BRCA mutations are the most well-known and common hereditary genetic drivers of breast cancer, with women who have a BRCA mutation being 5-8 times more likely to develop the disease. With a risk this high, it makes sense that much of the focus regarding breast cancer risk is on BRCA, but there are other mutations linked to breast cancer that clinicians also screen for when treating a patient. If any of these mutations are found during screening, notifying the patient’s close relatives of their genetic risk could save millions of lives through early detection.
Stanford Cancer Institute member Jennifer Caswell-Jin, MD, assistant professor of medicine, is focused on improving genetic screening for breast cancer mutations and better understanding the cancer on a molecular level. Her interdisciplinary work has earned her the SCI Fellowship Award, SCI Innovation Award, and SCI Equity Impact Research Grant, making her the only person to have been selected for these three Stanford Cancer Institute internal funding sources. She discussed genetic mutations beyond BRCA, challenges in genetic screening, and personalizing breast cancer treatment.
Genetic mutations driving breast cancer
5-10% of breast cancers are due to genetic or hereditary factors. BRCA, standing for Breast Cancer Associated Genes, comprises two genes: BRCA1 and BRCA2. Together, these genes account for 60% of all hereditary breast cancers. Discovered in the 1990s, these were the first known breast cancer mutations because they were seen frequently due to their high risk for breast cancer.
Researchers have since found more genes associated with breast cancer. Caswell-Jin says a typical breast cancer screening panel includes 15 genes for which scientists are confident about their risk. Included in this panel are more high-risk mutations like TP53, which is rarer than BRCA but has a higher risk for developing breast cancer, and PALB2, which has a similar risk as BRCA. ATM and CHEK2 gene mutations are also screened for and have a lower risk than BRCA but are more common in the population.
Some genetic mutations are associated with different types of breast cancer, which are characterized by the expression of three receptors that can be targeted with therapies to prevent the cancer’s spread: estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2). BRCA1 tends to cause more triple-negative breast cancers, an aggressive, challenging cancer that doesn’t express any of the three receptors, so there is a lack of targeted therapies to treat the cancer. TP53 mutations cause more triple-positive breast cancers, which express all three hormone receptors. ATM and CHEK2 mutations tend to cause breast cancers that express ER and don’t express HER2.
While it’s not yet understood why these genes have stronger associations with specific breast cancer types, the genetic differences within the types don’t affect the cancer’s treatment response. However, there is a promise for targeted therapies based on gene expression. PARP inhibitors, drugs that kill cancer cells by preventing them from repairing their DNA, are effective against BRCA-associated breast cancer, including triple-negative breast cancers that express BRCA1. Caswell-Jin says that there is a lot of active research in this area, and she hopes that researchers will find novel treatments for other cancers, as well.
Specific mutations may be more common in certain groups due to founder events, which occur when a genetic change arises in a population and, over many generations, is passed down often enough to become relatively frequent in that group. For example, founder events explain why certain CHEK2 mutations are more often seen in people of European or Ashkenazi Jewish ancestry, and why BRCA mutations are more common in Ashkenazi Jewish ancestry. However, because there are thousands of possible mutations across these genes, the overall likelihood of carrying a breast cancer risk gene is similar across populations.
“There's no significant difference in the chance that we would find a breast cancer risk gene of any type in one population as compared to another based on ethnicity or geography, because there are just so many ways you can mutate these genes to cause pathogenicity.”
The power of cascade testing to catch cancer early
When a cancer patient is found to have a hereditary genetic mutation associated with the cancer, the standard of care is cascade testing. The patient’s close relatives are screened for the mutation so they can monitor the development of that cancer and catch it early to increase the chances that the cancer can be treated effectively. Caswell-Jin says the estimate is that 1% of the U.S. population carries one of the breast cancer risk variants, amounting to 4 million people, and the vast majority are unaware of their risk.
“We know through modeling that if cascade genetic screening is done correctly, we can get to the point where most of the population knows about their genetic risk in advance of getting tested.”
