Capecitabine in Combination with Endocrine Therapy as Maintenance Therapy after Bevacizumab Plus Paclitaxel Induction Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: KBCSG-TR1214.

Optimal treatment strategies for hormone receptor (HR)-positive, HER2-negative advanced and/or metastatic breast cancer (AMBC) remain uncertain. We investigated the clinical usefulness of adding capecitabine to maintenance endocrine therapy after induction chemotherapy and the efficacy of reinduction chemotherapy. Patients who had received bevacizumab-paclitaxel induction therapy and did not have progressive disease (PD) were randomized to maintenance therapy with endocrine therapy alone (group E) or endocrine plus capecitabine (1657 mg/m2/day on days 1-21, q4w) (group EC). In case of PD after maintenance therapy, patients received bevacizumab-paclitaxel reinduction therapy. Ninety patients were randomized. The median progression-free survival (PFS) under maintenance therapy (primary endpoint) was significantly longer in group EC (11.1 {95% CI, 8.0-11.8} months) than in group E (4.3 {3.6-6.0} months) (hazard ratio, 0.53; p < 0.01). At 24 months from the induction therapy start, the overall survival (OS) was significantly longer in group EC than in group E (hazard ratio, 0.41; p = 0.046). No difference was found in the time to failure of strategy (13.9 and 16.6 months in groups E and EC, respectively). Increased capecitabine-associated toxicities in group EC were tolerable. Addition of capecitabine to maintenance endocrine therapy may be a beneficial option after induction chemotherapy for HR-positive, HER2-negative AMBC patients.

Superficial Angiomyxoma of the Nipple in a Japanese Woman: A Case Report and Review of Literature.

Superficial angiomyxoma is a rare, benign, multilobulated cutaneous tumor composed of stellate and spindle cells, a prominent myxoid matrix, and numerous blood vessels. Superficial angiomyxoma may be indistinguishable from cutaneous lesions of the Carney complex, although superficial angiomyxoma can occur independently of the complex. In this article, we present the case of a 39-year-old Japanese woman with a 40 × 30 mm, focally ulcerated, polypoid superficial angiomyxoma on the left nipple without any evidence of Carney complex. The development of superficial angiomyxoma on the nipples in a patient without the Carney complex is extremely rare. Indeed, only 3 cases of superficial angiomyxoma arising on the nipple have been reported to date, and this is the first such report in Japan. In such cases, the majority of superficial angiomyxoma of the nipples develop in premenopausal women. The possibility of superficial angiomyxoma should be considered for all polypoid nipple lesion, particularly in premenopausal women, and complete excision with follow-up observation should be performed.

Candidate biomarkers predictive of anthracycline and taxane efficacy against breast cancer.

BACKGROUND: Since breast cancer shows diversity in clinical behaviors, a standard therapy does not always lead to favorable outcomes. MATERIALS AND METHODS: The expression statuses of candidate markers, including topoisomerase-II alpha (TOP2A), beta-tubulin (B-tub), and tissue inhibitor of metalloprotease-1 (TIMP-1), were immunohistochemically evaluated in 70 breast cancer tissues from 68 patients with advanced breast cancers receiving chemotherapy. RESULTS: The response rates to anthracycline and taxane were 70.5% and 67.2%, respectively. Overall, 25.1% ± 29.7%, 8.32% ± 10.1%, and 16.37% ±17.5% of cancer cells in the tumors studied were positive for B-tub, TOP2A, and TIMP-1 expressions, respectively. However, positive molecule expression did not differ between patients who did and did not exhibit clinical responses to treatment. The proportion of TOP2A-positive cancer cells was significantly higher among anthracycline responders than among nonresponders in HR-negative cancer (15.4% ±17.5% vs. 2.0% ± 2.4%, respectively, P = 0.048), whereas TOP2A and TIMP-1 expression statuses did not differ in HR-positive cancer. When patients were stratified according to B-tub, TOP2A, or TIMP-1 expression statuses (B-tub ≥10% vs. <10%, TOP2A ≥5% vs. <5%, TIMP-1 ≤20% vs. >20%, respectively), the proportion of patients with ≥10% B-tub-positive cancer cells was significantly higher in taxane responders than in nonresponders (72.4% vs. 37.5%, respectively, P = 0.016). Anthracycline responders showed a trend to have a higher proportion of patients with either ≥5% TOP2A-positive cancer cells or ≤20% TIMP-1-positive cancer cells compared to nonresponders (86.7% vs. 61.5%, respectively, P = 0.066). CONCLUSION: Immunohistochemical TOP2A, TIMP-1, and B-tub expression analyses are expected to be useful for predicting tumor responses to chemotherapy.

