Unlocking the Future of Breast Cancer Treatment: Genomic Insights and the PI3K Pathway

Advances in genomic profiling continue to drive treatments for hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer. Over the past two-plus years, the US Food and Drug Administration (FDA) has approved three therapies (inavolisib, capivasertib, and elacestrant) for the treatment of HR+/HER2- metastatic breast cancer. Genomic testing is critical for identifying patients who may benefit from these targeted therapies.

Metastatic Diagnosis: Getting It Right at First-Line

Approximately 60% of patients with HR+/HER2- metastatic breast cancer will have at least one actionable alteration at metastatic diagnosis, most commonly involving PIK3CA, AKT1, PTEN, or ESR1. ¹ Approximately 40% of patients carry PIK3CA alterations at the time of metastatic diagnosis, with 20% presenting with mutations in PTEN, AKT1, and ESR1. ¹ Each of these genomic alterations can be paired with a specific targeted therapy; therefore, finding a test that accurately identifies each of these alterations is essential.

Some alterations can be particularly difficult to detect from a technical perspective. "Not all assays can detect PTEN loss, also known as PTEN deletion, which is essential for therapy selection in breast cancer,” says Mia Levy, MD, PhD, former Chief Medical Officer at Foundation Medicine and a nationally recognized leader in precision oncology and biomedical informatics. Dr. Levy explains that PTEN loss is found in 5.6% of HR+/HER- breast cancer patients, and so clinicians must use a test that can accurately identify this alteration, and not all assays detect PTEN loss well. Foundation Medicine’s tissue biopsy test, FoundationOne^®CDx, is the only CDx test matching metastatic breast cancer patients with AKT and PTEN alterations to a targeted therapy.²

PIK3CA alterations, while easier to detect than PTEN loss, also play a critical role in patient care, explains Dr. Levy. In general, these patients are less likely to respond to the standard first-line hormone therapies used to treat metastatic breast cancer. The approval of inavolisib, a new PIK3CA inhibitor, combined with standard hormone therapy plus a CDK4/6 inhibitor, has resulted in improved outcomes for patients, including a 57% reduction in risk of disease worsening or death. ^3,4

Progression and Resistance: New Alterations May Occur

"There are two different types of alterations we see," says Dr. Levy. "Those that we call driver mutations and then those that are acquired mutations or resistant mutations, which occur when the patient gets exposed to drug therapies and the tumor becomes resistant to those treatments." The ESR1 gene often develops resistance mutations after exposure to hormone therapy, for example, and patients who are ESR1+ may benefit from the drug elacestrant. Thus, as patients experience disease progression, clinicians should perform a new genomic profiling test to detect any acquired resistance mutations.

Typically, at the time of disease progression, a new tissue biopsy may be burdensome for the patient; therefore, the clinician will often use a liquid biopsy, which involves a simple blood draw. Although liquid biopsies can have compromised sensitivity when ctDNA levels are low, a liquid biopsy product, FoundationOne^®Liquid CDx, includes a complex biomarker in their report that allows the provider to determine if ctDNA levels are too low to yield a true negative result. Foundation Medicine validated this complex biomarker, called ctDNA tumor fraction*, by demonstrating concordance between FoundationOne^®Liquid CDx, a blood-based test, and FoundationOne^®CDx, a tissue-based test. This clinical validation study revealed that there is nearly a 100% concordance between liquid and tissue samples for short variants and rearrangements, including ESR1 alterations, when ctDNA tumor fraction is high.⁵

Although other labs have since introduced their versions of tumor fraction, Foundation Medicine remains the only CGP lab to report ctDNA tumor fraction as high or low, providing clarity to confidently determine next steps. This provides the clinician with clarity regarding when it may be necessary to obtain a new tissue biopsy for reflex testing to ensure that no actionable drivers are present that could help this patient find new targeted therapy or immunotherapy options.

Some clinicians, however, may choose to perform concurrent testing, where both tissue and liquid testing are ordered simultaneously, an ordering modality that has demonstrated improved patient outcomes, especially in particularly aggressive cancers such as non-small cell lung cancer.⁶ Some payers, such as UnitedHealthcare, the largest health plan in the United States, cover concurrent testing in patients with non-small lung cancer and metastatic breast cancer for this very reason.

Miss. Not. One.: A Precision Imperative

At the heart of Foundation Medicine's mission is the principle of Miss. Not. One. For Dr. Levy, this means testing every eligible person at the right time to ensure they receive the most effective therapy. “It’s three-dimensional,” she explains, “encompassing essential biomarkers, timing, and specimen types.” For breast cancer, in particular, this includes ensuring that assays detect critical biomarkers such as PTEN, AKT1, PIK3CA, and ESR1.

Miss. Not. One. also means that testing for patients with metastatic disease should occur before the selection of first-line therapy. Testing should then be repeated at disease progression. Depending on the patient’s circumstances, a provider may choose to begin testing with a tissue test, as that is still considered the gold standard at metastatic diagnosis, or the provider may opt for liquid-based testing at metastatic diagnosis due to other clinical factors. Liquid-based testing is often preferred at disease progression. Additionally, some providers may consider concurrent testing, particularly at the time of metastatic diagnosis.   

“Most importantly,” says Dr. Levy, “Miss. Not. One. is about continuing to innovate and develop new tests and biomarkers to help give the gift of time to patients living with cancer.”