Youngmee Kwon

Breast cancer subtypes and survival in patients with brain metastases

IntroductionBrain metastases (BM) occur in up to one third of patients with metastatic breast cancer (MBC), whose incidences and prognoses by breast cancer subtypes in BM have not been well delineated.MethodsRetrospective survival analyses were performed in 126 BM patients from 805 MBC patients treated at the National Cancer Center between August 2001 and April 2006, according to clinical characteristics, breast cancer subtypes, and receipt of trastuzumab. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth receptor-2 (HER2) statuses were tested by immunohistochemical (IHC) staining, and HER2 FISH analysis conducted for IHC 2+.ResultsThe proportion of HER2+/ER- (29% vs 16%) and triple-negative (37% vs 25%) tumors was higher in the 126 BM patients than those without BM. While median survival after recurrence was longer in patients with luminal A disease (median survival of luminal A vs luminal B vs HER2+/ER- vs triple-negative: p = 0.0246; 39.6 vs 27.4 vs 20.9 vs 15.5 months), survival was shorter from BM to death in luminal A and triple negatives (median survival: p = 0.0113; 4.0 vs 9.2 vs 5.0 vs 3.4 months). Receipt of trastuzumab after BM was a significant variable for survival in HER2+ patients. Multivariate analyses identified ER-negative, HER2-negative, or triple-negative, as well as older age, presence of leptomeningeal disease, and three or more extracranial disease sites, as poor prognostic factors for survival after BM.ConclusionMBC patients who developed BM had higher proportions of triple-negative and HER2+/ER- tumor status. Triple receptor status is a useful prognostic marker for predicting survival after BM in metastatic breast cancer patients.

Adipokines, insulin resistance, metabolic syndrome, and breast cancer recurrence: a cohort study.

IntroductionSeveral in vitro studies have suggested the effects of adipokines and insulin resistance on breast cancer cell proliferation and survival. However, little is known about the clinical significance of these findings.MethodsWe examined associations between breast cancer recurrence and adiponectin, leptin, insulin resistance, and metabolic syndrome (MetS) in a cohort of 747 patients from 2001 to 2004.ResultsAdjusted hazard ratios showed an inverse trend across the quartiles for serum adiponectin concentration in estrogen receptor (ER)/progesterone receptor (PR) -negative patients (P for trend = 0.027) but not in ER/PR-positive patients. Compared to the highest quartile for adiponectin level, the lowest quartile showed a hazard ratio of 2.82 (1.03 to 7.68). Homeostasis model assessment for insulin resistance (HOMA-IR) showed a positive trend for recurrence in the ER/PR-negative group (P for trend = 0.087) and a negative trend in the ER/PR-positive group (P for trend = 0.081). Leptin did not show any associations (P for trend >0.05). A linear trend was observed with the number of components of MetS in ER/PR-negative patients (P for trend = 0.044). This association disappeared when adjusted for adiponectin and HOMA-IR.ConclusionsAdiponectin and HOMA-IR have prognostic significance in breast cancer recurrence and interventions related to these factors may protect against recurrence in ER/PR-negative patients. These findings were not observed in the case of ER/PR-positive patients. Further evaluation of these insignificant associations is needed because it might be biased by adjuvant chemotherapy or other confounders.

Serum HER-2 concentration in patients with primary breast cancer

Objective: To evaluate whether serum HER-2/neu (HER-2) concentration is a valid index of HER-2 status in women with primary breast cancer, and to establish a normal reference range for serum HER-2 concentration in Korean women. Methods: Serum HER-2 concentration was measured and immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH) carried out on tissue samples from 86 consecutive female patients. The results of the three datasets were compared. The cut off value of HER-2 concentration was determined from the mean +2SD values derived from the serum of 93 healthy volunteers. Results: The IHC and FISH data were significantly correlated (p<0.01), but neither showed significant correlation with the serum HER-2 data. The cut off value of serum HER-2 was 10.2 μg/l, and the serum HER-2 concentration of patients with primary breast cancer ranged from 5.0 to 17.5 μg/l. Only five patients had a serum HER-2 value above the cut off value. Conclusions: Serum HER-2 concentration cannot be substituted for IHC or FISH to evaluate HER-2 status, nor can it be used as a diagnostic tumour marker in primary breast cancer, considering the low prevalence of serum HER-2 elevation.

