- The CREATE-X trial:
- Studied adjuvant capecitabine in patients with HER2-negative breast cancer:
- Who had residual invasive disease after neoadjuvant chemotherapy:
- Did not achieve a pathological complete response
- Who had residual invasive disease after neoadjuvant chemotherapy:
- It found that adding capecitabine:
- Improved disease-free survival (DFS) and overall survival (OS) compared to observation in that specific patient population
- The effect was more pronounced in certain subgroups:
- Particularly patients with triple-negative breast cancer
- In long-term follow-up, for example:
- 5-year DFS was higher in capecitabine arm vs control
- Studied adjuvant capecitabine in patients with HER2-negative breast cancer:
- So the key message of the Create -X trial:
- In patients who have residual disease after neoadjuvant chemotherapy (i.e. higher risk of relapse):
- Adding capecitabine may provide a survival benefit
- In patients who have residual disease after neoadjuvant chemotherapy (i.e. higher risk of relapse):
- Is CREATE-X Still Applicable Today?
- Yes:
- But one must interpret in light of modern advances
- Some important considerations:
- Population and treatment context have changed:
- In CREATE-X, many patients did not receive newer therapies that are more commonly used today (e.g. immunotherapy, targeted agents)
- The neoadjuvant regimens used then may differ from current ones (some now include platinum drugs, immunotherapy, etc.)
- Thus, whether the magnitude of benefit from capecitabine is identical in today’s more aggressive or modern regimens is uncertain
- Population and treatment context have changed:
- Yes:
- Evolving standard of care:
- In triple-negative breast cancer (TNBC):
- Immunotherapy (checkpoint inhibitors) is now incorporated into neoadjuvant and adjuvant settings in many protocols:
- Some patients receive pembrolizumab or other immune agents in the neoadjuvant plus adjuvant phase
- Immunotherapy (checkpoint inhibitors) is now incorporated into neoadjuvant and adjuvant settings in many protocols:
- In patients with germline BRCA mutations:
- Adjuvant PARP inhibitors (e.g. olaparib) have been shown to improve outcomes in high-risk disease, including non-pCR settings
- Newer antibody-drug conjugates (ADCs) and other novel therapies are being tested in residual disease settings:
- Sacituzumab govitecan in SASCIA trial:
- That could potentially surpass capecitabine in benefit
- Sacituzumab govitecan in SASCIA trial:
- In triple-negative breast cancer (TNBC):
- Subgroup-specific relevance:
- The benefit in the original CREATE-X was strongest in certain subtypes (especially TNBC)
- For hormone receptor–positive, HER2-negative disease:
- The benefit is less clear or more modest
- Some meta-analyses and reviews suggest that in modern TNBC:
- The role of capecitabine is still valid:
- Especially for patients with residual disease after standard therapy
- The role of capecitabine is still valid:
- Ongoing trials and unanswered questions:
- As newer therapies emerge, trials are ongoing to compare or combine capecitabine with immunotherapy or other agents in the post-neoadjuvant (residual disease) setting:
- One open question is whether capecitabine adds incremental benefit on top of modern therapies (immunotherapy, PARP inhibitors) or whether it’s supplanted in certain subgroups
- As newer therapies emerge, trials are ongoing to compare or combine capecitabine with immunotherapy or other agents in the post-neoadjuvant (residual disease) setting:
- My Bottom Line / Practical View:
- Yes, clinicians often still use the CREATE-X findings as a rationale for giving adjuvant capecitabine in patients with residual disease after neoadjuvant chemotherapy:
- Particularly in HER2-negative / triple-negative cases, when no more effective alternative is clearly indicated:
- But, the decision must be individualized:
- Consider what neoadjuvant therapy was used (did it include immunotherapy or platinum?)
- Consider patient risk factors, subtype (TNBC vs HR+), mutation status (BRCA), comorbidities, etc
- Consider newer options that may be more beneficial (e.g. PARP inhibitors in BRCA carriers, or ADCs if approved in that setting)
- But, the decision must be individualized:
- Particularly in HER2-negative / triple-negative cases, when no more effective alternative is clearly indicated:
- Yes, clinicians often still use the CREATE-X findings as a rationale for giving adjuvant capecitabine in patients with residual disease after neoadjuvant chemotherapy:
Rodrigo Arrangoiz MS, MD, FACS, FSSO 