Eunyoung Kang

Intratumoral heterogeneity of HER2 gene amplification in breast cancer: its clinicopathological significance

Intratumoral heterogeneity of human epidermal growth factor receptor 2 (HER2) gene amplification has been reported to occur with variable frequencies in breast cancers. However, there have been few studies of its clinicopathological significance. We used tissue microarrays to evaluate two aspects of intratumoral heterogeneity of HER2 gene amplification: regional heterogeneity and genetic heterogeneity. We examined 96 invasive breast cancers in which HER2 amplification had been diagnosed in whole sections, and determined the clincopathological characteristics of those tumors. HER2 regional heterogeneity, defined as the existence of amplification/negative or amplification/equivocal patterns in different tissue microarray cores of a tumor, was present in 17 (18%) of the 96 cases. HER2 genetic heterogeneity, defined as the presence of tumor cells with a HER2/chromosome enumeration probe 17 ratio higher than 2.2 in 5–50% of the tumor cells, was found in 11 cases (11%), all of which showed HER2 regional heterogeneity. The cases with intratumoral heterogeneity of HER2 gene amplification were characterized by low grade or equivocal HER2 amplification and equivocal (2+) HER2 expression in whole sections. The patients with intratumoral heterogeneity of HER2 gene amplification had significantly shorter disease-free survival times than those with homogeneous HER2 gene amplification, and this effect was also evident in subgroup analysis by hormone receptor status. In multivariate analysis, intratumoral HER2 heterogeneity retained its status as an independent prognostic factor for disease-free survival. In conclusion, intratumoral heterogeneity of HER2 gene amplification is present in a subset of HER2-amplified breast cancers, especially in cases with low-grade HER2 amplification and equivocal HER2 expression, indicating a need for HER2 testing on more representative, larger tumor samples for accurate assessment of HER2 status in such cases. The patients with this heterogeneity have decreased disease-free survival, suggesting that genetic instability, and hence aberrant HER2 amplification in subclones of such tumors, may be associated with breast cancer progression.

High EGFR gene copy number predicts poor outcome in triple-negative breast cancer

Epidermal growth factor receptor (EGFR) is frequently overexpressed in triple-negative breast cancer and is emerging as a therapeutic target. EGFR gene copy number alteration and mutation are highly variable and scientists have been challenged to define their prognostic significance in triple-negative breast cancer. We examined EGFR protein expression, EGFR gene copy number alteration and mutation of exon 18 to 21 in 151 cases of triple-negative breast cancer and correlated these findings with clinical outcomes. In addition, intratumoral agreement of EGFR protein overexpression and gene copy number alteration was evaluated. EGFR overexpression was found in 97 of 151 cases (64%) and high EGFR gene copy number was detected in 50 cases (33%), including 3 gene amplification (2%) and 47 high polysomy (31%). Five EGFR mutations were detected in 4 of 151 cases (3%) and included G719A in exon 18 (n=1), V786M in exon 20 (n=1), and L858R in exon 21 (n=3). One case had two mutations (G719A and L858R). High EGFR copy number, but not EGFR mutation, correlated with EGFR protein overexpression. Intratumoral heterogeneity of EGFR protein overexpression and EGFR copy number alteration was not significant. In survival analyses, high EGFR copy number was found to be an independent prognostic factor for poor disease-free survival in patients with triple-negative breast cancer. Our findings showed that EGFR mutation was a rare event, but high EGFR copy number was relatively frequent and correlated with EGFR overexpression in triple-negative breast cancer. Moreover, high EGFR copy number was associated with poor clinical outcome in triple-negative breast cancer, suggesting that evaluation of EGFR copy number may be useful for predicting outcomes in patients with triple-negative breast cancer and for selecting patients for anti-EGFR-targeted therapy.

FGFR1 is amplified during the progression of in situ to invasive breast carcinoma

IntroductionGene amplification is an important mechanism for activating oncogenes in malignant tumors. Although amplification of HER2, C-MYC, CCND1 and FGFR1 has been reported in breast cancers, their role in the progression of in situ to invasive breast carcinoma is unclear. To investigate this question we compared the amplification frequencies of these genes in pure ductal carcinoma in situ (DCIS), DCIS associated with invasive carcinoma, and invasive carcinoma.MethodsWe performed fluorescence in situ hybridization of the selected genes on tissue microarrays composed of 179 pure DCIS and 438 invasive carcinomas. Two hundred and sixteen of the latter had DCIS components, and in those cases we compared gene amplification in the intraductal and invasive components of each carcinoma.ResultsThe rate of amplification of FGFR1 was higher in invasive carcinomas than in the pure DCIS, but the opposite was true for HER2 amplification. These findings applied consistently to high-grade tumors, but not to low/intermediate-grade tumors. The amplification status of HER2, C-MYC, CCND1 and FGFR1 was generally similar in the matched invasive and DCIS components of the same tumors. However, FGFR1 amplification was more common in the invasive components than in the DCIS components. In survival analyses, FGFR1 amplification was found to be an independent prognostic factor for poor disease-free survival for all patients with invasive carcinoma and for the hormone receptor-positive subgroup.ConclusionAmplification of HER2, C-MYC and CCND1 seems to play a role in the early development of breast cancer, but not in its progression. However, the increased frequency of FGFR1 amplification in invasive carcinomas compared with pure DCIS and in the invasive components of individual tumors, and its association with decreased disease-free survival, suggests a role for FGFR1 amplification in the progression of breast cancer including in situ-to-invasive transition, as well as initiation.

