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Paving the Way for Better Outcomes in HER2+ Early Breast Cancer Treatment
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Trastuzumab deruxtecan and trastuzumab emtansine address key challenges such as recurrence and metastases in HER2+ early breast cancer treatment.
Optimizing treatment for early-stage human epidermal growth receptor 2 (HER2)-positive (HER2+) breast cancer (BC) requires a nuanced approach, integrating targeted therapies and personalized strategies to enhance outcomes and minimize recurrence risks for patients. Experts at the 2024 San Antonio Breast Cancer Symposium in San Antonio, Texas, offered meaningful insights into the novel antibody drug conjugates (ADCs) trastuzumab deruxtecan (T-DXd, Enhertu; Daiichi Sankyo) and trastuzumab emtansine (T-DM1, Kadcyla; Genentech) in the adjuvant and neoadjuvant setting, highlighting existing clinical challenges and approaches to overcoming them.1
Illustration of trastuzumab, pertuzumab antibody therapy | Image Credit: © LASZLO - stock.adobe.com
HER2-positive breast cancer accounts for about 20% of all breast cancer diagnoses, accounting for 297,790 women in 2023 alone. The development of novel therapies targeting HER2 receptors has significantly improved disease-free survival rates for patients with HER2+ early BC (EBC) over the past 50 years. In the 1980s, prognoses for these patients were very poor at a 35%, with a disease-free survival rate of just 35% when treated with local therapy alone. This has improved to 85% disease-free survival with the use of HER2-targeted therapies like T-DXd, T-DM1, and pertuzumab (Perjeta; Genentech), which have demonstrated improved safety and efficacy in the adjuvant and neoadjuvant settings.2
T-DXd is a novel antibody drug conjugate (ADC) that received FDA approval on April 5, 2024, for adult patients with unresectable or metastatic HER2+ solid tumors. This expanded its former treatment landscape beyond metastatic BC (MBC), colorectal, gastric, and non–small cell lung cancers. Key trial data, including the DESTINY-Breast03 (NCT03529110) and DESTINY-Breast06 (NCT04494425) trials, T-DXd showed significant improvements in PFS of 28 months for HER2+ MBC. The efficacy of the agent was supported by real-world results reported in DESTINY-Breast 12 trial (NCT04739761). In DESTINY-Breast 11 (NCT05113251), T-DXd is being evaluated in both the adjuvant and post-neoadjuvant settings.2-7
“DESTINY-Breast 11, with results anticipated next year, initially included 3 arms: T-DXd monotherapy for 8 cycles, T-DXd for 4 cycles followed by TCH [docetaxel (Docefrez; Sun Pharmaceutical Industries Europe B.V.), carboplatin (Paraplatin; Bristol-Myers Squibb), and trastuzumab (Herceptin; Herzuma, Ontruzant)], and AC [doxorubicin (Lipodox; Sun Pharma) and cyclophosphamide (Cytoxan; Amneal Pharmaceuticals, Inc)] for 4 cycles followed by TCH for 4 cycles,” said Gabe Sonke, MD, medical oncologist from the Netherlands Cancer Institute, Amsterdam, Netherlands. “However, based on the IDMC's [Independent Data Monitoring Committee] recommendation, the T-DXd monotherapy arm was closed prematurely. We are now awaiting the results from the remaining 2 arms, which will hopefully be presented next year."
T-DM1 is another novel HER2-targeted ADC composed of trastuzumab, a stable thioether linker, and the potent cytotoxic agent DM1. It was approved by the FDA in 2019 based on KATHERINE (NCT01772472), a randomized, multicenter, open-label trial of 1486 patients with HER2-positive EBC. The researchers assessed T-DM1 in the post-neoadjuvant setting, comparing invasive disease-free survival (IDFS) in patients receiving either T-DM1 or trastuzumab. According to the data, T-DM1 showed significant improvement in IDFS compared to trastuzumab. At 7-years the IDFS rate was 80% with T-DM1 and 67% with trastuzumab. The hazard ratio for IDFS was 0.50, indicating a 50% reduction in risk with T-DM1. When in the adjuvant setting, there was an (OS) survival benefit of 4.7% at 7 years.8-10
Beyond ADCs, endocrine therapy (ET) remains a critical treatment component for patients with HER2+ EBC. With the advent of targeted therapies, these therapies are primarily being used in combination with ADCs and their continued optimization is essential. This is especially important for premenopausal patients, where the use of ovarian function suppression plus an aromatase inhibitor yielded better outcomes based on data from an exploratory analysis of the HERA trial (NCT00045032).11
Joyce O'Shaughnessy, MD, medical oncologist at Texas Oncology, diplomate of the American Board of Internal Medicine, and founder of The School of Breast Oncology, suggested the potential to further optimize ET by combining it with CDK4/6 inhibitors as a strategy to improve outcomes for patients with high-risk, HER2+ EBC. Additionally, she mentions that using pathologic complete response (pCR) as a key end point in clinical study. Achieving a pCR, defined as no residual invasive disease in the breast and lymph nodes, is associated with improved long-term outcomes.
