Hj Kim

Short term results from GHRH analogue use in pre-menopausal breast cancer in Korea

BACKGROUNDnHormone receptor-positive, pre-menopausal breast cancer patients can be treated by chemotherapy and/or ovarian suppression therapy. We reported our experience of gonadotropin-releasing hormone analogue plus tamoxifen (GnRHa+T) or adriamycin and cyclophosphamide (AC) followed by tamoxifen (AC-->T) in pre-menopausal women with hormone-response, node-negative breast cancer.nnnMETHODSnWe retrospectively reviewed the records of 587 pre-menopausal women with hormone-responsive, node-negative breast cancer. Of these, 269 were treated with adriamycin and cyclophosphamide (AC) followed by tamoxifen (AC-->T), and 318 were treated with gonadotropin-releasing hormone analogue plus tamoxifen (GnRHa+T). Among them, 151 patients were treated by goserelin acetate 3.6 mg/kg and 125 patients were treated by leuprorelin acetate 3.75 mg/kg every 28 days subcutaneously.nnnFINDINGSnAt a median follow-up time of 30 months, eight patients had relapsed and three had died. DFS did not differ between the AC-->T and GnRHa+T groups. Of the three deaths, two were not related to breast cancer. The third patient, in the AC-->T group, died because of brain metastasis. GnRHa+T treatment had no effect on blood profile and did not cause the development of detrimental symptoms but decreased bone mineral density. The efficacy of leuprorelin was similar to that of goserelin.nnnINTERPRETATIONnGnRHa+T treatment can be an alternative treatment option in pre-menopausal women with endocrine-responsive, node-negative, breast cancer patients. The efficacy and tolerability of leuprorelin were similar to that of goserelin.

Abstract 1226: p53 signaling pathway acts as rescue mechanism to β1 integrin silencing in head and neck cancer cell line

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FLnnβ1 integrins aberrant expression has implicated a cancer progression and resistance to cytotoxic therapy. Moreover, cancer cells gained epithelial mesenchymal transition (EMT) features were more resistant to the detachment-induced cell death. In this regard, we investigated the mechanism by which β1-Integrin governs cell viability and verified whether the signaling pathway is associated with EMT features.nnCancer cell lines from head and neck cancer patients (AMC-HN3 and AMC-HN9) and well-known EMT cancer, MDA-MB231, were used in this study. To determine whether three cell lines reveal the epithelial EMT features, EMT markers such as Snail, vimentin, fibronectin and E-cadherin were evaluated by western blot analysis and immunofluroscence. To knockdown β1 integrin signal, β1 integrin small interfering RNA (siRNA) was transiently transfected into all cell lines. The cell viability was examined by looking at the results of propidium iodide staining, MTT assay, changes in the mitochondrial membrane potential and cell morphology.nnMDA-MB231 and AMC-HN9 cells possessed EMT features whereas AMC-HN3 cells were not shown EMT phenotype. β1 integrin silencing cell increased the sub G1 from 1.0% to 29.8%, increased the percentage of cells losing their mitochondrial membrane potential from 5.3% to 65.9% as well as the number of fragmented mitochondria in AMC-HN3 cells. In contrast, MDA-MB231 cells showed more resistance to silencing of β1 integrin, lower cell death rate from 0.6% to 9.6% and less changes in the mitochondrial membrane potential from 4.34% to 34.51%. Interestingly, AMC-HN9 cells showed complete resistance to β1 integrin blocking even though FAK phosphorylation signaling was blocked in AMC-HN9 cells, same as AMC-HN3 cells, which is a different response from typical EMT featured cells. When AMC-HN9 cells were treated to inhibit β1 integrin and p53 separately, it showed no response to changes in the cellular morphology, viability and apoptosis-related signal pathway; however, when it was given the combined β1 integrin and p53, apoptosis occurred in the cell line.nnIn this study, acquisition of the EMT features in cancer cells presented resistance to the β1 integrin inhibition. In addition, the activation of p53-p21 signaling pathway provided resistance to detachment-induced apoptosis in head and neck cancer cell line with EMT features.nnCitation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1226. doi:10.1158/1538-7445.AM2011-1226

Abstract P5-13-06: Concurrent gonadotropin-releasing hormone (GnRH) agonist administration with chemotherapy improves neoadjuvant chemotherapy responses in young premenopausal breast cancer patients

