An Overview of Clinical Development of Agents for Metastatic or Advanced Breast Cancer Without ERBB2 Amplification (HER2-Low)

Abstract

ImportanceErb-b2 receptor tyrosine kinase 2 (ERBB2; formerly HER2 [human epidermal growth factor receptor 2]) is an important prognostic and predictive factor in breast cancer. Anti-ERBB2 therapies have improved outcomes in ERBB2-positive breast cancer. However, based on current definitions, tumors with low ERBB2 expression are included in the ERBB2-negative subtype, and therefore, are ineligible for anti-ERBB2 therapies; patients with ERBB2-low (immunohistochemistry [IHC] 1 positive [+] or IHC 2+/in situ hybridization [ISH] negative [−]) tumors account for up to approximately 50% of breast cancer cases. Although the prognostic role of ERBB2-low needs to be defined, ERBB2 offers a potential therapeutic target in these patients.ObservationsMost breast cancer tumors have some ERBB2 expression, with ERBB2-low being more common in hormone receptor–positive than in hormone receptor–negative breast cancer. Although an early clinical study failed to demonstrate benefit of adjuvant trastuzumab for ERBB2-low disease, several novel anti-ERBB2 therapies have shown efficacy in ERBB2-low breast cancer, including the antibody-drug conjugate trastuzumab deruxtecan in a phase 3 trial, and trastuzumab duocarmazine and the bispecific antibody zenocutuzumab in early-phase studies. Although reports are conflicting, some differences in biology and patient outcomes have been found between ERBB2-low and ERBB2 IHC-0 breast cancer. Currently, no established guidelines exist for scoring ERBB2-low expression in breast cancer because the focus has been on binary classification as ERBB2-positive or ERBB2-negative. Additional interpretive cutoffs may be needed to select patients for treatment with effective agents in ERBB2-low breast cancer, along with standardized laboratory quality assurance programs to ensure consistent patient identification for eligibility for ERBB2-low targeting agents.Conclusions and RelevanceThis review suggests that ERBB2-low may be a distinct, clinically relevant breast cancer entity warranting reassessment of traditional diagnostic and therapeutic paradigms. Ongoing clinical trials and further investigations may provide optimized strategies for diagnosing and treating ERBB2-low breast cancer, including reproducible, consistent definitions to identify patients in this diagnostic category and demonstration of benefits of emerging therapies.

Discordance of HER2-low between primary tumors and matched distant metastases in breast cancer

“…The need to relativize the traditional dichotomization between HER2-positive and HER2-negative appeared at the latest with the results of the DESTINY-Breast04 trial, which demonstrated the superiority of trastuzumab-deruxtecan (T-DXd) vs chemotherapy of the physician's choice in patients with advanced HER2-low breast cancer [20]. In addition, other HER2targeting antibody-drug conjugates (ADCs) like trastuzumab duocarmazine showed promising activity in early studies [30]. In our previous study, we reported a rate of 48.3% HER2-low tumors, which was within the range of approximately half of HER2-negative breast cancer patients (31.0-60.6%) reported by Prat and coworkers in a recent review article [1,30].…”

“…In addition, other HER2targeting antibody-drug conjugates (ADCs) like trastuzumab duocarmazine showed promising activity in early studies [30]. In our previous study, we reported a rate of 48.3% HER2-low tumors, which was within the range of approximately half of HER2-negative breast cancer patients (31.0-60.6%) reported by Prat and coworkers in a recent review article [1,30]. Since 80-85% of all breast cancer tumors have a HER2negative phenotype, which was 85.2% in our study, a better understanding of this cohort has potential therapeutic implications for the majority of breast cancer patients.…”

The trichotomy of HER2 expression confers new insights into the understanding and managing for breast cancer stratified by HER2 status

“…In addition to BC with HER2-low, some ADCs are also effective for some BC patients classified as HER2-zero, thanks to the bystander effect of ADCs. 59,60 The emergence of ADCs has brought revolutionary changes to the HER2-low/zero BC field. There are still many different classes of drugs in academia that have shown therapeutic activity in this field.…”

“…Scholars have found that they can play a role in BC patients with HER2-low. 59,62,63 In addition, tri-specific antibodies are also gradually on the stage. Zheng et al 64 found that trispecific antibodies consisting of HER2, CD3, and CD28 arms can promote the regression of tumors with HER2 overexpression or low expression by stimulating CD4 T cells at a very low dose, which may provide the new drug development for the treatment of HER2-low/ zero BC.…”

A Brand New BRCA-CRisk Model Precisely Predicts the Prognosis of Patients With Breast Cancer and BRCA1/2 Mutation

“…Third, novel HER2 antibody-drug conjugates demonstrating efficacy in HER2-low-expressing breast cancers (BCs), which are currently defined as those with immunohistochemistry scores of 11 or 21 and a negative in situ hybridization assay, 4 have drawn great attention. Particularly, HER2-low patients have a high incidence of germline BRCA mutation and were recently confirmed to have a better survival than HER2-zero patients.…”