Stearns Elaborates on the Evolution of ADCs in HER2+ and HER2-Low Breast Cancer

Vered Stearns, MD, FASCO, discusses how DESTINY-Breast04 has shifted the treatment paradigm for patients with HER2-low breast cancer, the exploration of treatment combinations being optimized in breast cancer, and the expansion of the treatment paradigm in triple-negative breast cancer.

Vered Stearns, MD, FASCO

Vered Stearns, MD, FASCO

Antibody-drug conjugates (ADCs) continue to alter the management of breast cancer, including fam-trastuzumab deruxtecan-nxki (Enhertu) in patients with HER2-positive and HER2-low disease, according to Vered Stearns, MD, FASCO. She added that trials, such as the pivotal phase 3 DESTINY-Breast04 trial (NCT03734029) in patients with unresectable or metastatic HER2-low breast cancer, have been practice changing in the utilization of trastuzumab deruxtecan.1

“I look forward to further discussing with pathologists and other colleagues how to refine the evaluation of HER2 status within tumors. However, suffice to say that [there are] important new therapeutics for patients with HER2[-low disease], providing significant, substantial progression-free survival [PFS] and overall survival [OS] benefits,” Stearns said in an interview with OncLive® following an Institutional Perspectives in Cancer webinar on breast cancer.

In the interview, Stearns, who chaired the event, discussed how DESTINY-Breast04 has shifted the treatment paradigm for patients with HER2-low breast cancer, the exploration of treatment combinations being optimized in breast cancer, and the expansion of the treatment paradigm in triple-negative breast cancer (TNBC). Stearns is the director of the Women’s Malignancies Disease Group and a professor of oncology at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine.

OncLive®: How have genomic profiles shifted the treatment of patients across the breast cancer spectrum?

Stearns: Breast cancer is a common malignancy in the United States and in Western societies, and most women are diagnosed with early stages of HER2-positive disease. In the past few years and decades, we’ve refined our treatment algorithms based on broad categories that include patients who have hormone receptor [HR]–positive breast cancer vs HER2-positive breast cancer vs TNBC, which do not have the estrogen, progesterone, or HER2 receptors. But recent findings have allowed us to refine even more specific treatments for individual patients. Those include defining risk, based on genomic profiles; the presence of germline mutations, such as having a BRCA mutation; and immune-related biomarkers, which are still emerging.

In addition to our broad categories, we have had findings [in recent years] from large studies that provided us with additional information to [create] more individualized approaches to care for patients, such as genomic profiles to determine a need for chemotherapy in addition to endocrine therapy in patients with HR-positive breast cancer, or the use of new medications for patients based on germline mutations, such as BRCA mutations and immune biomarkers.

How has risk driven new adjuvant treatment strategies in early-stage HR-positive disease?

I addressed some of the main changes in our practice that occurred in recent years. First, I talked about endocrine manipulations, [which are] the most common adjuvant treatment in early-stage breast cancer. Traditionally, we have used 5 years of tamoxifen or aromatase inhibitors, or, in premenopausal women, ovarian suppression. Duration of treatment is a topic that continues to be discussed [to see if we can] refine the approach. One of the things I’m excited about is the ability to include biomarkers that will allow us to understand with more certainty who needs prolonged treatment vs 5 years or less or even no endocrine therapy.

We also discussed incorporating the CDK4/6 inhibitor abemaciclib [Verzenio] in high-risk patients with early-stage, HR-positive breast cancer, based on the phase 3 monarchE trial [NCT03155997]. This study demonstrated that patients with HR-positive, HER2-negative, early-stage breast cancer with a high risk of recurrence and a KI-67 score of 20% or more may be good candidates for the addition of abemaciclib to endocrine therapy, [which the FDA approved as a combination in October 2021].

How have oncologists optimized treatment to address over-treating patients?

I also talked a bit about neoadjuvant therapy and how the use of either chemotherapy with immunotherapy, such as pembrolizumab [Keytruda] in TNBC, or with anti–HER2 agents in HER2-positive disease can allow us to refine the need for additional treatment in patients. For example, if a patient receives a standard treatment in a neoadjuvant setting and has a complete resolution of their cancer or pathological complete response [pCR], they may not require a change or additional treatment following local therapy. But if there’s significant residual disease, we can use the data to maybe provide more therapy or alter the treatment plan.

If there is residual disease, one approach is to provide capecitabine [as maintenance therapy], based on the phase 3 CREATE-X trial [UMIN000000843].

In patients who receive the regimen from the phase 3 KEYNOTE-522 trial [NCT03036488] consisting of pembrolizumab plus paclitaxel/carboplatin, followed by pembrolizumab with doxorubicin and cyclophosphamide, [if they] have good resolution of their cancer, specifically a pCR, the question is whether they need to continue pembrolizumab beyond surgery. That is still an open question and a subject of new clinical trials.

Importantly, the FDA approved [neoadjuvant] pembrolizumab plus chemotherapy [followed by adjuvant single-agent pembrolizumab] for high-risk, early-stage TNBC. The benefit of this treatment that has been observed was irrespective of nodal status.

