Genetic Testing in Breast Cancer: The Rules Are Changing

Interview With Dr Allison Kurian

Lidia Schapira, MD


September 05, 2019

The cost of genetic and genomic testing has plummeted in recent years, and as a result, physicians now face new challenges both in recommending testing and interpreting the results.

Oncologist and epidemiologist Allison Kurian, MD, MSc, has dedicated her career to these issues at Stanford, where she directs the Women's Clinical Cancer Genetics Program.

Medscape contributor Lidia Schapira spoke to Kurian about this new era of more affordable and accessible genetic testing, particularly about when to test and how to interpret clinically challenging results for patients and families.

Cancer Genetics vs Cancer Genomics

How did you become involved in the field of cancer genetics?

I was always interested in disease prevention and thought that prevention should be the best way to reduce illness and suffering. The idea that we could find out beforehand if a person is high risk because of his or her genetics always appealed to me as a way to personalize cancer prevention. Also, I had a college roommate who had a hereditary cancer syndrome and passed away young; this was a personal motivating factor.

These days there may be some confusion about the difference between cancer genetics and cancer genomics. Can you give us a definition of each?

When we do a blood test or a saliva test for inherited cancer risk, we are testing the genes that we were born with, the genes that we got from our mother and father that are in every cell of our bodies. With tumor genomics, the tumor represents a collection of cells where the genes have gone haywire and have what we would describe as a genome of their own. These are genetic changes that we were not born with but that develop in the tumor. When we do tumor genomic profiling, we are looking at genetic changes that have happened over time as the cancer grew, which are often different from what someone is born with.

Who Is a Candidate for Genetic Testing?

In thinking about cancer genetics and breast cancer, which patients should be tested? When should a referring physician or primary care doctor think about testing a patient?

The answer has been changing recently in ways that are very interesting. Five or more years ago, we were very constrained by the high cost of genetic testing. Getting two genes tested, BRCA1 and BRCA2, could cost nearly $4000. This was a scarce resource in terms of insurance coverage and patient ability to pay out of pocket if not covered. Now, testing has become quite inexpensive—sometimes as low as $250 without insurance, and less than that for many genes.

Increasingly, we are testing people in a much broader way because we can.

The picture of who can be tested has changed. We used to say that if the person had about a 10% or higher chance of having a genetic mutation and that was something we as doctors and genetic counselors could figure out, that person would be a candidate for testing. Increasingly, we are testing people in a much broader way because we can. We may get to the point where we start moving toward testing nearly everyone, though we are not there yet.

Your research has shown that some patients who should get tested are not getting tested.

We have used population-based data, so the results are relevant for everybody undergoing genetic testing. We have learned that red flags include early cancer onset or a family history of many cancers. Only about half of women with these red flags report getting a genetic test. Our survey found various reasons for this. They often said they had not received advice from a healthcare provider to be tested.[1] Clearly that is a gap that needs to be addressed.

Which patients diagnosed with breast cancer should absolutely have genetic testing?

We would recommend testing for the following:

  • Any woman diagnosed under the age of 45;

  • Women diagnosed with triple-negative breast cancer, particularly if diagnosed under age 60;

  • Women with a strong family history, which usually means one first-degree relative (particularly if that person herself was young at diagnosis) or multiple first-degree relatives;

  • Anybody with a family history of ovarian cancer.

Important Role of the Genetic Counselor

What is the role of the genetic counselor in this process?

I'm a huge fan of genetic counselors; they are fantastic healthcare providers. They are trained in the psychological effects of learning about inherited risk and also in genetics. Their job is to assess the patient and her family history very thoroughly. They draw a family tree, a pedigree, with all the cancers and other diseases in the family, and make an estimate of which genes are relevant to test. For example, what does a family look like in terms of the possibility of having an inherited risk in a cancer gene like BRCA1 that gives high breast cancer risk? They will explain to the patient the pros and cons of genetic testing, what she might learn, and what she might not learn (ie, current limitations). Once testing is accomplished, they can explain the results to the patient. Perhaps the most important thing that genetic counselors do that we rarely see other healthcare providers do is help the patient inform her family members, and help her reach out to relatives who could benefit from genetic testing and get them appropriate testing and care.

We know a lot of the genes that cause specific diseases like breast cancer, but we are sure that we have not found them all.

Challenging Situations in Genetic Testing

If a woman has a very compelling family history but you don't find an abnormality in the testing, what advice do you give her and how do you follow her to keep her safe?

We deal with this often. We know a lot of the genes that cause specific diseases like breast cancer, but we are sure that we have not found them all. Sometimes you see a patient and suspect that there may be a problem because she got breast cancer at age 30 and she has relatives with breast cancers. In that case, we would say there is probably something inherited and we just are not smart enough to find it yet. In that case, we recommend taking care of that patient and any at-risk relatives using the protocols we developed for others with a known genetic mutation. This may involve intensive screening with additional screening tests like MRI and even other strategies to reduce risk.

Do you find that some patients are reluctant to be tested because they worry that the information could impact their future insurability or ability to get employed, or that privacy violations could occur down the line?

