Expanding Definitions of HER2 Expression Mediate the Role of ADCs in Breast Cancer


Erika P. Hamilton, MD, discusses the role of trastuzumab deruxtecan in HER2-positive and HER2-low breast cancer; the evolution of CDK4/6 inhibitors in hormone receptor–positive disease; and how genetic testing can match patients with personalized therapies and support further precision medicine research.

Erika P. Hamilton, MD

Erika P. Hamilton, MD

Antibody-drug conjugates (ADCs) have redefined the parameters of HER2 expression required for HER2-directed therapy and restructured treatment sequencing for patients with HER2-positive breast cancer, according to Erika P. Hamilton, MD, who noted that ADCs such as fam-trastuzumab deruxtecan-nxki (Enhertu) and patritumab deruxtecan are also at the forefront of therapies targeting brain metastases and HER3, respectively.

“HER2-positive metastatic disease is an area in which we’ve had much shuffling,” Hamilton said in an interview with OncLive® following a State of the Science Summit™ on breast cancer, which she chaired.

In the interview, Hamilton discussed the shifting role of trastuzumab deruxtecan in HER2-positive and HER2-low breast cancer; the evolution of CDK4/6 inhibitors in hormone receptor (HR)–positive disease; and how genetic testing across breast cancer subtypes can match patients with personalized therapies and support further precision medicine research.

Hamilton shared the next steps for research with trastuzumab deruxtecan in the context of the phase 3 DESTINY-Breast09 trial (NCT04784715), which is investigating the ADC as monotherapy or with pertuzumab (Perjeta) vs a taxane, pertuzumab, and trastuzumab (Herceptin) in patients with HER2-positive metastatic breast cancer.1 Additionally, she highlighted research with the HER3-directed ADC patritumab deruxtecan across breast cancer subtypes. A phase 2 study evaluating the efficacy of patritumab deruxtecan in patients with HER2-negative metastatic breast cancer demonstrated an overall response rate (ORR) of 35.0% (95% CI, 23.1%-48.4%) across all patients treated with the ADC and an ORR of 33.3% (95% CI, 17.3%-52.8%) in patients with HER3 expression of at least 75%.2

Hamilton is the director of Breast Cancer and Gynecologic Cancer Research at Sarah Cannon Research Institute in Nashville, Tennessee.

OncLive: Could you provide an overview of the HER2-positive metastatic breast cancer treatment landscape?

Hamilton: Trastuzumab and pertuzumab are the current standards in the first-line setting, typically given with a taxane. Trastuzumab deruxtecan has come up as a set second-line regimen, although multiple trials are ongoing to potentially move this agent earlier.

The third line and beyond is up in the air. We have tucatinib [Tukysa] in combination with capecitabine [Xeloda]. We have ado-trastuzumab emtansine [Kadcyla], which was displaced in the second-line setting. We have novel drugs like margetuximab-cmkb [Margenza], as well as other TKIs and novel chemotherapies with trastuzumab.

One of the big areas we’re evaluating in HER2-positive disease is brain metastases. As opposed to estrogen receptor [ER]–positive and triple-negative disease, HER2-positive disease has a high rate of brain metastases. Up to 50% of patients with metastatic HER2-positive disease will ultimately have [brain metastases]. We’re seeing good activity with tucatinib, and trastuzumab deruxtecan is showing encouraging brain activity as well, which is nice to see because this has been a difficult-to-treat area for several years.

What is the rationale for DESTINY-Breast09?

DESTINY-Breast09 is investigating trastuzumab deruxtecan, the new HER2-directed ADC that used to be [used in the] third line and was moved into the second line based on [data from the phase 3] DESTINY-Breast03 trial [NCT03529110]. [The ADC] was also approved for HER2-low disease based on [data from the] phase 3 DESTINY-Breast04 trial [NCT03734029]. DESTINY-Breast09 is moving trastuzumab deruxtecan into the first-line metastatic setting.

This is typically how drug development goes. We often see agents initially approved in later lines, and then moved up steadily through trials. We’re excited about this because trastuzumab deruxtecan has had the most compelling data in HER2-positive breast cancer that we’ve seen in years. We’re excited to give patients earlier access to a drug like this.

