more harmful to the cell4,5
DNA Repair May be compromised in Tumor Cells.

DNA Repair May Be Compromised in Tumor Cells

  • If SSBs and DSBs go unrepaired in normal cells, they can lead to the development of cancer4
  • Cancerous tumor cells continue to accumulate DNA damage as they grow6
    • This damage may be caused by errors in DNA damage repair processes or defects in cell cycle checkpoints6
  • Deficiencies in DNA repair mechanisms, including loss of PARP and BRCA function within the tumor cell, can accelerate the buildup of DNA damage, prompting potential tumor cell death1,2
BRCAm Tumors rely on PARP to Repair DNA.

BRCA-mutated Tumors Rely More on PARP to Repair DNA

  • BRCA-mutated tumor cells are more vulnerable to the effects of DNA damage compared with normal cells1
  • Mutations to the BRCA gene prevent BRCA-mutated tumor cells from using homologous recombination to repair damaged DSBs1
  • In the absence of homologous recombination, BRCA-mutated tumor cells have a greater reliance on PARP for DNA repair1
Targeting PARP may prevent DNA damage repair.  Loss of PARP May Result in selective and accelerated cancer cell death.

Targeting PARP May Prevent DNA Damage Repair. Loss of PARP May Result in Selective and Accelerated Cancer Cell Death

  • Disrupting PARP-mediated DNA repair has shown antitumor activity in BRCA-mutated tumor cells1,2
  • Loss of the PARP repair process, coupled with impaired ability to repair DSBs in BRCA-mutated tumor cells, may result in the accumulation of additional DNA damage, leading to potential tumor cell death1,2


There may be potential in disrupting the PARP repair mechanism in BRCA-mutated mBC

  • PARP proteins play an integral part of the tumor DNA repair process by helping to repair single-strand DNA breaks (SSBs) before they become more cytotoxic double-strand breaks (DSBs)4,5
  • BRCA-mutated tumor cells are prevented from using homologous recombination to repair these damaging DSBs, making them particularly reliant on PARP for DNA repair1
  • The underlying deficiencies in DNA repair pathways observed in BRCA-mutated mBC that lead to genomic instability may increase sensitivity to modalities that target PARP1

Research is focusing on the PARP repair mechanism in BRCA-mutated breast cancer.7

BRCA Mutations May Be More Prevalent Than Expected

BRCA gene mutations greatly increase cancer risk and are the most common cause of hereditary breast cancer. Although BRCA mutations can occur in any patient with breast cancer, they’re more common in certain breast cancer subtypes.8,9

In 2017, an estimated 255,180 new cases of invasive breast cancer were diagnosed in the United States10

BRCA Mutations are more prevalent in certain breast cancer subtypes. BRCA Mutations are more prevalent in certain breast cancer subtypes.

Remember: BRCA-mutated breast cancer cannot be easily identified based on patient or tumor characteristics alone.

Below, consider the common characteristics of a “typical” patient with a BRCA mutation. Then, contrast them against other patient characteristics you may not have considered9:

Patient characteristics commonly associated with BRCA-mutated metastatic breast cancer. Patient characteristics commonly associated with BRCA-mutated metastatic breast cancer.

Patients With BRCA-mutated mBC May Have Worse Outcomes

BRCA-mutated mBC has tumor characteristics that are linked to more aggressive disease and poor prognosis, including:

  • High grade19-21
  • Bulky disease22,23
  • Basal-like subtype (BRCA1)24-26
  • Visceral metastasis19,27
  • High mitotic activity22,28
  • Ki67 positivity27,29
  • Low ER/PR expression29,30
  • Luminal B subtype (BRCA2)16,31

Early Identification of BRCA Status May Offer Important Information3

BRCA testing helps patients and their families learn about their risk of developing breast, ovarian, and other familial cancers. Test results could also help determine options to manage cancer risk, such as enhanced screening, prophylactic surgery, and chemoprevention.3

Identify BRCA status according to testing guidelines in patients with mBC.

View the NCCN Guidelines® for Breast Cancer Screening and Diagnosis

NCCN=National Comprehensive Cancer Network® (NCCN®).

NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.


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