What is the role of adjuvant capecitabine in reducing the risk of recurrence in a patient with non-metastatic triple-negative breast cancer (TNBC) and a germline BRCA1 or BRCA2 mutation?

Adjuvant Capecitabine in TNBC with Germline BRCA1/2 Mutations

For patients with non-metastatic triple-negative breast cancer and germline BRCA1/2 mutations who have residual disease after neoadjuvant chemotherapy, adjuvant capecitabine significantly reduces recurrence risk and improves survival, but adjuvant olaparib is the preferred Category 1 recommendation based on the OlympiA trial; however, no data exist to guide selection between these agents or their sequencing. 1

Primary Treatment Decision Algorithm

For Patients with Residual Disease After Neoadjuvant Therapy:

First-line consideration: Adjuvant olaparib for 1 year (Category 1) 1

• This is the preferred option based on the OlympiA trial results
• Indicated for patients with germline BRCA1/2 mutations and TNBC with residual disease after preoperative chemotherapy

Alternative option: Adjuvant capecitabine (6-8 cycles) 1

• Strongly supported for TNBC patients with residual disease after standard anthracycline and/or taxane-based neoadjuvant therapy
• Improves disease-free survival (HR 0.70; 95% CI 0.53-0.92; P=0.01) and overall survival (HR 0.59; 95% CI 0.39-0.90; P=0.01) 1
• The benefit is particularly pronounced in TNBC (HR for death 0.52) 1

For Patients Treated with Upfront Surgery (No Neoadjuvant Therapy):

Adjuvant olaparib for 1 year (Category 1) 1

• Indicated if tumors are ≥pT2 or ≥pN1 disease after adjuvant chemotherapy
• Can be used concurrently with endocrine therapy if hormone receptors are present 1

Critical Evidence Gap and Clinical Dilemma

The fundamental limitation: Patients in the OlympiA trial did not receive capecitabine, so no data exist on sequencing or to guide selection of one agent over the other. 1

The ESMO guidelines explicitly state that the understanding of safety for the olaparib-capecitabine combination is insufficient to support use of this combination. 1

Efficacy Data for Capecitabine in TNBC

CREATE-X Trial Results (Foundation Evidence):

• Disease-free survival improvement: 74.1% vs 67.6% at 5 years (absolute difference 6.5%) 1, 2
• Overall survival improvement: 89.2% vs 83.6% (absolute difference 5.6%) 1, 2
• TNBC-specific benefit: DFS 69.8% vs 56.1% (HR 0.58; 95% CI 0.39-0.87) and OS 78.8% vs 70.3% (HR 0.52; 95% CI 0.30-0.90) 1, 2

Real-World Evidence:

Recent multicenter studies confirm the CREATE-X findings in diverse populations:

• Real-world data from three comprehensive cancer centers showed adjuvant capecitabine associated with improved recurrence-free survival (HR 0.70; 95% CI 0.54-0.91; P=0.008), distant recurrence-free survival (HR 0.71; 95% CI 0.54-0.93; P=0.01), and overall survival (HR 0.66; 95% CI 0.49-0.90; P=0.009) 3
• Korean real-world data demonstrated 3-year DDFS of 86.3% with capecitabine vs 74.4% without (P=0.019) and OS of 93.3% vs 83.8% (P=0.032) 4

Dosing and Tolerability Considerations

Standard Dosing:

Capecitabine 1,250 mg/m² orally twice daily on days 1-14 of a 21-day cycle for 6-8 cycles 1

Critical Toxicity Warning:

This dosing is associated with significantly higher toxicity in patients ≥65 years old, including treatment-related deaths. 1

• In the CALGB 49907 trial of elderly patients, there was a 34% rate of grade 3 or higher toxicity, including two protocol-related deaths 1

Common Adverse Events:

• Hand-foot syndrome: 73.4% any grade, 11.1% grade 3 1, 5
• Diarrhea: Grade 3/4 in 2.9% 1
• Neutropenia: Grade 3/4 in 6.3% 1

Real-World Dosing Patterns:

A retrospective US study found mean relative dose intensity across 8 cycles was only 60.2% (95% CI 0.554-0.650), significantly lower than the CREATE-X trial (60.2% vs 78.7%, p<0.001), indicating that the standard dose is poorly tolerated in diverse populations. 6

Clinical Implementation Pitfalls

Common Underutilization:

Real-world data shows that 45.1% of patients with TNBC and residual disease did not receive any adjuvant therapy, and less than one-third received adjuvant capecitabine despite clear survival benefits. 3

Sequencing with Radiation Therapy:

For sequencing of capecitabine or olaparib with radiation therapy, refer to specific institutional guidelines (NCCN BINV-I section). 1

Patients Receiving Neoadjuvant Pembrolizumab:

If pembrolizumab was given in combination with chemotherapy in the preoperative setting, adjuvant pembrolizumab is recommended based on KEYNOTE-522 trial data. 1 The interaction between adjuvant capecitabine and continuation of immunotherapy is unknown. 1

Practical Recommendation for BRCA-Mutated TNBC

Given the Category 1 evidence for olaparib in this specific population and the lack of safety data for combining olaparib with capecitabine, prioritize adjuvant olaparib for 1 year as the primary strategy. 1

Reserve capecitabine for:

• Patients who cannot tolerate or have contraindications to olaparib
• Patients who decline PARP inhibitor therapy
• Situations where olaparib is not accessible

The survival benefit from capecitabine in TNBC with residual disease is substantial (48% reduction in death risk), making it a highly effective alternative when olaparib cannot be used. 1, 2