That's a very important concern to address. When we began cancer genetic testing back in the mid- to late 1990s, we were a lot more worried about this. Fortunately, we have not seen much genetic discrimination, so patients and clinicians have become more comfortable with the notion that genetic discrimination is unlikely. A federal law was passed 10 years ago, the Genetic Information Nondiscrimination Act, which explicitly forbids discrimination in terms of health insurance or employment or treating this as a preexisting condition. Of course, it is important to talk about these things carefully with the patient.

Navigating the Variants of Uncertain Significance

What happens when you find an abnormality but you do not know enough about that abnormality to say that it confers an increased risk for cancer? I'm referring to variants of uncertain significance (VUS). What advice do you have for primary care physicians and other clinicians who follow these patients?

Everyone on our team groans when we see VUS. They are not harmful, but they are annoying, and no one likes to have a question mark about what all of this means. To the best of our knowledge, it means that we are not sure whether an observed change in a gene causes the resulting protein not to work and thus increases the risk for disease. Often, laboratories reclassify these VUS to normal or harmful as more information emerges from testing more patients.

Probably more than 90% of VUS get reclassified as normal (ie, not harmful). Studies show that when a patient has a VUS, they have a greater than 90% chance that it's not going to be harmful, so we do not treat it like a harmful gene mutation that would prompt differences in care. We do think that follow-up is necessary. The way that typically happens is through the lab that did the testing. They often are working to reclassify the VUS, and they typically will notify the doctor or other healthcare provider who ordered the test. It's a good idea for patients to keep in touch with their clinicians to find out if anything more has been learned about that result over time. Most of them do get reclassified.

Retesting, New Testing

Do patients who test negative or those who tested positive many years ago need to be retested? Do you look periodically at the information on all of your patients to see and recall those who perhaps would benefit from retesting?

We frequently see patients coming in for updated testing. Back when the testing was so expensive, it came out to about $1000 per gene. Thus it was difficult to test one or two genes more than BRCA1 and BRCA2. Now, with next-generation sequencing, testing costs the same (usually in range of $250) whether it includes only two or more than 100 genes. It's possible that patients got a negative result because they were only tested for two genes and yet they had family history or an early-onset cancer diagnosis. We often encourage those people to come in again and be tested for more genes. We often find an answer on repeat testing.

If a patient tested positive for a BRCA1 mutation, does she need to be tested again? Usually we would say only if there was something in the family history that was not explained. I'll give you an example: What if that patient has a very strong family history of colon cancer in addition to breast cancer? Because BRCA1 does not cause colon cancer, we might say, "Come in and be tested, and we'll see if we can find any colon cancer risk genes."

Thinking about the broader public health impact of genetic testing, what message should we send to the public about genetic testing?

Genetic testing can be extremely helpful to personalize patients' care, both for treating the cancer and for preventing second cancers in the patient and first cancers in their relatives. This is powerful information and it's important that patients who choose to be tested get good advice from their healthcare providers about what the results mean and what can be done about them. Often a genetic counselor is the most well informed of anyone in this space in terms of cancer genetics, particularly if a patient gets a positive result.

Often a genetic counselor is the most well informed of anyone in this space in terms of cancer genetics, particularly if a patient gets a positive result.

When Is the Best Time to Test?

When in the sequence of care for breast cancer is it important to do the testing? Can you give certain examples of situations where knowing the result of that genetic test actually impacts on the plan of care?

I would say that it's never too late. It's always helpful to know these results, even after the primary treatment of breast cancer, when most women survive and do very well. We need to think about how to take care of them in terms of second cancer risk in the future. But having said that, I think the ideal time to test is shortly after diagnosis of breast cancer and before surgery. Sometimes if the patient is found to have a high-risk mutation like BRCA1, that confers a higher risk of cancer happening again on the opposite breast. Some women might choose to do a double mastectomy instead of a lumpectomy, for example. They don't have to, and not every woman will, but it can be helpful to have that information before going into surgery. Increasingly we are seeing results of genetic tests influence our choice of medical therapies. The poly (ADP-ribose) polymerase (PARP) inhibitors were approved recently for treating advanced breast cancer, and they are in trials for early breast cancer.

Psychological Impact of Genetic Testing Results

What is the psychological impact and emotional load of hearing that one is a carrier of a mutation like BRCA1? What is it like when your patient is facing her own diagnosis and treatment, and learns that she is the carrier of a mutation and may have transmitted that to her sons and daughters?

It certainly is a lot to carry for a newly diagnosed patient. It's always a bad shock to be diagnosed with cancer, but often patients have had a suspicion that something was in the family. For example, a woman who has just been diagnosed with breast cancer may have seen other relatives be diagnosed. Believe it or not, sometimes it can be a relief to find the answer and know that this was something they had absolutely no role in causing—that it was something inherited, not something they did or did not do.

Despite being recently diagnosed, sometimes finding an answer about why the breast cancer happened can bring peace of mind. Certainly, there is a burden of knowing that relatives and siblings may have it and that children may have inherited it. Parents who passed it on may have complicated feelings as well. Often these are challenges for patients. Genetic counselors are trained to counsel about these issues, and we provide additional referrals as needed.

Early on when a patient has a positive test result (ie, a harmful mutation in BRCA1 or another gene), she may be worried about sharing this with her family, and relatives may not initially consider it good news. But ultimately, knowing about one's disease risk in advance is a gift. With advance warning, there are effective ways that we can prevent cancer or find it early, which leads to a much better outcome.


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