KOHBRA BRCA risk calculator (KOHCal): a model for predicting BRCA1 and BRCA2 mutations in Korean breast cancer patients.

The widely used Western BRCA mutation prediction models underestimated the risk of having a BRCA mutation in Korean breast cancer patients. This study aimed to identify predictive factors for BRCA1/2 mutations and to develop a Korean BRCA risk calculator. The model was constructed by logistic regression model, and it was based on the Korean Hereditary Breast Cancer study, in which 1669 female patients were enrolled between May 2007 and December 2010. A separate data set of 402 patients, who were enrolled from Jan 2011 to August 2012, was used to test the performance of our model. In total, 264 (15.8%) and 67 (16.7%) BRCA mutation carriers were identified in the model and validation set, respectively. Multivariate analysis showed that age at breast cancer diagnosis, bilateral breast cancer, triple-negative breast cancer (TNBC) and the number of relatives with breast or ovarian cancer within third-degree relatives were independent predictors of the BRCA mutation among familial breast cancer patients. An age <35 years at diagnosis, bilateral breast cancer, both breast and ovarian cancer and TNBC remained significant predictors in non-familial breast cancer cases. Our model was developed based on logistic regression models. The validation results showed no differences between the observed and expected carrier probabilities. This model will be a useful tool for providing genetic risk assessments in Korean populations.

A multi-institutional study of the prevalence of BRCA1 and BRCA2 large genomic rearrangements in familial breast cancer patients.

BACKGROUND: Large genomic rearrangements (LGRs) in the BRCA1/2 genes are frequently observed in breast cancer patients who are negative for BRCA1/2 small mutations. Here, we examined 221 familial breast cancer patients from 37 hospitals to estimate the contribution of LGRs, in a nationwide context, to the development of breast cancer. METHODS: Direct sequencing or mutation scanning followed by direct sequencing was performed to screen small mutations. BRCA1/2 small mutation-negative patients were screened for the presence of LGRs using a multiple ligation-dependent probe amplification (MLPA) assay. RESULTS: Using a combined strategy to detect the presence of small mutations and LGRs, we identified BRCA1/2 small mutations in 78 (35.3%) out of 221 familial breast cancer patients and BRCA1 LGRs in 3 (2.1%) out of 143 BRCA1/2 small mutation-negative patients: the deletion of exons 11-13, the deletion of exons 13-15, and whole gene deletion of exons 1-24. The novel deletion of exons 11-13 is thought to result from a non-homologous recombination event mediated by a microhomology sequence comprised of 3 or 4 base pairs: c.3416_4357 + 1863delins187 (NG_005905.2: g.33369_44944delins187). CONCLUSIONS: In this study, we showed that LGRs were found in 3.7% (3/81) of the patients who had mutations in BRCA1 or BRCA2, and 7.5% (3/40) of patients with mutations in BRCA1. This suggests that the contribution of LGRs to familial breast cancer in this population might be comparable to that in other ethnic populations. Given these findings, an MLPA to screen for mutations in the BRCA1 gene is recommended as an initial screening test in highly selective settings.

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 (age ≤ 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 (age <35 vs age ≥35; 10.0 vs 2.9%, p = 0.0007). 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 35 years 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.

Redd1 inhibits the invasiveness of non-small cell lung cancer cells.

Redd1 acts as a negative regulator of mTOR in response to various stress conditions, but its specific physiological role is currently unclear. In the present study, we showed that Redd1 inhibits the invasive activity of non-small cell lung cancer (NSCLC) cells. Interestingly, expression of Redd1 was extremely low in H1299 cells displaying high invasiveness, compared with that in H460 cells with lower invasive activity. Overexpression of Redd1 inhibited the invasive activity of H1299 cells, while suppression with specific siRNAs enhanced the invasiveness of H460 cells. Knockdown of the mTOR downstream substrate, S6K, resulted in a decrease in the invasive property of H1299 cells. Our results provide preliminary evidence that Redd1 inhibits the invasive activity of NSCLC cells via suppression of the mTOR downstream pathway.

Central washout sign in computer-aided evaluation of breast MRI: preliminary results.

