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.

Five-Year Overall Survival of Interval Breast Cancers is Better than Non- Interval Cancers from Korean Breast Cancer Registry.

Objective: Interval breast cancer (IC) is a limitation of breast cancer screening. We investigated data from a large scaled breast cancer dataset of patients with breast cancer who underwent breast cancer screening in order to recapitulate the overall survival (OS) of patients with ICs compared to those with non-ICs. Methods: A total of 27,141 patients in the Korean breast cancer registry with breast cancer who had ever participated in biannual national breast cancer screening programs between 2009 and 2013 were enrolled. We compared the social, pregnancy-associated, and pathologic characteristics between the IC and non-IC groups and identified the significant prognostic factors for OS. Results: The proportion of ICs was 1.3% (370/27,141) in this study population. ICs were correlated with age 45-55 years at diagnosis, higher levels of education, early menopause (<50 years), hormone replacement therapy, specific provinces (Kangwon, Kyungnam, Jeju, and Dae-jeon), and family history of breast cancer. Low-to-intermediate nuclear grade, early stage (stage 0-I), and low Ki-67 level were also correlated with IC proportion. Non-ICs were associated with an increased risk of five-year mortality (hazard ratio [HR] 7.4; 95% confidence interval [CI]:1.85-29.66; p = 0.005) compared to ICs. Lymph node metastasis, residence (Kyung-nam province), low education status, high histologic grade, and asymptomatic cancers increased the HR of five-year OS. Conclusion: ICs occurred unequally in specific province and relatively high-educated women in Korea. They were also diagnosed with early-stage breast cancer with a favorable recurrence risk, and their outcome was better than those of patients with other breast cancers in breast cancer screening.

T-Cell Immunoglobulin Mucin 3 Expression on Tumor Infiltrating Lymphocytes as a Positive Prognosticator in Triple-Negative Breast Cancer.

PURPOSE: T-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) is an emerging immune response molecule related to T-cell anergy. There has been tremendous interest in breast cancer targeting immune checkpoint molecules, especially in the triple-negative breast cancer (TNBC). This study was designed to investigate TIM-3 expression on tumor infiltrating lymphocytes (TILs), its relationships with clinicopathological para-meters and expression of programmed death receptor 1 (PD-1)/programmed death receptor ligand 1 (PD-L1), and its prognostic role. METHODS: Immunohistochemistry on tissue microarray blocks produced from 109 samples of invasive ductal carcinoma type TNBC was performed with antibodies toward TIM-3, PD-1, PD-L1 and breast cancer-related molecular markers. Associations between their expression and clinicopathological parameters as well as survival analyses were performed. RESULTS: TIM-3 was expressed in TILs from all 109 TNBCs, consisting of 17 cases (<5%), 31 cases (6%-25%), 48 cases (26%-50%), and 13 cases (>51%). High TIM-3 was significantly correlated with younger patients (p=0.0101), high TILs (p=0.0029), high tumor stage (p=0.0018), high PD-1 (p=0.0001) and high PD-L1 (p=0.0019), and tended to be associated with higher histologic grade, absence of extensive in situ components and microcalcification. High TIM-3 expression was significantly associated with a combinational immunophenotype group of high PD-L1 and high PD-1 (p<0.0001). High TIM-3 demonstrated a significantly better disease-free survival (DFS) (p<0.0001) and longer overall survival (OS) (p=0.0001), together with high TILs and high PD-1. In univariate survival analysis, high TIM-3 showed reduced relapse risk (p<0.0001) and longer OS (p=0.0003), together with high PD-1 expression. In multivariate analysis, high TIM-3 was statistically significant in predicting prognosis, showing better DFS (hazard ratio [HR], 0.0994; 95% confidence interval [CI], 0.0296-0.3337; p=0.0002) and longer OS (HR, 0.1109; 95% CI, 0.0314-0.3912; p=0.0006). CONCLUSION: In this study, we demonstrate that TIM-3 expression is an independent positive prognostic factor in TNBC, despite its association with poor clinical and pathologic features.

