Where Are We in the Treatment of Advanced Breast Cancer Today?

As an oncologist who specializes in the treatment of breast cancer, I spend a good deal of time in the clinic thinking about the best care and treatment options for each of my patients. No patient is the same, and now, more than ever, patients with advanced disease have many personalized care paths to consider when facing a new diagnosis or progression of their cancer. Over the past two decades, I’ve been lucky to witness the impressive shift in the way we think about treating advanced cancer – from the one-size-fits-all approach of hormone therapy and chemotherapy to the individualized approaches offered by targeted therapies and immunotherapies.

New targeted therapies for metastatic breast cancer increase the need for comprehensive genomic profiling

In the U.S. today, there are an estimated 200,000 women living with metastatic breast cancer.¹ In recent years, a growing number of targeted therapy options have been approved to treat these patients. However, this increase in treatment options has not been matched by the use of high-quality diagnostic tests needed to identify the most effective therapies for patients. These diagnostic tests, called comprehensive genomic profiling (CGP) or biomarker tests, can pinpoint mutations in a patient’s cancer that would make them a strong fit for certain therapies that can be less toxic than standard-of-care treatments like chemotherapy. 

But there’s hope on the horizon – while only 29% of metastatic breast cancer patients are currently receiving clinically validated CGP,² the number of biomarker-directed therapies that are approved for breast cancer is expected to grow, and with it, the overall testing rate (as seen in non-small cell lung cancer).³ This expected testing growth is especially promising for patients given the anticipated rise in metastatic breast cancer over the next few years to more than 245,000 cases.⁴

In 2023 and 2024, the U.S. Food and Drug Administration (FDA) approved three new targeted therapies for patients with hormone receptor-positive, HER2-negative, metastatic breast cancer: the oral SERD elacestrant for tumors with ESR1 mutations,⁵ the oral AKT inhibitor capivasertib for tumors with PIK3CA, AKT1 or PTEN alterations,⁶ and the oral PIK3CA inhibitor inavolisib for tumors with PIK3CA mutations.⁷ Inavolisib can be used in the first-line setting for patients who experience recurrent metastatic disease on or after completing adjuvant hormone therapy. These approvals make CGP testing essential for treatment decision making in the first-line setting at the time of metastatic diagnosis, as well as at the time of disease progression to assess for the emergence of acquired resistance alterations.

With the appropriate timing of testing and use of a high-quality CGP test, like Foundation Medicine’s FDA-approved FoundationOne®CDx and FoundationOne®Liquid CDx,⁸ up to 70% of breast cancer patients with hormone receptor-positive, HER2-negative disease will have one of these guideline-recommended actionable biomarkers detected,⁹ and that number increases to over 90% of these patients when including investigational biomarkers along with the guideline-recommended ones.¹⁰ However, with insufficient testing, patients are at risk for missing the opportunity to benefit from these new and emerging treatments.  

Blood biopsy vs. tissue biopsy for advanced breast cancer

What continues to be a hurdle in the most effective use of CGP is confusion around what type of CGP test, tissue versus blood, and the timing of testing at each stage of treatment.

Tissue CGP testing has several advantages for metastatic hormone receptor-positive breast cancer. In particular, PTEN loss is better detected using a tissue CGP test, like FoundationOne CDx, due to the higher tumor content needed to detect this type of alteration.⁹ While other CGP tests may cover PTEN mutations, not all tests cover or are validated to detect biallelic PTEN loss, leaving up to 5% of patients eligible for an AKT inhibitor undetected.¹⁰

Furthermore, in the first-line setting, many patients with metastatic hormone receptor-positive breast cancer have a low burden of disease and lower rates of tumor shed into the blood compared with later lines of therapy when the disease has progressed. Foundation Medicine’s ctDNA tumor fraction¹¹ is a determination of the amount of tumor DNA in the blood, and our data shows that in the first-line setting, only 40% of patients will have tumor shed with a ctDNA tumor fraction greater than 1%.⁹ When a blood-based CGP test is performed prior to the start of first-line therapy, 40% of patients will have an alteration detected in PIK3CA, AKT1, or PTEN.¹⁰  If no alteration is detected, tissue CGP testing is recommended as it may identify an additional 15% of patients with one of these actionable alterations to inform first-line therapy decisions.¹⁰

In my experience, liquid biopsy testing is especially useful in patients with a history of early-stage breast cancer who present with clinical suspicion of recurrent metastatic disease on imaging studies. These patients may be eligible for these newly approved targeted therapies in the first-line setting. Liquid biopsy generally has a faster overall turnaround time, given that the blood specimen can be collected immediately. Since the results are needed for first-line therapy decisions, a faster turnaround time is preferred. That said, most patients will have a tissue biopsy to confirm metastatic recurrence and re-confirm tissue IHC biomarkers for hormone receptors and HER2. If the liquid CGP is negative for alterations, tissue CGP should be considered.

At the time of disease progression, blood-based CGP testing can identify acquired mutations in the ESR1 gene and potential benefit from treatment with the new oral SERD elacestrant. Disease progression is associated with more tumor DNA shedding into the bloodstream, allowing liquid biopsy tests to detect targetable alterations. Additionally, ESR1 mutations have been shown to increase as disease progresses,⁹ and a high-quality, highly sensitive liquid biopsy test, like FoundationOne Liquid CDx, has a high depth of coverage for ESR1 mutations, as almost 50% of ESR1 mutations detected are under 0.5% variant allele frequency (VAF).¹⁰ If this biomarker is detected at progression, the newly approved ESR1 targeted therapy can be a treatment option to consider.

However, at progression, some patients may still not have enough tumor DNA in their blood for detection by a liquid biopsy, resulting in an indeterminate negative. FoundationOne Liquid CDx will indicate when a patient’s ctDNA tumor fraction is less than 1%, indicating a low level of tumor DNA shed, which helps physicians decide whether a new tissue biopsy should be considered to look for targetable biomarkers that are seen at progression, like ESR1.

Hope for the future of breast cancer treatment

Given the rapid rate of innovation we’ve seen over the last several years, I’m confident that we are in store for even more therapy options for physicians to consider for their patients in the future. In the past three years alone, Foundation Medicine’s CGP tests have been used to support more than 10 studies¹⁰ that focus on or include breast cancer, further illustrating the many targeted therapies still in our biopharmaceutical partners’ pipelines that may soon become available for this patient population.

With the projected increase in the use of CGP in breast cancer, I have more hope than ever that patients will have increasing opportunities to be accurately matched to the growing list of targeted therapies. Patients deserve more knowledge about their unique tumors, more options to treat their disease and most importantly, more time.