BACKGROUND: Although computer-aided evaluation (CAE) programs were introduced to help differentiate benign tumors from malignant ones, the set of CAE-measured parameters that best predict malignancy have not yet been established. PURPOSE: To assess the value of the central washout sign on CAE color overlay images of breast MRI. MATERIAL AND METHODS: We evaluated the frequency of the central washout sign using CAE. The central washout sign was determined so that thin, rim-like, persistent kinetics were seen in the periphery of the tumor. Then, sequentially, plateau and washout kinetics appeared. Two additional CAE-delayed kinetic variables were compared with the central washout sign for assessment of diagnostic utility: the predominant enhancement type (washout, plateau, or persistent) and the most suspicious enhancement type (any washout > any plateau > any persistent kinetics). RESULTS: One hundred and forty-nine pathologically proven breast lesions (130 malignant, 19 benign) were evaluated. A central washout sign was associated with 87% of malignant lesions but only 11% of benign lesions. Significant differences were found when delayed-phase kinetics were categorized by the most suspicious enhancement type (P < 0.001) and the presence of the central washout sign (P < 0.001). Under the criteria of the most suspicious kinetics, 68% of benign lesions were assigned as plateau or washout pattern. CONCLUSION: The central washout sign is a reliable indicator of malignancy on CAE color overlay images of breast MRI.

Analysis of BRCA1/2 variants of unknown significance in the prospective Korean Hereditary Breast Cancer study.

Genetic testing for BRCA1 and BRCA2 is crucial in diagnosing hereditary breast and ovarian cancer syndromes and has increased with the development of multigene panel tests. However, results classified as variants of uncertain significance (VUS) present challenges to clinicians in attempting to choose an appropriate management plans. We reviewed a total of 676 breast cancer patients included in the Korean Hereditary Breast Cancer (KOHBRA) study with a VUS on BRCA mutation tests between November 2007 and April 2013. These results were compared to the ClinVar database. We calculated the incidence and odds ratios for these variants using the Korean Reference Genome Database. A total of 58 and 91 distinct VUS in BRCA1 and BRCA2 were identified in the KOHBRA study (comprising 278 and 453 patients, respectively). A total of 27 variants in the KOHBRA study were not registered in the Single Nucleotide Polymorphism database. Among BRCA1 VUSs, 20 were reclassified as benign or likely benign, four were reclassified as pathogenic or likely pathogenic, and eight remained as VUSs according to the ClinVar database. Of the BRCA2 VUSs, 25 were reclassified as benign or likely benign, two were reclassified as pathogenic or likely pathogenic, and 33 remained as VUS according to the ClinVar database. There were 12 variants with conflicting interpretations of pathogenicity for BRCA1 and 18 for BRCA2. Among them, p.Leu1780Pro showed a particularly high odds ratio. Six pathogenic variants and one conflicting variant identified using ClinVar could be reclassified as pathogenic variants in this study. Using updated ClinVar information and calculating odds ratios can be helpful when reclassifying VUSs in BRCA1/2.

Triple-negative breast cancer: correlation between imaging and pathological findings.

OBJECTIVE: This study was designed to investigate the mammography and ultrasound findings of triple-negative breast cancer and to compare the results with characteristics of ER-positive/PR-negative/HER2-negative breast cancer and ER-negative/PR-negative/HER2-positive breast cancer. METHODS: From January 2007 to October 2008, mammography and ultrasound findings of 245 patients with pathologically confirmed triple-negative (n = 87), ER-positive/PR-negative/HER2-negative (n = 93) or ER-negative/PR-negative/HER2-positive breast cancers (n = 65) were retrospectively reviewed. We also reviewed pathological reports for information on the histological type, histological grade and the status of the biological markers. RESULTS: Triple-negative breast cancers showed a high histological grade. On mammography, triple-negative breast cancers usually presented with a mass (43/87, 49%) or with focal asymmetry (19/87, 22%), and were less associated with calcifications. On ultrasound, the cancers were less frequently seen as non-mass lesions (12/87, 14%), more likely to have circumscribed margins (43/75, 57%), were markedly hypoechoic (36/75, 57%) and less likely to show posterior shadowing (4/75, 5%). Among the three types of breast cancers, ER-negative/PR-negative/HER2-positive breast cancers most commonly had associated calcifications (52/65, 79%) on mammography and were depicted as non-mass lesions (21/65, 32%) on ultrasound. CONCLUSION: Our results suggest that the imaging findings might be useful in diagnosing triple-negative breast cancer.

