Won Ho Kil

Poor prognosis of single hormone receptor- positive breast cancer: similar outcome as triple-negative breast cancer

BackgroundResponse to endocrine therapy in breast cancer correlates with estrogen receptor (ER) and progesterone receptor (PR) status. Generally, hormone receptor-positive (HR+) breast cancers have favorable prognosis. In order to understand the exact clinical characteristics and prognosis of single HR-positive breast cancer (ER + PR- tumors and ER-PR+ tumors), we compared these tumors to double HR+ tumors as well as HR- negative tumors (ER-PR-).MethodsWe examined the clinical and biological features of 6,980 women with invasive ductal carcinoma, and these patients were stratified according to ER and PR expression as double HR+ (ER + PR+), single HR+ (ER + PR- and ER-PR+) and double HR-negative (HR-, ER-PR-) tumors.ResultsIn this study, 571 (8.2%) cases were single HR+ tumors, of which 90 (1.3%) were ER-PR+ tumors and 481 (6.9%) were ER + PR- tumors. Our multivariate analysis showed that in patients without HER2 overexpression ER + PR- tumors were associated with an increased risk of recurrence and death compared with ER + PR+ tumors, with a hazard ratio of 2.12 for disease-free survival (DFS) and 4.79 for overall survival (OS). In patients without HER2 overexpression ER-PR+ tumors had increased risk of recurrence and death compared with ER + PR+ tumor, with a hazard ratio of 4.19 for DFS and 7.22 for OS. In contrast, in patients with HER2 overexpression, the difference in survival between single HR+ tumors and double HR+ HR- tumors was not statistically significant. In patients without HER2 overexpression the DFS and OS of ER + PR- and ER-PR+ tumors were not significantly different from those of ER-PR- tumors.ConclusionWe have identified clinically and biologically distinct features of single HR+ tumors (ER–PR+ and ER + PR–) through comparison with both ER + PR+ and ER-PR- tumors. These differences were only significant in HER2- tumors, not in HER2+ tumors. Single HR+ tumors without HER2 overexpression (ER + PR-HER2- or ER-PR + HER2-) were associated with poorer survival than ER + PR + HER2- tumors, and had comparable poor survival to ER-PR-HER2- tumors (triple-negative breast cancer).

Zerumbone suppresses IL-1β-induced cell migration and invasion by inhibiting IL-8 and MMP-3 expression in human triple-negative breast cancer cells.

Inflammation is a key regulatory process in cancer development. Prolonged exposure of breast tumor cells to inflammatory cytokines leads to epithelial‐mesenchymal transition, which is the principal mechanism involved in metastasis and tumor invasion. Interleukin (IL)‐1β is a major inflammatory cytokine in a variety of tumors. To date, the regulatory mechanism of IL‐1β‐induced cell migration and invasion has not been fully elucidated. Here, we investigated the effect of zerumbone (ZER) on IL‐1β‐induced cell migration and invasion in breast cancer cells. The levels of IL‐8 and matrix metalloproteinase (MMP)‐3 mRNA were analyzed by real‐time polymerase chain reaction. The levels of secreted IL‐8 and MMP‐3 protein were analyzed by enzyme‐linked immunosorbent assay and western blot analysis, respectively. Cell invasion and migration was detected by Boyden chamber assay. The levels of IL‐8 and MMP‐3 expression were significantly increased by IL‐1β treatment in Hs578T and MDA‐MB231 cells. On the other hand, IL‐1β‐induced IL‐8 and MMP‐3 expression was decreased by ZER. Finally, IL‐1β‐induced cell migration and invasion were decreased by ZER in Hs578T and MDA‐MB231 cells. ZER suppresses IL‐1β‐induced cell migration and invasion by inhibiting IL‐8 expression and MMP‐3 expression in TNBC cells. ZER could be a promising therapeutic drug for treatment of triple‐negative breast cancer patients. Copyright

