Identifying Long-Term Survival Candidates among Patients with Isolated Locoregionally Recurrent Breast Cancer: Implications of the Use of Systemic Chemotherapy / 한국유방암학회지

Purpose@#We aimed to investigate the clinicopathologic factors associated with distant metastasis (DM) and post-recurrence overall survival (OS) after salvage treatments for isolated locoregional recurrence (ILRR) of breast cancer and identify long-term surviving patients for providing a more personalized therapy. @*Methods@#We analyzed 125 patients who underwent salvage local treatments for ILRR after initial curative breast surgery. @*Results@#Fifty-two (41.6%) patients experienced secondary recurrence or disease progression, of which 20 (38.5%) experienced a secondary locoregional recurrence and 40 (76.9%) experienced DM as the first site of failure. In multivariate analysis of distant metastasis free survival (DMFS) and post-recurrence OS, the initial pN2-3 stage, a disease-free interval of < 36 months, and non-curative resection for recurrent disease were independently poor prognosticators. The score for patients stratified according to the number of risk factors increased from 0 to 3; the corresponding 5-year DMFS rates were 91.4%, 53.0%, 35.9%, and 0% and the 5-year OS rates were 97.3%, 70.4%, 32.7%, and 25.0%, respectively (p < 0.001).Systemic chemotherapy reduced DM in patients with a score of 2–3, but it did not in those with a score of 0-1. @*Conclusion@#Our collective stratification can help with prognosis prediction for ILRR of breast cancer. Depending on the DM risk of patients, the potential combination of systemic therapy should be discussed further.

Metachronous Sporadic Sextuple Primary Malignancies Including Bilateral Breast Cancers / 한국유방암학회지

Multiple primary malignancies are defined as the presence of more than one malignant neoplasm with a distinct histology occurring at different sites in the same individual. They are classified as synchronous or metachronous according to the diagnostic time interval of different malignancies. Diagnosis of multiple primary malignancies should avoid misclassification from multifocal/multicentric tumors or recurrent/metastatic lesions.In multiple primary malignancies, with increase in the number of primary tumors, the frequency rapidly decreases. Here, we report an exceptionally rare case of a woman who was diagnosed with metachronous sporadic sextuple primary malignancies including bilateral breast cancers (gastric cancer, ovarian Sertoli-Leydig cell tumor, left breast cancer, thyroid cancer, right breast cancer, and rectal neuroendocrine tumor). The sextuple primary malignancies in this case involved 5 different organs: the stomach, ovary, thyroid, rectum, and bilateral breasts. Further studies are needed to elucidate the current epidemiologic status of patients with multiple primary malignancies.

Metachronous Sporadic Sextuple Primary Malignancies Including Bilateral Breast Cancers / 한국유방암학회지

Multiple primary malignancies are defined as the presence of more than one malignant neoplasm with a distinct histology occurring at different sites in the same individual. They are classified as synchronous or metachronous according to the diagnostic time interval of different malignancies. Diagnosis of multiple primary malignancies should avoid misclassification from multifocal/multicentric tumors or recurrent/metastatic lesions.In multiple primary malignancies, with increase in the number of primary tumors, the frequency rapidly decreases. Here, we report an exceptionally rare case of a woman who was diagnosed with metachronous sporadic sextuple primary malignancies including bilateral breast cancers (gastric cancer, ovarian Sertoli-Leydig cell tumor, left breast cancer, thyroid cancer, right breast cancer, and rectal neuroendocrine tumor). The sextuple primary malignancies in this case involved 5 different organs: the stomach, ovary, thyroid, rectum, and bilateral breasts. Further studies are needed to elucidate the current epidemiologic status of patients with multiple primary malignancies.

Prognostic influence of Korean public medical insurance system on breast cancer patients

PURPOSE: To investigate the prognostic influence of Korean public medical insurance system on breast cancer patients. METHODS: Data of 1,068 patients with primary invasive breast cancer were analyzed. Korean public medical insurance status was classified into 2 groups: National Health Insurance and Medical Aid. Kaplan-Meier estimator and Cox proportional hazards model were used for survival analysis. RESULTS: The Medical Aid group showed worse prognoses compared to the National Health Insurance group both in overall survival (P = 0.001) and recurrence-free survival (P = 0.006). The Medical Aid group showed higher proportion of patients with tumor size > 2 cm (P = 0.022), more advanced stage (P = 0.039), age > 50 years (P = 0.003), and low education level (P = 0.003). The Medical Aid group showed higher proportion of patients who received mastectomy (P < 0.001) and those who received no radiation therapy (P = 0.013). The Medical Aid group showed a higher rate of distant recurrence (P = 0.014) and worse prognosis for the triple negative subtype (P = 0.006). Medical insurance status was a significant independent prognostic factor in both univariate analysis and multivariate analysis. CONCLUSION: The Medical Aid group had worse prognosis compared to the National Health Insurance group. Medical insurance status was a strong independent prognostic factor in breast cancer. Unfavorable clinicopathologic features could explain the worse prognosis for the Medical Aid group. Careful consideration should be given to medical insurance status as one of important prognostic factors for breast cancer patients.

