Understanding the Molecular Subtypes of Breast Cancer

Read about luminal A, luminal B, HER2-enriched, and basal-like breast cancers—and how molecular subtyping guides breast cancer treatment

Breast cancer is not a single disease—it has different forms, each with unique biological traits that affect how the cancer grows and responds to treatment. To better understand these differences, researchers have identified four main molecular subtypes of breast cancer (also called intrinsic subtypes). These subtypes help predict how aggressive a tumor may be and which treatments are likely to be the most effective.

When a patient is diagnosed with breast cancer, doctors not only determine the size, stage, and grade of their tumor, but they generally classify it based on hormone receptor (estrogen and progesterone) and HER2 status as well. Each piece of information is important when making treatment decisions and plans. But breast tumors can also be classified by molecular subtype, which provides additional information about their biology and helps to create a fuller picture of the cancer beyond its size, grade, stage, or receptor status.

Read on to learn more about each of the four molecular subtypes of breast cancer, how doctors and researchers use these subtypes, and what it means to be diagnosed with a specific subtype.

What are molecular subtypes of breast cancer?

Depending on the tumor, a specific gene within its cells may be more or less active compared to the same gene in other cells. Examining these gene expression patterns allows reseachers to paint a  “molecular portrait” of each tumor, which can be classified  into four distinct breast cancer molecular subtypes: luminal A, luminal B, HER2-enriched, and basal-like.

BCRF investigator Dr. Charles Perou and colleagues made this key discovery and reported their work in a seminal 2000 paper that described the variation in gene expression profiles of 65 breast tumor samples.

Luminal A breast cancer

Luminal A tumors are characterized by higher levels of estrogen receptor (ER) and lower levels of Ki-67, a gene indicative of cellular proliferation, or how quickly cells grow and divide to make new cells. They tend to be progesterone receptor (PR)–positive and HER2-negative, and are more likely to be lower grade, meaning that the tumor cells look more like normal breast cells.

Because luminal A tumors typically respond well to hormone therapy, they tend to have the best prognosis of the four subtypes. They grow more slowly and have a lower risk of returning. As such, patients with this subtype have the highest rate of survival. Luminal A breast cancer is the most commonly observed subtype, accounting for about 50 to 60 percent of breast cancers.

Luminal B breast cancer

Luminal B tumors are also characterized by high levels of ER, but are more likely to be PR-negative, HER2-positive and have higher levels of Ki-67. They therefore tend to grow faster and are a higher grade, meaning that the tumor cells look very different from normal cells. Luminal B breast cancers have a worse prognosis than luminal A tumors.

Luminal B breast cancer may not respond as well to hormone therapy as luminal A breast cancer. However, they are more likely to respond to chemotherapy. Approximately 15 to 20 percent of tumors are classified as luminal B.

Basal-Like breast cancer

Basal-like tumors are often triple-negative (lacking ER, PR, and HER2), though not always. There is an 80 percent overlap between triple-negative breast cancers (TNBC) and tumors that comprise the basal-like molecular subtype. They tend to have higher rates of proliferation, are aggressive tumors that are more likely to spread and recur, and are more likely to be diagnosed in those carrying a BRCA1 gene mutation.

While basal-like breast cancers have a poorer prognosis than luminal A and B tumors, they tend to be responsive to chemotherapy. For basal-like tumors with BRCA mutations, PARP inhibitors may also be an option. 

More recently, Dr. Perou and other researchers have focused on classifying TNBC even further to identify treatment targets. Drilling down, they showed that a category of TNBC tumors could be described by the presence of immune cells. Those tumors are, therefore, more likely to respond to immunotherapy. With additional research and clinical studies, the cancer immunotherapy drug pembrolizumab (Keytruda®) was approved for advanced TNBC in 2020 and earlier stages of the disease in 2021.

Basal-like breast cancer is seen in about 10-15 percent of cases and is more likely to be diagnosed in younger patients and Black patients.

HER2-enriched breast cancer

HER2-enriched tumors often have high levels of the HER2 protein and tend to be ER-negative. Similar to basal-like tumors, they are often aggressive and fast growing, and are a higher tumor grade.

When left untreated, the prognosis for the HER2-enriched breast cancer is poor. Tumors of this subtype are more likely to be lymph node–positive and spread to the brain. However, prognosis has significantly improved since the discovery of HER2-targeting drugs. HER2-enriched tumors are typically responsive to trastuzumab (Herceptin®) and pertuzumab (Perjeta®), in combination with chemotherapy or other targeted drugs including kinase inhibitors like tucatinib (Tukysa®) or antibody-drug conjugates like trastuzumab (Kadcyla®) and fam-trastuzumab deruxtecan-nxki (Enhertu®). HER2-enriched breast cancer is seen in about 10 to 15 percent of cases.

What are breast cancer molecular subtypes used for?

Molecular subtyping gives doctors and researchers a deeper look into a tumor’s biology. They can help predict how aggressive a tumor is, whether it is likely to return or spread, and which treatments may be most effective. Researchers also use molecular subtyping to develop therapies beyond standard, existing treatments that target biological pathways or molecular drivers specific to a particular subtype.

While they are not typically used alone to inform treatment plans, molecular subtyping can help further refine treatment decisions. If a patient has luminal B breast cancer, for example, they may be more likely to need chemotherapy in addition to hormone therapy. Molecular subtyping can also help identify candidates for genomic tests such as Oncotype DX or Mammaprint, the results of which can determine if chemotherapy is necessary.

Ductal carcinoma in situ (DCIS), also known as stage 0 breast cancer, can also be categorized into similar molecular subtypes, enabling researchers to further examine what molecular drivers cause this precurser to breast cancer to become invasive.

Knowing the tumor’s “personality”

Each breast cancer tumor has its own “personality.” Some grow slowly and are likely to respond to one type of treatment, while others may be more aggressive and require  different or multiple forms of therapy.

The molecular subtypes of breast cancer are defined by their most basic, molecular-level biology. By classifying tumors by their biological traits, researchers and doctors better understand individual breast tumors, empowering them to choose the best treatments for each patient. Thanks to research supported by BCRF, more personalized and effective treatments are being developed, giving patients better options and hope for the future.