Breast density reduction as a predictor for prognosis in premenopausal women with estrogen receptor-positive breast cancer: an exploratory analysis of the updated ASTRRA study.

BACKGROUND: While the relationship between mammographic breast density reduction (MDR) and endocrine therapy efficacy has been reported in estrogen receptor (ER)-positive breast cancer, it is still unclear in premenopausal women, especially in the case of adding ovarian function suppression (OFS) to antihormone therapy. The authors investigated the impact of MDR on prognosis stratified by treatment based on the updated results of the ASTRRA trial. MATERIALS AND METHODS: The ASTRRA trial, a randomized phase III study, showed that adding OFS to tamoxifen (TAM) improved survival in premenopausal women with estrogen receptor-positive breast cancer after chemotherapy. The authors updated survival outcomes and assessed mammography before treatment and the annual follow-up mammography for up to 5 years after treatment initiation. Mammographic density (MD) was classified into four categories based on the Breast Imaging-Reporting and Data System. MDR-positivity was defined as a downgrade in MD grade on follow-up mammography up to 2 years after randomization, with pretreatment MD grade as a reference. RESULTS: The authors evaluated MDR in 944 of the 1282 patients from the trial, and 813 (86.2%) had grade III or IV MD. There was no difference in the MDR-positivity rate between the two treatment groups [TAM-only group (106/476 (22.3%)) vs. TAM+OFS group (89/468 (19.0%)); P =0.217). MDR-positivity was significantly associated with better disease-free survival (DFS) in the TAM+OFS group (estimated 8-year DFS: 93.1% in MDR-positive vs. 82.0% in MDR-negative patients; HR: 0.37; 95% CI: 0.16-0.85; P =0.019), but not in the TAM-only group ( Pinteraction =0.039). MDR-positive patients who received TAM+OFS had a favorable DFS compared to MDR-negative patients who received only TAM (HR: 0.30; 95% CI: 0.13-0.70; P =0.005). CONCLUSION: Although the proportion of MDR-positive patients was comparable between both treatment groups, MDR-positivity was independently associated with favorable outcomes only in the TAM+OFS group.

Multidisciplinary Shared Decision Making for Fertility Preservation in Young Women With Breast Cancer.

PURPOSE: Fertility preservation (FP) is an important issue for young survivors of breast cancer. Although international guidelines recommend pre-treatment fertility counseling for women with breast cancer, there is no standardized protocol or referral system for FP in South Korea. There are also barriers to discussing FP that make patient-centered decision making difficult. This study aimed to develop a shared decision making program for FP and compare the rates of FP procedures between the usual care and shared decision making groups. We hypothesized that multidisciplinary shared decision making for FP would increase the rate of FP procedures and patient satisfaction. METHODS: The multidisciplinary shared decision making for FP in young women with breast cancer (MYBC) is a multicenter, clustered, stepped-wedge, randomized trial. A total of 1100 patients with breast cancer, aged 19-40 years, from nine hospitals in South Korea, will be enrolled. They will be randomized at the institutional level and assigned to usual care and shared decision making groups. Four institutions, each of which can recruit more than 200 patients, will each become a cluster, whereas five institutions, each of which can recruit more than 50 patients, will become one cluster, for a total of five clusters. The shared decision making groups will receive multidisciplinary programs for FP developed by the investigator. The primary outcome is the rate of FP procedures; secondary outcomes include fertility results, satisfaction, and quality of life. Outcomes will be measured at enrollment, treatment initiation, and the 1-, 3-, and 5-year follow-ups after starting breast cancer treatment. DISCUSSION: A multidisciplinary shared decision making program for FP is expected to increase fertility rates and satisfaction among young patients with breast cancer. This study will provide the evidence to implement a multidisciplinary system for patients with breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05139641. Registered on December 1, 2021.

Adding Ovarian Suppression to Tamoxifen for Premenopausal Women With Hormone Receptor-Positive Breast Cancer After Chemotherapy: An 8-Year Follow-Up of the ASTRRA Trial.

