Understanding breast cancer heterogeneity, molecular profile

News organizations, and to some extent advocacy groups, speak of breast cancer as though it were a homogenous disease. That is a gross simplification.

In addition to differences based upon point of origin, such as ductal or lobular cancer, there are molecular differences which affect treatment options and cell aggressiveness. These four molecular types are luminal A, luminal B, HER2 positive and basal-like (triple negative). These molecular types may some day replace point-of-origin as our labels for breast cancer.

To understand molecular profiles, it’s helpful to understand a little bit about hormone receptors. They are proteins found inside and on the surface of cells. The proteins receive messages from substances in the bloodstream and tell the cells how to respond.

A cancer is called estrogen receptor positive (ER+) if it has receptors for estrogen; it is progesterone receptor positive (PR+) if it has progesterone receptors.

Being ER+ or PR+ means that the cancer may receive signals from estrogen or progesterone that could promote cancer growth. About two out of every three breast cancers test positive for hormone receptors.

molecular types of breast cancer

Luminal A

Luminal A accounts for half of all invasive breast cancers.

This type is (1) estrogen receptor (ER) and progesterone receptor (PR) positive and (2) HER2 negative. It typically has a low grade, which means the cancer cells look much like normal breast cells. It usually has a low Ki-67 measure of proliferation, so it doesn’t grow quickly.

Luminal A includes a wide range of low-grade variants, such as tubular carcinoma, cribriform carcinoma, low-grade invasive ductal carcinoma of “no specific type” (IDC NST) and classic lobular carcinoma. It is likely to respond to  endocrine therapy.

Luminal B

Luminal B accounts for about 20% of all invasive breast cancers.

In this variant, ER is positive, PR is negative, and HER2 is positive. Both the proliferation index rate expressed by Ki-67 and histological grades are higher in luminal B than luminal A.

Luminal B includes most grade 2 invasive ductal carcinoma of “no specific type (IDC NST) as well as micropapillary carcinoma.

This type has a variable response to endocrine therapy and chemotherapy; its prognosis is not as good as luminal A.

HER2 positive

HER2-positive breast cancer tests positive for a protein called human epidermal growth factor receptor 2 (HER2), which promotes the growth of cancer cells. A gene mutation leads to an excess of the HER2 protein.

In this breast cancer, ER/PR is usually negative and HER2/neu is strong positive. The Ki-67 expression of proliferation is high. Tumors are more likely to be of high grade and include lymph node metastasis.

HER2 positive breast cancers occur in about 1-out-of-5 patients and tend to be more aggressive than other types of breast cancer.

HER2 positive breast cancer is less likely respond to hormone therapy. This type of breast cancer  shows the highest sensitivity to trastuzumab (herceptin) therapy.  Trastuzumab may help block the HER2 protein and cause the cancer cells to die. According to Mayo, the prognosis is “quite good.”

About 20-30% of all breast cancers are HER2 positive.

Basal-like (triple negative)

The basal class has a pattern of expression that is similar to basal epithelial cells and normal myoepithelial cells of mammary tissue. It is typically ER/PR negative and HER2 negative (triple negative). It tends to have a higher grade (cells more mutated) and to have a high expression of the Ki-67 index, making it more aggressive.

About 10-20% of breast cancers are triple-negative. It is more likely to affect younger women, African Americans or Hispanics, and patients with a BRCA1 gene mutation.

Triple negative breast cancer does not response to endocrine therapy because the tumor cells lack the necessary receptors. It appears to be sensitive to platinum-based chemotherapy and poly (adenosine diphosphate-ribose) polymerase inhibitors.


Note: data on prevalence of these four types are not firm, as the ranges indicate. If you add all four using the top of the range, you get far more than 100%. 

Leave a Reply