Clinical Features of Li-Fraumeni Syndrome in Korea.

PURPOSE: Li-Fraumeni syndrome (LFS) is a hereditary disorder caused by germline mutation in TP53. Owing to the rarity of LFS, data on its clinical features are limited. This study aimed to evaluate the clinical characteristics and prognosis of Korean patients with LFS. MATERIALS AND METHODS: Patients who underwent genetic counseling and confirmed with germline TP53 mutation in the National Cancer Center in Korea between 2011 and 2022 were retrospectively reviewed. Data on family history with pedigree, types of mutation, clinical features, and prognosis were collected. RESULTS: Fourteen patients with LFS were included in this study. The median age at diagnosis of the first tumor was 32 years. Missense and nonsense mutations were observed in 13 and one patients, respectively. The repeated mutations were p.Arg273His, p.Ala138Val, and pPro190Leu. The sister with breast cancer harbored the same mutation of p.Ala138Val. Seven patients had multiple primary cancers. Breast cancer was most frequently observed, and other types of tumor included sarcoma, thyroid cancer, pancreatic cancer, brain tumor, adrenocortical carcinoma, ovarian cancer, endometrial cancer, colon cancer, vaginal cancer, skin cancer, and leukemia. The median follow-up period was 51.5 months. Two and four patients showed local recurrence and distant metastasis, respectively. Two patients died of leukemia and pancreatic cancer 3 and 23 months after diagnosis, respectively. CONCLUSION: This study provides information on different characteristics of patients with LFS, including types of mutation, types of cancer, and prognostic outcomes. For more appropriate management of these patients, proper genetic screening and multidisciplinary discussion are required.

Clinicopathological Factors Associated with Oncotype DX Risk Group in Patients with ER+/HER2- Breast Cancer.

Oncotype DX (ODX), a 21-gene assay, predicts the recurrence risk in early breast cancer; however, it has high costs and long testing times. We aimed to identify clinicopathological factors that can predict the ODX risk group and serve as alternatives to the ODX test. This retrospective study included 547 estrogen receptor-positive, human epidermal growth factor receptor 2-negative, and lymph node-negative breast cancer patients who underwent ODX testing. Based on the recurrence scores, three ODX risk categories (low: 0-15, intermediate: 16-25, and high: 26-100) were established in patients aged ≤50 years (n = 379), whereas two ODX risk categories (low: 0-25 and high: 26-100) were established in patients aged >50 years (n = 168). Factors selected for analysis included body mass index, menopausal status, type of surgery, and pathological and immunohistochemical features. The ODX risk groups showed significant association with histologic grade (p = 0.0002), progesterone receptor expression (p < 0.0001), Ki-67 (p < 0.0001), and p53 expression (p = 0.023) in patients aged ≤50 years. In patients aged >50 years, tumor size (p = 0.022), Ki-67 (p = 0.001), and p53 expression (p = 0.001) were significantly associated with the risk group. Certain clinicopathological factors can predict the ODX risk group and enable decision-making on adjuvant chemotherapy; these factors differ according to age.

Progranulin and Breast Cancer Mortality: 13-Year Follow-Up of a Cohort Study.

Background: We have reported that serum progranulin (PGRN) levels are clinically significant in predicting recurrence in patients with HR-positive breast cancer. The aim of the present study was to examine whether PGRN levels might be associated with breast cancer mortality. Methods: This was a cohort study of 695 newly diagnosed breast cancer patients who underwent curative surgery between 2001 and 2004. The relationship between breast cancer mortality and pre-operative serum PGRN levels in these patients with a median follow-up of 12.7 years was evaluated until May 2020. Results: A total of 118 (17%) deaths were identified in the cohort. According to the HR status, (10, 15, and 20)-year overall survival (OS) rates were (91.4, 81.1, and 75.9) % for HR-positive patients, and (76.5, 74.2, and 69.8) % for HR-negative patients, respectively (p = 0.003). Higher levels of PGRN were significantly associated with poor OS in the HR-positive group (p for trend = 0.001). In particular, hazard ratios for PGRN quartiles suggested a dose-response relationship, with the highest quartile having the worst OS in the HR-positive group (highest vs lowest: 15-year OS, (68.3 vs 90.0) %; 20-year OS, (62.3 vs 84.8) %, even after adjusting for age, tumor stage, and metabolic confounders. Conclusion: Pre-operative serum PGRN levels had clinical significance for predicting cancer mortality in breast cancer patients independent of tumor stage and metabolic parameters, especially in HR-positive tumors.

