The Cyclin D1 (CCND1) A870G polymorphism predicts clinical outcome to lapatinib and capecitabine in HER2-positive metastatic breast cancer

Abstract

Background: Lapatinib plus capecitabine emerged as an efficacious therapy in metastatic breast cancer (mBC). We aimed to identify germline single-nucleotide polymorphisms (SNPs) in genes involved in capecitabine catabolism and human epidermal receptor signaling that were associated with clinical outcome to assist in selecting patients likely to benefit from this combination.

Patients and methods: DNA was extracted from 240 of 399 patients enrolled in EGF100151 clinical trial (NCT00078572; clinicaltrials.gov) and SNPs were successfully evaluated in 234 patients. The associations between SNPs and clinical outcome were analyzed using Fisher's exact test, Kaplan-Meier curves, log-rank tests, likelihood ratio test within logistic or Cox regression model, as appropriate.

Results: There were significant interactions between CCND1 A870G and clinical outcome. Patients carrying the A-allele were more likely to benefit from lapatinib plus capecitabine versus capecitabine when compared with patients harboring G/G (P = 0.022, 0.024 and 0.04, respectively). In patients with the A-allele, the response rate (RR) was significantly higher with lapatinib plus capecitabine (35%) compared with capecitabine (11%; P = 0.001) but not between treatments in patients with G/G (RR = 24% and 32%, respectively; P = 0.85). Time to tumor progression (TTP) was longer in patients with the A-allele treated with lapatinib plus capecitabine compared with capecitabine (median TTP = 7.9 and 3.4 months; P < 0.001), but not in patients with G/G (median TTP = 6.1 and 6.6 months; P = 0.92).

Conclusion: Our findings suggest that CCND1A870G may be useful in predicting clinical outcome in HER2-positive mBC patients treated with lapatinib plus capecitabine.

Figures

Figure 1.

Interactions between CCND1 A870G polymorphism and treatment on response rate (RR), clinical benefit and time to tumor progression (TTP). The interactions between CCND1 A870G and treatment were analyzed by likelihood ratio test. There was a statistically significant interaction between CCND1 A870G and treatment in relation to (A) RR (P = 0.022) (B) clinical benefit, as defined as complete response, partial response or stable disease for at least 6 months (P = 0.040) and (C) TTP (P = 0.025), with those patients carrying the A-allele showing increased RR, clinical benefit and TTP with the addition of lapatinib compared with those patients who were homozygous for the G/G genotype.

Figure 2.

Recursive partioning analysis. (A) This comprehensive recursive partitioning analysis for time to tumor progression (TTP) in metastatic breast cancer patients only incorporated a total of 18 potential markers to define six distinct patient groups (node 1–6) on the basis of TTP with treatment of capecitabine monotherapy or combination chemotherapy of lapatinib plus capecitabine. (B) Patients treated with lapatinib plus capecitabine that carry the CCND1 870 (rs17852153) A/A or A/G and the MTHFR 1298 (rs1801131) A/A genotype have a longer TTP (10.8 months) compared with those patients who carry the CCND1 870 A/A or A/G and MTHFR 1298 A/C or C/C genotypes [5.6 months, hazard ratio (HR) = 2.34, 95% confidence interval (CI) 1.08–5.054] or the CCND1 870 G/G genotype (6.1 months; HR = 2.79, 95% CI 1.14–6.78). (C) While patients who were treated with capecitabine alone carried the TS 5′UTR 2R/3G, 3G/3C or 3G/3G demonstrated a longer TTP of 7.1 months within this patient population compared with patients carrying the TS 5′UTR 2R/2R, 2R/3C or 3C/3C and either human epidermal receptor 2 655 A/G (3.1 months; HR = 2.25, 95% CI 1.21–4.16) or A/A (4.0 months; HR = 1.16, 95% CI 0.57–2.39) genotypes. CCND1, cyclin D1; MTHFR, methylenetetrahydrofolate reductase; TS, thymidylate synthase.