Search

Objectives: To explore upper-limb disability with respect to health outcomes, operationalized by Disabilities of the Arm, Shoulder, and Hand, and to identify factors associated with each element of upper-limb disability over a 2-year period in breast cancer survivors., Design: Prospective cohort study., Setting: University hospital cancer center., Participants: Individuals (N=191) recruited from all the patients with newly diagnosed breast cancer before cancer surgery at a university hospital between April 2006 and March 2007., Interventions: Not applicable., Main Outcome Measures: We evaluated demographics, social variables, and upper-limb disability in a baseline assessment preoperatively. Follow-up evaluations were conducted in outpatient clinics 3 months after surgery and at 12 and 24 months after surgery. Linear regression models with the generalized estimating equations of the compound symmetry covariance structure were used., Results: Time since surgery was inversely associated with the impairment items score (β=-.20; 95% confidence interval [CI], -.49 to -.08) and positively associated with the activity limitation items score (β=.59; 95% CI, .29-.88). The impact of upper-limb disability preoperatively on the items involving both the activity limitation and participation restrictions scores was positive (β=2.89; 95% CI, .76-5.02) after adjusting for demographic, treatment type, and socioeconomic factors., Conclusions: Our study revealed that upper-limb impairment recovered with time after breast cancer surgery; however, upper-limb function-related activity and participation were reduced through 2 years after surgery., (Copyright © 2015 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: This study aimed to evaluate the survival benefit of different adjuvant chemotherapy regimens in patients with T1-2N0 triple-negative breast cancer., Methods: Of 67,321 patients who were registered in the Korean Breast Cancer Society nationwide database between January 1999 and December 2008, 4,033 patients with T1-2N0 triple-negative breast cancer were included. The overall survival of patients who did not receive adjuvant chemotherapy was compared with those treated with adjuvant anthracycline and cyclophosphamide (AC), 5-fluorouracil, anthracycline, and cyclophosphamide (FAC), or cyclophosphamide, methotrexate, and 5-fluorouracil (CMF)., Results: The median follow-up was 52.5 months. Chemotherapy was used in 87.4% of patients; it was used more commonly in patients with T2 tumors, those who were younger, had a higher histologic grade, and who showed lymphovascular invasion. The 5-year cumulative overall survival rate was 95.4%. Younger age, breast-conserving surgery, and adjuvant chemotherapy were significantly associated with improved overall survival. The 5-year cumulative overall survival rate of patients who did not receive adjuvant chemotherapy and those treated with AC, FAC, and CMF were 92.5%, 95.9%, 95.3%, and 95.9%, respectively. On multivariate analysis, the administration of any adjuvant chemotherapy regimen was significantly associated with improved overall survival (p=0.038). No significant difference in survival benefit was observed among the three different treatment groups., Conclusion: A standard adjuvant chemotherapy regimen with the least drug-related toxicity might be a reasonable treatment for patients with T1-2N0 triple-negative breast cancer.

The average age-specific cumulative risk (penetrance) of breast cancer has been studied for BRCA1 and BRCA2 mutation carriers living in Western countries, but not for those living in East Asian countries where the population breast cancer incidence is lower. From 2007 to 2011, the Korean Hereditary Breast Cancer study identified 151 BRCA1 and 225 BRCA2 mutation-carrying families from family cancer clinics. We estimated the hazard ratio (HR) for female carriers relative to the population, and hence the penetrance, using a modified segregation analysis of cancer family histories conditioned on ascertainment. The breast cancer HR estimates [95 % confidence interval (CI)] for BRCA1 and BRCA2 mutation carriers were 18 (3-103) and 11 (5-27), respectively. The breast cancer penetrance estimates (95 % CI) to age 70 years were 49 % (11-98) and 35 % (16-65) for BRCA1 and BRCA2 mutation carriers, respectively. The breast cancer HR and penetrance estimates were similar for Korean and Western women (all P > 0.4). The point estimates of breast cancer penetrance were similar to age 50 years, though less for Korean carriers at older ages. Breast cancer risk for Korean and Western mutation carriers might reflect underlying population risks which in turn likely reflect differences in environmental and lifestyle factors. This raises the possibility of identifying modifiers of cancer risk for carriers with implications for prevention.