Background Gonadotropin-releasing hormone (GnRH) agonist therapy for ovarian function preservation shows promising results. This study aimed to determine the oncologic efficacy of GnRH agonist treatment concurrent with chemotherapy in a neoadjuvant setting. Patients and Methods A retrospective analysis was performed on 332 cases of invasive breast cancer in patients who were Results The median age was 32 ± 3.9 and 36 ± 3.0 years old in the GnRH agonist group and neochemotherapy-alone group, respectively (P Conclusion Concurrent administration of GnRH agonists during neoadjuvant chemotherapy improved pCR rates and suppressed Ki-67 expression especially in HR-negative tumors. Citation Format: Yoon TI, Kim HJ, Yu JH, Sohn G, Ko BS, Lee JW, Son BH, Ahn SH. Concurrent gonadotropin-releasing hormone (GnRH) agonist administration with chemotherapy improves neoadjuvant chemotherapy responses in young premenopausal breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-13-06.

Abstract 81: Rapamycin increases radiosensitivity of cancer cells by induction of premature senescence.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DCnnAutophagy is frequently activated in radioresistant cancer cells. Rapamycin, mammalian target of rapamycin (mTOR) inhibitor, activates autophagy but enhances radiosensitivity. The mechanism of these actions by which such opposing functions coexist was investigated on radiation-resistant cancer cell lines (AMC-HN-9 and U-87) and the antitumor activity was evaluated in mice bearing xenografts of the cancer cells. Enhanced autophagic flux induced by radiation returned to untreated control levels. Treatment of the cancer cells with rapamycin leads to the potentiation and prolongation of radiation-induced autophagy, the increases in senescence-associated β-galactosidase activity, heterochromatin formation, and irreversible growth arrest. Furthermore, rapamycine resulted in a tumor regrowth delay and increased the level of β-galactosidase staining and the expression of heterochromatin markers in irradiated xenografts. These results suggest that even though autophagy is a survival mechanism in radioresistant cells, a persistent activation of autophagy by mTOR inhibitor induces premature senescence in these cells, eventually making the cells radiosensitive. Our data suggest a novel mechanism by which an inhibition of mTOR pathway increases autophagy but paradoxically increases radiosensitivity in radioresistant cancer cells.nnCitation Format: Hae Yun Nam, Myung Woul Han, Hyo Won Chang, Yoon Sun Lee, Myungjin Lee, Mi Ra Kim, Hyang Ju Lee, Ji Yung Jeoung, So Young Moon, Hyo Jung Kim, Sang Yoon Kim, Seong Who Kim. Rapamycin increases radiosensitivity of cancer cells by induction of premature senescence. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 81. doi:10.1158/1538-7445.AM2013-81

Abstract P6-06-54: Analysis of treatment and survival of pathologic occult breast cancer with axillary lymph node metastasis: Nationwide retrospective study

Objective Occult breast cancer (OBC) is a rare presentation which accounts for 0.3-1.0% of all breast cancers. In spite of limited information, there is no consensus regarding the prognostic factors and treatment of OBC. This retrospective study intends to evaluate the overall survival and prognostic factors of occult breast cancer (OBC) in Korea. Method This study included 142 pathologic occult breast cancer patients from January 1990 to December 2009, identified from Korean Breast Cancer Society cancer registry. All patients had pathologically positive axillary lymph node (N1-N3) along with pathologically & radiologically negative in-breast lesion (T0/Tx) based on retrospective review of database. Among 142 patients, 32 patients had only axillary lymph node dissection (ALND), 56 patients had breast conserving operation (BCO) with ALND and 54 patients had mastectomy with ALND. 96 patients (96%) had N1 disease, 23 patients (16.2%) had N2 disease and 23 patients (16.2%) had N3 disease. Results There was no significant statistical difference in overall survival among different operation method, which is ALND only, BCO with ALND, mastectomy with ALND (p = 0.061), considering that 12 patients (37.5%) among 32 patients who only had ALND had N3 disease comparing that only 7 (12.5%) out of 56 patients and 4 (7.4%) out of 54 patients had N3 disease in BCO with ALND and mastectomy with ALND group separately. Univariate analysis revealed that only nodal status was significant prognostic factor (p = 0.0004), and other factors including radiotherapy (p = 0.696), chemotherapy (p = 0.302), estrogen receptor positivity (p = 0.144), progesterone receptor positivity (p = 0.254), total number of removed lymph node (p = 0.586) didn9t show statistical difference in overall survival. Conclusions This study suggests that OBC patients who only had ALND showed similar outcomes when comparing with patients who had BCO with ALND or mastectomy with ALND. Also only nodal status might be independent predictors for poor outcomes of occult breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-54.