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

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

The role of the addition of ovarian suppression to tamoxifen in young women with hormone-sensitive breast cancer who remain premenopausal or regain menstruation after chemotherapy (ASTRRA): study protocol for a randomized controlled trial and progress.

BACKGROUND: Ovarian function suppression (OFS) has been shown to be effective as adjuvant endocrine therapy in premenopausal women with hormone receptor-positive breast cancer. However, it is currently unclear if addition of OFS to standard tamoxifen therapy after completion of adjuvant chemotherapy results in a survival benefit. In 2008, the Korean Breast Cancer Society Study Group initiated the ASTRRA randomized phase III trial to evaluate the efficacy of OFS in addition to standard tamoxifen treatment in hormone receptor-positive breast cancer patients who remain or regain premenopausal status after chemotherapy. METHODS: Premenopausal women with estrogen receptor-positive breast cancer treated with definitive surgery were enrolled after completion of neoadjuvant or adjuvant chemotherapy. Ovarian function was assessed at the time of enrollment and every 6 months for 2 years by follicular-stimulating hormone levels and bleeding history. If ovarian function was confirmed as premenopausal status, the patient was randomized to receive 2 years of goserelin plus 5 years of tamoxifen treatment or 5 years of tamoxifen alone. The primary end point will be the comparison of the 5-year disease-free survival rates between the OFS and tamoxifen alone groups. Patient recruitment was finished on March 2014 with the inclusion of a total of 1483 patients. The interim analysis will be performed at the time of the observation of the 187th event. DISCUSSION: This study will provide evidence of the benefit of OFS plus tamoxifen compared with tamoxifen only in premenopausal patients with estrogen receptor-positive breast cancer treated with chemotherapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00912548 . Registered May 31 2009. Korean Breast Cancer Society Study Group Register KBCSG005 . Registered October 26 2009.

Malignant Adenomyoepithelioma of the Breast and Responsiveness to Eribulin.

Adenomyoepithelioma (AME) of the breast is an uncommon tumor characterized by its dual differentiation into luminal cells and myoepithelial cells. In most cases these tumors have a benign clinical course, but distant metastases have been reported. We present the case of a 51-year-old woman diagnosed with malignant AME. The patient underwent a right modified radical mastectomy, and pathological examination confirmed the diagnosis of malignant AME. Ten months after the operation, multiple hepatic, pleural, and abdominal wall metastases were detected. A number of palliative chemotherapeutic agents were tried, including anthracycline and taxanes. However, the disease continued to progress, and superior vena cava syndrome developed as a result of direct tumor invasion. The patient received salvage eribulin monotherapy. After two cycles of this treatment, her clinical symptoms were ameliorated, and a computed tomography scan showed a partial response. Eribulin chemotherapy was thus effective in treating malignant AME in this case.

Treatment and survival of patients with occult breast cancer with axillary lymph node metastasis: a nationwide retrospective study.

BACKGROUND AND OBJECTIVES: Occult breast cancer (OBC) accounts for 0.3-1.0% of all breast cancers and is a rare presentation of the disease. The present retrospective study examined the overall survival and prognostic factors associated with OBC in Korea. METHOD: The study included 142 OBC patients identified from the Korean Breast Cancer Society cancer registry from January 1990 to December 2009. All patients had pathologically positive axillary lymph nodes (N1-N3) and pathologically and radiologically negative in-breast lesions (T0/Tx) based on a retrospective review of the database. RESULTS: No statistically significant differences in overall survival were observed between patients undergoing axillary lymph node dissection (ALND) only (80.8%), breast conserving surgery (BCS) with ALND (98.0%), and mastectomy with ALND (92.5%) with P-value of 0.061. Nodal status was a significant prognostic factor (P = 0.004) on univariate analysis. When compared with T1 patients group, T0/TxN1 patients showed better survival than T1N1 patients (hazard ratio [HR] 0.253; 95% confidence interval, 0.104-0.618; P = 0.003), but T0/TxN2, T0/TxN3 patients showed similar survival to T1N2, T1N3 patients. CONCLUSIONS: OBC patients treated with ALND only showed comparable outcomes to those undergoing ALND combined with BCS or mastectomy. Nodal status may be an independent predictor of poor outcome in OBC patients.

