Do Breast Cancers With A Low Level Of Estrogen Receptors Behave More Like The More Aggressive Triple-negative Cancers?
In 1896 Sir George Thomas Beatson discovered that breast cancer in some women responded favorably when the women had their ovaries removed. It wasn’t until the 1970s that Elwood Jensen discovered what we now call the estrogen receptor. These receptors sit on the surface of a cancer cell. When they bind to estrogen, they enter the nucleus of the cell, interact with DNA, and result in cancer cell growth. As we became capable of measuring how much cancer was rich in estrogen receptors, our ability to predict whose cancer would react favorably to a host of anti-estrogen treatments i.e., tamoxifen, aromatase inhibitors such as Arimidex® (anastrozole), and Femara® (letrozole), and Aromasin® (exemestane).
Early in the days of estrogen receptor measurements, studies suggested that any number of cells (as low as 1%) carrying the estrogen receptor (ER) were considered positive and considered for antiestrogen therapy. More recent studies now call these findings into question. Most breast cancers are either strongly ER-positive or ER-negative (such as triple-negative). Breast tumors in which only 1-10% of cancer cells carry the estrogen receptor are called ER-low tumors. Only about 5% of breast cancers are ER-low.
As a rule, tumors that are ER-positive tend to be less aggressive and respond to antiestrogen therapy than ER-negative tumors, which tend to be more aggressive and not respond to antiestrogen therapy. One large study found that 62% of ER-low tumors behaved like triple-negative tumors while 30% were found to carry the HER-2 gene which is usually associated with more aggressive ER-negative tumors. Another study confirmed that only about 8% of ER-low tumors behave like ER-positive tumors. The other hormone receptor measured routinely in breast cancers is the progesterone receptor (PR). One group of researchers found that 70-90% of ER-positive tumors carried the PR whereas a positive test for PR was found in only 30-50% in the low-ER group. They also found, as alluded to above, that HER-2 positive tumors went from 10-14% in the high-ER tumors to 24-28% in the low-ER group.
Response to endocrine (anti-estrogen) therapy and survival
Comparing low-ER tumors to others would be meaningless if there was no impact on therapy. One study of nearly 10,000 patients found that the ER-high positive group had substantially better survival than ER-low positive patients. However, when the authors examined studies comparing ER-low tumors with ER-negative tumors they found no difference in survival! A second study of 16,000 patients confirmed that patients with ER-low tumors had poor responses to endocrine (anti-estrogen) therapy.
Which antiestrogen therapy is optimal, and for how long?
One potential approach which has been backed up by preclinical studies showed that three years of low-dose tamoxifen could have the recurrence rate of certain breast tumors with very limited toxicity. One might consider this potential approach to patients with ER-low tumors. As you likely know, postmenopausal women can use either aromatase inhibitors or tamoxifen as treatment for breast cancer. This does not apply however to premenopausal women who are largely limited to drugs like tamoxifen. Large clinical trials have shown that aromatase inhibitor drugs or more effective in improving survival when compared to tamoxifen. It may also be true, that those aromatase inhibitors may have an advantage over tamoxifen in patients with ER-low tumors.
Other potential therapeutic approaches
Based on all this data, ER-low breast cancers appear comparable to ER-negative tumors. We have known for some time that many patients, that carry one of the commonly inherited breast cancer genes (BRCA1, BRCA2) are found to be triple-negative (ER-negative, PR-negative, and HER-2 negative). The group of patients who test negative for an inherited breast cancer gene but nonetheless are found to be triple-negative has been called a BRCAness. Patients who inherit one of the BRCA2 genes may be susceptible to treatment by a new class of drugs called PARP inhibitors. It may therefore be the case that patients with ER-low tumors may similarly respond to treatment by PARP inhibitors. Clinical trials are now ongoing.
Another new class of drugs called CDK4/6 inhibitors has been shown to be effective in conjunction with endocrine therapy as a first-line treatment after surgery for ER-positive, HER-2 negative breast cancers. One of these CDK4/6 inhibitors, Abemaciclib (Kisqali®) appears particularly effective. In one of the clinical trials, this drug scene particularly effective in patients with PR-low and high-grade aggressive tumors, not dissimilar to ER-low breast cancer.
Finally, one of the newer approaches to aggressive triple-negative breast cancers is the use of a form of immunotherapy called checkpoint inhibitors. Researchers suggest that there may be some important and meaningful clinical activity using this new class of drugs and ER-low cancers.
Clinical suggestions for ER-low breast cancers.
- Researchers suggest that patients with ER-low breast cancers undergo tumor molecular testing i.e., Oncotype Dx or MammaPrint, to look for estrogen sensitivity on a molecular or genetic level.
- “Although low ER expression has a less favorable prognosis and less benefit from endocrine therapy than tumors with higher ER expression levels, there was a consensus that endocrine therapy (anti-estrogen) should still be recommended for patients with estrogen receptor levels greater than 1%.”
- Adjuvant chemotherapy should continue to play an important role for this subgroup of patients that are axillary lymph node-positive or have other indications for adjuvant therapy.
- The use of the CDK inhibitors, particularly abemaciclib, appears promising.
- One might consider, particularly in a clinical trial setting, a shortened course of endocrine therapy such as the need to extend therapy beyond five years.
Dr. Alan Stolier, MD, FACS, clinical breast oncologist, shares his expert medical perspective with a series of educational and scientific articles.