Triple Positive Breast Cancer: When Your Tumor Is ER+, PG+, and HER2+

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You’ve probably heard about estrogen receptor-positive breast cancer and HER2 positive breast cancer. You may have also heard about triple negative breast cancer. But what is triple positive breast cancer?

It’s not uncommon for a breast cancer to be estrogen receptor positive (ER+), progesterone receptor positive (PgR+), and HER2/neu positive (HER2+). How are these triple positive breast cancers different from other subtypes of breast cancer with regard to both the behavior of the tumor and treatments that work best?

What else should you know and what is the prognosis?

Definition

The term “triple positive breast cancer” is unfamiliar to many people. In fact, some may think it is a typo and that we are really thinking about triple negative breast cancer.

This is because studies on "triple positive" breast cancer are fairly new on the scene, even though triple positive tumors appear to be a distinct subtype of breast cancer. On testing, these tumors are found to be ER+, PgR+, and HER2/neu+.

With both estrogen receptor and HER2 positive breast cancers, there are protein receptors on the surface of the breast cancer cells which are responsible for driving the growth of the cancer. Normal breast cells have estrogen and HER2 receptors. In the case of receptor-positive tumors, there are a significantly increased number of these receptors. A mutation or an increased number of genes (gene amplification) results in the production of more of these proteins.

When estrogen binds to estrogen receptors, it stimulates the growth of the cell. With HER2, it is growth factors which bind to the receptor to stimulate growth. In HER2 positive breast cancer cells, there are up to 100 times as many of these receptors as in normal breast cells.

While there is still some controversy over triple positive breast cancer being a distinctive subtype, these cancers appear to act differently with regard to both the behavior of the cancer and the response to treatment.

Overall, triple positive tumors tend to act most like estrogen receptor positive and HER2 negative tumors, although there are similarities between triple positive and triple negative breast cancer as well.

Triple Positive vs. HER2+

Breast cancers which are HER2 positive can vary significantly from each other. In general, tumors that are HER2 positive tend to be more aggressive, have lower survival rates, and do not often respond to hormonal therapy. HER2 positive tumors which are also estrogen receptor positive (triple positive) however, may behave more like estrogen receptor positive tumors and may be less aggressive in addition to responding to hormonal treatment.

To understand triple positive breast cancer more in depth, it may be helpful to look at some of the differences between HER2 positive and HER2 negative breast cancer.

Triple Positive vs. ER+

Tumors which are triple positive tend to be more aggressive than those that are ER+ alone. Hormonal therapy may be less effective, and chemotherapy, at least with early-stage tumors, may be less effective. Triple-negative breast cancers are also more likely to have positive lymph nodes than those that are estrogen receptor positive alone.

Triple Positive vs. Triple Negative

At first glance, it would seem that the prognosis of triple positive breast cancer would be highest, followed by tumors that are only estrogen receptor positive or HER2 positive, followed by tumors that are triple negative.

That doesn't seem to be the case and tumors which are triple positive share some characteristics with those which are triple negative. While some triple negative tumors act more like ER+ tumors, some of these tumors bare similarities to triple-negative tumors based on these tumors being aggressive, occurring at a younger age, having a higher tumor grade at diagnosis, and having a greater likelihood to recur both locally, regionally, and metastatically.

Prevalence

Triple positive breast cancer is not uncommon. It's thought that roughly 20 to 25 percent of breast cancers (15 to 30 percent in some studies) are HER2 positive. More common, roughly 70 percent of breast cancers are estrogen receptor positive, most of these being progesterone receptor positive as well.

Of cancers which are HER2 positive, around 50 percent are also estrogen receptor positive, although the estrogen receptor expression may be at lower levels. Overall, roughly 10 percent of tumors might, by deduction, be considered triple positive, though large-scale studies looking at the epidemiology are lacking. In addition, the degree of estrogen positivity can vary between these tumors.

Treatment Approaches

What breast cancer treatments work best for triple positive breast cancer?

It would seem that tumors that are both estrogen receptor and HER2 positive would respond twice as well to treatment. Shouldn't treatments for HER2 positive breast cancer that also impact estrogen receptors add up to a better prognosis than treatment for ER+ or HER2+ tumors alone?

Sadly, this isn't the case. For some tumors, using these two therapies together may cause overtreatment and increase the risk of side effects. But even when both treatments are indicated, they are less effective.

