Genetic Testing For Breast Cancer Can Be Life-Saving For Some: For Others, It Only Causes Confusion and Stress

Genetic testing has undeniable benefits. If a patient is found to carry mutations in their BRCA1 or BRCA2 genes, they face a substantially increased risk of developing breast cancer. They can opt to have their breasts removed prior to developing breast cancer or undergo frequent cancer screening to vigilantly manage their risk.

Dr. Rebecca Arend, an Associate Scientist at the University of Alabama-Birmingham (UAB) Comprehensive Cancer Center Experimental Therapeutics Program, explains BRCA mutation. 

The flip side is that testing can now identify many genes that do not have clear associations with breast cancer. They are called variants of uncertain significance (VUS), a term that can sound sinister to patients without meaning to be. According to the American Society of Breast Surgeons (ASBrS), "variants of uncertain significance are not clinically actionable, and these patients should be managed based on their individual risk factors." Despite this qualification, VUS can cause significant stress for patients, who do not know what to do after discovering that they carry one.

Ultimately, it is important for patients to know about various aspects of genetic testing so that they can have an educated decision with their physicians about pursuing such testing.

What Is Genetic Testing For Cancer?

Genes control all aspects of the body and its function. When genes go rogue through mutations, they can increase the risk of developing certain cancers. Some genetic mutations are notorious for doing so, including those in the BRCA1, BRCA2, and PALB2 genes. Some other mutations may only be an indication of a change in the genetic makeup without an increased risk of cancer development. Genetic testing looks for both kinds of mutations.

With appropriate use, such testing can identify patients with increased risk and flag them for closer screening or preventative treatments. Indiscriminate use, on the other hand, can lead to undue, unjustifiable stress for the patients without any benefits.

Which Mutations Are Important to Look for in Breast Cancer?

Dr. Julie R. Gralow, the Chief Medical Office and the Executive Vice President of the American Society of Clinical Oncology, tells SurvivorNet that, "Germline genetic testing for inherited predisposition for breast (and ovarian) cancer can include just BRCA1/2 testing or a more comprehensive gene panel that might include 15-25 genes."

Related: Genetic Testing for Breast Cancer: What is This Type of Test? And What Do My Results Mean?

The infamous BRCA1 and BRCA2 gene changes are still the most important ones to look for in breast cancer. Together, they are responsible for about half of all hereditary breast cancers. In a person without mutations, these genes work to prevent cells from dividing haphazardly and uncontrollably. Mutations prevent these genes from doing their job and can allow unchecked growth of breast, ovarian, and other tissues. This voracious growth paves the path for cancer development.

BRCA1 and BRCA2 gene mutations increase the risk of developing breast cancer by up to 85% during their lifetime. To break it down, only 13% of all women will develop breast cancer during their lifetimes. If they carry the mutations, this increases their risk to a staggering 45%-72%, depending upon their exact mutation.

The presence of such mutations can have a significant impact on the treatment options for women carrying them.  "Presence of a BRCA1/2 gene mutation (or others associated with high risk) may impact surgical decision-making in a patient who is newly diagnosed with breast cancer," says Dr. Gralow. "It should not really impact treatment of the current cancer (eligibility for lumpectomy versus mastectomy), but the presence of such a mutation carries a very high risk of developing a second breast cancer, so bilateral mastectomy is a reasonable consideration to reduce risk of second cancer."

Recent research has also identified other mutations, which may also increase the risk of breast cancer development. These include changes in the PALB2, ATM, CHEK2, KRAS, CDH1, TP53, PTEN, and numerous other genes. Modern genetic testing panels can look for mutations in more than 80 genes at once.

What are some Popular Genetic Test Panels?

Breast cancer genetic testing began with Myriad Genetics when they introduced a genetic test for the two BRCA genes more than two decades ago. This test used to cost thousands of dollars. Testing has since expanded exponentially in its scope and become far cheaper and more accessible. Some modern gene panels can analyze more than 80 genes, which could contribute to the development of breast, ovarian, colon, and many other cancers. Popular panels include but are not limited to:

• MyRisk by Myriad Genetics: This is a direct-to-consumer test that analyzes 35 genes that may be relevant to the clinical management of numerous cancers. Breast cancer is one of them. Notably, it integrates genetic analysis with family and personal history to provide a more holistic assessment of cancer risk. It can be performed on any patient, including those who have not yet developed breast cancer. After obtaining the results, the patient and their physician can decide on a number of preventative or treatment strategies.
• 23andMe DNA Testing: A direct-to-consumer test, 23andMe has been approved by the FDA to test for genes that may contribute to many cancers, including breast and prostate cancers.
• Invitae multi-cancer panel: Another direct-to-consumer text, which tests more than 80 genes to screen patients for proclivity towards certain inherited cancers, including breast.
• Color Health Genomics Test: This test is ordered via a physician and assesses 30 genes to screen for mutations that may lead to a higher risk of cancer development. They include genes that are relevant for colon, stomach, melanoma, pancreatic, uterine, and breast cancers.
• OncotypeDX: The test is administered to women diagnosed with early-stage, hormone receptor-positive (Estrogen, Progesterone), and HER2-negative breast cancers. It is ordered by a physician and requires cancer tissue usually extracted from either biopsy or surgery. It analyzes 21 genes and outputs a numeric score, which ranges from 0-100. The higher the score, the more the chance of cancer returning after treatment. Such people are usually given chemotherapy in addition to hormone therapy to mitigate their risk.
• Guardant360 CDx This is a blood test sometimes called a liquid biopsy, which analyzes dozens of genes recommended by the National Comprehensive Cancer Network (NCCN). This includes the 55 genes relevant to cancers, including breast cancer. It is usually done in a patient with a later stage breast cancer, such as stage III and IV, and can guide the selection of the most efficacious treatment option.

