Breast cancer (BC) is the most common cancer among women worldwide. Between 15 and 25% of diagnosed breast cancer are characterized by an over expression of the HER2 protein, which promotes the growth of cancer cells. This makes HER2-positive breast cancer a more aggressive type with a lower overall survival rate.
Fortunately, advances in medicine have led to the development of targeted therapies that can significantly improve patient outcomes.
The stage of HER2-positive breast cancer significantly influences the chosen treatment. For patients with Stage II and III, the recommended approach by the European Society of Medical Oncology (ESMO) Guidelines begins with neoadjuvant therapy, which is treatment given before surgery. The goal of neoadjuvant therapy is to shrink the tumor,making it easier to remove surgically and to assess the cancer’s response to treatment.
After neoadjuvant treatments, about 50-65% of patients achieve a pathological complete response (pCR)—meaning no detectable cancer cells in the tissue sample after neoadjuvant therapy. This is an indicator of a positive outcome and reduced risk of recurrence.
Current guidelines recommend using a combination of chemotherapy and monoclonal antibodies that specifically target the overexpressed HER2 protein as neoadjuvant therapy for HER2+ breast cancer. The NeoSphere trial supported the use of dual HER2 blockade with trastuzumab and pertuzumab in combination with chemotherapy in the neoadjuvant setting. It showed that this approach not only increases the likelihood of achieving pCR,compared to trastuzumab alone but also leads to better long-term outcomes.
Chemotherapy in neoadjuvant regimens involves a combination of anthracyclines and taxanes, or taxanes with carboplatin, known as multi-agent chemotherapy. Anthracycline-based regimens have historically been the first option for HER2-positive breast cancer. However, with newer treatments that combine multiple anti-HER2 agents, several trials have explored combinations that do not include anthracyclines. The goal is to reduce side effects and enhance patients' quality of life.
Once the surgery is complete, adjuvant therapy, treatment given post-surgery, can be tailored based on the pCR status. For patients who achieve pCR, the adjuvant therapy is predominantly trastuzumab administrated for 1year. This recommendation is based on the findings from the HERA trial, which contrasted2 years versus 1 year of treatment, showing that prolonging the same anti-HER2therapy beyond 12 months does not enhance efficacy. Conversely, the debate around the adequacy of shorter durations of trastuzumab is ongoing and somewhat contentious.
For patients who do not achieve pCR, the KATHERINE trial provided essential guidance. This study evaluated the efficacy of trastuzumab emtansine (T-DM1), an antibody-drugconjugate, as an alternative to trastuzumab alone. The results showed thatT-DM1 is more effective in reducing the risk of recurrence for patients with residual disease after neoadjuvant therapy, and it is now recommended in these cases.
Several clinical questions regarding the optimal neo/adjuvant treatment in HER2+ breast cancer remain unanswered. Who benefits from pertuzumab when added to trastuzumab and chemotherapy? What is the optimal chemotherapy backbone in combination with dual HER2 blockade? Which patients can receive a shortened duration of trastuzumab?
Diverse clinical trials, including PHERGAIN, ADAPT-TP, and ADAPT-HER2+/HR-, looked at patients who achieved a pCR after receiving a less intense treatment plan. The results showed that many of these patients remained cancer-free for up to 5 years without needing additional adjuvant chemotherapy, highlighting the importance of optimizing treatment to achieve pCR.
Recent treatment advances now make it possible to reduce the amount of chemotherapy needed for patients with HER2+ tumors. Instead of using strong multi-drug combinations,some patients can now be treated with just one drug, like paclitaxel. However, selecting the right patients for this de-escalated regimen remains a challenge.
A small proportion of patients with pCR will eventually experience disease recurrence: according to a large patient-level pooled analysis, the 3-year event-free survival rate is approximately 95%. The challenge, when a complete response is achieved, is to identify the remaining 5% of high-risk patients who might need more intensive treatment while avoiding unnecessary treatment for those likely to have a good outcome.
HER2DX is the first prognostic and predictive tool for complementing the diagnosis of early-stageHER2-positive breast cancer and helping to select the optimal treatment for each patient.
HER2DX is an in vitro diagnostic assay that analyzes tissue from HER2+ breast tumors taken from a sample that has already been diagnosed. It combines clinical information (tumor size and lymph node involvement) and gene expression of 27 genes involved in 4 key biological processes related to tumor development.
HER2DX provides two critical pieces of information:
HER2DX has already been validated in over 2,000 patients. The information provided has been validated in retrospective clinical studies, a type of research that looks back at existing records and patient data to identify patterns, correlations, and outcomes.
Now, the DEFINITIVE project, a prospective clinical trial funded by the European Commission, aims to demonstrate that tailoring treatment in early-stageHER2-positive breast cancer using HER2DX improves the quality of life without affecting outcome and survival rates.
It is a 5-year international phase III prospective clinical trial conducted in 44 centers in 7 countries involving 304 patients with early-stage (stage II to IIIA) HER2-positive breast cancer seeking to prove HER2DX value in daily clinical practice.
The goal is to compare treatment guided by HER2DX versus treatment based on local physician judgement and guidelines, focusing on clinical efficacy -such as response rate to neoadjuvant therapy, disease recurrence, and metastasis -and on patient-reported outcomes, including quality of life throughout and after treatment.
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