Navigating HER2+ Breast Cancer: From Diagnosis to Treatment Options

Breast cancer presents as a complex and highly heterogeneous disease, characterized by significant inter- and intra-tumoral variability. Current clinical classifications rely on the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) to stratify breast cancer into 3 major immunohistochemical subtypes - ER+HER2 negative, HER2 positive and Triple-Negative breast cancer. Advanced analyses employing transcriptional and genomic profiling have revealed a more granular stratification of breast cancer into several distinct molecular subtypes.



HER2-positive breast cancer affects about 20% of patients and represents a particularly aggressive subtype with a high risk of metastasis.



The current standard of care for high-risk HER2-positive breast cancer involves a combination of chemotherapy and dual anti-HER2 therapy. Two monoclonal antibodies that bind to HER2 receptors, trastuzumab and pertuzumab showed 50-70% pathological complete response rates (pCR) in clinical trials. As therapies evolve and move to earlier stages, personalized treatment is key. Early detection significantly increases the likelihood of successful treatment outcomes and the possibility of less invasive procedures.



HER2DX® from Reveal Genomics is the first genomic tool for patients with early-stage HER2+ breast cancer that is intended to help healthcare professionals to select the best treatment option for patients with early-stage HER2+ breast cancer. HER2DX® measures the expression of 27 genes from Formalin-Fixed, Paraffin-Embedded (FFPE) breast cancer tissues, along with the expression of 4 genomic signatures tracking immune activation, tumor cell proliferation, luminal differentiation, and expression of the HER2 amplicon (including ERBB2). The information obtained from the genomic signatures is combined with tumor and nodal stages to build a relapse risk score and a pathological complete response (pCR) likelihood score.



HER2-positive breast cancer prognosis has dramatically improved due to technological advancements, such as Antibody Drug Conjugates (ADCs) that revolutionized anti-cancer therapy.



These targeted therapies enhance chemotherapy effectiveness by delivering potent cytotoxic drugs directly to tumor cells, minimizing exposure to healthy tissues. AstraZeneca and Daiichi Sankyo are jointly developing and commercializing Enhertu, a HER2-directed antibody-drug conjugate (ADC) for patients with HER2-low metastatic breast cancer whose disease progressed after prior systemic therapy in the metastatic setting, or recurred during or within six months of completing adjuvant chemotherapy. HER2+ tumors. HER2-low breast cancers represent 15-20% of all breast cancers. Despite being classified as HER2-negative, some tumors still exhibit some level of HER2 expression. Until the approval of Enhertu by FDA, there were no targeted therapies specifically for HER2-low and HER2-ultralow metastatic breast cancer.

A major hurdle in HER-directed therapy is development of resistance requiring treatment adjustments. Liquid biopsies, by enabling the identification of effective biomarkers, have revolutionized the way clinicians understand breast cancer at the molecular level. Biomarkers in cell-free DNA (cfDNA) and circulating tumor cells (CTCs), as well as specific nucleic acid fractions like circulating tumor DNA (ctDNA), circulating tumor RNA (ctRNA), microRNAs (miRNAs), exosomes, proteins, metabolites etc., can capture unique genetic information of the tumor to advance early detection and continuous monitoring of treatment response. These biomarkers are present at very low levels in the blood, however several enrichment and sensitive detection technologies have emerged that could improve the diagnostic accuracy of breast cancer. The emerging use of paired plasma and CSF (cerebrospinal fluid ) liquid biopsies offers a potential advancement in the management of HER2-positive breast cancer patients with brain metastasis.

Ongoing research focuses on identifying and validating reliable biomarkers, resistance mechanisms, and novel therapies to optimize treatment and potentially eliminate the need for surgery in some patients.