Breast cancer treatment and research have evolved dramatically over the last few decades with the discovery of novel biomarkers, the development and approval of new therapies, and a deeper understanding of the disease itself.
While it is an exciting time for breast cancer research and clinical practice, the rate at which the field is evolving poses challenges for clinicians who are trying to adapt their practice to a rapidly changing landscape as well for those in drug development.
In this article, we’ll discuss how real-world evidence (RWE) can answer questions that inform drug discovery, development and clinical practice. We’ll share three case studies that illustrate the role that RWE can play in advancing breast cancer research and providing answers to many lingering questions about the future of cancer care.
Case study #1
A retrospective comparative effectiveness study of first-line CDK4/6 inhibitors plus aromatase inhibitors
Cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) combination therapy is the standard first line therapy for HR+/HER2- metastatic breast cancer (mBC). Palbociclib was the first CDK 4/6i to be approved by the FDA in 2015, followed by abemaciclib and ribociclib in 2017.
For a long-time the three CDK 4/6i’s were considered to be equivalent in terms of clinical efficacy because they had all shown a similar progression-free survival (PFS) benefit when compared with aromatase inhibitors (AIs) alone.
However, results from the RCTs later showed that ribociclib was the only CDK 4/6i that was shown to have a statistically significant overall survival benefit when combined with an AI. To compare the overall survival (OS) of patients who received first-line palbociclib plus AI versus those who received either ribociclib or abemaciclib plus AI for HR+/HER2- MBC, researchers leveraged the US nationwide Flatiron Health EHR-derived de-identified database, which is comprised of over 750,000 patients with breast cancer. Of the 750,000 patients in the database, 9,770 met the criteria to be included in the study. After inverse probability of treatment weighting (IPTW), baseline demographics and clinical characteristics were generally balanced between the 3 groups (standardized difference < 0.1). This represents the largest real-world comparative analysis of OS between the 3 CDK 4/6i’s in combination with AIs to date.
Contrary to the results from the RCTS, this study found no statistically significant survival difference between these three agents when combined with AIs.
Case study #2
A post-authorization safety study of trastuzumab emtansine or TDM1 in patients with HER2+ metastatic breast cancer and a low left ejection fraction
Trastuzumab emtansine (TDM1) was approved by the FDA in 2013 for the treatment of patients with HER2+ mBC who were previously treated with trastuzumab and taxanes. The approval was based on Phase III trial results demonstrating that TDM1 significantly improved PFS and OS when compared to lapatinib plus capecitabine.
However, patients treated with TDM1 are at risk of developing cardiac dysfunction and patients with baseline left ventricular ejection fraction (LVEF) below 50 percent had been excluded from the trials. As a result, limited safety data was available for patients with decreased LVEF.
As part of the post-approval risk management plan (RMP), the European Pharmacovigilance Risk Assessment Committee (PRAC) sought information that evaluated the use of TDM1 in patients with LVEF between 40-49 percent prior to initiating treatment.
The retrospective study included patients with HER2+ mBC (either Stage IV or recurrent disease) who had been treated with TDM1 between January 1, 2013 and May 31, 2018 and had evidence of LVEF recorded 60 days prior to the initiation of the drug. The primary cohort also needed to have a baseline LVEF of 40-49 percent. In order to identify these patients, Flatiron created a novel cardiac LVEF variable from our oncology EHR, which involved processing deep unstructured information in a new way. Of approximately 2000 patients with mBC initiating TDM1, 32 (1.6%) had an LVEF measurement of 40-49% at baseline.
The study set out to determine whether patients with low LVEF are at higher risk than those with a cardiac history when receiving TDM1. Researchers looked for events including congestive heart failure (CHF), decrease in cardiac function, CHF signs and symptoms and composite cardiovascular disease. The study suggests that the occurrence of events in patients with low LVEF is similar to those with a cardiac history.
As a result of this study, two sections of the TDM1 label in Europe were updated with safety information for patients with LVEF between 40-49 percent, which means clinicians will now have the option of treating their patients with this drug and they will have information to allow for a discussion with the patient. What’s more, the study sponsor was able to submit the data approximately five years sooner than a traditional prospective registry study would have allowed.
Case study #3
Testing patterns & prevalence of PIK3CA, AKT1 & PTEN alterations among patients with HR+/HER2- metastatic breast cancer in the United States
Biomarkers play a key role in the treatment of mBC and have become increasingly important in recent years. Caivasertib, which is a pan-AKT inhibitor, was approved by the FDA in 2023 for patients with HR+/HER2- advanced or metastatic breast cancer and one or more alterations in PIK3CA, AKT1 and PTEN.
The approval was based on a randomized control trial (RCT) which demonstrated that treatment with capivasertib + fulvestrant significantly improved PFS compared with fulvestrant alone in patients who met this criteria.
Unlike diseases such as non-small cell lung cancer (NSCLC), molecular testing in breast cancer is a relatively new paradigm shift, and understanding how next-generation sequencing testing is being incorporated into real-world practice can help to identify potential gaps in care and illuminate the impact of new targeted therapies.
In this study, researchers used the broader Flatiron Health de-identified database, which includes all patients diagnosed with mBC, to assess testing rates as well as the Flatiron-Foundation Medicine clinico-genomic database — which includes patients in the Flatiron network who were diagnosed with mBC and also underwent Foundation Medicine next-generation sequencing (NGS) testing — to assess prevalence rates. They looked at patients that were at least 18 years old, diagnosed with HR+/HER2- mBC between January 1, 2017 and June 30, 2022 and had not been treated with HER2-targeted therapy or enrolled in a trial. In total, 9,669 patients from the Flatiron Health EHR-derived database and 3,274 patients from the Flatiron Health Foundation Medicine clinico-genomic dataset were eligible for the analysis.
Researchers found that 40 percent of patients with mBC received NGS testing during the set time frame. Among patients tested, 53 percent had a PIK3CA, AKT1 and/or PTEN alteration. The results show that there is an opportunity to increase NGS testing in patients diagnosed with mBC and that a large percentage of patients have alterations in PIK3CA, AKT1 and PTEN. Armed with such information, clinicians may be able to improve patient care by ensuring patients receive the appropriate biomarker testing and personalized treatment.
Unlocking critical insights at scale
The Flatiron de-identified database can help researchers understand the full patient journey, providing details such as their stage, whether or not they underwent surgery and radiation therapy, what systemic therapies they received, and whether or not they recurred. The dataset also includes highly detailed biomarker information and real-world endpoint data that has been validated, including real-world measures of progression and response rate and mortality, thus allowing researchers to better understand clinical outcomes.
With a growing network of over 750,000 global breast cancer patients spanning early and metastatic disease settings, Flatiron can power more breast cancer studies than ever before with cohorts that enable greater breadth and depth of analysis. To learn more about how we can support breast cancer research across the therapeutic development lifecycle, reach out to us.