Androgen Receptor as a Predictive Marker for Pathologic Complete Response in Hormone Receptor-Positive and HER-2-Negative Breast Cancer with Neoadjuvant Chemotherapy.

PURPOSE: This study investigated pathological complete response (pCR) according to androgen receptor (AR) in breast cancer patients undergoing neoadjuvant chemotherapy and estimated the relationship between AR expression and clinicopathological factors. Materials and Methods: We identified 624 breast cancer patients who underwent surgery after neoadjuvant chemotherapy at the National Cancer Center in Goyang, Korea from April 2016 to October 2019. We retrospectively collected the clinicopathologic information and AR expression results and analyzed the data according to cancer stage, hormonal receptor (HR) status, human epidermal growth factor receptor 2 (HER2) status, tumor subtype, and pCR. RESULTS: Among the 624 breast cancer patients, 529 (84.8%) were AR-positive (AR+) patients and 95 (15.2%) were AR-negative (AR-) patients. AR+ patients showed more estrogen receptor (ER) positivity, progesterone receptor (PR) positivity, HER2-positivity, and HR-positive and HER2-negative (HR+/HER2-) subtype. The rate of pCR was 31.4% (196/624). AR- patients had a significantly higher rate of pCR than AR+ patients (AR- 43.2% vs. AR+ 29.3%, p=0.007). The tumor factors associated with pCR were early stage, histologic grade 3, ER-negative, PR-negative, AR-negative, HER2-positive, and high Ki-67 values. In univariable analysis, AR+ significantly decreased the state of pCR (odds ratio, 0.546; 95% confidence interval, 0.349 to 0.853; p=0.008). According to tumor subtype, AR- tumor showed higher pCR rate in HR+/HER2- subtype (AR- 28.6% vs. AR+ 7.3%, p=0.022). CONCLUSION: AR expression is predominant in the HR+/HER2- subtype. AR- is significantly associated with the pCR rate in breast cancer patients, especially within HR+/HER2- subtype. When determining neoadjuvant chemotherapy for the HR+/HER2- subtype, AR expression can be considered as a pCR predictive marker.

Matrix Metalloproteinase-1 (MMP1) Upregulation through Promoter Hypomethylation Enhances Tamoxifen Resistance in Breast Cancer.

BACKGROUND: Tamoxifen (tam) is widely used to treat estrogen-positive breast cancer. However, cancer recurrence after chemotherapy remains a major obstacle to achieve good patient prognoses. In this study, we aimed to identify genes responsible for epigenetic regulation of tam resistance in breast cancer. METHODS: Methylation microarray data were analyzed to screen highly hypomethylated genes in tam resistant (tamR) breast cancer cells. Quantitative RT-PCR, Western blot analysis, and immunohistochemical staining were used to quantify expression levels of genes in cultured cells and cancer tissues. Effects of matrix metalloproteinase-1 (MMP1) expression on cancer cell growth and drug resistance were examined through colony formation assays and flow cytometry. Xenografted mice were generated to investigate the effects of MMP1 on drug resistance in vivo. RESULTS: MMP1 was found to be hypomethylated and overexpressed in tamR MCF-7 (MCF-7/tamR) cells and in tamR breast cancer tissues. Methylation was found to be inversely associated with MMP1 expression level in breast cancer tissues, and patients with lower MMP1 expression exhibited a better prognosis for survival. Downregulating MMP1 using shRNA induced tam sensitivity in MCF-7/tamR cells along with increased apoptosis. The xenografted MCF-7/tamR cells that stably expressed short hairpin RNA (shRNA) against MMP1 exhibited retarded tumor growth compared to that in cells expressing the control shRNA, which was further suppressed by tam. CONCLUSIONS: MMP1 can be upregulated through promoter hypomethylation in tamR breast cancer, functioning as a resistance driver gene. MMP1 can be a potential target to suppress tamR to achieve better prognoses of breast cancer patients.