Abstract P3-01-02: Correlation of Mammographic breast density and tumor characteristics in Korean breast cancer patients

Introduction: Western studies have demonstrated high breast density as a strong risk factor for breast cancer, it is poorly understood whether breast density affects the diverse phenotypes of breast cancer. We examined the association between various tumor characteristics and mammographic breast density in women with breast cancer. Methods: We conducted a cross-sectional analysis in 910 Korean women diagnosed with breast cancer to evaluate the associations between breast density and tumor size, lymph node status, lymphovascular invasion, histologic grade, estrogen receptor, progesterone receptor, HER2. Breast density was classified as fatty (percent density less than 50% by a computer-assisted thresholding program, named “Cumulus™”; n = 470) or dense (percent density 50% or more; n = 440) for the cancer-free breast at the time of operation. Logistic regression was used to examine whether the relationships were modified by adjustment for body mass index, age at diagnosis, age at first birth, menopausal status, history of breast-feeding, and breast cancer staging. Results: Total 910 patients were involved, the mean age and median age at the operation was 48 years old (range 20–82), and the mean percent density was 48.09 (SD = 9.62 %: normally distributed, Kolmogorov-Smirnov test p = 0.32). Crude analysis shows that tumor size over than 0.5cm were more likely to have dense breasts compared with women with a tumor size p = 0.001 for tumor sizes 0.6–1.0cm; OR = 2.02, 95% CI = 1.09–3.74, p = 0.03 for tumor sizes 1.1–1.5cm; OR = 1.8, 95% CI = 0.97–3.33, p = 0.06 for tumor sizes 1.6–2.0cm; and OR = 1.64, 95% CI = 0.92–2.94, p = 0.1 for tumor sizes 2.1cm or more). PD and histologic grade shows reverse association between histologic grade 1 and grade 2,3. Progesteron receptor positive patients tend to have more dense(OR = 1.27, 95% CI=0.97–1.66, p = 0.07) breast than receptor negative patients, although after adjustment of age the statistical significant disappeared. Percent density was not significantly associated with, ER ( p = 0.74), HER2 ( p = 0.72). Conclusion: These results suggest that breast density is associated with tumor size and histologic grade and progesterone receptor positivity. Additional studies are needed to address whether these associations are due to just density masking the detection of some tumors, biological causation, or both. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-01-02.

P3-09-06: Changes of Serum Vitamin D According to the Breast Cancer Treatment.

Background: Vitamin D deficiency is associated with increased breast cancer risk and decreased breast cancer survival. The purpose of this study was to determine the effect of breast cancer adjuvant treatment to the vitamin D status, as measured by the serum hydroxyvitamin D (25OHD) in breast cancer patients. Patients and Methods: For 589 patients who was diagnosed as a non metastatic breast cancer in 2009 at the asan medical center, blood was prospectively analyzed in batches for serum 25 OHD level at basal and at 6 and 12month. We excluded the patients who took a vitamin D supplementation and got a neoadjuvant chemotherapy. Vitamin D sufficiency was defined as serum as 30ng/ml or greater, insufficiency as 20 to 29 ng/ml and insufficiency as less than 20ng/ml. Results: At baseline, mean serum 25OHD was greater in summer (April to Oct) than Winter(Nov to May) (28.2ng/ml vs 32.9ng/ml respectively, p=0.000). The patients who did not get a chemotherapy and antihormonal therapy as baseline, the patient with chemotherapy showed decreased serum 25OHD level than who without chemotherapy in 6 month but not in 12 month (p=0.003, vs p=0.156 respectively). The patients who had taken anti-hormonal therapy showed significant increasing serum 25OHD in 6 month and 12 months (p=0.000 both). For the patients who got both chemotherapy and anti-hormonal therapy, the changes of serum 25OHD level is smaller than the patients who got a chemotherapy only. For the patients who got a chemotherapy, 57% of patients were vitamin D sufficient at baseline, but 27% of patients in 6 month and 49% in 12 month (p=0.001). Conclusion: Vitamin D status was worsen during chemotherapy but recovered after chemotherapy. Anti hormonal therapy make the serum vitamin D level increased. The translational research about the effect of chemotherapy and anti-hormonal therapy to the vitamin D status should be warranted. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-09-06.

