Arthralgia is the most common side effect in breast cancer patients receiving aromatase inhibitor (AI) therapy. Few studies have evaluated the risk factors, onset, and incidence of musculoskeletal pain in these patients. This study identifies the risk factors of AI-related severe arthralgia and their prevalence.
All the clinical and pathological records of postmenopausal patients diagnosed with invasive breast cancer using AI at Samsung Medical Center from January 2005 to November 2007 were reviewed. Multivariate logistic regression analyses were performed to evaluate the risk factors of AI-associated musculoskeletal symptoms (AIMSS) and factors associated with AI discontinuance.
Among 299 patients, 69 patients (23%) experienced musculoskeletal symptoms attributed to AI use. In multivariate logistic regression analysis, no statistically significant outcome was found to confirm the risk factors for the development of AIMSS. Among the 69 patients who experienced AI-associated musculoskeletal symptoms, 29 (39.7%) discontinued AI use. Multivariate logistic regression analyses revealed an association of prior tamoxifen use with discontinuance of AI (P < 0.01; odds ratio, 4.27; 95% confidence interval, 1.74 to 10.50).
Prior use of tamoxifen is related to discontinuation of AI due to AI-associated severe arthralgia. Special monitoring and proper pain control for these patients should be considered during the treatment period.
Aromatase inhibitors; Aromatase inhibitor-associated musculoskeletal symptoms; Prior tamoxifen
The available research work on types of treatment and the efficacy of adjuvant chemotherapy in older Korean patients is insufficient. Henceforth, this report assessed treatment patterns and the relationship between chemotherapy and survival in elderly Korean breast cancer patients.
We identified women over 55 years of age diagnosed with breast cancer from the period 1995 to 2006. Clinicopathologic features and treatment methods were compared for three groups divided on the basis of age: 55 to 59 years, 60 to 69 years, and over 70 years old. The effects of chemotherapy on survival were compared overall and individually for each group.
A total of 832 patients over 55 years of age were included in the present investigation. No statistical differences were observed between the three age groups in clinicopathologic features including tumor size, grade, and stage. However, patients in the elderly group received mastectomy more often when compared to the younger groups (p<0.001). In contrast, there was a decline in radiation treatment and chemotherapy with older age (p<0.001). Overall, patients who received chemotherapy had a significantly increased breast cancer specific survival and overall survival rate when compared to the non-chemotherapy groups (p=0.022). Among the estrogen receptor positive group, no statistical significance was achieved in the survival benefit of chemotherapy. However, in estrogen receptor-negative patients, overall, the chemotherapy groups showed a better survival rate than the non-chemotherapy patients and a similar trend was observed in each age group except in the group comprising of 70 years old patients.
This study describes the survival benefit of adjuvant chemotherapy in Korean patients over 55 years of age, especially in hormone receptor-negative patients. Hence, based on the results of the present report and considering the similarity of clinicopathologic features between age groups, it is proposed that age alone should not be a determinant factor of treatment methods.
Aged; Breast; Carcinoma; Chemotherapy; Survival
To examine the immunohistochemical alterations associated with the histological dedifferentiation of thyroid carcinomas, we performed staining for HBME-1, high molecular weight cytokeratin (HCK), CK 19, thyroid transcription factor-1 (TTF-1) and E-cadherin (E-CD) on 125 various types of thyroid carcinomas. The HBME-1 staining was strong and diffuse in follicular carcinoma (FC), papillary carcinoma (PC), and poorly differentiated carcinoma (PDC), while it was rare in undifferentiated carcinoma (UC) as well as in benign lesions. Strong, diffuse staining for CK19 and HCK was predominantly found in PC, and these markers were not much found in other carcinomas. TTF-1 uniformly stained the tumor cells of all cases of PC, FC and Hurthle cell carcinoma (HC) and 42% of the PDC, while there was only focal staining in one case of the UC. Compared to the strong, diffuse reactivity in the benign lesions, E-CD staining was noted in 67% of PC, 80% of FC, 83% of HC, 58% of PDC and none of the UC. These results suggest that HBME-1 may be a marker for well-differentiated carcinomas while CK19 and HCK are phenotypic markers for papillary carcinoma. The loss or reduced expression of TTF-1 and E-CD may be markers for dedifferentiation.