How is pCR used to guide subsequent therapy in early-stage HER2-positive disease?

Regarding patients with stage II/III clinical breast cancer that’s HER2­-positive, [we have considered] neoadjuvant chemotherapy and an anti–HER2 therapy. Our most common regimen has been docetaxel/carboplatin with trastuzumab [Herceptin] and pertuzumab [Perjeta]. If a patient has a pCR, they continue with trastuzumab and pertuzumab. If there is not a pCR, it is important to transition the patients to ado-trastuzumab emtansine [T-DM1; Kadcyla]. Patients who have small, node-negative breast cancer, in those that are estrogen receptor [ER]–positive, my approach is still to consider surgery first, because some of these patients may be able to benefit from less treatment, such as adjuvant paclitaxel and trastuzumab, or docetaxel/carboplatin plus trastuzumab.

How have PARP inhibitors become engrained in the adjuvant treatment of BRCA-mutated breast cancer?

The phase 3 OlympiA trial [NCT02032823], which reported in 2021 and was updated more recently in 2022, has changed the landscape of treatment for patients with early-stage breast cancer who carry a BRCA mutation.

In the study, patients have received prior standard-of-care therapy, including chemotherapy and local therapy, were randomized to receive maintenance olaparib [Lynparza] or placebo for 1 year. The study investigator’s reported significant improvement in [disease]-free survival. More recently, with a median follow up of 3.5 years, there was a significant OS benefit [with olaparib]. I have been incorporating this treatment for my patients who meet the criteria of this study.

Raquel Nunes, MD, of Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, discussed advances in the treatment of HR-positive/HER2-negative breast cancer. In what populations have oral selective estrogen receptor degraders (SERDs) shown the most benefit?

My colleague discussed updates related to the treatment of patients with metastatic HR-positive breast cancer, and there have been numerous recent advances. However, one of the topics that we remain excited about is the incorporation of oral SERDs into treatment of this disease entity. In particular, the phase 3 EMERALD trial [NCT03778931] was reported recently in which patients received either investigator’s choice of endocrine treatment vs the oral SERD elacestrant [RAD-1901].

Importantly, recent presentations have demonstrated that the oral SERD was associated with significant improvement in PFS, and this improvement was seen in all patients, particularly in patients with tumors harboring an ESR1 mutation. This is an agent being reviewed now by the FDA and one I hope can be added to our treatment portfolio soon.

Antonio Wolff, MD, of Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, discussed new approaches for the management of HER2-positive breast cancer. How have the phase 3 DESTINY-Breast03 (NCT03529110) and DESTINY-Breast04 trials helped move the space forward?

ADCs have emerged and continued to have a role in our clinic. In particular, trastuzumab deruxtecan has been used primarily in our patients who have HER2-positive breast cancer, initially as a third-line and beyond therapy. But, more recently, based on DESTINY-Breast03, [it has been used as] a second-line therapy.

Results from DESTINY-Breast04 were presented at the 2022 ASCO Annual Meeting and published in the New England Journal of Medicine.2 The data showed that trastuzumab deruxtecan provided significant benefits to patients, which we today designate as having tumors with HER2-low disease.

Carlos A. Santa-Maria, MD, MSCI, of Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, spoke about updates in TNBC. How have combination treatments pushed this space forward?

My colleague gave us an update regarding the role of immune checkpoint inhibitors in metastatic TNBC. I’m excited, as we do have a pembrolizumab approval with chemotherapy, demonstrating PFS and OS benefit in patients who have PD-L1–positive metastatic TNBC. Moreover, pembrolizumab can be combined with paclitaxel, nab-paclitaxel [Abraxane], or gemcitabine. Data are in the first-line setting.

Pembrolizumab has also produced [activity as] monotherapy in patients that have MSI [microsatellite instability]–high disease or a high tumor mutation burden. Moving forward, we will learn about additional immune checkpoint inhibitors that may be providing benefits to patients in this setting and for patients with other tumor subtypes. I’m also hopeful that we can refine the biomarkers that will provide predictions of benefit to these and emerging immune checkpoint inhibitors.

What is your hope for the future of breast cancer treatment?

Breast cancer continues to be a common diagnosis in Western society. Many patients will have early disease, and with multidisciplinary treatment and some of the new approaches that were discussed here, most will survive their cancer. Our job is to optimize the treatment for individual patients to reduce potential morbidity and long-term adverse effects [AEs] to our patients for them to live well beyond their initial diagnosis.

Patients with metastatic disease also have many options today. Those treatment options provide them improved PFS and OS benefits. Again, our job is to try and determine other ways to improve their life with cancer and to minimize potential AEs. I’m excited about new treatment approaches, and for some of the emerging treatments and biomarkers that will help us refine treatment.


  1. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients (pts) with HER2-low unresectable and/or metastatic breast cancer (mBC): results of DESTINY-Breast04, a randomized, phase 3 study. J Clin Oncol. 2022;40(suppl 17):LBA3. doi:10.1200/JCO.2022.40.17_suppl.LBA3
  2. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022. 387(1):9-20. doi:10.1056/NEJMoa2203690
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