Treatment Strategies Evolve With Increased Disease Specification in HER2+ Breast Cancer

Adrienne G. Waks, MD

Deciding whether to escalate or de-escalate therapy in patients with HER2-positive breast cancer requires a deep and developing understanding of patient characteristics, such as pathologic complete response (pCR) and the presence of residual disease, according to Adrienne G. Waks, MD.

Treatment goals in early breast cancer should include finding the least toxic therapies that still produce positive long-term responses and survival outcomes, Waks explained in a presentation on patient candidacy for escalation or de-escalation of HER2-directed therapy in the curative breast cancer setting, which she shared at the 21st Annual International Congress on the Future of Breast Cancer^® East.

“We already have a nice de-escalation standard in stage I disease,” Waks said. “We are also making progress in understanding whether we can further de-escalate for our patients with stage I disease who will do incredibly well in the long term with some amount of HER2-targeted therapy.”

In an interview with OncLive^®, Waks, an instructor in medicine at Harvard Medical School and the associate director of Clinical Research at Dana-Farber Cancer Institute, shared details from her presentation, highlighting clinical trials such as the phase 2 ADEPT trial (NCT04569747) that are studying emerging treatment escalation and de-escalation strategies in early stage HER2-positive breast cancer. She also elaborated on the future of immunotherapy in this setting and explained the significance of establishing biomarkers beyond pCR to help more patients receive effective, tailored therapies.

OncLive^®: What is important for colleagues to know about deciding when to escalate or de-escalate HER2-directed therapy in patients with breast cancer, and what research is helping to frame these decisions?

Waks: [In my presentation, I spoke about] the evolving and hopefully exciting strategies in how we manage and individualize treatment for early stage HER2-positive breast cancer, which includes stage I, II, and III disease that’s being treated in the curative setting. I focused separately on stage I disease and stage II and III disease, because we manage them separately.

The [phase 2] APT trial [NCT00542451], which has been around for [a decade] now, guides how we currently manage patients with standard-of-care [paclitaxel plus trastuzumab (Herceptin)], the TH regimen. That was 1 of the landmark de-escalation trials.

Now, there are many other exciting trials going on, such as the [phase 2] ATEMPT 2.0 trial [NCT04893109], which is building on the original [phase 2] ATEMPT trial [NCT01853748] with adjuvant ado-trastuzumab emtansine [T-DM1; Kadcyla]. I’m leading the ADEPT trial, which is looking at a completely chemotherapy-sparing regimen of subcutaneous trastuzumab, pertuzumab [Perjeta], [and hyaluronidase-zzxf (Phesgo)] combined with endocrine therapy for HER2-positive and hormone receptor [HR]–positive patients.

We will need to wait a couple of years to see the results [of these trials]. The question is: How low can we go? How little is still enough to maintain these excellent long-term outcomes that we see? That’s what’s exciting right now in stage I disease.

In stage II and III disease, we typically use much more treatment because these patients have a higher anatomic burden of disease. Much of what’s going on right now is promising, but we’ll need to wait to see the trial results come out.

The main idea is escalating or de-escalating based on response to a neoadjuvant regimen, such as a pCR-based de-escalation strategy. Although there are other ways that we can potentially de-escalate, many of the big trials right now are centered around de-escalating in the adjuvant setting after a patient achieves a pCR to an abbreviated neoadjuvant regimen. The [phase 2] CompassHER2-pCR [NCT04266249] and Decrescendo [NCT04675827] trials are looking at neoadjuvant [paclitaxel, trastuzumab, and pertuzumab], the THP regimen, and then de-escalating in the adjuvant setting for patients who have a pCR to [that regimen].

In the realm of escalation, patients who have residual disease at surgery after their neoadjuvant regimen will have a higher risk of relapse. This is especially true for patients with HR-negative disease, and not as true for patients with HR-positive disease. Part of what’s interesting and important in this realm of escalating after a non pCR is how we should be thinking differently about patients with HR-positive and HR-negative disease.

We have a number of interesting and hopefully promising escalation regimens that are being looked at in the adjuvant setting for those patients with residual disease, including trials like [the phase 3] CompassHER2 RD trial [NCT04457596], which will look at T-DM1 plus or minus tucatinib [Tukysa] for patients with residual disease. The [phase 3] DESTINY-Breast05 trial [NCT04622319] will compare T-DM1 with fam-trastuzumab deruxtecan-nxki [Enhertu] in patients with residual disease. And the [phase 3] Astefania trial [NCT04873362] is looking at adding atezolizumab [Tecentriq] to T-DM1 in patients with residual disease. Those are all big, randomized trials that are going to take a number of years to produce results but hopefully will yield some interesting results for the patients who are at higher risk of relapse.