HBME-1 antigen; Keratin; thyroid nuclear factor 1; Cadherins; Thyroid Neoplasms
Diagnostic utility of E-cadherin (E-CD) and cytokeratin (CK) subtype profiling in effusion cytology was investigated, employing immunocytochemistry on cellblock sections available from 211 metastatic carcinomas (MC), 6 mesotheliomas and 73 reactive mesothelial hyperplasias (MH). E-CD and monoclonal carcinoembryonic anti-gen (mCEA) stained 85% (120/141) and 65% (138/211) of MC, respectively. E-CD staining of MC was frequently heterogeneous (76/120) and absent in all anaplastic carcinomas (0/2). E-CD stained none (0/57) of MH while mCEA and epithelial membrane antigen (EMA) stained 12% (9/73) and 32% (16/32) of MH, respectively. Of 6 mesotheliomas, E-CD focally stained in 2 while mCEA stained none and EMA stained all. CK20 and CK17 stained none of MH or mesotheliomas. CK20 stained 15% of MC and CK 17 stained 22% of MC. CK5/6 and high molecular weight CK stained all mesotheliomas, 56% and 88% of MH, 26% and 39% of MC, respectively. MC showed predominant CK7+/20- expression, with the exceptions of MC from mucinous type of colon/rectum and ovary showing predominant CK20 positive. E-CD may be a useful positive marker for MC in effusion cytology, although it may focally stain in some mesotheliomas. Any positive staining for CK20 of MC suggests MC from the gastrointestinal tract or ovary among others.
Pleural Effusion; Ascites; Carcinoma; Mesothelioma; Neoplasms, Mesothelial; Cadherins; Keratin; Cytokeratin 20; Keratin 7
We investigated the relationship between BRCA mutations, pathological findings, and magnetic resonance imaging (MRI) features in patients with breast cancer at risk for the mutation.
Genetic testing for BRCA mutations was performed in 275 breast cancer patients with at least one risk factor for the mutation. Using the breast imaging reporting and data system MR lexicon, morphological and kinetic features were reviewed on MRI scans of 230 tumors in 209 patients. The relationship between BRCA mutations, pathologic findings, and MRI data was examined, and disease recurrence was estimated.
BRCA mutations were detected in 48 patients (23.0%), of which 21 (10.0%) were in BRCA1, and 25 (12.0%) in BRCA2. Additionally, two patients (1.0%) had mutations in both genes. Cancers in patients with BRCA1 mutations more frequently showed a higher nuclear grade (p=0.0041), and triple-negative (TN) phenotype (p<0.0001). On MRI scans, the cancers were seen as mass-type in 182 out of 230 lesions (79.1%), and nonmass type in 48 cases (20.9%). Among the features indentified by MRI, rim enhancement was significantly associated with molecular subtypes based on immunohistochemistry (p<0.0001), and nuclear grade (p=0.0387) in multiple logistic regression analysis. Rim enhancement on MRI, along with advanced pathologic N stage, was associated with increased disease recurrence (p=0.0023) based on multivariate analysis. However, the proportion of mass and nonmass tumors, and the distribution of morphological shape, margin, internal enhancement, and kinetic features assessed by MRI were not different according to BRCA mutation status.
BRCA1 mutations were associated with aggressive pathological characteristics, and the TN phenotype. Rim enhancement was frequently seen on MRI scans of high-grade cancers and in the TN phenotype. And it was a significant predictor of disease recurrence. However, a direct association with BRCA mutations was not observed.
BRCA1 genes; Breast neoplasms; Magnetic resonance imaging; Recurrence
Rhabdomyosarcoma (RMS) of the breast is rare and there is scant information about the clinical behavior and treatment strategies. We report an adolescent female patient with metastatic RMS of the breast from the anus. An 18-year-old female patient was referred to our clinic due to palpable mass in the left breast. At age seven, she was diagnosed with acute lymphoblastic leukemia and treated with chemoradiation therapy. After 10 years of complete remission state, she presented with anal mass which was diagnosed as RMS and she received chemoradiation therapy. After 1 year of complete remission state, she noticed a palpable mass in her left breast. The breast mass was diagnosed as metastatic RMS based on core needle biopsy specimen. The RMS in breast was excised for the decreasing tumor burden despite of another metastatic lesion. Although rarely reported, metastasis of RMS should be considered as a cause of breast mass. Tissue biopsy is recommended when clinically suspected lesion is detected.
