Blackwell on Recent Advances in HER2-Positive Breast Cancer

Kimberly L. Blackwell, MD

In stage I breast cancer, adjuvant trastuzumab (Herceptin) and paclitaxel were investigated in HER2-positive patients with small tumors measuring up to 3 cm. Historically, these patients would not receive trastuzumab; however, after a median follow-up of 4 years, the 3-year invasive disease-free survival rate was 98.7% (95% CI, 97.6-99.8) in patients who received trastuzumab and paclitaxel.¹

The ongoing AFFINITY trial, which is examining chemotherapy and trastuzumab with or without pertuzumab (Perjeta) in the adjuvant setting, may have a big impact on adjuvant treatment for HER2-positive breast cancer once the data are released, says Blackwell.

There are also several studies investigating the antibody-drug conjugate ado-trastuzumab emtansine (T-DM1; Kadcyla).

These include the ADAPT study, which demonstrated a pathological complete response (pCR) rate of 40.5% with T-DM1 as neoadjuvant treatment in patients with HER2-positive and HR-positive early breast cancer.²

OncLive: How has the use of trastuzumab evolved?

In an interview with OncLive, Blackwell discussed these studies, as well as other significant research in HER2-positive breast cancer.Blackwell: I think the biggest advance in the past year or 2 is a better understanding of the poor prognosis for a woman with stage I breast cancer that is HER2-positive who does not receive adjuvant trastuzumab. We tend to think of very small TIb and TIa tumors as very low risk for recurrence. However, we now have several retrospective studies looking at risk of recurrence in patients who do not get trastuzumab and who have small tumors.

Even as early as 2009, there were data that suggested that small HER2-positive tumors had the same or worse prognosis as triple-negative cancer. At the San Antonio Breast Cancer Symposium in 2015, the 2Netherlands group collected data on HER2-positve patients who either received trastuzumab or didn’t. What they found is that a woman’s chance of recurrence was reduced by half if she received trastuzumab, even with the smallest of tumors.

I think that really set the stage for innovative trials that have been done, including one study published in The New England Journal of Medicine, in 2015. This looked at 12 weeks of paclitaxel and trastuzumab for stage I HER2-positive breast cancer.

Do these studies have the potential to change the standard of care?

It also, more importantly, set the stage for the randomized ATEMPT study, which is randomizing stage I HER2-positive breast cancer patients to either 12 weeks of paclitaxel or trastuzumab or T-DM1. It seems that when a tumor is driven to HER2, it has a poor prognosis, and even in the smallest tumors, these women benefit from using HER2-targeted agents.This data has shaped my practice. In patients who have very small HER2-driven tumors, before, I wouldn’t have recommended trastuzumab across the board, but now based on that study, I am. This is practice-changing.

However, there are no data that giving trastuzumab without chemotherapy works. When you make the decision that you are going to recommend or offer trastuzumab in small tumors, the downside is that it’s always administered with chemotherapy. That made it a harder decision historically because all the stage I HER2-positive breast cancers were excluded from the previous studies and we really had no data to draw on for decision making.

What role does pertuzumab play in HER2-positive disease?

Now we do, and what that data show is that trastuzumab helps women with HER2-positive breast cancer. It is always difficult to make these recommendations knowing that you have to give it in conjunction with chemotherapy. I think that is where the stage is set for either lessening the chemotherapy backbone to trastuzumab or supporting trials like the ATEMPT study that aim to incorporate the drugs that don’t have the side of effects of chemotherapy, like T-DM1.For women facing stage II breast cancer that is HER2-driven or stage III breast cancer, the data now suggest that pertuzumab added to chemotherapy plus trastuzumab backbone, adds something, at least in the neoadjuvant setting.

I think the approval of pertuzumab in the neoadjuvant setting has really set a standard of care for stage II and III breast cancer. The preferred regimen is now to incorporate pertuzumab to what you were going to give anyway, chemotherapy and trastuzumab.

Are there questions that remain regarding the use of pertuzumab in HER2-positive breast cancer?

What’s on the horizon for the use of T-DM1?

The data suggest that there is not a lot of added toxicity, but you get a near doubling in the complete pathologic response rate. For me, adding pertuzumab in the neoadjuvant setting is a fairly easy recommendation based on its approval in this setting.The real question is, does the benefit we see in the neoadjuvant setting translate to the adjuvant setting? We really will not have that answer until the results of AFFINITY are available in the next year or so.Right now it does not carry an approval in the adjuvant setting or in the early stage setting, so its role is really in the metastatic setting outside of a clinical trial. However, we obtained very intriguing data from the ADAPT study, which investigated women with intact tumors in the neoadjuvant setting with ER-positive, HER2-positive breast cancer.

What are the biggest advantages of T-DM1?

What was seen in that study was a little over 40% complete pathological response rate with single-agent T-DM1. Patients tolerated it well. I would be really excited to see a study looking at T-DM1 in the adjuvant setting, but as far as I know they are not available at the moment.The drug itself doesn’t have the toxicities that we see with traditional chemotherapy. The things that patients really hate about receiving chemotherapy—hair loss, nausea, and vomiting—don’t exist with T-DM1. We make a lot of women’s hair fall out to help just a few. That is why I would like to see it in the adjuvant setting.

References

1. Tolaney SM, Barry WT, Dang CT. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med. 2015;372(2):134-141.
2. Harbeck N, Gluz O, Christgen M, et al. Efficacy of 12-weeks of neoadjuvant TDM1 with or without endocrine therapy in HER2-positive hormone-receptor-positive early breast cancer: WSG-ADAPT HER2+/HR+ phase II trial. J Clin Oncol. 2015;33 (suppl; abstr 506).