This is an important area for biomarker research as well, because not all patients who have a pCR are going to be [the same]; a few of those patients are still going to relapse. Likewise, there are many patients with residual disease who will never have a relapse. Just escalating and de-escalating on the basis of pCR is going to be part of the battle, but probably not enough to serve all of our patients best.

There’s a lot of exciting biomarker work going on that we need to do an even better job of incorporating into these prospective trials. Many gene signatures are looking at markers like HER2 expression, estrogen receptor [ER] signaling, ESR1 expression, immune biomarkers, and immune activation signatures. Outside of pCR and non pCR, we can bring these biomarkers into the mix to help us understand who needs more treatment and who needs less treatment so we can achieve the best outcomes for everybody.

What are your thoughts on immunotherapy agents such as atezolizumab continuing to be explored in HER2-positive disease, even though immunotherapy in this population hasn’t been incredibly successful?

The results of the [phase 3] IMpassion050 trial [NCT03726879] disappointingly showed that atezolizumab did not add anything to pCR rates with chemotherapy plus a HER2-directed neoadjuvant regimen. We’ll have to wait for the event-free survival [EFS] data, but that [trial was] discouraging for immunotherapy and checkpoint blockade in the curative setting for HER2-positive disease. [These negative data were seen in] both in the intent-to-treat population and in the PD-L1–positive population.

The [phase 2] KATE3 trial [NCT04740918] is going on in the metastatic setting, a totally different setting, and is looking at T-DM1 plus or minus atezolizumab for patients with PD-L1–positive disease. [This study is] based on some suggestive results from the original [phase 2] KATE2 trial [NCT02924883] that implied a potential benefit to adding the checkpoint blockade for the PD-L1–positive subset of patients.

We’ll see what the EFS data show from IMpassion050, and then we’ll see what the KATE3 trial results show. What we’ll be doing with immune checkpoint blockade in HER2-positive disease is up in the air right now, both in the early and the later stage disease settings.

In addition to pCR as a current primary driving force behind de-escalated and escalated approaches, what other patient characteristics or features are being used to inform these treatment decisions?

Many exciting clinical trials are using the presence of pCR vs residual disease to help us decide how we escalate and de-escalate. However, some key data suggest that we should be thinking more broadly than that. The first and most obvious example is in HR-positive disease. pCR is probably a good biomarker in patients with HR-negative disease, However, in HR-positive disease, whether a patient has a pCR does not tie nearly as strongly to whether they’ll relapse in the future, so pCR probably is not as adequate of a marker in those patients.

There’s some exciting work being done in HER2-positive breast cancer with respect to gene signatures that could possibly be applied in the ER-positive or HR-positive subtype to help us understand who has a higher risk of relapse vs non-relapse. There have been some exciting data presented recently looking at RNA signatures. For example, PAM50 subtypes like luminal A certainly seem to have a lower risk of relapse long term, but that does not mean those patients are going to be more likely to have a pCR.

Likewise, at [the 2022 ASCO Annual Meeting], an interesting abstract looked at patients who have ER-positive disease but are luminal A vs patients who have high immune activation signatures. This research clearly showed how immune activation signatures can reveal patients who have a lower long-term relapse risk, specifically in ER-positive disease. It suggested that pCR isn’t meaningful in patients with HR-positive disease, and that rather, we need to be looking deeper into the gene expression to understand who may relapse and who may not.

RNA signatures may be an important [factor], beyond pCR, to help us understand who may do well and who may do less well in the long term. There’s an exciting biomarker being developed called HER2DX, which is an RNA expression–based assay combining markers [such as] HER2 expression, ER signaling, ESR1 expression, immune genes, and proliferation genes. HER2DX is being developed specifically as a biomarker in HER2-positive disease and is trying to tease apart who will have a pCR and, more importantly, who has a higher or lower risk of relapse in the long term. There’s a lot of interesting development going on around RNA signatures that will help us refine this more.

Another tool that is early in development, but which might be interesting to us, is circulating tumor DNA [ctDNA]. Looking at patients who have a pCR and who also clear their ctDNA could be interesting and promising for helping us de-escalate therapy. [We could] note the point at which they clear their ctDNA and which step of their neoadjuvant or adjuvant therapy [they were on at the time]. To operationalize ctDNA, we’ll have to make those results available quickly so that they can be clinically useful. This is a work in progress that has much promise.

There’s also the idea of using tools like a response on a positron emission tomography [PET] scan, which is what the [phase 2] PHERGain trial [NCT03161353] did. This trial limited the category of responders to [trastuzumab plus pertuzumab] to patients in whom they saw a certain level of response on a PET scan. This was an interesting idea and gave the investigators increased confidence in de-escalating among that subset of patients. In addition to biomarkers, these imaging-based approaches and the ctDNA approach will hopefully help us move beyond pCR.