Developmental hemispheric asymmetry of interregional metabolic correlation of the auditory cortex in deaf subjects

The functional connectivity of the auditory cortex might be altered in deaf subjects due to the loss of auditory input. We studied the developmental changes of functional connectivity of the primary auditory cortex (A1) in deaf children, deaf adults, and normal hearing adults by examining interregional metabolic correlation with (18)F-FDG PET. The mean activity of FDG uptake in the cytoarchitectonically defined A1 region served as a covariate in the interregional and interhemispheric correlation analysis. A1 metabolic rate was correlated with that of the ipsilateral superior temporal lobe in both normal and deaf subjects. This correlated area was larger in deaf children than in deaf or normal hearing adults. Concerning the functional connectivity of A1, a hemispheric asymmetry was found in that the extent of interregional correlation was clearly larger in the right than in the left hemisphere. This asymmetry was particularly pronounced in the younger deaf children. Both extent and asymmetry of the functional connectivity of A1 subsided with age. Contrary to this, a correlation between the left and the right primary auditory cortices was absent in younger deaf children but became apparent as they grew older.

Complementary and alternative medicine use and assessment of quality of life in Korean breast cancer patients: a descriptive study

PurposeThe worldwide use of complementary and alternative medicine (CAM) among cancer patients has increased, with breast cancer patients being more likely to use CAM compared with any other cancer patients. However, few surveys have systematically described CAM use among Korean breast cancer patients. This study investigated the use of CAM among patients who were diagnosed with breast cancer, along with the relevant demographic and clinical factors related to CAM use. We also compared the difference in quality of life between CAM users and nonusers.MethodsA total of 661 patients were invited to participate in this study during routine clinic visits, with 425 patients ultimately participating. Three hundred ninety-nine questionnaires were completed and used in the final analysis. Quality of life was evaluated based on the Korean versions of the EORTC QLQ-C30 and EORTC QLQ-BR23.ResultsPrevious or current CAM usage was reported by 229 patients (57.4%). Independent factors related to CAM use were marital status, cancer stage, and coexisting illness. The common types of CAM use included exercise therapy (43.2%) and ingestion of vitamins and minerals (41.9%). The reasons for CAM use were to boost the immune system (53.2%), promote health (46.8%) and prevent recurrence (37.7%). Large proportions (70.4%) of CAM users did not discuss their CAM use with their physicians. Only a small number of CAM users (2.5%) answered that they were unsatisfied with their CAM use, with most CAM users reporting that they would continue their CAM use. Quality of life was not significantly different between CAM users and nonusers.ConclusionsA significant number of patients with breast cancer have used CAM, and health care providers should be aware of the variety of CAM methods and their patients’ CAM uses for the proper management of breast cancer.

Factors Associated with Re-excision after Breast-Conserving Surgery for Early-Stage Breast Cancer

Purpose Re-excisions after breast-conserving surgery (BCS) for breast cancer cause delays in the adjuvant treatment, increased morbidity, and leads to poor aesthetic results. Thus, efforts to reduce the re-excision rate are essential. This study aimed to conclusively determine the re-excision rate and the factors associated with re-excision after BCS. Methods We retrospectively reviewed the medical records and pathological reports of 711 cases that underwent BCS for early-stage breast cancer. Univariate and multivariate analyses were performed. Results Of the 711 cases of BCS, 71 (10.0%) required re-excision. Patients in the re-excision group were younger than those in the no re-excision group. Non-palpable lesions, the presence of non-mass-like enhancement at magnetic resonance imaging, multifocality, the presence of a ductal carcinoma in situ (DCIS) component, and an infiltrative tumor border were also significantly associated with re-excision. Multivariate analysis indicated that younger age, non-palpable lesions, multifocal lesions, and the presence of a DCIS component were factors which were independently associated with re-excision. Tumors located in the lower inner quadrant had a relatively high involved resection margin rate as well as a narrow resection margin width, especially at the superior and medial margins. Lateral margins showed a tendency toward a wider resection margin width. Conclusion At our institution, the rate of re-excision was low despite the lack of an intraoperative frozen section. Patients with non-palpable or multifocal tumors, a DCIS component, or those who were younger than 50 years were more likely to require re-excision after BCS. These factors should be considered when planning surgical management of early-stage breast cancer. Positive resection margin rates and margin widths differed on a directional basis based on tumor location, and these differences were considerable.

