Testing for gBRCA in People with Cancer

Testing for germline BRCA1/2 mutations, also known as gBRCA testing, is important in making treatment decisions for people with some types of cancer. While many people are familiar with genetic testing as a method to find people at risk for developing cancer in the first place, people who have recurrent or metastatic cancers of the breast, ovary, pancreas, or prostate may benefit from testing as a way to guide treatment choices as well.

For example, with metastatic breast cancer, the presence of a BRCA mutation might mean that a certain type of therapy is more likely to be effective or may suggest which type of chemotherapy will work best.

The importance of testing for gBRCA mutations in some metastatic cancers cannot be overemphasized. For example, gBRCA testing in metastatic breast cancer is considered a significant unmet need since there are now approved therapies for these tumors that traditionally carry a relatively poor prognosis. The situation is similar with some metastatic ovarian, prostate, and pancreatic cancers.

Benefits of Testing

Before going into the details of gBRCA testing, it's helpful to look at the big picture.

For people who have cancers related to gBRCA mutations, the benefits of testing may include:

• Guidance in making treatment decisions (for people with recurrent or metastatic breast, ovarian, pancreatic, or prostate cancer)
• Predicting the response to treatment (such as response to chemotherapy)
• Estimating prognosis
• The ability to screen for other cancers that may be associated with the mutation (for example, BRCA2 mutations raise the risk not only of breast cancer, but ovarian cancer, pancreatic cancer, prostate cancer, and more)
• The ability to educate family members about the mutation so that they can also consider testing

For people who do not have cancer, gBRCA testing may allow a person to be proactive with testing or preventive treatment.

According to one study, testing all women (not just those with a family history) over the age of 30 for mutations in BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, and PALB2 would not only prevent thousands of deaths from ovarian and breast cancer in the U.S., but would also reduce overall healthcare costs.

Basics

In order to understand the importance of gBRCA testing in making treatment decisions, it's important to discuss gene mutations and cancer, as well as how these, in turn, can affect treatment options.

Gene Mutations and Cancer

Simplistically, cancer occurs when a series of gene mutations in a normal cell causes that cell to become a cancer cell. While there are many different types of gene mutations that may occur, the mutations that "drive" the growth of a cancer are referred to as "driver mutations."

Genes are like a blueprint: they code for different proteins, and it is the abnormal proteins produced by abnormal genes that alter the normal regulation of growth.

Mutations may occur in either proto-oncogenes (which then become oncogenes) or tumor-suppressor genes. Oncogenes code for proteins that lead to the growth of the cell (in different ways), while tumor-suppressor genes code for proteins that work to repair damage to DNA in cells (or eliminate cells that cannot be repaired so they don't continue to divide and become a cancerous tumor). The BRCA genes are tumor-suppressor genes.

Hereditary (Germline) vs. Acquired (Somatic) Mutations

The mutations responsible for cancer can either be acquired after birth and present only in the tissue that becomes cancerous (somatic mutations), or they can be hereditary (germline mutations), which are present in every cell of the body and passed down from parents. Most cancers are associated with acquired gene mutations.

BRCA Gene Mutations

BRCA genes are tumor-suppressor genes that code for proteins that repair damaged DNA in cells. BRCA1 stands for breast cancer susceptibility gene 1, and BRCA2 for breast cancer susceptibility gene 2.

Among the general population, BRCA gene mutations are found in roughly 0.2% of the population in the United States, but this number rises to 6% among those who have been diagnosed with breast cancer and to up to 20% in people who have familial breast cancer.

When BRCA mutations are present in a tumor, they may be either hereditary or acquired. Normal cells with BRCA mutations have difficulty repairing DNA damage, which can lead to cancer. Yet this principle is important in cancer cells as well.

Some types of cancer treatments cause damage to the DNA in cancer cells. Those that already have a BRCA mutation are less able to repair this damage, and hence are more likely to die.

Non-BRCA Gene Mutations

It's important to note that there are non-BRCA mutations that raise breast cancer risk as well as non-BRCA mutations that raise ovarian cancer risk. In addition to gBRCA testing, testing for some of these other mutations may be helpful in guiding treatment.

For example, most non-BRCA gene mutations associated with ovarian cancer are also in tumor-suppressor genes, and these tumors may respond to similar treatments.

Testing Options

Testing for gBRCA may be done on either tumor tissue or via a blood test. A blood test can determine if a person has a hereditary BRCA mutation, since this mutation would be present in every cell of the body (the "g" in testing stands for germline).

Testing can also be done on tissue, though, in this case, it may not be clear whether the mutation is hereditary or acquired.

Who Should Be Tested?

