Sei Hyun Ahn

Population-based Breast Cancer Statistics in Korea during 1993-2002: Incidence, Mortality, and Survival

In 2002, breast became the most common cancer site in Korean women. Using national breast cancer incidence data during 1993-2002, crude, age-standardized, and age-specific rates for incidence and mortality were calculated. Survival was examined for cases diagnosed during 1993-2002 and followed up to 2004. Observed survival was calculated using the life table method and relative survival using the Ederer II method. Age-standardized incidence rates in female increased from 14.5 in 1993 to 26.2 per 100,000 in 2002. Age-specific incidences showed peaks in women in their forties. Mortality rates increased from 3.7 in 1993 to 4.6 per 100,000 in 2002 and showed peaks in women in their fifties. Five-year relative survival for female breast cancer diagnosed during 1993-2002 was 82.2%. When we examined the secular trends using cases diagnosed 1993-1999 for complete 5-yr follow-up, the 5-yr relative survival increased from 75.2% in 1993 to 83.5% in 1999. The data from this study will provide valuable information to plan and evaluate actions against breast cancer including national breast cancer screening.

Effect of BRCA1/2 mutation on short-term and long-term breast cancer survival: a systematic review and meta-analysis

Reports of BRCA genetic mutations and risk of death or recurrence are inconsistent. This study aimed to compare overall and disease-free breast cancer survival rates between BRCA1/2 mutation carriers and non-carriers for short-term and long-term outcomes separately. We searched the PUBMED and EMBASE databases and retrieved 452 articles using keywords that included breast cancer, BRCA mutation, and survival. Seventeen articles were selected for systematic review and among them 11 were included in our meta-analysis. We used the random-effects model to calculate the summary hazard ratio and corresponding 95% confidence interval. BRCA1 mutation carriers had significantly lower short-term and long-term overall survival rates (OSR) relative to non-carriers (HRxa0=xa01.92 [95% CIxa0=xa01.45–2.53]; 1.33 [1.12–1.58], respectively), while both short-term and long-term OSR of BRCA2 carriers did not differ from non-carriers (HRxa0=xa01.30 [95% CIxa0=xa00.95–1.76]; 1.12 [95% CIxa0=xa00.86–1.45], respectively). For short-term progression-free survival rate (PFSR), BRCA1 mutation carriers had a significantly lower rate than non-carriers (HRxa0=xa01.54 [95% CIxa0=xa01.12–2.12]), while BRCA2 mutation carriers had a similar PFSR (HRxa0=xa01.23 [95% CIxa0=xa00.96–1.58]). For long-term PFSRs, we found no significant results. Our results suggest that BRCA1 mutation decreases short-term and long-term OSRs and short-term PFSR, however, BRCA2 mutation does not affect either short-term or long-term survival rate, which is attributed to the different carcinogenic pathways for BRCA1 and BRCA2.

Exploratory clinical trial of (4S)-4-(3-[18F]fluoropropyl)-L-glutamate for imaging xC- transporter using positron emission tomography in patients with non-small cell lung or breast cancer.

Purpose: (4S)-4-(3-[18F]fluoropropyl)-l-glutamate (BAY 94-9392, alias [18F]FSPG) is a new tracer to image xC− transporter activity with positron emission tomography (PET). We aimed to explore the tumor detection rate of [18F]FSPG in patients relative to 2-[18F]fluoro-2-deoxyglucose ([18F]FDG). The correlation of [18F]FSPG uptake with immunohistochemical expression of xC− transporter and CD44, which stabilizes the xCT subunit of system xC−, was also analyzed. Experimental Design: Patients with non–small cell lung cancer (NSCLC, n = 10) or breast cancer (n = 5) who had a positive [18F]FDG uptake were included in this exploratory study. PET images were acquired following injection of approximately 300 MBq [18F]FSPG. Immunohistochemistry was done using xCT- and CD44-specific antibody. Results: [18F]FSPG PET showed high uptake in the kidney and pancreas with rapid blood clearance. [18F]FSPG identified all 10 NSCLC and three of the five breast cancer lesions that were confirmed by pathology. [18F]FSPG detected 59 of 67 (88%) [18F]FDG lesions in NSCLC, and 30 of 73 (41%) in breast cancer. Seven lesions were additionally detected only on [18F]FSPG in NSCLC. The tumor-to-blood pool standardized uptake value (SUV) ratio was not significantly different from that of [18F]FDG in NSCLC; however, in breast cancer, it was significantly lower (P < 0.05). The maximum SUV of [18F]FSPG correlated significantly with the intensity of immunohistochemical staining of xC− transporter and CD44 (P < 0.01). Conclusions: [18F]FSPG seems to be a promising tracer with a relatively high cancer detection rate in patients with NSCLC. [18F]FSPG PET may assess xC− transporter activity in patients with cancer. Clin Cancer Res; 18(19); 5427–37. ©2012 AACR.

