How Do BRCA Mutations Affect Cancer Survival Rates?

Survival Differences in Hereditary Breast Cancer

puzzle pieces interaction of breast cancer, brca mutations, and survival Photo©Kagenmi   

Many people have become concerned about "genetic" or hereditary breast cancer. We know that BRCA  mutations can significantly increase your risk of developing breast cancer. But for those who do get breast cancer, how does survival compare to those who develop breast cancer but don't have these gene mutations? We now have several studies that have looked at this question.

Certainly, it is terrifying to learn that you carry one of these mutations. If you do carry a BRCA mutation it can mean many extra tests, heart-wrenching decision making, and grueling treatments if cancer should develop. But new research about long-term survival with these mutations may reduce some of your fears.

It's necessary, however, to look at these studies as a whole. Some studies have only looked at young women. Others have looked at different time intervals when evaluating survival. And yet others have evaluated what treatments might improve survival the most for women with BRCA mutations.

Let's begin by reviewing BRCA mutations, why they are important in the development of breast cancer, and how these cancers may differ from non-hereditary breast cancers, and then talk about what we've learned from a survival standpoint.

BRCA Mutations—Definition and Function of BRCA Genes

We know that cancer usually develops after a series of DNA gene mutations take place. Our genes are like a blueprint that carries the design for proteins made in our bodies. The instructions carried on genes carry the directions for making proteins ranging from the enzymes that break down our food, to the proteins that work to keep us free from cancer.

The term mutation refers to any type of damage to DNA which changes its composition. Our DNA is made up of 46 chromosomes, 23 from our mothers and 23 from our fathers. Genes, in turn, are sections of chromosomes that carry the directions for manufacturing specific proteins. These directions are made up like a string of letters (base pairs) that function as a code.

If the letters (bases) in a gene are mixed up, the directions can be inaccurate and thus be a blueprint for an abnormal protein. Sometimes bases are added (additions), sometimes they are deleted (deletion mutations) and sometimes they are rearranged. (There are also other changes that may occur as well). What happens after a mutation is either inherited or acquired during adulthood, depends on the function of the specific gene.

BRCA genes are tumor suppressor genes. They code for proteins that suppress the growth of tumors such as breast cancer and ovarian cancer. Specifically, BRCA genes code for proteins that are responsible for repairing damage to DNA in our cells (they repair breaks in double-stranded DNA).

Each of our cells contains two BRCA genes, one copy from our mother and one copy from our father. BRCA genes are autosomal recessive, meaning that both copies of the gene must be mutated in order for a cancer related to the gene mutation to develop. Since most people inherit only one mutated gene (this is written as BRCA1/2), having a BRCA mutation increases your risk for cancer (carries a genetic predisposition to cancer) but does not mean that you will develop cancer. In order for cancer to begin the other copy of the gene will need to be mutated. This second mutation is usually acquired (from DNA damage due to the environment, lifestyle choices, or the normal metabolism of cells).

It can be terribly confusing when we talk about these different types of mutations, though it explains why not everyone with a BRCA mutation will develop cancer. The two mutations that lead to breast cancer in the majority of women who are BRCA+ and develop breast cancer include a germ-line mutation and an acquired mutation.

  • Germ-line or inherited mutations (this includes the BRCA mutations as discussed here) are passed from a mother or father to a child at conception.
  • Somatic or acquired mutations (mutations that occur as a result of DNA damage related to the environment, lifestyle factors, or even normal metabolic processes in cells) occur at any time during a person's life.

(There are also cancer-related genes called oncogenes that are inherited in an autosomal dominant fashion so that only one copy of a mutated gene is needed to drive the growth of a cancer, but this is beyond the scope of this article).

Understanding BRCA Mutations

When talking about the risk of BRCA mutations, it's important to point out that we aren't talking about one specific change to DNA. Rather there are hundreds of different ways in which BRCA genes can be mutated. As noted above, these genes could have an extra base (letter), a missing base, or the bases could be rearranged in some way.

There are some differences in cancer risk between BRCA1 and BRCA2 mutations, as well as the particular type of mutation present in a gene. The overall risk of breast cancer in women without a BRCA mutation is around 12 percent. For those who have a BRCA1 mutation, the average risk is 55 to 65 percent (and can be as high as 87 percent). For those with a BRCA2 mutation, around 45 percent of women will develop breast cancer by the age of 70.

Ovarian cancer occurs in roughly 1.3 percent of women in general. For those with BRCA1 mutations, 39 percent are expected to develop ovarian cancer, while 11 to 17 percent of those with a BRCA2 mutation will develop the disease.

There are other cancers which can be associated with BRCA mutations as well, such as prostate cancer, pancreatic cancer, and even lung cancer.

Differences in Breast Cancers in Women With BRCA Mutations

There are some differences in breast cancers between women who have BRCA mutations and those who do not have these mutations.This is important as some of these differences might account for differences in survival.

BRCA mutations are more common in younger women who develop breast cancer. For those under the age of 40, it's thought that upwards of 10 percent of cancers are associated with being BRCA positive. In contrast, the number is closer to 5 percent in older women with the disease.

Breast cancers in women with BRCA mutations tend to have cancers with a higher tumor grade. Tumor grade is a measure of the aggressiveness of the tumor.

Breast cancers in women with BRCA mutations (especially BRCA1 mutations) are less likely to be estrogen receptor or progesterone receptor positive. They are also less likely to be HER2 positiveHormone receptors, as well as HER2, are receptors on the surface of breast cancer cells to which estrogen or growth factors bind to drive the course of cancer.

