ADJUVANT CAPECITABINE added to standard neoadjuvant chemotherapy failed to significantly improve disease-free or overall survival in patients with early triple-negative breast cancer in the large phase III CIBOMA/2004-01_GEICAM/2003-11 (CIBOMA/GEICAM) trial.¹ However, extended treatment with adjuvant capecitabine did significantly improve both disease-free and overall survival in a prespecified subgroup of patients with a non–basal-like phenotype.

Miguel Martín, MD, PhD

“Patients with early-stage triple-negative breast cancer are typically treated with surgery and chemotherapy, and sometimes radiotherapy. Despite effective neoadjuvant and adjuvant chemotherapies with anthracyclines and taxanes, the relapse rate is high. Up to 10% of those with stage I will relapse, as will 15% to 20% of those with stage II disease and 25% to 50% of those with stage III disease. We need new approaches to this disease,” said lead author Miguel Martín, MD, PhD, of the Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid. Dr. Martín presented the results of the CIBOMA/GEICAM trial at the 2018 San Antonio Breast Cancer Symposium (SABCS).¹

“We were disappointed to find that the addition of adjuvant capecitabine to the standard treatment did not significantly improve survival. However, given that we found a subset of the patients with non–basal-like disease seemed to have a significant benefit from capecitabine, plus data from the CREATE-X trial² showed adjuvant capecitabine significantly reduced the rate of relapse and improved overall survival when administered to patients with breast cancer who had residual disease after neoadjuvant chemotherapy, we strongly recommend that patients with triple-negative breast cancer discuss adjuvant capecitabine with their oncologists.”

“We strongly recommend that patients with triple-negative breast cancer discuss adjuvant capecitabine with their oncologists.”

— Miguel Martín, MD, PhD

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Study Details

“CAPECITABINE IS approved for the treatment of breast cancer after failure of anthracyclines and taxanes. We hypothesized that patients could have an advantage with this drug and that a non–cross-resistant agent could rescue patients pretreated with anthracyclines plus or minus taxanes,” Dr. Martín told listeners.

The CIBOMA/GEICAM trial enrolled 876 patients with centrally confirmed early triple-negative breast cancer treated with prior standard neoadjuvant chemotherapy using anthracyclines and taxanes. Patients had received six cycles of prior standard chemotherapy, except for patients with node-negative disease, who could have only four cycles. All patients had cancer-free surgical margins and were stratified for four factors: institution, presence or absence of basal phenotype according to immunohistochemistry (IHC) staining of CK5/6 and/or epidermal growth factor receptor (EGFR), number of lymph nodes (0 vs 1–3 vs ≥ 4), and type of prior chemotherapy (anthracycline alone vs anthracycline/taxane). They were randomly assigned 1:1 to receive oral capecitabine at 1,000 mg/m2 twice daily for 14 days every 3 weeks for 8 cycles vs observation.

Dr. Martín explained that the low rate of neoadjuvant chemotherapy was related to the fact that the study was started 14 years ago, when neoadjuvant chemotherapy was not a standard of care.

At baseline, patient and tumor characteristics were well balanced between the two study arms. The median patient age was 50, about one-third were premenopausal and two-thirds were postmenopausal, and about 60% had stage II disease. Of the study patients, 55% were node-negative, 28% had 1 to 3 positive nodes, and about 16% had 4 or more positive nodes. About 25% had a pathologic complete response to neoadjuvant chemotherapy; one-third had anthracycline-based neoadjuvant therapy, and two-thirds received anthracycline plus taxane-based chemotherapy.

Key Results

THE MEDIAN follow-up was 7.3 years. For the primary endpoint of disease-free survival, the results in the whole study population did not significantly differ. At 5 years, 79.6% of the capecitabine arm and 76.8% of the observation arm were disease-free and alive. Similarly, overall survival was comparable between the two arms: 86.2% and 85.8% at 5 years. Expected 5-year survival for this population is 64.7%, according to our registries in Spain, Dr. Martín noted.

However, a prespecified subgroup analysis showed a significant survival benefit with capecitabine among patients with non–basal-like triple-negative breast cancer (ie, IHC-negative for EGFR and CK5/6). Among this subgroup, 5-year disease-free survival was 82.6% with capecitabine vs 72.9% with observation—a significant 47% improvement (P = .02). Overall survival was also significantly superior for the capecitabine-treated patients: 89.5% were alive at 5 years vs 79.6%—representing a 58% improvement (P = .007). “In the non–basal-like population, capecitabine reduced mainly distant relapses in the liver and brain,” Dr. Martín noted.

In the overall population, disease-free survival events were reported in 23.4% of the capecitabine group and 28% of the observation group. Among those with non–basal-like breast cancer, events occurred in 17.6% of the capecitabine group and 30% of the observation group. The rate of distant recurrence in the overall population was 14.3% with capecitabine vs 15.4% with observation; in the non–basal-like group, distant recurrence was reported in 10.9% vs 16.4% of the observation group.

“Our study is not finished....We are in the era of personalized medicine, and the goal is to identify which subgroups of patients benefit from the addition of capecitabine.”

— Miguel Martín, MD, PhD

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“The intriguing finding that patients with non–basal-like triple-negative breast cancer experienced fewer disease-free survival events should be interpreted with caution. The interaction test was negative for disease-free survival but statistically significant for overall survival,” Dr. Martín said.

Tolerance was as expected, with 86.3% of patients completing the planned 8 cycles of capecitabine.

Clinical Implications

“OUR STUDY is not finished,” noted Dr. Martín. “We plan to look at the genomic characteristics of the patients. We are in the era of personalized medicine, and the goal is to identify which subgroups of patients benefit from the addition of capecitabine.”

Dr. Martín continued: “In clinical practice, patients are not distinguished between basal-like and non–basal-like phenotypes. All triple-negative breast cancer is treated the same way. In my view, this is a mistake. We need to find the right drug for the right patient. Pharmaceutical companies are not interested in this type of investigation. We need trials to identify the optimal therapy for the different subtypes of breast cancer, but I am not optimistic about funding,” Dr. Martín stated. ■

DISCLOSURE: Dr. Martín has received honoraria as a speaker from Pfizer and Lilly; has served as an advisor for AstraZeneca, Novartis, Roche-Genentech, Pfizer, GlaxoSmithKline, PharmaMar, Taiho Oncology, and Lilly; and has received research grants from Novartis and Roche.

REFERENCES

1. Martín M, Barrios CH, Torrecillas L, et al: Efficacy results from CIBOMA/2004-01_GEICAM/2003-2011 study: A randomized phase III trial assessing adjuvant capecitabine after standard chemotherapy for patients with early triple negative breast cancer. 2018 San Antonio Breast Cancer Symposium. Abstract GS1-10. Presented December 5, 2018.

2. Masuda N, Lee S-J, Ohtani S, et al: Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med 376:2147-2159, 2017.