Han Highlights the Need for Personalized Treatment in HER2+ Early-Stage Breast Cancer | OncLive

Han Highlights the Need for Personalized Treatment in HER2+ Early-Stage Breast Cancer

July 15, 2020

Heather Han, MD, discusses ongoing clinical trials within the field of HER2-positive breast cancer and the future of personalized treatment for this patient population.

The field of HER2-positive breast cancer has expanded immensely in recent years, with the FDA approvals of trastuzumab (Herceptin), pertuzumab (Perjeta), neratinib (Nerlynx), and ado-trastuzumab emtansine (T-DM1; Kadcyla), according to Heather Han, MD, who added that more work needs to be done to identify biomarkers and better personalize treatment.

Results from the phase 3 APHINITY trial demonstrated the benefit of adding pertuzumab to trastuzumab and chemotherapy in the adjuvant settingfor patients with operable HER2-positive breast cancer. The combination showed improvement in patients who were considered to be high-risk with lymph node–positive disease, which Han explained was the most important finding from the study. After 71.4 months of median follow-up, the 6-year overall survival (OS) rate with the combination was 94.8% (HR, 0.85; 95% CI, 0.67-1.07; P = .17).1

Another key trial in the space, the phase 3 KATHERINE study, enrolled patients with HER2-positive early breast cancer who did not respond to trastuzumab-based neoadjuvant chemotherapy. Patients were randomized to receive either adjuvant T-DM1 or trastuzumab. At the interim analysis, results showed that invasive disease-free survival (iDFS) was significantly higher with T-DM1 compared with trastuzumab (HR, 0.50; 95% CI, 0.39-0.64; P <.001). The estimated percentage of patients free of invasive disease at 3 years was 88.3% in the T-DM1 arm versus 77.0% in the trastuzumab arm.2

“If a patient achieved a pathologic complete response (pCR) following neoadjuvant therapy, they had an excellent outcome,” Han explained. “However, if a patient did not have a pCR, then they didn't do as well. We already knew that data; it's not perfect, but it's a very good, reasonable surrogate marker that we use in the clinical setting. Now, I can tell my patients that even though they did not have a pCR, we have this new treatment that they can receive [that is] well tolerated and that they will have a better prognosis following this treatment.”

In an interview with OncLive, as part of the virtual Institutional Perspectives in Cancer™ on Breast Cancer, Han, a medical oncologist and research director of Breast Oncology at Moffitt Cancer Center, further discussed ongoing clinical trials within the field of HER2-positive breast cancer and the future of personalized treatment for this patient population.

OncLive: Could you provide a brief overview of the current landscape of HER2+ breast cancer, beyond trastuzumab?

Han: In recent years, more therapies have been added to the early-stage HER2-positive breast cancer treatment paradigm to improve outcomes. Since trastuzumab was introduced in 1998, the outcomes of [patients with] HER2-positive breast cancer have improved significantly; however, we still have room for further improvement. We now have medications, such as pertuzumab, T-DM1, and neratinib, so more HER2-targeted therapies [are available]. We also have looked to see which patients can receive less therapy, because when more agents are added, even though these are targeted treatments and their overall toxicities are better than some of the conventional cytotoxic treatments, there are more toxicities. We [may be able to give] less therapy for a patient with lower risk, such as someone with early-stage or stage I breast cancer.

The field is moving toward stratifying specific patient risk groups, so we can individualize or personalize treatment based on their risk. Not every patient should receive the same intense therapy. We hope to be able to [better] individualize [treatment] in the near future. Obviously, we have to continue to work harder to find better biomarkers in order for us to be able to stratify the risk. Currently, the only biomarker we really have is the patient's stage at initial presentation; that is typically just tumor size and lymph node status. [Other factors] that we consider now is whether a patient has any residual tumor following neoadjuvant therapy and whether they received preoperative therapy. We will continue to work harder to find those better markers.

Focusing on therapy for high-risk disease, could you discuss the APHINITY trial and the updated data that have been reported?

