Complete pathological responses may help inform treatment de-escalation in early stages of HER2+ breast cancer
De-escalation of treatment may be a viable option for patients with early-stage HER2-positive breast cancer. By evaluating pathological complete responses (pCRs) as a meaningful endpoint for these patients, oncologists could determine which patients should continue with less treatment versus those who have 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 therapy with trastuzumab emtansine (T-DM1; Kadcyla) as the standard of care for patients with HER2-positive breast cancer at a early stage who do not get pCR. Although the primary endpoint of KATHERINE has been invasive disease-free survival (iDFS), more recent clinical trials have used pCR as the primary endpoint to give researchers an earlier picture of the effectiveness of treatments. for these patients.
“We know that not all patients with HER2-positive early breast cancer are the same. We learn where we can de-escalate therapy and do less, and which patients are at higher risk and need more [treatment]”, Dempsey said. “It’s an exciting place to be, so that we don’t over-treat patients and ensure that those with high-risk disease get more therapy.”
In an interview with Live®Dempsey, hematologist/oncologist at 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.
Live®: What are the key considerations when discussing treatment for HER2-positive early-stage breast cancer?
Dempsey: HER2-positive early breast cancer is an exciting area right now. We advance science to tailor our treatment to each patient. We know that not all patients with HER2-positive early breast cancer are the same. We learn where we can de-escalate therapy and do less, and which patients are at higher risk and need more [treatment]. It’s an exciting place to be, so as not to over-treat patients and to ensure that those with higher-risk disease receive more therapy.
What is the difference between how physicians traditionally define risk in this context and how it is done today?
Traditionally, when thinking about a patient’s type of breast cancer risk, it is based on stage, [such as] thinking stage I breast cancer is lower risk, and maybe stage II and III are higher risk. We are learning more now about biology. Biology seems to take center stage in many situations. An important way we have learned to capture information about biology is to use pCR as a meaningful endpoint for our clinical trials.
[We are] use the neoadjuvant space to provide treatment, then assess whether a patient has achieved pCR, defined as all cancer in the operative specimen that has been killed as a result of chemotherapy. This allows us to determine which patients had a good response and may need less treatment compared to patients who had residual invasive disease and need more treatment.
What escalation strategies are available for patients who have residual disease?
For early stage patients. HER2-positive breast cancer that does not reach pCR after neoadjuvant chemotherapy, the current standard of care is 14 cycles of adjuvant T-DM1, as seen in the KATHERINE trial, which showed improvement impressive iDFS, compared to trastuzumab [Herceptin]. So that’s our standard of care.
We have several exciting trials underway in this space, as patients who do not achieve pCR have poorer outcomes and require escalation of care. One study is the Phase 3 CompassHER2 RD trial [NCT04457596], which is opened at the Lynn Cancer Institute in Boca Raton, Florida. This trial randomizes patients to receive tucatinib [Tukysa] or placebo in addition to T-DM1, in hopes of improving iDFS and preventing central nervous system recurrence, which is a devastating complication of HER2-positive breast cancer.
Another ongoing trial is the DESTINY-Breast05 Phase 3 trial. [NCT04622319]which randomizes patients with residual disease to fam-trastuzumab deruxtecan-nxki [Enhertu] or T-DM1. We eagerly await the results of CompassHER2 RD and DESTINY-Breast05.
How has patient compliance been in this population, in your experience?
It is important to be upfront with patients at the start of treatment about what to expect in the event of side effects. [AEs] and to assure them that we will support them through [therapy]. We will be watching them closely and helping them with AEs.
In general, I found compliance to be good. Our patients are motivated and want to do whatever they need to do to have the best chance of recovery. I have found that in my current population compliance is good. Previously, I worked in a public health facility and [factors such as work and family] may make it difficult to access all tours. It was common to hear. As breast oncologists, we need to be aware of our patient population.
If patients need to use telehealth more, we need to see our patients as whole people and not just breast cancer. I try to circumvent these factors to make compliance as best as possible and use our new Zoom world to offer telehealth to patients to improve compliance.
Why is it important to use pCR as a meaningful endpoint in clinical trials?
The adoption of pCR as a meaningful clinical trial endpoint has been significant for the field of HER2-positive breast cancer. There had been previous concerns about whether pCR would match more traditional clinically meaningful endpoints, 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 significant endpoints.
This has allowed clinical trials to provide data sooner, since a primary pCR endpoint will be reached much sooner than any of the other trial endpoints. Meanwhile, our patients need better treatments, and this information from pCR allows us to sort out which patient needs more and which patient means no more. [treatment]. Overtreatment is something the breast oncology world is trying hard to eliminate. Assessing pCR, especially in patients with HER2-positive breast cancer, is an exciting way to ensure that we are tailoring our treatment to the patient.