HER2+ Breast Cancer Treatment Approaches Becomes More Individualized

Sara A. Hurvitz, MD

Although trastuzumab (Herceptin) has been the mainstay of treatment for some time now in the treatment landscape of HER2-positive breast cancer, several new treatment options have surfaced with subsequent FDA approvals. The addition of these new therapeutic options to the armamentarium has led to more personalized treatment approaches in this patient population in order to provide prolonged survival outcomes.

Trastuzumab in combination with chemotherapy has been available in the field for the treatment of patients with HER2-positive disease, but pertuzumab (Perjeta) is now available in either the neoadjuvant or adjuvant setting. In addition, neratinib (Nerlynx) has received approval for the treatment of this patient population in the extended adjuvant setting, and ado-trastuzumab emtansine (Kadcyla; T-DM1) is available in the adjuvant setting for patients with residual disease following neoadjuvant trastuzumab-based therapy.

Another regimen some physicians may use in this space is neoadjuvant docetaxel, carboplatin, and trastuzumab with pertuzumab (TCH+P). To make the best treatment decision for their patients, physicians should consider a number of factors, such as tumor size, nodal status, and hormone receptor (HR) co-expression.

Sara A. Hurvitz, MD, says that in her practice, she uses neoadjuvant therapy in most patients to evaluate the sensitivity of their tumor to neoadjuvant-based chemotherapy. She will then likely follow this with TCH+P if it is appropriate for the patient. Patients with residual disease could go on to receive neoadjuvant T-DM1, or some may also receive neratinib. Hurvitz will also include pertuzumab in a patient’s treatment plan if they have very high-risk disease that may be node positive as well.

In an interview with Targeted Oncology, Hurvitz, director of the Breast Oncology Program, medical director of the Clinical Research Unit, University of California, Los Angeles, Jonsson Comprehensive Cancer Center, reviewed the 4 currently approved treatment options for patients with HER2-positive breast cancer and discussed how physicians could use the data to make treatment decisions in the adjuvant and neoadjuvant setting.

TARGETED ONCOLOGY: What are the most exciting advances we’ve seen recently in the treatment landscape of HER2-positive breast cancer?

Hurvitz: It’s a very exciting time right now. Relating to the treatment of early-stage HER2-positive breast cancer. We now have 4 different therapies available to us for the treatment of this disease. Not only trastuzumab added to chemotherapy, but also pertuzumab in the neoadjuvant or adjuvant setting, neratinib in the extended adjuvant setting, and T-DM1 in the adjuvant setting for patients who have residual disease after neoadjuvant trastuzumab-based therapy. Deciding which patient needs this much therapy is really kind of tricky.

We know from the neoadjuvant studies that the addition of pertuzumab to trastuzumab improves pathologic complete response (pCR) rates. We also know that patients who don't achieve a pCR after standard neoadjuvant trastuzumab-based therapy have a very high risk of disease recurrence. T-DM1 was evaluated in the adjuvant setting for patients who had residual disease after standard neoadjuvant therapy and was shown to substantially improve the invasive disease-free survival (DFS) rate for patients by about 11% absolute risk reduction, so this is a very important improvement in invasive DFS as well as distant recurrence. This has been adopted widely in patients whose disease has not fully responded to neoadjuvant therapy.

We also have 2 adjuvant therapies available to us, including pertuzumab, which is studied in the APHINITY study. This, given with trastuzumab in the adjuvant setting with 74 months of follow-up, is shown to significantly improve invasive DFS, but that improvement appears to be restricted to patients who have node-positive disease. The toxicity that comes with adding a year of pertuzumab in the adjuvant setting is diarrhea primarily. There's more diarrhea, especially when given concurrently with chemotherapy. Neratinib is another agent that's approved in the extended adjuvant setting, so after patients have completed a year of trastuzumab, they receive a year of the oral tyrosine kinase inhibitor neratinib. This was studied in the ExteNET study and was shown to improve the invasive DFS rate by about 2.5%. If you just look at those with HR co-expression, it’s about 4.5%, so my own strategy for patients sitting in front of me is to look at their risk assessment and to treat as many patients as I can in the neoadjuvant setting to test the sensitivity of their tumor to neoadjuvant trastuzumab-based chemotherapy and give them a regimen like TCH+P. Those who have residual disease will go on to receive T-DM1 in the adjuvant setting. Some may also receive neratinib after T-DM1, although that study didn't allow patients to receive T-DM1 if their tumor was HR-positive and node-positive. I think that neratinib would make sense. If they, on the other hand, have a pCR with neoadjuvant therapy, then I go on and complete the trastuzumab. I might also include pertuzumab if they have very high-risk disease at the beginning that was node positive. That’s how I approach it now in an era where we have 4 agents available to us.