A genome-wide association study identifies a genetic variant in the SIAH2 locus associated with hormonal receptor-positive breast cancer in Japanese.

In Japan, breast cancer is the most common cancer among women and the second leading cause of cancer death among women worldwide. To identify genetic variants associated with the disease susceptibility, we performed a genome-wide association study (GWAS) using a total of 1086 Japanese female patients with hormonal receptor-positive (HRP) breast cancer and 1816 female controls. We selected 33 single-nucleotide polymorphisms (SNPs) with suggestive associations in GWAS (P-value of <1 × 10(-4)) as well as 4 SNPs that were previously implicated their association with breast cancer for further replication by an independent set of 1653 cases and 2797 controls. We identified significant association of the disease with a SNP rs6788895 (P(combined) of 9.43 × 10(-8) with odds ratio (OR) of 1.22) in the SIAH2 (intron of seven in absentia homolog 2) gene on chromosome 3q25.1 where the involvement in estrogen-dependent diseases was suggested. In addition, rs3750817 in intron 2 of the fibroblast growth factor receptor 2 gene, which was reported to be associated with breast cancer susceptibility, was significantly replicated with P(combined) of 8.47 × 10(-8) with OR=1.22. Our results suggest a novel susceptibility locus on chromosome 3q25.1 for a HRP breast cancer.

A genome-wide association study identifies locus at 10q22 associated with clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients in Japanese.

Although many association studies of polymorphisms in candidate genes with the clinical outcomes of breast cancer patients receiving adjuvant tamoxifen therapy have been reported, genetic factors determining individual response to tamoxifen are not fully understood. To identify genetic polymorphisms associated with clinical outcomes of patients with tamoxifen treatment, we conducted a genome-wide association study (GWAS). We studied 462 Japanese patients with hormone receptor-positive, invasive breast cancer receiving adjuvant tamoxifen therapy. Of them, 240 patients were analyzed by genome-wide genotyping using the Illumina Human610-Quad BeadChips, and two independent sets of 105 and 117 cases were used for replication studies. In the GWAS, we detected significant associations with recurrence-free survival at 15 single-nucleotide polymorphisms (SNPs) on nine chromosomal loci (1p31, 1q41, 5q33, 7p11, 10q22, 12q13, 13q22, 18q12 and 19p13) that satisfied a genome-wide significant threshold (log-rank P= 2.87 × 10(-9)-9.41 × 10(-8)). Among them, rs10509373 in C10orf11 gene on 10q22 was significantly associated with recurrence-free survival in the replication study (log-rank P= 2.02 × 10(-4)) and a combined analysis indicated a strong association of this SNP with recurrence-free survival in breast cancer patients treated with tamoxifen (log-rank P= 1.26 × 10(-10)). Hazard ratio per C allele of rs10509373 was 4.51 [95% confidence interval (CI), 2.72-7.51; P= 6.29 × 10(-9)]. In a combined analysis of rs10509373 genotype with previously identified genetic makers, CYP2D6 and ABCC2, the number of risk alleles of these three genes had cumulative effects on recurrence-free survival among 345 patients receiving tamoxifen monotherapy (log-rank P= 2.28 × 10(-12)). In conclusion, we identified a novel locus associated with recurrence-free survival in Japanese breast cancer patients receiving adjuvant tamoxifen therapy.