What is the mechanism of action of patritumab deruxtecan, and how might this agent fit into the HER2-positive treatment paradigm?

Patritumab deruxtecan has the same linker and payload on the Daiichi construct as trastuzumab deruxtecan or datopotamab deruxtecan, but instead of having a HER2 or TROP2 antibody on the front end, it has a HER3 antibody. [Patritumab deruxtecan has the] same linker and payload but is targeting HER3. Ian Krop, MD, PhD, [of Yale Cancer Center in New Haven, Connecticut], presented data at the 2022 ASCO Annual Meeting showing its activity across all 3 subtypes of breast cancer: HR-positive disease, triple-negative disease, and HER2-positive disease. At the 2023 ASCO Annual Meeting, I presented data [with this agent] in patients with HR-positive disease or triple-negative breast cancer [TNBC] showing compelling activity with this new ADC.

Based on the presentation by Denise Yardley, MD, of Sarah Cannon Research Institute, what did the phase 3 NATALEE trial (NCT03701334) show about the efficacy of adjuvant ribociclib (Kisqali) plus an aromatase inhibitor in patients with HR-positive, HER2-negative early breast cancer?

NATALEE was exciting at the 2023 ASCO Annual Meeting. We have 1 FDA-approved CDK4/6 inhibitor in the adjuvant setting for high-risk patients. The [phase 3] monarchE trial [NCT03155997] led to the approval of abemaciclib [Verzenio]. NATALEE is also in the adjuvant setting, but instead of just being for patients who are high risk, it also includes patients who are intermediate risk, such as patients who do not have as many lymph nodes involved.

[The data presented at the 2023 ASCO Annual Meeting were] an early look at this trial; 74.7% of patients are still receiving ribociclib. However, we saw a 3.3% difference in [3-year] invasive disease–free survival [rates favoring ribociclib plus endocrine therapy over endocrine therapy alone]. With more maturity, we hope this translates to a bigger benefit and more patients being cured.

Some of the differences with ribociclib in NATALEE is it’s given for duration of 3 years, instead of 2 years with abemaciclib. [Patients also received ribociclib at a starting dose of] 400 mg in the adjuvant setting. Ribociclib can [cause] neutropenia, and we give it at 600 mg in the metastatic setting.

This is encouraging. [Ribociclib is] not currently FDA approved. However, [the NATALEE data] may eventually lead to an FDA approval, and [then we will] have more than 1 CDK4/6 inhibitor in the adjuvant setting. With the [findings from] NATALEE, more patients [may have access to ribociclib] than those [eligible for abemaciclib] in monarchE, which [included] a narrow population of patients with ultra-high-risk disease.

As discussed by Paolo Tarantino, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, how does sacituzumab govitecan-hziy (Trodelvy) fit into the treatment paradigm for patients with pretreated HR-positive disease?

Sacituzumab govitecan is another ADC. Those seem to be what we spend much of our time talking about, between trastuzumab deruxtecan being approved, sacituzumab govitecan being approved, and multiple new ADCs coming as well.

Sacituzumab govitecan is approved for patients with TNBC and those with HR-positive breast cancer. Patients with HR-positive disease should [first] exhaust their endocrine therapies. We’re not looking to give ADCs, or “chemo-substitutes,” up front. We still want patients to receive their endocrine therapies. Once patients’ tumors have become endocrine resistant, we consider chemotherapy.

Sacituzumab govitecan was [investigated] in patients who had already received chemotherapy, such as capecitabine or paclitaxel. We want to use ADCs. Whether we’re talking about trastuzumab deruxtecan or sacituzumab govitecan, these ADCs, in multiple breast cancer subtypes, are knocking the socks off chemotherapy, and in many cases, are better tolerated. [These are] encouraging data.

Regarding the presentation by Howard A. Burris, MD, of Sarah Cannon Research Institute, what is the importance of comprehensive molecular profiling in TNBC?

