What to Test and When: A Molecular Approach to Advanced HR+ Breast Cancer

Breast cancer isn’t one disease. And in hormone receptor-positive (HR+) breast cancer, timing matters just as much as the mutations themselves.

Hormone receptor-positive (HR+) breast cancer accounts for nearly 70% of all breast cancer diagnoses. Most patients are diagnosed at an early stage, often before the disease becomes advanced. But even in early-stage HR+ disease, recurrence is a looming concern: up to 30% of early-stage cases will eventually progress to advanced or metastatic disease.

If progression occurs, treatment decisions become more complex—and molecular profiling plays a critical role in guiding the next step forward.

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Understanding Standard of Care in Advanced HR+ Disease

For patients with advanced or metastatic HR+ breast cancer, first-line treatment typically includes a combination of an aromatase inhibitor (AI) and a CDK4/6 inhibitor. These are oral therapies used to suppress estrogen production and inhibit cancer cell growth.

But while these regimens are standard, genomic testing isn’t always performed upfront.

The truth is patients are going to be placed on these first-line therapies regardless because of their original HR+ status. While there is potential for identifying a rare & actionable biomarker at diagnosis, most physicians test at progression—not at diagnosis.

This presents a challenge: by the time progression occurs, the tumor biology may have changed—and the resistance mechanisms driving that progression may not be detectable in the original tissue biopsy. Time to treatment is of the essence in advanced breast cancer, and only using a lagging indicator such as imaging to detect progression may lead to delays in finding the best treatments or missed treatment opportunities altogether.

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Key Biomarkers to Consider at Progression

Once a patient progresses on AI + CDK4/6i therapy, identifying actionable or resistance mutations becomes essential.

Here are the biomarkers most relevant to second-line decision-making in advanced HR+ breast cancer:

• ESR1 – Acquired mutation that confers resistance to aromatase inhibitors; often emerges only after exposure to treatment
• PIK3CA, AKT1, PTEN – Alterations in the PI3K/AKT/mTOR pathway may qualify patients for targeted therapies (e.g., alpelisib or capivasertib)
• PALB2, BRCA1/2 (somatic or germline) – Mutations in DNA repair genes linked to PARP inhibitor use
• HER2 activating mutations – Can be present even in HER2 IHC-negative patients

You wouldn’t expect to find ESR1 variants at diagnosis- it’s an acquired resistance mutation that develops over time. It’s important to understand that ESR1 alterations are best detected in the blood.

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Why Liquid Biopsy Is Ideal at Progression

For patients who progress on endocrine therapy, re-biopsy is often not feasible or may provide an incomplete picture.

• Tissue may be inaccessible (e.g., bone-only metastases)
• Metastatic sites may not be reflected in tissue biopsy due to tumor heterogeneity
• Resistance mutations may emerge in sites not biopsied

Liquid biopsy, via Northstar Select®, provides a non-invasive alternative to re-biopsy—capturing emerging mutations in real time from a simple blood draw.

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The Case for Monitoring: Northstar Response®

Imaging can be inconclusive—especially in bone-only disease. In these scenarios, Northstar Response provides molecular insight into tumor burden, using a tumor methylation score (TMS™) to precisely quantify change over time.

Northstar Response is a convenient and tissue-free measure of disease progression that could provide doctors a reliable signal to order another profiling test like Select to look for meaningful new targetable alterations. In the published SERENA6 study, patients whose treatment was switched upon detection of ESR1 in the blood, as Select can do, saw a median progression-free survival of 16 months vs. 9.2 months in those who remained on standard care (AI + CDK4/6 inhibitor).

Despite this, many providers still wait for radiographic progression before changing therapy. Response offers a new option: quantify molecular progression before it appears on imaging with only a blood draw.

In patients with bone-only metastases, imaging isn’t always enough. A rising TMS score can prompt earlier action.

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Bringing it Together

Not all HR+ breast cancer responds to treatment the same way. As therapy-induced resistance mutations can emerge at anytime, our testing strategy and method must be adaptable and enable real-time insight to be gathered. By combining molecular profiling (Select) with treatment monitoring (Response), providers can make smarter, faster decisions—and patients can stay ahead of their disease.

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