Education Level Is a Strong Prognosticator in the Subgroup Aged More Than 50 Years Regardless of the Molecular Subtype of Breast Cancer: A Study Based on the Nationwide Korean Breast Cancer Registry Database.

PURPOSE: This study investigated the role of the education level (EL) as a prognostic factor for breast cancer and analyzed the relationship between the EL and various confounding factors. MATERIALS AND METHODS: The data for 64,129 primary breast cancer patients from the Korean Breast Cancer Registry were analyzed. The EL was classified into two groups according to the education period; the high EL group (≥ 12 years) and low EL group (< 12 years). Survival analyses were performed with respect to the overall survival between the two groups. RESULTS: A high EL conferred a superior prognosis compared to a low EL in the subgroup aged > 50 years (hazard ratio, 0.626; 95% confidence interval [CI], 0.577 to 0.678) but not in the subgroup aged ≤ 50 years (hazard ratio, 0.941; 95% CI, 0.865 to 1.024). The EL was a significant independent factor in the subgroup aged > 50 years according to multivariate analyses. The high EL group showed more favorable clinicopathologic features and a higher proportion of patients in this group received lumpectomy, radiation therapy, and endocrine therapy. In the high EL group, a higher proportion of patients received chemotherapy in the subgroups with unfavorable clinicopathologic features. The EL was a significant prognosticator across all molecular subtypes of breast cancer. CONCLUSION: The EL is a strong independent prognostic factor for breast cancer in the subgroup aged > 50 years regardless of the molecular subtype, but not in the subgroup aged ≤ 50 years. Favorable clinicopathologic features and active treatments can explain the main causality of the superior prognosis in the high EL group.

The Effect of Reproductive Factors on Breast Cancer Presentation in Women Who Are BRCA Mutation Carrier.

PURPOSE: Germline mutations in the BRCA1 and BRCA2 genes confer increased risks for breast cancers. However, the clinical presentation of breast cancer among women who are carriers of the BRCA1 or BRCA2 (BRCA1/2 carriers) mutations is heterogenous. We aimed to identify the effects of the reproductive histories of women with the BRCA1/2 mutations on the clinical presentation of breast cancer. METHODS: We retrospectively analyzed clinical data on women with proven BRCA1 and BRCA2 mutations who were recruited to the Korean Hereditary Breast Cancer study, from 2007 to 2014. RESULTS: Among the 736 women who were BRCA1/2 mutation carriers, a total of 483 women had breast cancers. Breast cancer diagnosis occurred at significantly younger ages in women who experienced menarche at ≤14 years of age, compared to those who experienced menarche at >14 years of age (37.38±7.60 and 43.30±10.11, respectively, p<0.001). Additionally, the number of full-term pregnancies was significantly associated with the age of diagnosis, especially in women with the BRCA2 mutation. The prevalence of advanced stages (stage II or III vs. stage I) of disease in parous women was higher than in nulliparous women (68.5% vs. 55.2%, p=0.043). This association was more pronounced in women with the BRCA2 mutation (hazard ratio, 2.67; p=0.014). CONCLUSION: Our results suggest that reproductive factors, such as the age of onset of menarche and the presence of parity, are associated with the clinical presentation patterns of breast cancer in BRCA1/2 mutation carriers.

Determinants of rapamycin sensitivity in breast cancer cells.