US screening for detection of nonpalpable locoregional recurrence after mastectomy.

PURPOSE: To assess the value of screening ultrasonography (US) in the detection of nonpalpable locoregional recurrence following mastectomy for breast cancer and to describe the US appearances of occult recurrent cancers. MATERIALS AND METHODS: During a 36-month period, 1180 consecutive US screenings were performed for mastectomy sites and ipsilateral axillary fossae in 468 asymptomatic women who had undergone mastectomy for breast cancer. All US results were divided into three groups: negative findings, probably benign nodules, and suspicious for malignant nodules. The final diagnoses were based on pathology results and clinical or sonographic follow-up for more than 12 months. The diagnostic performance of US for detecting nonpalpable locoregional recurrence was assessed. The US appearances of occult recurrent cancers were retrospectively reviewed. RESULTS: Of the 468 patients assessed, 19 (4.1%) showed "suspicious for malignant nodules"; of these lesions, 10 were malignant. One false-negative case was identified. The sensitivity and specificity were 90.9% and 98.0%, respectively. A biopsy positive predictive value of 52.6% was observed. Cancer detection rates were 2.1% with US screenings of mastectomy sites and ipsilateral axillary fossae. The common US features of occult recurrences at the mastectomy sites were irregular shaped, not-circumscribed marginated, and hypoechoic masses with intratumoral vascularities. The most common location was within the deep muscle layer. CONCLUSION: Although locoregional recurrence infrequently occurs after mastectomy for breast cancer, screening US enables detection of nonpalpable cancer before it can be detected by clinical examination. Routine follow-up US can be advocated for early detection of nonpalpable locoregional recurrent cancer.

Reliability of reconstructed breast flap after chemotherapy and radiotherapy in immediate breast reconstruction.

BACKGROUND: Postmastectomy adjuvant therapy is used to prevent locoregional recurrence and improve overall breast cancer specific survival rates. However, it can adversely affect the cosmetic results of reconstruction. Therefore, the authors examined flap stability and patients' satisfaction with immediate breast reconstruction after adjuvant therapy. METHODS: We retrospectively reviewed the medical records of 204 patients from January 2006 to November 2011. For complication rates, the authors categorized the patients who underwent the immediate breast reconstruction into 4 groups: adjuvant chemotherapy and radiotherapy group, adjuvant chemotherapy only group, adjuvant radiotherapy only group, and the group that did not undergo adjuvant therapy. For comparison of patients' satisfaction, the study was performed with an additional 16 patients who had undergone delayed breast reconstruction. RESULTS: Regarding complication rates, the group that had undergone adjuvant therapy showed no significant difference compared to the group that did not undergo adjuvant therapy. In evaluating the patients' satisfaction, there was no significant difference. CONCLUSIONS: Even after adjuvant therapy, immediate breast reconstruction showed good results with respect to flap stability and patients' satisfaction. Immediate breast reconstruction and adjuvant therapy is a safe and useful option for breast cancer patients.

Quantitative DNA methylation and recurrence of breast cancer: a study of 30 candidate genes.

