Daisy Trial: Testing New Metastatic Breast Cancer Treatments

Researchers are constantly working to improve treatments for metastatic breast cancer, a stage where cancer has spread beyond the breast and nearby lymph nodes. Clinical trials play a critical role in evaluating new therapies and identifying which patients benefit most. The DAISY trial is examining how tumor characteristics influence treatment response.

Metastatic Breast Cancer Subtypes

Breast cancer is classified into subtypes based on molecular markers that affect treatment and outcomes. The DAISY trial categorizes participants accordingly to assess therapy response.

Hormone Receptor-Positive

This subtype is defined by estrogen (ER) and/or progesterone receptors (PR) on cancer cells. These tumors rely on hormone signaling for growth, making endocrine therapy a primary treatment. Common therapies include tamoxifen, letrozole, and fulvestrant. Targeted agents like CDK4/6 inhibitors, such as palbociclib, have improved outcomes by disrupting cell cycle progression. However, resistance can develop, necessitating ongoing research. The DAISY trial is exploring how hormone receptor-positive tumors with varying HER2 expression respond to antibody-drug conjugates.

HER2-Positive

HER2-positive breast cancer is driven by overexpression of the human epidermal growth factor receptor 2 (HER2), which promotes aggressive tumor growth. Targeted therapies like trastuzumab and pertuzumab have significantly improved survival by blocking HER2 signaling. More recently, antibody-drug conjugates like trastuzumab deruxtecan (T-DXd) have shown efficacy by delivering cytotoxic agents directly to HER2-expressing cells. The DAISY trial is evaluating how different HER2 expression levels affect treatment response, particularly in patients previously classified as HER2-negative.

Triple-Negative

Triple-negative breast cancer (TNBC) lacks ER, PR, and HER2 expression, making it more difficult to treat. This aggressive subtype has higher recurrence rates and fewer targeted options. Standard care includes chemotherapy, but immune checkpoint inhibitors like pembrolizumab and PARP inhibitors such as olaparib have expanded treatment choices. The DAISY trial is investigating whether TNBC tumors with low HER2 expression may respond to HER2-directed antibody-drug conjugates.

HER2 Expression Levels In The Trial

HER2 expression has traditionally been classified as positive or negative based on immunohistochemistry (IHC) and in situ hybridization (ISH) testing. Tumors with an IHC score of 3+ or HER2 gene amplification are considered HER2-positive and typically respond to HER2-targeted therapies. Tumors with an IHC score of 0 or 1+ have been categorized as HER2-negative, while those with an IHC score of 2+ but no gene amplification fall into an intermediate zone.

The DAISY trial is challenging this binary classification by assessing whether HER2-low tumors, previously deemed ineligible for HER2-directed treatments, might still benefit from antibody-drug conjugates like T-DXd. Unlike traditional monoclonal antibodies that rely on strong HER2 inhibition, T-DXd delivers a cytotoxic payload that remains effective even in tumors with minimal HER2 presence. Preliminary findings suggest that HER2-low metastatic breast cancer, including hormone receptor-positive and triple-negative subtypes, may respond to this therapy.

The trial is also evaluating whether HER2 heterogeneity—where some tumor regions exhibit higher expression while others remain HER2-low or negative—affects treatment response. Advanced imaging and molecular profiling techniques are being used to quantify HER2 heterogeneity and refine patient selection criteria.

Mechanism Of Antibody-Drug Conjugates

Antibody-drug conjugates (ADCs) combine monoclonal antibodies with cytotoxic agents to selectively target tumor cells while minimizing harm to healthy tissues. Their effectiveness depends on three key components: the monoclonal antibody, the linker, and the cytotoxic payload.

The monoclonal antibody targets a specific antigen on cancer cells. In HER2-directed ADCs, the antibody binds to HER2 receptors, ensuring selective uptake by tumor cells. Once attached, the ADC undergoes receptor-mediated endocytosis, allowing the cytotoxic payload to be delivered inside the cell.

The linker connects the antibody to the cytotoxic agent and must remain stable in circulation to prevent premature drug release. Once inside the cell, the linker breaks down to release the cytotoxic payload. Advances in linker technology have improved drug stability and activation within tumor cells.

The cytotoxic payload, typically a potent chemotherapy drug, disrupts key cellular processes such as microtubule formation or DNA replication. Unlike conventional chemotherapy, which affects both healthy and cancerous cells, ADCs deliver these agents directly to tumor cells, enhancing efficacy while reducing toxicity. Trastuzumab deruxtecan (T-DXd), for example, employs a topoisomerase I inhibitor that interferes with DNA replication, leading to cancer cell death.

Tissue Sampling And Biomarker Methods

Accurate tumor assessment in the DAISY trial relies on precise tissue sampling and biomarker analysis. Biopsies are conducted at multiple time points to monitor tumor changes. Core needle biopsies provide sufficient material while minimizing discomfort. Liquid biopsies, which analyze circulating tumor DNA (ctDNA) from blood samples, are also being explored as a less invasive alternative.

Advanced biomarker techniques help determine HER2 expression levels and other molecular features. Immunohistochemistry (IHC) remains the standard for assessing HER2 protein levels, but quantitative mass spectrometry and RNA sequencing are being integrated to detect subtle variations. Digital pathology and AI-driven image analysis enhance accuracy by reducing observer variability. These innovations refine patient selection, ensuring those with HER2-low tumors are appropriately identified for antibody-drug conjugate therapy.