Clinical Effectiveness of Hypofractionated Proton Beam Therapy for Liver Metastasis From Breast Cancer.

BACKGROUND: Few studies of proton beam therapy (PBT) for patients with liver metastasis from breast cancer (LMBC) are available to date. The aim of the present study was to evaluate the clinical effectiveness of PBT for patients with LMBC. MATERIAL AND METHODS: Seventeen patients with LMBC treated with PBT were included in this study. The median prescribed dose of PBT was 66 GyE (range, 60-80) in 10 fractions, 5 times a week. In patients with LMBC receiving PBT, freedom from local progression (FFLP), progression-free survival (PFS), and overall survival (OS) rates were assessed. RESULTS: The median follow-up time was 34.2 months (range, 11.5-56.1). The median FFLP time was not yet reached, and the 3-year FFLP rates were 94.1% (95% confidence interval [CI], 82.9-105.3). The median times of PFS and OS were 7.9 months (95% CI, 5.3-10.5) and 39.3 months (95% CI, 33.2-51.9), respectively, and the 3-year PFS and OS rates were 19.6% (95% CI, -1.8-41.0) and 71.7% (95% CI, 46.8-96.6), respectively. Grade 3 or higher adverse events were not observed. CONCLUSION: PBT for patients with LMBC showed promising FFLP and OS with safe toxicity profiles. These findings suggest that PBT can be considered a local treatment option in patients with LMBC.

ELOVL2: a novel tumor suppressor attenuating tamoxifen resistance in breast cancer.

Epigenetic events have successfully explained the cause of various cancer types, but little is known about tamoxifen resistance (TamR) that induces cancer recurrence. In this study, via genome-wide methylation analysis in MCF-7/TamR cells we show that elongation of very-long chain fatty acid protein 2 (ELOVL2) was hypermethylated and downregulated in the samples from TamR breast cancer patients (n = 28) compared with those from Tam-sensitive (TamS) patients (n = 33) (P < 0.001). Strikingly, in addition to having tumor suppressor activity, ELOVL2 was shown to recover Tam sensitivity up to 70% in the MCF-7/TamR cells and in a xenograft mouse model. A group of genes in the AKT and ERa signaling pathways, e.g., THEM4, which play crucial roles in drug resistance, were found to be regulated by ELOVL2. This study implies that the deregulation of a gene in fatty acid metabolism can lead to drug resistance, giving insight into the development of a new therapeutic strategy for drug-resistant breast cancer.

Analysis of the tumor characteristics in young age breast cancer patients using collaborative stage data of the Korea Central Cancer Registry.

PURPOSE: This study aimed to evaluate tumor characteristics in young age (20-39 years old) breast cancer (YABC) patients in Korea. MATERIALS AND METHODS: We identified 10,897 breast cancer patients from 2010 to 2015. The data were collected through 10% systematic sampling of the Korea National Cancer Incidence Database (KNCI DB). Tumor size, lymph node status, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status were collected according to the Collaborative Stage version 2 (CSv2) Data Collection System. RESULTS: Of the 10,897 patients, 1245 (11.4%) were YABC patients. They were found to have larger tumors (T2: 41.6% in 20-39 age group vs 36.4% in 40-49 age group vs 36.5% in 50-59 age group vs 38.4% in ≥ 60 age group; T3: 10.1% vs 7.3% vs 6.5% vs 6.2%, P < .0001), greater rates of lymph node involvement (41.2% vs 32.7% vs 35.7% vs 32.5%, P < .0001), higher tumor grade (High grade: 26.8% vs 19.4% vs 23.5% vs 22.1%, P < .0001), and a larger proportion of triple-negative subtype (18.2% vs 11.0% vs 12.2% vs 13.5%, P < .0001). Compared to the 40-49 age group, breast cancer-related survival (BCRS) rates were worse (91.74% vs 95.04%, P < .0001), and the characteristics of YABC patients were associated with higher risk of death from breast cancer. CONCLUSION: YABC patients have more aggressive tumor characteristics and worse survival rates. Therefore, we need to identify high-risk groups among YABC patients and support active surveillance in them. These findings from a national cohort provide important information for establishing a national cancer care strategy to manage YABC patients.