The Korean Hereditary Breast Cancer (KOHBRA) Study: Protocols and Interim Report

AIMSnThe primary aims of the Korean Hereditary Breast Cancer (KOHBRA) study are to estimate the prevalence of BRCA1/2 mutations and ovarian cancer among a high-risk group of patients with hereditary breast cancer and their families.nnnMATERIALS AND METHODSnThe KOHBRA study is a prospective multicentre cohort identifying cases and their families. Between May 2007 and May 2010, the KOHBRA study enrolled up to 2000 subjects. All participants received genetic counselling and BRCA genetic testing; the clinical information and blood samples for blood banking were collected. An interim analysis of the prevalence of BRCA1/2 mutations and ovarian cancer in Korean subjects was determined from the initial 975 patients who presented to 33 centres.nnnRESULTSnBy April 2009, a total of 167 mutation carriers among 853 probands were identified. The prevalence of the BRCA mutation was as follows: 24.8% (106/428) for breast cancer patients with a family history of breast/ovarian cancers; 11.3% (24/212) for patients with early-onset (<35 years) breast cancer without a family history; 22.1% (15/68) for patients with bilateral breast cancer; male breast cancer in 8.3% (1/12); and 33.4% (1/3) for patients with breast and ovarian cancer.nnnCONCLUSIONSnThe results of this study suggest that the prevalence of BRCA mutations in Korean subjects is similar to the prevalence reported among Western cohorts. However, weak family history and non-familial early-onset of breast cancer were significant factors associated with carrying the BRCA mutation in Korean breast cancer patients. Completion of the KOHBRA study is needed to confirm these findings.

Different prognostic significance of CD24 and CD44 expression in breast cancer according to hormone receptor status

OBJECTIVEnCD44(+)CD24(-/low)-expressing tumor cells have been studied as tumorigenic stem cells in vitro study. This study was designed to determine the clinical implication of the CD44 and CD24 expression in breast cancer.nnnMETHODSnTissue microarray blocks containing 643 consecutive cases of invasive breast carcinomas from 1993 to 1998 were immunostained for CD44 and CD24. The median follow-up period was 127 months.nnnRESULTSnCD44(-)CD24(+) phenotype was associated with frequent hormone receptor positivity and Her2/neu positivity (Pxa0=xa00.000; Both). The CD44(+)CD24(-) phenotype was inversely associated with lymph node metastasis (Pxa0=xa00.002), and it showed positive associations with prolonged disease-free survival (DFS; Pxa0=xa00.003) and overall survival (OS; Pxa0=xa00.002). 10-year DFS and OS were 68.9% and 74.6% for CD24 negative group, 55.6% and 60.9% for CD24 positive group (Pxa0=xa00.001; Both). 10-year DFS and OS were 62.2% and 68.1% for CD44 negative group, 73% and 77.7% for CD44 positive group (Pxa0=xa00.012, Pxa0=xa00.013, respectively). In a multivariate analysis, CD24 expression was negatively related to OS only in the receptor positive group (Hazard ratioxa0=xa02.03; Pxa0=xa00.003; 95% CI: 1.27-3.24) and CD44 expression was positively related to OS only in the hormone receptor negative group (hazard ratioxa0=xa00.58; Pxa0=xa00.022; 95% CI: 0.36-0.92).nnnCONCLUSIONSnThe CD44(+)CD24(-) group is considered a favorable prognostic subgroup in breast cancer. CD24 expression was a poor prognosis marker in hormone receptor positive breast cancer, and CD44 expression was a good prognostic marker in the receptor negative group.