PURPOSE: Rapamycin inhibits the serine-threonine kinase mammalian target of rapamycin (mTOR), blocking phosphorylation of p70 S6 kinase (S6K1) and 4E-binding protein 1 (4E-BP1) and inhibiting protein translation and cell cycle progression. Rapamycin and its analogues are currently being tested in clinical trials as novel-targeted anticancer agents. Although rapamycin analogues show activity in clinical trials, only some of the treated patients respond. The purpose of this study is to identify determinants of rapamycin sensitivity that may assist the selection of appropriate patients for therapy. EXPERIMENTAL DESIGN: Breast cancer cell lines representing a spectrum of aberrations in the mTOR signaling pathway were tested for rapamycin sensitivity. The expression and phosphorylation state of multiple components of the pathway were tested by Western blot analysis, in the presence and absence of rapamycin. RESULTS: Cell proliferation was significantly inhibited in response to rapamycin in 12 of 15 breast cancer cell lines. The ratio of total protein levels of 4E-BP1 to its binding partner eukaryotic initiation factor 4E did not predict rapamycin sensitivity. In contrast, overexpression of S6K1, and phosphorylated Akt independent of phosphatase and tensin homologue deleted from chromosome 10 status, were associated with rapamycin sensitivity. Targeting S6K1 and Akt with small interfering RNA and dominant-negative constructs, respectively, decreased rapamycin sensitivity. Rapamycin inhibited the phosphorylation of S6K1, ribosomal S6 protein, and 4E-BP1 in rapamycin-resistant as well as -sensitive cells, indicating that its ability to inhibit the mTOR pathway is not sufficient to confer sensitivity to rapamycin. In contrast, rapamycin treatment was associated with decreased cyclin D1 levels in the rapamycin-sensitive cells but not in rapamycin-resistant cells. CONCLUSIONS: Overexpression of S6K1 and expression of phosphorylated Akt should be evaluated as predictors of rapamycin sensitivity in breast cancer patients. Furthermore, changes in cyclin D1 levels provide a potential pharmacodynamic marker of response to rapamycin.

Characteristics of BRCA1/2 Mutation-Positive Breast Cancers in Korea: A Comparison Study Based on Multicenter Data and the Korean Breast Cancer Registry.

PURPOSE: Mutations in BRCA genes are the main cause of hereditary breast cancer in Korea. The aim of this study was to investigate the characteristics of breast cancers involving BRCA1 (BRCA1 group) and BRCA2 (BRCA2 group) mutations. METHODS: We retrospectively reviewed the medical records of patients with BRCA1 (BRCA1 group) or BRCA2 (BRCA2 group) mutation positive breast cancer from multiple centers and compared the data to that of the Korean Breast Cancer Society registry (registry group). RESULTS: The patients of the BRCA1 group were diagnosed at a younger age (median age, 37 years) and had tumors of higher histological (61.3% with histological grade 3) and nuclear (37.5% with nuclear grade 3) grade than those of the registry group. In addition, the frequency of ductal carcinoma in situ in the BRCA1 group was lower (3.7%) than in the registry group, and the BRCA1 group were more likely to be triple-negative breast cancer (61.3%). Patients in the BRCA2 group were also younger at diagnosis (mean age, 41 years) and were more likely to have involvement of the axillary node than the registry group (45.5% vs. 33.5%, p=0.002). The BRCA1 and BRCA2 groups did not show a correlation between tumor size and axillary node involvement. CONCLUSION: We report the characteristics of BRCA mutation positive breast cancer patients in the Korean population through multicenter data and nation-wide breast cancer registry study. However, BRCA-mutated breast cancers appear highly complex, and further research on their molecular basis is needed in Korea.

Chromatin CKAP2, a new proliferation marker, as independent prognostic indicator in breast cancer.

BACKGROUND: The level of proliferation activity is a strong prognostic or predictive indicator in breast cancer, but its optimal measurement is still in debate, necessitating new proliferation markers. In the present study, the prognostic significance of the CKAP2-positive cell count (CPCC), a new proliferation marker, was evaluated, and the results were compared with those for the mitotic activity index (MAI). METHODS: This study included 375 early-stage breast cancer samples collected from two institutions between 2000 and 2006. Immunohistochemical staining was performed using a CKAP2 monoclonal antibody. Cox proportional hazard regression models were fitted to determine the association between the CPCC and relapse-free survival (RFS) amongst three groups formed on the basis of the CPCC or MAI value: groups 2 and 3 showing the middle and highest values, respectively, and group 1 the lowest. RESULTS: After adjustment for age, T stage, N stage, HER2 status, estrogen receptor status, progesterone receptor status, institution, and year of surgical resection, the CPCC was associated with a significantly worse RFS {hazard ratio [HR]  = 4.10 (95% CI: 1.64-10.29) for group 2; HR  = 4.35 (95% CI: 2.04-10.35) for group 3}. Moreover, its prognostic significance was similar to or higher than that based on the MAI {HR  = 2.05 (95% CI: 0.94-4.65) for group 2; HR  = 2.35 (95% CI: 1.09-5.10) for group 3}. In subgroup analyses, the CPCC showed a prognostic significance in the luminal A and triple-negative subgroups, but not in the HER2-positive subgroup. CONCLUSIONS: Chromatin CKAP2 is an independent prognostic marker for RFS in early-stage breast cancer, and could potentially replace the MAI in clinical evaluation of proliferation activity. Additionally, our study results suggest that the prognostic significance of proliferation activity differs among the various subgroups of breast cancer.

