Breast Cancer Mutations: BRCA, PALB, ATM, CHEK2

About 20% of breast cancers are believed, at this time, to be connected to an inherited alteration in DNA. In families with an inherited alteration of DNA, multiple generations of people may have breast and related cancers. The best-known examples of inherited alterations are BRCA1 and BRCA2.

Knowledge about inherited breast cancers is changing quickly. Today, what doctors and researchers are telling patients is based on what they know so far, but it is important to check back in with providers and specialty genetics clinics every few years to learn about updates. So, for example, laboratories used to test just at the BRCA1 and BRCA2 genes when investigating whether a patient had increased elevated risk for breast cancer. Now, in 2020, laboratories are looking at 30 genes - including the ATM, CHEK2, and PALB2 genes.

As personalized approaches to cancer treatment evolve, efforts are also being made to link specific treatments to genetic characteristics of either the tumor itself or of the inherited mutations that gave rise to the cancer. So far, targeted treatments have been developed for a few of the many identified alterations; in these cases, there are improved odds that the cancer will respond to treatment. Universities and pharmaceutical companies are investing substantially in ongoing research, aimed at finding not only more targeted therapies but more effective ones.

 

Dr. Kala Visvanathan, of Johns Hopkins University, explains inherited breast cancer.

Dr. Kala Visvanathan, of Johns Hopkins University, explains inherited breast cancer.

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So, when we think about Breast Cancer one of the ways that we separate different types of Breast Cancer are those that are sporadic and those that are familial.
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By familial what we mean is that they are inherited.
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The first thing to say is that most cancers are not inherited and what that means is they are not due to a mutation in a gene that is associated with increased cancer risk. Right, so, most cancers are thought to be due to a combination of genetic and environmental factors. Okay. About 20% of Breast Cancers, they are probably due to an inherited alteration in DNA. And a good example which lot of people know about is BRCA1 and 2. Right. And so, there is a distinct difference. What you see often in a family where there is an inherited alteration of DNA, you might see multiple generations of individuals who have had cancer so Breast Cancer you might see more family members with only onset Breast Cancers sometimes or other cancers associated with this alteration. Whereas in a family where sporadic you would see maybe they have no family history of Breast Cancer.
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So when we think about genetic testing and we think about the treatment of Breast Cancer or even identifying individuals with a higher risk for Breast Cancer. All of these areas are still evolving. We don’t have all the answers and there is a lot of change happening. So what we are telling you today is what we know today. But I often tell people as they need to check in with their providers or check in with specialty clinics every few years to understand the updates. It is totally an emerging field and a good example of that is probably five years ago we might just do testing for BRCA1 and 2. So two genes we look for alterations in. And now we are looking at 30 genes. Five years ago we just focused on Breast and Ovarian Cancer in an individual who had a family history of that. Now we think we should test for all common cancers. Right. Some people do 90 genes, so all of this is evolving. Another area that there is a lot of effort is all of these new treatments for Breast Cancer and the third area is how do we better define individuals who are at higher risk or lower risk. That again is an area where we try to combine more risk factors and novel markers.
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So, again nothing is standing still so you need to again check in with your provider, check in with experts about this every few years to understand what the state-of-the-art is at that time.

We included experiences of people with inherited breast cancer or increased genetic risk for breast cancer in the qualitative research study described on this website because inherited breast cancer, like Lynch syndrome and polyposis syndromes, is distinctive in a few ways.  They are conditions for which our knowledge is constantly changing over time as more is learned about genomic testing, inherited disease risk and the possibility of individualizing testing and treatment (this is sometimes called “precision medicine”).

As understanding about the genetics of these disorders evolves, people often find that:

  • Their predicted risk for future cancers may change over time (e.g., lifetime risk for cancers associated with a particular mutation turns out to be less than it was initially thought to be),
  • The number of gene mutations associated with each of these conditions/syndromes increases over time,
  • Hereditary cancer risks are increasingly identified through tumor typing (testing of tumor/cancer tissue) and not only by genetic screening (blood testing),
  • Answers to current questions about hereditary risks lead to more new questions that will require continued research
  • Guidelines for management of these syndromes are constantly being revised to keep up with new medical knowledge, so it is important to keep in touch with healthcare professionals.

Hereditary breast cancer shares these features with other cancer risks inherited through families. It differs in some other ways, each of which can significantly impact patient experience.

More-Known and Less-Known Mutations

Mutations in the BRCA1 and BRCA2 genes are among the earliest identified mutations related to cancer risk, and remain the most widely recognized by the public. While each is associated with multiple forms of cancer, each has a particularly strong association with breast cancer.   

Mutations in the BRCA gene were identified several decades ago, but genetic tests have continually improved. Early tests for the BRCA1 and BRCA2 genes only screened for a handful of genetic variants. People we interviewed who had had genetic testing long ago described how the knowledge they were able to gain from those results was incomplete.  When Sarah was tested in 2012, for example, what she learned felt incomplete. “They tested for 15 markers,” she says, “They were all negative …. it's almost like it didn't mean anything.” When Desiree was tested 15 years ago, genetic screening was sufficiently expensive, so her insurance screened for only a few variants.

 

Desiree’s testing for BRCA left her with inconclusive results.

Desiree’s testing for BRCA left her with inconclusive results.

