Testing for gBRCA in People with Cancer

Importance in Breast, Ovarian, Pancreatic, and Prostate Cancer

Testing for germline BRCA1/2 mutations (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 one type of therapy (PARP inhibitors) may be effective or might 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.

Testing for gBRCA is important not only to determine the risk of developing cancer, but to guide and predict the response to treatment for people living with some types of cancer.

lab tech doing genetic testing for bBRCA in a cancer patient
Istockphoto.com/Stock Photo©ClaudioVentrella

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 the 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 as to 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 health care 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 that codes 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) and tumor suppressor genes code for proteins that work to repair damage to DNA in cells (or eliminate cells that cannot be repaired so that 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 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 up to 20% of 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 cancers).

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

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

Testing may be recommended for people with metastatic prostate cancer and pancreatic cancer as well.

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

Testing for gBRCA should be done at the time a person is diagnosed with metastatic breast or ovarian cancer, whether the cancer was stage 4 at the time of diagnosis, or if a distant recurrence of a previous early-stage cancer.

BRCA and Cancer Treatment

Testing for gBRCA is recommended with some types of cancer as it 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 take place in many forms.

A few of these include 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 cells to die), 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 (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 the treatment.

PARP Inhibitors

PARP inhibitors are a type of cancer treatment that inhibits 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, in which 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:

Chemotherapy Response

The response of a tumor to chemotherapy may also vary depending on whether or not 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 that is HER2 negative (either estrogen receptor positive or triple negative) 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.

In this setting, a 2017 study found that using Lynparza offered a greater survival benefit than other treatments that are currently approved. 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 patient 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 and the treatment options for those who have already been diagnosed.

Hereditary gene mutations are common in women with epithelial ovarian cancer, and some researchers recommend testing all women with the disease not only for BRCA mutations, but 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 1/2 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, and studies with these medications have 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, as only 10% to 30%.

Clearly, there is room for physicians 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 may also be recommended for people with metastatic pancreatic cancer. In 2019, Lynparza was also 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 that people who fit these criteria and were treated with Lynparza had longer progression-free survival. While only a minority (around 20%) responded such 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 also mutations in DNA repair genes such as ATM, CDK12, CHEK2, and PALB2). 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 (For People Without Cancer)

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

  • Have had breast cancer diagnosed before age 50
  • Have had breast cancer in both breasts
  • Have had both breast and ovarian cancer, or both breast and ovarian cancers have occurred in the same family
  • Have had more than one BRCA-related cancer, for example, both breast cancer and pancreatic cancer
  • Have had more than one family member with breast cancer
  • Have a male relative with breast cancer
  • Have a relative already diagnosed with a BRCA mutation
  • Are 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

While current NCCN guidelines recommend gBRCA testing on people with stage 4, HER2 negative breast cancer, there may be some advances in testing people with early stage disease as well (beyond the screening recommendations for people without cancer noted above).

For example, learning that you carry a BRCA mutation might urge some women to choose a double mastectomy vs. a single mastectomy. Other women may prefer a single mastectomy, but may choose to extend the length of time that they use tamoxifen or an aromatase inhibitor after treatment.

A Word From Verywell

Genetic testing for people with some metastatic cancers to guide treatment is clearly important, but 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 stay abreast of 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.

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