BACKGROUND: The need for new prognostic factors in breast cancer is ever increasing as breast cancer management evolves. Aberrant DNA methylation plays a pivotal role in cancer development and progression; DNA methylation-based biomarkers may provide independent prognostic information. We used pyrosequencing to investigate the prognostic potential of quantitative DNA methylation of a large set of candidate genes in a Korean single-institution series of operable breast cancer. METHODS: Absolute DNA methylation in 20 candidate genes from an initial set of 30 genes was measured by pyrosequencing of bisulfite converted DNA in 121 fresh frozen breast cancer cases. Survival analyses used continuous and categorized (quintile-based) gene methylation data with time to recurrence (TTR) as an endpoint. Prognostic abilities of gene-only and risk-score models were explored. RESULTS: Median follow-up was 5.1 years; 25 recurrences (21%) were observed. Nodal status, methylation of TWIST1, SLIT2 (both as continuous and categorized variables) and APC, HLA-A, NKX2-5, SERPINB5, SFN (as categorized variables) were significantly prognostic; grade showed a prognostic trend. A multivariate model containing nodal status, grade and TWIST1 was a best fit (p< 0.001) in stepwise regression; risk-score based on this model separated patients into 3 distinct risk-groups (p< 0.001). A gene-only model based on TWIST1 and SFN also classified patients into distinct risk-groups (p=0.009). CONCLUSIONS: This study shows that accurate quantitative measurement of DNA methylation by pyrosequencing identifies a small set of genes with independent prognostic potential in breast cancer. These genes complement the current clinico-pathological prognostic factors and appear to be potential biomarkers that warrant further validation.

Application of an endo-GIA for ligation of the cystic duct during difficult laparoscopic cholecystectomy.

BACKGROUND/AIMS: Laparoscopic cholecystectomy has become the gold standard modality for treating gallbladder disease. There are many techniques for the ligation of a dilated and inflamed cystic duct. The aim of this study is to assess the efficacy and applicability of an Endo-GIA for dilated cystic duct ligation. METHODOLOGY: From October 1992 to September 2009, 3413 patients underwent laparoscopic cholecystectomy for gallbladder disease at the Dong-A Medical Center, and 92 (2.7%) patients' cystic ducts were ligated by an Endo-GIA. We retrospectively analyzed these 92 cases. RESULTS: The cystic ducts were successfully ligated with an Endo-GIA in 88 patients. Four patients required conversion to open surgery. The mean operation time was 111.9 minutes. The mean length of the hospital stay was 4.1 days. Postoperative complication occurred in 16 patients (17%). The follow-up period ranged from 0.5 to 75 months. CONCLUSIONS: Endo-GIA is safe and feasible. Postoperative complication occurred in 16 patients after application of an Endo-GIA. However, those complications were successfully managed by conservative treatment. The rate of complications was comparable to the best results from most of the large series in the West. Therefore, using an Endo-GIA could be attempted in carefully selected patients with difficult cases of laparoscopic cholecystectomy.

Susceptibility for breast cancer in young patients with short rare minisatellite alleles of BORIS.

In this study, we characterized two blocks of minisatellites in the 5' upstream region of the BORIS gene (BORIS-MS1, -MS2). BORIS-MS2 was found to be polymorphic; therefore, this locus could be useful as a marker for DNA fingerprinting. We assessed the association between BORIS-MS2 and breast cancer by a case-control study with 428 controls and 793 breast cancers cases. Rare alleles in the younger group (age, <40) were associated with a statistically significant increased risk of breast cancer (odds ratio, 4.84; 95% confidence interval, 1.06-22.22; and P = 0.026). A statistically significant association between the short rare alleles and cancer was identified in the younger group (8.02; 1.01-63.83; P = 0.021). Kaplan-Meier estimates showed that poor prognosis was associated with patients who contained the rare alleles. Our data suggest that the short rare alleles of BORIS-MS2 could be used to identify the risk for breast cancer in young patients.

Clinical outcomes and breast cancer subtypes in patients with brain metastases.

