Ovarian cancer is the fifth-leading cause of cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system. The high mortality rate is mainly because ovarian cancer is often diagnosed at a late stage, by which time the patient has a poor prognosis.
In the last few years, targeted treatments have emerged, expanding treatment options and reinforcing the role of biomarkers and biomarker testing, especially in advanced ovarian cancer.
Ovarian Cancer Awareness month is an opportunity to highlight key moments in the evolution of biomarker-driven approaches in advanced ovarian cancer care.
- The DNA repair pathway has become a target for cancer treatment
Approximately one quarter of women with ovarian cancer have a genetic mutation — in some cases the mutation is inherited (called germline); in other cases, it is not inherited but is present only in their tumor (somatic). At the molecular level, we know that healthy cells have multiple mechanisms that monitor and repair the trillions of DNA in our cells that get damaged every day by natural causes and environmental factors. Double-strand breaks (DSBs) represent the most harmful type of DNA damage. If left unattended, DSBs will cause mutations, chromosome aberrations, and genome instability, which could eventually lead to cell death and severe physiological disorders, such as neurodegeneration, immunodeficiency, and cancer.
Fortunately, most of this damage is fixed through various complex DNA repair processes. Repair enzymes recognize structural imperfections and work to maintain genome integrity and prevent cells from transforming into malignant tumors or cancers. But some errors make it past these mechanisms, thus becoming permanent mutations.
Poly (ADP-ribose) polymerase, or PARP, for instance, is an enzyme involved in the DNA repair process, also called DNA Damage Response (DDR). PARPs identify DNA damage and signals the need for repair, acting as a repair crew to help fix damaged cells.
- PARP enzyme plays an integral role in DNA damage repair
PARP inhibitors were developed to block the activity of PARP in specific cancer cells. By blocking this enzyme, DNA inside the cancerous cells is less likely to be repaired, leading to cell death and possibly slowing down tumor growth. First introduced as a novel cancer targeting strategy in 2005, PARP was initially found to selectively kill BRCA1/2 mutated tumor cells, a pivotal discovery that ushered in new synthetic lethal therapeutic approaches in clinical oncology. But that has since changed with the discovery of other gene mutations in the DDR pathways.
Of the pathways that mobilize to repair a cell’s broken DNA, two are specialized to repair double-strand DNA breaks: non-homologous end joining (NHEJ) and homologous recombination (HR). Homologous recombination repair (“HRR”) is a pathway that restores the original DNA sequence by using a matched DNA strand as a template for the repair process.
Loss of function to perform HRR — considered homologous recombination deficiency (“HRD”) — represents a cell’s inability to faithfully repair its own DNA. HRD can be caused by multiple factors, including acquired or inherited mutations in any of the pathway’s genes, such as BRCA1 or BRCA2, changes in gene expression, or other unknown causes. Approximately 50 percent of ovarian cancers are homologous recombination deficient; and half of these women test positive for BRCA mutations, the most commonly recognized type of HRD which is a component of HRD.
Tumors that are HRD positive can be sensitive to DNA damaging agents. In fact, PARP inhibitors show synthetic lethality when combined with genetic abnormalities in many DNA damage response (DDR) pathway components, such as mutations in the ATM, ATR, BRCA1/2, CHEK1, CHEK2, PALB2, and RAD51 genes.
- Using biomarkers is critical to better understand tumor types and inform treatment decisions
For that reason, biomarker testing — both germline (inherited) and tumor testing — is becoming a standard of care for a number of cancers. While germline testing can help assess familial risk, both germline and tumor testing can help gain insight into the likely course of disease and guiding treatment decisions by identifying patients most likely to respond from select therapies, including certain types of chemotherapy and PARP inhibition.
Different testing approaches are taken to assess for HRD, whether testing for mutations known to cause HRD, such as BRCA1, BRCA2, or ATM, or testing for the genomic instability known to result from it.
Detecting mutations in BRCA and other genes in the HRR pathway is a way to evaluate the cause of the HRD. This is done by testing for genes that are directly involved with the HRR pathway, using single-gene or comprehensive genomic panel tests that are able to detect the effects of HRD on a genome-wide scale. This is performed by detecting certain characteristic genomic rearrangements that are signs of instability as a result of HRD — regardless of the underlying genetic driver.
There are two types of tests to consider:
- Molecular genetic testing: study single genes or short lengths of DNA to identify variations or mutations that lead to a genetic disorder.
- Genomic testing: looks broadly at all genes, including interactions of those genes with each other and with the person’s environment
Genomic instability testing using tumor tissue identifies HRD in approximately 50% of patients. Tumor testing for mutations in HRR identifies more patients than germline testing. Understanding the differences among the various testing options will help inform a comprehensive treatment plan.
We’ve gained a deeper understanding of the molecular make up of cancers and the complex processes that underlie cancer development and progression. Through precision medicine, we are able to determine how different biomarkers are used to aid in the treatment of advanced ovarian cancer, more specifically, homologous recombination-deficient tumors, which includes tumors with a BRCA1 or BRCA2 mutation.