With breast cancer, gBRCA testing should be done at the time of diagnosis for those who have metastatic HER2-negative disease (stage 4 breast cancer) at the time of diagnosis. This is referred to as de novo metastatic breast cancer.

In addition, women with early-stage breast cancer that is not metastatic meet the criteria for genetic testing if they are young (45 years or less) at diagnosis or have a family history of breast cancer.

Testing for gBRCA should also be performed for women who have an early-stage breast cancer that recurs at a distant site (and subsequently has become stage 4).

With all forms of ovarian cancer, it's recommended that gBRCA testing (as well as testing for other mutations that raise risk) be performed at the time of diagnosis or when an early-stage ovarian cancer recurs.

Testing is also recommended for all people with pancreatic cancers (regardless of whether it is metastatic). In prostate cancer, testing is recommended in certain high-risk people without metastases and in all people with metastatic disease.

Test results usually take roughly two weeks to be returned to your healthcare provider.

BRCA and Cancer Treatment

Testing for gBRCA is recommended with some types of cancer, since the results may guide treatment choices with PARP inhibitors or chemotherapy.

When cancer cells (as well as normal cells) are damaged, they have a number of ways in which they can try to repair the damage. This damage to DNA can also occur in a variety of ways, such as by causing a mismatch in bases that make up the alphabet of DNA or by causing double-stranded breaks in the DNA. In turn, a number of complex pathways are used to repair specific types of DNA damage.

Since many types of cancer treatment are designed to damage cancer cell DNA (and subsequently, cause the cancer cells to die off), understanding these pathways is important in finding ways to prevent the cells from repairing the damage so that they survive.

BRCA mutations cause cells to be unable to repair double-stranded breaks in DNA. When cells containing these mutations experience double-stranded breaks in DNA, they are dependent on proteins called poly (ADP-ribose) polymerases, or PARPs, to repair the breaks.

How well a cancer cell can repair the damage caused by treatment (such as the use of PARP inhibitors or chemotherapy) plays a role in the effectiveness of treatment.

PARP Inhibitors

PARP inhibitors are a type of cancer treatment that affect PARPs. Used alone, PARP inhibitors cause cells to be unable to repair damage caused by single-stranded breaks in DNA. When combined with BRCA mutations (that, as noted, result in a cell being unable to repair double-stranded breaks in DNA), cancer cells, theoretically, should be more likely to die.

This has now been found to be the case in studies, which have found tumors that lack the ability to repair double-stranded DNA breaks (due to BRCA or other gene mutations) are very sensitive to the blocking of repair of single-stranded DNA breaks caused by a PARP inhibitor.

FDA-approved PARP inhibitors that are approved for one or more types of cancer harboring a BRCA mutation include:

• Lynparza (olaparib)
• Rubraca (rucaparib)
• Talzena (talazoparib)
• Zejula (niraparib)
  

Chemotherapy Response

The response of a tumor to chemotherapy may also vary depending on whether the tumor harbors a gBRCA mutation. Platinum-based chemotherapy drugs, such as Platinol (cisplatin) and Paraplatin (carboplatin), work as DNA cross-linking agents. For this reason, they should theoretically be more active with tumors that contain a BRCA mutation.

This has now been seen in clinical trials, in which platinum agents such as Platinol tend to be more effective in treating tumors that harbor a BRCA mutation.

Metastatic Breast Cancer

Women who have metastatic breast cancer and a hereditary germline BRCA mutation tend to have a poor prognosis, but with the use of gBRCA testing, options are improving.

According to National Comprehensive Cancer Network (NCCN) clinical guidelines, testing for gBRCA mutations should be done in all people with metastatic breast cancer at the time of diagnosis.

The medication Lynparza was approved in 2018 for women who have metastatic HER2-negative breast cancer as well as a known or suspected germline BRCA mutation. As of early 2022, Lynparza has been approved for use as part of systemic therapy to treat early-stage breast cancer with a BRCA1 or BRCA2 mutation that has previously been treated with chemotherapy—either before or after surgery.

In this setting, a 2017 study found that using Lynparza offered a greater survival benefit than other currently approved treatments. Progression-free survival was 2.8 months longer, and the risk of progression or death was reduced by 42%.

As noted, some people who have non-BRCA hereditary gene mutations associated with breast cancer may also be candidates for PARP inhibitors. A 2020 case report in Nature noted that one person with metastatic breast cancer with a PALB2 mutation had a dramatic response to Lynparza.

Ovarian Cancer

As with breast cancer, BRCA mutations may affect both the risk of developing ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, as well as the treatment options for those who have already been diagnosed.

