My name is Dr. Mridula George. I am one of the breast medical oncologists at Rutgers Cancer Institute of New Jersey. I primarily treat women with breast cancer, both early-stage breast cancer and metastatic breast cancer.

Today, I am just going to focus on how I treat early-stage HER2-positive breast cancer. HER2-positive breast cancer is diagnosed in about 15-20% of women diagnosed with breast cancer. HER2 overexpression is associated with an aggressive clinical course.

In the last two decades, we have had multiple drugs that have been approved that target specifically the HER2. This has changed the landscape of this disease. The addition of HER2-targeted agents have been studied in the metastatic setting, the adjuvant setting, the neoadjuvant setting.

The first agent that was approved for HER2-positive breast cancer was trastuzumab, or trastuzumab, and was studied in the metastatic setting and was shown to improve overall survival compared to just chemotherapy alone. Since then, this drug was studied in the adjuvant setting as well and was shown to improve overall survival and disease-free survival.

Multiple studies have been done looking at HER2-targeted agents in the neoadjuvant setting. On one of the first studies, which was a randomized study that looked at the role of trastuzumab in the neoadjuvant setting, was the NOAH study.

It looked at the combination of trastuzumab and chemotherapy compared to chemotherapy alone, and showed that there was an improvement in survival. The investigators behind NOAH also started looking at the pathologic complete response rate, which is the absence of invasive cancer in the breast and the axilla.

Multiple studies have been done since then using pathologic complete response (CR) rate, or partial CR as the primary end point. Partial CR has been shown to be a reliable surrogate parameter for long-term outcome.

Besides trastuzumab, there have been other HER2-targeted agents that have entered the market. There have been studies looking at dual targeting of HER2, so using 2 anti-HER2 therapies instead of one.

The NeoSphere study looked at the combination of trastuzumab and pertuzumab. Trastuzumab binds to the extracellular domain and pertuzumab is a tyrosine kinase inhibitor that attacks the intracellular domain.

The combination was studied in the NeoSphere study and the study showed that the pCR rates was higher with the combination of trastuzumab, pertuzumab, and chemotherapy compared to just single-agent HER2-targeting agents, either trastuzumab alone, or pertuzumab alone, or dual anti-HER2 therapy without chemotherapy.

The other study, the TRYPHAENA, was a phase II study which also looked at the combination of trastuzumab and pertuzumab, but they studied it with different chemotherapy backbone. One was an anthracycline-based chemotherapy and the second arm was a non-anthracycline-based chemotherapy.

The study showed that the combination of dual anti-HER2 therapy with chemotherapy had a higher partial CR rate and there was no difference between the anthracycline-based arm and a non-anthracycline-based arm.

That is a big question among oncologists when we treat patients in the neoadjuvant setting, do we have to give them an anthracycline-based chemotherapy or a non-anthracycline-based chemotherapy?

The TRAIN-2 study was done to answer this question. It looked at an anthracycline-based chemotherapy versus a non-anthracycline-based chemotherapy and patients received trastuzumab and pertuzumab.

The study showed that there was not a significant difference in pathologic complete response with the anthracycline-based chemotherapy backbone verses and a non-anthracycline-based chemotherapy backbone.

Multiple de-escalation studies have been done and they are currently in the process as well. There is the CompassHER2 study, which is looking at the admission of carboplatin and continuing patients on docetaxel, a paclitaxel with trastuzumab and pertuzumab. That study is currently underway and enrolling patients.