Prevalence of BRCA1 and BRCA2 mutations in Korean breast cancer patients

The incidence of breast cancer in Korea has been increasing in recent years, such that it is now the most common female cancer. Breast cancer in Korea is characterized by an earlier age of onset than in Western countries, suggesting that it would be related with genetic background. We assayed germline mutations in the BRCA genes to evaluate their genetic pathology in Korean breast cancer patients. The study subjects consisted of 173 patients at clinically higher risk and 109 unselected patients. Germline mutations in the entire coding sequences of the BRCA1 and BRCA2 genes were analyzed by Conformation-Sensitive Gel Electrophoresis (CSGE), and any aberrantly-sized band was sequenced. BRCA mutations were present in 12.7% of the high risk patients, compared with 2.8% of the unselected patients. Among high risk patients, mutations were most prevalent in patients with a family history of breast or first-degree ovarian cancer (22.1%), followed by those with male breast cancer (20%), bilateral breast cancer (20%), multiple organ cancer including breast (13%) and younger breast cancer patients (aged <35 yr) (8.1%). Moreover, BRCA mutations were detected in 34.8% of patients having two high-risk factors. These findings suggest that BRCA gene mutation analysis should be performed on Korean patients with high-risk factors for breast cancer.

The CHEK2 1100delC mutation is not present in Korean patients with breast cancer cases tested for BRCA1 and BRCA2 mutation

The germline CHEK2 1100delC mutation is a low penetrance breast cancer susceptibility allele, frequently observed in patient with family history of breast cancer and/or young age and the frequency varied according to race or ethnicity. In this study, we evaluated the significance of CHEK2 1100delC in predisposition to breast cancer by assessing its frequency in a material of 493 Korean breast cancer patients who had been screened for BRCA1 and BRCA2 mutations (42 patients had deleterious mutation of BRCA1/2). Mutation detection of CHEK2 1100delC was based upon analysis of primer extension products generated for previously amplified genomic DNA using a chip based MALDI-TOP mass spectrometry platform. After overall measurement automatically, assays which had bad peaks were checked again manually. None of the 493 Korean patients with breast cancer who were candidate for BRCA1 and BRCA2 test carried the 1100delC mutation observed in Caucasians with limited frequency. In the previous studies, we observed higher or comparable prevalence of BRCA1 and BRCA2 mutations in Korean patients with breast cancer compared to Caucasian breast cancer population. In the present study, we evaluated the role of a CHEK2 1100delC as a susceptibility mutation of breast cancer in the Korean population. However, our results suggest that this mutation is absent or may be very infrequent in Korean patients with breast cancer who have high risk of BRCA1 and BRCA2 mutation, making its screening irrelevant from the practical point view.

Prevalence of BRCA1 and BRCA2 mutations in non-familial breast cancer patients with high risks in Korea: The Korean Hereditary Breast Cancer (KOHBRA) Study

