O’Regan Weighs Escalation, De-Escalation Approaches in Early-Stage HER2+ Breast Cancer

Ruth O’Regan, MD

As the HER2-positive breast cancer paradigm continues to evolve, the challenge of determining when to escalate and de-escalate treatment, and for which patients, has become exceedingly more pronounced, according to Ruth O’Regan, MD, who added that several efforts are underway to provide much needed insight.

“The outcomes of [patients with] HER2-positive breast cancer have improved dramatically over the past 10 to 20 years,” said O’Regan. “Now, the real questions are: How do we manage individual patients? How can we tailor approaches so that patients receive the therapy that they need without being [overtreated]?”

Escalation is a reasonable approach for patients who are considered to be high risk, such as those with node-positive disease, according to O’Regan. Preoperative treatment is often used in patients who don't achieve a pathologic complete response (pCR); thus, escalation would be an appropriate in that setting, she added. For these patients, the use of adjuvant ado-trastuzumab emtansine (T-DM1; Kadcyla) rather than trastuzumab (Herceptin) alone or with pertuzumab (Perjeta) would be acceptable, according to O’Regan, based on data from the KATHERINE trial.

“Understanding when we can de-escalate therapy is another very important [challenge], particularly since these agents do have some toxicities, some of which are longer-term,” added O’Regan. To date, de-escalation is restricted to patients with stage I HER2-positive disease, where paclitaxel and trastuzumab is often used for 12 weeks followed by 1 year of trastuzumab, based on data from the APT trial, according to O’Regan.

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on Breast Cancer, O’Regan, professor and chief of the Division of Hematology, Medical Oncology and Palliative Care within the Department of Medicine and associate director of Clinical Research at the University of Wisconsin Carbone Cancer Center, further discussed the challenges faced with personalizing treatment in early-stage HER2-positive breast cancer.

OncLive®: Could you start by discussing the use of pertuzumab and the data from the APHINITY trial? In which patients and setting is the benefit of this agent most pronounced?

O’Regan: The phase 3 APHINITY trial examined the addition of pertuzumab to standard trastuzumab-based chemotherapy in patients with early-stage HER2-positive breast cancer. Previously, [this approach resulted in] a pretty modest difference in favor of pertuzumab; [the benefit] appeared to be restricted to patients with node-positive disease.

[We] recently [saw] updated [findings] that also included some survival data. [The regimen] really continues to show a fairly modest benefit [with] pertuzumab. This analysis was restricted to patients with node-positive disease. However, in contrast with [what was previously seen], there appeared to be benefit in both estrogen receptor (ER)–positive and ER-negative disease. Overall, when we use pertuzumab [in the] adjuvant [setting], most of us will restrict its use to those with node-positive disease.

[That being said], we use a lot of preoperative treatment, so it's unusual for us to have patients with node-positive disease who require adjuvant therapy. We do see it, but it's just not that common. For most of us, we would use [pertuzumab] preoperatively with trastuzumab-based chemotherapy. In the adjuvant setting, we would use [pertuzumab] in patients who have a pCR and were node positive before they started preoperative treatment.

Do you believe that the field is shifting away from the utilization of anthracyclines? Will that help to reduce the risk of cardiomyopathy and cardiac death in those receiving trastuzumab?

What we know from the original metastatic trial that was done for HER2-positive disease is that if you give trastuzumab with an anthracycline or after an anthracycline, there is a risk of drops in ejection fraction and even [the possibility of] heart failure. That was seen in the original adjuvant trials; the rate is about 3% to 4% for heart failure. However, this is obviously a very significant, long-term AE [associated with] this treatment.

We’re using anthracyclines less and less for HER2-positive, early-stage disease. This [shift] is supported by data examining non-anthracycline–based regimens. If you look in the preoperative setting, several trials have examined these regimens and have shown very high pCR rates with a minimal impact on the heart. I used to see drops in EF, but not actual heart failure, per se.

Overall, I personally don't use anthracyclines at all unless I have a patient [who may] have a heterogeneous cancer where some of the cells [have] HER2 [positivity] and some of them do not. I might consider [the use of] anthracyclines [for that patient], where you're treating as if they have ER-positive or triple-negative breast cancer. However, generally, apart from that, we very rarely use anthracyclines anymore.