PURPOSE: To determine the updated long-term outcomes of the Addition of Ovarian Suppression to Tamoxifen in Young Women With Hormone-Sensitive Breast Cancer Who Remain Premenopausal or Regain Vaginal Bleeding After Chemotherapy (ASTRRA) trial. PATIENTS AND METHODS: This study is a post-trial follow-up of the ASTRRA trial, involving 1,483 premenopausal women younger than 45 years treated with definitive surgery after completing adjuvant or neoadjuvant chemotherapy for estrogen receptor-positive breast cancer. Patients were randomly assigned in a 1:1 ratio to complete 5 years of tamoxifen (TAM) alone (TAM-only) or 5 years of TAM with ovarian function suppression (OFS) for 2 years (TAM + OFS). The primary end point was disease-free survival (DFS), and the secondary end point was overall survival (OS). RESULTS: At 106.4 months of median follow-up, there was a continuous significant reduction in the DFS event rate in the TAM + OFS group. The 8-year DFS rate was 85.4% in the TAM + OFS group and 80.2% in the TAM-only group (hazard ratio [HR], 0.67; 95% CI, 0.51 to 0.87). There were no significant differences in OS between the two groups. The OS rate was 96.5% in the TAM + OFS group and 95.3% in the TAM-only group (HR, 0.78; 95% CI, 0.49 to 1.25). CONCLUSION: Adding OFS for 2 years to adjuvant TAM with a longer follow-up resulted in consistent DFS benefits, suggesting that adding OFS to TAM should be considered for patients who remain in a premenopausal state or resume ovarian function after chemotherapy.

Increased EAT volume after anthracycline chemotherapy is associated with a low risk of cardiotoxicity in breast cancer.

PURPOSE: Chemotherapy-induced cardiotoxicity is a critical issue for patients with breast cancer. Change of epicardial adipose tissue (EAT) is associated with cardiac dysfunction. The objective of this study was to investigate the relationship between EAT and chemotherapy-induced cardiotoxicity. METHODS: This retrospective study analyzed EAT on chest computed tomography (CT) of patients with early breast cancer using automatic, quantitative measurement software between November 2015 and January 2020. Changes in EAT before and after initiation of chemotherapy were compared according to the type of anticancer drug. Subclinical cardiotoxicity was defined as worsening ≥ 10% in left ventricular ejection fraction to an absolute value > 50% with a lower limit of normal measured with standard echocardiography. RESULTS: Among 234 patients with breast cancer, 85 were treated with adjuvant anthracycline-based (AC) and 149 were treated with non-anthracycline-based (non-AC) chemotherapy. There was a significant increase in EAT volume index (mL/kg/m2) at the end of chemotherapy compared to that at the baseline in the AC group (3.33 ± 1.53 vs. 2.90 ± 1.52, p < 0.001), but not in the non-AC group. During the follow-up period, subclinical cardiotoxicity developed in 20/234 (8.6%) patients in the total population [13/85 (15.3%) in the AC group and 7/149 (4.8%) in the non-AC group]. In the multivariable analysis, EAT volume index increment after chemotherapy was associated with a lower risk of subclinical cardiotoxicity in the AC group (Odds ratio: 0.364, 95% CI 0.136-0.971, p = 0.044). CONCLUSIONS: Measurement of EAT during anthracycline-based chemotherapy might help identify subgroups who are vulnerable to chemotherapy-induced cardiotoxicity. Early detection of EAT volume change could enable tailored chemotherapy with cardiotoxicity prevention strategies.

Prognosis of pregnancy after breast cancer diagnosis according to the type of treatment: A population-based study in Korea by the SMARTSHIP group.

BACKGROUNDS: In this study, we evaluated the incidence and outcomes of pregnancy after breast cancer was diagnosed in women of childbearing age. Additionally, we evaluated the prognosis of patients who became pregnant after breast cancer, according to the treatment. METHODS: This was a retrospective cohort study of women aged 20-45 years who were surgically treated for breast cancer between 2004 and 2014 using the Korean National Health Insurance database. The patients were classified into six groups according to the treatment. Propensity score matching was applied to the cohort to analyze the risk of breast cancer-associated mortality after pregnancy and childbirth. RESULTS: Of the 45,765 patients who had been newly diagnosed with breast cancer, 1826 (4%) became pregnant after breast cancer diagnosis. Among the pregnant group, the HR of the risk of death was 0.15 (95% CI, 0.06 to 0.36) for patients who became pregnant ≥49 months after the diagnosis. In patients who received endocrine therapy and chemotherapy, the pregnant group had better prognosis than the non-pregnant group. There was no significant difference between the pregnant group and the non-pregnant group in patients who received chemotherapy and trastuzumab with or without endocrine therapy. CONCLUSION: The risk of death was low in women who became pregnant ≥49 months after the diagnosis of breast cancer. The prognosis of pregnant women was non-inferior to that of non-pregnant women, even in women who received trastuzumab. These findings provide reassurance to patients with HER2-positive cancer who are considering future pregnancy.