Efficacy of everolimus with exemestane versus exemestane alone in Asian patients with HER2-negative, hormone-receptor-positive breast cancer in BOLERO-2.

BACKGROUND: The addition of mTOR inhibitor everolimus (EVE) to exemestane (EXE) was evaluated in an international, phase 3 study (BOLERO-2) in patients with hormone-receptor-positive (HR(+)) breast cancer refractory to letrozole or anastrozole. The safety and efficacy of anticancer treatments may be influenced by ethnicity (Sekine et al. in Br J Cancer 99:1757-62, 2008). Safety and efficacy results from Asian versus non-Asian patients in BOLERO-2 are reported. METHODS: Patients were randomized (2:1) to 10 mg/day EVE + EXE or placebo (PBO) + EXE. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, response rate, clinical benefit rate, and safety. RESULTS: Of 143 Asian patients, 98 received EVE + EXE and 45 received PBO + EXE. Treatment with EVE + EXE significantly improved median PFS versus PBO + EXE among Asian patients by 38 % (HR = 0.62; 95 % CI, 0.41-0.94). Median PFS was also improved among non-Asian patients by 59 % (HR = 0.41; 95 % CI, 0.33-0.50). Median PFS duration among EVE-treated Asian patients was 8.48 versus 4.14 months for PBO + EXE, and 7.33 versus 2.83 months, respectively, in non-Asian patients. The most common grade 3/4 adverse events (stomatitis, anemia, elevated liver enzymes, hyperglycemia, and dyspnea) occurred at similar frequencies in Asian and non-Asian patients. Grade 1/2 interstitial lung disease occurred more frequently in Asian patients. Quality of life was similar between treatment arms in Asian patients. CONCLUSION: Adding EVE to EXE provided substantial clinical benefit in both Asian and non-Asian patients with similar safety profiles. This combination represents an improvement in the management of postmenopausal women with HR(+)/HER2(-) advanced breast cancer progressing on nonsteroidal aromatase inhibitors, regardless of ethnicity.

The prevalence of BRCA mutations among familial breast cancer patients in Korea: results of the Korean Hereditary Breast Cancer study.

The primary aim of this study was to estimate the prevalence of BRCA1/2 mutations among familial breast cancer (BC) patients in Korea. We analyzed 775 familial BC patients who were enrolled in the Korean Hereditary Breast Cancer (KOHBRA) study and treated at 36 institutions between May 2007 and May 2010. Patients with familial BC were defined as BC patients with family histories of BC or ovarian cancer (OC) in any relatives. All probands received genetic counseling and BRCA genetic testing was performed after obtaining informed consent. The mean age of BC diagnosis was 43.6 years. The numbers of probands with family histories of BC only and OC only were 682 and 93, respectively. The overall prevalence of the BRCA mutation among familial BC patients was 21.7 % (BRCA1 9.3 % and BRCA2 12.4 %). Subgroup analyses observed prevalences of the BRCA mutation as follows: 19.6 % among patients with BC family history only (BRCA1 7.6 % and BRCA2 12.0 %) and 36.6 % among patients with OC family history only (BRCA1 21.5 % and BRCA2 15.1 %). Most of the subgroups satisfied the 10 % probability criteria to undergo BRCA testing. However, the prevalence of the BRCA mutations among subgroups that had 2 BC patients in a family with both age at diagnosis of more than 50 years old did not reach the 10 % criteria (4.1 %). Korean familial BC patients are good candidates for BRCA testing even when they have family histories of single breast cancers. However, proband age at diagnosis should be carefully considered when selecting patients for testing.

Application of sonoelastography: comparison of performance between mass and non-mass lesion.