Tamoxifen-resistant breast cancers show less frequent methylation of the estrogen receptor β but not the estrogen receptor α gene

No reports have examined the association between tamoxifen resistance and the methylation of the estrogen receptor (ER) α and β genes. Therefore we investigated the methylation patterns of the ER genes in the tamoxifen-resistant tumors. We used bisulfite genomic sequencing and reverse transcriptase PCR to determine the methylation patterns and mRNA expression of the two ER genes from control (n=68) and tamoxifen-resistant tissues (n=34) chosen by an age-matched sampling method. Bisulfite genomic sequencing allowed us to reveal the methylation of the ERα gene in 15 of the control tumors (22.1%) and in 11 tumors of the resistant group (32.4%). The methylation of ERβ was observed in 40 control tumors (58.8%) and in 8 recurrent tumors (23.5%). The methylation rate of the ERβ but not the ERα in the control group was significantly higher than in its counterpart (ERα, P=0.261; ERβ, P=0.001). Among the methylated tumors mean methylation density of ERα and ERβ in the resistant cases was significantly elevated (ERα, P=0.014; ERβ, P<0.001). Furthermore, the expression rate of ERβ mRNA was higher among the tumor in the resistant group than in the control with marginal significance (77.8% vs. 38.1%, P=0.109). Additionally, in the cancers from the resistant cases, the cells showed a higher percentage of positive staining for Ki67 than those from the control group (P=0.001). Our study indicates that there is an inverse relationship between the methylation rate of the ERβ gene and tamoxifen resistance. The tamoxifen-resistant tumors showed more dense methylation of the ERβ gene than control tumors. Although the number of case samples was limited, our results support the hypothesis that hypermethylation of the ERβ gene negatively affects the development of tamoxifen resistance.

Decreased Identification Rate of Sentinel Lymph Node after Neoadjuvant Chemotherapy

We prospectively studied the feasibility of sentinel lymph node biopsy (SLNB) after neoadjuvant chemotherapy by comparing the identification rate and the false-negative rate (FNR) with the results obtained from the patients without chemotherapy. From October 2001 to March 2003, a total of 284 consecutive patients who underwent SLNB and axillary lymph node dissection (ALND) at the Center for Breast Cancer, National Cancer Center were enrolled. Of the 284 patients, 54 underwent neoadjuvant chemotherapy prior to operation. The sentinel lymph node (SLN) was mapped by radioactive colloid alone or in combination with blue dye. All SLNs were evaluated by 2 mm serial sections after hematoxylin-eosin staining. The overall SLN identification rate was 91.9% (261/284): 72.2% (39/54) of the patients after chemotherapy and 96.5% (222/230) of the patients without chemotherapy. These results suggest that preoperative chemotherapy significantly affects lymphatic mapping (p< 0.001). Among the patients with chemotherapy, there were 3 false negatives in 39 successfully mapped tumors, yielding an FNR of 11.1% (3/27), a negative prediction value (NPV) of 80.0% (12/15), and an accuracy of 92.3% (36/39). There were 10 false negatives among 222 successfully detected patients without chemotherapy, yielding an FNR of 9.9% (10/101), an NPV of 92.4% (121/131), and an accuracy of 95.5% (212/222). These results were not statistically different when compared (p > 0.05). Although the SLN identification rate significantly decreased after neoadjuvant chemotherapy, SLNB could accurately predict axillary status. Thus SLNB can be an alternative to ALND even after neoadjuvant chemotherapy in cases of successful identification of the SLN.