[Based on] the BCIRG 006 study, there was a suggestion that for patients with 4 or more positive lymph nodes you should consider an anthracycline. However, more recent data have not shown that to be true; it appears that non-anthracycline–based regimens, such as docetaxel plus carboplatin and trastuzumab (TCH), or TCH plus pertuzumab, are just as effective as anthracycline-based regimens.

At least we can now tell our patients that they may [experience] a drop in EF but the likelihood of actually having heart failure is very low with these non-anthracycline–based regimens. Of course, we [continue to] monitor their EF while they receive HER2-directed therapy.

With all of the advances made in HER2-positive disease, understanding when it is appropriate to escalate versus de-escalate treatment is important. What is your approach for this?

Escalation is a reasonable approach for patients with high-risk cancers, such as those with node-positive breast cancer. We [often] use preoperative treatment in patients who don't have a pCR, so therapy escalation would be appropriate in that setting. If patients don't have a pCR, based on the KATHERINE study, we would use T-DM1 as their adjuvant treatment rather than just trastuzumab alone or with pertuzumab.

The other place where this [approach] comes in is with neratinib (Nerlynx), which is approved for [use as] extended therapy in HER2-positive disease. In patients who have completed trastuzumab, the use of neratinib has been shown to improve outcomes. Although the outcome is improved, [this benefit is] restricted to [those with] ER-positive, HER2-positive disease; it is not seen in ER-negative, HER2-positive disease. Those are the 2 areas are where escalation would be considered.

Neratinib has been shown to be effective in patients who did not achieve a pCR and are considered to be higher risk. The only caveat with using neratinib is that the exteNET study accrued patients who received trastuzumab, not T-DM1, so we don't really have any data in that setting. However, for someone who does not have a pCR and has an ER-positive breast cancer, using T-DM1 and then considering neratinib is completely reasonable.

De-escalation is currently restricted to [patients with] stage I HER2-positive breast cancer, where most of us would use paclitaxel and trastuzumab for 12 weeks followed by 1 year of trastuzumab, based on the APT trial. We also have some data from the ATEMPT trial showing that the use of T-DM1 in that setting is also reasonable, although it's not approved at this time point. Both of those are [considered to be] de-escalation [approaches] because you're using less chemotherapy in those settings.

However, the big question is: Are there patients where we don't need to give chemotherapy at all? If you look at some of the trials that have been done, you do get a pCR in a percentage of patients by using HER2-directed therapy and endocrine therapy at the same time—particularly if they have ER-positive disease. The trials have not been definitive, but overall, there are probably about 20% to 30% of patients [who experience benefit]—probably those with triple-positive breast cancers. [In these patients,] we can potentially get away [with not using] chemotherapy, but further research in this area is definitely warranted.

You mentioned the exteNET study. Could you expand on the key lessons learned from that research?

The exteNET study looked at extending HER2 therapy after patients have completed 1 year of trastuzumab. Investigators took patients who completed their year of trastuzumab and were considered to be high risk; these patients had node-positive disease or did not achieve a pCR after preoperative treatment. They were randomized to receive either placebo or neratinib with the addition of endocrine therapy if the cancer was ERpositive. [Results showed] a benefit for neratinib; however, if you look at the subgroup analysis, there was stratification based on ER positivity. The benefit [of the approach] was restricted to patients with ER-positive, HER2-positive breast cancer; no benefit was observed in those with ER-negative, HER2-positive disease.

In Europe, neratinib is only approved for [patients with] ER-positive disease. Some further exploratory analyses of that trial have shown that in patients who did not achieve a pCR and started neratinib within 1 year of finishing trastuzumab, there was an even more profound benefit with neratinib in the ER-positive subgroup. This is an important consideration for patients who do have high-risk, HER2-positive disease if it’s ER positive.

What are some of the key remaining challenges?

Determining what the best approach is for a patient. What I mean by that is, where do you need to escalate therapy and where can you de-escalate therapy? There's continued research ongoing to [address those questions]. For example, a very interesting trial looked at doing PET imaging after 2 cycles of HER2-directed therapy alone and then basically adding in chemotherapy if there a PET response was not observed. [Investigators continued] the non-chemotherapy regimen in patients who looked like they were responding to HER2-directed therapy.

Those kinds of approaches are going to be important because all the chemotherapy agents come with toxicities that can be significant. We would like to avoid chemotherapy if we could. De-escalation is very important, but [so is] knowing when to escalate therapy for patients to further improve outcomes.