Abstract P1-01-08: Lymph Node Ratio as an Alternative to pN Staging in Node Positive Breast Cancer: A report from the Korean Breast Cancer Society

Background: To compare the lymph node ratio(LNR) and pN staging as a prognostic predictor and find out high risk subgroup which can not predict prognosis using pN staging. Patients and Methods: Using information from two large databases, including Korean nationwide registry, we compared the survival using LNR and pN stage parameters by Cox regression analysis. Moreover survival data were analysed according to age subgroups and intrinsic subtypes. Results: In an analysis of 2264 node positive patients from single institution, adjusted cancer specific mortality risks of low (≥0.20), intermediate (>0.20 and ≥0.65) and high risk (>0.65) LNR groups were 1(reference), 1.9 (95%CI, 1.6 to 2.4), 4.6(95%CI, 3.6 to 5.8). The difference of mortality risk between LNR parameters were wider than that of N1, N2 and N3 in DFS, CSS, OS. In contrast to LNR risk categories, survival curve in pN1 and pN2 overlapped in the patients below 35 years old. Survival curve in pN1 and pN2 also overlapped in patients in her2/neu enriched as well as triple negative subtype. These finding were validated by an analysis of nationwide registry data on 15488 node positive patients. The patients who had N1 and LNR2-3 disease showed poor DFS (HR 1.7 95% CI 1.4 to 2.2) and CSS (HR 1.6, 95% CI 1.1 to 2.2) compared with the patients who had N2 and LNR1 disease. Conclusion: LNR define breast cancer prognosis more adequate than the pN categories especially high risk breast cancer like young age, her2/neu enriched and triple negative intrinsic subtype. It is more reasonable that treatment decision like radiotherapy might be depend on the LNR than pN staging. We argue that LNR should be considered as an alternative to pN staging. Figures available in online version. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-01-08.

Do stem cell markers have significant implication in breast cancer? Immunohistochemical study for CD44 and CD24.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 AbstractsnnAbstract #5058 nnBackground: We reported that breast cancer expressing CD44+CD24-/low showed a favorable prognosis in contrary to the in vitro/in vivo studies. We further followed this data up to 99 months and analyzed it according to CD44 expression, CD24 expression and hormone expression. Design: immunohistochemical stainings for CD44s and CD24 as well as prognostic markers including estrogen receptor, progesterone receptor, p53, and Her2/neu were done using tissue microarray blocks containing 645 consecutive cases of invasive breast carcinomas from 1993 to 1998. Mean follow up periods were 99.5 months. Cases were categorized into four subgroups (CD44-/CD24+, CD44+/CD24+, CD44-/CD24-, CD44+/CD24-) based on the immunohistochemical staining results and compared them with clinicopathologic parameters. Immunostainings for CD44s and CD24 interpreted as positive if at least 1% of tumor cells show distinct membranous and/or cytoplasmic stainings. In the positive group of CD24, we categorized it as three subgroups according to the degree of positivity. Results: CD44+CD24-/low group showed inversely associated with lymph node metastasis and the tumor stage than other subgroups ( p =0.001 and p =0.018, respectively). And CD44+CD24-/low group was showed an increase in disease free survival and overall survival (p=0.003, p=0.002) In the subgroup analysis of CD24 expression (0, grade 1, grade 2, grade 3), the incidence of metastasis and death was more frequently observed in the cases with the higher expression of CD24. (DFS: p=0.03, OS: p=0.001). With respect to the CD44, CD44- group showed frequent metastasis and death (p=0.01, both) however, for the receptor positive groups, not CD44 but CD24 expression resulted negatively to the overall survival significantly(p=0.01, Relative risk=1.90) on multivariate analysis. For the receptor negative groups, especially triple negative group, lack of CD44 expression made overall decreased to 50%(p=0.03, hazard ratio=0.5) Conclusion: In contrast to cell line studies, CD44+CD24-/low phenotype is considered a favorable prognostic subgroup of breast cancer associated with less frequent nodal metastasis, lower tumor stage and infrequent distant metastasis. For receptor positive breast caner, CD24 expression effect DFS, OS significantly, and For receptor negative group, especially triple negative breast cancer, Lack of CD44 expression made and effect OS inversely.nnCitation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5058.

Prognostic Effect of Sesrum 25 Hydroxyvitamin D Levels in Breast Cancer Patients.

BackgroundThere is increasing evidence that vitamin D has been linked to breast cancer risk, but prognosis effect are unknown. We investigated the possible association between vitamin D and breast cancer prognosis by comparing serum vitamin D levelMethodsFrom June to December 2006, serum 25 OHD were measured in 310 Korean women with breast cancer at the Asan Medical Center. Clinical, Pathologic, and dietary data were accessed to examine prognostic effects of serum 25 OHDResultsMean age was 48.7 years, mean serum 25OHD was 31.4±16.1ng/ml. 25OHD levels were deficient( Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1052.