Treating patients who had early-stage triple-negative breast cancer (TNBC) with the chemotherapeutic agent capecitabine (Xeloda®; Genentech/Roche) after they completed surgery and standard chemotherapy did not significantly improve disease-free or overall survival compared with observation, according to data from the randomized, phase III GEICAM/CIBOMA clinical trial presented at the 2018 San Antonio Breast Cancer Symposium (SABCS), held in San Antonio, TX, December 4–8, 2018.
Triple-negative breast cancer (TNBC) is a form of breast cancer that does not have any of the receptors that are commonly found in breast cancer, including the hormones estrogen (ER+), progesterone (PR+) and a protein called human epidermal growth factor (HER2). The disease is more frequently diagnosed in younger and premenopausal women and is highly prevalent in African American women.
Because TNBC lacks the receptors for estrogen, progesterone and HER2, patients do not benefit from hormonal or trastuzumab-based therapies. Surgery and chemotherapy, individually or in combination, are considered to be the only available treatment options.
Capecitabine is an oral antimetabolite and pre-prodrug of 5-Flurouracil (5-FU) and is rapidly converted in its main metabolites 5′-deoxy-5-fluorocytidine (5′-DFCR) which takes place mainly in the liver by carboxyl-esterase and 5′-deoxy-5-fluoro-uridine (5′-DFUR) by cytidine deaminase in liver and tumor tissue. This is in turn, converted to 5-FU intracellularly by thymidine phosphorylase, an enzyme that is often expressed in tumor tissue. The drug is approved for the treatment of various forms of cancers, including metastatic breast cancer. However the drug has not been used as a standard in the treatment of triple-negative breast cancer.
In clinical trials, capecitabine, which is often used as second-line monotherapy in patients whose disease is resistant to anthracycline, taxane, or both, has been shown to be effective in patients with metastatic breast cancer. Results from one study, the CREATE-X trial*, showed that capecitabine had a statistically significant survival advantage compared with no additional therapy. 
“Patients with early-stage triple-negative breast cancer are usually treated with surgery and chemotherapy, and sometimes radio therapy,” said Miguel Martín, MD, Ph.D, professor of medicine and head of the Medical Oncology Service at Hospital Gregorio Marañón, Universidad Complutense, Madrid, Spain.
“New therapeutic approaches are urgently needed, however, because the risk of relapse is high: 7 to 10% of those with stage 1 disease relapse, 15 to 20% of those with stage II disease, and 25 to 50% of those with stage III disease.”
“We were disappointed to find that adding adjuvant capecitabine to the standard treatment did not significantly improve disease-free or overall survival,” Martín continued.
“However, given that we found a subset of the patients with non basal-like disease seemed to have a significant benefit from capecitabine, and data from the CREATE-X trial showed that adjuvant capecitabine significantly reduced the rate of relapse and improved overall survival when administered to breast cancer patients with residual disease after neoadjuvant chemotherapy, we strongly recommend that patients with triple-negative breast cancer discuss adjuvant capecitabine with their oncologists.”
Martín and colleagues randomized 876 patients with early-stage triple-negative breast cancer who had been treated with surgery and chemotherapy in the trial to eight cycles of capecitabine or observation.
After a median follow-up of 7.3 years, five-year disease-free survival was 79.6% among the 448 patients randomized to capecitabine and 76.8% among the 428 patients randomized to observation.
“The improvement in five-year disease-free survival was not statistically significant, meaning that the trial result is formally negative,” Martín explained.
“There was a nonsignificant trend in favor of capecitabine, but the trial had only 876 participants, which means it was not statistically powered to identify small but clinically relevant differences,” Martín noted.
“One possible reason for the discrepancy in the results of the CREATE-X trial and our trial may be that the populations had different prognostic features; the risk of relapse of our population was much less than in the CREATE-X trial.”
In subgroup analyses, Martín and colleagues found that among the 248 patients with non-basal like disease, as defined by immunohistochemistry, those randomized to adjuvant capecitabine were 49% less likely to experience a disease event and 52% less likely to die
compared with those randomized to observation.
“This is an intriguing finding,” said Martín. “However, it should be interpreted with caution because the interaction test was negative for disease-free survival (p=0.0694), although it was statistically significant for overall survival (p=0.0052).”
According to Martín, the main limitation of the study is the limited power of the trial to show small but clinically relevant improvements in outcome with capecitabine due to the sample size and the lower than expected number of relapse events in the control group.
This study was supported by Roche, which also provided capecitabine.
 Maintenance Treatment With Capecitabine Versus Observation in Breast Cancer Patients – NCT00130533
 Masuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I, Kuroi K, Im SA, et al. Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. N Engl J Med. 2017 Jun 1;376(22):2147-2159. doi: 10.1056/NEJMoa1612645.
 A phase III randomized study of capecitabine as adjuvant chemotherapy versus observation in breast cancer with pathologic residual tumors after preoperative chemotherapy(JBCRG-04) – UMIN000000843
*The Capecitabine for Residual Cancer as Adjuvant Therapy or CREATE-X trial was a multicenter, open-label, randomized, phase III trial designed to evaluate the efficacy and safety of adjuvant capecitabine monotherapy in patients with HER2-negative primary breast cancer who had residual invasive disease after the receipt of standard neoadjuvant chemotherapy containing anthracycline, taxane, or both.
Featured Image: Attendees chat during the Career Development Forum during the Annual San Antonio Breast Cancer Symposium in San Antonio, TX. Courtesy: 2018 © MedMeetingImages/Todd Buchanan. Used with permission.
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