Germline breast cancer susceptibility genes, tumor characteristics, and survival.

BACKGROUND: Mutations in certain genes are known to increase breast cancer risk. We study the relevance of rare protein-truncating variants (PTVs) that may result in loss-of-function in breast cancer susceptibility genes on tumor characteristics and survival in 8852 breast cancer patients of Asian descent. METHODS: Gene panel sequencing was performed for 34 known or suspected breast cancer predisposition genes, of which nine genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, and TP53) were associated with breast cancer risk. Associations between PTV carriership in one or more genes and tumor characteristics were examined using multinomial logistic regression. Ten-year overall survival was estimated using Cox regression models in 6477 breast cancer patients after excluding older patients (≥75years) and stage 0 and IV disease. RESULTS: PTV9genes carriership (n = 690) was significantly associated (p < 0.001) with more aggressive tumor characteristics including high grade (poorly vs well-differentiated, odds ratio [95% confidence interval] 3.48 [2.35-5.17], moderately vs well-differentiated 2.33 [1.56-3.49]), as well as luminal B [HER-] and triple-negative subtypes (vs luminal A 2.15 [1.58-2.92] and 2.85 [2.17-3.73], respectively), adjusted for age at diagnosis, study, and ethnicity. Associations with grade and luminal B [HER2-] subtype remained significant after excluding BRCA1/2 carriers. PTV25genes carriership (n = 289, excluding carriers of the nine genes associated with breast cancer) was not associated with tumor characteristics. However, PTV25genes carriership, but not PTV9genes carriership, was suggested to be associated with worse 10-year overall survival (hazard ratio [CI] 1.63 [1.16-2.28]). CONCLUSIONS: PTV9genes carriership is associated with more aggressive tumors. Variants in other genes might be associated with the survival of breast cancer patients. The finding that PTV carriership is not just associated with higher breast cancer risk, but also more severe and fatal forms of the disease, suggests that genetic testing has the potential to provide additional health information and help healthy individuals make screening decisions.

Unmet needs and quality of life of caregivers of Korean breast cancer survivors: a cross-sectional study.

PURPOSE: As the survival rates of cancer patients have been increasing due to early diagnosis and technological advances in treatment, their caregiver burden has also emerged as an important issue. In view of this situation, this study aims to investigate the unmet needs and quality of life of caregivers of Korean breast cancer survivors. METHODS: A multicenter cross-sectional interview survey was performed among 160 caregivers of Korean breast cancer survivors. Caregivers who gave written informed consent to participate completed the Comprehensive Needs Assessment Tool for Cancer Caregivers and EuroQol-5 Dimensions. RESULTS: The mean age of the caregivers was 46.4 years, 44.4% (71 of 160) were spouses of patients, and 52.5% (84 of 160) were personally taking care of cancer survivors. Unmet needs were highest in the 'healthcare staff' domain and the item with the highest level of unmet needs was 'needed information about the current status of the patient's illness and its future courses.' Poorer quality of life was closely related to higher levels of unmet needs. In multiple regression analysis, older age, employment, the presence of religion, and higher levels of stress and despair in daily life were associated with higher levels of unmet needs. CONCLUSION: The most prevalent unmet need in Korean breast cancer caregivers was found in the 'healthcare staff' domain, and their quality of life was closely related to unmet needs. Therefore, healthcare staff is required to make efforts to accurately identify breast cancer caregivers vulnerable in terms of unmet needs and address their unmet needs.

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.

Physicians' Awareness of the Breast Cancer Survivors' Unmet Needs in Korea.

