A genetic signature for HER2-low tumors has been found that may solve a problem for those seeking wider use of drugs targeting such cancers, particularly antibody drug congugate (ADC) Enhertu (trastuzumab-deruxtecan/T-DXd). ADCs carry a payload that helps them be especially effective.
Their 20-gene signature, the team says, shows promise in distinguishing between HER2 0 and HER2-low expressing tumors, including those scored as 1+ at IHC, and in developing a selection approach for ADC candidates.
The study was published in Nature Scientifice Reports, and the lead author was Serena Di Cosimo of Milan’s Fondazione IRCCS Istituto Nazionale Dei Tumori.
In August 2022, the U.S. Food and Drug Administration (FDA) approved Enhertu for the treatment of patients with unresectable or metastatic HER2-low breast cancer. The drug was the first approved therapy for patients with the newly identified HER2-low breast cancer subtype.
Of the more than 287,000 news cases of breast cancer diagnosed in the U.S. last year, between 80% and 85% were previously considered to be HER2-negative subtype. Of those cases, as many as 60% of patients previously classified as having HER2-negative subtype can now be considered as HER2-low.
Assessment of Human Epidermal growth factor Receptor 2 (HER2) status is a standard practice in breast cancer diagnostics. Patients with breast cancer scoring 3+ at immunohistochemistry (IHC) and/or exhibiting gene amplification at in situ hybridization (ISH) are deemed HER2-positive. Tumors are considered negative for the marker when IHC scores are 0, 1+, or 2+ without amplification.
However, emerging evidence is challenging this binary classification.
For instance, in the DESTINY-Breast04 study, T-DXd demonstrated a 50% reduction in the risk of progression, and a 36% reduction in the risk of death in patients with HER2-low (IHC 1+, and 2+ without amplification) metastatic breast cancer (MBC). This finding led to the ongoing DESTINY-Breast06 trial, which is evaluating T-DXd in patients with even lower HER2 expression in MBC – IHC 0 or 1+. This level is referred to as ultralow.
Concerns have arisen regarding the reproducibility such testing in daily practice. Until now, pathologists have not needed to differentiate between IHC 0, with incomplete and faint staining in ≤ 10% of tumor cells, and IHC 1+, same staining intensity in > 10% of tumor cells. Nor have they been required to distinguish IHC 1+ from 2+ showing weak to moderate staining.
This team aimed to analyze breast cancer gene expression profile (GEP) with respect to HER2 IHC categories, and to train a genomic classifier for identifying HER2-low tumors.
In clinical trials evaluating ADCs, HER2-low breast cancer is defined through protein immunohistochemistry scoring (IHC) 1+ or 2+ without gene amplification. However, in daily practice, the accuracy of IHC is compromised by inter-observer variability.
The team “…aimed to identify HER2-low breast cancer primary tumors by leveraging gene expression profiling. A discovery approach was applied to gene expression profile of institutional INT1 (n = 125) and INT2 (n = 84) datasets.”
They identified differentially expressed genes (DEGs) in each specific HER2 IHC category 0, 1+, 2+ and 3+. A HER2-low signature was computed based on HER2 IHC category-specific DEGs. The twenty genes included in the signature were significantly enriched with lipid and steroid metabolism pathways, peptidase regulation, and humoral immune response.