Objective: The aim of our study was to determine the rate of participation in genetic testing, to determine the reasons for non-participation and to identify the factors affecting participation in BRCA genetic testing for high-risk patients., Methods: This study was performed through a retrospective review of 804 individuals who underwent genetic counseling for BRCA1/2 gene mutations at Seoul National University Bundang Hospital between July 2003 and September 2012., Results: In total, 728 (90.5%) individuals underwent BRCA1/2 mutation screening after the initial genetic counseling; 88.2% of 647 probands and 100% of 157 family members were screened. In multivariate analysis, family history of breast cancer and younger age were independent variables affecting participation in genetic testing. Of the 132 people who initially declined genetic testing, 58 (43.9%) postponed the decision, 30 (22.7%) needed time to discuss the issue with family members, 22 (16.7%) did not want to know if they had a BRCA1/2 mutation, and 22 (16.7%) declined the test because of financial problems. When analyzing refusal of testing according to the time period before and after the implementation of national health insurance coverage for BRCA1/2 genetic testing, the critical reason given for refusal was different. After insurance coverage, refusal for financial reason was decreased from 61.1 to 9.6%., Conclusions: A family history of breast cancer and a younger age were important factors associated with participation in genetic testing. National health insurance decreased the proportion of individuals who did not participate in testing owing to a financial reason. In genetic counseling, we have to understand these issues and consider several factors that may influence an individual's decision to be tested., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The Korean Hereditary Breast Cancer (KOHBRA) study was established to evaluate the prevalence and spectrum of BRCA1/2 mutations in Korean breast cancer patients at risk for hereditary breast and ovarian cancer. A total of 2953 subjects (2403 index patients and 550 family members of affected carriers) from 36 centers participated in this study between May 2007 and December 2013. All participants received genetic counseling and BRCA genetic testing. In total, 378 mutation carriers among 2403 index patients were identified. The prevalence of BRCA mutations in specific subgroups was as follows: 22.3 % (274/1228) for breast cancer patients with a family history of breast/ovarian cancers, 8.8 % (39/441) for patients with early-onset (<35 years) breast cancer without a family history, 16.3 % (34/209) for patients with bilateral breast cancer, 4.8 % (1/21) for male patients with breast cancer, and 37.5 % (3/8) for patients with both breast and ovarian cancer. From an analysis of the mutation spectrum, 63 BRCA1 and 90 BRCA2 different mutations, including 44 novel mutations, were identified. The c.7480 (p.Arg2494Ter) mutation in BRCA2 (10.1 %) was the most commonly identified in this cohort. The KOHBRA study is the largest cohort to identify BRCA mutation carriers in Asia. The results suggest that the prevalence of BRCA mutations in familial breast cancer patients is similar to that among Western cohorts. However, some single risk factors without family histories (early-onset breast cancer, male breast cancer, or multiple organ cancers) may limit the utility of BRCA gene testing in the Korean population.

The aim of this study was to evaluate the outcomes and patterns of recurrence in the different subtypes of breast cancer. We analyzed 1432 stage I-III breast cancer patients who had undergone surgery at Seoul National University Bundang Hospital between June 2003 and August 2011. Five subtypes were defined according to estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER2), and Ki-67. Overall survival (OS) and breast cancer-free interval (BCFI) rates were estimated using the Kaplan-Meier method. Site-specific recurrence was estimated using Gray's test. The median follow-up period was 53 months. There were 22 local recurrences, 18 cases of contralateral breast cancer, 19 regional nodal recurrences, and 70 distant metastases. The 5-year BCFIs by subtype were luminal B-HER2 (+), 94.2 %; luminal A, 93.9 %; luminal B-HER2 (-), 91.4 %; HER2, 83.1 %; and triple-negative, 81.9 % (p < 0.001). Cases with the luminal A had a 5-year OS rate of 98.3 % that was the longest compared to those of cases with luminal B-HER2 (-), 95.8 %; luminal B-HER2 (+), 98.0 %; HER2, 90.8 %; and triple-negative, 89.9 % (p < 0.001). The triple-negative had a higher rate of local recurrence at the first site than others (p = 0.013). HER2 and triple-negative had higher rates of nodal recurrence at the first site than others (p < 0.001). The outcomes and patterns of site-specific recurrence in Korean breast cancer patients were different for each subtype. Defining recurrence patterns by breast cancer subtypes can help determine the appropriate method of surveillance and treatment.