Prognostic Role of KRAS mRNA Expression in Breast Cancer / 한국유방암학회지

Breast Sparganosis Presenting with a Painless Breast Lump: Report of Two Cases

Sparganosis is a parasitic infestation caused by sparganum, a plerocercoid tapeworm larva of the genus Spirometra. Since the first case of human sparganosis reported in 1908, sparganosis has been a global disease, and is common in China, Japan, and Southeast Asian countries. Consumption of raw snakes, frogs, fish, or drinking contaminated beverages are sources of human infections. Human sparganosis usually manifests in subcutaneous fat in areas such as the abdomen, genitourinary tract, and limbs. Breast sparganosis cases are rare, representing less than 2% of total cases of human infections. Complete surgical extraction of the sparganum is the treatment of choice. Because of the rarity of the disease, clinical suspicion is vital to reach the diagnosis of breast sparganosis. Here we report 2 rare cases of breast sparganosis presenting with a painless breast lump, both treated with surgical excision and sparganum extraction.

ABT-737 ameliorates docetaxel resistance in triple negative breast cancer cell line

PURPOSE: This study aimed to validate the synergistic effect of ABT-737 on docetaxel using MDA-MB-231, a triple negative breast cancer (TNBC) cell line overexpressing B-cell lymphoma-2 (Bcl-2). METHODS: Western blot analysis was performed to assess expression levels of Bcl-2 family proteins and caspase-related molecules. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell cycle distribution was determined by flow cytometry analysis. Benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (z-VAD-fmk) was used for pretreatment to assess the role of caspases. RESULTS: Cell viability of MDA-MB-231 after combination treatment with ABT-737 and docetaxel was significantly lower than that after docetaxel or ABT-737 monotherapy based on MTT assay (both P < 0.001), with a combination index of 0.41. The proportion of sub-G1 population after combination treatment was significantly higher than that after docetaxel or ABT-737 monotherapy (P = 0.001, P = 0.003, respectively). Pretreatment with z-VAD-fmk completely restored cell viability of MDA-MB-231 from apoptotic cell death induced by combination therapy (P = 0.001). Although pro-caspase-8 or Bid did not show significant change in expression level, pro-casepase-9 showed significantly decreased expression after combination treatment. Cleaved caspase-3 showed increased expression while poly (ADP-ribose) polymerase cleavage was induced after combination treatment. However, hypoxia-inducible factor 1-alpha and aldehyde dehydrogenase 1 totally lost their expression after combination treatment. CONCLUSION: Combination of ABT-737 with docetaxel elicits synergistic therapeutic effect on MDA-MB-231, a TNBC cell line overexpressing Bcl-2, mainly by activating the intrinsic pathway of apoptosis. Therefore, adjunct of ABT-737 to docetaxel might be a new therapeutic option to overcome docetaxel resistance of TNBCs overexpressing Bcl-2.

Prognostic influence of 3-dimensional tumor volume on breast cancer compared to conventional 1-dimensional tumor size

PURPOSE: The prognostic influence of 3-dimensional tumor volume (Tv) on breast cancer compared to conventional 1-dimensional tumor size (T) was investigated. METHODS: Analysis was performed on a cohort of 8,996 primary breast cancer patients who were initially diagnosed with TNM stage I–III. Tumor size was defined as the maximum tumor dimension, and Tv was calculated by the equation of (4π× r1 × r2 × r3)/3; r1, r2, and r3 were defined as half of the largest, intermediate, and shortest dimension of the tumor, respectively. Tv was classified into Tv1, Tv2, and Tv3 according to the cut off values of 2.056 cm3 and 20.733 cm3. RESULTS: The survival curves according to both the T and Tv categories were clearly differentiated (all P < 0.001), as were those for staging by T and Tv (all P < 0.001). In T1 and T2 tumors, the Tv1 group showed superior survival over the Tv2 group (T1, P < 0.001; T2, P = 0.001). Univariate and multivariate analysis both indicated that Tv was a significant prognostic factor (both P < 0.001). The receiver operating characteristic curve showed that the area under the curves were 0.712 (P < 0.001) for Tv and 0.699 (P < 0.001) for T. Positive correlations were observed between the number of positive nodes and T (coefficient = 0.325; P < 0.001), and between the number of positive nodes and Tv (coefficient = 0.321; P < 0.001). CONCLUSION: Tv classification works well for predicting the prognosis of breast cancer, and it is a better predictor than conventional T classification in several aspects. Further studies are needed to validate the practical usefulness of Tv classification in clinical settings.

