Advancements in Breast Cancer Biomarkers

One in 8 American women will develop breast cancer, making it the most common form of cancer in females, other than skin cancer. This sounds pretty scary, but remember that 7 in 8 women will not get breast cancer. An estimated 2,650 new cases of invasive breast cancer were also diagnosed in American men in 2021.

Traditionally, oncologists have diagnosed breast cancer using mammograms, ultrasound and molecular bioimaging. However, these techniques tend to detect breast cancer when it is in the later stages. Biomarkers have transformed diagnosis and treatment, and play a pivotal role in the management of breast cancer.

"Biomarker testing has allowed us to move well beyond a 'one size fits all' approach for treating men and women with breast cancer," said Deanna J. Attai, M.D., an associate clinical professor of surgery at the David Geffen School of Medicine at the University of California Los Angeles.

"Biomarkers are widely used in providing cancer care," stated Bhavana Pathak, M.D., a board-certified internist, hematologist and medical oncologist at MemorialCare Cancer Institute at Orange Coast Medical Center in Fountain Valley, California.

"Sometimes biomarkers can be diagnostic of a disease, sometimes they can predict response to therapy, and sometimes they can be prognostic or tell us how a patient might do compared to someone without that biomarker," she said.

Oncologists use three cornerstone molecular biomarkers—ER, PR and HER2—for optimized clinical decision-making for breast cancer patients.

"The introduction of ER, PR and HER2 biomarker testing is one of the fundamental features we look at when deciding how to treat a patient with breast cancer and has revolutionized treatments since the latter half of the 20th century," Pathak said.

• ER (estrogen receptor): In some breast cancers, the cells have receptors (proteins) that attach to estrogen and progesterone, which are hormones that assist cancer in its growth. Knowing the hormone receptor status of your breast cancer is essential. If estrogen and progesterone can be stopped from attaching to the receptors, this can help prevent cancer from growing and spreading. If breast cancer has estrogen receptors, it is known as ER-positive.
• PR (progesterone receptor): Similarly, if breast cancer has progesterone receptors, it is PR-positive.

Pathak explained that the presence of ER/PR receptor positivity in breast cancer indicates the patient will likely respond to a category of therapy called endocrine treatment, by manipulation of the estrogen/progesterone pathways that could drive breast cancer growth. Nowadays, more specific targeted therapies have also emerged in conjunction with these endocrine therapies.

• HER2 (human epidermal growth factor receptor 2): This is a protein involved in normal cell growth. In some types of cancer, including breast cancer, the body might make this protein in larger than average amounts. If breast cancer is HER2-positive, then the breast cancer cells have higher than normal levels of HER2. HER2-positive breast cancers are known to grow and spread faster than other breast cancers. However, they are much more likely to respond to treatment.

"The presence of HER2/neu receptors indicates that a patient will be responsive to HER2-directed therapies, such as [the drug] trastuzumab and now newer generations of HER2 drugs," Pathak said. "What's interesting is that while we may find these receptors also in normal tissues of the body, its prevalence in cancerous tissue has made it a particularly unique target for therapy development."

"Treatments such as chemotherapy and endocrine therapy are based on the commonly tested biomarkers, as well as additional genomic tumor profiling such as Oncotype DX or MammaPrint," Attai explained.

Oncologists use genomic tests to see how active specific genes are in cancer tumors:

• Oncotype DX: This is a predictive test that determines how likely breast cancer is to spread elsewhere in the body or reoccur. Clinicians can also use it to guide treatment and decipher whether you will benefit from chemotherapy in addition to hormone therapy.
• MammaPrint: This is a test that analyzes the activity of specific genes in early-stage breast cancer. It helps to show whether some ER-positive, HER2-negative breast cancers are likely to spread.

"Biomarkers and genomic tests allow us to more precisely target the specific tumor type with treatments that it will most likely respond to," Attai said.

"The theme of early detection and early treatment, in any stage of cancer care, is an extremely important goal," Pathak said. "As patients develop more advanced forms of breast cancer, other circulating biomarkers, which we call 'tumor markers,' found in blood studies are sometimes used to track the course of a patient's cancer."

However, there is controversy around using tumor markers because some conditions other than breast cancer can cause them to elevate, Pathak explained. Hence, the use of tumor markers is not uniformly recommended by cancer societies, or they are not utilized as the sole predictor of a patient's course.

"There are new and emerging biomarkers which fall more into the category of molecular/genetic testing, such ctDNA [circulating tumor DNA]," Pathak said.

These tests detect fragments of the genetic information from cancer cells that are shed into the body or bloodstream at a very early level.

"Some of these tests are commercially available, and many are still being studied in clinical trials," Pathak said. "One limitation is the concern for heterogeneity or variation of tumor, which may give us different information [sometimes positive or falsely negative for a particular marker] based on what is being released from the tumor."

Research into biomarkers is ongoing and progressing all the time for breast cancer care.

"There is emerging research regarding individual and tumor gene expression [such as BRCA mutations], and efficacy of specific chemotherapy agents," Attai said.

Research suggests that the androgen receptor may be targeted in some cases—the androgen receptor is expressed in more than 70 percent of breast cancers, Attai explained. Other research areas include targeting specific proteins or enzymes within the cancer cell or growth and metabolic pathways.

"If we widen our scope of the term 'biomarker' and look for molecular alterations within tumors, called mutations, these are often being used every day to predict treatment to particular types of therapy," Pathak said.

Pathak used the example of metastatic breast cancers with the PIK3CA mutations, which may predict response to a particular medication, alpelisib. This drug works by blocking the signals that cause cancer cells to multiply.

"We are on the forefront of both detection and treatment of patients with breast cancer, being informed nearly daily to weekly by the hard work of patients and scientists at the front lines of this emerging research," Pathak said.