Research Spotlight: Comprehensive genomic profiling of ESR1, PIK3CA, AKT1, and PTEN in HR(+)HER2(-) metastatic breast cancer: prevalence along treatment course and predictive value for endocrine therapy resistance in real-world practice
Bhave MA, Quintanilha, JCF, Tukachinsky H, et al. Comprehensive genomic profiling of ESR1, PIK3CA, AKT1, and PTEN in HR(+)HER(-) metastatic breast cancer: prevalence along treatment course and predictive values for endocrine therapy resistance in real-world practice. Breast Cancer Research and Treatment. 14 June 2024. https://link.springer.com/article/10.1007/s10549-024-07376-w
Background:
Although most patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) benefit from first-line endocrine therapy with an aromatase inhibitor, second-line endocrine monotherapy has shown little benefits, likely due to acquired resistance mechanisms, such as ESR1 mutations. As the treatment landscape for HR-positive, HER2-negative MBC evolves, comprehensive genomic profiling (CGP) for ESR1 mutations and PI3K/AKT pathway genomic alterations could help with monitoring for acquired resistance and aid in therapy decisions.
Study details:
This study aimed to inform optimal clinical considerations for CGP using tissue biopsies and liquid biopsies in patients with HR-positive, HER2-negative MBC. Researchers assessed records from a de-identified, real-world clinico-genomic database for patients who received tissue or liquid biopsy testing at Foundation Medicine during routine clinical care at approximately 280 U.S. cancer centers between January 2011 through December 2023.
This study included a total of 5,780 and 1,670 HR-positive, HER-negative MBC patients with tissue and liquid biopsies, respectively. The prevalence of ESR1 mutations and PI3K/AKT pathway alterations in tissue biopsies and liquid biopsies was assessed at the start of successive lines of therapy. Real-world progression free-survival and overall survival were compared between groups to evaluate clinical outcomes.
At the start of first-line therapy, 8-10% of tissue and liquid biopsies had ESR1 mutations, while 38-55% of tissue and liquid biopsies had alterations in the PI3K/AKT pathway. The prevalence of ESR1 mutations clearly increased across the lines of therapy, with up to 33% harboring an ESR1 mutation detected by tissue biopsy and 39% detected by liquid biopsy at the time of third-line therapy. Baseline ESR1 mutations were associated with less favorable outcomes as patients with ESR1 mutations receiving first-line aromatase inhibitors and cyclin-dependent kinase inhibitors had worse real-world time to treatment discontinuation and real-world progression-free survival than patients with ESR1 wild-type status.
Why this matters:
CGP can help oncologists better understand why HR-positive, HER2-negative MBC patients show resistance to certain therapies and how to optimize first and subsequent lines of therapy due to acquired resistance mechanisms.
Additionally, the study reinforces the benefit of considering tissue biopsy for first-line treatment decisions in these patient cases, and leveraging subsequent highly validated liquid biopsy to detect acquired genomic alterations in second-line therapy and beyond. Highly validated liquid biopsies, such as FoundationOne®Liquid CDx, that include an evaluation of circulating tumor DNA tumor fraction (ctDNA TF), a representation of the amount of tumor DNA circulating in each blood sample, are essential for accurately interpreting liquid biopsy results that are negative for the detection of genomic alterations. When the results from a FoundationOne Liquid CDx test show ctDNA TF of less than 1% and no actionable genomic alterations, this study suggests considering an additional tissue biopsy for detecting genomic alterations to help guide treatment decisions for second-line therapy and beyond.
View the full publication in Breast Cancer Research and Treatment.