Age at interview: 56
Cancer-Related Experience: Cancer
Type of Inherited Risk: Family history of cancer
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Although I did have genetic testing done, unfortunately, when I had the testing done, I didn't have great insurance. And so they did not agree to do the full panel of genetic testing. And so they kind of gave me a inconclusive, that it leaned towards not having BRCA, but they couldn't be 100% sure. And it is something that I do think about, now that we've moved so far in the genetic testing world, and that the cost has come down, et cetera, that I will revisit that in the future. So at this particular time, I don't know. I am saying I am not BRCA-positive. But I can't say definitively, just because of the test that I did have.

Although information about BRCA mutations can be incomplete, people identified with them may have greater awareness of their genetic risk than people with more recently identified mutations.

 

Amy is concerned that too little is known, so far, about PALB2.

Amy is concerned that too little is known, so far, about PALB2.

Age at interview: 30
Cancer-Related Experience: Elevated risk
Type of Inherited Risk: Identified breast cancer mutation
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I’m PALB2 positive. What, what does that mean? Nobody knows what that means. And like I said, you google it, and you really don’t find much on it. it worries me just how, little research, and results, and whatever it takes to find out exactly what it can cause, because I am worried its ovaries as well, and I just don’t know about it. 

 

Janet S. says BRCA is better known and better researched than the ATM mutation she has

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Janet S. says BRCA is better known and better researched than the ATM mutation she has

Age at interview: 55
Cancer-Related Experience: Cancer
Type of Inherited Risk: Identified breast cancer mutation
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My gene is ATM gene, it's a rare breast cancer gene. There's not a whole lot known about it. Of course, BRCA is, I think, the top. And because it's at the top, it gets most of the research. ATM is not at the very end, but...about 90% toward the end. It's a very rare.

Inherited Breast Cancer Risks and Genetically-Targeted Treatment

A number of new therapies have emerged for breast cancer that are targeted to particular genetic mutations - including treatments for metastatic cancer which had previously been considered ‘untreatable’. Clinical advances like these bring great hope to people who face inherited cancer risks. But the contrast between these emerging genetically-targeted treatments and the persisting unknowns about the origins and implications of hereditary breast cancer risks can also feel quite poignant.

 

Irina finds hope in genetically-targeted treatments for breast cancer.

Irina finds hope in genetically-targeted treatments for breast cancer.

Age at interview: 45
Cancer-Related Experience: Elevated risk
Type of Inherited Risk: Identified breast cancer mutation
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The woman who was diagnosed with terminal breast cancer,

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She had metastases everywhere. She like couldn't breathe. All disappeared, and it, it is experimental, and immunotherapy is not an answer to everything, and it has its side effects, and all the stuff. I understand that. But again, 20 years ago, that experimental treatment wasn't available, and she wouldn't get those two years of life, or however many years more she has. So that gives a lot of hope. And all those treatments, they just get better and better. And there is more and more that scientists find out. And moving faster to get to patients also is very encouraging. That, that gives me a lot of hope.

 

The contrast between treatment advances and persisting questions about hereditary risk leave Janet S. in tears.

The contrast between treatment advances and persisting questions about hereditary risk leave Janet S. in tears.

Age at interview: 55
Cancer-Related Experience: Cancer
Type of Inherited Risk: Identified breast cancer mutation
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How can it affect grandchildren I don't even have? That just, for something so small to have such a potentially far-reaching impact, it just, it doesn't even seem real. I mean, for me to go through this is one thing. The potential of my daughter going through this is something I can't even really let myself think about. But when I take a further step, and I put it into people that haven't even been born yet, it just boggles my mind. And it makes me angry. And I don't know what I'm angry at. You know, I want to-- there's a part of me that says, if science has done so much, then why can't it do that? And I know the naivete of that statement. I understand that perfectly. And the rational side of me realizes that that's a naive question, but the human and the mother side of me says that that is a very legitimate question.

Differing Perceptions of Breast Cancer Risk among Men and Women

Most people think about women when they think about breast cancer. This association is made stronger by advocacy campaigns linking breast cancer to pink ribbons and pink outfits, which, as one of our interviewees put it, communicates “feminine energy” and “feminine symbolism”. Our participants also noted that the connection between women and breast cancer create some misimpressions; One being that only women – and not men – can get breast cancer. As Lisa J. put it, “I've had men say, men can't get breast cancer, and it's like, yes, you can. You have breasts. You have a mom. She could have passed the BRCA gene to you, because you can get it.” Another is that hereditary breast cancer risk can only be passed through the mother’s side of the family. In Amy’s words, “You know, this isn’t right. There's a chance, a 50% chance that if my dad has it, that I have it, doesn't matter if it's maternal or paternal.”

Breast Cancer Risk and Prophylactic Treatment Choices

Some forms of breast cancer are related to estrogen levels. The people identified with these forms of breast cancer are encouraged to take hormone-suppressing medications such as Tamoxifen - whether the person is female or male. This is not unique to hereditary cancers, however because mutations in the BRCA1 and BRCA2 genes lead to such large increases in cancer risk, those identified with these mutations are routinely prescribed hormone-suppressing medications. Ronnie, for example, noted that prior to her genetic testing she was “having a hard time deciding whether to take tamoxifen or not” given its various side effects. But a positive genetic test made it clear to her that she should go ahead, because “Tamoxifen is one of the few things that actually helps for genetic breast cancer.” 

Our module on breast cancer includes a more complete exploration of people’s experiences with Tamoxifen and other treatment medications.