Tripathy Outlines Where the HER2+ Early-Stage Breast Cancer Landscape Stands

Advancements in HER2 testing methods and the development of treatment approaches outside of traditional platinum-based chemotherapy have allowed clinicians to better customize therapy options for patients with early-stage breast cancer, including deescalating therapy for a significant portion of patients, according to a presentation given by Debu Tripathy, MD, during the 41st Annual Miami Breast Cancer Conference.

“It’s important to do HER2 testing reliably and to ask your pathologist if you have questions,” Tripathy explained. “Also, remember the partitioning that we’re doing in terms of patients who can get deescalated therapy for stage 1 [disease] and those who are going to need more intensive therapy. [Additionally], cardiac monitoring is important, and explaining the decision-making to patients is also important because they’re going through a lot with testing—it’s good to get them up to speed with what’s going on.”

In an interview with OncLive®, Tripathy, a professor and chairman in the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, discussed the highlights of his presentation, explaining the importance of HER2 testing as well as taking stock of the present and future of the HER2-positive breast cancer treatment paradigm. Tripathy also shared insights from another presentation he gave at the conference on CDK4/6 inhibitors in metastatic breast cancer.

OncLive: What is the significance of HER2 testing in the treatment of patients with breast cancer?

Tripathy: The first and most important thing about treating HER2-positive breast cancer is making sure that we have checked the receptor status. This is a standard part of the diagnosis of any breast cancer. The proper technique for the biopsy or the surgical specimen, depending on which it is and how to preserve and fix it, and then staining it [as well as additional] details are important. There are protocols for all of this.

The interpretation is somewhat complicated and is based on the staining intensity and number of cells. Generally speaking, the ratio of grading—0, 1,2, or 3—is used to determine positivity and an immunohistochemical score of 3 is automatically HER2 positive. Patients who are [HER2] 2+ need to undergo FISH analysis, and that’s based on both the HER2 copy number as well as the ratio; typically, a ratio of greater than 2 will automatically qualify them. HER2 1+ is also important now with certain indications, particularly with the use of fam-trastuzumab deruxtecan-nxki [Enhertu] which is also approved for HER2-low breast cancer, including HER2 1+ and 2+ but FISH negative.

What is the current state of the HER2+ breast cancer treatment paradigm?

The treatment of HER2-positive breast cancer depends on the situation regarding the stage. When a patient presents initially, we obtain a clinical stage. For patients who have clinical stage 1 disease, based on tumor size and lymph node assessment by imaging, we typically treat with deescalated therapy.

The [phase 2] APT trial [NCT00542451] showed that one can get very good disease control in the mid 90% range. Patients who have clinical stage 1 breast cancers will go to surgery first and if they maintain stage 1 based on the lymph node assessment, then we use the deescalated therapy: Weekly paclitaxel for 12 weeks given with trastuzumab [Herceptin], with trastuzumab continuing for a full year. During that time, if the tumor is hormone receptor-positive, [the patient] will be on endocrine therapy. This has allowed us to use less toxic treatments.

On the other hand, if a patient presents with disease greater than clinical stage 1—2 centimeters or positive nodes—then we use neoadjuvant therapy. This allows us to downstage the tumor and may allow [for] less or more conservative surgery, a higher rate of breast-preserving surgery, and maybe even fewer [involved] lymph nodes that may also affect not only the extent of surgery but radiation as well. Typically, the regimens that we’re using here are a little more escalated [such as] a taxane along with dual antibody therapy—both trastuzumab and pertuzumab [Perjeta] are used.

[Additionally], some clinicians are still using platinum-based chemotherapy with the TCHP regimen of docetaxel or paclitaxel, along with carboplatin, trastuzumab, and pertuzumab. It’s not clear how much the platinum is contributing—we’ve never done randomized trials to see if we can exclude it—but many do exclude it due to the toxicities or at least that’s the first one that would be discontinued with toxicities. This is important because the achievement of a pathologic complete response [pCR] is used in making decisions. Patients who do have a pCR in both the primary tumor and the lymph nodes will continue on dual antibody therapy to complete a full year and endocrine therapy is used for those who are hormone receptor-positive during that time. However, those who do not achieve a pCR are treated with ado-trastuzumab emtansine [Kadcyla] and it’s typically 14 cycles every 3 weeks to complete the year of treatment.

What challenges and unmet needs persist in the treatment of patients with HER2+ breast cancer?

We would like to have a more accurate and reproducible method for HER2 quantification. We use immunohistochemistry and FISH, [however], that may not tell the whole story; there may be some patients who have identical immunohistochemical and FISH results but respond to HER2-targeted therapy differently for factors other than expression of the gene.

There are many other mediators of the HER2 signal transduction, and it may be that we need a more global assessment. There have been attempts to develop RNA expression profiles where one looks at the tumor and trains a data set where we know who achieved a pCR and who did not, and then we see if we can identify what those genes are and what the pattern is. If the concordance is good and we feel that we can reproducibly obtain the degree of responsiveness, it may allow us to use this instead of more cumbersome technologies. Also, we may be able to make better decisions. For example, we may be able to identify in future patients who can get deescalated therapy, even though they have node-positive disease, or we may find these stage 1 tumors that are more dangerous than we knew and need more intensive therapy. I believe it will allow us to customize our treatment better. There is an assay called HER2DX that has shown preliminarily the evidence to do this, and it’s now being tested in a prospective trial.

During the 41st Annual Miami Breast Cancer Conference, you also presented ‘Real-World Strategies for Utilizing CDK4/6 Inhibitors in Metastatic Breast Cancer,’ what were some highlights from this discussion?

We covered a lot of ground in that presentation and [one topic] was how we can extend our knowledge about CDK4/6 inhibitor use beyond that of the randomized trials. We consider randomized trials to be the gold standard for determining whether one treatment is better than another, and certainly that is the case.

However, there are certain things that clinical trials cannot do. For example, the eligibility criteria for clinical trials require patients have a good performance status. They omit patients with comorbidities, and they may not enroll the diversity that is seen in the general population depending on where the trials are being run. For all of those reasons, real-world data that may be more representative of the population and the comorbidities could be helpful. These [data] can come from many sources, such as electronic medical records, insurance data, and claims data that are available in a deidentified fashion.

One example of this is that when palbociclib [Ibrance] was approved, 99% of the patients enrolled [in the trials supporting the approval] were female, and some of the trials only allowed female patients. Getting real-world data from the Flatiron database, which is a large payment and reimbursement database, allowed us to get information on both safety and efficacy in male patients and it extended the label. We need [real-world data] to complement our clinical trial data.

Reference

Tripathy D. Customizing treatment for early-stage HER2+ disease. Presented at: 41st Annual Miami Breast Cancer Conference. March 7-10, 2024; Miami, Florida.