Q&A with Sara M. Tolaney, MD, MPH: Testing and Treatment Advancements for Women With HER2-Positive Breast Cancer

What do the current guidelines recommend with respect to HER2 testing for women with breast cancer?

TOLANEY: Currently, any patient who has an invasive breast cancer should have their tu­mor tested for estrogen receptor (ER), progesterone receptor, and HER2. HER2 is among the standard receptors that should be tested on all patients with newly diagnosed invasive breast cancer.

What do you view as the biggest challenges and unmet needs with respect to HER2 testing in breast cancer?

TOLANEY: One challenge comes up when we run into these cases where the findings are equivocal. The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines have done a great job trying to address these challenges. An ex­ample of this is if you have a patient who comes back with an immunohistochemical test that is 2 +, a fluorescence in situ hybridization (FISH) ratio that is under 2, and a HER2 copy number over 6; or, she has a FISH ratio greater than 2, but her HER2 copy number is under 4. These equivocal test results usually require retesting.

Another challenge is concordance of immunohistochemical (IHC) test results at different sites. We know that the level of concordance with IHC testing, particularly in patients who have low HER2 expression, is not great, and is another area of unmet need. It brings up the challenge that drugs are now being developed to target HER2-low cancers, yet we’ve created a test that is supposed to have a dichotomous result. You’re supposed to either be HER2-positive or HER2-negative, and yet now we have drugs that are developed in HER2-low area, in which you have 1 + or 2 + staining, but FISH is not amplified. It’s going to be a big challenge for us as these newer agents become available [to know] which will work even when someone has a tiny bit of HER2 expression. We need to have a more quantitative measure of HER2 expression to help guide us and direct us in these patients who have low expression.

Can you discuss your own general approach to HER2 testing, given the gaps and uncertainties in current guidelines?

TOLANEY: HER2-directed therapies have revolutionized outcomes for patients with HER2-positive disease. This breast cancer subtype was thought to be associated with higher rates of recurrence than hormone receptor-positive, and even triple-negative breast cancer, in some data sets. Yet now, with HER2-directed therapy, outcomes are very similar to patients who have HER2-negative disease. Understanding if someone has HER2-positive disease is critical in making treatment decisions for patients and has a large impact on their outcomes.

Several questions arise with regard to HER2-testing. If you have a patient who is HER2-positive based on a core biopsy for newly diagnosed breast cancer, then you give them pre­operative therapy. Do you need to retest their tissue for HER2 at the time of surgery after they’ve received the neoadjuvant therapy? Is that necessary? They already have a positive test. The ASCO/CAP [guidelines] address this and suggest retest­ing in some cases. Say, for instance, that there wasn’t optimal testing on the core; maybe there was very minimal tissue. Or, [maybe] it was surprising that HER2 was positive on that initial core biopsy, given the pathology of the underlying can­cer—for example, if the patient had a type cancer that would rarely be HER2-positive, then you probably should retest it. Additionally, if there’s a new site of disease, such as in a multi­focal cancer, and one site looks a little different than the other site, but only one site was tested for HER2, then you probably should test the other site. The practical issue is though, Does it change your management? The truth is, we now have data based on the subgroup analyses from KATHERINE to suggest that if someone had an initial HER2-positive cancer, then had preoperative therapy, and had residual disease, but you retest and it’s HER2-negative, there still seems to be benefit from adjuvant [ado-trastuzumab emtansine] (T-DM1; Kadcyla).

So, I would test in cases where there’s some uncertainty about the HER2 status—when there’s discordance with histopathologic features, or if there’s multifocal disease where there’s concern—but in truth, you’re probably going to end up giving adjuvant T-DM1. One issue is when to retest on the postoperative specimen. The other issue is when to re­biopsy someone who has metastatic disease. The rate of gaining HER2 is quite low. It’s the same with loss of HER2: It isn’t quite as frequent as we see loss of ER, but it’s very important to confirm receptor status before making treat­ment decisions. Always biopsy and retest receptors, as­suming it’s feasible to do so from the tissue that’s available, before starting therapy in the metastatic setting.

What is known about HER2 heterogeneity in breast cancer and what are the implications for treatment planning?

TOLANEY: When we say HER2 heterogeneity, what we re­ally mean is that a tumor has one focus that is known to be truly HER2-positive, but then has another area that is HER2-negative. It is therefore not uniformly HER2-positive. We see HER2 heterogeneity in probably about 10% of cases of HER2-positive breast cancers.