Adolescent; Anus; Breast; Neoplasm metastasis; Rhabdomyosarcoma
To present the author's experience with various treatment methods of granulomatous lobular mastitis (GLM) and to determine effective treatment methods of GLM.
Fifty patients who were diagnosed with GLM were classified into five groups based on the initial treatment methods they underwent, which included observation (n = 8), antibiotics (n = 3), steroid (n = 13), drainage (n = 14), and surgical excision (n = 12). The treatment processes in each group were examined and their clinical characteristics, treatment processes, and results were analyzed respectively.
Success rates with each initial treatment were observation, 87.5%; antibiotics, 33.3%; steroids, 30.8%; drainage, 28.6%; and surgical excision, 91.7%. In most cases of observation, the lesions were small and the symptoms were mild. A total of 23 patients underwent surgical excision during treatment. Surgical excision showed particularly fast recovery, high success rate (90.3%) and low recurrence rate (8.7%).
The clinical course of GLM is complex and the outcome of each treatment type are variable. Surgery may play an important role when a lesion is determined to be mass-forming or appears localized as an abscess pocket during breast examination or imaging study.
Breast; Granulomatous mastitis; Treatment; Excision
Hypermethylation of the tumor suppressor genes is frequently observed in the tumor development and progression. However, the correlation between the hypermethylation of the tumor suppressor genes, CDH1 and the axillary lymph node (ALN) metastasis is not fully elucidated. To verify the role of the CDH1 promoter hypermethylation in the ALN metastasis and prognosis, we compared the methylation status of the CDH1 genes in the primary lesion and the paired metastatic ALNs.
We selected a total of 122 paraffin-embedded specimens of the primary and paired metastatic lymph node from 61 breast cancer patients and analyzed the frequency of hypermethylation in the primary and metastatic lymph node using the methylation-specific polymerase chain reaction. In addition, the methylation status of CDH1 was analyzed with the clinicopathologic characteristics, the disease-free survival and disease-specific survival.
The hypermethylation of CDH1 gene was identified in 54 (88.5%) of the 61 patients who had axillary metastasis. The hypermethylation status of the CDH1 gene was significantly increased in the metastatic ALNs compared with that in the primary tumors (60.7% vs. 45.9%, p<0.001). The hypermethylation status of the CDH1 genes in the metastatic ALNs was associated with a poor histologic grade (p=0.041) and the patients who had methylated tumor in the primary lesion showed worse disease-free survival than the patients who did not have methylated tumor (p=0.046).
This study suggests that hypermethylation of the CDH1 gene may play a pivotal role in the metastasis of the axillary lymph node and the breast cancer recurrence.
Breast neoplasms; Lymph nodes; Methylation; Recurrence; Tumor suppressor genes
IBTR! 2.0 is a web-based nomogram that predicts the 10-year ipsilateral breast tumor recurrence (IBTR) rate after breast-conserving therapy. We validated this nomogram in Korean patients.
The nomogram was tested for 520 Korean patients, who underwent breast-conserving surgery followed by radiation therapy. Predicted and observed 10-year outcomes were compared for the entire cohort and for each group, predefined by nomogram-predicted risks: group 1, <3%; group 2, 3% to 5%; group 3, 5% to 10%; group 4, >10%.
In overall patients, the overall 10 year predicted and observed estimates of IBTR were 5.22% and 5.70% (p=0.68). In group 1, (n=124), the predicted and observed estimates were 2.25% and 1.80% (p=0.73), in group 2 (n=177), 3.95% and 3.90% (p=0.97), in group 3 (n=181), 7.14% and 8.80% (p=0.42), and in group 4 (n=38), 11.66% and 14.90% (p=0.73), respectively.
In a previous validation of this nomogram based on American patients, nomogram-predicted IBTR rates were overestimated in the high-risk subgroup. However, our results based on Korean patients showed that the observed IBTR was higher than the predicted estimates in groups 3 and 4. This difference may arise from ethnic differences, as well as from the methods used to detect IBTR and the healthcare environment. IBTR! 2.0 may be considered as an acceptable nomogram in Korean patients with low- to moderate-risk of in-breast recurrence. Before widespread use of this nomogram, the IBTR! 2.0 needs a larger validation study and continuous modification.
