Breast cancer is a major health challenge, and research focuses on understanding its causes. While many cases are linked to factors acquired over a lifetime, a distinct subset is tied to inherited genetic changes. This involves identifying germline mutations passed down through generations that significantly elevate an individual’s lifetime risk. Recognizing the role of genetics provides a pathway toward proactive management and prevention, allowing for a highly personalized health strategy.
Understanding Inherited Versus Sporadic Risk
Breast cancer cases are categorized based on their origin: sporadic and inherited. Sporadic cancer accounts for the vast majority of diagnoses and occurs due to accumulated mutations in a cell’s DNA over a person’s lifetime. These mutations are random, resulting from aging, environmental exposures, and lifestyle factors, and are not passed down.
Inherited breast cancer is caused by a germline mutation, a change present in the DNA of every cell passed down from a parent. These hereditary cases make up a smaller proportion, estimated at five to ten percent of all breast cancer diagnoses. Inherited mutations confer a much higher lifetime risk compared to the general population. When a person inherits one of these altered genes, they have a 50% chance of passing it on to each child. The presence of these inherited mutations often leads to cancer diagnoses at an earlier age and may involve multiple family members on the same side of the family.
Primary Genetic Markers for Breast Cancer
The most recognized genetic markers for inherited breast cancer are the BRCA1 and BRCA2 genes (BReast CAncer gene 1 and 2). These genes are normally involved in DNA repair and maintaining the stability of the cell’s genetic material, functioning as tumor suppressor genes. When a pathogenic mutation occurs in either gene, this repair mechanism is compromised, increasing the likelihood of uncontrolled cell growth.
Women who inherit a pathogenic BRCA1 variant face an estimated lifetime breast cancer risk ranging from 44% to 78% by age 70, with BRCA2 variants conferring a similar risk of 31% to 56%. These mutations are also linked to an increased risk of other cancers, including ovarian, prostate, and pancreatic cancers. Tumors developing in BRCA1 carriers are often triple-negative breast cancer, a subtype that can be more aggressive.
Genetic panel testing screens for other genes that contribute to inherited risk, often at a lower penetrance than BRCA. The PALB2 gene (Partner and Localizer of BRCA2) is considered the third most common high-risk breast cancer gene. A mutation in PALB2 is estimated to confer a lifetime breast cancer risk of 35% to 53%.
Other genes like ATM and CHEK2 are also frequently included in these panels and are classified as moderate-penetrance genes. ATM is involved in responding to DNA damage, while CHEK2 plays a role in cell cycle arrest and DNA repair. Pathogenic variants in these genes are associated with an increased breast cancer risk, though the estimates are lower than for BRCA1.
The Process of Genetic Counseling and Testing
The journey to determine inherited risk begins with genetic counseling. A genetic counselor is a specialized healthcare provider who performs a comprehensive risk assessment based on personal and family history of cancer. This consultation establishes if a person meets the criteria for testing, which often includes having breast cancer diagnosed at a young age, having multiple relatives with breast or ovarian cancer, or having a known mutation in the family.
During the counseling session, the provider explains the potential risks, benefits, and limitations of genetic testing, ensuring informed consent. They discuss the specific genes to be tested, which may be just the BRCA genes or a broader panel of dozens of genes. The counselor also helps the individual prepare for the potential psychological impact of receiving a positive result, which affects future medical and personal decisions.
The genetic test involves a blood draw or collection of a saliva sample, which is sent to a specialized laboratory for analysis. The lab sequences the DNA to look for pathogenic variants or mutations in the targeted genes. Results can take several weeks to return, and the subsequent meeting with the genetic counselor is essential for interpretation.
Results are reported as positive, negative, or a Variant of Uncertain Significance (VUS). A positive result means a pathogenic mutation was found, confirming an elevated inherited risk. A negative result means no known mutation was found in the genes tested, but it does not rule out the possibility of a mutation in a gene not included on the panel.
A VUS is a change in the gene sequence whose cancer risk significance is currently unknown. These uncertain results often require further research and monitoring over time.
Strategies for Managing Elevated Inherited Risk
Once an elevated inherited risk is confirmed, such as through a positive result for a BRCA mutation, individuals have several proactive strategies to manage their health. These options fall into three categories: intensified surveillance, chemoprevention, and prophylactic surgery. The choice of strategy is personal and requires discussion with a multidisciplinary medical team.
Increased surveillance focuses on detecting cancer at the earliest stage when it is most treatable. For high-risk individuals, this means starting screening at a younger age and using multiple imaging modalities. Current guidelines often recommend alternating annual mammograms with annual breast magnetic resonance imaging (MRI), beginning between ages 25 and 40, depending on the specific mutation and family history.
Chemoprevention involves using certain medications to reduce the risk of cancer development. Drugs like tamoxifen and raloxifene can block the effects of estrogen on breast tissue, helping prevent the growth of hormone-sensitive tumors. Tamoxifen is often the primary option for premenopausal women, while postmenopausal women may have additional choices, such as raloxifene or aromatase inhibitors.
The most effective risk-reducing measure is prophylactic surgery, which involves removing healthy tissue before cancer develops. A risk-reducing mastectomy removes both breasts and can reduce breast cancer risk by over 90% in high-risk women. For women with mutations that also increase ovarian cancer risk, such as BRCA1, a risk-reducing salpingo-oophorectomy (removal of the ovaries and fallopian tubes) is often recommended, as it lowers the risk of both cancers.