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The most common subtype of breast cancer is hormone receptor (HR) positive and HER2 negative breast cancer. In the past decade, several new drugs have been approved to treat advanced breast cancer of this subtype. These drugs target specific mutations that drive cancer growth, such as mutations in CDK4/6, ESR1, PIK3CA, AKT, and PTEN.

While most of these drugs are approved for second-line therapy, the combination of endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i) such as palbociclib, ribociclib, or abemaciclib is the preferred first-line treatment. However, not all patients respond to CDK4/6i therapy, developing resistance either inherently or over time resulting in short progression-free survival.

A substudy of the TREnd trial also known as c-TREnd study, published in , explores circulating tumor DNA (ctDNA) analysis as a prognostic tool for HR-positive, HER2-negative advanced breast cancer patients treated with palbociclib. The TREnd trial (phase II, open-label, multicenter) examined the efficacy of palbociclib (alone or combined with ET) in postmenopausal women with HR-positive breast cancer who progressed on prior ET.

In the c-TREnd study, ctDNA analysis was performed in plasma samples from 46 patients at three time points: before treatment (T0), after the first cycle (T1), and at disease progression (T2).

Researchers found that mutations in ESR1 and PI3K pathway genes at T0 correlated with a worse prognosis. Notably, an increased risk of progression was observed mainly in patients with ESR1 mutations receiving palbociclib with ET, suggesting these mutations confer resistance to ET. Additionally, ctDNA analysis at T2 revealed new mutations emerging in some patients, possibly induced by the treatment itself.

These findings hold promise for future treatment decisions. ctDNA analysis could identify patients at higher risk of progression on CDK4/6i, allowing for more tailored treatment plans. The study also highlights the importance of investigating mutations beyond single genes and exploring treatment-induced mutations to overcome CDK4/6i resistance.

Although promising, some limitations need to be addressed. The study involved a relatively small sample size, limiting the generalizability of the findings. Further validation in larger cohorts is necessary. A larger sample size would provide more robust data on the frequency of specific mutations and their correlation with treatment response.

Arun Kumar, MD, is a Hematology/Oncology fellow PGY-5 at Medstar Georgetown University Hospital in Washington, D.C. Nour Abu-Irhayem, MBBS, is an internal medicine residency applicant in the United States. Zeeshan Solangi, MD, is a Clinical Instructor of Medicine at Yale University Hospital in New Haven, Connecticut.

Read the study here and an interview about it here.