PURPOSE: Physicians' awareness of their cancer patients' unmet needs is an essential element for providing effective treatment. This study investigated the accuracy of physicians' awareness of breast cancer survivors' unmet needs in Korea. METHODS: A cross-sectional interview survey was performed among 106 physicians and 320 Korean breast cancer survivors. The Comprehensive Needs Assessment Tool was administered to physicians and cancer survivors after obtaining their written informed consent to participate. Data were analyzed using t-test, analysis of variance, and multiple regression analysis. RESULTS: The level of unmet needs was highest in the hospital service domain (mean ± standard deviation: 2.19 ± 0.82), and the top-ranked unmet need item was "wished my doctor to be easy, specific, and honest in his/her explanation" (2.44 ± 0.93). Higher unmet needs were correlated with the presence of a genetic counseling clinic. They were not associated with age, sex, marital status, religion, department, working period, type of institution, number of staff, and number of operations. In multiple regression analysis, the presence of a genetic counseling clinic was associated with a higher level of recognition for psychological problems, social support, hospital service, and information and education needs. Physicians overestimated breast cancer survivors' unmet needs in all domains, compared to their self-reported unmet needs. The discordance in the perceived unmet needs was highest in the 'family/personal relationship problems' domain. CONCLUSIONS: Physicians who treat Korean breast cancer survivors rated the level of unmet needs of breast cancer survivors as highest in the hospital service domain. The presence of a genetic counseling clinic in physicians' institutions was associated with a higher perception of survivors' unmet needs. Physicians overestimated the level of unmet needs in Korean breast cancer survivors. Efforts to reduce these discordances are needed to implement optimal survivorship care.

Isoflavone intake on the risk of overall breast cancer and molecular subtypes in women at high risk for hereditary breast cancer.

PURPOSE: We investigated the association between isoflavone (ISF) intake and hereditary breast cancer (BC) risk, particularly by molecular subtype, in East-Asian BRCA1/2 mutation carriers and non-carriers at a high risk of hereditary breast cancer (i.e., family history of BC (FHBC) and early-onset BC [EOBC, age < 40 years]). METHODS: The association between ISF intake and BC risk by molecular subtypes was assessed in 1709 participants (407 BRCA1/2 carriers, 585 FHBC non-carriers, 586 EOBC non-carriers, and 131 unaffected non-carriers) from the Korean Hereditary Breast Cancer Study using hazard ratios (HRs) and 95% confidence intervals (CIs) in weighted Cox regression models. Daily ISF intake was assessed using a validated food frequency questionnaire. We evaluated gene-environment interactions between BRCA1/2 mutation and ISF intake in 1604 BC cases by calculating the case-only odds ratios (CORs) and 95% CIs in logistic regression models. RESULTS: ISF intake was inversely associated with luminal A BC risk in BRCA2 mutation carriers and FHBC non-carriers (HR = 0.14, 95% CI = 0.04-0.50 for high intake [ISF intake ≥ 15.50 mg/day]; HR = 0.27, 95% CI = 0.11-0.69 for high intake, respectively). We observed a reduced risk of triple negative BC (TNBC) in BRCA1 carriers and FHBC non-carriers (HR = 0.09, 95% CI = 0.02-0.40 for high intake; HR = 0.19, 95% CI = 0.05-0.69 for high intake, respectively). In the case-only design, an interaction between BRCA1 mutation carrier status and ISF intake emerged in TNBC patients (COR = 0.39, 95% CI = 0.16-0.95). CONCLUSIONS: This study suggests that ISF intake is inversely associated with BC risk in women at high risk of hereditary BC and that the effect could differ by molecular subtypes.

Long-term risk of congestive heart failure in younger breast cancer survivors: A nationwide study by the SMARTSHIP group.

BACKGROUND: There is a controversy about late-onset congestive heart failure (CHF) among breast cancer survivors. This study investigated the incidence rate and risk factors of late-onset CHF more than 2 years after the breast cancer diagnosis. METHODS: A nationwide, retrospective study was conducted with the National Health Information Database. With 1:3 age- and sex-matched noncancer controls, Cox proportional hazard regression models were used to analyze the incidence and risk factors of late CHF. The cumulative incidence rate of late CHF was evaluated with a Kaplan-Meier analysis and a log-rank test. RESULTS: A total of 91,227 cases (286,480 person-years) and 273,681 controls (884,349 person-years) were evaluated between January 2007 and December 2013. The risks of late CHF were higher in cases than controls (hazard ratio [HR], 1.396; 95% confidence interval [CI], 1.268-1.538). Younger survivors (age ≤ 50 years) showed a higher risk of late CHF than their younger counterparts (HR, 2.903; 95% CI, 2.425-3.474). Although older age was a risk factor for late CHF, older survivors (age ≥ 66 years) showed no difference in the risk of late CHF in comparison with their counterparts (HR, 0.906; 95% CI, 0.757-1.084). Anthracyclines and taxanes were risk factors for late CHF, although trastuzumab, radiation, and endocrine therapy were not. CONCLUSIONS: Young breast cancer survivors have a greater risk of late CHF than the young population without cancer. More attention should be paid to young breast cancer survivors who receive taxane- or anthracycline-based regimens over the long term.