Breast neoplasms; Nomograms; Radiotherapy; Recurrence; Validation studies
The p16INK4a gene methylation has been reported to be a major tumorigenic mechanism.
We evaluated the methylation status of the p16INK4a genes in 231 invasive breast cancer and 90 intraductal carcinoma specimens using a methylation-specific polymerase chain reaction and p16 protein expression using immunohistochemistry. The quantity of cell-free methylated p16INK4a DNA in the plasma samples of 200 patients with invasive breast cancer was also examined using a fluorescence-based real-time polymerase chain reaction assay.
The frequencies of p16INK4a methylation in invasive and intraductal tumors were 52.8% (122/231) and 57.8% (52/90), respectively. The p16 protein was overexpressed in 145 of the 231 invasive carcinomas (62.8%) and 63 of the 90 intraductal carcinomas (70%). High p16 expression in invasive carcinomas correlated significantly with a high histologic grade, a negative estrogen receptor and progesterone receptor status, p53 immunoreactivity and high Ki-67 expression with immunohistochemistry. In addition, the methylation index of p16INK4a was significantly higher in the cancer patients than the normal controls (p<0.001).
High p16 immunoreactivity correlated with a loss of differentiation in breast carcinomas and high frequency of p16INK4a promoter methylation in both invasive and intraductal carcinomas, suggesting it may be involved in the pathogenesis of breast cancer.
Breast; Neoplasms; p16; Methylation; Immunohistochemistry
We investigated the relationship between BRCA mutations and the distribution of familial cancers other than breast or ovary in high-risk breast cancer patients.
Patients with breast cancer who had at least one of the following risk factors were enrolled: reported family history of breast or ovarian cancer; 40 years of age or younger age at diagnosis; bilateral breast cancer; or male gender. Genetic testing for BRCA mutation and questionnaires about personal and family histories of malignancies were performed.
Among the 238 eligible patients, 49 (20.6%) patients had BRCA1/2 mutations, which were more frequent in patients with multiple risk factors (p<0.0001). There were 271 members of 156 (65.5%) families who had histories of other primary cancer. The distribution of the families was 119 (63.0%) and 37 (75.5%) in the BRCA-negative and positive group, respectively (p=0.0996). Multiple familial cancers occurred in 70 families, which were significantly more frequent in BRCA-positive families (p=0.0034). By ordinal logistic regression, the occurrence of multiple familial cancers was associated with BRCA mutations (p=0.0045), not with other risk factors. The most common site of disease was the stomach, which is the most common in nationwide. And the proportional incidence of pancreatic cancer (6.8%) was significantly higher than that of nationwide cancer statistics (2.4%, p=0.0137).
BRCA mutations in high-risk breast cancer patients were associated with multiple risk factors and multiple family members with other primary cancers. Genetic counseling based on accurate information should be provided to families with BRCA mutation carriers.
Breast neoplasms; BRCA1; BRCA2; Familial cancer
Invasive pleomorphic lobular carcinoma (IPLC) is a very rare and distinct morphological variant of invasive lobular carcinoma (ILC), characterized by nuclear atypia and pleomorphism contrasted with the cytologic uniformity of ILC. This study evaluated clinicopathologic characteristics and prognosis of IPLC compared with invasive ductal carcinoma (IDC).
We retrospectively reviewed the medical records of 35 patients with IPLC and 6,184 patients with IDC, not otherwise specified. We compared the clinicopathologic characteristics, relapse-free survival (RFS) and disease specific survival (DSS) of patients who were surgically treated between January 1997 and December 2010.
Patients with IPLC presented at an older age with larger tumor size, worse histologic grade, higher rates of N3 stage, more multifocal/multicentric tumors, and more nipple-areolar complex involvement than those of patients with IDC. During the follow-up period, the IPLC group experienced five cases (14.3%) of disease recurrence and three cases (8.6%) of disease specific mortality compared with 637 cases (10.4%) of recurrence and 333 cases (5.4%) of disease specific mortality in the IDC group. Univariate analysis using the Kaplan-Meier method revealed that the IPLC group showed a significantly poorer prognosis than that of the IDC group (RFS, p=0.008; DSS, p<0.001). However, after adjusting for clinicopathologic factors, a multivariate analysis showed no statistical differences in RFS (p=0.396) and DSS (p=0.168) between the IPLC and the IDC groups.