Profiling is important because [it helps us] find actionable [mutations]. It’s also important to move the field forward. If we don’t look for [mutations], we can’t design trials based on certain molecular alterations. We currently have drugs for breast cancer that are approved for TRK-mutated disease and tumor mutational burden–high disease, as well as for ESR1 mutations and PI3K alterations in ER-positive disease.

Especially in TNBC, which is not a homogenous tumor type, as patients with TNBC have many different drivers, [genetic testing] helps us direct patients [to appropriate] clinical trials, and may ultimately advance the field in terms of treating patients for the individual cancer and alterations they have and not using a one-size-fits-all approach with chemotherapy and non-targeted agents.

Based on the presentation by Andrew McKenzie, PhD, of Sarah Cannon Research Institute, what should clinicians know when testing for HER2 in patients with breast cancer?

There have been some changes with HER2. Traditionally, with drugs like ado-trastuzumab emtansine, the first ADC in breast cancer, we were trying to pick out patients with high HER2 expression, either 3+ by immunohistochemistry [IHC] or fluorescence in situ hybridization [FISH] positive. Trastuzumab deruxtecan changed that. This drug appeared to have activity even when HER2 expression was low, an IHC of 2+ that’s FISH negative or an IHC of 1+. Interestingly, the activity looks the same whether a patient is IHC 1+ or 2+, telling us patients don’t need much HER2 expression for a drug like trastuzumab deruxtecan to work. Now, with data from the [phase 2] DAISY trial [NCT04132960], we’re seeing responses even in [patients with] IHC 0.

At the 2023 ASCO Annual Meeting, data [showed] that the more [we perform] biopsies, the more likely we are to find an IHC-positive HER2 result, and that patients who had [received] 4 or 5 biopsies were guaranteed to have at least HER2-low disease. That raises several question: Should all patients receive trastuzumab deruxtecan? Do we need to select for this? Is IHC the best test for a drug like trastuzumab deruxtecan? HER2 IHC was never designed to pick out the lows or to differentiate a 0 result from a 1+ result. It was designed to pick out the highs, 3+. More quantitative methods of testing HER2 are being investigated.

This is an evolving field that may extend into other ADCs as well. For example, we don’t test TROP2 to give sacituzumab govitecan, and data from the 2023 ASCO Annual Meeting regarding patritumab deruxtecan [showed] that we didn’t need to pick patients with HER3-high disease to show benefit with that ADC, either.

What is your main message for colleagues regarding how the current breast cancer treatment paradigm may propel future advances?

Breast cancer [management] is rapidly changing considering the number of agents, targeted agents, and novel endocrine backbones in ER-positive disease; the emergence of immunotherapy and ADCs for TNBC; and new ADCs and a new way of thinking about expression in HER2-positive disease. It’s important for us to continue to enroll patients to clinical trials to determine optimal sequencing, [find] mechanisms of resistance to ADCs, and ultimately profile patients so we can find treatment regimens that are personalized for their cancers.

What breast cancer research is Sarah Cannon Research Institute participating in?

We have a great clinical trial menu right now. Regarding breast cancer drugs, we have many ADCs. [We are] seeing fantastic activity with both approved ADCs and those that aren’t approved. We have multiple new endocrine-targeting drugs. We’re seeing fulvestrant [Faslodex] move out of favor [and be replaced with] novel selective estrogen receptor degraders, PROTACs [proteolysis targeting chimeras], CERANs [complete estrogen receptor antagonists], and selective estrogen receptor modulators. We’ll see more endocrine backbones and targeted agents. Profiling is a big emphasis for us [so we can] match patients and their tumors onto the right clinical trials for them.


  1. Trastuzumab deruxtecan (T-DXd) with or without pertuzumab versus taxane, trastuzumab, and pertuzumab in HER2-positive metastatic breast cancer (DESTINY-Breast09). ClinicalTrials.gov. Updated July 19, 2023. Accessed July 25, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04784715
  2. Hamilton EP, Dosunmu O, Shastry M, et al. A phase 2 study of HER3-DXd in patients (pts) with metastatic breast cancer (MBC). J Clin Oncol. 2023;41(suppl 16):1004. doi:10.1200/JCO.2023.41.16_suppl.1004
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