Volume-based Metabolic Tumor Response to Neoadjuvant Chemotherapy Is Associated with an Increased Risk of Recurrence in Breast Cancer

PURPOSE To evaluate the prognostic value of a volume-based metabolic tumor response to neoadjuvant chemotherapy in patients with locally advanced breast cancer. MATERIALS AND METHODS This study was approved by the institutional review board, with waivers of informed consent. One hundred sixty-seven patients (mean age, 44 years; range, 22-68 years) with clinical stage II or III breast cancer who underwent fluorine 18 fluorodeoxyglucose positron emission tomography/computed tomography scans at baseline and after completion of neoadjuvant chemotherapy between July 2006 and June 2013 were selected. The association between the metabolic response parameters and the disease-free survival was assessed by using a Cox proportional hazards regression model and time-dependent receiver operating characteristic curve analysis. Metabolic response parameters included the maximum standardized uptake value (SUVmax), the total metabolic tumor volume (MTVtotal), and the relative decrease in SUVmax and MTVtotal. RESULTS In the Cox model, posttreatment SUVmax (P = .029) and MTVtotal (P = .028) and relative decreases in SUVmax (P = .032) and MTVtotal (P = .005) after neoadjuvant chemotherapy were significantly associated with disease-free survival after adjusting for pretreatment clinical stage, yp stage, and tumor subtype. In the time-dependent receiver operating characteristic curve analysis, MTVtotal after neoadjuvant chemotherapy had the highest association with outcome compared with the other parameters (P < .001). MTVtotal of up to 0.2 cm(3) after neoadjuvant chemotherapy was significantly associated with a favorable outcome in patients who did not achieve pathologic complete response after neoadjuvant chemotherapy. CONCLUSION The volume-based metabolic tumor response to neoadjuvant chemotherapy is associated with an increased risk of recurrence, regardless of tumor subtype and pathologic tumor response.

Comparison of the Characteristics of Medullary Breast Carcinoma and Invasive Ductal Carcinoma

Purpose Medullary breast carcinomas (MBC) have been known to represent a rare breast cancer subtype associated with a more favorable prognosis than invasive ductal carcinomas (IDC). The purpose of this study was to compare the clinicopathologic characteristics and outcomes of MBC with those of IDC. Methods We retrospectively reviewed medical records of patients with invasive breast cancer who were managed surgically from August 1995 to June 2010. Results Fifty-two patients were identified with MBC and 5,716 patients were identified with IDC. The clinicopathologic features, disease-free survival (DFS), and overall survival (OS) of patients with MBC were compared with those of patients with IDC. The MBC group presented at a younger age (p=0.005) and had a significant association with a higher histological grade (p=0.003) and nuclear grade (p<0.001) as well as negative estrogen receptor (p<0.001) and progesterone receptor (p<0.001) status. Lymphatic invasion was absent (p<0.001) and lymph node metastasis was rare (p<0.001). The DFS and OS did not differ significantly between the two groups (5-year DFS: 88.0% vs. 89.2%, p=0.920; 5-year OS: 93.4% vs. 94.4%, p=0.503). In multivariate analysis, the factors associated with DFS and OS were nuclear grade, histological grade, tumor size, lymph node metastasis, estrogen receptor status, progesterone receptor status, and human epidermal growth factor receptor 2 status, chemotherapy, and hormone therapy. However, DFS and OS were not significantly different between IDC and MBC according to histological type itself (DFS: hazard ratio 0.85, 95% confidence interval 0.12-6.05, p=0.866; OS: hazard ratio 1.49, 95% confidence interval 0.21-10.77, p=0.692). Conclusion Although MBC has specific clinicopathologic features, its prognosis does not differ from IDC and is determined by prognostic factors such as tumor size and lymph node metastasis. Therefore, patients with MBC also require the same intensive treatment provided for IDC.

Invasive Pleomorphic Lobular Carcinoma of the Breast: Clinicopathologic Characteristics and Prognosis Compared with Invasive Ductal Carcinoma

Purpose 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). Methods 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. Results 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. Conclusion 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.

