An Overview of Triple-Positive Breast Cancer

When Your Breast Cancer is Estrogen-, Progesterone-, and HER2-Positive

It’s not uncommon for breast cancer to be estrogen-receptor-positive (ER+), progesterone-receptor-positive (PgR+), and HER2/neu-positive (HER2+)—what's referred to as triple-positive breast cancer. While there is some controversy over triple-positive breast cancer being a distinctive subtype of the disease, these cancers appear to act differently than other breast cancers with regard to both cell behavior and the response to treatment.

Knowing the hormone receptor status of your tumor is imperative, because it helps you and your doctor make the best decisions about your treatment course. With triple-positive breast cancer, however, this is often more complicated than it may seem.

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Tumor Behavior

Normal breast cells have estrogen and human epidermal growth factor receptor 2 (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 this overproduction.

When estrogen binds to estrogen receptors, it stimulates the growth of the cell. With HER2, it is growth factors that bind to the receptor to stimulate growth.

With triple-positive breast cancer, both are at play.

Prevalence

It's thought that roughly 20 percent to 25 percent of breast cancers (15 percent to 30 percent in some studies) are HER2-positive. Roughly 70 percent of breast cancers are estrogen-receptor-positive, most of these being progesterone-receptor-positive as well.

Of cancers that 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.

Triple-Positive vs. HER2+

Breast cancers that 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 that are also estrogen-receptor-positive (triple-positive), however, may behave more like estrogen-receptor-positive tumors and HER2-negative tumors, being less aggressive and more responsive to hormonal treatment.

There are similarities between triple-positive and triple-negative breast cancer as well.

Triple-Positive vs. ER+

Tumors that 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-positive 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 triple-positive breast cancer would offer the best prognosis, followed by tumors that are estrogen-receptor-positive or HER2-positive, and triple-negative tumors having the worst outcomes. However, that doesn't appear to be the case. While some triple-positive tumors act more like ER+ tumors, some of these tumors bare similarities to triple-negative tumors in that they are more aggressive, occur in younger people, have higher tumor grades at diagnosis, and pose a greater likelihood to recur both locally, regionally, and metastatically.

Treatment Approaches

It would seem that tumors that are both estrogen-receptor and HER2-positive would respond twice as well to treatment. Sadly, this isn't the case. For some tumors, using these two therapies together may cause over treatment 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 that behave more like ER+/HER2 neg (luminal A) tumors.

But the reduced effectiveness of hormonal therapies has been noted as well. 

Issues With Resistance

Cancers that 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 responses to hormonal therapy or HER2-targeted therapy aren't always what one may 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 that 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 on this, 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/HER2-negative tumors, suggesting a good prognosis.

That said, potential crosstalk between the HER2 and estrogen receptors may lead 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 white/non-Hispanic women to Hispanic and Asian women, Asian and Pacific Islanders were found to have lower mortality than white/non-Hispanic women with triple-positive tumors.

A Word From Verywell

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, the potential for decreased response to drugs that target one type is a concern. Further research is needed to look for answers, as well as ways to reduce the crosstalk that leads to resistance.

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