Homologous Recombination Deficiency Positive Advanced Ovarian Cancer

When cells cannot repair certain types of DNA damage properly, cancer may develop. In advanced ovarian cancer, a condition called homologous recombination deficiency affects about half of all patients and plays a crucial role in determining which treatments may work best.

Table of contents

• What Is Homologous Recombination Deficiency
• HRD in Advanced Ovarian Cancer
• Testing for HRD
• What HRD Testing Involves
• Treatment Implications of HRD Status

What Is Homologous Recombination Deficiency

Our bodies constantly work to repair damage to DNA, the genetic material inside our cells. One important repair system is called homologous recombination repair, or HRR, which fixes serious breaks in DNA strands^[1]. When this repair system does not work properly, the condition is called homologous recombination deficiency, or HRD^[1].

HRD occurs when the body fails to repair double-strand breaks in DNA. Over time, the unrepaired or incorrectly repaired DNA leads to an accumulation of mutations, ultimately causing cancer^[4]. When DNA repair is deficient, cells must rely on other, more error-prone backup systems to fix the damage. This leads to widespread genetic instability and leaves permanent marks on the genome called genomic scars^[4].

HRD can be caused by several factors. The most well-known causes are mutations in genes called BRCA1 and BRCA2, which produce proteins that help repair damaged DNA^[4]. However, BRCA mutations are not the only cause. Other gene alterations and changes in how genes are turned on or off, known as epigenetic factors, can also lead to HRD^[2].

HRD in Advanced Ovarian Cancer

HRD is an important characteristic, or biomarker, of advanced ovarian cancer. Approximately 50% of women with advanced ovarian cancer have tumors that test positive for HRD^[3][6]. In the specific subtype called high-grade serous ovarian carcinoma, which is the most common form of ovarian cancer, over half of all cases exhibit HRD^[6][8].

Many people assume that HRD is only related to BRCA gene mutations. While BRCA1 and BRCA2 are key HRD genes, they account for only about half of HRD-positive cases^[2][3]. Approximately one in four women with advanced ovarian cancer has a BRCA mutation detected by tumor testing, but women without a BRCA mutation may still have tumors with HRD^[6]. In fact, even if a patient tests negative for BRCA mutations, they could still be HRD-positive^[3].

Non-BRCA causes of HRD include mutations in other genes involved in DNA repair, such as CDK12, PALB2, CHEK1, CHEK2, RAD51B, RAD51C, RAD51D, ATM, BARD1, BRIP1, FANCL, H2AX, and RAD54L^[2]. These genetic changes, along with epigenetic factors, can all lead to homologous recombination deficiency.

Testing for HRD

HRD testing provides important diagnostic information for people with ovarian cancer. This information helps healthcare professionals personalize treatment options^[4]. The test checks for BRCA1 or BRCA2 mutations and also looks for genomic scars—permanent marks left behind by defective DNA repair^[4].

An HRD test is a type of genomic test or biomarker test that looks at all the genes in a tumor’s DNA. It can identify both inherited mutations, which are passed down from parents, and acquired mutations, which develop during a person’s lifetime^[3][14]. The test identifies changes that affect how cancer cells behave and can inform treatment recommendations^[14].

Healthcare professionals measure genomic instability by looking at three independent signs of genomic scarring. These include genomic loss of heterozygosity (gLOH) and large-scale state transitions (LST)^[2][4]. Identifying these markers can assess HRD status from all causes, not just from BRCA alterations^[2].

The results of HRD testing show whether a tumor is HRD-positive or HRD-negative. A tumor is considered HRD-positive if either a BRCA mutation is detected or the genomic scar score is high. A tumor is HRD-negative if no BRCA mutation is detected and the genomic scar score is low^[2].

What HRD Testing Involves

If you have been diagnosed with advanced ovarian cancer, it is recommended to get an HRD test as soon as possible after diagnosis^[14]. The first step is asking your doctor about getting the test. Your healthcare team may be able to use tissue from your original biopsy to conduct the HRD test, so you may not need an additional procedure^[14].

Testing includes taking a tumor tissue sample, either during surgery or through a biopsy, which is a procedure to remove a small piece of tissue^[3][14]. The sample is then analyzed in a laboratory.

It is important to understand that HRD testing is different from genetic testing. HRD testing is a tumor test that examines the DNA in cancer cells. Genetic testing, on the other hand, examines specific inherited genes in your overall DNA using a blood or saliva sample^[3][14]. Genetic tests can help identify the potential risk of developing certain diseases, including some cancers, by detecting inherited mutations such as BRCA mutations^[3].

Treatment Implications of HRD Status

Knowing your tumor’s HRD status helps your healthcare team treat your unique type of cancer. Getting tested may help them identify the most appropriate treatments for you^[13][14].

HRD represents a positive predictive biomarker for the clinical use of certain therapies in ovarian cancers^[1]. HRD-positive tumors may be more sensitive to specific treatments called PARP inhibitors and platinum-based chemotherapy^[1][2]. PARP inhibitors are targeted treatments that work by blocking another DNA repair pathway, causing cancer cells with already-deficient DNA repair to die^[2].

Studies have shown that patients with HRD-positive tumors respond better to platinum-based chemotherapy and have improved progression-free survival when treated with PARP inhibitors compared to those without HRD^[8][11]. In Chinese patients with high-grade serous ovarian carcinoma, HRD status predicted response to platinum-based chemotherapy, with platinum-sensitive rates of 97% in HRD-positive patients with BRCA mutations and 90% in HRD-positive patients without BRCA mutations, compared to 74% in HRD-negative patients^[8].

Depending on your tumor’s HRD status and other factors, treatment for advanced ovarian cancer may include surgery, chemotherapy, and targeted therapy^[13][14]. Tumor testing for HRD can help inform maintenance therapy options for patients with advanced ovarian cancer^[6].