Mutational Analysis of Triple-Negative Breast Cancer Using Targeted Kinome Sequencing / 한국유방암학회지

Purpose@#Triple-negative breast cancer (TNBC) does not have defined therapeutic targets and is currently treated with chemotherapy only. Kinase dysregulation triggers cancer cell proliferation and metastasis and is a crucial therapeutic target for cancer. In this study, targeted kinome sequencing of TNBC tumors was performed to assess the association between kinome gene alterations and disease outcomes in TNBC. @*Methods@#A kinome gene panel consisting of 612 genes was used for the targeted sequencing of 166 TNBC samples and matched normal tissues. Analyses of the significantly mutated genes were performed. Genomic differences between Asian and non-Asian patients with TNBC were evaluated using two Asian TNBC datasets (from Seoul National University Hospital [SNUH] and Fudan University Shanghai Cancer Center [FUSCC]) and three nonAsian TNBC datasets (The Cancer Genome Atlas [TCGA], METABRIC, and Gustave Roussy).The prognostic value of kinome gene mutations was evaluated using tumor mutational burden (TMB) and oncogenic pathway analyses. Mutational profiles from the TCGA were used for validation. @*Results@#The significantly mutated genes included TP53 (60% of patients), PIK3CA (21%), BRCA2 (8%), and ATM (8%). Compared with data from non-Asian public databases, the mutation rates of PIK3CA p.H1047R/Q were significantly higher in the SNUH cohort (p = 0.003, 0.048, and 0.032, respectively). This was verified using the FUSCC dataset (p = 0.003, 0.078, and 0.05, respectively). The TMB-high group showed a trend toward longer progression-free survival in our cohort and the TCGA TNBC cohort (p = 0.041 and 0.195, respectively). Kinome gene alterations in the Wnt pathway in patients with TNBC were associated with poor survival in both datasets (p = 0.002 and 0.003, respectively). @*Conclusion@#Comprehensive analyses of kinome gene alterations in TNBC revealed genomic alterations that offer therapeutic targets and should help identify high-risk patients more precisely in future studies.

A Randomized Controlled Trial for Doing vs. Omitting Intraoperative Frozen Section Biopsy for Resection Margin Status in Selected Patients Undergoing Breast-Conserving Surgery (OFF-MAP Trial) / 한국유방암학회지

Purpose@#Intraoperative frozen section biopsy is used to reduce the margin positive rate and re-excision rate and has been reported to have high diagnostic accuracy. A majority of breast surgeons in the Republic of Korea routinely perform frozen section biopsy to assess margins intraoperatively, despite its long turnaround time and high resource requirements. This study aims to determine whether omitting frozen section biopsy for intraoperative margin evaluation in selected patients is non-inferior to performing frozen section biopsy in terms of resection margin positivity rate. @*Methods@#This study is a phase III, randomized controlled, parallel-group, multicenter non-inferiority clinical trial. Patients meeting the inclusion criteria and providing written informed consent will be randomized to the “frozen section biopsy” or “frozen section biopsy omission” group after lumpectomy. Patients with clinical stage T1–T3 disease who are diagnosed with invasive breast cancer by core-needle biopsy and plan to undergo breast-conserving surgery will be included in this study. If a daughter nodule, non-mass enhancement, or microcalcification is identified on preoperative imaging, these features must be within 1 cm of the main mass for inclusion in the trial. The target sample size is 646 patients per arm. The primary endpoint will be the resection margin positive rate, and the secondary endpoints include the reoperation rate, operating time, residual cancer after reoperation, residual cancer after re-excision according to the frozen section biopsy result, resection volume, patient quality of life, and cost-effectiveness.Discussion: This is the first randomized clinical trial utilizing frozen section biopsy for intraoperative margin evaluation and aims to determine the non-inferiority of omitting frozen section biopsy in selected patients compared to performing frozen section biopsy.We expect that this trial will help surgeons perform the procedure more efficiently while ensuring patient safety.

Radiologic and Pathologic Findings of Atypical Ductal Hyperplasia in the Male Breast: Case Report and Literature Review

In this case report, we present the radiologic and pathologic findings of atypical ductal hyperplasia (ADH) in the male breast. It is well known that a high-risk lesion such as ADH is a precursor of breast cancer in females. However, the clinical significance of these lesions in the male breast is still uncertain because male breasts mainly consist of ducts without lobule formation, unlike the female breast. To our knowledge, imaging findings of ADH in the male breast have not been reported previously, except for a few studies on the pathologic findings of these lesions. Through this paper, we would like to present the possible imaging features of this high-risk lesion in the male breast and review the related literature.