Criteria for identifying residual tumours after neoadjuvant chemotherapy of breast cancers: a magnetic resonance imaging study.

We investigated magnetic resonance imaging (MRI) criteria identifying residual tumours in patients with triple-negative and human epidermal growth factor receptor type 2-positive (HER2+) breast cancer following neoadjuvant chemotherapy. Retrospectively, 290 patients were included who had undergone neoadjuvant chemotherapy and definitive surgery. Clinicopathological features, as well as lesion size and lesion-to-background parenchymal signal enhancement ratio (SER) in early- and late-phase MRIs, were analysed. Receiver operating characteristic (ROC) analyses evaluated diagnostic performances. Maximal MRI values showing over 90% sensitivity and negative predictive value (NPV) were set as cut-off points. Identified MRI criteria were prospectively applied to 13 patients with hormone receptor-negative (HR-) tumours. The lesion size in HR-HER2-tumours had the highest area under the ROC curve value (0.92), whereas this parameter in HR + HER2 + tumours was generally low (≤ 0.75). For HR-tumours, both sensitivity and NPV exceeded the 90% threshold for early size > 0.2 cm (HR-HER2-) or > 0.1 cm (HR-HER2 +), late size > 0.4 cm, and early SER > 1.3. In the prospective pilot cohort, the criteria size and early SER did not find false negative cases, but one case was false negative with late SER. Distinguishing residual tumours based on MRI is feasible in selected triple-negative and HER2 + breast cancer patients.

Sentinel Lymph Node Biopsy in Breast Cancer Patients With Pathological Complete Response in the Axillary Lymph Node After Neoadjuvant Chemotherapy.

PURPOSE: Sentinel lymph node biopsy (SLNB) alone following neoadjuvant chemotherapy (NAC) remains controversial in patients with breast cancer who are initially lymph node-positive. The present study aimed to evaluate the impact of SLNB and axillary lymph node dissection (ALND) on breast cancer recurrence and survival in patients who converted from lymph node-positive to pathological node-negative (ypN0) after NAC. METHODS: This single-center retrospective study included 223 patients who converted to axillary lymph node-negative status after NAC and underwent breast and axillary surgery between January 2006 and December 2015. This study compared the overall survival (OS), disease-free survival (DFS), ipsilateral axillary lymph node recurrence rates and incidence of postoperative complications, especially, arm lymphedema and shoulder stiffness between SLNB and ALND. RESULTS: This study included 223 patients with axillary pathological complete response (pCR) after NAC and surgery. The SLNB and ALND groups included 94 and 129 patients, respectively. The median follow-up time was 57 (range, 6-155) in the SLNB group and 99 (range 2-159) months in the ALND group. The corresponding 5-year OS and DFS rates were 96.3% and 94.2% (p = 0.392), and 89.2% and 86.4% (p = 0.671), respectively. Four patients (4.3%) in the SLNB group and nine (7.0%) in the ALND group developed locoregional recurrences. Ipsilateral axillary lymph node recurrence and distant metastasis were observed in one (1.1%) and three (2.3%) patients, and in 10 (10.6%) and 11 (8.5%) patients, respectively. Patients in the ALND group were more likely than their SLNB counterparts to experience complications, such as shoulder stiffness (9 [7.0%] vs. 4 [4.3%] patients, p = 0.57). The rate of lymphedema in the ALND group was three times that in the SLNB group (35 [27.1%] vs. 8 [8.5%] patients, p < 0.001). CONCLUSION: As an alternative to ALND, SLNB has oncological safety in patients with axillary pathological complete response after NAC.

