HER2+/ER- Breast Cancer: Neoadjuvant Therapy Options

Hope S. Rugo, MD:So, a patient like this, she’s in her early 50s when I’m starting to think about treatment options. I’ve now helped her to understand the importance of neoadjuvant therapy. We’ve talked a little bit about the prognosis and how that’s going to help us a lot when we see how her tumor responds. And then we need to talk about treatment, because for every treatment decision, it has to be a risk-versus-benefit analysis. We really need to understand what the toxicities are and what’s the benefit to her. For us, going into it, it’s like a no-brainer, right? You gotHER2-positiveER-negative stage 2 disease; you need chemotherapy and aHER2-targeted therapy. There’s no question. But we need the patient to really feel that as strongly as we do and understand it close to as well as we do in terms of the benefit.

We explain the rationale and then we talk about treatment options. In order to talk about treatment options for this patient, I need to understand what her substantial risks are for developing cardiac toxicity; so, whether she has high blood pressure, is on medications, and has had any radiation to her chest. Diabetes we don’t know of as a risk factor, but I like to find out about it because of the issue of giving steroids with the chemotherapy. Neuropathy with taxanes. There are a lot of common intercurrent illnesses that play a role in terms of a decision about one treatment or another, how much treatment to give based on response. Because, of course, we want to try and maintain quality of life as much as possible; not just during treatment, but after.

She’s 51, no hypertension, no medical problems. No reason to suspect she’d have an increased risk of heart toxicity. That means that she has 2 different treatment regimens available to her: standard anthracycline with taxanes given sequentially versus the taxane given first with the anthracycline given sequentially. So, we call that ACT or TAC. Or the regimen that is the Ts—docetaxel—and carboplatin together. Both of those regimens have been very effective inHER2-positive disease when combined withHER2-targeted therapy in the form of trastuzumab. So, that’s really what I go through with patients.

Our first decision point is what regimen. And for some patients, TCH (docetaxel, carboplatin, trastuzumab) is a better approach than either ACTH (Adriamycin, cyclophosphamide, Taxol, Herceptin) or TAC (Taxotere, Adriamycin, and cyclophosphamide). We tend to give the taxane first. For some patients, that’s the better regimen. For other patients, it isn’t. For example, if I have patient who’s trying to maintain fertility, I don’t want to give them TCH if I can avoid it because it’s going to cause more permanent variant suppression.

The second question we have is whether or not we should add in a second antibody, pertuzumab. It’s FDA approved based on 2 different studies: the TRYPHAENA trial as well as the NeoSphere trial. The first trial that really led to this information was NeoSphere, where patients who were getting neoadjuvant therapy forHER2-positive breast cancer received either the standard, which was docetaxel and trastuzumab; docetaxel, trastuzumab, and pertuzumab; just the antibodies, pertuzumab and trastuzumab; or docetaxel and pertuzumab. So, 4 arms with about 70 patients in each arm. What we found was that the pathologic complete response rate was higher in the patients who received the double antibodies plus docetaxel. So, that was very exciting information. Now, it’s important to keep in mind that patients didn’t get an anthracycline before surgery. They went to surgery to evaluate the impact of the antibodies and chemotherapy. And then after surgery, they received anthracycline.

The disease-free survival from that study has also been reported. Although the confidence intervals overlap, so you can’t tell any difference statistically, numerically, the patients who got trastuzumab and docetaxel versus the triple regimen were the best, too, with the triple regimen being maybe a little better. The antibodies alone were a little bit lower, and the pertuzumab and docetaxel was a little bit lower. But overall, the whole thing overlapped, so it’s hard to tell anything.

So, then the other study that actually helped to give data to the FDA for approval of pertuzumab in the neoadjuvant setting was this TRYPHAENA trial, where actually the primary goal of the study was to understand, if you gaveHER2-targeted therapy along with anthracyclines, would you have a better outcome or not and would you have more heart failure or not? So, 2 questions. And what they showed was they didn’t have any more heart failure. But again, they evaluated patients with a short endpoint. So, I don’t know what they’re like in 2 years or if they have a cardiac problem when they get older.

But they also showed that they had good PCR rates regardless—patients who had no cancer at the time of surgery in their breast and nodes. The patients got pertuzumab, and they tolerated the regimen TCHP (docetaxel, carboplatin, trastuzumab, pertuzumab) very well, and the pathologic complete response rate was very similar to what we would have expected from an anthracycline-based regimen. Based on that data, a lot of people have used TCHP as well as the anthracycline regimen. For this patient, I just have to talk with her. I think TCHP might be a better regimen for her. Then you go to surgery, you finish those 6 cycles of TCHP—or when we use the alternative regimen, we give 12 weeks of paclitaxel with pertuzumab and trastuzumab every 3 weeks for 4 doses—and then we give AC 4 doses, and then we start the trastuzumab after the AC after checking an echocardiogram.

So, I think that all those regimens give a lot of options to our patients, and we’ve started now talking a little bit more about the APHINITY data with our patients and saying, “You know, this is what it showed in node-positive orER-negative orER-positive.” That’s hopeful, I think, as well. And we also are very proactive about educating people about diarrhea. In the APHINITY trial, 18% of patients who got TCHP had grade 3 diarrhea. You really want to make sure those people go home with Imodium, that they’re really aware of the issue each time they get the pertuzumab infusion. What I’ve found is that once you’re done with chemotherapy, the diarrhea largely improves. Sometimes, we deal with rash.

Transcript edited for clarity.

• A 53-year-old woman was referred to a breast surgeon after finding a mass in her left breast
  • PMH: unremarkable
  • FH: no history of cancer in first-degree relatives
  • PE: revealed a 6 X 5-cm, non-fixed mass in the left inferior breast without skin changes or nipple discharge, and palpable lymphadenopathy in the left axilla
  • ROS: clear
• Mammogram confirmed a left-sided, poorly defined spiculated mass. Ultrasound shows a 5.3-cm solid mass and enlargement of 2 left axillary nodes with thickened cortex
• Pathology results:
  • Core needle biopsy from the breast mass confirmed grade 3 invasive ductal carcinoma
    • ER—,PR—,HER2IHC 3+
    • FISH,HER2copy number, 15;HER2:CEP17 ratio, 7
  • Fine-needle aspiration of one left axillary lymph nodes was positive for carcinoma
• Staging: T2bN1M0