# Integrating Molecular Phenotyping into Treatment Algorithms for Advanced Oestrogen Receptor-Positive Breast Cancer

## TL;DR

This paper reviews how molecular profiling can improve treatment decisions for advanced estrogen receptor-positive breast cancer by integrating genetic insights into clinical strategies.

## Contribution

The paper uniquely integrates molecular phenotyping with clinical treatment algorithms for advanced ER-positive breast cancer.

## Key findings

- Molecular profiling helps identify genomic alterations driving resistance and progression in ER-positive breast cancer.
- Oral SERDs and PI3K/AKT/mTOR inhibitors show clinical benefit in selected biomarker populations.
- ctDNA monitoring can detect resistance and guide therapeutic escalation in real time.

## Abstract

Breast cancer is the most common cancer in women worldwide, and most cases are oestrogen receptor (ER) positive. These cancers are usually treated with hormone (endocrine) therapy and targeted drugs, which have greatly improved survival outcomes. However, many patients eventually stop responding to treatment, as the cancer develops resistance. Research has shown that ER-positive breast cancer is not one single disease but rather a group of subtypes driven by different genetic changes. New technologies, such as next-generation sequencing and blood tests that detect tumour DNA (ctDNA), allow for the identification of genetic differences. This can help guide more personalised treatment decisions. Promising new therapies include oral selective oestrogen receptor degraders and drugs targeting growth pathways such as PI3K/AKT/mTOR inhibitors. Wider access to molecular testing and ongoing drug development are essential to bring precision medicine to all patients.

Breast cancer is the most common malignancy and leading cause of cancer-related mortality among women worldwide. Oestrogen receptor (ER)-positive disease accounts for the majority of cases, where endocrine and targeted therapies have substantially improved survival. Nevertheless, resistance to therapy remains inevitable, emphasising the need for precision strategies informed by molecular profiling. The molecular landscape of ER-positive breast cancer is increasingly complex, characterised by diverse genomic alterations driving resistance and progression. Advances in next-generation sequencing and circulating tumour DNA (ctDNA) technologies enable the dynamic assessment of tumour heterogeneity and clonal evolution, informing prognostication and guiding biomarker-driven therapy. Uniquely, this review integrates molecular phenotyping with clinical treatment algorithms for advanced ER-positive breast cancer, providing a practical framework to translate genomic insights into patient care. Key genomic alterations and targeted strategies with demonstrated clinical benefit, including oral selective ER degraders (SERDs) and PI3K/AKT/mTOR inhibitors in selected biomarker populations, are highlighted. Emerging targets, such as human epidermal growth factor 2 (HER2) mutations, and the potential of ctDNA monitoring to detect resistance and guide therapeutic escalation are also discussed. Incorporating molecular profiling, as recommended by international guidelines, into routine clinical decision making can personalise therapy and optimise patient outcomes. Addressing real-world challenges, including cost and accessibility, will be critical to achieving equitable implementation of precision oncology for patients with ER-positive breast cancer worldwide.