Epidermal growth factor receptor (EGFR) is frequently overexpressed in triple-negative breast cancer and is emerging as a therapeutic target. EGFR gene copy number alteration and mutation are highly variable and scientists have been challenged to define their prognostic significance in triple-negative breast cancer. We examined EGFR protein expression, EGFR gene copy number alteration and mutation of exon 18 to 21 in 151 cases of triple-negative breast cancer and correlated these findings with clinical outcomes. In addition, intratumoral agreement of EGFR protein overexpression and gene copy number alteration was evaluated. EGFR overexpression was found in 97 of 151 cases (64%) and high EGFR gene copy number was detected in 50 cases (33%), including 3 gene amplification (2%) and 47 high polysomy (31%). Five EGFR mutations were detected in 4 of 151 cases (3%) and included G719A in exon 18 (n=1), V786M in exon 20 (n=1), and L858R in exon 21 (n=3). One case had two mutations (G719A and L858R). High EGFR copy number, but not EGFR mutation, correlated with EGFR protein overexpression. Intratumoral heterogeneity of EGFR protein overexpression and EGFR copy number alteration was not significant. In survival analyses, high EGFR copy number was found to be an independent prognostic factor for poor disease-free survival in patients with triple-negative breast cancer. Our findings showed that EGFR mutation was a rare event, but high EGFR copy number was relatively frequent and correlated with EGFR overexpression in triple-negative breast cancer. Moreover, high EGFR copy number was associated with poor clinical outcome in triple-negative breast cancer, suggesting that evaluation of EGFR copy number may be useful for predicting outcomes in patients with triple-negative breast cancer and for selecting patients for anti-EGFR-targeted therapy.

Triple-negative breast cancer (TNBC) accounts for 12-24 % of all breast cancers. Here, we studied 221 familial breast and/or ovarian cancer patients from 37 hospitals using a comprehensive approach to identify large genomic rearrangements (LGRs) as well as sequence variants, and investigated the association between BRCA1/2 mutational status and TNBC. We performed direct sequencing or mutation scanning followed by direct sequencing. Then, 143 BRCA1/2 mutation-negative patients were screened for LGRs. In this study, the prevalence of BRCA1/2 mutations was high (36.9 %). The prevalence of BRCA1 mutations was similar to that of BRCA2 mutations: 49.4 versus 50.6 %, respectively. TNBC was diagnosed in 35.2 % of BRCA1/2 mutation carriers and 57.1 % of BRCA1 mutation carriers. Conversely, two-thirds of TNBC patients carried BRCA1/2 mutation(s), and about half were BRCA1 mutation carriers. When stratified by the mutated gene, TNBC prevalence in BRCA1 mutation carriers was significantly lower when there was a family history of ovarian cancer. Our multinomial logistic regression model demonstrated that no single factor was sufficient, and at least two factors, such as a patient with family history of both breast cancer and ovarian cancer or a patient diagnosed at a relatively young age (<40 years) with a TNBC phenotype, are necessary to indicate BRCA1/2 genetic testing in this population. Our results suggest that TNBC is a strong predictor for the presence of a BRCA1 mutation in this population, but additional risk factors should also be evaluated to ascertain a 10 % or higher prior probability of BRCA1/2 mutation testing.

The objective of this study was to identify factors that affect the decision to undergo risk-reducing salpingo-oophorectomy (RRSO) in BRCA1 or BRCA2 mutations carriers in South Korea. The medical records of 124 women who had been found to have BRCA1 or BRCA2 gene mutation at our institution between May 2003 and December 2011 were reviewed. The carriers were divided into RRSO and non-RRSO groups for comparison of their clinicopathologic, socio-economic, and psychosocial factors. Of the 71 carriers eligible for RRSO, 21 had undergone RRSO. In univariate analysis, classification of carriers into 3 groups by decade of life (4th, 5th, or 6th and later decade) and subsequent analysis revealed that 52.6% of carriers in the 5th decade had undergone RRSO, a rate significantly higher than that of the other age groups (p = 0.007). The RRSO rate was higher in carriers with a personal history of breast cancer than in those without (39.2% vs. 5.0%, p = 0.004), in carriers with a family history of breast cancer than in those without (35.5% vs. 11.8%, p = 0.065), and in carriers with a family history of ovarian cancer than in those carriers without a family history (66.7% vs. 24.2%, p = 0.016). Multivariate analysis identified age and personal history of breast cancer as independent factors affecting the decision to undergo RRSO. Age and personal history of breast cancer are important factors in the decision to undergo, and should thus be considered when counseling BRCA1/2 mutation carriers.