Prevalence and phenotype of BRCA mutation can vary by race. The purpose of this study is to evaluate the prevalence of BRCA1/2 mutations in non-familial breast cancer patients with high risks in Korea. A subset of 758 patients was selected for this study from the KOHBRA nationwide multicenter prospective cohort study. Mutations in BRCA1/2 genes were tested using fluorescent-conformation sensitive gel electrophoresis, denaturing high performance liquid chromatography or direct sequencing. Mutation of BRCA1/2 genes were identified in 65 (8.6%) patients among total 758 patients [BRCA1 mutation: 25 (3.3%), BRCA2 mutation: 40 (5.3%)]. According to risk groups, mutation of BRCA1/2 genes were identified in 53 (8.5%) of 625 early onset patients (agexa0≤40), in 22 (17.7%) of 124 bilateral breast cancer patients, in 3 (50.0%) of 6 breast and ovarian cancer patients, in one (5.9%) of 17 male breast cancer patients, in 5 cases (7.6%) of 66 multiple organ cancer patients. The most common mutation was 509C>A for BRCA1 and 7708C>T for BRCA2. The prevalence of BRCA1/2 mutations by age in early onset patients was significantly different (agexa0<35 vs agexa0≥35; 10.0 vs 2.9%, pxa0=xa00.0007). BRCA1/2 mutations for non-familial Korean breast cancer patients were detected at a high rate, particularly, in patients with early onset of less than 35xa0years of age, bilateral breast cancer, and breast and ovarian cancer. Individualized genetic counseling should be offered for non-familial breast cancer patients with these risk factors.

Young age is associated with ipsilateral breast tumor recurrence after breast conserving surgery and radiation therapy in patients with HER2-positive/ER-negative subtype

Young breast cancer patients are more likely than old patients to experience ipsilateral breast tumor recurrence (IBTR) after breast conserving surgery (BCS). However, the pathological processes underlying this relationship have not been elucidated. We investigated the effect of young age on IBTR in a Korean cohort of women with different molecular subtypes of breast cancer. We analyzed data of 2,102 consecutive breast cancer patients who underwent BCS and post-surgical radiation therapy (RT) at two Korean institutions between 2000 and 2005. Patients were classified as young (≤40xa0years; Nxa0=xa0513) or old (>40xa0years; Nxa0=xa01,589). Breast cancer subtype was determined by estrogen receptor (ER), progesterone receptor (PR), and HER2. Median follow-up duration was 61xa0months.xa0The 5-year IBTR rate was 3.4% in young patients and 1.1% in old patients (Pxa0<xa00.001). Univariate analysis indicated that IBTR rate in young patients with luminal A and HER2 subtypes was significantly greater than in old patients with these subtypes (Pxa0=xa00.015 and Pxa0<xa00.001, respectively). Multivariate analysis, which used luminal A subtype in old patients as reference, indicated that HER2 subtype in young patients was associated with increased risk of IBTR (hazard ratio, HRxa0=xa012.24; 95% CI: 2.54–57.96). Among old patients, HER2 subtype was not associated with increased IBTR. In conclusion, young women had a higher rate of IBTR after BCS and RT than old women. This difference is mainly among women with HER2 subtype. Aggressive local control and adjuvant therapy should be considered for young women with HER2 subtype breast cancer.

Bioinformatic and metabolomic analysis reveals miR-155 regulates thiamine level in breast cancer.

microRNA-155 (miR-155) is one of the well-known oncogenic miRNA implicated in various types of tumors. Thiamine, commonly known as vitamin B1, is one of critical cofactors for energy metabolic enzymes including pyruvate dehydrogenase, alpha ketoglutarate dehydrogenase, and transketolase. Here we report a novel role of miR-155 in cancer metabolism through the up-regulation of thiamine in breast cancer cells. A bioinformatic analysis of miRNA array and metabolite-profiling data from NCI-60 cancer cell panel revealed thiamine as a metabolite positively correlated with the miR-155 expression level. We confirmed it in MCF7, MDA-MB-436 and two human primary breast cancer cells by showing reduced thiamine levels upon a knock-down of miR-155. To understand how the miR-155 controls thiamine level, a set of key molecules for thiamine homeostasis were further analyzed after the knockdown of miR-155. The results showed the expression of two thiamine transporter genes (SLC19A2, SLC25A19) as well as thiamine pyrophosphokinase-1 (TPK1) were decreased in both RNA and protein level in miR-155 dependent manner. Finally, we confirm the finding by showing a positive correlation between miR-155 and thiamine level in 71 triple negative breast tumors. Taken altogether, our study demonstrates a role of miR-155 in thiamine homeostasis and suggests a function of this oncogenic miRNA on breast cancer metabolism.