O'Regan Assesses Treatment Courses and Durations in Early-Stage HR+ Breast Cancer

Ruth O'Regan, MD

There are several genomic assays and corresponding data sets that physicians can use to assess the risk of recurrence for a patient with early-stage hormone receptor (HR)—positive, HER2-negative breast cancer and their need for chemotherapy or endocrine therapy alone.

However, because a lot of these data fall short in terms of extended endocrine therapy and patients with node-positive disease, physicians should err on the side of caution when it comes to higher-risk patients until those results read out, explained Ruth O’Regan, MD.

“The use of genomic subtyping in early-stage estrogen receptor (ER)—positive breast cancer has really allowed us to make much more robust decisions for our patients. We've made huge strides in avoiding chemotherapy for patients with early-stage ER-positive breast cancer,” said O’Regan. “The remaining questions are, ‘How do we manage patients with node-positive disease? For premenopausal patients, can we get away with ovarian suppression rather than chemotherapy? Who are the patients who need longer durations of endocrine therapy?’”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Breast Cancer, O’Regan, a professor of medicine, Hematology/Oncology Division, at University of Wisconsin School of Medicine and Public Health and Carbone Cancer Center, discussed current approaches to treatment escalation and de-escalation, as well as the use of retrospective molecular profiling, which may help address some unanswered questions in the field.

OncLive^®: What are the current escalation and de-escalation approaches that can be applied to practice in early-stage, HR-positive/HER2-negative breast cancer?

O'Regan: The TAILORx study, which prospectively looked at the 21-gene recurrence score, showed that patients with a score of up to 25 derived no benefit from chemotherapy. That is a huge advance. However, investigators did notice that women under the age of 50 experienced some benefit from chemotherapy, particularly when their scores were between 16 and 25. The higher the score, the greater the benefit with chemotherapy for those patients. The question is, “Do all those patients really need chemotherapy, or could some of those patients get away with ovarian suppression, given that only 15% of patients in the TAILORx study got ovarian suppression?” That may be another way to potentially de-escalate therapy for patients. Overall, it's a huge advance for patients with node-negative disease to be able to avoid chemotherapy.

Furthermore, an analysis from the SOFT and TEXT trials supports the use of ovarian suppression in these patients. The analysis showed that if you use what's called a composite risk score, which is kind of like a 21-gene recurrence score. You're able to risk stratify patients who need ovarian suppression with endocrine therapy versus endocrine therapy alone. Some of the molecular profiling from the SOFT and TEXT trials will be very useful in determining which patients need ovarian suppression.

Next, what do you do for patients with node-positive disease? There are some prospective data from the MINDACT study showing that you can predict prognosis for patients with N1 disease using the 70-gene signature. However, it didn’t tell us who needed chemotherapy. There are some retrospective data with the 21-gene recurrence score indicating, just as what was seen in the MINDACT study, that patients who have a low 21-gene recurrence score also have a very good prognosis and may not need chemotherapy. The data from the RxPONDER study will give us a definitive way to look at that.

The other question for early-stage, ER-positive disease is how long patients need treatment. There are pretty robust data saying that 10 years of tamoxifen is superior to 5 years of tamoxifen. The data are much murkier when you look at aromatase inhibitors (AIs). This is a very important question because we know there are patients who have late recurrences. If we knew who these patients were, we could focus on optimizing therapy with longer or perhaps more aggressive therapy upfront with the addition of ovarian suppression, or perhaps with the addition of some of the newer agents, like CDK inhibitors. There is a lot of work to be looked at in that setting as well.

Extended therapy is another important area because we know there is increased toxicity with longer therapy. There are some data with molecular profiling that may be able to help us move forward in determining which patients need longer treatment. There are 6 different assays that are being looked at in that setting.

What other types of analyses have been done regarding TAILORx since the main findings were reported at the 2018 ASCO Annual Meeting?

The main question is, “What is going to pan out with longer follow-up?” We know that the very low-risk cancers, the cancers with recurrence scores less than 10, have an incredibly favored prognosis of at least 9 years—with recurrences in the range of 3% at distant sites. We want to see if that's been changed with longer follow-up, as these ER-positive breast cancers can recur indefinitely. Following those data will be very important.

Other things to look at that might be interesting are what type of chemotherapy patients with high recurrence scores received as a to determine who needs an anthracycline versus who can get away with a taxane-based regimen.

The other big thing is the RxPONDER study, in which patients with a recurrence score less than 25 and with 1 to 3 positive lymph nodes are randomized to endocrine therapy alone or endocrine therapy plus chemotherapy. That data are going to be very important, because then we can extrapolate the data from the 21-gene recurrence score to patients with node-positive disease. However, it does beg the question that, “If we don't see any benefit in patients with N1 disease and a recurrence score up to 25, will it have any benefit in patients with N2 disease or N3 disease?” These are all things that we're going to have to look at going forward.

Will CDK4/6 inhibitors take on a role in the early-stage setting? Will they eventually phase out chemotherapy?

That is a key question. The problem with ER-positive breast cancers is that even the ones that have high recurrence scores don't get much benefit from chemotherapy. If you look at the preoperative setting, only a minority of patients with recurrence scores above 25 who receive chemotherapy achieve a pathologic complete response (pCR). We know pCR is important for luminal B cancers—or high recurrence score cancers. The problem with that is that there is a majority of patients who are not benefitting from chemotherapy; that will be the group for which we'd really like to be able to incorporate CDK4/6 inhibitors into treatment.

Some of the adjuvant studies are risk stratifying for these higher-risk cancers. That's going to be the way forward, by taking what's been successful in the metastatic setting, both the CDK4/6 inhibitors and the mTOR inhibitors, such as everolimus (Afinitor) and I would presume that we may also see some adjuvant studies with the PI3K inhibitors as well.

Both the mTOR inhibitors and the PI3K inhibitors appear to work in hormone-refractory disease, which is essentially what luminal B cancers are. We can’t forget to look at those agents in that setting as well. The lower-risk cancers that do well with endocrine therapy may not justify the addition of either CDK4/6 inhibitors or some of the other targeted agents, given the added toxicity and also the cost of the agents. Ultimately, we don't know, but the adjuvant studies and all that data will be looked at very closely.

Are any trials examining whether extended therapy with AIs is beneficial?

We have seen a lot of trials looking at that question already. The largest one is the NSABP-B14 study, which compared 10 years of an AI with 5 years. Although it showed a benefit, it was mainly restricted to contralateral breast cancers. It's unclear if that justifies the added toxicity of the 10 years of therapy. The NCIC CTG MA.17 re-randomization study also showed a benefit of extending AIs out to 10 years. Again, the benefit was primarily restricted to contralateral breast cancers.

The bottom line is that there are not clear data to support doing it. That said, if you have a very high-risk patient, I would keep them on an AI because there could potentially be a benefit. It's unlikely that we'll see another big adjuvant study trying to address this question. Molecular profiling on the existing studies may be helpful in determining which patients may benefit from the longer duration of therapy. I know several companies are looking at doing molecular profiling on the NSABP-B14 study because they always have tissue available; that would be an ideal trial to look at.