Lessons for pharmacogenomics studies: association study between CYP2D6 genotype and tamoxifen response.

We earlier reported a significant association between the cytochrome P450 2D6 (CYP2D6) genotype and the clinical outcome in 282 Japanese breast cancer patients receiving tamoxifen monotherapy. Although many research groups have provided evidence indicating the CYP2D6 genotype as one of the strongest predictors of tamoxifen response, the results still remain controversial. We hypothesized that concomitant treatment was one of the causes of these controversial results. We then studied 167 breast cancer patients who received tamoxifen-combined therapy to evaluate the effects of concomitant treatment on the association analysis and observed no significant association between CYP2D6 genotype and recurrence-free survival (P=0.44, hazard ratio: 0.64, 95% confidential interval: 0.20-1.99 in patients with two variant alleles vs. patients without a variant allele). When we carried out two subgroup analyses for nodal status and tumor size, we observed a positive association between the CYP2D6 genotype and the clinical outcome only in patients who received tamoxifen monotherapy. This study explained a part of the discrepancies among the reported results.

Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients.

PURPOSE: The clinical efficacy of tamoxifen is suspected to be influenced by the activity of drug-metabolizing enzymes and transporters involved in the formation, metabolism, and elimination of its active forms. We investigated relationships of polymorphisms in transporter genes and CYP2D6 to clinical outcome of patients receiving tamoxifen. PATIENTS AND METHODS: We studied 282 patients with hormone receptor-positive, invasive breast cancer receiving tamoxifen monotherapy, including 67 patients who have been previously reported. We investigated the effects of allelic variants of CYP2D6 and haplotype-tagging single nucleotide polymorphisms (tag-SNPs) of ABCB1, ABCC2, and ABCG2 on recurrence-free survival using the Kaplan-Meier method and Cox regression analysis. Plasma concentrations of tamoxifen metabolites were measured in 98 patients receiving tamoxifen 20 mg/d. RESULTS: CYP2D6 variants were significantly associated with shorter recurrence-free survival (P = .000036; hazard ratio [HR] = 9.52; 95% CI, 2.79 to 32.45 in patients with two variant alleles v patients without variant alleles). Among 51 tag-SNPs in transporter genes, a significant association was found at rs3740065 in ABCC2 (P = .00017; HR = 10.64; 95% CI, 1.44 to 78.88 in patients with AA v GG genotypes). The number of risk alleles of CYP2D6 and ABCC2 showed cumulative effects on recurrence-free survival (P = .000000055). Patients carrying four risk alleles had 45.25-fold higher risk compared with patients with

A retrospective study on TS mRNA expression and prediction of the effects of adjuvant oral 5-fluorouracil in breast cancer.

Nucleic acid-metabolizing enzymes, such as thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP) and orotate phosphoribosyl transferase (OPRT), have attracted attention as candidates for response determinants of 5-fluorouracil (5-FU). Whether the expression levels of these enzymes can be adopted as valuable parameters for 5-FU sensitivity in breast cancer has yet to be elucidated. In the present study, intratumoral mRNA expression of TS, DPD, TP and OPRT were determined in formalin-fixed paraffin-embedded surgical specimens collected from 217 breast cancer patients, using the Danenberg Tumor Profile method, which combines microdissection and real-time-polymerase chain reaction. The significance of these enzymes as prognostic and 5-FU efficacy-predicting factors was evaluated. Our data showed that a low DPD expression is related to a high nuclear grade and other factors including hormone receptor-negativity. Low expression levels of TP were found in hormone receptor-negative tumors. TS and OPRT expression were not related to various clinicopathological factors, but patients with a high TS mRNA expression showed a significantly poorer prognosis in cases where 5-FU was not administered. The efficacy of 5-FU was more significant when administered for more than 6 months in the group with a high TS mRNA expression. These data suggest that TS mRNA expression in breast cancer tissue is an ideal predictor of outcomes for patients with no administration of 5-FU, and of the efficacy of 5-FU.