Tripathy Highlights Neoadjuvant Advances in HER2+ Breast Cancer

Debu Tripathy, MD

The treatment paradigm for the neoadjuvant setting of HER2-positive breast cancer continues to evolve, offering new opportunities to improve patient outcomes, according to Debu Tripathy, MD.

The addition of trastuzumab (Herceptin) to standard chemotherapy has become standard of care in both the neoadjuvant and adjuvant setting, but other agents, such as pertuzumab (Perjeta), have been shown to demonstrate an increase in the complete pathologic response rate (pCR) beyond that which is seen with trastuzumab and chemotherapy alone.

“Pertuzumab, which showed a larger increase of pCR, was also shown in other trials to have improved survival in the metastatic setting on all bases of that data—not only the neoadjuvant data, but the long-term data in metastatic disease,” said Tripathy.

OncLive: Please provide an update on neoadjuvant treatment strategies in HER2-positive breast cancer.

In an interview with OncLive at the 2017 Miami Breast Cancer Conference (MBCC), Tripathy, a professor and chairman in the Department of Breast Medical Oncology, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed current and emerging treatment strategies in the neoadjuvant setting for patients with HER2-postive breast cancer.Tripathy: The use of neoadjuvant therapy for HER2-positive breast cancer is an area of increasing understanding, knowledge, and interest. We know that patients clearly achieve a higher chance of a pCR with the addition of trastuzumab to standard chemotherapy. This occurs in both the neoadjuvant and adjuvant settings, which had led to it being the standard of care.

We also know that patients who achieve a pCR tend to have a better disease-free survival, particularly those patients who are HR-negative. We have begun to use this platform to test new drugs. Lapatinib (Tykerb) and pertuzumab were 2 drugs that had been tested in large scale trials and both drugs increase the pCR beyond that which is seen with trastuzumab and chemotherapy alone.

Pertuzumab, which showed a larger increase in pCR, was also shown in other trials to have improved survival in the metastatic setting on all bases of that data—not only the neoadjuvant data but the long-term data in metastatic disease. The FDA approved pertuzumab in the neoadjuvant setting using a new pathway that they had developed over the past few years. That was contingent upon an adequately powered adjuvant trial showing an improvement in the disease-free survival. Nevertheless, that accelerated FDA approval of pertuzumab has now made it the standard of care because it improves the pCR.

The NeoSphere trial, which looked at docetaxel with either trastuzumab or trastuzumab plus pertuzumab followed by FEC (fluorouracil, epirubicin, and cyclophosphamide). The pertuzumab combination arm showed a higher pCR rate.

The TRYPHAENA trial showed pertuzumab in 3 different arms: [The first arm received pertuzumab, trastuzumab, and FEC, followed by pertuzumab, trastuzumab, and docetaxel; the second arm received FEC, followed by pertuzumab, trastuzumab, and docetaxel; and the third arm received pertuzumab, trastuzumab, docetaxel, and carboplatin. pCR was similar in all 3 arms.]

Those 2 trials together laid the foundation for either anthracycline or nonanthracycline containing a pertuzumab therapy.

What are the advantages to the patients? Presumably, the additional downstaging may further increase the number of patients that can have a breast-conserving surgery.

I believe this has helped us understand which therapies improve pCR and which of those may have an impact on disease-free survival.

Are there any trials that are ongoing or upcoming that are testing even more agents that might have better responses?

What were the main takeaways from your presentation at MBCC?

This platform is now being used with many different drugs, including immunotherapy or other HER2-pathway inhibitors, to further explore how we might improve not only local control, but ultimately prioritize trials that can show which drugs added to standard therapy can have an impact on disease-free and overall survival. Yes. There are several ongoing trials looking at immunotherapy. There are also studies looking at protein antagonists, as well as trials that are looking at other modifiers of signal transductions, such as AKT inhibitors and PI3-kinase inhibitors. Those are the ones that are furthest along that will help us know which agents should be prioritized to be tested in the adjuvant setting.There are several takeaways. The most important is determining what is the best standard right now for neoadjuvant therapy for HER2-positive cancers. The first decision is should one even use neoadjuvant therapy? In my opinion, patients who may have stage I disease may be better served by a surgery first. If confirmed to be stage I, the patients might benefit from a less aggressive therapy that has fewer adverse events, such as weekly paclitaxel and then trastuzumab for a year. But, if they are stage II or higher, I believe pertuzumab is a standard of care and is preferable because the patient receives better downstaging.

Is there anything else you would like to highlight?

The early results of the APHINITY trial showed that pertuzumab improves disease-free survival with trastuzumab and not only at the time of chemotherapy. We may now be using it in addition, not only for better pCR, but also for improvement in overall disease-free survival. It’s important for patients with HER2-positive breast cancer and triple-negative breast cancer to have a multidisciplinary evaluation, seeing both a surgical oncologist and medical oncologist.

Then, of course, it’s always good to have radiation oncology opinions and have pathology and radiology available for any questions. A true multidisciplinary evaluation makes sure that all the options can be reviewed with a patient. Sometimes if patients go to surgery first, they may have lost the opportunity, for example to receive pertuzumab if it wasn't used in the neoadjuvant setting. That's a broader key point that can be made with these data.