Metaplastic breast cancer: Clinicopathological features and its prognosis

Aims The prognosis of metaplastic breast cancer (MBC) is reportedly worse than that of triple-negative invasive ductal carcinoma (TN-IDC), but the determinants of poor prognosis are not yet known. Methods Patients from two Korean cancer centres were included in this study (67 MBC and 520 TN-IDC). Characteristics of the two disease groups, including clinical parameters, histological features, chemoresponsiveness, disease recurrence and survival estimates, were evaluated. Results MBC presented with larger tumours, more frequent distant metastasis and higher histological grade compared with TN-IDC (p<0.001). All but nine patients with MBC had triple-negative disease. Disease-free survival and overall survival (OS) of MBC were worse than TN-IDC (p<0.001). Multivariable analysis of disease-free survival revealed MBC type as an independent prognostic factor (HR 2.53; 95% CI 1.32 to 4.84) along with lymph node metastasis and implementation of breast conserving surgery. For OS, MBC type remained a significant prognostic factor (HR 2.56; 95% CI 1.18 to 5.54). Chemoresponsiveness of MBC and TN-IDC were similar in both neoadjuvant (p=1.000) and advanced disease settings (p=0.508). For a given MBC type, risk factors for disease recurrence included the presence of a squamous component (HR 4.0; 95% CI 1.46 to 10.99) and lymph node metastasis (HR 4.76; 95% CI 1.67 to 13.60); the risk factor for OS was initial distant metastasis (HR 10.77; 95% CI 2.59 to 44.76). Conclusions MBC had worse survival outcomes compared with TN-IDC. Poor prognosis for MBC was likely caused by frequent recurrence with high initial stage and the unique biology of MBC itself.

Phase II Parallel Group Study Showing Comparable Efficacy Between Premenopausal Metastatic Breast Cancer Patients Treated With Letrozole Plus Goserelin and Postmenopausal Patients Treated With Letrozole Alone As First-Line Hormone Therapy

PURPOSE Goserelin and letrozole in premenopausal patients can result in clinical outcomes comparable to those obtained by letrozole alone in postmenopausal patients with metastatic breast cancer (MBC). PATIENTS AND METHODS A total of 73 patients with hormone-responsive MBC were included. Of those, 35 premenopausal patients received goserelin (3.6 mg subcutaneously every 28 days) plus letrozole (2.5 mg orally daily), and 38 postmenopausal patients received letrozole alone as their first-line endocrine therapy in a metastatic setting. RESULTS Baseline characteristics were similar in the two groups, except for a younger age (median, 41 v 53.5 years; P < .001) and a shorter disease-free interval (median, 1.8 v 3.3 years; P = .03) in the premenopausal group. Clinical benefit rates were comparable between the two groups (77% v 74%; P = .77). With the median follow-up of 27.4 months, there was no statistical difference in the median time to progression between the two groups (9.5 months [95% CI, 6.4 to 12.1 months] v 8.9 months [95% CI, 6.4 to 13.3 months]). In patients who did not receive bisphosphonate, letrozole +/- goserelin caused a greater loss of bone mineral density at 6 months compared with that of patients receiving bisphosphonate treatment (premenopausal group, -16.7% v 53.9%; P = .002 and postmenopausal group, -13.3% v 17.4%; P = .04 at the lumbar spine). CONCLUSION Clinical efficacies in premenopausal MBC patients with combined letrozole and goserelin therapy were comparable to those in postmenopausal patients treated with letrozole alone. Although letrozole +/- goserelin resulted in a modest increase in bone resorption, concurrent treatment with bisphosphonate could prevent bone loss at 6 months.

True hermaphroditism and mixed gonadal dysgenesis in young children: a clinicopathologic study of 10 cases.

