HER2DX Genomic Assay Predicts Pathological Response in Early Stage HER2-Positive Breast Cancer

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence.

The HER or ERBB family of receptors, consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Patients with HER2-positive breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes.

HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2. It binds to the extracellular subdomain IV of the receptor and disrupts ligand independent HER2 downstream cell signaling pathways. PERJETA® (Pertuzumab) is a recombinant, humanized, monoclonal antibody that binds to the HER2 subdomain II and blocks ligand dependent HER2 heterodimerization with other HER receptors, ie., HER3, HER1 and HER4. Thus Trastuzumab along with Pertuzumab provide a more comprehensive blockade of HER2 driven signaling pathways, which has been attributed to differing mechanisms of action and synergistic interaction.

In the NeoSphere Phase II trial, among patients with locally advanced, inflammatory, or early HER2-positive breast cancer, the addition of Pertuzumab to Trastuzumab and Docetaxel led to a statistically significant and clinically meaningful 16.8% increase in pathologic Complete Response rate (pCR) in the breast and a 17.8% increase in total pCR in the breast and axilla. Further, the addition of one year of Pertuzumab to Trastuzumab-based chemotherapy improved invasive Disease Free Survival, but this benefit was restricted to patients with node-positive disease and no Overall Survival benefit was observed. The benefits of Pertuzumab in early-stage HER2-positive disease were modest. Biomarkers beyond HER2 status are therefore needed, to guide the use of Pertuzumab in the treatment of early-stage HER2-positive breast cancer.

HER2DX (Reveal Genomics) is a novel clinically available genomic test that measures the expression of 27 genes from Formalin-Fixed, Paraffin-Embedded (FFPE) breast cancer tissues. This assay integrates biologic information such as Immune infiltration, luminal differentiation, tumor cell proliferation and HER2 amplicon expression from 4 gene signatures, with clinical data such as tumor stage and nodal stage.

The present study was conducted to determine if the use of HER2DX genomic assay in pretreatment baseline tissue samples of patients with early-stage ERBB2-positive breast cancer, predicted response to neoadjuvant Trastuzumab-based chemotherapy with or without Pertuzumab. This analysis is a retrospective, multicenter, observational study conducted in Spain from 2018 to 2022. In addition, a combined analysis with 2 previously reported trials of neoadjuvant cohorts, with results from the assay (DAPHNe and I-SPY2) was performed. All patients had Stage I-III ERBB2 (HER2) positive breast cancer, and clinical T1- T2 and node-positive disease was present in 72.9% and 63.9% patients, respectively, and 67.7% tumors were hormone receptor positive. The mean age was 50 years and all patients had Formalin-Fixed Paraffin-Embedded tumor specimens available prior to starting therapy. Patients received Trastuzumab, 8 mg/kg IV as a loading dose, followed by 6 mg/kg IV every 3 weeks in combination with Docetaxel, 75 mg/m2 IV every 3 weeks and Carboplatin AUC of 6 IV every 3 weeks for 6 cycles, or this regimen plus Pertuzumab, 840 mg IV as a loading dose, followed by an 420 mg IV every 3 weeks for 6 cycles. HER2DX genomic assay was evaluated in 155 patients with ERBB2-positive breast cancer. The main outcome measures were the association of baseline assay-reported pathologic Complete Response (pCR) score with pCR in the breast and axilla, as well as association of baseline assay-reported pCR score with response to Pertuzumab.

The overall pCR rate was 57.4%. The assay-reported pathologic Complete Response (pCR) score showed statistically significant association with pCR in the breast and axilla following Trastuzumab-based chemotherapy independent of Pertuzumab use. The pCR rates in the breast and axilla in the assay-reported pCR-high and pCR-low groups were 75.0% and 28.3%, respectively (Odds Ratio=7.85; P<0.001). In the combined analysis of DAPHNe and I-SPY2 trials (N=282), assay-reported pCR-high tumors had an increase in pCR rate in the breast and axilla with the use of Pertuzumab (Odds Ratio=5.36; P<0.001), and this benefit was not seen in the assay-reported pCR-low tumors (Odds Ratio=0.86; P=0.77). A statistically significant interaction was observed between the assay-reported pCR score and the effect of Pertuzumab on pCR in the breast and axilla.

It was concluded that HER2DX genomic assay provides clinically meaningful information to guide therapeutic decisions, and can predict pCR following neoadjuvant Trastuzumab-based chemotherapy with or without Pertuzumab, independent of known clinical-pathological variables and intrinsic subtype. This assay could guide therapeutic decisions regarding the use of neoadjuvant Pertuzumab and can reliably identify patients who might be ideal candidates for neoadjuvant taxane, Trastuzumab and Pertuzumab.

Assessment of a Genomic Assay in Patients With ERBB2-Positive Breast Cancer Following Neoadjuvant Trastuzumab-Based Chemotherapy With or Without Pertuzumab. Bueno-Muiño C, Echavarría I, López-Tarruella S, et al. JAMA Oncol. Published online April 27, 2023. doi:10.1001/jamaoncol.2023.0187