TARGETED ONCOLOGY: Are there any biomarkers being examined in the HER2-positive space to better tailor treatment options for patients?

Hurvitz: Biomarkers have been evaluated in a number of clinical trials to help us determine whether or not a certain therapy is necessary or will likely benefit a patient or not—biomarkers, such as tumor-infiltrating lymphocytes (TIL), PD-L1 expression, PIK3CA mutations in the tumor, or HR co-expression. All of these have been looked at; nothing right now is helping us determine who should or shouldn't receive HER2-targeted therapy. Everyone with HER2-positive breast cancer should receive trastuzumab, and we have to use factors like nodal status and HR co-expression to determine which therapies to use.

There were data presented recently at the ASCO Annual Meeting, and then at the ESMO Annual Congress as well in 2019, looking at biomarkers from the KATHERINE study to see if there was a patient subset that may or may not benefit from T-DM1. What they showed was that everyone benefited from the addition of T-DM1 in the adjuvant setting as long as they had residual disease at the time of surgery after standard neoadjuvant therapy, so patients benefit better regardless of whether the tumor was HR-positive, regardless of whether there was a PIK3CA mutation, regardless of nodal status, and regardless of the size of the residual disease at the time of surgery. There were some interesting data looking at levels of HER2 expression, and what happens between the baseline biopsy prior to starting neoadjuvant therapy and the tumor tissue taken at the time of surgery. What this analysis showed was that HER2 expression does appear to drop overall after standard neoadjuvant trastuzumab-based therapy, but a decrease in the level of HER2 expression at the time of surgery does not identify patients who will not benefit from T-DM1. Everybody benefits from T-DM1, especially those patients with high HER2 expression at the time of surgery, but even those patients with low HER2 expression.

TARGETED ONCOLOGY: What are some of the most pressing challenges in this space?

Hurvitz: Although we have really improved outcomes for patients that are pushing the DFS to 90% and above even for patients who are identified with higher-risk HER2-positive early-stage disease, there are unmet needs. Certainly, we do know that patients sometimes will have tumors recur only in the central nervous system (CNS) because most of the therapies that we're using with the exception of neratinib do not penetrate the blood-brain barrier, and so, a metastatic recurrence can be seen exclusively in the brain, sparing the rest of the body and the extracranial system. I think ongoing studies are looking at whether we can reduce the incidence of metastatic recurrences in the brain. We have data from ExteNET with neratinib, as well as neratinib in the metastatic setting, showing that neratinib does delay the time to a CNS metastatic recurrence. There are newer drugs like tucatinib (Tukysa)-based therapies that are being explored in the adjuvant setting to see if we can reduce the incidence of CNS metastases, so that's a huge area of unmet need right now.

TARGETED ONCOLOGY: What is the key take home message here?

Hurvitz: The take home message for the treatment of HER2-positive early-stage disease right now is we have many options available, so deciding how much to use for a particular patient does depend on a number of factors, such as tumor size, nodal status, HR co-expression, etc. All of these things will help us come together and make a plan in terms of what's best for the individual patient. Not all patients need 2 chemotherapy or 3 chemotherapy drugs with trastuzumab. We have data from the APT study that paclitaxel/trastuzumab yields very good DFS out to 7 years. Balancing whether we de-escalate therapy or escalate therapy does need to take into consideration all of these risk factors, and this is an algorithm that is ever evolving. Paying attention to CME activities, going to conferences, and keeping abreast of the new information is what's going to make us stronger clinicians for our patients.