The Confusion Begins

Who is an Appropriate Candidate for Genetic Testing?

According to Dr. Gralow, "This testing can be done in people without cancer but with a family history of the disease (or a family member with a known mutation), or in someone diagnosed with breast/ovarian cancer."

The NCCN recommends testing only select patients with risk factors for hereditary breast cancer. These include but are not limited to patients who were younger than 45 years old when they were diagnosed with breast cancer, those with a strong family history of this cancer, and those with Ashkenazi Jewish heritage. "BRCA mutations are very high in the Ashkenazi Jewish population," notes Dr. P Rani Anne', professor in the Department of Radiation Oncology at Thomas Jefferson University, Philadelphia, PA.

However, ASBrS recommends offering genetic testing for all patients diagnosed with breast cancer: "Genetic testing should be made available to all patients with a personal history of breast cancer… If genetic testing is performed, such testing should include BRCA1/BRCA2 and PALB2…" For patients without a personal diagnosis of breast cancer, they recommend abiding by the NCCN criteria.

The difference of opinion on who should be offered genetic screening is not limited to the NCCN and ASBrS. American College of Medical Genetics, the American Society of Clinical Oncology, the American College of Obstetricians and Gynecologists, The Society for Gynecologic Oncology, and many other national societies have genetic screening criteria that differ at least slightly from each other, per the United States Preventive Services Taskforce.

Moreover, there is evidence that some guidelines may miss patients with hereditary breast cancer genes, which may be caught by others. According to data presented at the 2022 NCCN Annual conference, 13.8% of the patients who had mutations relevant to breast cancer development did not meet the NCCN criteria for genetic testing. They did, however, meet the ASBrS criteria.

Dr. Elizabeth Comen, a medical oncologist at Memorial Sloan Kettering Cancer Center, explains genetic testing for breast cancer. 

A lack of guidelines agreed upon by all the eminent medical societies creates an unnecessarily complex and challenging path for any physician evaluating the appropriateness of testing the genes of their patients.

In the words of Dr. Gralow, "Increasingly, we are offering genetic testing to a broader and broader group of women diagnosed with breast cancer. Those with the highest risk of having a familial genetic mutation are younger age, strong family history of breast/ovarian cancer, and triple-negative breast cancer. Many in the field feel that it should be offered to virtually all cancer patients."

The Confusion Continues…

The confusion surrounding genetic testing is not limited to just appropriate patient selection.

There is a significant mystery surrounding the meaning and importance of labeled VUS. "More people have VUS than have the cancer-causing genes," notes Dr. Anne'. She continues, "this prevalence exacerbates the basic issue with VUS, which is that no one knows what to do with them in terms of cancer prevention or care."

VUS genes are neither pathogenic (cancer-causing) nor benign according to the latest scientific knowledge. However, science is a forever-changing field. Many a time, Future research will be able to discriminate the current VUS into pathogenic or benign. Until that happens, neither the physicians nor the patient knows what to do with the VUS genes.

A reasonable approach could be to ignore these VUS genes during clinical decision-making. Yet the possibility that some of these VUS will be discovered to be cancer-causing in the future can cause stress for many patients. The VUS debate is further complicated by the fact that a gene labeled VUS by one genetic panel may not be classified as such by another.

"Variants of unknown significance can cause some confusion," says Dr. Gralow, "but it doesn't mean that the testing should not have been done. It means that not enough families have been tested that have that variant, so it's not clear if cancer tracks with that change or not (this is more common in racial and ethnic minority populations, and in genes only rarely mutated and associated with cancer risk). It is important to be able to discuss why the results are "uncertain" in some instances, and how likely the abnormality is likely to result in increased cancer risk based on its location in the gene."

Then there is the issue of false positives and false negatives associated with all diagnostic tests. A false positive test result means that while the test says that a person has a particular disease, they do not. Conversely, a false negative test inaccurately labels a person with the disease as disease-free. Although estimates vary, the percentage of false results has been reported to be as high as 40%. Dr. Anne' stresses: "You can always do this testing, but you have to understand that there are significant false negative and positive rates with these tests. This is murky territory."

These issues surrounding genetic testing make it challenging for physicians to decide whether to order such a test or not. All the while, they cause unwarranted confusion and sometimes debilitating stress to patients.

What Should A Patient Know When Considering Genetic Testing?

Navigating the current landscape of genetic testing can be daunting. While widespread, direct-to-consumer, and affordable testing has made the accessibility of such tests a problem of the past, the issue of selecting whom to screen has only gotten more confusing. Thus, if you are considering getting tested, you should be aware of the following information:

• The vast majority of breast cancers are not hereditary, meaning that they were not caused by mutations in your genes. Only 5-10% of the cases are hereditary.
• "The best place to begin is likely your primary care provider (PCP) or Gynecologist," per Dr. Anne'. Have an honest discussion with them about your concerns regarding cancer and discuss appropriate next steps.
• If appropriate, your PCP may refer you to a genetic counselor, who will assess your individual risk for various cancers based on your personal and family history. Dr. Gralow "strongly recommends that all patients be referred for genetic counseling prior to undergoing genetic testing, for discussion about possible implications and outcomes of results."
• If you are at an increased risk, the genetic counselor may recommend an appropriate, reliable genetic screening panel. While convenient, direct-to-consumer genetic panels may not be the best solution. Once the results are known, counseling can help with interpretation of results and what the future cancer risk is (breast and other cancers)," per Dr. Gralow.
• Remember that genetic testing is not an exact science at present. It carries the risk of false positives or negatives. The former may cause undue stress and confusion, while the latter may lull you into a false sense of security.
• Regardless of the test and your results, you will need a medical expert to explain what the test results specifically mean for you.

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