Overview of Triple-Positive Breast Cancer

In triple-positive breast cancer, tumor growth is spurred by three things: estrogen receptors (ER), progesterone receptors (PgR), and a breast-cell protein called HER2. You may see it written as ER+, PgR+, HER2+.

Some controversy exists over triple-positive breast cancer being a distinctive subtype of the disease. Nevertheless, 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 healthcare provider 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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What Does 'Receptor Positive' Mean?

Normal breast cells have estrogen and human epidermal growth factor receptor 2, or 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 the hormone estrogen binds to estrogen receptors, it stimulates the growth of the cell. The same is true with progesterone. With HER2, growth factors bind to this receptor to stimulate growth.

With triple-positive breast cancer, all of these are at play. This may affect the treatment and prognosis of these breast cancers.

Prevalence

It's thought that roughly 20% to 25% of breast cancers are HER2-positive, though the range is 15% to 30% in some studies. Roughly 70% of breast cancers are estrogen-receptor, or ER, positive, with most of these being progesterone-receptor-positive as well.

Of cancers that are HER2-positive, around 50% are also ER-positive, although the ER expression, may be at lower levels.

Overall, roughly 10% of breast cancer tumors might 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-Positive

Breast cancers that are HER2-positive can vary significantly. In general, tumors that are HER2-positive tend to be:

• More aggressive
• Associated with lower survival rates
• Less responsive to hormonal therapy

HER2-positive tumors that are also ER-positive (triple-positive), however, may behave more like ER-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-Positive

Tumors that are triple-positive tend to be more aggressive than those that are ER-positive alone. Hormonal therapy may be less effective, and chemotherapy, at least with early-stage tumors, may also be less effective.

Triple-positive breast cancers are also more likely to have positive lymph nodes than those that are ER-positive alone. This may influence the triple-positive breast cancer symptoms experienced.

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 ER-positive or HER2-positive, with 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-positive tumors, some of these tumors bear similarities to triple-negative tumors. These include cancers that:

• Are more aggressive
• Occur in younger people
• Have higher tumor grades at diagnosis
• Pose a greater likelihood to recur both locally, regionally, and metastatically

Treatment Approaches

It would seem that tumors that are both ER- and HER2-positive would respond twice as well to treatment. Sadly, this isn't the case. For some tumors, using these two therapies together is less effective and may increase the risk of side effects.

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-positive/HER2-negative (luminal A) tumors. However, the reduced effectiveness of hormonal therapies has been noted as well. 

Cancers that are triple-positive may behave differently than would be expected based on HER2 or ER positivity alone. They may be affected by the relationship between these receptors, an interaction that's referred to 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 ER signaling (related to being ER-positive) 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 is thought that using the combination of HER2 therapy (for example, Herceptin) and hormonal therapy, such as Tamoxifen or Faslodex (fulvestrant), may restore some of the ER 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

In general, the behavior and response of triple-positive breast cancer tumors are similar to estrogen-positive/HER2-negative tumors. A retrospective study done from the California Cancer Registry looked at 123,780 cases of stages 1–3 primary invasive breast cancer in women.

The difference in 5-year survival between those with triple-positive tumors and those with estrogen-positive/HER2-negative tumors was less than 1% for stage 1 and 2.2% for stage 2. There was no statistically significant difference in 5-year survival between the two subtypes in stage 3.

That said, potential crosstalk between the HER2 and estrogen receptors may lead to resistance to both hormonal and HER2-directed treatments.

A Word From Verywell

There is uncertainty regarding 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.