Comparison of Quality of Life Based on Surgical Technique in Patients with Breast Cancer

OBJECTIVE More than 80% of women with breast cancer survive for more than 5 years; quality of life is an important issue in these patients. The aim of this study was to assess differences in quality of life among patients who have undergone breast-conserving surgery, total mastectomy and immediate reconstruction after total mastectomy. METHODS A cross-sectional study was conducted during follow-up visits. Women who underwent surgical treatment at least 2 years prior were eligible if they were aged 20-70 years and had a diagnosis of breast cancer (Stages 0-III). Quality of life was evaluated based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire breast cancer-specific module, Rosenberg Self-esteem Scale, Beck Depression Index, Body Image Scale and sexual scale of the Cancer Rehabilitation Evaluation System. RESULTS A total of 407 patients completed the questionnaires; 254 were treated with breast-conserving surgery, 122 with total mastectomy and 31 with reconstruction after total mastectomy. The mean period between surgery and the survey was 49 months. Women in the breast-conserving surgery group showed better outcomes than women in the total mastectomy and reconstruction after total mastectomy groups with respect to emotional-social function, nausea/vomiting, financial difficulty, body image, arm symptoms and self-esteem. Patients in the reconstruction after total mastectomy group had significantly better outcomes on the sexual scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire breast cancer-specific module and arm symptoms than the total mastectomy group. CONCLUSIONS Quality of life was better in the breast-conserving surgery group than in the total mastectomy or reconstruction after total mastectomy groups, and the total mastectomy and reconstruction after total mastectomy groups had similar quality of life. Efforts to evaluate and improve the quality of life of patients with breast cancer should be continued.

Prediction of Postoperative Complications Using Multidimensional Frailty Score in Older Female Cancer Patients with American Society of Anesthesiologists Physical Status Class 1 or 2.

BACKGROUND Even low-risk, elderly patients are at increased risk for postoperative morbidity compared with their younger counterparts. We sought to evaluate the role of a scoring model in predicting adverse surgical outcomes in low-risk, older, female cancer patients. STUDY DESIGN From October 2011 to May 2014, two hundred and eighty-one low-risk female patients (aged 65 years and older, American Society of Anesthesiologists class 1 or 2) undergoing curative cancer surgery were included. The Multidimensional Frailty Score (MFS) was calculated by comprehensive geriatric assessment. The primary end point was postoperative complication (eg, pneumonia, urinary tract infection, delirium, acute pulmonary thromboembolism, and unplanned ICU admission). Secondary outcomes were length of hospital stay and institutionalization. RESULTS Twenty patients experienced postoperative complications and 15 patients were discharged to nursing facilities. The fully adjusted odds ratio (OR) per 1-point increase in MFS was 1.412 (95% CI, 1.012-1.969; p = 0.042) for postoperative complications, 1.377 (95% CI, 0.935-2.026; p = 0.105) for institutionalization, and 1.411 (95% CI, 1.110-1.793; p = 0.005) for prolonged hospital stay. The high-risk group (MFS ≥7) showed an increased risk for postoperative complications (OR = 8.513; 95% CI, 2.210-32.785; p = 0.002), institutionalization (OR = 1.291; 95% CI, 0.324-5.152; p = 0.717), and prolonged hospital stay (OR = 2.336; 95% CI, 1.090-5.006; p = 0.029) compared with the low-risk group (MFS <7), after adjusting confounders. CONCLUSIONS Multidimensional Frailty Score based on a preoperative comprehensive geriatric assessment is useful for predicting postoperative complications and prolonged hospital stay, even in low-risk elderly women who are undergoing cancer surgery.

Ipsilateral and contralateral central lymph node metastasis in papillary thyroid cancer: Patterns and predictive factors of nodal metastasis†

The aims of this study were to evaluate the rate and risk factors of ipsilateral and contralateral central lymph node (CLN) metastases in patients with papillary thyroid cancer (PTC).

Comprehensive spectrum of BRCA1 and BRCA2 deleterious mutations in breast cancer in Asian countries

Approximately 5%–10% of breast cancers are due to genetic predisposition caused by germline mutations; the most commonly tested genes are BRCA1 and BRCA2 mutations. Some mutations are unique to one family and others are recurrent; the spectrum of BRCA1/BRCA2 mutations varies depending on the geographical origins, populations or ethnic groups. In this review, we compiled data from 11 participating Asian countries (Bangladesh, Mainland China, Hong Kong SAR, Indonesia, Japan, Korea, Malaysia, Philippines, Singapore, Thailand and Vietnam), and from ethnic Asians residing in Canada and the USA. We have additionally conducted a literature review to include other Asian countries mainly in Central and Western Asia. We present the current pathogenic mutation spectrum of BRCA1/BRCA2 genes in patients with breast cancer in various Asian populations. Understanding BRCA1/BRCA2 mutations in Asians will help provide better risk assessment and clinical management of breast cancer.