Our data suggest that patients with IPLC present with poor prognostic factors such as large tumor size, poor histologic grade and advanced stage at diagnosis. These aggressive clinicopathologic characteristics may result in poor clinical outcomes. Although our study could not link IPLC histology to poor prognosis, considering the aggressive characteristics of IPLC, early detection and considerate treatment, including proper surgical and adjuvant intervention, could be helpful for disease progression and survival.
Breast; Lobular carcinoma; Prognosis
This study evaluated the treatment results and the necessity to irradiate the supraclavicular lymph node (SCN) region in pathological N0-N1 (pN0-N1) patients with locally advanced breast cancer treated with neoadjuvant chemotherapy (NAC) followed by surgery and radiotherapy (RT).
Between 1996 and 2008, 184 patients with initial tumor size >5 cm or clinically positive lymph nodes were treated with NAC followed by surgery and RT. Among these patients, we retrospectively reviewed 98 patients with pN0-N1. Mastectomy was performed in 55%. The pathological lymph node stage was N0 in 49% and N1 in 51%. All patients received adjuvant RT to chest wall or breast and 56 patients (57%) also received RT to the SCN region (SCNRT).
At 5 years, locoregional recurrence (LRR)-free survival, distant metastasis-free survival, disease-free survival (DFS), and overall survival rates were 93%, 83%, 81%, and 91%, respectively. In pN0 patients, LRR was 7% in SCNRT- group and 5% in SCNRT+ group. In pN1 patients, LRR was 7% in SCNRT- group and 6% in SCNRT+ group. There was no significant difference of LRR, regardless of SCNRT. However, in pN1 patients, there were more patients with poor prognostic factors in the SCNRT+ group compared to SCNRT- group. These factors might be associated with worse DFS in the SCNRT+ group, even though RT was administered to the SCN region.
Our study showed the similar LRR, regardless of SCNRT in pN0-pN1 breast cancer patients after NAC followed by surgery. Prospective randomized trial is called for to validate the role of SCNRT.
Adjuvant radiotherapy; Breast neoplasms; Lymphatic irradiation; Neoadjuvant therapy
Occult breast cancer is a type of breast cancer without any symptoms on the breasts or any abnormalities upon radiologic examination such as mammography. In males, there are few cases of breast cancer, the rate of diagnosis of occult breast cancer is very low, and little is known about this disease. We experienced two cases of occult breast cancers manifesting as axillary lymph node metastasis in men. They had a palpable lesion on axillary area several years ago and had not seen a doctor about it. As such there was no abnormality on evaluations for cancer except for axillary lymph node showing signs of carcinoma (primary or metastatic) on biopsy and estrogen receptor-positive and progesterone receptor-positive on immunohistochemistry. The patients were diagnosed with occult breast cancer, and treatments were performed. Herein, we report the rare cases of occult breast cancers in men.
Axilla; Breast neoplasms; Male; Neoplasm metastasis; Occult primary neoplasms
We describe two cases of post-radiation sarcoma after breast cancer treatment. The first patient was a 61-year-old woman who underwent partial mastectomy of the right breast and adjuvant whole breast irradiation 7 years previously. Subsequently, a rapidly growing mass from the anterior arc of the right fifth rib was incidentally detected on an abdomino-pelvic computed tomography scan. The second patient was a 70-year-old woman who received neoadjuvant chemotherapy and a partial mastectomy of the left breast 9 years ago. Adjuvant irradiation was delivered to the whole breast and supraclavicular region. Subsequently, an approximate 8 cm mass developed in the left axillary area. Both patients received wide excision of the tumor with negative resection margins. The pathological diagnoses were osteosarcoma and undifferentiated pleomorphic sarcoma, respectively. Although post-radiation sarcomas are rare complications with a poor prognosis, enhanced awareness and early detection by clinicians are essential to improve outcomes via curative surgical resection.
