Pathologic Complete Responses Can Help Inform Therapy De-escalation in Early-Stage, HER2+ Breast Cancer

Naomi Dempsey, MD

The de-escalation of therapy can be a viable option for patients with early-stage, HER2-positive breast cancer. By evaluating pathological complete responses (pCRs) as a meaningful end point for these patients, oncologists could determine which patients should continue with less therapy vs those who experience residual invasive disease and need to continue treatment, according to Naomi Dempsey, MD.

Data from the phase 3 KATHERINE trial (NCT01772472) established 14 cycles of adjuvant trastuzumab emtansine (T-DM1; Kadcyla) as the standard of care for patients with early-stage, HER2-positive breast cancer who do not achieve a pCR. Although the primary end point in KATHERINE was invasive disease-free survival (iDFS), more recent clinical trials have used pCR as a primary end point to give investigators an earlier picture of the efficacy of treatments for these patients.

“We know that not every patient with early-stage, HER2-positive breast cancer is the same. We are learning where we can de-escalate therapy and do less, and which patients are at higher risk and need more [treatment],” Dempsey said. “That is an exciting place to be in, so that we are not over-treating patients and ensuring those who have higher-risk disease are getting more therapy.”

In an interview with OncLive^®, Dempsey, a hematologist/oncologist with the Lynn Cancer Institute at Boca Raton Regional Hospital, discussed the role of de-escalation therapy in early-stage, HER2-positive breast cancer and provided highlights from ongoing clinical trials in the space.

OncLive^®: What are the main considerations when discussing early-stage, HER2-positive breast cancer treatment?

Dempsey: Early-stage, HER2-positive breast cancer is an exciting area right now. We are moving the science forward to tailor our treatment for each patient. We know that not every patient with early-stage, HER2-positive breast cancer is the same. We are learning where we can de-escalate therapy and do less, and which patients are at higher risk and need more [treatment]. That is an exciting place to be in, so that we are not over-treating patients and ensuring those who have higher-risk disease are getting more therapy.

What is the difference between how physicians traditionally defined risk in this setting vs how that is done today?

Traditionally, when thinking about what kind of risk of breast cancer a patient has, it's been based on stage, [such as] thinking that stage I breast cancer is a lower risk, and maybe stage II and III are higher risk. We are learning more now about biology. Biology seems to trump stage in a lot of situations. An important way that we have learned to capture information on biology is by using pCR as a meaningful end point for our clinical trials.

[We are] using the neoadjuvant space to provide treatment, then evaluating if a patient achieved a pCR, defined as all the cancer in the surgical specimen having been killed as a result of the chemotherapy. This allows us to determine which patients had a good response and maybe need less therapy vs the patients who had residual invasive disease and need more therapy.

What escalation strategies are available for patients who do have residual disease?

For patients with early-stage. HER2-positive breast cancer who do not achieve a pCR after neoadjuvant chemotherapy, the current standard of care is 14 cycles of adjuvant T-DM1, as seen in the KATHERINE trial, which showed an impressive improvement in iDFS, compared with trastuzumab [Herceptin]. Therefore, that is our standard of care.

We have multiple exciting trials happening in this space, because patients who do not achieve a pCR have worse outcomes and require an escalation in care. One study is the phase 3 CompassHER2 RD trial [NCT04457596], which is open at the Lynn Cancer Institute in Boca Raton, Florida. This trial randomizes patients to receive tucatinib [Tukysa] or placebo in addition to T-DM1, with the hopes of improving iDFS and preventing a central nervous system recurrence, which is a devastating complication of HER2-positive breast cancer.

Another ongoing trial is the phase 3 DESTINY-Breast05 trial [NCT04622319], which randomizes patients with residual disease to either fam-trastuzumab deruxtecan-nxki [Enhertu] or T-DM1. We look forward to the results of both CompassHER2 RD and DESTINY-Breast05.

How has patient compliance been in this population, in your experience?

It is important to be up front with patients at the beginning of therapy about what they can expect for adverse effects [AEs] and to ensure them that we’re going to support them through [therapy]. We're going to monitor them closely and help them with the AEs.

In general, I’ve found that compliance is good. Our patients are motivated, and they want to do whatever they need to do to have the highest chance of cure. I found that in my current population, compliance is good. I previously worked in a public health-care setting and [factors such as work and family] can make it hard to come to all of the visits. This was common to hear. As breast oncologists, we need to be cognizant of our patient population.

If patients need to utilize more telehealth, we need to think of our patients as a whole person and not just a breast cancer. I try to work around those factors to make compliance the best that it can be and utilize our new Zoom world to offer telehealth to patients to help improve compliance.

What is the importance of using pCR as a meaningful end point in clinical trials?

The adoption of pCR as a meaning clinical trial end point has been important for the field of HER2-positive breast cancer. There had been previous concerns about if pCR would equate to the more traditional clinically meaningful end points, such as overall survival, progression-free survival, or event free survival. Several studies have shown that there is a correlation between pCR and our traditional meaningful end points.

This has allowed clinical trials to provide data sooner, since a primary end point of pCR will be reached much sooner than 1 of the other trial end points. Meanwhile, our patients are in need of better treatments, and this information of pCR allows us to triage which patient needs more and which patient does not mean more [treatment]. Overtreatment is something that the world of breast oncology has been trying in earnest to eliminate. Evaluating pCR, particularly among patients with HER2-positive breast cancer, is an exciting way to ensure that we're tailoring our treatment to the patient.