When a person receives a breast cancer diagnosis, it is common for many questions to arise: Why did it happen? Could I have prevented it? Are my daughters, sisters, or other family members also at risk?
This last question in particular, although less well known, has scientific support: a small proportion of breast cancers may be related to genetic alterations inherited within families. This does not mean that cancer is passed directly and inevitably from parents to children. What can be inherited is a predisposition, meaning a genetic variant that increases the probability of developing breast cancer over the course of a lifetime.
Currently, it is estimated that approximately 5% to 10% of breast cancers are associated with germline mutations, genetic alterations that are present from birth and can come from either parent.
BRCA1 and BRCA2: the best-known genes, but not the only ones
You have probably heard of the BRCA genes, whose name literally comes from the abbreviation for BReast CAncer, because they were originally identified by scientists searching for the genes responsible for hereditary forms of breast cancer in the 1990s. And having these genes is not dangerous. In fact, both genes normally participate in DNA repair and help prevent cells from growing and dividing uncontrollably. However, inherited pathogenic mutations in these genes can alter their activity and increase the risk of developing cancer.
However, next-generation sequencing (NGS) technologies have made it possible to study numerous genes simultaneously, and researchers have found that BRCA1 and BRCA2 are only part of the story.
Many families with significant histories of breast cancer do not carry mutations in these genes, but instead in other, less well-known genes such as PALB2, TP53, PTEN, CDH1, STK11, CHEK2, ATM, BARD1, RAD51C, and RAD51D, among others.
Therefore…
Having a mutation does not mean you will develop cancer
Just like BRCA1 and BRCA2, we have other genes that participate in essential functions within our cells. When these genes carry an inherited pathogenic variant, some of these protective mechanisms may function differently or may not function properly. As a result, the risk that a cell will accumulate alterations that favor the development of cancer may increase.
But risk does not mean destiny.
A person may inherit a cancer-related variant and never develop the disease, just as a person without one may still develop cancer. To describe how likely it is that a genetic alteration will actually manifest clinically, a concept called penetrance is used.
High-penetrance genes can produce substantial increases in risk, while moderate-penetrance genes are associated with smaller increases. In hereditary breast cancer, high-penetrance genes are classified as those associated with a lifetime risk greater than 50% or a relative risk more than five times higher than average. Moderate-penetrance genes may be associated with risks of approximately 20% to 50%.
This is why two people who carry different genetic variants do not necessarily have the same level of risk.
It is also important to clarify that breast cancer risk does not depend on a single cause. It results from an interaction between genetics, family history, age, hormonal factors, exposures, and lifestyle.
Breast cancer risk has been proposed to be assessed by considering both modifiable factors — lifestyle and exposures where some degree of intervention may be possible — and non-modifiable factors, such as age, certain family histories, some reproductive characteristics, and inherited genetic variants. Patients can then be classified into average-, moderate-, or high-risk groups so that prevention and screening strategies can be adapted accordingly.
This means that a person’s risk should not be evaluated only by asking: “Has anyone in your family had breast cancer?”
Figure 1. Role of BRCA1/2 in DNA repair. Loss of BRCA1/2 function can impair DNA repair, promoting DNA damage accumulation and tumor development.
Are all breast cancers the same?
No. And this point is essential for understanding why genetics may also be relevant after a diagnosis.
“Breast cancer” is a term that includes diseases with different biological characteristics. One of the most common ways to differentiate them is by studying certain receptors present on tumor cells through biopsy:
- Estrogen receptor (ER)
- Progesterone receptor (PR)
- Human Epidermal Growth Factor Receptor 2 (HER2)
Depending on whether these receptors are present or absent, tumors can generally be grouped into categories such as:
Hormone receptor-positive breast cancer: expresses ER and/or PR and may be susceptible to treatments targeting these hormonal pathways.
HER2-positive breast cancer: has high levels of HER2 and may be susceptible to therapies specifically targeting this protein.
Triple-negative breast cancer: does not express ER, PR, or HER2, so treatment strategies directed against these three targets are not applicable in the same way. For this reason, it is currently considered one of the more difficult types of breast cancer to treat.
And this is where a particularly interesting connection between genetics and tumor biology appears.
Some genes are associated with specific types of breast cancer
Not all inherited alterations are distributed in the same way across different breast cancer subtypes.
Variants in BRCA1, BRCA2, PALB2, BARD1, and RAD51C, for example, have been associated with triple-negative breast cancer. Alterations in ATM and CHEK2 are more frequently associated with estrogen receptor-positive tumors, while TP53 and NF1 show associations with HER2-positive tumors.
This information demonstrates why breast cancer is increasingly being studied from an individualized perspective.
Figure 2. Major molecular subtypes of breast cancer based on hormone receptor (HR) and HER2 expression, highlighting differences in prevalence, treatment targets
Why is it important to know your risk before cancer develops?
Because a person considered to be at high risk may require a different surveillance program than someone at average risk. In high-risk individuals, additional monitoring methods may be considered, including breast magnetic resonance imaging, as well as other risk-reduction strategies depending on each clinical situation. This is particularly relevant in some hereditary predispositions because tumors may develop at younger ages.
Knowing your family history is also part of understanding your risk
This does not mean that everyone with a family member who has had cancer should assume that an inherited mutation is present. Most breast cancers are not hereditary, but that does not make genetics irrelevant.
For a subset of affected individuals and families, identifying a predisposition may provide important information about surveillance, prevention, and, in patients who already have cancer, even certain treatment decisions.
That is why talking with family members about cancer history, knowing the ages at which relatives were diagnosed, and communicating that information to the medical team may be much more important than it seems.
Genetics cannot tell us with certainty who will develop breast cancer. What it can do is help us better understand who may be at higher risk and why.
Main reference:
Patel, M. M., & Adrada, B. E. (2024). Hereditary Breast Cancer: BRCA Mutations and Beyond. Radiologic clinics of North America, 62(4), 627–642. https://doi.org/10.1016/j.rcl.2023.12.014
Other references:
Michaels, E., Worthington, R. O., & Rusiecki, J. (2023). Breast Cancer: Risk Assessment, Screening, and Primary Prevention. The Medical clinics of North America, 107(2), 271–284. https://doi.org/10.1016/j.mcna.2022.10.007
Larkin L. (2023). Breast cancer genetics and risk assessment: an overview for the clinician. Climacteric : the journal of the International Menopause Society, 26(3), 229–234. https://doi.org/10.1080/13697137.2023.2184254