Breast neoplasms; Radiation-induced neoplasms; Radiotherapy; Sarcoma
Overexpression of HER2 correlates with more aggressive tumors and increased resistance to cancer chemotherapy. However, a functional comparison between the HER2high/HER3 and the HER2low/HER3 dimers on tumor metastasis has not been conducted. Herein we examined the regulation mechanism of heregulin-β1 (HRG)-induced MMP-1 and -9 expression in breast cancer cell lines. Our results showed that the basal levels of MMP-1 and -9 mRNA and protein expression were increased by HRG treatment. In addition, HRG-induced MMP-1 and -9 expression was significantly decreased by MEK1/2 inhibitor, U0126 but not by phosphatidylinositol 3-kinase (PI-3K) inhibitor, LY294002. To confirm the role of MEK/ERK pathway on HRG-induced MMP-1 and -9 expression, MCF7 cells were transfected with constitutively active adenoviral-MEK (CA-MEK). The level of MMP-1 and -9 expressions was increased by CA-MEK. MMP-1 and -9 mRNA and protein expressions in response to HRG were higher in HER2 overexpressed cells than in vector alone. The phosphorylation of HER2, HER3, ERK, Akt, and JNK were also significantly increased in HER2 overexpressed MCF7 cells compared with vector alone. HRG-induced MMP-1 and -9 expressions were significantly decreased by lapatinib, which inhibits HER1 and HER2 activity, in both vector alone and HER2 overexpressed MCF7 cells. Finally, HRG-induced MMP-1 and MMP-9 expression was decreased by HER3 siRNA overexpression. Taken together, we suggested that HRG-induced MMP-1 and MMP-9 expression is mediated through HER3 dependent pathway and highly expressed HER2 may be associated with more aggressive metastasis than the low expressed HER2 in breast cancer cells.
breast neoplasms; HER2 protein, human; heregulin-β1; matix metalloproteinase 1; matrix metalloproteinase 9; mitogen-activated protein kinase 1; neoplasm metastasis
Internal mammary lymph node (IMLN) metastasis is an important prognostic indicator in breast cancer. However, the necessity of internal mammary sentinel lymph node biopsy for accurate staging, for choosing adjuvant treatment, and as a prognostic indicator, has remained controversial.
From January 2001 to December 2006, 525 female breast cancer patients underwent radical surgery after preoperative lymphatic scintigraphy. We retrospectively analyzed the follow-up results, recurrences, and deaths of all patients.
There was no significant difference in the clinicopathological characteristics between the axilla and the IMLN groups. The median follow-up period was 118.8 months (range, 7-122 months) in the axilla group and 107.7 months (range, 14-108 months) in the IMLN group. During the median follow-up period, the breast cancer-related death rate in the axilla group was 3.6%, which was not significantly different from that of the IMLN group (1.3%) (p=0.484). The five-year survival rates did not differ between the two groups (p=0.306). The overall recurrence rate and the locoregional recurrence rate also did not differ between the two groups (p=0.835 and p=0.582, respectively). The recurrence rate of IMLN (both ipsilateral and contralateral) metastasis was very low, accounting for 0.5% in the axilla group and 1.3% in the IMLN group (p=0.416).
The long-term follow-up results showed that there was no significant difference in both overall outcome and regional recurrence between the two groups. Therefore, the requirement for identification of nodal basins outside the axilla or IMLN sentinel biopsy should be reconsidered.
Breast; Carcinoma; Internal mammary; Prognosis; Sentinel lymph node biopsy
C-C chemokine receptor type 7 (CCR7) plays an important role in chemotactic and metastatic responses in various cancers, including breast cancer. In the present study, the authors demonstrated that microRNA (miRNA) let-7a downregulates CCR7 expression and directly influences the migration and invasion of breast cancer cells.
The expression of CCR7, its ligand CCL21, and let-7a was detected in breast cancer cell lines and in breast cancer patient tissues. Synthetic let-7a and an inhibitor of let-7a were transfected into MDA-MB-231 and MCF-7 breast cancer cells, respectively, and cell proliferation, cell migration, and invasion assays were performed. To confirm the fact that 3'UTR of CCR7 is a direct target of let-7a, a luciferase assay for the reporter gene expressing the let-7a binding sites of CCR7 3'UTR was used. An in vivo invasion animal model system using transparent zebrafish embryos was also established to determine the let-7a effect on breast cancer cell invasion.