Analysis of the effect of breast magnetic resonance imaging on the outcome in women undergoing breast conservation surgery with radiation therapy.

It remains uncertain whether MRI identification of additional foci of disease leads to improved outcome. We undertook a study to evaluate the influence of breast MRI on early and long‐term outcome.

A functional comparison between the HER2(high)/HER3 and the HER2(low)/HER3 dimers on heregulin-β1-induced MMP-1 and MMP-9 expression in breast cancer cells.

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.

Tubular Carcinoma of the Breast: Clinicopathologic Features and Survival Outcome Compared with Ductal Carcinoma In Situ

Purpose Tubular carcinoma (TC) of the breast is an uncommon histological subtype of invasive breast cancer with an excellent prognosis compared with standard invasive ductal carcinoma. Recent studies suggested a possible precursor role for low grade ductal carcinoma in situ (DCIS) in the development of TC. The goal of this analysis was to understand the clinicopathologic features and outcomes of TC by comparing TC with DCIS. Methods A retrospective review identified 70 patients with TC and 1,106 patients with DCIS between 1995 and 2011. Student t-test and Fisher exact test were used to compare the clinicopathologic characteristics of TC patients with those of DCIS patients. The Kaplan-Meier method and Cox regression analysis were used to determine disease-free survival (DFS) rates. Results Compared to DCIS, TC exhibited favorable clinicopathologic characteristics such as a lower nuclear grade (92.3%), higher expression of hormonal receptors (estrogen receptor-positive, 92.9%; progesterone receptor-positive, 87.0%), and less frequent overexpression of human epidermal growth receptor 2 (12.9%). DFS did not differ significantly between the TC and DCIS groups (5-year DFS, 100% vs. 96.7%; 10-year DFS, 92.3% vs. 93.3%; p=0.324), and cancer-specific deaths were not noted in either group. However, axillary lymph node involvement was observed in six (8.6%) of the 70 patients with TC. Three of these patients had small tumors (≤1 cm). Conclusion In our study cohort, TC was associated with an excellent prognosis and a low rate of lymph node metastasis. However, lymph nodes metastases were found even in patients with small tumors (≤1 cm). Axillary staging must be considered for all patients with TC of the breast.

Aromatase inhibitor-associated musculoskeletal symptoms: incidence and associated factors.

Purpose 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. Methods 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. Results 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). Conclusion 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.

Ovarian function preservation with GnRH agonist in young breast cancer patients: Does it impede the effect of adjuvant chemotherapy?

BACKGROUND Concurrent endocrine therapy with chemotherapy had a concern of potential antagonism. However, gonadotropin-releasing hormone (GnRH) agonist has been used concurrently with chemotherapy to prevent premature ovarian failure for young breast cancer patients. The aim of this study was to determine the impact of concurrent use of GnRH agonists on relapse-free and overall survival, and to establish the oncologic safety of ovarian protection with GnRH agonists. METHODS Premenopausal women aged between 20 and 40 years who received adjuvant chemotherapy for breast cancer from January 2002 to April 2012 were classified into two groups; One treated with GnRH agonists for ovarian protection during chemotherapy, and the other without ovarian protection. A propensity score matching strategy was used to create matched sets of two groups with age, pathologic stage, hormone receptor, and Her2 status. RESULTS A total of 101 patients treated with concurrent GnRH agonist during chemotherapy were compared with 335 propensity score matched patients. Among them, 81.2% were younger than 35 years and 58.4% were hormone responsive. Survival analysis using stratified Cox regression showed that women treated with concurrent GnRH agonists had better recurrence-free survival (adjusted Hazard ratio 0.21, p = 0.009; unadjusted Hazard ratio 0.33, p = 0.034). CONCLUSIONS Ovarian protection using GnRH agonists can be safely considered for young women with breast cancer in terms of oncologic outcomes. Further studies are needed to assess the long-term outcomes of concurrent GnRH agonist use with chemotherapy.