Studies looking at early breast cancers have found less benefit from HER2 targeted therapies when the level of both receptors is high. These are the tumors which behave more like ER+/HER2 neg (luminal A) tumors. But the reduced effectiveness of hormonal therapies has been noted as well. Why wouldn't this be the case, and why would it not be even more effective? To understand this we have to look at "crosstalk" between estrogen and HER2 receptors.

HER2/Estrogen Receptor Crosstalk

Cancers which are triple positive may behave differently than would be expected based on HER2 or estrogen receptor positivity alone and may be affected by the relationship between these receptors. This interaction between the receptors is referred to by researchers as "crosstalk."

The crosstalk between HER2 and ER may work to signal hormonal resistance. In other words, communication between the receptors (say HER2 and ER) may result in anti-estrogen therapy being less effective in triple positive tumors. In a similar fashion, activation of estrogen receptor signaling (related to being ER+) may result in resistance to HER2-targeted therapies. This could explain some of the variability in HER2 positive tumors, some of which respond much better than others to HER2 blocking drugs.

It may be this "crosstalk" that explains why we don't see the responses to hormonal therapy or HER2 targeted therapy we would expect.

It is thought that using the combination of HER2 therapy (for example, Herceptin) and hormonal therapy (such as Tamoxifen or Faslodex (fulvestrant)), however, may restore some of the estrogen receptor resistance to hormonal therapy.

In addition, some breast cancer chemotherapy regimens work better or worse for HER2 positive tumors. But while chemotherapy may be of less benefit with early-stage disease, it is of strong benefit in metastatic disease.

Metastatic Triple Positive Cancer

Metastatic triple positive breast cancer is usually treated differently from metastatic HER2 positive breast cancer. Unlike tumors which are HER2 positive alone, there appears to be a clear and significant survival benefit to using chemotherapy along with HER2 blocking therapy. This may be followed by hormonal therapy (such as an aromatase inhibitor).

Prognosis

Since there are few studies, it is hard to predict the prognosis for triple positive breast cancer. The behavior and response of many of these tumors are similar to estrogen positive but HER2 negative tumors, suggesting a good prognosis. That said, we've noted that there may be crosstalk between the HER2 and estrogen receptors which leads to resistance to both hormonal and HER2 directed treatments.

It appears that the prognosis may be better for women with triple-positive tumors who are postmenopausal. In one study comparing caucasian women to Hispanic and Asian women, Asian and Pacific Islanders were found to have a lower mortality than white/non-Hispanic women with triple positive tumors.

A Word From Verywell

Controversy remains over whether triple positive breast cancer is a distinct subtype of the disease, though both the behavior of these tumors as well as the response to treatment seems to indicate this is the case. Overall, these tumors tend to "act" most like estrogen receptor positive, HER2 negative tumors, but there are significant variations.

There is uncertainty over the best treatment approach for triple positive tumors, and it appears that there are different subsets based on the degree of expression of ER and more. In addition, there is likely crosstalk between the different types of receptors, which can lead to a decreased response to drugs that target one type. Further research is needed to look for answers, as well as ways to reduce the crosstalk which leads to resistance.

As with any type or subtype of breast cancer, it's important to educate yourself about your disease. Ask a lot of questions, learn how to research your cancer, and be your own advocate in your care. Becoming involved in a breast cancer support community can be very helpful, as this is a resource through which to not only gain support in your journey but to learn about the latest findings in treatment.

Sources:

Negi, P., Kingsley, P., Jain, K. et al. Survival of Triple Negative versus Triple Positive Breast Cancers: Comparison and Contrast. Asian Pacific Journal of Cancer Prevention. 2016. 17(8):3911-6.

Schott, A. Adjuvant Trastuzumab Benefit in Patients Diagnosed With Triple-Positive Breast Cancer. JAMA Oncology. 2016. 2(8):1047-8.

Vici, P., Pizzuti, L., Natoli, C. et al. Triple Positive Breast Cancer: A Distinct Subtype?. Cancer Treatment Reviews. 2015. 41(2):69-76.

Vici, P., Pizzuti, L., Sperduti, A. et al. ”Triple Positive” Early Breast Cancer: An Observational Multicenter Retrospective Analysis of Outcome. Oncotarget. 2016. 7(14):17932-17944.

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