First, a higher expression of both CCR7 and CCL21 in malignant tissues than in their normal counterparts from breast cancer patients was observed. In addition, a reverse correlation in the expression of CCR7 and let-7a in breast cancer cell lines and breast cancer patient tissues was detected. Synthetic let-7a decreased breast cancer cell proliferation, migration, and invasion, as well as CCR7 protein expression in MDA-MB-231 cells. The let-7a inhibitor reversed the let-7a effects on the MCF-7 cells. The 3'UTR of CCR7 was confirmed as a direct target of let-7a by using the luciferase assay for the reporter gene expressing let-7a CCR7 3'UTR binding sites. Notably, when analyzing in vivo invasion, MDA-MB 231 cells after synthetic let-7a transfection were unable to invade the vessels in zebrafish embryos.
The results from the present study suggest that targeting of CCL21-CCR7 signaling is a valid approach for breast cancer therapy and that let-7a directly binds to the 3'UTR of CCR7 and blocks its protein expression, thereby suppressing migration and invasion of human breast cancer cells. Furthermore, the present study underscores the therapeutic potential of let-7a as an antitumor and antimetastatic manager in breast cancer patients.
Mucinous carcinoma (MC) of the breast is a rare histologic type of mammary neoplasm. The objective of this study was to evaluate the long-term disease-free survival (DFS) and overall survival (OS) of MC.
We conducted a retrospective analysis of all MC cases reported to a database between 1994 and 2010. Clinicopathological characteristics and survival of 268 MC cases were reviewed and compared with 2,455 invasive ductal carcinoma-not otherwise specified (IDC-NOS) cases.
The MC cases were of a younger age, involved less lymph nodes, lower stage, more expression of hormonal receptors, and less HER2 overexpression compared to the IDC-NOS cases. The 5-year DFS rate for MC was 95.2% compared to 92.0% for IDC-NOS. The 5-year OS rate for MC was 98.9% compared to 94.9% for IDC-NOS. Multivariate analysis using Cox regression revealed that the mucinous type was a significant prognostic factor for DFS with lower nodal status (N stage) and hormonal therapy. For OS, only N stage was the most significant prognostic factor followed by adjuvant chemotherapy and adjuvant hormonal therapy.
MC was shown to be associated with a better DFS than IDC-NOS, but it had a similar OS. Nodal status and adjuvant therapy appear to be more significant predictors of prognosis than histologic subtype.
Adenocarcinoma; Breast; Invasive ductal carcinoma; Mucinous; Prognosis
The frequency of immediate breast reconstruction (IBR) is increasing, and the types of reconstruction used are diverse. Adjuvant chemotherapy is a life-saving intervention in selected high-risk breast cancer patients. The aim of our study was to determine how IBR and type of reconstruction affect the timing of the initiation of chemotherapy.
We obtained data from female breast cancer patients treated by mastectomy with IBR (IBR group) and without IBR (mastectomy only group) who received adjuvant chemotherapy between January 1, 2008, and December 31, 2010. We retrospectively collected data including patient characteristics, disease characteristics, treatment details, and treatment outcomes from our institutional electronic patient database and medical treatment records. The reconstruction types were categorized as deep inferior epigastric perforator (DIEP) flap, latissimus dorsi (LD) flap and tissue expander/implant (TEI).
In total, 595 patients were included in this study. Of these patients, 43 underwent mastectomy with IBR (IBR group) and 552 patients did not undergo reconstruction (mastectomy only group). There was significant difference in the timing of the initiation of chemotherapy between the two groups (p<0.0001). There were no cases of delays of more than 12 weeks. In the IBR group, 20 patients received TEI, 9 patients were treated by the insertion DIEP flaps, and 14 patients were treated by LD flaps. There were no significant differences in the timing of chemotherapy according to the type of reconstruction (p=0.095).
IBR delays the initiation of chemotherapy, but does not lead to omission or significant clinical delay in chemotherapy. Further, the type of reconstruction does not affect the timing of chemotherapy.
Adjuvant chemotherapy; Breast neoplasms; Breast reconstruction
Recently, several clinicians have reported the advantages of simplicity and cosmetic satisfaction of absorbable mesh insertion. However, there is insufficient evidence regardint its long-term outcomes. We have investigated the surgical complications and postoperative examination from the oncologic viewpoint.