True hermaphroditism (TH) refers to individuals who have both unequivocal ovarian tissue and testicular elements regardless of their karyotypes; whereas mixed gonadal dysgenesis (MGD) refers to individuals who usually have a differentiated gonad on one side and a streak gonad or streak testis on the other side. A differential diagnosis between the TH and MGD has important clinical implications for gender assignment and the decision for early gonadectomy; however, variable clinical and histological features frequently lead to the confusion of TH with MGD. We reviewed the clinicopathological features of TH (n = 4) and MGD (n = 6) in young children to identify which morphological features are important for a differential diagnosis between the two conditions. In both conditions, the testicular compartment was composed of immature seminiferous tubules lined by immature Sertoli cells and primitive germ cells; this finding was not helpful for a differential diagnosis. The ovarian compartment in TH cases showed numerous primordial follicles containing primary oocytes with a few primary or antral follicles; however, ovarian compartments in patients with MGD were characterized by primitive sex-cordlike structures with or without germ cell components within the ovarian-type stroma, mimicking gonadoblastomas in two cases and granulosa cell or Sertoli cell tumors in three cases. Hormonal profiles, cytogenetic results, and an internal duct system were not helpful in a differential diagnosis. In conclusion, a differential diagnosis between TH and MGD is largely dependent on the histological features of the gonads. Therefore, examination of all resected or biopsied tissue and the application of strict histological criteria are important.

The invasive lobular carcinoma as a prototype luminal A breast cancer: A retrospective cohort study

BackgroundAlthough the invasive lobular carcinoma (ILC) is the second most frequent histologic subtype in Western countries, its incidence is much lower in Asia, and its characteristics are less well known.MethodsWe assessed the clinical characteristics and outcomes of 83 Korean patients (2.8%) with ILC for comparison with 2,833 (97.2%) with the invasive ductal carcinoma (IDC), including 1,088 (37.3%) with the luminal A subtype (LA-IDC).ResultsThe mean age of all patients was 48.2 years, with no significant differences among the groups. Compared to IDC, ILC showed a larger tumor size (≥T2, 59.8% vs. 38.8%, P = 0.001), a lower histologic grade (HG 1/2, 90.4% vs. 64.4%, P < 0.001), more frequent estrogen receptor positive (90.4% vs. 64.4%, P < 0.001), progesterone receptor positive (71.1% vs. 50.1%, P < 0.001) and HER2 negative (97.5% vs. 74.6%, P < 0.001) status, and lower Ki-67 expression (10.3% ± 10.6% vs. 20.6% ± 19.8%, P < 0.001), as well as being more likely to be of the luminal A subtype (91.4% vs. 51.2%, P < 0.001). Six (7.2%) ILC and 359 (12.7%) IDC patients developed disease recurrence, with a median follow-up of 56.4 (range 4.9-136.6) months. The outcome of ILC was close to LA-IDC (HR 0.77 for recurrence, 95% CI 0.31-1.90, P = 0.57; HR 0.75 for death, 95% CI 0.18-3.09, P = 0.70) and significantly better than for the non-LA-IDC (HR 1.69 for recurrence, 95% CI 1.23-2.33, P = 0.001; HR 1.50 for death, 95% CI 0.97-2.33, P = 0.07).ConclusionsILC, a rare histologic type of breast cancer in Korea, has distinctive clinicopathological characteristics similar to those of LA-IDC.

Adenocarcinoma Arising in Gastric Heterotopic Pancreas: A Case Report

A heterotopic pancreas in the gastrointestinal tract is mostly found incidentally and its malignant transformation is extremely rare. We describe the second case of adenocarcinoma arising in a gastric heterotopic pancreas of an asymptomatic 35-yr-old man in Korea. Esophagogastroduodenoscopy revealed a submucosal tumor with an irregular central umbilication in the gastric antrum. A wedge resection specimen demonstrated a submucosal oligolocular cystic mass (1.7×1.4×1.2 cm) with a solid portion. Microscopically, the cystic portion was composed of dilated pancreaticobiliary type ducts with adjacent small foci of periductal glandular structures. The adenocarcinoma components in the solid area infiltrated the proper muscle and the overlying mucosa of the stomach. The transitional area between the benign ductal structures and the adenocarcinoma component was found. The follow-up course was uneventful 5 months postoperatively.