The Molecular Map: A Guide to Biomarker-Driven Therapy

In the past, a one-size-fits-all approach was often used for breast cancer treatment. Now, precision medicine is a revolutionary approach that tailors diagnosis and treatment to the individual patient and their specific tumor characteristics. This method focuses on identifying specific biomarkers to help guide treatment decisions.¹
Standard testing for breast cancer includes checking for 3 key biomarkers:²

• Estrogen receptor (ER)
• Progesterone receptor (PR)
• Human epidermal growth factor receptor 2 (HER2)

This testing helps classify breast cancer into its main subtypes:²

• Hormone receptor-positive (or negative)
• HER2-positive (or negative)
• Triple negative

However, the field of biomarkers is rapidly expanding. In advanced and metastatic breast cancer, additional biomarkers can be tested to further personalize care and identify resistance to standard treatments. This article will explore key biomarkers beyond the standard 3, including HER2-low and ESR1 mutations, and discuss their implications for targeted therapy.²

HER2-low: A new subtype

HER2-low breast cancer is a distinct new type of breast cancer with low levels of the HER2 protein. This new classification provides a better understanding of individual tumors and can offer new potential treatment options for patients. HER2-low status is defined by an immunohistochemistry (IHC) score of 1+ or a score of 2+ with a negative fluorescence in situ hybridization (FISH) test result.³
In the past, patients with HER2-low breast cancer were treated as if they were HER2-negative. However, a groundbreaking phase 3 clinical trial, DESTINY-Breast04, showed that the antibody-drug conjugate trastuzumab deruxtecan (T-DXd/Enhertu®) prolonged both progression-free survival (PFS) and overall survival (OS) in patients with HER2-low metastatic breast cancer. This drug is designed to specifically target HER2 proteins and deliver a chemotherapy agent directly to the cancer cells.^3,4
In 2022, the US Food and Drug Administration (FDA) approved fam-trastuzumab deruxtecan-nxki for the treatment of patients with unresectable or metastatic HER2-low breast cancer who have previously received chemotherapy in certain settings. And, in 2025, fam-trastuzumab deruxtecan-nxki was FDA-approved to treat unresectable or metastatic HR-positive, HER2-low or HER2-ultralow breast cancer that has progressed on at least 1 endocrine therapy in the metastatic setting.^3-5
These approvals are groundbreaking and have opened the door to new treatment possibilities for many patients.^3-5

ESR1 mutations and endocrine resistance

For patients with hormone receptor-positive breast cancer, endocrine therapy is a common treatment. However, some metastatic breast cancers can develop a mutation in the ESR1 gene, which is a key player in the progression and treatment resistance of these cancers.⁶
ESR1 mutations are rare in primary tumors but are found in 10 to 50 percent of metastatic, endocrine therapy-resistant cases. These mutations can cause the estrogen receptors to become "stuck" in the "on" position, telling cancer cells to grow even when endocrine therapies are used to block or lower estrogen.⁶
The presence of an ESR1 mutation is linked to a shorter progression-free survival with aromatase inhibitor treatment. While endocrine therapies may still be partially effective in some cases, the presence of these mutations can guide treatment decisions.⁶
A recent development in this area is the FDA approval of imlunestrant, an oral selective estrogen receptor degrader (SERD). This drug is approved for adults with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer who have progressed following at least one line of endocrine therapy.⁷
In the phase 3 EMBER-3 trial, imlunestrant monotherapy showed a statistically significant improvement in progression-free survival (PFS) compared with standard endocrine therapy in the ESR1-mutated population, with a median PFS of 5.5 months versus 3.8 months. This provides a new, targeted therapeutic option for a patient population with a high degree of endocrine resistance.⁷

Transforming the treatment landscape

In the era of precision medicine, treatment decisions for advanced breast cancer can be complex. Clinicians are moving away from a one-size-fits-all approach and using patient and tumor characteristics to inform a more personalized treatment regimen. The integration of artificial intelligence and machine learning, particularly through "decision tree" models, holds promise for helping to select the right therapy based on a patient's molecular profile.⁸
The use of biomarkers in advanced breast cancer has transformed the treatment landscape, allowing for a more precise and effective approach to care. Beyond the traditional ER, PR, and HER2 testing, the identification of additional biomarkers like HER2-low, HER2-ultralow, and ESR1 mutations provides new therapeutic opportunities.^2,6,8
By utilizing a molecular map of a patient's tumor, oncologists can make informed, data-driven decisions to select the most appropriate therapy, ultimately improving patient outcomes and minimizing unnecessary side effects. As research continues to uncover new biomarkers and targeted treatments, the future of breast cancer care will likely be increasingly personalized and precise.^2,6,8