Materials and Methods
From February 2008 to March 2009, 34 breast cancer patients underwent curative surgery with absorbable mesh insertion in Samsung Medical Center. Patient characteristics and follow up results including complications, clinical and radiological findings were retrospectively investigated.
The mean age of the study population was 50.1±8.9 years old (range 31-82) with a mean tumor size of 3±1.8 cm (range 0.8-10.5), and the excised breast tissue showed a mean volume of 156.1±99.8 mL (range 27-550). Over the median follow-up period of 18±4.6 months (range 3-25), mesh associated complications, including severe pain or discomfort, edema, and recurrent fluid collection, occurred in nine patients (26.5%). In three cases (8.8%), recurrent mastitis resulted in mesh removal or surgical intervention. In the postoperative radiologic survey, the most common finding was fluid collection, which occurred in five patients (16.1%), including one case with organizing hematoma. Fat necrosis and microcalcifications were found in three patients (9.7%).
Absorbable mesh insertion has been established as a technically feasible, time-saving procedure after breast excision. However, the follow-up results showed some noticeable side effects and the oncologic safety of the procedure is unconfirmed. Therefore, we suggest that mesh insertion should be considered only in select cases and should be followed-up carefully.
Breast neoplasms; mastectomy; segmental; absorbable implants
The aim of the current study was to determine the incidence, clinical presentation, and treatment outcomes of "bone-only metastases" in patients with breast cancer and to analyze the impact of hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status on prognosis.
Materials and Methods
Between 1994 and 2007, of 968 patients with metastatic breast cancer who underwent palliative management at Samsung Medical Center, 565 (57%) relapsed with distant metastases. Of the 968, 146 (15%) had bone-only metastases during a median follow-up period of 75 months. Among the 146 patients with bone-only metastases, 122 (84%) were relapsed patients after curative surgery and 24 (26%) were initially metastatic cases.
The median time from primary surgery to bone-only metastases of the 122 patients was 37 months (95% confidence interval [CI], 27 to 46 months). Bone-only metastases were more common in the HR-positive group than in the other subtypes (85% for HR+; 8.2% for HER2+; 6.8% for triple negative. Among all 146 patients, 75 (51%) were treated with hormone therapy. The median post-relapse progression-free survival was 15 months (95%CI, 13 to 17 months). The median overall survival was much longer in the HR+ patients than the HER2+ and triple negative breast cancer patients with marginal statistical significance (65 vs. 40 vs. 40 months, p=0.077).
Breast cancer patients with "bone-only metastases" had excellent clinical outcomes. Further study is now warranted to reveal the underlying biology that regulates the behavior of this indolent tumor, as it should identify 'favorable tumor characteristics' in addition to 'favorable preferential metastatic site.'
Bone; Neoplasm metastasis; Breast neoplasms; Estrogen receptors; Progesterone receptors; HER2
Epithelial-mesenchymal transition (EMT), a switch of polarized epithelial cells to a migratory, fibroblastoid phenotype, is considered a key process driving tumor cell invasiveness and metastasis. Using breast cancer cell lines as a model system, we sought to discover gene-expression signatures of EMT with clinical and mechanistic relevance. A supervised comparison of epithelial and mesenchymal breast cancer lines defined a 200-gene EMT signature that was prognostic across multiple breast cancer cohorts. Immunostaining of LYN, a top-ranked EMT signature gene and Src-family tyrosine kinase, was associated with significantly shorter overall survival (P=0.02), and correlated with the basal-like (“triple-negative”) phenotype. In mesenchymal breast cancer lines, RNAi-mediated knockdown of LYN inhibited cell migration and invasion, but not proliferation. Dasatinib, a dual-specificity tyrosine kinase inhibitor, also blocked invasion (but not proliferation) at nanomolar concentrations that inhibit LYN kinase activity, suggesting that LYN is a likely target and invasion a relevant endpoint for dasatinib therapy. Our findings define a prognostically-relevant EMT signature in breast cancer, and identify LYN as a mediator of invasion and possible new therapeutic target (and theranostic marker for dasatinib response), with particular relevance to clinically-aggressive basal-like breast cancer.
Breast cancer; epithelial-mesenchymal transition; transcriptional profiling; LYN; dasatinib