Women With Certain Genetic Mutations Have Higher Risk of Cancer in Opposite Breast
Among women diagnosed with breast cancer, mutations in the BRCA1, BRCA2, CHEK2, and PALB2 genes up the risk of cancer in the opposite breast — called contralateral breast cancer by doctors — according to a study.
The research was published online on Jan. 9, 2023, by the Journal of Clinical Oncology. Read “Contralateral Breast Cancer Risk Among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2.”
Genetic mutations linked to breast cancer
Genes are short segments of DNA (deoxyribonucleic acid) found in chromosomes. DNA contains the instructions for building proteins. And proteins control the structure and function of all the cells that make up your body.
Think of your genes as an instruction manual for cell growth and function. Changes or mistakes — called mutations by scientists — in the DNA are like typographical errors. They may provide the wrong set of instructions, leading to faulty cell growth or function. When there is a mutation in a gene, that same mutation appears in all the cells that contain the same gene. It’s like having an instruction manual in which all the copies have the same typographical error.
There are two types of DNA changes: those that are inherited and those that happen over time. Inherited DNA changes are passed down from parent to child. Inherited DNA changes are called germline mutations.
DNA changes that happen over the course of a lifetime — as a result of the natural aging process or exposure to chemicals in the environment — are called somatic mutations.
Some mutations are harmless, but others can cause diseases or other health issues. Mutations that negatively affect health are often called pathogenic variants by doctors.
Two of the most well-known genetic mutations that raise the risk of breast and ovarian cancer are in the BRCA1 and BRCA2 genes. Women who inherit a mutation in either of these genes — from their mothers or fathers — have a much higher-than-average risk of developing breast cancer and ovarian cancer.
Still, there are other genetic mutations that can increase breast cancer risk. Research suggests that mutations in the ATM, CHEK2, and PALB2 genes can double breast cancer risk. Although not as common as BRCA mutations, these mutations have been found in 2% to 3% of women diagnosed with breast cancer.
Among women with breast cancer, the risk of developing cancer in the opposite breast is estimated to be about 0.5%.
Despite understanding the link between BRCA1, BRCA2, ATM, CHEK2, and PALB2 gene mutations and higher breast cancer risk, we don’t know how much any of these mutations increases the risk of developing a new cancer in the opposite breast. In this study, the researchers wanted to estimate contralateral risk.
About the study
The researchers used information from the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. The CARRIERS consortium is a group of 17 large studies in the United States that want to improve our understanding of genetic and environmental risk factors for breast cancer. The studies include more than 32,000 women diagnosed with breast cancer and more than 32,000 women of similar ages with no history of breast cancer. All the women in the studies had genetic testing. The studies also include information on contralateral breast cancer diagnoses among the women with a history of breast cancer.
In their analysis, the researchers included a total of 15,104 women. The researchers compared rates of contralateral breast cancer among women with BRCA1, BRCA2, ATM, CHEK2, and PALB2 mutations and women who didn’t have mutations in these genes.
Among the women:
half were younger than 62 when they were diagnosed with breast cancer and half were older
half were followed for more than 11 years and half were followed for shorter periods of time
63% were white
15% were Black
26.8% were pre-menopausal
73.2% were post-menopausal
75.5% were diagnosed with hormone receptor-positive breast cancer
46.4% took hormonal therapy medicine after surgery
Women diagnosed with hormone receptor-negative breast cancer were more likely to be:
Black
younger
pre-menopausal
When looking at the rates of genetic mutations, the researchers found that:
116 women had an ATM mutation
132 women had a BRCA1 mutation
170 women had a BRCA2 mutation
232 women had a CHEK2 mutation
97 women had a PALB2 mutation
Overall, 11.2% of contralateral breast cancer cases were diagnosed in women who had one of the five mutations.
Contralateral breast cancer was diagnosed in:
711 women with none of the mutations
7 women with an ATM mutation
31 women with a BRCA1 mutation
33 women with a BRCA2 mutation
19 women with a CHEK2 mutation
7 women with a PALB2 mutation
The researchers’ analysis found that women with a mutation in the BRCA1, BRCA2, and CHEK2 genes had a higher risk of contralateral breast cancer than women who didn’t have one of those mutations. Contralateral breast cancer risk was:
2.7 times higher in women with a BRCA1 mutation
3 times higher in women with a BRCA2 mutation
1.9 times higher in women with a CHEK2 mutation
Although women with a PALB2 mutation didn’t have an overall increase in contralateral breast cancer risk, women diagnosed with hormone receptor-negative breast cancer who had a PALB2 mutation were nearly three times more likely to develop contralateral breast cancer than women who didn’t have the same mutation.
All these increases in contralateral breast cancer risk were statistically significant, which means they were likely because of the mutations and not just because of chance.
Women with an ATM mutation didn’t have a statistically significant increase in contralateral breast cancer risk.
The researchers also wanted to see if the risk of contralateral breast cancer was different based on:
race
menopausal status
age at diagnosis
The risk of contralateral breast cancer among white women was similar to the overall results.
Black women with mutations had a higher risk of contralateral breast cancer than white women. The risk of contralateral breast cancer was:
2.5 times higher for Black women with a BRCA1 mutation
3.2 times higher for Black women with a BRCA2 mutation
9.2 times higher for Black women with a CHEK2 mutation who were diagnosed with hormone receptor-positive breast cancer
4.8 times higher for Black women with a PALB2 mutation diagnosed with hormone receptor-negative breast cancer
Among pre-menopausal women:
BRCA1 and BRCA2 mutations were linked to a higher risk of contralateral breast cancer
CHEK2 mutations were linked to a higher risk of contralateral breast cancer in women diagnosed with hormone receptor-positive disease
PALB2 mutations were linked to a higher risk of contralateral breast cancer in women diagnosed with hormone receptor-negative disease
Among post-menopausal women, a BRCA2 mutation was the only mutation linked to a higher risk of contralateral breast cancer.
Only 2.6% of the women in the study who were initially diagnosed with breast cancer at age 65 or older had one of the five mutations. During follow-up, only three cases of contralateral breast cancer were diagnosed in this group of women:
one case in a woman with an ATM mutation
one case in a woman with a BRCA1 mutation
one case in a woman with a PALB2 mutation
“These are the first population-based numbers out there for these three genes beyond BRCA1 and BRCA2,” Fergus Couch, PhD, the Zbigniew and Anna M. Scheller Professor of Medical Research at the Mayo Clinic Comprehensive Cancer Center, said in a statement. “It is also one of the largest studies to provide estimates of contralateral breast cancer risk by age at diagnosis, menopausal status, and race [and] ethnicity in germ line mutation carriers.”
What this means for you
The study’s results may help women who have been diagnosed with breast cancer make more informed choices about treatment and ongoing monitoring.
If you have a BRCA1, BRCA2, CHEK2, or PALB2 mutation, you and your doctor can develop a personalized screening strategy to detect cancer in the opposite breast based on the characteristics of the cancer you were originally diagnosed with, as well as the level of risk associated with the mutation.
You and your doctor also can discuss whether contralateral prophylactic mastectomy — removing the other healthy breast — is a good option for your unique situation and preferences.
— Last updated on February 22, 2023 at 7:13 PM