What's promising is that the APHINITY trial continued to show us the benefit of adding pertuzumab to trastuzumab and chemotherapy in the adjuvant setting. The interim second analysis showed that, still, in terms of iDFS, the absolute benefit [was still there]. Actually, the degree of benefit was even higher than what we had been presented a few years ago. That's very encouraging.

Obviously, it is too early for us to see an OS benefit. As such, we will still need to continue to follow those patients for us to get better, longer, follow-up data down the road. We're eager to have these OS data in the future. What was [most] important was that the benefit was really for patients who are high risk, which is defined by lymph node–positive disease.

This trial continued to show us that the benefit was for patients who had positive lymph node status. For example, I wouldn't really routinely add pertuzumab in the adjuvant setting for a patient who has lymph node–negative disease.

You also discussed de-escalation for low-risk disease. How is adjuvant paclitaxel plus trastuzumab being used in this space?

[With regard to] the APT trial, we now have long-term, 7-year follow-up data that were published last year and showed that patients have excellent outcomes when they were treated with the minimum 12 weeks of paclitaxel and 1 year of trastuzumab treatment. This treatment was given to patients with low-risk, mostly stage 1 disease. We are currently using this treatment for patients who have stage 1 breast cancer when they clinically present. The patient would go for surgery first and then we will get a specific pathologic stage of that individual patient. If pathology still shows that the patient has early stage 1 breast cancer with the node negativity and a small tumor less than 2 centimeters, I would give this specific treatment for those patients using de-escalation instead of a stronger combination chemotherapy and more targeted HER2 therapy. Instead of that, we will use this [combination] for this patient because it is very well tolerated.

What are the data that have been reported with adjuvant T-DM1?

The KATHERINE study had a very smart design because instead of only including patients who have HER2-positive disease—that's what we traditionally used to do—they picked patients who were treated with neoadjuvant chemotherapy in combination with trastuzumab. Some of the patients also received pertuzumab after it was approved for use in the neoadjuvant setting. If a patient did not achieve a pCR following neoadjuvant [therapy], then only those patients were eligible to be randomized to receive either trastuzumab or T-DM1 for 14 doses. Results showed that patients who received T-DM1 did better than trastuzumab alone with an improvement of iDFS of up to 11%, which was remarkable. This trial, again, was a smart design because we know that pathologic status following neoadjuvant therapy is a very important prognostic marker. We already knew from many studies and meta-analyses that pCR is very important.

Now, we are able to further stratify 1 treatment based on this data. What that means to us is that, in the past, the patient received neoadjuvant therapy and then we get the pathology. [From there], we saw that more than half of patients would not have pCR, even with all the efforts that we made to achieve that. [At that time], we didn't really have anything else to offer. [Patients] would receive the exact same treatment knowing that their prognosis is not as good as the other patients who achieved a pCR. It's really exciting for me to now have another option to offer patients as standard of care, in addition to a clinical trial that patients might be eligible to enroll on.

What is your take-home message to your colleagues?

It's important to understand tumor biology or the prognostic markers [in order] to offer the best treatments to our patients. We have made significant progress, but there is more room to improve. We can individualize therapy by understanding the tumor better. Clinically speaking, all these options are available and we have to continue to [enroll] more patients on clinical trials. Many exciting clinical trials are ongoing. For example, at Moffitt Cancer Center, we have a tumor vaccine trial, which is an immunotherapy trial that's funded by the Department of Defense and it's very exciting. Many other trials that are available across the country. I can't emphasize enough for us to continue working towards a cure for patients with breast cancer.

References

  1. Piccart M, Procter M, Fumagalli D, et al. Interim overall survival analysis of APHINITY (BIG 4-11): A randomized multicenter, double-blind, placebo-controlled trial comparing chemotherapy plus trastuzumab plus pertuzumab versus chemotherapy plus trastuzumab plus placebo as adjuvant therapy in patients with operable HER2-positive early breast cancer. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract GS1-04. https://bit.ly/38XGjSM.
  2. Von Minckwitz G, Huang C-S, Mano MS, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-628. doi:10.1056/NEJMoa1814017

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