Optimizing the Management of HER2+ Inflammatory Breast Cancer - Episode 4

APHINITY Trial: Adjuvant Pertuzumab and Trastuzumab

May 29, 2018

Debu Tripathy, MD:The APHINITY trial was designed to test the addition of pertuzumab to a standard nonanthracycline or anthracycline-containing chemotherapy backbone along with trastuzumab. Patients were randomized to get standard chemotherapy with trastuzumab, and that was given either with or without pertuzumab during the chemotherapy phase, overlapping with the taxane, as well as during the maintenance phase.

The study enrolled patients who had higher-risk node-negative cancers, defined as cancers that were greater than 1 cm. Or, if they were in the 0.5-cm to 1-cm range, they had to be high grade or hormone receptor—negative. Of course, it also included node-positive patients. Both hormone receptor statuses were included. The main outcome measure here was the standard invasive-disease–free survival. The study did meet its endpoint, showing a statistically significant improvement in disease-free survival. The core take-home message of this trial was that pertuzumab does indeed add benefit. It was a statistically significant difference. The absolute difference was rather small in the lower-risk patients, but I think all of us would agree that in higher-risk patients, the use of pertuzumab is clearly justified.

Fortunately, there didn’t seem to be added risks in terms of cardiotoxicity, which is one of the risks that we’re always concerned about with HER2-targeted therapy. The number of patients who had cardiac events was no higher in the pertuzumab-containing arm. There were some toxicities that were more frequent. Most notable was diarrhea, which is a known side effect of adding pertuzumab, particularly to the chemotherapy part. That was seen at a higher rate.

I think that the APHINITY trial was really an adjuvant trial, where patients had surgery first. There, it’s a little more defined. I think for the most part, it was stage 2 disease or higher. Even stage 1 patients were included in the study, but they were at higher risk. That’s probably where the controversy is—where you’d draw the risk line. But certainly for higher risk, node-positive, or even stage 2A disease, that would be an appropriate therapy. These patients are at higher risk of recurrence.

The additional thing I would say, though, is that patients who got neoadjuvant therapy were not included in the APHINITY trial, but we also know what their risk is. Those patients already had pertuzumab approved by the FDA on the basis of a higher complete pathologic response rate, and it was approved specifically with chemotherapy. But as you look at the NeoSphere trial and the TRYPHAENA trial—those were the 2 neoadjuvant trials that led to the approval of pertuzumab in the neoadjuvant setting—and you combine them with the findings of the APHINITY trial, I would say that our standard is now going to be to use both trastuzumab and pertuzumab with chemotherapy, and then to use them for the maintenance phase as well.

We do not have a randomized trial that really tests just the maintenance phase, where, for example, patients might get trastuzumab and pertuzumab along with chemotherapy, and then one group gets just trastuzumab and the other group gets both antibodies for maintenance. We don’t have that study, so my default is really to use both antibodies for the duration.

What it really boils down to is, what is the residual risk you’re predicting for this patient? We know that the odds of recurrence were reduced by about a third. A third of a very small residual number is going to be a small number indeed. If the patient just has a 3%, 4%, or 5% risk of recurrence, they’re just lowering it by maybe 1%. However, with any number that’s higher than that, you now get into reasonable numbers in terms of a difference between recurrence or not. Really, the best metric to use—of course, this an estimation—is the literature to guide you in predicting what is the residual risk that this patient has. I would say that someone with inflammatory breast cancer, even someone who did achieve a complete pathologic response, still has a good 20%, 25%, or maybe even as high as 30% risk of recurrence, despite having a PCR.

Transcript edited for clarity.

60-year-old Woman WithHER2+ Inflammatory Breast Cancer

  • A 60-year-old woman presented to her gynecologist with redness, tenderness, and swelling of her right breast over the last 2 weeks
    • PMH: HTN managed with HCTZ/triamterene
    • FH: unremarkable
    • PE: palpable mass in the right inferior breast with skin thickening; no palpable lymphadenopathy
    • ROS: clear, no fever
  • Breast ultrasound revealed a solid right-sided 3.8-cm mass at the 10:00 position with no posterior acoustic shadowing; abnormal enlargement of 2 right axillary lymph nodes
  • Core needle biopsy of the breast mass revealed high grade infiltrating ductal carcinoma;HER2+
  • Fine needle biopsy of a right axillary node confirmed carcinoma
  • Punch biopsy of the skin showed dermal lymphatic invasion with carcinoma cells
  • PET/CT staging showed increased uptake over right breast, diffusely, and with at least 2 nodes seen in the right axillary basin; no evidence of distant metastases
  • Clinical staging: T4dN1M0
  • She received neoadjuvant therapy consisting of dose-dense AC X 4-THP X 4; physical exam was consistent with a complete clinical response
  • She then underwent right modified radical mastectomy; pathology showed a complete pathologic response
  • Following surgery, she was treated with adjuvant trastuzumab + pertuzumab to complete one year of monoclonal antibody therapy
  • The patient completed radiation therapy to the right chest wall and regional nodes
  • She was placed on letrozole