Nan Soon Wong

Hormone Receptor and c-ERBB2 Status in Distant Metastatic and Locally Recurrent Breast Cancer Pathologic Correlations and Clinical Significance

Estrogen receptor (ER), progesterone receptor (PR), and c-ERBB2 (HER2/neu) are therapeutically and prognostically important markers in the management of breast carcinoma. They are not always analyzed in distant metastatic and locally recurrent breast cancers. We compared immunohistochemical expression in a series of primary breast carcinomas with their distant metastases (n = 72) and local recurrences (n = 45) and analyzed the impact of any changes on survival. Discordance rates between primary and metastatic and between primary and locally recurrent lesions, respectively, were 18% (13/72) and 13% (6/45) for ER, 42% (30/72) and 33% (15/45) for PR, and 7% (5/72) and 2% (1/45) for c-ERBB2. There was statistically significant discordance between primary and metastatic PR status (P = .017; kappa = 0.201). Among locally recurrent tumors, 15 (33%) of 45 revealed discordance for PR (P = .006; kappa = 0.366). We observed a trend for shorter survival among women with ER- metastatic and locally recurrent tumors regardless of the primary tumor ER status. Our findings suggest a benefit for routine evaluation of ER, PR, and c-ERBB2 status in distant metastatic and locally recurrent breast cancer for therapeutic and prognostic purposes.

Triple Negative Breast Cancer: Outcome Correlation With Immunohistochemical Detection of Basal Markers

We earlier evaluated the relationship of 653 triple negative breast cancers (TNBC) with basal immunophenotypic expression by using antibodies to basal cytokeratins (CK5/6, CK14, CK17, 34βE12), p63, smooth muscle actin (SMA), epidermal growth factor receptor, and CD117, and found that a triple panel of CK14, 34βE12 and epidermal growth factor receptor determined 84% of our cases to be basal-like. Women with basal-like TNBC tended to be younger (P=0.04), have histologically higher-grade tumors (P=0.047), with positive nodal status (P=0.047), than those whose tumors were nonbasal-like. Using univariate Cox regression analysis, tumor size (P=0.003), histologic grade (P=0.006), and nodal status (P=0.017) were significant factors for disease-free survival (DFS) among TNBC, whereas age (P=0.004), tumor size (P=0.001), histologic grade (P<0.001), nodal status (P=0.011), lymphovascular invasion (P=0.032), and pushing borders (P=0.042) were important for overall survival (OS). On multivariate analysis, age was statistically significant for both DFS and OS (P=0.033, 0.001 respectively), whereas histologic grade was important for OS (P<0.001). Kaplan Meier curves showed CK17 positivity to impact adversely on DFS (P=0.003) and OS (P=0.014), whereas CD117 positive staining was accompanied by diminished OS (P=0.036). SMA expression in TNBC however, revealed a trend for improved DFS (P=0.05). Our findings indicate that basal-like TNBC are associated with adverse clinicopathologic parameters, and that individual biologic markers of CK17, CD117, and SMA have prognostic implications on survival. Possibilities exist for future targeted therapy for this challenging group of breast cancers.

The English and Chinese versions of the five-level EuroQoL Group's five-dimension questionnaire (EQ-5D) were valid and reliable and provided comparable scores in Asian breast cancer patients

ObjectiveTo examine the measurement properties of and comparability between the English and Chinese versions of the five-level EuroQoL Group’s five-dimension questionnaire (EQ-5D) in breast cancer patients in Singapore.MethodsThis is an observational study of 269 patients. Known-group validity and responsiveness of the EQ-5D utility index and visual analog scale (VAS) were assessed in relation to various clinical characteristics and longitudinal change in performance status, respectively. Convergent and divergent validity was examined by correlation coefficients between the EQ-5D and a breast cancer-specific instrument. Test–retest reliability was evaluated. The two language versions were compared by multiple regression analyses.ResultsFor both English and Chinese versions, the EQ-5D utility index and VAS demonstrated known-group validity and convergent and divergent validity, and presented sufficient test–retest reliability (intraclass correlation = 0.72 to 0.83). The English version was responsive to changes in performance status. The Chinese version was responsive to decline in performance status, but there was no conclusive evidence about its responsiveness to improvement in performance status. In the comparison analyses of the utility index and VAS between the two language versions, borderline results were obtained, and equivalence cannot be definitely confirmed.ConclusionThe five-level EQ-5D is valid, responsive, and reliable in assessing health outcome of breast cancer patients. The English and Chinese versions provide comparable measurement results.