Despite cascade testing being the standard of care, it is difficult to do well. Clinicians have to focus on the patient during treatment, and due to patient privacy concerns, clinicians don’t contact the patient’s family to inform them of potential risk. Because of this, the burden to initiate cascade testing falls on the patient to inform their family, resulting in fewer than 20% of eligible relatives who undergo testing and causing disparities in who gets tested. Stanford Cancer Institute member Allison Kurian, MD, found that breast and ovarian cancer patients of non-white ethnicity underwent genetic testing at about 75% the rate of white patients.
Caswell-Jin says, “We also know there are lower rates of testing in people who have lower education levels and people who live in rural areas. A huge area of concern in our field is trying to make sure this really effective information about genetic risk can reach everyone.”
To address these disparities, Caswell-Jin and Kurian lead PROACT, an online platform powered by artificial intelligence that implements genetic risk education and gives family members access to low-cost genetic testing.
“The hope is that we can implement this in clinics across the population to lower the barriers to effective cascade testing, so that we can get the millions of people who have genetic risk, and want to know about it, aware of that risk, and start protecting them from cancer,” says Caswell-Jin.
Next-generation treatments promise precision and personalization
From a research standpoint, Caswell-Jin is interested in understanding the unique molecular factors and pathways that drive breast cancer tumor development and how these findings can be translated to develop more precise and personalized therapies. She collaborated with Stanford Cancer Institute member Christina Curtis, PhD, on a study classifying breast cancer tumors into three genomic archetypes that develop early when the tumor is forming, persist into metastatic disease, and shape the tumor microenvironment.
“It’s becoming more and more clear that we’re going to be able to divide breast cancer much more narrowly based on specific drivers of this cancer, both in terms of the cancer pathways driving it and vulnerabilities that led to the way the tumor looks and exists and that may make it more vulnerable to certain treatments,” says Caswell-Jin.
She highlights Curtis’s research with organoids, small, 3D clusters of cells that mimic a specific organ's structure and function. These organoids are created from tissues donated by breast cancer patients to evaluate the efficacy of different treatments on specific breast cancer subtypes. Once effective drugs are identified, she hopes the findings will lead to a clinical trial that tests the drugs in patients based on their subtype and provides immediate feedback on effectiveness.
“That whole path is really exciting. We start with the huge amount of data on breast cancer patients, try to identify novel subtypes, find those patients in the clinic, build organoids from their tumor tissue, test new drugs on those organoids, and then hopefully open a clinical trial as we develop new drugs and test them in real time in the patients.”
We’re moving very fast, and I fully expect that in the next couple of decades, we’ll see massive changes in the personalization and targeting of different subtypes of breast cancer."
As a breast cancer physician who spends most of her clinic time treating metastatic breast cancer patients, Caswell-Jin is hopeful that future immunotherapies, especially cancer vaccines, will successfully treat metastatic disease. Advances in technology, such as artificial intelligence and spatial technologies, are providing new insight into how breast cancer tumor cells interact with a patient’s immune environment and are identifying new pathways and biomarkers associated with breast cancer.
“We’re moving very fast, and I fully expect that in the next couple of decades, we’ll see massive changes in the personalization and targeting of different subtypes of breast cancer.”
Addressing disparities
As treatments and tools for identifying those at risk become more advanced, Caswell-Jin identifies disparities in implementation as one of breast cancer’s biggest challenges.
“How do we make sure that everyone has access to that level of really highly specialized care? It’s one of those situations where, as advances happen and they reduce mortality, it gets even harder to implement them effectively across the population.”
The first step in addressing disparities is to examine what is currently happening with implementation at the population level. Newly developed data tools will allow researchers to evaluate electronic medical data across the country in real time so they understand how breast cancer care is being implemented nationwide. After understanding the gaps, she posits that digital tools, such as decision tools built into electronic medical records, will help clinicians navigate increasingly complicated screening and treatment guidelines so patients receive the best care.
While challenges persist, Caswell-Jin is hopeful about the future.
“Breast cancer is a success story. There’s been a 58% reduction in mortality since 1975. Three-quarters of that reduction is due to treatment and a quarter to advances in screening. I think the field is going to continue to move quickly in treatment and screening advances, and we’re going to continue to see breast cancer mortality plummet.”