Metastatic Breast Cancer - Biomarkers and Mutations That Matter
- Metastatic breast cancer often presents as a recurrence of a prior early-stage breast cancer, although it can be a new diagnosis.
- With metastatic disease, the site of distant spread is typically biopsied and tested for the Estrogen Receptor, Progesterone Receptor, HER2, and Ki67. If you have a prior diagnosis of breast cancer, which is now metastatic, these markers are often the same.
- ER, PR and HER2 presence or absence help determine specific systemic therapy treatments. Medications will try to target ER/PR when present or HER2 when present.
- Somatic tumor testing for tumor DNA mutations with next-generation sequencing (NGS) and germline testing for inheritable DNA mutations is also performed with metastatic disease.
- The presence of germline or inherited BRCA 1/2 in combination with ER, PR, and HER2 helps to determine most first, second, and often third-line therapies.
- Other mutations identified in somatic testing of tumor DNA with next-generation sequencing (NGS) or inherited germline mutations of DNA are often used to select targeted therapies later in treatment once you have been through several different therapies that have become ineffective.
Breast Cancer Testing in Metastatic Disease
Breast cancer is most commonly diagnosed in the early stages when it is localized. Typically, when a patient presents with advanced breast cancer that is metastatic, it has originated from the prior early-stage cancer, which has now spread to distant sites. It is uncommon to have an initial diagnosis of metastatic breast cancer.Read More
- Estrogen receptor (ER)
- Progesterone receptor (PR)
- Human epidermal growth factor receptor 2 (HER2)
How Can Testing Help Determine If The Cancer Has Returned?In the uncommon situation where you present with a diagnosis of metastatic disease and no prior history of breast cancer, much of the workup and testing that helps guide future therapies is the same as early-stage disease.
If there is a prior history of breast cancer, a new biopsy is often obtained and compared to the old biopsy from the prior breast cancer. If a cancer recurs or spreads distantly, the expression of these markers (ER, PR, HER2) often remains the same.
If there is a difference in these receptors, it can mean this is a new cancer or separate breast cancer that developed, which is unrelated to the prior breast cancer. Because for most breast cancers, if they recur or spread to distant sites, they will often have the same markers from when they were diagnosed the first time.
This can change treatment if it is thought to be a new and separate breast cancer versus a recurrence of a prior disease.
How are these results used to guide metastatic breast cancer treatment?
Patients whose cancer is ER or PR positive are called hormone receptor-positive breast cancer, while patients whose cancer is HER2-positive (regardless of ER or PR) have HER2-positive breast cancer. The absence of all of these markers makes it triple-negative breast cancer.
The presence or absence of these markers tells us how the cancer will act and what targeted therapies specific to these markers are effective.
For metastatic disease, the primary treatment is medication, also called systemic therapy. Local treatments like surgery are typically not used. The exact type of medication used is highly dependent on these markers. For example, in hormone receptor-positive cancers, it is often recommended to use endocrine therapy, which targets these receptors. In HER2-positive breast cancers, we primarily use medications targeting HER2. The first-line therapy, as well as even second and third-line therapies, are determined by these markers. This means that when you are diagnosed with metastatic breast cancer, the markers present guide recommendations for the initial treatment and the treatments after that, which are used when the disease becomes resistant to current therapy.
What Other Testing is Important in Metastatic Breast Cancer?
With a diagnosis of metastatic breast cancer, molecular testing of the tumor, often with next-generation sequencing (NGS), should be performed to identify mutations in the tumor DNA that are targets for directed therapy. This testing can also help with future enrollment into clinical trials.
Additionally, testing for inheritable DNA mutations, or germline mutations, should be performed if not already done. This can also identify DNA mutations that are targets for specific treatments and also allow families to test themselves if the results are positive.
What Does Germline Testing Look For?
Germline testing primarily tests for BRCA1 and BRCA2, although your healthcare team may recommend a multigene panel that looks for other inheritable DNA mutations, including:
What Does Somatic Tumor Testing Look For?
Somatic or tumor-based testing of the tumor with next-generation sequencing (NGS) or PCR looks for several parts of the cancer DNA to determine if there are targetable mutations. Mutations that are often looked for include:
- Somatic (not inherited) BRCA1 and BRCA2
- HER2 activating mutations
How Can Tumor Mutation and Inheritable Mutation Testing Change Treatment?
Inherited (germline) Mutations:
If a known germline mutation is identified, it can change treatment recommendations, and it also indicates that other family members should get tested so they can protect themselves in the future with early screening and detection of cancers.
“In regards to mutations, one of the most important mutations we look at in breast cancer is the BRCA 1 or 2 mutations,” says Dr. Abdou. If present or absent, it helps to guide many first and second-line treatment decisions for metastatic cancer, meaning the initial therapy used when a patient is diagnosed with metastatic disease. “It helps us determine whether you’re eligible for specific targeted treatments called PARP inhibitors,” says Dr. Abdou. Again, this information is used in addition to other markers (ER, PR, HER2, Ki67) to guide treatment recommendations.
PALB2 is another known mutation that has emerging uses, often used later in the treatment course if applicable.
Tumor (Somatic) Mutations:
Somatic tumor testing typically looks for mutations that can be targeted in the downstream treatment of the disease. This means that if a specific mutation is identified, targeted therapy for that mutation is considered after you have undergone multiple other therapies.
This is a field of ongoing research, with new mutations and targeted therapies continuing to be identified. Both inherited (germline) and tumor (somatic) mutation testing can potentially make you eligible for enrollment for clinical trials depending on the test results and the site where you are receiving your care. If you have further questions regarding molecular testing and enrollment in clinical trials, please consult with your healthcare team.