Breast Cancer: Adding Pertuzumab as a Neoadjuvant Treatment Option

Ruth O’Regan, MD:If I was seeing this patient in my clinic, I would recommend that she get a preoperative approach with a combination of chemotherapy and HER2-directed therapy. I would, generally, for a patient of this age, think about using a combination of docetaxel, carboplatin, trastuzumab, and pertuzumab given every 3 weeks for 6 cycles, then having surgery, and then continuing with the trastuzumab for a total of a year. A lot of oncologists would take an approach where they would give an anthracycline-based regimen as a part of their treatment approach, but also combining pertuzumab and trastuzumab with a taxane in a patient like this. I probably wouldn’t do that for this patient because we know that from one of the initial adjuvant NSABP studies, that patients who are over the age of 50 have an increased risk of cardiomyopathy if they get an anthracycline, and then get trastuzumab-based treatment. So, my preference for a patient like this would be to use the docetaxel/carboplatin/trastuzumab/pertuzumab regimen.

As far as the NCCN Guidelines, they pretty much reflect the FDA approvals for treatment in the preoperative setting for HER2-positive breast cancers. It is recommended that you use a regimen that contains both trastuzumab and pertuzumab, either with a taxane and then an anthracycline approach, or with docetaxel and carboplatin. They’re the regimens that were approved by the FDA, and they’re the ones that the NCCN recommends. Another reason to consider a preoperative approach is because, currently, pertuzumab is only approved in the preoperative setting. It’s not approved in the adjuvant setting yet, although NCCN does support its use in the adjuvant setting. Personally, because we don’t have data, I do not use pertuzumab in the adjuvant setting. I only use it in the preoperative setting, but I know a lot of people do use it adjuvantly. But, I think, at least in the preoperative setting, you know you’re getting this drug that we know quite significantly improves response rate compared to trastuzumab and chemotherapy alone for your patients.

The NeoSphere study was designed to look at a number of different approaches incorporating pertuzumab and trastuzumab in the preoperative setting. So, what they did was they took patients with HER2-positive breast cancer, who were candidates for preoperative approach, and randomized them into 1 of 4 arms preoperatively. One was a standard regimen with a taxane and trastuzumab, which is what we were using at that time point. There was a second arm which looked at a taxane, and in the study was docetaxel, along with trastuzumab, but added in pertuzumab. And then, there was a third arm, which was docetaxel plus pertuzumab. Then, a very interesting fourth arm was pertuzumab and trastuzumab with no chemotherapy. The patients then went to surgery, and the primary endpoint in the study was pathologic complete response. After surgery, however, the patients who had gotten a taxane, preoperatively, went on to get an anthracycline-based regimen along with trastuzumab later on for a year. The patients in the non-chemotherapy arm, who preoperatively got pertuzumab and trastuzumab, went on to get a taxane and anthracycline since they completed the year of trastuzumab.

So, what the study showed was that the pathologic complete response rate was highest in the patients who got docetaxel, pertuzumab, and trastuzumab. It was significantly better in terms of pathologic complete response to the other 3 arms. The other interesting thing was in the non-chemotherapy arm, the pertuzumab/trastuzumab, there was almost 20% pathologic complete response rate. It suggests that maybe some of these patients don’t actually need chemotherapy. And this trial showed, as all of these preoperative HER2-positive trials have shown, that the pathologic complete response rate is higher when the cancers are hormone receptor—negative and HER2-positive compared to being hormone receptor–positive and HER2-positive. We don’t know why that is, but it’s certainly a very consistent finding across all the trials that have been done.

In terms of selecting a regimen for patients with HER2-positive breast cancer in the preoperative setting, I think a lot of it is our own experience and choice in terms of whether you use an anthracycline or not. I usually pay a lot of attention to toxicity profile. My preference is usually to use docetaxel, carboplatin, trastuzumab, and pertuzumab without an anthracycline, but there are certain patients where I would consider using an anthracycline. Now, there are toxicities with both regimens. The docetaxel/carboplatin/trastuzumab/pertuzumab, or the TCHP, regimen can cause quite a bit of neutropenia, and you almost always have to use growth factors in these patients. But, you are avoiding an anthracycline that can certainly potentially increase the risk of cardiomyopathy, which obviously is a bigger concern because long-term toxicities are always more concerning than acute toxicities.

The other thing to be aware of is when you combine pertuzumab and trastuzumab in this setting, you do tend to get more diarrhea. There are reports of patients getting quite seriously ill with typhlitis after those regimens, so you really have to pay attention to the toxicities of these agents. In general, I use mainly TCHP, particularly in patients that are a little bit older and I want to avoid an anthracycline.

Case Scenario 1:

• This is a post-menopausal 58-year-old female in whom a mass was discovered in her right breast during her annual mammography.
• Her gynecologist referred her to a breast surgeon; results of her biopsy revealed 3 cm ductal carcinoma
• Pathology shows: ER— & PR–, HER2 IHC 3+
• Clinical staging; T2aN1M0
• Her surgeon discussed the patient’s case at the Breast Tumor Board and it was suggested that the patient be referred to a medical oncologist for consideration of HER2-targeted neoadjuvant therapy.
• The surgeon shared his opinion with the patient who agreed to go to the medical oncologist to discuss her options.