Adding Ovarian Suppression to Tamoxifen for Premenopausal Breast Cancer: A Randomized Phase III Trial.

PURPOSE: The addition of ovarian function suppression (OFS) for 5 years to tamoxifen (TAM) for treatment of premenopausal patients with breast cancer after completion of chemotherapy has beneficial effects on disease-free survival (DFS). This study evaluated the efficacy of adding 2 years of OFS to TAM in patients with hormone receptor-positive breast cancer who remain in a premenopausal state or resume ovarian function after chemotherapy. PATIENTS AND METHODS: We enrolled 1,483 premenopausal women (age ≤ 45 years) with estrogen receptor-positive breast cancer treated with definitive surgery after completing adjuvant or neoadjuvant chemotherapy. Ovarian function was assessed every 6 months for 2 years since enrollment on the basis of follicular-stimulating hormone levels and vaginal bleeding history. If ovarian function was confirmed to be premenopausal at each visit, the patient was randomly assigned to complete 5 years of TAM alone (TAM-only) group or 5 years of TAM with OFS for 2 years that involved monthly goserelin administration (TAM + OFS) group. DFS was defined from the time of enrollment to the time of the first event. RESULTS: A total of 1,293 patients were randomly assigned, and 1,282 patients were eligible for analysis. The estimated 5-year DFS rate was 91.1% in the TAM + OFS group and 87.5% in the TAM-only group (hazard ratio, 0.69; 95% CI, 0.48 to 0.97; P = .033). The estimated 5-year overall survival rate was 99.4% in the TAM + OFS group and 97.8% in the TAM-only group (hazard ratio, 0.31; 95% CI, 0.10 to 0.94; P = .029). CONCLUSION: The addition of 2 years of OFS to TAM significantly improved DFS compared with TAM alone in patients who remained premenopausal or resumed ovarian function after chemotherapy.

Body mass index and risk of breast cancer molecular subtypes in Korean women: a case-control study.

BACKGROUND: Our main objective of this research was to analyze the effect of BMI on breast cancer risk according to various subtypes of breast cancer stratified with menopausal status. METHODS: By using a case-control study setting, we recruited a total of 16,190 female breast cancer patients aged between 35 and 80 years from 2003 to 2010. These breast cancer patients were then individually matched by age to control female group (1:2 ratios of cases and controls). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated via multivariable logistic regression by setting normal BMI range (18.5-22.9) as the reference group. RESULTS: In premenopausal women, the risk of breast cancer of triple-negative subtype increased (OR 1.60, 95% CI 1.27-2.02) in obese II (BMI ≥ 30) women and in underweight women, it was Luminal A (OR 1.24, 95% CI 1.06-1.45) and HER2 express subtype (OR 1.43, 95% CI 1.26-1.62) that showed increased risk of breast cancer. In postmenopausal women, Luminal A (OR 2.35, 95% CI 2.01-2.75), Luminal B HER2 negative (OR 1.81, 95% CI 1.46-2.25) and triple-negative subtype (OR 2.25, 95% CI 1.85-2.72) showed higher risk of breast cancer in obese II women. CONCLUSION: Our findings suggest that the effect of BMI on breast cancer differs according to various subtypes and hormone receptors and to menopausal status.

Unmet needs and related factors of Korean breast cancer survivors: a multicenter, cross-sectional study.