Background: Soy intake is associated with a lower risk of breast cancer. However, it is unclear whether the same reduction in risk associated with high soy intake is also applicable to familial or genetic breast cancer., Objective: The aim of this study was to assess the dietary factors among carriers and noncarriers of BRCA mutations in the Korean Hereditary Breast Cancer Study (KOHBRA)., Design: The KOHBRA Study is an ongoing project composed of affected breast cancer patients and familial members of breast cancer cases with BRCA mutations. To assess the association between dietary diversity and breast cancer risk, an HR was estimated by comparing affected subjects with their familial nonaffected members. To assess the interaction between the combination of BRCA mutation and diet diversity, the case-only OR (COR) was estimated by comparing BRCA mutation carriers and noncarriers only in affected subjects., Results: Soy product intake was associated with a lower risk of breast cancer in carriers (HR: 0.39; 95% CI: 0.19, 0.79 for the highest quartile). The highest quartile of meat intake was associated with a higher risk of breast cancer regardless of BRCA mutation in carriers (HR: 1.97; 95% CI: 1.13, 3.44) and noncarriers (95% CI: 1.41; 1.12, 1.78). The associations of meat intake and soybean intake for breast cancer were more prominent in BRCA2 mutation carriers. In the analysis with only cases, the highest quartile of soy intake, but not meat intake, was associated with BRCA-related breast cancer (COR: 0.57; 95% CI: 0.36, 0.91)., Conclusion: Our study suggests that soy product consumption is associated with lower breast cancer risk and it had an interaction with BRCA mutation.

Purpose: Systematic educational programs and genetic counseling certification courses for hereditary breast/ovarian cancer (HBOC) have not yet been introduced in Korea. We provided and evaluated the effects of genetic counseling education on Korean healthcare providers' knowledge, awareness, and counseling skills for patients at high risk of HBOC., Methods: A 3-day educational program was conducted for healthcare providers who were interested in genetic counseling for patients at high risk of HBOC. Participants who completed a knowledge test and satisfaction questionnaire were included in the present sample. Pre-post comparisons were conducted to determine the effects of the intervention., Results: Significant differences between preprogram and postprogram knowledge scores were observed (p=0.002). Awareness (p<0.001) and confidence (p<0.001) regarding genetic counseling significantly increased after the training. Doctors and participants with fewer years of work experience performed well on the knowledge test. Previous educational experience was correlated with increased confidence in knowledge and counseling skills., Conclusion: Genetic counseling education regarding HBOC improved knowledge and awareness of HBOC and enhanced confidence in the counseling process. The effects varied according to occupation and participants' previous education. The implementation of systematic educational programs that consider participant characteristics may improve the effects of such interventions.

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.

Restricted shoulder mobility is a major upper limb dysfunction related to lower quality of life and disability after breast cancer surgery. We hypothesized that sodium hyaluronate-carboxymethyl cellulose (HA-CMC) applied to the surface of the pectoralis major muscle after mastectomy would significantly reduce pain and improve range of motion (ROM) of the shoulder in breast cancer patients. We conducted a double-blind, randomized controlled study to evaluate the clinical efficacy and safety of HA-CMC in the prevention of upper limb dysfunction after total mastectomy (TM). A total of 99 women with breast cancer were randomly assigned to one of two groups. In the HA-CMC group (n = 50), a mixed HA-CMC was applied to the surface of the pectoralis major and serratus anterior muscle after TM. In the control group (n = 49), TM was performed without the use of HA-CMC. The primary outcomes were ROM of the shoulder and motion-related pain assessed using a numeric rating scale measured before surgery (T0) and 3 (T1) and 6 months (T2) after surgery. Secondary outcomes included disabilities of the arm, shoulder, and hand (DASH) and the pectoralis minor length test. Compared with the control group, the HA-CMC group showed greater reductions in postoperative restriction of total shoulder ROM (sum of flexion and horizontal abduction) at 3 months (10.20°, P = 0.004). Mean pain levels related to flexion and horizontal abduction were significantly lower in the HA-CMC group (-1.32 and -0.93, respectively, P < 0.05). The DASH score was lower (-4.94; P = 0.057) in the HA-CMC group at T2. No adverse effect was observed in either group. These results provide evidence that HA-CMC may provide pain relief and improve ROM of the shoulder without causing adverse effects. The effect on pectoralis tightness should be investigated in further studies.

