Diagnostic Manager, Oncology
Senior Global Medical Affairs Leader, Diagnostics, Oncology Business Unit
Precision medicine connects the right patient to the right therapy and is bringing significant improvements in cancer patient care. Our understanding of DNA Damage Response (DDR), one of our key scientific platforms, and the role it plays in cancer is enabling us to push our research further to target a broad range of cancers including difficult to treat or aggressive cancers.1
Damage to DNA occurs on a daily basis, and the DDR describes the multiple ways in which DNA damage is detected and repaired. Two key factors influence the DDR – the type of DNA damage, and when the damage occurs during the cell division.2 While some types of DNA damage are repaired quickly, complex DNA damage takes longer to repair. In this scenario, pathways are activated to pause cell division and allow time for repair.
Importantly, most cancers have a greater dependency on the DDR, due to the loss of one or more DDR capabilities during the development of cancer.3 By understanding and identifying these dependencies, we can use precision medicine approaches and targeted DDR inhibitors to maximise DNA damage and selectively kill cancer cells. This provides a targeted approach to cancer treatment with the potential to improve patient outcomes across multiple tumour types.1-2,4
The Value of HRR and HRD
DNA double-strand breaks, or DSBs, are the most genotoxic form of DNA damage. Healthy cells can effectively fix DSBs via Homologous Recombination Repair (HRR), which is an efficient, mostly error-free pathway for DSB repair. Using the second copy of the gene as a DNA template these proteins work in a coordinated way to repair the break and restore genome integrity.
Cells with mal-functioning HRR rely on error-prone pathways such as Non-Homologous End-Joining to repair DSBs, leading to the accumulation of genetic aberrations and genomic instability. Such aberrations can be loss or rearrangement of sections of DNA, including entire genes. This phenotype of loss of HRR capability and the associated genomic instability is called Homologous Recombination Deficiency, or HRD.5,6
Exploiting HRD and genetic mutations in cancers
Poly ADP-ribose polymerase (PARP) inhibitors can exploit HRD in cancer cells by blocking PARP enzyme activity6, preventing DNA single-strand break repair and trapping PARP onto the DNA. In replicating cells this can lead to DNA double-strand breaks that would normally be repaired through the HRR pathway. In HRD tumours, for example, those with breast cancer susceptibility gene 1/2 (BRCA1/2) loss of function mutations, PARP inhibitor therapy can result in an unsupportable level of genomic instability and cancer cell death.1,7
Clinical utility has been demonstrated with PARP inhibitors in four tumour types (ovarian, prostate, breast, and pancreatic) where patients were selected for tumours displaying homologous recombination deficiency. Pathogenic mutations in the BRCA genes are the archetypal cause of homologous recombination deficiency and BRCA testing has proved an effective diagnostic tool. Recent clinical studies have explored the use of diagnostics that go ‘beyond BRCA’. These are commonly referred to as ‘HRR gene panel’ and ‘HRD Genomic Instability’ tests.
2 methods of finding defects in tumours
- One method is to sequence HRR genes to look for pathogenic, or deleterious, mutations that disrupt function[KG(2] . This is called an HRR gene panel test, which can be thought of as testing for mutations that cause HRD.
- Another approach is to detect and quantify the genomic aberrations that result from loss of HRR capability and are characteristic of the HRD phenotype. This is called an HRD genomic instability assay, also known as a scar test.
This 3D animation explains the principles behind HRR gene panel and HRD genomic instability testing and how these diagnostic tests work, and in which clinical settings they have found utility.
Using the right test to identify the right patient for the right treatment
Precision Medicine is bringing a revolution not just in the introduction of novel treatments, but also the associated molecular diagnostics to identify patients most likely to benefit. Diagnostic science is often complex, so we are committed to unravelling this complexity and providing tools that build awareness and confidence in the use of diagnostics. We are committed to pushing the boundaries of science and harnessing our DDR targets to contribute to the value of precision medicine and achieve the best possible outcomes for patients.
1. Ledermann et al. (2016). Homologous recombination deficiency and ovarian cancer. European Journal of Cancer, 60, pp.49-58.
2. Ciccia et al. (2010). The DNA Damage Response: Making it Safe to Play with Knives. Molecular Cell, 40(2), pp.179-204.
3. Hakem. (2008). DNA-damage repair; the good, the bad, and the ugly. The EMBO Journal, 27, pp.589–605.
4. O'Connor (2015). Targeting the DNA Damage Response in Cancer. Molecular Cell, 60(4) pp.547-560. doi:10.1016/j.molcel.10.040
5. Heeke et al. (2018). Prevalence of Homologous Recombination–Related Gene Mutations Across Multiple Cancer Types. JCO Precision Oncology, 2018.
6. da Cunha Colombo Bonadio et al. (2018). Homologous recombination deficiency in ovarian cancer: a review of its epidemiology and management. Clinics (Sao Paulo, Brazil), 73(suppl 1), e450s.
7. Morales et al. (2014). Review of poly (ADP-ribose) polymerase (PARP) mechanisms of action and rationale for targeting in cancer and other diseases. Critical reviews in eukaryotic gene expression, 24(1), pp.15–28.
Date of preparation: March 2021