BACKGROUND: Identification of specific needs in patients with cancer is very important for the provision of patient-centered medical service. The aim of this study was to investigate the unmet needs and related factors of Korean breast cancer survivors. METHODS: A multicenter, cross-sectional, interview survey was performed among 332 Korean breast cancer survivors. The Comprehensive Needs Assessment Tool for cancer patients was administered to survivors who gave written informed consent to participate. Data were analyzed using t-test, ANOVA and multiple regression analysis. RESULTS: The level of unmet needs was highest in the domain 'Information and education' (mean ± SD; 1.70 ± 1.14) and the item with the highest level of unmet needs was 'Needed help in coping with fear of recurrence' (2.04 ± 1.09). Unmet needs were correlated with age, stage, multiplicity, HER2, treatment state, marital status, employment, psychosocial status, and problems in EQ-5D dimensions. In multiple regression analysis, the 50-59 age group showed a higher level of recognition for physical symptom needs and the unemployed group expressed greater needs for information and education. Survivors with multiplicity had greater needs in the domains of healthcare staff and physical symptom. The stress group showed high levels of needs in all domains except religious support. The group with thoughts of suicide showed higher levels of unmet needs for physical symptom. CONCLUSION: Most prevalent unmet needs in Korean breast cancer survivors were found in the 'information and education' domain. The 50-59 age group, unemployment, multiplicity, stress and suicidal thoughts were associated with higher levels of unmet needs among Korean breast cancer survivors. Our findings revealed more vulnerable breast cancer survivors with unmet needs and physicians should take a precision approach to satisfy unmet needs of these survivors.

Reclassification of BRCA1 and BRCA2 variants of uncertain significance: a multifactorial analysis of multicentre prospective cohort.

BACKGROUND: BRCA1 and BRCA2 (BRCA1/2) variants classified ambiguously as variants of uncertain significance (VUS) are a major challenge for clinical genetic testing in breast cancer; their relevance to the cancer risk is unclear and the association with the response to specific BRCA1/2-targeted agents is uncertain. To minimise the proportion of VUS in BRCA1/2, we performed the multifactorial likelihood analysis and validated this method using an independent cohort of patients with breast cancer. METHODS: We used a data set of 2115 patients with breast cancer from the nationwide multicentre prospective Korean Hereditary Breast Cancer study. In total, 83 BRCA1/2 VUSs (BRCA1, n=26; BRCA2, n=57) were analysed. The multifactorial probability was estimated by combining the prior probability with the overall likelihood ratio derived from co-occurrence of each VUS with pathogenic variants, personal and family history, and tumour characteristics. The classification was compared with the interpretation according to the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG/AMP) guidelines. An external validation was conducted using independent data set of 810 patients. RESULTS: We were able to redefine 38 VUSs (BRCA1, n=10; BRCA2, n=28). The revised classification was highly correlated with the ACMG/AMP guideline-based interpretation (BRCA1, p for trend=0.015; BRCA2, p=0.001). Our approach reduced the proportion of VUS from 19% (154/810) to 8.9% (72/810) in the retrospective validation data set. CONCLUSION: The classification in this study would minimise the 'uncertainty' in clinical interpretation, and this validated multifactorial model can be used for the reliable annotation of BRCA1/2 VUSs.

BRCA1/2-negative, high-risk breast cancers (BRCAX) for Asian women: genetic susceptibility loci and their potential impacts.

"BRCAX" refers breast cancers occurring in women with a family history predictive of being a BRCA1/2 mutation carrier, but BRCA1/2 genetic screening has failed to find causal mutations. In this study, we report the findings of the genetic architecture of BRCAX with novel and redefined candidate loci and their potential impacts on preventive strategy. We performed a genome-wide association study involving 1,469 BRCAX cases from the Korean Hereditary Breast Cancer study, and high-risk breast cancer cases (1,482 Asians and 9,902 Europeans) from the Breast Cancer Association Consortium. We also evaluated the previously reported susceptibility loci for their roles in the high-risk breast cancers. We have identified three novel loci (PDE7B, UBL3, and a new independent marker in CDKN2B-AS1) associated with BRCAX, and replicated previously reported SNPs (24 of 92) and moderate/high-penetrance (seven of 23) genes for Korean BRCAX. For the novel candidate loci, evidence supported their roles in regulatory function. We estimated that the common low-penetrance loci might explain a substantial part of high-risk breast cancer (39.4% for Koreans and 24.0% for Europeans). Our study findings suggest that common genetic markers with lower penetrance constitute a part of susceptibility to high-risk breast cancers, with potential implications for a more comprehensive genetic screening test.

Pegfilgrastim for primary prophylaxis of febrile neutropenia in breast cancer patients undergoing TAC chemotherapy.