Association of CYP2C19*2 and associated haplotypes with lower norendoxifen concentrations in tamoxifen-treated Asian breast cancer patients

AIM The aim was to examine the influence of CYP2C19 variants and associated haplotypes on the disposition of tamoxifen and its metabolites, particularly norendoxifen (NorEND), in Asian patients with breast cancer. METHODS Sixty-six CYP2C19 polymorphisms were identified in healthy Asians (n = 240), of which 14 were found to be tightly linked with CYP2C19*2, CYP2C19*3 and CYP2C19*17. These 17 SNPs were further genotyped in Asian breast cancer patients receiving tamoxifen (n = 201). Steady-state concentrations of tamoxifen and its metabolites were quantified using liquid chromatography–mass spectrometry. Non-parametric tests and regression methods were implemented to evaluate genotypic–phenotypic associations and haplotypic effects of the SNPs. RESULTS CYP2C19 functional polymorphisms and their linked SNPs were not significantly associated with plasma concentrations of tamoxifen and its main metabolites N-desmethyltamoxifen, (Z)-4-hydroxytamoxifen and (Z)-Endoxifen. However, CYP2C19*2 and its seven linked SNPs were significantly associated with lower NorEND concentrations, MRNorEND/NDDM and MRNorEND/(Z)-END. Specifically, patients carrying the CYP2C19*2 variant allele A had significantly lower NorEND concentrations [median (range), GG vs. GA vs. AA: 1.51 (0.38–3.28) vs. 1.28 (0.30–3.36) vs. 1.15 ng ml−1 (0.26–2.45, P = 0.010)] as well as significantly lower MRNorEND/(Z)-END [GG vs. GA vs. AA: 9.40 (3.27–28.35) vs. 8.15 (2.67–18.9) vs. 6.06 (4.47–14.6), P < 0.0001] and MRNorEND/NDDM [GG vs. GA vs. AA: 2.75 (0.62–6.26) vs. 2.43 (0.96–4.18) vs. 1.75 (1.10–2.49), P < 0.00001]. CYP2C19 H2 haplotype, which included CYP2C19*2, was also significantly associated with lower NorEND concentrations (P = 0.0020), MRNorEND/NDDM (P < 0.0001) and MRNorEND/(Z)-END (P < 0.0001), indicating significantly lower formation rates of NorEND. CONCLUSION These data highlight the potential relevance of CYP2C19 pharmacogenetics in influencing NorEND concentrations in tamoxifen-treated patients, which may influence treatment outcomes.

ETV6 disruption does not predict indolent clinical behavior in secretory breast carcinoma.

Mabel Wong, MRCP,* Ana Richelia Jara-Lazaro, MD, Raymond Chee Hui Ng, FRACP,* Alvin Soon Tiong Lim, PhD, Poh Yian Cheok, BSc, Tse-Hui Lim, MSc, Puay Hoon Tan, FRCPA, and Nan Soon Wong, FAMS *Department of Medical Oncology, National Cancer Centre, Singapore; Department of Pathology, Singapore General Hospital, Singapore; Oncocare Cancer Centre, Mt Elizabeth Medical Centre, Singapore; and Department of Clinical Sciences, Duke-NUS, Singapore

Predictors of Hand-Foot Syndrome and Pyridoxine for Prevention of Capecitabine–Induced Hand-Foot Syndrome: A Randomized Clinical Trial