OBJECTIVES: The purpose of this study was to determine the performance of the conventional ultrasonography (US) and sonoelastography (SE) in three conditions of all lesions, confined to mass, and confined to non-mass lesion and to compare the performance of each modality between mass and non-mass lesion. MATERIALS AND METHODS: A total 364 patients with 375 lesions were evaluated with US and subsequently SE before performing US-guided biopsy. Two radiologists retrospectively analyzed conventional US and elasticity images by consensus. The US findings were classified as mass or non-mass lesion. With final pathology as reference, in each case of all lesions, masses, and non-mass lesions, areas under the ROC curves (Az) were calculated and compared for the two techniques. The comparison of Az values between the curves for US and SE, and between the curves for mass and non-mass lesion was performed. RESULTS: Among 375 lesions, 104 (28%) lesions were malignant and 271 (72%) lesions were benign. 36 (9.6%) of 375 lesions were classified as non-mass lesion at US. There were statistically significant difference of performance between US and SE in cases of all lesion (p=0.003) and mass (p=0.023). However, there was no statistically significant difference of performance in case of non-mass lesion (p=0.5). Comparisons of the Az values of US and SE between mass and non-mass lesions were not statistically significant (p=0.745, p=0.415, respectively). CONCLUSION: There was no statistically significant difference of performance of US and SE between mass and non-mass lesion.

Background enhancement in breast MR: correlation with breast density in mammography and background echotexture in ultrasound.

OBJECTIVE: This study aimed to determine whether background enhancement on MR was related to mammographic breast density or ultrasonographic background echotexture in premenopausal and postmenopausal women. MATERIALS AND METHODS: We studied 142 patients (79 premenopausal, 63 postmenopausal) who underwent mammography, ultrasonography, and breast MR. We reviewed the mammography for overall breast density of the contralateral normal breast according to the four-point scale of the BI-RADS classification. Ultrasound findings were classified as homogeneous or heterogeneous background echotexture according to the BI-RADS lexicon. We rated background enhancement on a contralateral breast MR into four categories based on subtraction images: absent, mild, moderate, and marked. All imaging findings were interpreted independently by two readers without knowledge of menstrual status, imaging findings of other modalities. RESULTS: There were significant differences between the premenopausal and postmenopausal group in distribution of mammographic breast density, ultrasonographic background echotexture, and degree of background enhancement. Regarding the relationship between mammographic density and background enhancement, there was no significant correlation. There was significant relationship between ultrasonographic background echotexture and background enhancement in both premenopausal and postmenopausal groups. CONCLUSION: There is a significant correlation between ultrasonographic background echotexture and background enhancement in MR regardless of menopausal status. Interpreting breast MR, or scheduling for breast MR of women showing heterogeneous background echotexture needs more caution.

The Korean Hereditary Breast Cancer (KOHBRA) study: protocols and interim report.

AIMS: The 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. MATERIALS AND METHODS: The 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. RESULTS: By 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. CONCLUSIONS: The 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.

A phase II study of neoadjuvant docetaxel plus doxorubicin (KBCS-01) in stage II, III breast cancer.

BACKGROUND: This multicenter phase II study was conducted to evaluate the response and safety of a combination of docetaxel plus doxorubicin as neoadjuvant therapy for stage II, III breast cancer. METHODS: Patients with stage II or III breast cancer underwent three cycles of neoadjuvant chemotherapy with doxorubicin 50 mg/m2 and docetaxel 75 mg/m2 every 3 weeks followed by curative surgery. Prophylactic GCSF was not used. RESULTS: Ninety patients were enrolled in the study and 86 were evaluable for efficacy. The median age was 43 years (range, 30-69). The mean relative dose intensity was 0.98 for docetaxel and 0.98 for doxorubicin. Breast-conserving surgery was performed in 12 (13.7%) patients. The clinical overall response rate was 86% and pathologic complete response was 10.5%. Grade 3/4 neutropenia was observed in 26% of total 258 cycles and febrile neutropenia was observed in 15.8%. Pneumonia was observed in one patient and grade 3 mucositis was observed in three patients. CONCLUSION: Docetaxel and doxorubicin was an effective and well-tolerated neoadjuvant chemotherapy for stage II and III breast cancer. Clinical benefit of this treatment will be confirmed by survival data with long term follow up.