Refining Risk-Adapted Therapy in ER+ Breast Cancer

Eleftherios (Terry) P. Mamounas, MD, MPH, FACS

The risk of recurrence for women with early-stage estrogen receptor (ER)–positive breast cancer remains stable 5 to 20 years after diagnosis, leading the field to develop, and now refine, tailored treatment strategies that take into account each patient’s clinical and genomic classifiers, said Eleftherios (Terry) P. Mamounas, MD, MPH, FACS.

“We have to better identify who is at risk [of recurrence] and who can benefit from [extended] therapy. Over the next few years, we’re going to work to refine these algorithms so we can give clinicians a way to calculate the magnitude of benefit the patient is expected to have,” said Mamounas. “Then, you can make a decision regarding whether to treat or not, taking into account how the patient tolerated the original endocrine therapy.”

In an interview with OncLive, Mamounas, medical director of the Comprehensive Breast Program at the University of Florida Health Cancer Center, discussed the risk of late recurrence in early breast cancer, current approaches to extended adjuvant endocrine therapy, and ongoing research evaluating assays aimed at capturing both the risk of late recurrence and benefit from extended endocrine therapy.

OncLive: What do we know about late recurrence in breast cancer?

Mamounas: In early-stage breast cancer, particularly for ER-positive early-stage breast cancer, the risk of recurrence is pretty stable over time, unlike, for example, triple-negative breast cancer, where the risk of recurrence peaks in the first 2 to 3 years. After 5 to 6 years, the risk of recurrence goes down to almost 0%. We can tell those patients that they’re probably out of the woods after 6 years. However, in ER­-positive breast cancer, several studies have shown that most of the recurrences and deaths occur after the first 5 years. Studies have shown that the rate of distant recurrence is very stable from year 5 to year 20. This depends, to some extent, on the original tumor presentation. Smaller tumors have less risk than larger tumors, and node-positive patients have more risk than node-negative patients. Even grade III tumors recur faster than grade I or II tumors.

In the trials that have been conducted after 2000, the rates appear to be a little lower because we’re doing a better job of treating and detecting the disease earlier. Now that we know late recurrence occurs at a steady state, the question becomes: What do you do in terms of intervention? For patients with ER-positive disease, we give endocrine therapy for 5 years. Then, we questioned whether we should extend endocrine therapy or switch the endocrine therapy from tamoxifen to an aromatase inhibitor (AI) or tamoxifen for 5 years versus tamoxifen for 10 years—even, an AI for 5 years versus 10 years. Now we have data to show that giving longer treatment appears to be more effective. Specifically, in terms of tamoxifen, switching from tamoxifen to an AI aromatase inhibitor, and extending the AI to 10 years or sometimes 7 to 8 years.

How do you determine whether to recommend extended adjuvant endocrine therapy?

We know extended adjuvant therapy works, and to what extent. For example, tamoxifen after tamoxifen or tamoxifen after an AI confers significant benefit. There’s a little bit less benefit with sequential AI administration. In general, all these studies have shown an overall small absolute benefit; it’s not a home run. It’s about a 4% to 7% absolute benefit in decreasing distant recurrence.

That means that 95% of patients probably don’t need the intervention because either they won’t recur without it or they will recur with it. We need to do a better job in identifying patients who actually need the additional treatment.

To do so, we looked at multiple strategies. Primary tumor characteristics are important. If a patient has a bigger tumor or positive nodes, their risk of recurrence is higher than a patient with a smaller, node-negative tumor of low grade. Clinical pathologic algorithms have been developed, one of which is the CTS5 calculator. [The calculator factors in] tumor size, nodal status, grade, and age of the patient. By putting those things together in an algorithm, you can predict what will happen after 5 years. Patients who are high risk are more likely to benefit more from endocrine therapy.

There’s also technology that can evaluate circulating tumor DNA that allows us to get insight on what’s going on in the blood several years after surgery. This has the potential to inform a patient’s residual risk of recurrence.

We are also evaluating genomic classifiers. Commercially available genomic assays have been developed to determine a patient’s risk of early recurrence and need for adjuvant chemotherapy. However, we have seen that some of these commercially available assays also predict risk of late recurrence from year 5 to year 15, even up to year 20. We can integrate these assays with our clinical pathologic algorithms to further refine these models.

We’re trying to identify predictors of [response to] extended endocrine therapy. A patient may be at high risk, but they may not [respond] to extended adjuvant endocrine therapy. The characteristics of the tumor at the time of surgery can predict possibly benefit from extended adjuvant endocrine therapy.

The Breast Cancer Index is another commercially available test. If the HOXB13/IL17BR ratio is high, the benefit from extended adjuvant endocrine therapy is higher. If the ratio is low, the benefit is essentially nonexistent. The test has been put through 3 randomized clinical trials and has consistently shown that if you have a higher ratio, you can identify populations that receive a lot of benefit from extended endocrine therapy and vice versa.

We’re evaluating this as part of a bigger protocol in the NSABP42 trial to see if we can further validate some of these findings. We’re looking not only at the risk of late recurrence, but also the prediction of benefit from extended endocrine therapy.

What is your take-home message for your colleagues?

Extended endocrine therapy works. It provides significant improvement in disease-free survival (DFS). There’s no real improvement in survival except for adjuvant tamoxifen that was shown in one trial. Most of the AI trials, extended AIs improve DFS and distant DFS but not overall survival.

Extended duration of adjuvant endocrine therapies have toxicities. Tamoxifen as well as AIs have arthralgias and myalgias. The AIs decrease bone mineral density. Also, there’s thromboembolic events for tamoxifen, arterial thrombotic events with AIs, osteoporotic fractures; a lot of things can happen. There’s also patient fatigue. Patients don’t want to take the drug forever. There are things, apart from toxicity, that you have to take into account.