BRCAPRO and Myriad II are widely used models for predicting BRCA1/2 mutation probability before genetic testing. However, the accuracy of these models in Koreans is not known. This study was performed to evaluate the accuracy of the BRCAPRO and Myriad II models. Two hundred thirty-six women with breast cancer who underwent comprehensive BRCA1/2 genetic testing at our hospital between 2003 and 2010 were included in this study. We evaluated the performance of each model by comparing the numbers of observed versus predicted mutation carriers. We calculated sensitivity, specificity, and predictive values at 10 % estimated probability. Forty-six individuals were identified to carry a deleterious BRCA mutation. The prevalence of BRCA mutation (19.5 %) was significantly higher than that predicted by BRCAPRO (9.0 %, p = 0.001) and Myriad (5.6 %, p < 0.001). In familial breast cancer patients, BRCA mutation rate (observed 22.7 %) was underestimated by both BRCAPRO (expected 11.4 %, p = 0.006) and Myriad II (expected 6.4 %, p < 0.001). Subgroup analyses showed that both models underestimated the risk of BRCA mutation in patients with a family history of breast cancer (probands' age at breast cancer diagnosis >50 years), with only one relative with breast cancer, and with non-familial early-onset breast cancer or bilateral breast cancer. Using a 10 % cut-off, the sensitivities were 47.8 % (BRCAPRO) and 50.0 % (Myriad), and positive predictive values were 44.9 % (BRCAPRO) and 43.4 % (Myriad). Both BRCAPRO and Myriad II underestimated the risk of BRCA1/2 mutation in Koreans. Our findings suggest that these models are less sensitive in Korean women, and therefore a new BRCA mutation prediction model based on Korean data is needed for proper genetic counseling.

Intratumoral heterogeneity of human epidermal growth factor receptor 2 (HER2) gene amplification has been reported to occur with variable frequencies in breast cancers. However, there have been few studies of its clinicopathological significance. We used tissue microarrays to evaluate two aspects of intratumoral heterogeneity of HER2 gene amplification: regional heterogeneity and genetic heterogeneity. We examined 96 invasive breast cancers in which HER2 amplification had been diagnosed in whole sections, and determined the clincopathological characteristics of those tumors. HER2 regional heterogeneity, defined as the existence of amplification/negative or amplification/equivocal patterns in different tissue microarray cores of a tumor, was present in 17 (18%) of the 96 cases. HER2 genetic heterogeneity, defined as the presence of tumor cells with a HER2/chromosome enumeration probe 17 ratio higher than 2.2 in 5-50% of the tumor cells, was found in 11 cases (11%), all of which showed HER2 regional heterogeneity. The cases with intratumoral heterogeneity of HER2 gene amplification were characterized by low grade or equivocal HER2 amplification and equivocal (2+) HER2 expression in whole sections. The patients with intratumoral heterogeneity of HER2 gene amplification had significantly shorter disease-free survival times than those with homogeneous HER2 gene amplification, and this effect was also evident in subgroup analysis by hormone receptor status. In multivariate analysis, intratumoral HER2 heterogeneity retained its status as an independent prognostic factor for disease-free survival. In conclusion, intratumoral heterogeneity of HER2 gene amplification is present in a subset of HER2-amplified breast cancers, especially in cases with low-grade HER2 amplification and equivocal HER2 expression, indicating a need for HER2 testing on more representative, larger tumor samples for accurate assessment of HER2 status in such cases. The patients with this heterogeneity have decreased disease-free survival, suggesting that genetic instability, and hence aberrant HER2 amplification in subclones of such tumors, may be associated with breast cancer progression.

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.