A very interesting trial was done by my colleagues Otto Metzger, MD, and Ian Krop, MD, PhD, in which they took patients who were diagnosed with HER2-positive disease and biopsied their tumors in 2 different locations, gave them preoperative therapy with T-DM1 and pertuzumab, and then took them to surgery. The question was, “Is heterogeneity of HER2 associated with pathologic complete response (pCR) to T-DM1 with pertuzumab?” What they found was that none of the HER2-heterogeneous patients had a pCR to T-DM1 plus pertuzumab, suggesting that these agents are working purely by targeting chemothera­py to that HER2 cell. ADCs that do not have bystander effect are not going to be completely therapeutically sufficient for a heterogeneous cancer.

We also saw this from the KRISTINE trial results, with preoperative T-DM1 and pertuzumab. Patients who had either low or heterogenous HER2 expression had higher rates of local-regional progression in the preoperative set­ting. HER2 heterogeneity has an impact in response to drugs like T-DM1, but now, newer antibody-drug conju­gates (ADCs), such as trastuzumab deruxtecan (Enhertu), can work by bystander effect. They do seem to have activity in these heterogeneous cancers. This is likely because they’re able to use the HER2 in the area that’s HER2-posi­tive [and] target the cancer. Then the drug, the payload, can diffuse through the cell membrane into neighboring cells, even cells that are HER2-negative, and still kill them.

Can you briefly review the historical frontline standards of care for HER2-positive MBC? What do you consider to be the first-, second-, and third-line standards of care?

TOLANEY: For HER2-positive metastatic disease, our first-line standard has traditionally been a taxane with trastu­zumab and pertuzumab. This was based on the CLEOPATRA study, which showed significant improvement in both pro­gression-free survival (PFS) and an unprecedented improve­ment in overall survival (OS), with a 16-month improvement from the addition of pertuzumab to taxane and trastuzum­ab. The EMILIA study suggested superiority of T-DM1 over capecitabine and lapatinib. Based on these study results, our second-line standard has usually been T-DM1.

More recently, in the third-line setting, we have the choice of either capecitabine plus trastuzumab and tu­catinib or trastuzumab deruxtecan. These choices come from data in the HER2CLIMB trial suggesting that the capecitabine + tucatinib + trastuzumab regimen was supe­rior to capecitabine + trastuzumab. This study demonstrated a significant improvement in both PFS and OS. The benefit was seen in patients both with and without brain metas­tases. The trial [results were] quite unprecedented, demonstrating survival benefit in patients [with] active brain metastases. In the third-line setting, many [clinicians] will choose that HER2CLIMB regimen. An alternative in someone would be trastuzumab deruxtecan. This is a novel ADC with a high drug to antibody ratio that has a topoisomerase payload. A single-arm, phase 2 demonstrated a 16-month PFS with trastuzumab deruxtecan as a single agent which was very impressive, because in that trial, the patients had received a median of 6 prior lines of therapy for metastatic disease. We’ve never seen such a prolonged PFS in this setting. Additionally, the response rate for 60% in this heavily pretreated population. When making decisions for patients in the third line, physicians will consider whether a patient has brain metastases and think about a patient’s underly­ing comorbidities. Trastuzumab deruxtecan is associated with about a 10% to 12% risk of interstitial lung disease, and this is something to keep in mind; if someone has un­derlying pneumonitis, trastuzumab deruxtecan would be contraindicated. We have a plethora of options even beyond the third-line setting, usually consisting of chemotherapy and trastuzumab thereafter.

Can you provide an overview of the emerging treatment landscape for HER2-positive MBC after progression on multiple HER2-targeted agents?

TOLANEY: It really is quite an exciting time, because we’ve seen 3 FDA approvals just this past year for regimens in the metastatic HER2-positive space, and other agents, including margetuximab, are currently under review with the FDA. The landscape for metastatic HER2-positive disease is very rapidly evolving. What’s particularly exciting is the opportunity to improve outcomes for patients who have brain metastases. We know that about 50% of patients with metastatic HER2-pos­itive disease will develop brain metastases and we’ve struggled with trying to address the disease in the central nervous system, particularly after someone has had progression after local therapy. Now with tucatinib, we have an agent that has survival benefit in this population, which we have never seen before. It’s definitely a very exciting time.

The other area of excitement is that we’re seeing disease control that is much more prolonged than ever before. [We’ve never seen] heavily pretreated HER2-positive disease with novel ADCs, such as trastuzumab deruxtecan, [have] PFS rates in the 16-month range in a patient population with a median of 6 prior therapies for metastatic disease. These new HER2-directed therapies are going to dramatically change outcomes for HER2-positive patients.