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Background: Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3B (APOBEC3B) is implicated in anti-viral immune response and cancer mutagenesis. Germline APOBEC3B deletion is associated with increased susceptibility to breast cancer. We aimed to evaluate the association between germline APOBEC3B deletion and clinical phenotypes of breast cancer in Korean patients with operable breast cancer. Methods: Mononuclear blood cell DNA of 103 patients with operable breast cancer was collected at Seoul National University Bundang Hospital in 2009. The DNA was sequenced to analyze APOBEC3B deletion status. Further, tumor-infiltrating lymphocytes (TILs) and programmed cell death-ligand 1 (PD-L1) expression in tumor cells were measured using immunohistochemistry. Results: Median age of breast cancer diagnosis was 46 (25–72). In APOBEC3B deletion analysis, 10 (9.7%), 36 (35.0%), and 57 (55.3%) patients were identified as two-copy deletion (A3Bdel/del), one–one copy deletion (A3Bdel/wt), and no deletion (A3Bwt/wt), respectively. For other cancer susceptibility gene alterations, 9 (8.7%) patients were identified as pathogenic variants: RAD51D (n = 1), GJB2 (n = 1), BRCA1 (n = 1), BRCA2 (n = 2), ATM (n = 1), USH2A (n = 1), RET (n = 1), BARD1 (n = 1). We observed no significant association between germline APOBEC3B deletion with any clinicopathologic features of breast cancer, such as age, family history of cancer, and bilateral breast cancer. Further, according to follow-up observations, APOBEC3B deletion was not predictive of disease-free survival. In ER+ subtype, a trend toward better survival was observed in patients with A3Bdel/del genotype as compared to patients with A3Bdel/wt and A3Bwt/wt genotype (log-rank, P = 0.25). In patients with sufficient tumor samples for the assessment of TIL (n = 63) and PD-L1 (n = 71), the A3Bdel/del genotype was significantly associated with high TILs (> 10%) than other tumor genotypes (6/7 patients in A3Bdel/del vs. 13/24 in A3Bdel/wt vs. 15/32 in A3Bwt/wt: Fisher's exact test, P = 0.029). However, PD-L1 expression was not associated with APOBEC3B deletion status (1/7 patients > 1% PD-L1 in A3Bdel/del vs. 4/26 in A3Bdel/wt vs. 8/38 in A3Bwt/wt: P = 0.901). Conclusion: We identified germline APOBEC3B deletion in 9.7% of Korean patients with operable breast cancer. The relationship between A3Bdel/del genotype and high TILs suggests that patients carrying this genotype could be potential candidates for immunotherapy. [ABSTRACT FROM AUTHOR]

Purpose: A positive resection margin after breast conserving surgery (BCS) is the most important risk factor for tumor recurrence. In 2012, Seoul National University Hospital (SNUH) breast surgery team developed a nomogram for predicting positive resection margins before BCS to provide individual surgical plans that could reduce local recurrence without increasing re-excision rates. The purpose of this study was to validate this nomogram using an external cohort and to test if addition of surgeon-related factor could improve its use as a predictive model. Methods: A total of 419 patients with breast cancer who underwent BCS from January to December 2018 were retrospectively reviewed. Using the SNUH BCS nomogram, risk score for positive resection margins was calculated for 343 patients. The predictive accuracy of the nomogram was assessed, and multivariable logistic regression analyses were performed to evaluate the nomogram's predictive variables. Results: The positive resection margin rate of the current external validation cohort was 13.5% (46 out of 343), compared to 14.6% (151 out of 1034) of the original study. The discrimination power of the SNUH BCS nomogram as measure by area under the receiver operating characteristics curve (AUC) was 0.656 [95% confidence interval (CI) 0.576–0.735]. This result is lower than expected value of 0.823 [95% CI 0.785–0.862], the AUC of the original study. Multivariable logistic regression analysis showed that, among the five nomogram variables, presence of tumor size discrepancy greater than 0.5 cm between MRI and ultrasonography (OR 2.445, p = 0.019) and presence of ductal carcinoma in situ on needle biopsy (OR 2.066, p = 0.048) were significantly associated with positive resection margins. Finally, the nomogram score was re-calculated by adding each surgeon's resection margin positive rate as odds ratio and the AUC was increased to 0.733. Conclusions: Validation of the SNUH BCS nomogram was not successful in the current study as much as its original publication. However, we could improve its predictive power by including surgeon-related factor. Before applying a published nomogram as a preoperative predictive model, we suggest each institution to validate the model and adjust it with surgeon-related factor. Addition of new factors to currently available nomograms holds promise for improving its applicability for breast cancer patients at the actual clinical level. [ABSTRACT FROM AUTHOR]

