Breast cancer (BC) is the most diagnosed cancer in women worldwide. In 2023, almost 300,000 cases of female breast cancer were diagnosed in the United States, of which approximately 20% wereHER2-positive.
Cancer is the result of an uncontrollable growth of cells that leads to tumor development. In HER2-positive BC, cells grow uncontrollably because of the excessive presence of the human epidermal growth factor receptor 2 (HER2). This protein is present on the surface of breast cells and captures signals from the outside, helping them to grow and repair normally. But, if there are too many proteins, breast cells receive too many signals and grow unchecked.
Identifying breast cancer as HER2-positivefacilitates clinical decision-making for guiding treatment with anti-HER2targeted therapies.
HER2 is routinely assessed in clinical practice in tumor biopsy samples using two methods:
The pathologist grades the extent of the staining. The results using these techniques can be ambiguous and are dependent on standardization and inter-observer variability, which hinders clinical decisions in the use of anti-HER2 therapy. The situation gets more complicated when HER2 heterogeneity appears.
HER2 intratumor heterogeneity refers to the variation in the expression levels of the HER2 protein within different areas of a single tumor. Within the same mass of cells, subpopulations with higher levels of HER2 expression may coexist with others with low or normal levels.
Diagnostic guidelines of the American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) define HER2 heterogeneity as HER2 positivity by FISHin 5-50% of tumor cells. HER2 heterogeneity has been reported in up to 40%of breast cancers and directly impacts the treatment selection. Treatments that target HER2 might be effective in parts of the tumor with high HER2 expression but less effective or ineffective in parts with low HER2 expression.
The presence of HER2 heterogeneity can influence the overall prognosis of the patient. A recent prospective clinical trial draws an association betweenHER2 heterogeneity and the lack of achieving a pathological complete response(pCR), the absence of detectable cancer cells in tissue samples after a patient has received treatment before surgery. None of the patients with HER2 heterogeneity achieved pCR after following dual HER2-targeted therapy, while55% of patients not classified as HER2 heterogeneous had a pCR.
Given the relatively poor response toanti-HER2 targeted therapy in patients with breast cancer, it is of great utility to rely on diagnostic tools that predict the potential evolution of the disease and guide medical doctors in choosing the optimal treatment. This heterogeneity means that different patients respond differently to the same treatment, opening a window to refine the treatment in every clinical case, either by de-escalating or escalating according to the specific characteristics of the tumor and the patient.
HER2 heterogeneity is also suspected to be related to treatment resistance, which places in the spotlight the goal of expanding the number of patients cured in the early setting and preventing recurrence. Accurate diagnostics, considering as much information as possible,allow accurate and tailored treatment selection, improving patient outcomes and quality of life.
The ASCO–CAP guidelines have continued to evolve to improve the accuracy and clinical utility of HER2 testing by providing specific algorithms. In the mission to improve patients’ quality of life through accurate treatment selection, REVEAL GENOMICS has developed HER2DX®.
HER2DX® is the first gene expression-based diagnostic tool to optimize HER2-positive breast cancer treatment, taking into account not only clinical but biological information about the tumor. It bridges the gap of HER2heterogeneity for prognostic and predictive purposes, helping healthcare professionals choose the optimal treatment for each patient.
The analysis of 27 genesi nvolved in 4 key biological processes related to tumor development is combined with tumor size and involvement of lymph nodes and integrated into an artificial intelligence algorithm that provides scores to predict disease evolution and guide treatment choices.
The DEFINITIVE project, a prospective clinical trial, is being conducted to validate its use. Funded by the European Commission, is a 5-year international phase III prospective clinical trial conducted in 44 centers in 7 countries involving 304 patients with early-stage (stage IIto IIIA) HER2-positive breast cancer.
Besides demonstrating that a personalized treatment guided by HER2DX® improves patients’ quality of life without affecting the outcome and survival rates, the study llustrates the value of this tool in daily clinical practice.
The study aims to compare the efficacy of treatment tailored by HER2DX® to that recommended by physicians based on local guidelines, focusing on the response rate during surgery to neoadjuvant treatment, the one given before surgery, alongside other clinical outcomes such as disease recurrence and metastasis.
It also evaluates health-related quality of life outcomes using consistent questionnaires and analyze the safety and tolerability of treatments by assessing adverse effects in terms of incidence, duration, and severity. Furthermore, the research measures physicians' confidence in therapeutic decisions when using the HER2DX® test compared to traditional methods, and assess the financial impact, including both direct and indirect costs, on hospitals and public health systems.
Additionally,the study explores the impact on work productivity through potential treatment de-escalation based on HER2DX® results, aiming to provide a comprehensive understanding of how HER2DX-guided therapy could influence overall treatment outcomes, costs, and quality of life,leading to its implementation in daily clinical practice.
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