Prognostic Influence of Preoperative Fibrinogen to Albumin Ratio for Breast Cancer / 한국유방암학회지

PURPOSE: Elevated serum concentration of fibrinogen and decreased serum concentration of albumin have been reported to be markers of elevated systemic inflammation. We attempted to investigate the prognostic influence of preoperative fibrinogen to albumin ratio (FAR) for breast cancer. METHODS: Data from 793 consecutive primary breast cancer patients were retrospectively analyzed. Serum levels of fibrinogen and albumin were tested before curative surgery. Subjects were grouped into two groups according to the cutoff value determined by performing the receiver operating characteristic curve analysis: the high FAR group (FAR>7.1) and the low FAR group (FAR≤7.1). Overall survival was assessed using the Kaplan-Meier estimator. Independent prognostic significance was analyzed using the Cox proportional hazards model. RESULTS: The high FAR group had a worse prognosis compared to the low FAR group (log-rank test, p<0.001). The prognostic effect of FAR was more significant than that of single markers such as fibrinogen (log-rank test, p=0.001) or albumin (log-rank test, p=0.001). The prognostic effect of FAR was prominent in the stage II/III subgroup (log-rank test, p<0.001) and luminal A-like subtype (log-rank test, p<0.001). FAR was identified as a significant independent factor on both univariate (hazard ratio [HR], 2.722; 95% confidence interval [CI], 1.659–4.468; p<0.001) and multivariate analysis (HR, 2.622; 95% CI, 1.455–4.724; p=0.001). CONCLUSION: Preoperative FAR was a strong independent prognostic factor in breast cancer. Its prognostic effect was more prominent in the stage II/III subgroup and in the luminal A-like subtype. Therefore, preoperative FAR can be utilized as a useful prognosticator for breast cancer patients. Further studies are needed to validate its applications in clinical settings.

Can We Skip Intraoperative Evaluation of Sentinel Lymph Nodes? Nomogram Predicting Involvement of Three or More Axillary Lymph Nodes before Breast Cancer Surgery / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The American College of Surgeons Oncology Group Z0011 trial reported that complete dissection of axillary lymph nodes (ALNs) may not be warranted in women with clinical T1-T2 tumors and one or two involved ALNs who were undergoing lumpectomy plus radiation followed by systemic therapy. The present study was conducted to identify preoperative imaging predictors of ≥ 3 ALNs. MATERIALS AND METHODS: The training set consisted of 1,917 patients with clinical T1-T2 and node negative invasive breast cancer. Factors associated with ≥ 3 involved ALNs were evaluated by logistic regression analysis. The validation set consisted of 378 independent patients. The nomogram was applied prospectively to 512 patients who met the Z0011 criteria. RESULTS: Of the 1,917 patients, 204 (10.6%) had ≥ 3 positive nodes. Multivariate analysis showed that involvement of ≥ 3 nodes was significantly associated with ultrasonographic and chest computed tomography findings of suspicious ALNs (p < 0.001 each). These two imaging criteria, plus patient age, were used to develop a nomogram calculating the probability of involvement of ≥ 3 ALNs. The areas under the receiver operating characteristic curve of the nomogram were 0.852 (95% confidence interval [CI], 0.820 to 0.883) for the training set and 0.896 (95% CI, 0.836 to 0.957) for the validation set. Prospective application of the nomogram showed that 60 of 512 patients (11.7%) had scores above the cut-off. Application of the nomogram reduced operation time and cost, with a very low re-operation rate (1.6%). CONCLUSION: Patients likely to have ≥ 3 positive ALNs could be identified by preoperative imaging. The nomogram was helpful in selective intraoperative examination of sentinel lymph nodes.

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 / Journal of the Korean Cancer Association, 대한암학회지

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 ( 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.