Illustration of metastatic breast cancer cells spreading through bloodstream | Image Credit: © Sara_P - stock.adobe.com
Certain biomarkers, such as high tumor-infiltrating lymphocytes and high HER2 expression, are associated with higher pCR rate compared with presence of PIK3CA mutations and intratumoral heterogeneity, which are associated with lower pCR rates.
"The presence of intratumoral heterogeneity, where not all tumor cells express HER2, was associated with lower pCR rates in the neoadjuvant setting,” stated O'Shaughnessy.
These findings suggests that biomarkers including HER2 expression, genomic risk scores, and intratumoral heterogeneity within the tumor can potentially predict therapy response, aiding in better treatment decisions for individual patients. Additionally, researchers from the ARIADNE trial (NCT05900206) are exploring use of biomarkers or early response assessment to guide treatment intensification or de-escalation in the neoadjuvant setting.12
The overall goal of de-escalation strategies is to optimize the therapeutic index to maximize efficacy, as well as minimize the toxicity and treatment burden for patients. For many who are cured with current standard treatments, there may be opportunities to reduce the treatment burden by de-escalating therapy through omitting methods such as omitting chemotherapy (CTx) or reducing the duration of HER2-targeted therapy in select low-risk patients.
Another approach is de-escalated regimens, which have the potential to maintain long-term outcomes. This is particularly relevant for premenopausal patients, where CTx can have significant adverse effects like neuropathy and amenorrhea. Eliminating or reducing CTx in HER2+ EBC treatment can minimize toxicity, improve quality of life, and avoid overtreatment for patients. Using biomarkers and early response assessment, O’Shaughnessy suggested that it may be possible to identify the 10% to 20% of patients who are at higher risk of recurrence who may benefit from more intensive treatments without compromising OS.
“Can we identify the 10% of patients who still relapse, and can we improve the efficacy for these patients? And conversely, can we reduce the treatment burden for the 90% of patients who are cured?” she questioned.
There are various potential approaches for integrating de-escalation such as the aforementioned use of biomarkers, as well as MRI-based response assessments to guide treatment de-escalation in patients receiving 3, 6, or 9 cycles of CTx based on their early response. This method of de-escalation aims to minimize CTx exposure for those with favorable early responses. CTx-free regimens using HER2-targeted therapy alone in select patients has shown benefit in the PHERGain trial (NCT03161353) evaluating neoadjuvant and adjuvant pertuzumab plus trastuzumab without CTx, showing excellent 3-year outcomes.13
Vial of chemotherapy | Image Credit: © Bernard Chantal - stock.adobe.com
Given the insights from the PHERGain trial and other de-escalation strategies, there are significant opportunities to refine HER2+ BC treatment approaches for high-risk patients and those with residual disease. Patients with RCB-2 and RCB-3 residual disease after neoadjuvant therapy have a higher risk of recurrence, even with chemotherapy and HER2-targeted therapy. Data from the KATHERINE trial indicates that adding T-DM1 to standard trastuzumabled to improved IDFS and OS for this population.
Emerging and novel therapies continue to pave the way to improved treatments for patients with HER2+ EBC, addressing challenges such as central nervous system (CNS) metastases. HER2-targeted agents including tucatinib (Tukysa; Array BioPharma) and T-DXd have become particular points of interest to researchers. According to data from the HER2CLIMB trial (NCT02614794), 47% of patients achieved a CNS response rate and a 35% CNS progression-free, indicating effectiveness of tucatinib in managing CNS metastases in HER2+ BC.14
Another emerging agent gaining attention is neratinib (Nerlynx; Puma Biotechnology, Inc), an oral pan-HER tyrosine kinase inhibitor, for use as adjuvant therapy for patients who completed trastuzumab. In the ExteNET trial (NCT00878709), researchers randomized patients to receive either neratinib or placebo for 1 year after finishing their adjuvant trastuzumab. The data showed a 2.5% absolute improvement in 5-year IDFS compared with placebo, a 7.4% improvement in 5-year IFDS, and a 9.1% improvement in OS. Based on these results, neratinib received regulatory approval in the European Union for the extended adjuvant treatment of hormone receptor-positive and HER2+ EBC.15
Optimizing treatment for HER2+ EBC requires a nuanced approach, integrating targeted therapies and personalized strategies to enhance outcomes and minimize recurrence risks for patients. The future of HER2+ EBC treatment holds great promise with the development of HER2-targeted therapies, such as T-DXd and T-DM1. However, several challenges persist including managing the risk of recurrence, CNS metastases, and ensuring optimal integration of endocrine therapy. By fostering collaboration among clinicians, researchers, and patients, we can overcome the remaining challenges and ensure that every patient receives the best possible care, paving the way for improved outcomes, quality of life, and long-term survival.