In other words, "triple negative" breast cancers are more common in women with BRCA mutations. In general, triple negative breast cancers are more challenging to treat, as neither hormonal therapies nor HER targeted agents will be effective.

On a positive note, breast cancers in women with BRCA mutations tend to respond better to neoadjuvant chemotherapy (chemotherapy given prior to surgery) than those without these mutations.

BRCA Mutations vs. Non-BRCA Familial Breast Cancer (BRCAX)

It's often confusing to talk about BRCA mutations and hereditary breast cancer. BRCA mutations are a cause of hereditary breast cancer but not all hereditary breast cancers are due to BRCA mutations. Overall, BRCA mutations account for 20 to 25 percent of hereditary breast cancers and 5 to 10 percent of breast cancers overall.

Hereditary breast cancers not related to BRCA mutations are referred to as non-BRCA familial breast cancer or BRCAX. Gene mutations that are linked to breast cancer include those in ATM CDH1, CHEK2, PALB2, PTKN, STK11, and TP53. There are likely many more waiting for discovery, but the research is still in the early stages.

Survival With and Without a BRCA Mutation (2018 Study)

When talking about survival with BRCA mutations it's important to note that we are talking about statistics. We have information on how the "average" person with the "average" BRCA mutation may do and their outcome. But since there are many specific variations in these mutations, and people choose different ways to manage their cancer, statistics don't necessarily predict the outcomes of individual people. People aren't statistics.

A 2018 study published in Lancet Oncology has been the largest study to compare breast cancer survival in those with BRCA mutations relative to those who have sporadic breast cancer. on survival with breast cancer related to BRCA mutations.

The group of women aged 40 and under was followed for 10 years, with survival evaluated at the one, five, and 10 years after diagnosis. After 10 years, the survival rates for those who were BRCA positive and BRCA negative were the same. In fact, in the first few years, those with BRCA mutations and triple negative breast cancer had somewhat better outcomes than those who had sporadic triple negative disease. Those who had BRCA mutations were more likely to have a double mastectomy, but there was no difference is survival between those who had a mastectomy or a lumpectomy with radiation.

Limitations and Comparison With Other BRCA Survival Studies

The 2018 study mentioned above was encouraging but had some important limitations when looking at survival with BRCA mutated breast cancers.

Age: The study looked only at women under the age 40, and there are some important differences between young women with breast cancer and older women with the disease. We don't know if these results would be the same if older women were compared.

Duration of study: One problem with the 2018 study is that it only followed women for 10 years. Women who have BRCA mutations are much more likely to develop a second breast cancer in their other breast which might make a difference after the10 year study period.

A longer study which followed women with early-stage breast cancer (stage 1 and 2) and BRCA1 and BRCA2 mutations out 20 years did show increased survival in women who had a bilateral mastectomy (removal of the non-cancerous breast as well). In fact, having had a double mastectomy halved the risk of death for these women in the period between 10 and 20 years after their initial diagnosis.

The majority of deaths in that period were among people who developed a second primary breast cancer in their other (contralateral) breast. The average time span between the development of the first breast cancer and the second (unrelated) breast cancer was 5.7 years. This study reinforced the thought that evaluating the best treatment options may need longer-term studies.

Type of surgery: The type of surgery a woman with a BRCA mutation undergoes, as noted in the longer study above, may make a difference. In the 2018 study, there was no difference in survival between people who had a lumpectomy or those who had a mastectomy or double mastectomy. This could be different if the women were followed beyond 10 years. Since many of these women may be expected to live several decades, this is important to note.

Other treatments may affect survival as well. A 2013 study also found that survival was similar between BRCA positive and BRCA negative women at 10 years. That study did find, however, that for women with BRCA1 mutations and early-stage breast cancer, removing the ovaries and fallopian tubes (oophorectomy) improved survival. Other studies have also noted this improvement in survival with oophorectomy.

Mutation testing: As noted earlier, gene mutation testing is still in its infancy. There could have been false results in the study as different methods of testing were used.

Other risk factors: One study which found that breast cancer survival rates were actually higher in those who had BRCA mutations but there were a few exceptions. Women of Ashkenazi Jewish heritage and those with metastatic breast cancer had a lower survival rate if BRCA positive.

Previvors: The 2018 study has been mentioned in reference to those without breast cancer. It's important to note that the purpose of the study was to look at survival in women who already had breast cancer and a BRCA mutation. This study did not look at "previvors," the term used to describe women with BRCA mutations who are at risk but have not yet had breast cancer.

A Word From Verywell

Many people have asked whether those who have a BRCA mutation have differences in survival from those with non-hereditary breast cancer. A 2018 study was reassuring in some ways, but a longer duration of evaluation is needed to truly know if differences exist as well as to determine the most effective treatment options for women who have BRCA positive breast cancer. Of course, there are many factors beyond survival that must be evaluated when looking at treatments.

Looking at these studies, it's obvious that we have much to learn about hereditary breast cancer. In fact, we still know little about non-BRCA related gene mutations and breast cancer risk.

If you've been diagnosed with breast cancer, take time to research your cancer. With medicine changing so rapidly it's important for everyone to be their own advocate in their cancer care. Every woman is different and the best treatments for one woman may not be the same for another. It's important for each woman diagnosed with the disease to choose treatments that are best for her alone and to honor her own wishes.

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