For women with early-stage estrogen-receptor positive breast cancer, adjuvant endocrine therapy is known to decrease the likelihood of recurrence and improve survival, while omitting the therapy is associated with a higher risk of death.
For that reason, current guidelines, including those from the National Comprehensive Cancer Network, recommend adjuvant endocrine therapy (AET) for patients with estrogen-receptor positive (ER+) breast cancers.
But these and other guidelines do not make recommendations for a class of tumors deemed estrogen receptor low positive, often referred to as “ER-low,” a category in which ER is seen expressed in between 1% and 10% of cells. This is because benefits of endocrine therapy have not been demonstrated in patients with ER-low disease.
The findings showed that omitting endocrine therapy after surgery and chemotherapy was associated with a 25% higher chance of death within 3 years in ER-low patients.
Endocrine therapy, the investigators say, should therefore be offered to all patients with ER-low cancers, at least until it can be determined which subgroups are most likely to benefit.
How Was the Study Conducted?
Grace M. Choong, MD, of the Mayo Clinic in Rochester, Minnesota, and her colleagues, looked at 2018-2020 data from the National Cancer Database for more than 350,000 female patients with stages 1-3, ER+ breast cancer. From among these they identified about 7000 patients with ER-low cancers who had undergone adjuvant or neoadjuvant chemotherapy.
“We specifically wanted to focus on those treated with chemotherapy as these patients have a higher risk of recurrence in our short interval follow-up,” Dr. Choong said during her presentation.
Patients’ median age was 55 years, and three-quarters of them were White. Their tumors were more likely to be HER2-negative (65%), PR-negative (73%), have higher Ki-67 expression, and have a higher clinical stage (73% grade III).
Forty-two percent of patients did not undergo AET as part of their treatment regimen, with various tumor factors seen associated with AET omission. At a median 3 years of follow-up, 586 patients had died. After the researchers controlled for age, comorbidities, year of diagnosis, tumor factors, and pathologic stage, the effect of omitting AET still resulted in significantly worse survival: (HR 1.25, 95% CI: 1.05-1.48, P = .01).
Mortality was driven by patients with residual disease after neoadjuvant chemotherapy, who comprised nearly half the study cohort. In these patients, omission of endocrine therapy was associated with a 27% higher risk of death (HR 1.27, 1.10-1.58). However, for those with a complete pathological response following chemotherapy, omission of endocrine therapy was not associated with a higher risk of death (HR 1.06; 0.62-1.80).
The investigators noted several limitations of their study, including a retrospective design and no information available on recurrence or the duration of endocrine therapy.
Why Is Endocrine Therapy So Frequently Omitted in This Patient Group?
Matthew P. Goetz, MD, of the Mayo Clinic, the study’s corresponding author, said in an interview that in Sweden, for example, ER-low patients are explicitly not offered endocrine therapy based on Swedish guidelines.
In other settings, he said, it is unclear what is happening.
“Are patients refusing it? Do physicians not even offer it because they think there is no value? We do not have that granular detail, but our data right now suggests a physician should be having this conversation with patients,” he said.
Which ER-Low Patients Are Likely To Benefit?
The findings apply mostly to patients with residual disease after chemotherapy, and underlying biological factors are likely the reason, Dr. Goetz said.
ER-low patients are a heterogeneous group, he explained.
“In genomic profiling, where we look at the underlying biology of these cancers, most of the ER-low cancers are considered the basal subtype of triple negative breast cancer. Those patients should have absolutely zero benefit from endocrine therapy. But there is another group, referred to as the luminal group, which comprises anywhere from 20% to 30% of the ER-low patients.”
Dr. Goetz said he expects to find that this latter group are the patients benefiting from endocrine therapy when they have residual disease.
“We are not yet at the point of saying to patients, ‘you have residual disease after chemotherapy. Let’s check your tumor to see if it is the basal or luminal subtype.’ But that is something that we are planning to look into. What is most important right now is that clinicians be aware of these data, and that there is a suggestion that omitting endocrine therapy may have detrimental effects on survival in this subgroup of patients.”
Are the Findings Compelling Enough To Change Clinical Practice Right Away?
In an interview about the findings, Eric Winer, MD, of the Yale Cancer Center in New Haven, Connecticut, cautioned that due to the retrospective study design, “we don’t know how doctors made decisions about who got endocrine therapy and who didn’t.”
The patients with the worst tumors tended not to get endocrine therapy, Dr. Winer noted, and despite attempts to adjust for this, “in any large data set like this, unlike in a randomized trial, you just can’t control for all the bias.”
What Should Doctors Tell Patients?
“In the setting of significant side effects from endocrine therapy, we’re still less certain about the benefits of endocrine therapy here than in somebody with an ER-high tumor,” Dr. Winer cautioned.
Nonetheless, he said, the new findings certainly suggest that there may be a benefit for endocrine therapy in patients with ER-low tumors, and doctors should make this known to patients. “It may not be the strongest evidence, but it’s evidence,” he said. “This is very much a question to be raised between the doctor and the patient.”
Dr. Choong and colleagues’ study was funded by a Mayo Clinic Breast Cancer SPORE grant. Dr. Goetz reported consulting fees and research support from pharmaceutical manufacturers, including AstraZeneca, Pfizer, Lilly, and Novartis. Dr. Choong and Dr. Winer reported no financial conflicts of interest.