Women 65+ May Benefit from Genetic Tests for Breast Cancer Risk

For the first time, researchers estimate the prevalence of pathogenic variants of breast cancer predisposition genes beyond BRCA1/2 in older women.

Researchers: Lauren Teras, PhD, Alpa V. Patel, PhD, James M. Hodge, PhD
Institution:
American Cancer Society
Area of Focus: Population Science

“It was previously believed that women diagnosed with breast cancer after age 65 were unlikely to have been born with any high-risk breast cancer mutations. This study shows that some women older than 65, such as those diagnosed with triple-negative breast cancer, are still likely to have genetic mutations and should be offered genetic counseling and testing.”—Lauren Teras, PhD

The Challenge: Current guidelines do not recommend genetic counseling and testing for most women over age 65 because they’re assumed to have a small chance of having a pathogenic variant in one of the high-penetrance genes (also known as high-risk genes)—BRCA1, BRCA2, and PALB2.

Widely used guidelines developed by the National Comprehensive Cancer Network (NCCN) also don’t recommend hereditary cancer testing (genetic testing) or yearly breast cancer screening MRIs for women older than age 65. One of the reasons is because few studies have specifically looked at predisposition genes in women over age 65 – either those who have been diagnosed with breast cancer, or those who haven’t.

For women older than 65, better estimates of the remaining lifetime risk of breast cancer linked with having a pathogenic variant in a predisposition gene are needed. Knowing more about breast cancer risk can help a woman and her doctors make informed decisions about:

  • The best ways to manage her care based on what personal risk of developing breast cancer she may have.
  • The treatment most likely to be successful if she develops breast cancer.
  • How and when to talk with family members about the possibility of inherited risks for breast cancer.

The Research: The United States-based Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium conducted the largest study to date of women in the United States diagnosed with breast cancer after age 65.

Several American Cancer Society (ACS) epidemiologists participated in the study, including Lauren R. Teras, PhD, Alpa V. Patel, PhD, and James M. Hodge, MPH. Some of the many other contributors included ACS grantee Julie Palmer, PhD, and former ACS grantees Jeffrey N. Weitzel, MD, and Fergus Couch, PhD, who was the study’s senior author.

They reviewed data from about 27,000 women over age 65, with about half having
a diagnosis of breast cancer. Data came
from epidemiologic studies that included the ACS Cancer Prevention Studies, CPS-II and CPS-3.

The consortium published their findings from this study, showing that:

  • Women older than age 65 who had estrogen-receptor negative (ER-) breast cancer, including triple-negative breast cancer (TNBC), had more pathogenic variants in the high-risk predisposition genes BRCA1, BRCA2, and PALB2 than expected for this age group.
  • Between 3% and 4.5% of women diagnosed with TNBC after age 60 had pathogenic variants in the high-risk predisposition genes.
  • In contrast, after the age of 65, very few women without a family history or ER- breast cancer had these pathogenic genetic variants.

For women older than 65, this study provided evidence on:

Who should be considered for genetic counseling and testing. The authors state that this study provides evidence that women older than 65 should be considered for genetic counseling and testing when they have an ER- breast cancer (including TNBC) to help guide their care.

Who doesn’t need genetic counseling and testing. The authors confirm that women older than age 65 who don’t have a family history or an ER- subtype of cancer would not benefit from genetic counseling and testing because they have a low likelihood of having a pathogenic variant in a high-penetrance gene, such as BRCA1 or BRCA2.

Inheriting Cancer Risks: Some Basic Terms

Permanent changes in the DNA sequence of a gene are called gene mutations. Some scientists think that “gene variant” is a more accurate term because changes in DNA do not always lead to disease. Sometimes they’re used as synonyms.

Genetic variants can have a large or small effect on the likelihood of developing a particular disease. The term “pathogenic” refers to something that causes a disease. When genetic variants lead to disease, they’re called pathogenic variants, or pathogenic mutations.

Genes that are vulnerable to cancer-causing variants or changes are called cancer-predisposition genes. In some cases, a cancer-predisposition gene is inherited, or passed along from generation to generation. Several dozen cancer-predisposition genes have been identified, and about 5 to 10% of all cancers result directly from those that are inherited from a parent.

For example, BRCA1 and BRCA2 are inherited cancer predisposition genes. Mutations on these genes increase the risk for developing certain cancers.

The term penetrance is used to describe how many people carrying a mutation or cancer predisposition gene will eventually develop cancer. If everyone who inherits a mutation develops cancer, that mutation is said to have complete penetrance. If some people don’t, it’s incomplete or reduced penetrance. If most people with an inherited mutation develop cancer, that mutation has high penetrance. For example, pathogenic variations on the BRCA1 and BRCA2 genes are high-penetrance gene mutations. Other gene mutations are in categories considered to be moderate- or low-penetrance.

Who might benefit from enhanced breast cancer screening. Based on their findings, the authors also support enhanced breast cancer screening (such as MRI) for women over age 65 who have BRCA1 or BRCA2 mutations and possibly also those with CHEK2 and PALB2 mutations, whether or not they’ve been diagnosed with breast cancer. If a woman has been diagnosed with breast cancer, MRI screening could be used to look for second cancers or recurrence. 

Family members with the same pathogenic variants may also benefit from enhanced breast cancer screening. These women and their family members may also want to talk with their doctors about the pros and cons of preventive surgery to remove their breasts and/or ovaries to prevent future cancers in those areas.

Why Does It Matter? The knowledge gained about the prevalence of pathogenic variants in breast cancer predisposition genes can be used to inform appropriate care, including guidelines for genetic counseling and testing as well as guidelines for breast cancer screening and other risk-management strategies for:

  • Women older than 65 in the general population
  • Women diagnosed with an ER- subtype after age 65
  • Women diagnosed with TNBC at any age
  • Family members of older women found to have pathogenic variants in high-risk predisposition genes.