Hereditary gene mutations are common in women with epithelial ovarian cancer. As a result, some researchers recommend testing all women with the disease not only for BRCA mutations, but also for non-BRCA mutations that are associated with ovarian cancer risk. This is true whether or not a person has a family history of the disease.

In one study, close to 20% of women with high-grade serous ovarian cancer were found to harbor a germline BRCA mutation. Of these women, over 40% had no family history of ovarian cancer (and would not have otherwise been screened based on current guidelines at the time).

A 2018 study looked at the effectiveness of a PARP inhibitor in women with ovarian cancer with a gBRCA mutation. Women who had been diagnosed and then treated with surgery and chemotherapy were treated with either Lynparza or a placebo. The risk of progression or death among those taking Lynparza was 70% lower than those who received a placebo after a median follow-up of 3.5 years.

In addition to Lynparza, Rubraca and Zejula are also approved for ovarian cancer (though the indications, such as whether they are used for treatment or maintenance, and required prior lines of therapy, vary).

Other Mutations

While most of the research has focused on the value of PARP inhibitors in women with ovarian cancer and BRCA mutations, women who have mutations in non-BRCA genes that are associated with gene repair also appear to respond better to PARP inhibitors (specifically Lynparza) than standard therapy. Studies with these medications have also found significantly improved progression-free survival.

(For those who wish to have a more technical description, these genes are referred to as homologous-recombination deficiency genes, or HRD genes.)

Despite the benefit of knowing gBRCA status in ovarian cancer, far too few women are being tested. According to a 2017 study, the chance that these women had been referred for gBRCA testing or genetic counseling was low, at only 10% to 30%.

Clearly, there is room for healthcare providers to improve when it comes to testing. But for now, people with these cancers can be their own advocates by learning about their disease and asking important questions, such as whether gBRCA testing should be done.

Pancreatic Cancer

Testing for gBRCA mutations is also recommended for all people with pancreatic cancer. In 2019, Lynparza was approved for maintenance therapy for people with metastatic pancreatic cancer harboring a gBRCA mutation, and whose cancer has not progressed for at least 16 weeks while receiving chemotherapy with a platinum-based drug.

The approval was based on a 2019 study that showed people who fit these criteria and were treated with Lynparza had longer progression-free survival. While only a minority (around 20%) responded to the point that their tumors shrank completely or partially on the treatment, the responses that did occur were relatively long-lasting.

Prostate Cancer

Prostate cancer is another cancer that may be affected by BRCA mutations, either through an increased risk, or relative to treatment options for those diagnosed.

For men who have metastatic prostate cancer, it's thought that one-fourth to almost one-third have mutations that interfere with DNA repair. BRCA mutations are most common, but mutations in DNA repair genes such as ATM, CDK12, CHEK2, and PALB2 are also found. It is these men who might benefit from a PARP inhibitor as part of their prostate cancer treatment.

Both Lynparza and Rubraca (alone or in combination with other treatments) have been found to improve progression-free survival in men with refractory prostate cancer harboring these gene mutations. The drugs Zejula and Talzena are also being evaluated in clinical trials.

Screening

As noted earlier, some researchers believe that all women should be screened for BRCA mutations, even those who do not have a family history. In some cases, this is particularly important. Indications that suggest a genetic predisposition to cancer due to a BRCA mutation include:

• Having breast cancer diagnosed before age 50
• Having had breast cancer in both breasts
• Having had both breast and ovarian cancer, or both breast and ovarian cancers have occurred in the same family
• Having more than one BRCA-related cancer—for example, both breast cancer and pancreatic cancer
• Having more than one family member with breast cancer
• Having a male relative with breast cancer
• Having a relative already diagnosed with a BRCA mutation
• Being of Ashkenazi (Eastern European) Jewish ancestry. BRCA mutations are much more common in this group compared to the general population. BRCA mutations are also more common in people from other parts of Europe, including Iceland, Norway, and Denmark.

Screening in Early-Stage Breast Cancer

Current NCCN guidelines recommend gBRCA testing for all people with metastatic breast cancer, This can help guide your and your healthcare provider's treatment decisions. For example, learning that you carry a BRCA mutation might prompt some women to choose a double mastectomy over a single mastectomy.

A Word From Verywell

Genetic testing for people with some metastatic cancers to guide treatment is clearly important, but still underutilized. While improvements are being made every day in the treatment of cancer, the sheer quantity of research can make it challenging for even the most meticulous oncologist to keep current on all the advances.

This is particularly true when it comes to understanding the genetic changes that drive tumor growth. Taking time to learn about your cancer, becoming involved in online cancer communities, and being your own advocate may not only be empowering emotionally, but in some cases may affect outcomes as well.