BACKGROUND: The principal objective of this study was to assess clinical outcomes by breast cancer subtype in patients with brain metastases. METHODS: Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status was evaluated via immunohistochemical staining. Four survival time intervals were compared according to the subtype (ER+/HER2-, HER2+, triple negative (TN)). RESULTS: 20 (30.3%) of the 66 patients in this study were ER+/HER2-, 20 (30.3%) were HER2+, and 26 (39.4%) were TN. The disease-free survival rates of ER+/HER2-, HER2+, and TN patients were 30.0, 17.0, and 17.9 months, respectively (p = 0.040). The median time intervals from distant metastasis to brain metastasis were 20.6, 19.5, and 9.0 months, respectively (p = 0.012). The times from initial diagnosis to brain metastasis were 52.9, 33.6, and 25.5 months, respectively (p = 0.026). However, the overall survival rates did not differ significantly (p = 0.276). CONCLUSIONS: Patients with TN breast cancer were more likely to develop distant metastasis earlier, and also evidenced poor overall survival. Triple receptor status may be employed as a prognostic marker for breast cancer patients with brain metastases.

Metaplastic breast carcinoma with extensive osseous differentiation: a case report.

We present a case of a 77-year-old female who had a metaplastic breast carcinoma with extensive osseous differentiation. Her mammogram showed a largely calcified mass, but the pathology revealed that the calcification was ossification. The radiologic differentiation between an osteoid matrix and a dense calcification is discussed. Radiologic and pathologic correlation is also provided.

Sutureless intestinal anastomosis with the biofragmentable anastomosis ring: experience of 632 anastomoses in a single institute.

PURPOSE: Uncertainty with the safety of the biofragmentable anastomosis ring makes surgeons hesitate in its widespread use in intestinal surgery. This study was designed to evaluate the validity of the biofragmentable anastomosis ring as a routine anastomotic device in enterocolic surgery. METHODS: The study analyzed the nine-year experience of 632 biofragmentable anastomosis ring anastomoses performed in 617 patients: 525 (83 percent) as elective procedures and 107 (17 percent) as emergency. Three classic types of anastomosis, end-to-end (n=354), end-to-side (n=263), and side-to-side (n=15), were performed with a standard technique. RESULTS: Anastomotic sites included ileocolic/ileorectal in 283 patients (45 percent), colorectal in 148 (23 percent), enteroenteric in 101 (16 percent), and colocolic in 100 patients (16 percent). Anastomotic leakage with clinical relevance was observed in five patients (0.8 percent): three elective cases, and two emergency (2 colorectal anastomoses and 1 ileorectal required diversions). Among 13 instances (2.1 percent) with postoperative intestinal obstruction, only 1 required relaparotomy for closed-loop obstruction. Seven patients (1.1 percent; 4 elective cases, and 3 emergency) died postoperatively; no deaths were directly related to the biofragmentable anastomosis ring technique. CONCLUSIONS: Our data suggest that the anastomosis using the biofragmentable anastomosis ring is a uniform and highly reliable technique even in high-risk emergency surgery. Along with its clinical validities, clinical application of the biofragmentable anastomosis ring in different types of anastomoses in enterocolic surgery is expected to be expanded with a high level of technical safety.

Gene expression profiling of breast cancers with emphasis of beta-catenin regulation.

To gain molecular understanding of carcinogenesis of breast cancer, gene expression profiles were analyzed using cDNA microarray representing 4,600 cDNAs in 10 breast cancer samples and the adjacent noncancerous breast tissues from the same patients. The alterations in gene expression levels were confirmed by reversetranscription PCR in four randomly selected genes. Genes that were differently expressed in cancer and noncancerous tissues were identified. 106 (of which 55 were known) and 49 (of which 28 were known) genes were up- or down-regulated, respectively, in greater than 60% of the breast cancer samples. In cancer tissues, genes related to cell cycle, transcription, metabolism, cell structure/motility and signal transduction were mostly up-regulated. Furthermore, three cancer tissues showing immunohistochemically aberrant accumulation of beta-catenin in the nucleus and/or cytoplasm revealed down-regulation of Siah and Axin genes and up-regulation of Wnt and c-myc genes. These findings were highly consistent with Wnt signaling pathway associated with beta-catenin regulation previously suggested by others. Our studies, therefore, provide not only a molecular basis to understand biological processes of breast cancer but also useful resources to define the mechanism of beta-catenin expression in tumorigenesis of breast cancer.