Exon splicing analysis of intronic variants in multigene cancer panel testing for hereditary breast/ovarian cancer.

The use of multigene panel testing for patients with a predisposition to breast/ovarian cancer is increasing as the identification of variants is useful for diagnosis and disease management. We identified pathogenic and likely pathogenic (P/LP) variants of high-and moderate-risk genes using a 23-gene germline cancer panel in 518 patients with hereditary breast and ovarian cancers (HBOC). The frequency of P/LP variants was 12.4% (64/518) for high- and moderate-penetrant genes, namely, BRCA2 (5.6%), BRCA1 (3.3%), CHEK2 (1.2%), MUTYH (0.8%), PALB2 (0.8%), MLH1 (0.4%), ATM (0.4%), BRIP1 (0.4%), TP53 (0.2%), and PMS2 (0.2%). Five patients possessed two P/LP variants in BRCA1/2 and other genes. We also compared the results from in silico splicing predictive tools and exon splicing patterns from patient samples by analyzing RT-PCR product sequences in six P/LP intronic variants and two intronic variants of unknown significance (VUS). Altered transcriptional fragments were detected for P/LP intronic variants in BRCA1, BRIP1, CHEK2, PARB2, and PMS2. Notably, we identified an in-frame deletion of the BRCA1 C-terminal (BRCT) domain by exon skipping in BRCA1 c.5152+6T>C-as known VUS-indicating a risk for HBOC. Thus, exon splicing analysis can improve the identification of veiled intronic variants that would aid decision making and determination of hereditary cancer risk.

Role of aldehyde dehydrogenases, alcohol dehydrogenase 1B genotype, alcohol consumption, and their combination in breast cancer in East-Asian women.

The associations between genetic polymorphisms in ADH1B (rs1229984) and ALDH2 (rs671), alcohol consumption, the effect of a combination of the two polymorphisms, and breast cancer risk were studied in a population of East-Asian women. In this study, 623 breast cancer cases and 1845 controls, aged 40 or above, were included. The association between ALDH2 polymorphism and breast cancer risk was validated in 2143 breast cancer cases and 3977 controls. Alcohol consumption increased the risk of breast cancer regardless of ADH1B and ALDH2 genotypes. The rs671 polymorphism of ALDH2 was independently associated with increased breast cancer risk (OR = 1.27, 95% CI = 1.02-1.58 per increment of A). The ADH1B rs1229984 polymorphism, and combined effects of the rs671 and rs1229984 polymorphisms, did not reveal any significant association with breast cancer. Stratification by menopausal status revealed that rs671 gene polymorphisms were significantly associated with breast cancer only in postmenopausal women (OR = 1.45, 95% CI = 1.03-2.05 per increment of A). This is the first study to demonstrate an independent association between ALDH2 gene variants and breast cancer in Asian women. Further studies are warranted to further elucidate the etiology of breast cancer as it relates to alcohol consumption in Asian women.

Comparing the Characteristics and Outcomes of Male and Female Breast Cancer Patients in Korea: Korea Central Cancer Registry.