Unexpected Appendiceal Pathologies and Their Changes With the Expanding Use of Preoperative Imaging Studies

PURPOSE: The preoperative diagnosis of acute appendicitis is often challenging. Sometimes, pathologic results of the appendix embarrass or confuse surgeons. Therefore, more and more imaging studies are being performed to increase the accuracy of appendicitis diagnoses preoperatively. However, data on the effect of this increase in preoperative imaging studies on diagnostic accuracy are limited. We performed this study to explore unexpected appendiceal pathologies and to delineate the role of preoperative imaging studies in the diagnosis of acute appendicitis. METHODS: The medical records of 4,673 patients who underwent an appendectomy for assumed appendicitis between 1997 and 2012 were reviewed retrospectively. Pathological results and preoperative imaging studies were surveyed, and the frequencies of pathological results and preoperative imaging studies were investigated. RESULTS: The overall rate of pathology compatible with acute appendicitis was 84.4%. Unexpected pathological findings, such as normal histology, specific inflammations other than acute appendicitis, neoplastic lesions, and other pathologies, comprised 9.6%, 3.3%, 1.2%, and 1.5%, respectively. The rate of unexpected pathological results was significantly reduced because of the increase in preoperative imaging studies. The decrease in normal appendices contributed the most to the reduction while other unexpected pathologies did not change significantly despite the increased use of imaging studies. This decrease in normal appendices was significant in both male and female patients under the age of 60 years, but the differences in females were more prominent. CONCLUSION: Unexpected appendiceal pathologies comprised 15.6% of the cases. Preoperative imaging studies reduced them by decreasing the negative appendectomy rate of patients with normal appendices.

Prognostic Influence of BCL2 on Molecular Subtypes of Breast Cancer / 한국유방암학회지

PURPOSE: We aimed to reveal the prognostic influence of B-cell CLL/lymphoma 2 (BCL2) on molecular subtypes of breast cancer. METHODS: We analyzed 9,468 patients with primary breast cancer. We classified molecular subtypes according to the National Comprehensive Cancer Network (NCCN) and St. Gallen guidelines, mainly on the basis of the expression of hormonal receptor (HR), human epidermal growth factor receptor 2 (HER2), and Ki-67. RESULTS: Regarding NCCN classification, BCL2 was a strong favorable prognostic factor in the HR(+)/HER2(–) subtype (p<0.001) and a marginally significant favorable prognosticator in the HR(+)/HER2(+) subtype (p=0.046). BCL2 had no prognostic impact on HR(–)/HER2(+) and HR(–)/HER2(–) subtypes. In relation to St. Gallen classification, BCL2 was a strong favorable prognosticator in luminal A and luminal B/HER2(–) subtypes (both p<0.001). BCL2 was a marginally significant prognosticator in the luminal B/HER2(+) subtype (p=0.046), and it was not a significant prognosticator in HER2 or triple negative (TN) subtypes. The prognostic effect of BCL2 was proportional to the stage of breast cancer in HR(+)/HER2(–), HR(+)/HER2(+), and HR(–)/HER2(–) subtypes, but not in HR(–)/HER2(+) subtype. BCL2 was not a prognostic factor in TN breast cancer regardless of epidermal growth factor receptor expression. CONCLUSION: The prognostic influence of BCL2 was different across molecular subtypes of breast cancer, and it was largely dependent on HR, HER2, Ki-67, and the stage of cancer. BCL2 had a strong favorable prognostic impact only in HR(+)/HER2(–) or luminal A and luminal B/HER2(–) subtypes, particularly in advanced stages. Further investigations are needed to verify the prognostic influence of BCL2 on molecular subtypes of breast cancer and to develop clinical applications for prognostication using BCL2.

Analysis of the Relationship between Body Mass Index and Breast Cancer Incidence in Korean Women

PURPOSE: Obesity in women has been shown to have correlation with breast cancer incidence. The proportion of Korean women who are obese has increased recently. However, there is no large-scale study evaluating the relationship between obesity and breast cancer incidence in Korea. In this study, we tried to identify the relationship between obesity and breast cancer incidence in Korean women by using body mass index (BMI). METHODS: A retrospective analysis was performed using single-center data of 28,631 patients screened with breast ultrasonography or mammography between January 2009 to December 2013 in Seoul National University Hospital Healthcare System Gangnam Center. Their clinical characteristics were evaluated. The correlations between breast cancer incidence with BMI and other factors were analyzed using univariate and multivariate logistic regression models. RESULTS: A total of 28,631 patients were enrolled; 67 patients were diagnosed with breast cancer. Among patients without breast cancer, the proportion of patients with BMI under 23 was 68.1%, whereas it was 56.7% among patients with breast cancer (p=0.036). In univariate analysis, patients with a BMI over 25 had an odds ratio of 2.09 for breast cancer compared with those with a BMI under 23 (p=0.012). In addition, patients with a waist circumference over 85 cm had an odds ratio of 1.69 for breast cancer compared with the others (p=0.042). In multivariate analysis, BMI also had significant correlation with breast cancer incidence (odds ratio=1.87, p=0.035). CONCLUSION: An increase in BMI has positive correlation with breast cancer incidence in Korean women. However, a multi-centered prospective study is needed for further evaluation.