Importance Hand-foot syndrome (HFS) is a common adverse effect of capecitabine treatment. Objective To compare the incidence and time to onset of grade 2 or greater HFS in patients receiving pyridoxine vs placebo and to identify biomarkers predictive of HFS. Design, Setting, and Participants This single-center, randomized double-blind, placebo-controlled phase 3 trial conducted at National Cancer Centre Singapore assessed whether oral pyridoxine could prevent the onset of grade 2 or higher HFS in 210 patients scheduled to receive single-agent capecitabine chemotherapy for breast, colorectal, and other cancers. Interventions Patients were randomized to receive concurrent pyridoxine (200 mg) or placebo daily for a maximum of 8 cycles of capecitabine, with stratification by sex and use in adjuvant or neoadjuvant vs palliative setting. Patients were withdrawn from the study on development of grade 2 or higher HFS or cessation of capecitabine. Main Outcomes and Measures Primary end point was the incidence of grade 2 or higher HFS in patients receiving pyridoxine. Secondary end points included the time to onset (days) of grade 2 or higher HFS and identification of biomarkers predictive of HFS, including baseline folate and vitamin B12 levels, as well as genetic polymorphisms with genome-wide arrays. Results In this cohort of 210 patients (median [range] age, 58 [26-82] years; 162 women) grade 2 or higher HFS occurred in 33 patients (31.4%) in the pyridoxine arm vs 39 patients (37.1%) in the placebo arm (P = .38). The median time to onset of grade 2 or higher HFS was not reached in both arms. In univariate analysis, the starting dose of capecitabine (odds ratio [OR], 1.99; 95% CI, 1.32-3.00; P = .001), serum folate levels (OR, 1.27; 95% CI, 1.10-1.47; P = .001), and red blood cell folate levels (OR, 1.25; 95% CI, 1.08-1.44; P = .003) were associated with increased risk of grade 2 or higher HFS. In multivariate analyses, serum folate (OR, 1.30; 95% CI, 1.12-1.52; P < .001) and red blood cell folate (OR, 1.28; 95% CI, 1.10-1.49; P = .001) were the only significant predictors of grade 2 or higher HFS. Grade 2 or higher HFS was associated with 300 DNA variants at genome-wide significance (P < 5 × 10−8), including a novel DPYD variant (rs75267292; P = 1.57 × 10−10), and variants in the MACF1 (rs183324967, P = 4.80 × 10−11; rs148221738, P = 5.73 × 10−10) and SPRY2 (rs117876855, P < 1.01 × 10−8; rs139544515, P = 1.30 × 10−8) genes involved in wound healing. Conclusions and Relevance Pyridoxine did not significantly prevent or delay the onset of grade 2 or higher HFS. Serum and red blood cell folate levels are independent predictors of HFS. Trial Registration clinicaltrials.gov Identifier: NCT00486213

Measurement Properties of the Eight-Item Abbreviated Functional Assessment of Cancer Therapy—Breast Symptom Index and Comparison With Its 37-Item Parent Measure

CONTEXT The Functional Assessment of Cancer Therapy--Breast Symptom Index (FBSI) is an eight-item instrument extracted from the Functional Assessment of Cancer Therapy--Breast (FACT-B). There has been no formal assessment of this eight-item version. OBJECTIVES This study aimed to examine the measurement properties of and comparability between the English and the Chinese versions of the FBSI and to compare it with its parent instrument, the FACT-B, in breast cancer patients in Singapore. METHODS This was an observational study of 271 breast cancer patients. Known-group validity of FBSI scores was assessed using four health indicators. Convergent and divergent validity was examined by correlation coefficients between the FBSI and the FACT-B. Responsiveness was assessed in relation to longitudinal changes in performance status. Test-retest reliability was evaluated by the intraclass correlation coefficient. Multiple regression analyses were performed to compare the scores on the two language versions. Receiver operating characteristic curve analyses were used for comparison between the FBSI and the FACT-B. RESULTS For both language versions, the FBSI demonstrated known-group validity, convergent and divergent validity, and sufficient test-retest reliability (intraclass correlation coefficient = 0.75-0.77). The English version was responsive to changes in performance status. The Chinese version was responsive to decline in performance status, but there was no conclusive evidence about its responsiveness to improvement in performance status. No practical significant difference was found in the outcomes between the two language versions despite minor difference in one item. The FBSI performed comparably with the FACT-B. CONCLUSION The English and Chinese versions of the FBSI are valid and reliable and provide comparable FBSI scores. The English version is responsive to change, whereas the responsiveness of the Chinese version warrants further study.