PURPOSE: This study aimed to determine the incidence of male breast cancer (MBC) and its survival outcomes in Korea, and to compare these results to those for female breast cancer (FBC). MATERIALS AND METHODS: We searched the Korea Central Cancer Registry and identified 227,122 breast cancer cases that were diagnosed between 1999 and 2016. Demographic and clinical characteristics and overall survival (OS) rates were estimated according to sex, age, histological type, and cancer stage. RESULTS: The 227,122 patients included 1,094 MBC cases and 226,028 FBC cases. Based on the age-standardized rate, the male: female ratio was 0.0055:1. The most common ages at diagnosis were 60-69 years for MBC and 40-49 years for FBC (p < 0.001). Male patients were less likely than female patients to receive adjuvant radiotherapy (7.5% vs. 21.8%, p < 0.001) or adjuvant chemotherapy (40.1% vs. 55.4%, p < 0.001). The 5-year OS rates after diagnosis were 88.8% for all patients, although it was significantly lower for MBC than for FBC (76.2% vs. 88.9%, p < 0.001). In both groups, older age (≥ 60 years) was associated with shorter survival. The 5-year OS rates for the invasive histological types were 75.8% for men and 89.0% for women. The 5-year OS rates in both groups decreased with increasing cancer stage. CONCLUSION: MBC was diagnosed at older ages than FBC, and male patients were less likely to receive radiotherapy and chemotherapy. The survival outcomes were worse for MBC than for FBC, with even poorer outcomes related to older age, the inflammatory histological types, and advanced stage. It is important that clinicians recognize the differences between FBC and MBC when treating these patients.

Comparison of clinical outcomes between sentinel lymph node biopsy and axillary lymph node dissection in a single-center Z0011-eligible breast cancer cohort.

Purpose: The ACOSOG Z0011 trial has proven the oncological safety of sentinel lymph node biopsy (SLBx) for node negative breast cancer. Accordingly, treatment paradigm including axilla surgery was changed. We retrospectively reviewed breast cancer patients to evaluate the clinical effect of paradigm shift in breast cancer surgery after applying the Z0011 criteria. Methods: All women who underwent breast-conserving surgery at the National Cancer Center between January 1, 2000, and December 31, 2015, were enrolled and classified according to the Z0011 criteria. The primary endpoint of the study was the disease-free survival rates, and the secondary was the adverse events, especially arm lymphedema. Results: Total 361 patients were enrolled the study (271 axillary lymph node dissection [ALND] group, 90 SLBx group). After the Z0011 guideline was adopted in our institute, the use of ALND decreased, and lymph node sampling (removing only a few axillary lymph nodes) replaced ALND. The total mean number of retrieved nodes were more in ALND group (13.02) than SLBx group (3.43). However, there was no difference in the mean number of positive nodes between two groups (2.34 in ALND group vs. 1.12 in SLBx group, P=0.001). During follow-up, 25 patients experienced disease recurrence: 22 from the ALND group and three from the SLBx group. All of died seven patients were from the ALND group. The ALND group had more complications than the SLBx group (P=0.02). Arm edema occurred more frequently in the ALND group (29.5%) than in the SLBx group (5.6%), although without statistical significance (P=0.07). Conclusion: In our study, we concluded that SLBx can be used safely in Z0011-eligible cohort without increased risk of locoregional recurrence. Moreover, we found that omission of ALND is favored to reduce some serious complications such as arm lymphedema.

The Sentinel Lymph Node Biopsy Using Indocyanine Green Fluorescence Plus Radioisotope Method Compared With the Radioisotope-Only Method for Breast Cancer Patients After Neoadjuvant Chemotherapy: A Prospective, Randomized, Open-Label, Single-Center Phase 2 Trial.

BACKGROUND: This study aimed to compare the sentinel lymph node (SLN) identification rates for breast cancer patients after neoadjuvant chemotherapy (NAC) between the dual method (DM) of indocyanine green fluorescence (ICG-F) plus a radioisotope (RI) and RI alone. METHODS: This randomized study enrolled 130 patients who received NAC for breast cancer and 122 patients who received SLN biopsy (SLNB) using either DM (n = 58) or RI only (n = 64). The study compared the identification rate, number of SLNs, and detection time of SLNB. RESULTS: Among the 122 patients, 113 (92.6%) were clinically node-positive before NAC. The SLN identification rate was 98.3% in the DM group and 93.8% in the RI group (p = 0.14). The DM group and the RI group were similar in the average number of SLNs (2.2 ± 1.13 vs. 1.9 ± 1.33; p = 0.26) and the time to detection of the first SLN (8.7 ± 4.98 vs. 8.3 ± 4.31 min; p = 0.30). In the DM group, transcutaneous lymphatic drainage was visualized by fluorescence imaging for 65.5% (38 of 58) of the patients. The SLN identification rate was 94.7% using ICG-F and 93% using RI (p = 0.79). During and after the operation, no complications, including allergic reactions or skin necrosis, occurred. CONCLUSIONS: This study is the first randomized trial to use ICG-F for SLNB in breast cancer patients after NAC. The DM including ICG-F could be a feasible and safe method for SLNB in initially node-positive breast cancer patients with NAC.

