Find care now
If you are experiencing a medical emergency, please call 911 or seek care at an emergency room.
This article was written by D. Max Smith, PharmD, BCPS.
New pharmacogenetic research answers questions about genetics and dosing of the breast cancer drug ribociclib and opens more discussion on precision medicine based on genetic ancestry—not race or ethnicity.
Though cancer medication is designed to help the body eliminate the disease, in some cases, a patient’s DNA can work against the therapy. Genetic variants, called drug-gene associations, might make a medication less effective or cause side effects such as nausea, vomiting, or severe illness.
MedStar Health is a leader in investigating drug-gene associations—a field called pharmacogenetics that studies how genetic variants in individuals and ancestries cause the medication to be less effective or have side effects.
These studies often uncover additional questions that must be answered to provide better patient care.
Such was the case with our study that was published in September in npj Breast Cancer, a journal in the Nature portfolio. Sandra Swain, MD, vice president, MedStar Genetic Medicine, and associate dean for Research Development at Georgetown University Medical Center, noted that the U.S. Food and Drug Administration (FDA) label for ribociclib, part of a treatment for medication-resistant metastatic breast cancer, recommended a reduced dosage for patients prescribed CYP3A inhibitors. CYP3A inhibitors reduce the processing, or metabolism, of ribociclib leading to increased ribociclib exposure.
Dr. Swain and I then wondered, if a drug interaction that reduces CYP3A function increases ribociclib exposure, what happens if a patient has a genetic variant that affects CYP3A function?
CYP3A5 is a gene that contributes to CYP3A function. Interestingly, only about 15% of patients of European ancestry have normal CYP3A5 function. The genetic variant causing widespread reduced CYP3A5 function in European ancestry is less common in other populations. For example, approximately 85% of patients of African ancestry have normal CYP3A5 metabolism, which may affect how ribociclib is processed and therefore affect dose requirements and outcomes.
Dr. Swain’s note raised two critical questions among our team:
- Did the studies leading up to the approval of ribociclib have adequate representation of different groups?
- Is ribociclib exposure affected by CYP3A5 function, specifically CYP3A5 genotype?
So, in collaboration with the National Cancer Institute and with funding from the Breast Cancer Research Foundation (BCRF), we conducted the LEANORA clinical trial to answer these questions—and to open further discussion about the need for intentional diversity of patients in clinical trials.
Identifying two problems to study.
The FDA approved ribociclib as one of four drugs in CDK4/6i, a combination therapy added to endocrine therapy for HR+/HER2- metastatic breast cancer when a patient’s cancer becomes resistant to frontline therapy.
CDK4/6i was researched in the MONALEESA clinical trials, three extensive studies that enrolled more than 2,000 patients. However, just 2% of the people in these trials identified as having African ancestry. This is concerning in several ways:
- The study population was primarily women of European ancestry who likely possessed reduced CYP3A5 metabolism.
- Possible continuation of disparities in care—research has shown that Black women typically have worse breast cancer outcomes
- It is unclear if ribociclib dose requirements would be similar in a population that had functional CYP3A5 metabolism.
Considering these concerns, we designed our study to address the pharmacogenetic possibilities and the underrepresentation of African genetic ancestry in previous research.
No association between CYP3A5 genotype and ribociclib exposure.
Fourteen self-identified Black patients and three self-identified non-Hispanic white patients with HR+/HER2− advanced breast cancer completed our clinical trial. The analysis focused on self-identified Black patients. Half of these patients had a CYP3A5 function, and half lacked CYP3A5 function. All patients received ribociclib and endocrine therapy as the standard of care.
Our data showed no significant difference in ribociclib exposure or in the occurrence of adverse events between patients who did or did not have CYP3A5 function. Both groups reported similar medication side effects, which included:
- Low white blood cell counts
- Nausea
- Vomiting
- Diarrhea
- High levels of transaminases, a liver enzyme
- Increased creatine, a natural chemical source of energy
This is good news for patients and providers. This is one less lab test they’ll need to get the appropriate medication dose.
I am actively involved with the Clinical Pharmacogenetics Implementation Consortium (CPIC), an international committee that helps clinicians access pharmacogenetics tools. Through CPIC, we encourage more diverse clinical trials like the LEANORA study and genetic testing tools to help providers reduce drug-gene interactions.
Related reading: First-of-its-Kind Research Finds Racial Disparities in Cardiac Clinical Trials Start Before Enrollment.
Diversity is vital in clinical studies.
Genetics plays a more significant role in understanding cancer care as we move toward personalized treatment options. Pharmacogenetic research allows us to make more precise recommendations to give patients with specific conditions the best outcomes.
However, we can only be successful if we include diverse patients in clinical trials and change our terminology to avoid unintentional bias.
Almost no one in the U.S. is 100% a specific genetic ancestry. So, researchers are leaning away from terms such as “race,” “ethnicity,” or “geographic origin.” Those inaccurate terms can lead to assumptions and incorrect correlations that negatively impact patient outcomes.
Instead, MedStar Health researchers use the term “genetic ancestry” to guide our dosing recommendations. This term is more accurate—it is not geography-based and might carry less unintentional bias. This shift in perspective, paired with modern genetic testing capabilities, can help us pinpoint appropriate treatments and dosages and avoid assumptions based on perceived or self-identified heritage.
Though the LEANORA clinical trial did not find a significant difference for a specific drug-gene association, many other trials have uncovered significant findings that guide medication recommendations.
Diverse patient participation in clinical trials is critical to revealing more precise medication practices. We can keep working toward safer, more personalized cancer therapies for everyone.
Disclosure: Dr. Smith and Dr. Swain report no personal financial interests related to the study.
