Leveraging Genomics to Inform Care for Patients with Advanced Breast Cancer

Unlocking New Possibilities in Advanced Breast Cancer Care Through Genomic Insights 

Comprehensive genomic profiling (CGP) has become a powerful tool in oncology, enabling clinicians to identify genomic alterations that can guide targeted therapy options for patients. This approach is especially crucial for the 70% of advanced breast cancers classified as hormone receptor-positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-). As the therapeutic landscape for these patients expands, the role of CGP continues to grow in significance. 

The field of CGP has seen rapid advances in recent years. In late 2023, the U.S. Food and Drug Administration (FDA) approved two new guideline-recommended therapies for HR+, HER2- advanced breast cancer: elacestrant for patients with ESR1 mutations and the combination of capivasertib plus fulvestrant for those with PIK3CA, AKT, or PTEN alterations in the PI3K/AKT signaling pathway. Building on this progress, the FDA approved another combination therapy in late 2024: inavolisib plus palbociclib and fulvestrant for patients with PIK3CA alterations.

At the 2024 San Antonio Breast Cancer Symposium (SABCS®), experts from Foundation Medicine’s Pioneers in Practice underscored how genomic insights are transforming treatment strategies, paving the way for more personalized and effective care for patients with advanced breast cancer.

Tissue and Liquid Biopsy – Complementary Tools for Advanced Breast Cancer Care

 The ability to detect molecular alterations is critical in treating advanced breast cancer. Many of these abnormalities, including mutations in the PI3K/AKT pathway genes (PIK3CA, AKT1, and PTEN) and ESR1, are single base pair changes or insertions/deletions. Both FoundationOne^®Liquid CDx and FoundationOne^®CDx can identify these essential biomarkers, providing oncologists with invaluable insights for tailoring patient care. 

 Tissue biopsy (TBx) offers the advantage of high DNA concentration for analysis, making it a gold standard for genomic profiling. However, obtaining tissue samples can be time-intensive and limited by availability. In contrast, liquid biopsy (LBx) offers a faster, more accessible alternative but faces challenges due to variability in how tumors shed DNA. These differences can impact the ability to detect specific abnormalities, particularly in samples with low levels of circulating tumor DNA (ctDNA).

 Each biopsy type has a vital role in the patient care continuum. TBx is recommended at the initial diagnosis of metastatic breast cancer and confirmation of HR and HER2 status. LBx is a valuable tool for tracking tumor progression and the genomic evolution induced by treatment. FoundationOneLiquid CDx, with its ability to determine ctDNA tumor fraction^*, provides confidence in negative results for short variants and rearrangements when ctDNA tumor fraction is high. Confirmatory tissue testing is advised to ensure accuracy when samples have a low ctDNA tumor fraction. The frequency of cases with high ctDNA tumor fraction increases over multiple lines of hormone therapy. Clinical guidelines were recently updated to include the value of ctDNA fraction measurements to guide decision-making, noting that a test that can determine high or low tumor fraction was particularly useful. Foundation Medicine is the only company with a liquid biopsy with a validated ctDNA tumor fraction cut-off to guide next steps.⁵

 Choosing the Right Tool: Using Genomics to Guide Advanced Breast Cancer Treatment

PTEN: Tissue Biopsy

 When selecting the best biopsy tool to guide therapy for advanced breast cancer, understanding the strengths of tissue and liquid biopsies is essential. Tissue biopsy (TBx) excels in identifying PTEN mutations due to its higher DNA concentration. This is particularly important because, by the third line of therapy, PTEN homozygous loss—a potentially actionable alteration—can be detected in approximately 5.6% of patients. Identifying these mutations allows oncologists to consider therapies like capivasertib combined with fulvestrant, which expand patient treatment options beyond first-line endocrine therapy, which is often ineffective at stopping disease progression. Both FoundationOne CDx and FoundationOne Liquid CDx have comprehensive reporting of PTEN.

ESR1: Liquid Biopsy^¶

In contrast, liquid biopsy (LBx) offers unique advantages for monitoring tumor evolution. LBx’s ability to capture tumor heterogeneity across multiple metastatic sites makes it an ideal tool for detecting these mutations. Clinical guidelines now specify that ESR1 is better detected in liquid biopsies than tissue⁵. ESR1 mutations, for example, are found in about 10% of patients at initial diagnosis but can increase to 25-30% by the third line of therapy, likely due to the selective pressure of endocrine treatments. FoundationOne Liquid CDx detects alterations in ESR1 that often emerge as therapy progresses. With 8-10%^1,2 of tissue and liquid biopsies having ESR1 mutations at first-line, knowing ESR1 status early enables more precise treatment planning, enhancing the likelihood of successful outcomes. 

PIK3CA: Liquid Biopsy

 Similarly, LBx is effective for identifying PIK3CA alterations, enabling oncologists to add inavolisib to the standard of care and improve progression-free survival.^3,4 By leveraging TBx and LBx appropriately, clinicians can ensure advanced breast cancer treatment is informed by the most relevant and actionable genomic insights. FoundationOne Liquid CDx is the first and only CGP liquid biopsy with a CDx indication for first-line therapy for recurrent, metastatic HR+ HER2- breast cancer.

 Miss. Not. One.: A Commitment to Comprehensive Care

 Foundation Medicine’s initiative to “Miss. Not. One.” reflects its dedication to ensuring no actionable genomic alteration is overlooked. This effort has been driven by close collaboration with scientists, clinicians, and patients to develop two complementary tools: FoundationOne CDx and FoundationOne Liquid CDx.

 Foundation Medicine’s tissue and liquid CGP each detect all 13 guideline-recommended somatic biomarkers for advanced breast cancer^†, providing a comprehensive foundation for tailored treatment decisions. Additionally, they serve as companion diagnostics for many genomic targets, helping clinicians align therapies with each patient’s unique genomic profile.

By leveraging the strengths of both tests, Foundation Medicine empowers oncologists with the insights needed to guide precision oncology, ensuring advanced breast cancer care is as thorough and effective as possible.