Interaction Effect Between Breast Density and Reproductive Factors on Breast Cancer Risk in Korean Population.

BACKGROUND: This study was conducted to explore the effect of known risk factors, focusing on risk factors including age at menarche, age at menopause, number of children, family history of breast cancer, and age at first birth according to breast density, in consideration of interaction among East-Asian women. METHODS: Case-control study with 2,123 cases and 2,121 controls with mammographic density was conducted. Using the mammographic film, breast density was measured using Breast Imaging-Reporting and Data System. To identify the association of selected reproductive factors including age at menarche, age at menopause, number of children, family history of breast cancer, and age at first birth according to breast density, stratified analysis was conducted according to breast density groups and interaction effects was assessed. The results were presented with adjusted OR and 95% CIs. RESULTS: Significant interaction effect between age at first birth and breast density on breast cancer (P = 0.048) was observed. Women with age at first birth ≥ 28 years old showed increased breast cancer risk in extremely dense breast group (≥ 75%) (OR = 1.627, 95% CI = 1.190-2.226). However, women with fatty breast (< 50%) and heterogeneously dense breast (50%-75%) did not show an increased association. Age at menarche, age at menopause, number of children, and family history of breast cancer did not show significant interaction with breast cancer and similar risk patterns were observed. CONCLUSIONS: Age at first birth showed significant interaction with breast density on breast cancer risk. Further studies considering biologically plausable model between exposure, intermediate outcomes and breast cancer risk with prospective design need to be undertaken in East Asian women.

Different Patterns of Risk Reducing Decisions in Affected or Unaffected BRCA Pathogenic Variant Carriers.

PURPOSE: The purpose of this study was to investigate decision patterns to reduce the risks of BRCArelated breast and gynecologic cancers in carriers of BRCA pathogenic variants. We found a change in risk-reducing (RR) management patterns after December 2012, when the National Health Insurance System (NHIS) of Korea began to pay for BRCA testing and riskreducing salpingo-oophorectomy (RRSO) in pathogenic-variant carriers. MATERIALS AND METHODS: The study group consisted of 992 patients, including 705 with breast cancer (BC), 23 with ovarian cancer (OC), 10 with both, and 254 relatives of high-risk patients who underwent BRCA testing at the National Cancer Center of Korea from January 2008 to December 2016.We analyzed patterns of and factors in RR management. RESULTS: Of the 992 patients, 220 (22.2%) were carriers of BRCA pathogenic variants. About 92.3% (203/220) had a family history of BC and/or OC,which significantly differed between BRCA1 and BRCA2 carriers (p < 0.001). All 41 male carriers chose surveillance. Of the 179 female carriers, 59 of the 83 carriers (71.1%) with BC and the 39 of 79 unaffected carriers (49.4%) underwent RR management. None of the carriers affected with OC underwent RR management. Of the management types, RRSO had the highest rate (42.5%) of patient choice. The rate of RR surgery was significantly higher after 2013 than before 2013 (46.3% [74/160] vs. 31.6% [6/19], p < 0.001). CONCLUSION: RRSO was the preferred management for carriers of BRCA pathogenic variants. The most important factors in treatment choice were NHIS reimbursement and/or the severity of illness.

Primary Malignant Melanoma of the Breast: A Report of Two Cases.