PURPOSE: Primary prophylaxis with granulocyte colony-stimulating factor can effectively prevent febrile neutropenia (FN) during breast cancer treatment. The aims of this study were to evaluate the incidence of FN and the ANC profile in patients undergoing chemotherapy and pegfilgrastim primary prophylaxis. METHODS: Patients receiving 6 cycles of adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC) chemotherapy were included in this study. Pegfilgrastim was administered with analgesics 24 hours after treatment. Laboratory tests were performed on day 0 (before chemotherapy) and ANC was measured daily starting day 5 until it were restored to 1,000/mm3. Bone pain was checked via the numeral rating scale (NRS). RESULTS: A total of 61 patients and 366 cycles were evaluated. Mean age was 49.2 ± 7.1 years. FN was seen in 5 patients (16.4%) and 12 cycles (3.3%) with pegfilgrastim. Grades 3 and 4 neutropenia was seen in 91.5% of cycles with FN. The ANC nadir was most commonly seen at day 7 and the mean ANC nadir depth was 265.7/m3. Age was negatively correlated with nadir depth (r = -0.137, P = 0.009). Severe pain higher than NRS 7 occurred in less than 20% of patients after the administration of pegfilgrastim. CONCLUSION: Incidence of FN was low during the chemotherapy by primary prophylaxis with pegfilgrastim. The ANC nadir was seen on day 7 after chemotherapy. Bone pain with pegfilgrastim was well tolerated during TAC chemotherapy.

Risk Reduction of Breast Cancer by Childbirth, Breastfeeding, and Their Interaction in Korean Women: Heterogeneous Effects Across Menopausal Status, Hormone Receptor Status, and Pathological Subtypes.

OBJECTIVES: The purpose of this study was to examine the associations of childbirth, breastfeeding, and their interaction with breast cancer (BC) risk reduction, and to evaluate the heterogeneity in the BC risk reduction effects of these factors by menopause, hormone receptor (HR) status, and pathological subtype. METHODS: BC patients aged 40+ from the Korean Breast Cancer Registry in 2004-2012 and controls from the Health Examinee cohort participants were included in this study after 1:1 matching (12 889 pairs) by age and enrollment year. BC risk according to childbirth, breast-feeding, and their interaction was calculated in logistic regression models using odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: BC risk decreased with childbirth (3+ childbirths relative to 1 childbirth: OR, 0.66; 95% CI, 0.56 to 0.78 and OR, 0.80; 95% CI, 0.68 to 0.95 in postmenopausal and premenopausal women, respectively); and the degree of risk reduction by the number of children was heterogeneous according to menopausal status (p-heterogeneity=0.04), HR status (p-heterogeneity<0.001), and pathological subtype (p-heterogeneity<0.001); whereas breastfeeding for 1-12 months showed a heterogeneous association with BC risk according to menopausal status, with risk reduction only in premenopausal women (p-heterogeneity<0.05). The combination of 2 more childbirths and breastfeeding for ≥13 months had a much stronger BC risk reduction of 49% (OR, 0.51; 95% CI, 0.45 to 0.58). CONCLUSIONS: This study suggests that the combination of longer breastfeeding and more childbirths reduces BC risk more strongly, and that women who experience both 2 or more childbirths and breastfeed for ≥13 months can reduce their BC risk by about 50%.

Development of second primary cancer in Korean breast cancer survivors.

PURPOSE: Breast cancer survivors have slightly increased the risk of second primary cancers. Breast, colon, uterine, and ovarian cancers are common secondary cancers in breast cancer survivors. In this study, we assessed the development of second primary cancers of breast cancer survivors in Korea. METHODS: Medical records of patients with breast cancer in 3 tertiary medical institutions were reviewed retrospectively. We evaluated secondary malignancy diagnosed at least 2 months after the breast cancer diagnosis. Based on the International Classification of Disease-9 codes of malignancies, secondary primary breast cancer records were evaluated with person-year adjustment. The standardized incidence ratio (SIR) was assessed using national cancer incidence. RESULTS: A total of 3,444 treatment records were included from 3 medical centers. The cumulative incidence of overall second primary cancers was 2.8% (n = 93). The SIR was significantly higher in all sites (1.56; 95% confidence interval [CI], 1.26-1.91), endometrial cancer (5.65; 95% CI, 2.06-12.31), biliary tract cancer (3.96; 95% CI, 1.19-8.60), and thyroid cancer (2.29; 95% CI, 1.67-3.08). CONCLUSION: The incidence of cancer was higher in breast cancer survivors compared to general population. Surveillance of secondary cancer in this group should be recommended individually considering the benefit related to the prognosis of primary breast cancer.