Delay of Treatment Initiation Does Not Adversely Affect Survival Outcome in Breast Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Previous studies examining the relationship between time to treatment and survival outcome in breast cancer have shown inconsistent results. The aim of this study was to analyze the overall impact of delay of treatment initiation on patient survival and to determine whether certain subgroups require more prompt initiation of treatment. MATERIALS AND METHODS: This study is a retrospective analysis of stage I-III patients who were treated in a single tertiary institution between 2005 and 2008. Kaplan-Meier survival analysis and Cox proportional hazards regression model were used to evaluate the impact of interval between diagnosis and treatment initiation in breast cancer and various subgroups. RESULTS: A total of 1,702 patients were included. Factors associated with longer delay of treatment initiation were diagnosis at another hospital, medical comorbidities, and procedures performed before admission for surgery. An interval between diagnosis and treatment initiation as a continuous variable or with a cutoff value of 15, 30, 45, and 60 days had no impact on disease-free survival (DFS). Subgroup analyses for hormone-responsiveness, triple-negative breast cancer, young age, clinical stage, and type of initial treatment showed no significant association between longer delay of treatment initiation and DFS. CONCLUSION: Our results show that an interval between diagnosis and treatment initiation of 60 days or shorter does not appear to adversely affect DFS in breast cancer.

Risk Factors Associated with Distant Metastasis and Survival Outcomes in Breast Cancer Patients with Locoregional Recurrence / 한국유방암학회지

PURPOSE: To decide the optimal treatment for breast cancer patients with locoregional recurrence (LRR), it is important to determine which group has the highest risk of subsequent distant metastasis (DM). We aimed to investigate the factors associated with DM in patients with LRR. METHODS: We reviewed the data of 208 patients with LRR as the first event after primary surgery for breast cancer at our institution between 1997 and 2010, to identify significant factors associated with DM. Subsequently, Kaplan-Meier curves and the Cox regression method were used to analyze the correlation between clinical factors and survival. RESULTS: DM occurred in 33.2% (68/208) of LRR patients. The median DM-free interval was 23 months. Some clinical factors were associated with DM in univariate analysis, including the type of primary surgery (p=0.026), tumor size (p=0.005), nodal status (p=0.011), and administration of initial adjuvant chemotherapy (p=0.001). In addition, regional rather than local recurrence and a disease-free interval (DFI; duration between primary surgery and LRR) < or =30 months were also significant (p<0.001 for both). However, only a shorter DFI reached significance in multiple logistic regression analysis. Cox regression analysis of DM-free survival showed that both a shorter DFI and regional recurrence were significant factors with hazard ratios of 2.1 (95% confidence interval [CI], 1.21-3.65) and 1.85 (95% CI, 1.04-3.28), respectively. CONCLUSION: DFI was the most important factor associated with subsequent DM in patients with LRR as a first event of failure.

The Clinical Impact of 21-Gene Recurrence Score on Treatment Decisions for Patients with Hormone Receptor-Positive Early Breast Cancer in Korea / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The 21-gene (Oncotype DX) recurrence score (RS) assay is useful in predicting the benefits of adjuvant chemotherapy for early breast cancer patients and is widely used in Western countries. However, to date, it has not gained much popularity in East Asia. We analyzed the results from five institutions' experience from using the 21-gene assay and examined the impact of assay results on decision making of chemotherapy in Korean breast cancer patients and the associations between RS and clinicopathologic characteristics. MATERIALS AND METHODS: The 21-gene assay was performed on 212 patients with estrogen receptor-positive early breast cancer in five institutions. Each center made systemic treatment decisions both before and after the knowledge of assay results. RESULTS: Among the 212 patients, 132 (62.3%) had a low RS of or = 31. Histologic grade, presence of micrometastases, Ki-67, and presence of lymphatic invasion were statistically associated with the RS results. Treatment decisions were changed in 115 of 212 patients (54.2%) in 109 of 212 (51.4%) from chemotherapy plus hormone therapy to hormone therapy, and in six of 212 (2.8%) from hormone therapy to chemotherapy plus hormone therapy. CONCLUSION: The 21-gene breast cancer assay proved to have a significant impact on treatment decision- making. The test reduces chemotherapy use in more than 50% of Korean estrogen receptor-positive, early breast cancer patients.