Evaluation of three polygenic risk score models for the prediction of breast cancer risk in Singapore Chinese

Genome-wide association studies (GWAS) have proven highly successful in identifying single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. The majority of these studies are on European populations, with limited SNP association data in other populations. We genotyped 51 GWAS-identified SNPs in two independent cohorts of Singaporean Chinese. Cohort 1 comprised 1294 BC cases and 885 controls and was used to determine odds ratios (ORs); Cohort 2 had 301 BC cases and 243 controls for deriving polygenic risk scores (PRS). After age-adjustment, 11 SNPs were found to be significantly associated with BC risk. Five SNPs were present in <1% of Cohort 1 and were excluded from further PRS analysis. To assess the cumulative effect of the remaining 46 SNPs on BC risk, we generated three PRS models: Model-1 included 46 SNPs; Model-2 included 11 statistically significant SNPs; and Model-3 included the SNPs in Model-2 but excluded SNPs that were in strong linkage disequilibrium with the others. Across Models-1, -2 and -3, women in the highest PRS quartile had the greatest ORs of 1.894 (95% CI = 1.157–3.100), 2.013 (95% CI = 1.227–3.302) and 1.751 (95% CI = 1.073–2.856) respectively, suggesting a direct correlation between PRS and BC risk. Given the potential of PRS in BC risk stratification, our findings suggest the need to tailor the selection of SNPs to be included in an ethnic-specific PRS model.

Abstract 1647: Evaluation of breast cancer susceptibility loci in Chinese women from Singapore

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Genome-wide association studies (GWAS) have identified several breast cancer susceptibility loci associated with European populations, some of which were also found to be associated with breast cancer among women in China. Women in Singapore are predominantly of Chinese ancestry with an urbanized lifestyle, with breast cancer rates approaching those of the West. To explore the role of these breast cancer susceptibility variants, a Taqman-based microfluidics strategy was established to carry out fast track replication of 22 SNPs for 1,146 cases and 1,534 controls to identify significant risk variants for breast cancer. Interestingly, the most significant SNP [rs2046210; odds ratio (OR), 1.4; 95% confidence interval, 1.2-1.6; P=7x10−6], residing in 6q25.1, had been initially identified in a Chinese population, suggesting a strong and consistent association of this SNP with Chinese ancestry. SNPs in FGFR2 (rs2981579, rs1219648, rs2981582, rs112000014), 8q24 (rs13281615), and MAP3K1 (rs16886165) showed significant associations similar to those observed in women of European ancestry, with ORs ranging from 1.1 to 1.7 (P=5x10−5 to 0.04). Ranking of the SNPs in terms of their ORs for Singaporean Chinese women was compared to that from Western and Chinese studies. The ranking for Singaporean Chinese women resembled, but was not identical to, that of women in China, reflecting the effect of ethnicity. Comprehensive annotation of the genotyping data with associated clinicopathological features enabled the identification of significant SNPs associated with tumour size, lymph node metastasis, and estrogen/progesterone receptor status. Findings from this study implicate 6q25.1 and FGFR2 as the most important susceptibility loci for Asian women of Chinese ancestry and may guide future fine-mapping studies to identify causal variants. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1647. doi:1538-7445.AM2012-1647

Randomized phase II study of metronomic chemotherapy (MC) plus aromatase inhibitor (AI) versus MC alone in postmenopausal hormone receptor-positive, metastatic breast cancer (MBC), with correlative circulating endothelial cell (CEC), circulating endothelial progenitor cell (CEP), VEGF, and VEGFR levels.

TPS127 Background: Neoadjuvant AI plus MC achieves greater suppression of Ki67 and VEGF in primary breast cancer compared to AI alone (Bottini A et al. J Clin Oncol; 24: 3623, 2006). We previously showed that this combination is active in MBC even among women previously exposed to AI, and hypothesized that MC may reverse AI resistance (T Wai Ming et al. 2009 IMPAKT Breast Cancer Conference, Abstract 308). This study aims to determine if continuation of AI enhances efficacy of MC compared to MC alone in MBC progressing on AI; and whether methotrexate and prednisolone are necessary components of MC. Methods: Primary Objectives: Clinical benefit (CR+PR+SD ≥ 24 weeks) of MC plus AI versus MC alone. Secondary Objectives: PFS, safety, correlating response with angiogenesis biomarkers, contribution of methotrexate and prednisolone to MC activity assessed by change in biomarkers during serial introduction of each drug over a 6 week lead in period. Study Design: Randomized phase II design, 35 patients per arm plan...