Primary malignant melanoma of the breast (PMMB) is a rare tumor with only a few case reports available in the literature. We report two cases of PMMB, one derived from the breast parenchyma and the other from the breast skin. The first case consisted of atypical epithelioid cells without overt melanocytic differentiation like melanin pigments. The tumor cells showed diffuse positivity for S100 protein, tyrosinase, and BRAF V600E. However, the tumor cells were negative for cytokeratin, epithelial membrane antigen, and HMB-45. The second case showed atypical melanocytic proliferation with heavy melanin pigmentation. The tumor cells were positive for S100 protein, HMB-45, tyrosinase, and BRAF V600E. These two cases represent two distinct presentations of PMMB in terms of skin involvement, melanin pigmentation, and HMB-45 positivity. Although PMMB is very rare, the possibility of this entity should be considered in malignant epithelioid neoplasms in the breast parenchyma.

Predicting Response to Neoadjuvant Chemotherapy in Patients With Breast Cancer: Combined Statistical Modeling Using Clinicopathological Factors and FDG PET/CT Texture Parameters.

PURPOSE: The aim of this study was to develop a combined statistical model using both clinicopathological factors and texture parameters from F-FDG PET/CT to predict responses to neoadjuvant chemotherapy in patients with breast cancer. MATERIALS AND METHODS: A total of 435 patients with breast cancer were retrospectively enrolled. Clinical and pathological data were obtained from electronic medical records. Texture parameters were extracted from pretreatment FDG PET/CT images. The end point was pathological complete response, defined as the absence of residual disease or the presence of residual ductal carcinoma in situ without residual lymph node metastasis. Multivariable logistic regression modeling was performed using clinicopathological factors and texture parameters as covariates. RESULTS: In the multivariable logistic regression model, various factors and parameters, including HER2, histological grade or Ki-67, gradient skewness, gradient kurtosis, contrast, difference variance, angular second moment, and inverse difference moment, were selected as significant prognostic variables. The predictive power of the multivariable logistic regression model incorporating both clinicopathological factors and texture parameters was significantly higher than that of a model with only clinicopathological factors (P = 0.0067). In subgroup analysis, texture parameters, including gradient skewness and gradient kurtosis, were selected as independent prognostic factors in the HER2-negative group. CONCLUSIONS: A combined statistical model was successfully generated using both clinicopathological factors and texture parameters to predict the response to neoadjuvant chemotherapy. Results suggest that addition of texture parameters from FDG PET/CT can provide more information regarding treatment response prediction compared with clinicopathological factors alone.

Prognostic impact of skeletal muscle volume derived from cross-sectional computed tomography images in breast cancer.

PURPOSE: This study aimed to determine whether the prognosis of breast cancer is affected by muscle or fat volume as measured from computed tomography (CT) images. METHODS: We identified 1460 patients with chest CT who were diagnosed as having breast cancer at the National Cancer Center, Korea, between January 2001 and December 2009. Using CT images of 10-mm slices, we measured the cross-sectional areas of skeletal muscle and adipose tissue at the 3rd lumbar vertebrae, and derived their volumes. The skeletal muscle volume, fat volume, and muscle-to-fat ratio were evaluated for association with overall survival (OS) and recurrence-free survival (RFS). RESULTS: The median skeletal muscle and fat volumes among the patients were 93.3 cc (range 39.6-236.9) and 420.1 cc (range 19.5-1392.3), respectively. Patients with higher muscle volume had better prognosis than those with lower muscle volume [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.34-0.92, P = 0.022 for OS; HR 0.72, 95% CI 0.52-0.99, P = 0.046 for RFS]. However, body mass index (BMI) and fat volume were not associated with prognosis. In addition, muscle volume was a significant prognosticator for OS, regardless of BMI (HR 0.55, 95% CI 0.32-0.93, P = 0.034 in BMI < 25.0; HR 0.44, 95% CI 0.21-0.91, P = 0.026 in BMI ≥ 25.0). Among older patients (≥ 50), those with higher muscle volume showed better OS and RFS (HR 0.44, 95% CI 0.23-0.85, P = 0.015; HR 0.55, 95% CI 0.34-0.90, P = 0.017, respectively). CONCLUSION: This study demonstrated that breast cancer patients with higher skeletal muscle volume showed more favorable prognosis.