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Targeting the HRD biomarker may improve outcomes for ovarian cancer patients

HRD and PARP inhibitors
Doctors have identified a genetic feature—or biomarker—called homologous recombination deficiency that’s leading to positive outcomes for patients with ovarian cancer.

Ovarian cancer has historically been a difficult cancer to treat. Its symptoms aren’t always obvious, making the cancer difficult to diagnose early. Most cases of ovarian cancer are diagnosed in advanced stages, resulting in a poor five-year survival rate. But now, doctors and scientists have identified a genetic feature—or biomarker—that’s leading to positive outcomes for ovarian cancer treatments. Homologous recombination deficiency (HRD) occurs when genes that regulate the homologous recombination repair (HRR) pathway are damaged and the cells are unable to fix their broken DNA. Up to 50 percent of women with advanced ovarian cancer have HRD-positive cancer cells. Patients who have tumors with HRD are responding well to a relatively new type of targeted therapy drug called poly (ADP-ribose) polymerase (PARP) inhibitors.  

“This has been such a mover and shaker in the ovarian cancer world,” says Ruchi Garg, MD, Gynecologic Oncologist and National Program Director of Gynecologic Oncology at Cancer Treatment Centers of America® (CTCA). “It has been a game-changer. The side effects are fewer, in comparison to chemotherapy. Some patients may have anemia, low platelets or nausea, but the majority stabilize over time. And long-term side effects and risks such as myelodysplastic syndrome are rare.”

Alphabet soup

Cancer terms, abbreviations and acronyms often get conflated and cause confusion. To better understand why some ovarian cancer patients may be responding well to new targeted therapy treatments, here’s a glossary of some of the terms described in this article:

BRCA: Breast cancer gene. Mutations in the BRCA 1 and BRCA 2 genes may increase the risk of several cancers, especially breast and ovarian cancers.

HRR: Homologous recombination repair. HRR is a signaling pathway in cells that allow them to fix damage in the double strand of a DNA helix.

HRD: Homologous recombination deficiency. HRD occurs when HRR fails because genes are damaged or signals between receptors are interrupted.

dMMR: Mismatch repair deficiency. This occurs when cells can’t repair mistakes in DNA caused during the division process.

MSH-H: High micro-satellite instability. Microsatellites are strands of repetitive DNA that can become unstable if a cell has dMMR.

PARP: Poly (ADP-ribose) polymerase. These proteins are used to help cells repair themselves. PARP inhibitors are used to treat ovarian and other cancers.

Fixing what’s broken

When a car breaks down, it’s often because a part has worn out, broken or malfunctioned. If you can’t fix the part or find a replacement, the car may wind up in the scrap heap. 

The same happens to some cells in our body. As a matter of course, the human body’s DNA is continually damaged and repaired. One such repair process is known as homologous recombination. Even cancer cells, which are healthy cells that have mutated and grow unchecked, get damaged and need to fix portions of their DNA in order to survive. In some cases, the cells are able to repair themselves, allowing them to continue to contribute to a cancer’s growth.

But sometimes, cancer cells have features that make it difficult to find a way to fix their broken strands of DNA, and they’re permanently shut down. Scientists are learning more about these processes in cancer cells and have developed drug therapies designed to short-circuit repair mechanisms to keep those flawed cancer cells permanently in the scrap heap.

HRR and HRD

One such repair pathway is HRR, which uses a complex set of signals between genes to fix double strands of DNA. Disruptions in those signals, or damage to the genes, may lead to HRD. Scientists have known that HRD may be found in ovarian tumors with BRCA1 and BRCA2 gene mutations, but they’re also discovering that tumors without those mutations may also have HRD.

Besides ovarian cancer, HRD may be found in other cancers, including:

PARP inhibitors, often in combination with other drugs, have been approved to treat HRD-positive ovarian cancers.

dMMR and MSI-H

HRR and HRD are similar to dMMR and MSI-H, but work differently and fix different types of damage. When cells can’t fix mismatches in their DNA, it may cause repetitive stretches of DNA called microsattelites to become unstable. MSI-H and dMMR may be found in many cancers, including:

In 2017, the FDA approved the checkpoint inhibitor drug pembrolizumab (Keytruda®) to treat cancers with dMMR or MSI-H. It was the first cancer treatment approved based on a tumor’s genetic feature rather than its primary location

BRCA, HRD and PARP inhibitors

It has long been known that having a BRCA mutation—BRCA1 or BRCA2—significantly increases the risk of breast cancer in both genders, as well as ovarian, prostate and pancreatic cancers. Medical researchers are finding that women with BRCA-associated ovarian cancer are having encouraging responses to PARP inhibitors. The PARP enzyme is responsible for helping cells repair DNA damage, and in the case of cancer, helping cancer cells survive. PARP inhibitors block DNA repair in cancer cells, causing them to die. As with all targeted therapies, PARP inhibitors are designed to target the cancer cells while leaving healthy cells alone.

PARP inhibitors were first approved in 2014 to treat recurrent BRCA-associated ovarian cancer, but more recent studies have found they may also be beneficial as a first-line treatment for women who are newly diagnosed with advanced disease. Additionally, the FDA has approved PARP inhibitors for certain BRCA-associated pancreatic and prostate cancers

In one study on advanced-stage BRCA-associated ovarian cancer patients, the PARP inhibitors decreased the chance of progression or death by as much as three-and-a-half years in the upfront maintenance setting, according to Dr. Garg. “In recurrent cancers, the numbers decrease, but there’s still a significant advantage,” she says.

Until recently, doctors have focused on the presence of BRCA gene mutations to help determine treatment options for ovarian cancers. More recently, researchers have learned that HRD may occur in ovarian tumors that do not have BRCA mutations. They also have learned, Dr. Garg says, that PARP inhibitors may benefit cancer patients who are positive both for BRCA or HRD without BRCA.

The key to finding out whether you may benefit from a PARP inhibitor is to undergo genetic testing, done via blood sample, as well as genomic testing of the cancerous tumor, which is performed by analyzing a tumor sample. Testing for a BRCA mutation should be done as soon as a patient receives a cancer diagnosis. If the results are positive, Dr. Garg says, PARP inhibitors should be used “almost 100 percent” of the time, either as treatment (for recurrent cancer) or as maintenance even when used as a first-line approach upfront.

“The take-home message is that 100 percent of these patients need to get germline [hereditary] and tumor genomic testing,” she says. “If they haven’t had it done in the beginning of their cancer journey, then whatever point they’re at, they need to get tested. This testing is the recommended standard of care, but lots of people fall through the cracks. There are only so many gynecologic oncologists or medical oncologists in the country who are up to date on gynecologic cancers, so a lot of these patients are not getting the most up-to-date or specialized care.”

Learn about the difference between ovarian, fallopian tube and peritoneal cancers.