Purpose: Although gene expression profiling provides critical information, knowledge remains limited regarding the differential effects of molecular subtype on clinical course. This study evaluated the impact of molecular status on long-term patterns of failure in patients with non-metastatic breast cancer. Methods: We analyzed data from 1181 individuals with invasive breast cancer undergoing surgery plus PORT from 2003 to 2011. Molecular subtypes were defined as luminal A (LA), luminal B (LB)-HER2(−), LB-HER2(+), HER2, and triple-negative (TN) based on the 2013 St. Gallen Consensus criteria. Competing risks analysis and baseline hazard rate function plots were used to explore subtype-specific recurrence patterns. Results: The 10-year overall survival rates of LA, LB-HER2(−), LB-HER2(+), HER2, and TN groups were 96, 93, 94, 84, and 85%, respectively ( P < 0.001). Distant metastatic events differed significantly according to molecular subtype ( P < 0.001). In competing risks regression analysis, initial development of distant metastasis was the highest with TN tumors, followed by HER2, LB-HER2(−), and LB-HER2(+) subtypes ( P = 0.005). Regarding preferential sites of distant metastasis, the risk of initial brain metastasis was significantly higher with HER2 tumors, followed by TN tumors ( P = 0.001). A low-level but sustained metastatic risk increment was observed in luminal tumors, whereas TN and HER2 subtypes showed a short-term risk surge within 5 years. Conclusion: From the significant impact of molecular profile on distant metastasis, subtype-specific individualization of systemic treatment and close surveillance are suggested. The preferential and long-term risk of brain metastasis in the HER2 subtype underlines the importance of alternative anti-HER2 therapies. [ABSTRACT FROM AUTHOR]

Purpose: Breast cancer patients undergoing axillary lymph node dissection (ALND) are at risk of lymphedema (LE). Successful management of LE relies on early diagnosis using sensitive modalities. In the current study, we explored the effectiveness of a surveillance program for lymphedema management (SLYM) compared to standard care. Methods: Breast cancer patients who underwent ALND in Seoul National University Bundang Hospital from January 2008 to December 2015 were included in this prospective study. The SLYM commenced in May 2011. The LE outcomes of patients treated prior to initiation of the SLYM were compared with those of patients after SLYM implementation. Results: A total of 707 patients were included, 390 in the SLYM group and 317 in the historical control (HC) group. A total of 203 patients (28.7 %) had episodes of all-stage LE during follow-up. Of these, 126 (19.7 %) were in the surveillance group and 77 (24.3 %) in the HC group. The overall 5-year cumulative incidence of LE (greater than stage 3) was 25 (95 % CI 15.4-34.6) (6.4 %) in the SLYM group and 48 (95 % CI, 15.4-34.6) (15.1 %) in the HC group. In the SLYM group, poor compliance had a significant impact on LE incidence ( OR = 2.98, P = 0.002). Low level of self-monitoring and insight scores were significantly related to LE incidence ( OR = 1.31, P = 0.025) after adjusting for age, body mass index, the type of surgery chosen, radiation therapy, and chemotherapy. With a cut-off of 29.5 days from operation to the first visit to the LE clinic, the sensitivity was 60 % and the specificity 61 % in terms of predicting a LE event. Conclusions: Surveillance improves LE prevention compared to clinical evaluation. The first visit to the LE clinic should be made within 1 month after surgery. In the first year, visits should be made at intervals of less than 3 months. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

To investigate clinical, pathological, and familial characteristics of Korean patients with double heterozygosity for BRCA1 and BRCA2 mutations, six breast tumors of five patients who carried deleterious mutations in both of the genes were included. Medical records of the patients were reviewed and genetic testing by direct sequencing was undertaken to detect mutations in BRCA1 and BRCA2. Seven frameshift and three nonsense mutations were identified, and four mutations are novel in the Breast Cancer Information Core. There were no Ashkenazi founder mutations detected. The mean age at diagnosis for breast cancer was 33 years. All six tumors were infiltrating ductal carcinoma and poorly differentiated. Pathologic stage was I or II, and immunohistochemistry showed negative immunoreactivity for estrogen receptor and Her-2/neu in all tumors. Positive immunoreactivity for progesterone receptor was found only in one tumor. Three patients had familial history of breast, ovarian or other cancers. One patient who was diagnosed for breast cancer at the age of 26 had two maternal family members of metachronous bilateral breast cancer. Another patient who experienced metachronous bilateral breast cancer had maternal history of ovarian and esophageal cancer. In summary, Korean patients with double heterozygosity for BRCA1 and BRCA2 were young at diagnosis of breast cancer. Tumors were early stage, high grade, and almost triple-negative phenotype. All familial history of breast, ovary or other cancer was maternal. Close surveillance and accurate risk assessment should be provided for the patients with mutations in the both of the genes. [ABSTRACT FROM AUTHOR]