Can We Skip Intraoperative Evaluation of Sentinel Lymph Nodes? Nomogram Predicting Involvement of Three or More Axillary Lymph Nodes before Breast Cancer Surgery / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The American College of Surgeons Oncology Group Z0011 trial reported that complete dissection of axillary lymph nodes (ALNs) may not be warranted in women with clinical T1-T2 tumors and one or two involved ALNs who were undergoing lumpectomy plus radiation followed by systemic therapy. The present study was conducted to identify preoperative imaging predictors of ≥ 3 ALNs. MATERIALS AND METHODS: The training set consisted of 1,917 patients with clinical T1-T2 and node negative invasive breast cancer. Factors associated with ≥ 3 involved ALNs were evaluated by logistic regression analysis. The validation set consisted of 378 independent patients. The nomogram was applied prospectively to 512 patients who met the Z0011 criteria. RESULTS: Of the 1,917 patients, 204 (10.6%) had ≥ 3 positive nodes. Multivariate analysis showed that involvement of ≥ 3 nodes was significantly associated with ultrasonographic and chest computed tomography findings of suspicious ALNs (p < 0.001 each). These two imaging criteria, plus patient age, were used to develop a nomogram calculating the probability of involvement of ≥ 3 ALNs. The areas under the receiver operating characteristic curve of the nomogram were 0.852 (95% confidence interval [CI], 0.820 to 0.883) for the training set and 0.896 (95% CI, 0.836 to 0.957) for the validation set. Prospective application of the nomogram showed that 60 of 512 patients (11.7%) had scores above the cut-off. Application of the nomogram reduced operation time and cost, with a very low re-operation rate (1.6%). CONCLUSION: Patients likely to have ≥ 3 positive ALNs could be identified by preoperative imaging. The nomogram was helpful in selective intraoperative examination of sentinel lymph nodes.

Axillary Lymph Node to Primary Breast Tumor Standardized Uptake Value Ratio from FDG-PET/CT Imaging for Predicting the Necessity for Nodal Dissection in Primary Breast Tumors

PURPOSE: Accurate preoperative detection by radiologic assessment is necessary to specifically identify patients with at least three positive nodes, who can directly undergo axillary lymph node (ALN) dissection, and avoid unnecessary surgical procedures. We evaluated the usefulness of the standardized uptake value (SUV) ratio of ALN in primary breast tumor, using 18F-fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT) and magnetic resonance imaging (MRI) to predict the necessity of ALN dissection during breast cancer surgery. METHODS: In this retrospective study we enrolled 316 consecutive patients with invasive breast cancer. The SUV ratio of ALN to primary breast tumor uptake was calculated. Optimal cutoff values were determined by receiver operating characteristic curve analysis for predicting the presence of ≥3 ALN metastases. Diagnostic performance of FDG-PET and MRI features for the prediction of ≥3 ALN metastases were determined by sensitivity, specificity, and diagnostic odds ratio (DOR). A subgroup analysis for FDG-avid tumors was also performed. RESULTS: Of the 316 patients, 36 (11.4%) showed involvement of ≥3 ALNs, with 101 (32%) having at least one metastatic lymph node. Axillary 18F-FDG uptake was positive in 75 patients (23.7%), and the optimal ratio of maximum SUV of axillary lymph node and primary tumor for determining ALN dissection was 0.3. MRI scans revealed suspicious ALN involvement in 147 patients (46.6%). The sensitivity and specificity of MRI detection were 88.9% and 56.2%, respectively, while for SUVLN/T ratio, they were 69.4% and 86.8%, respectively. DOR values for MRI and SUVLN/T ratio were 10.37 and 9.7, respectively. The area under the curve (AUC) was improved to 0.896 (95% confidence interval [CI], 0.817–0.975) for the SUVLN/T ratio in patients with FDG-avid primary tumors (FDG ≥3.9, n=108), but the MRI AUC was worsened (0.681; 95% CI, 0.569–0.793). The DOR, sensitivity, and specificity for the SUVLN/T ratio of FDG-avid cancers were 25.68, 89.0% and 86.0%, respectively. CONCLUSION: SUVLN/T ratio outperformed MRI features in predicting the need for ALN dissection in FDG-avid primary breast cancer. PET/CT may be a potential noninvasive diagnostic technique for identifying the presence of ≥3 ALN metastases.

Delay of Treatment Initiation Does Not Adversely Affect Survival Outcome in Breast Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Previous studies examining the relationship between time to treatment and survival outcome in breast cancer have shown inconsistent results. The aim of this study was to analyze the overall impact of delay of treatment initiation on patient survival and to determine whether certain subgroups require more prompt initiation of treatment. MATERIALS AND METHODS: This study is a retrospective analysis of stage I-III patients who were treated in a single tertiary institution between 2005 and 2008. Kaplan-Meier survival analysis and Cox proportional hazards regression model were used to evaluate the impact of interval between diagnosis and treatment initiation in breast cancer and various subgroups. RESULTS: A total of 1,702 patients were included. Factors associated with longer delay of treatment initiation were diagnosis at another hospital, medical comorbidities, and procedures performed before admission for surgery. An interval between diagnosis and treatment initiation as a continuous variable or with a cutoff value of 15, 30, 45, and 60 days had no impact on disease-free survival (DFS). Subgroup analyses for hormone-responsiveness, triple-negative breast cancer, young age, clinical stage, and type of initial treatment showed no significant association between longer delay of treatment initiation and DFS. CONCLUSION: Our results show that an interval between diagnosis and treatment initiation of 60 days or shorter does not appear to adversely affect DFS in breast cancer.

Risk Factors Associated with Distant Metastasis and Survival Outcomes in Breast Cancer Patients with Locoregional Recurrence / 한국유방암학회지

PURPOSE: To decide the optimal treatment for breast cancer patients with locoregional recurrence (LRR), it is important to determine which group has the highest risk of subsequent distant metastasis (DM). We aimed to investigate the factors associated with DM in patients with LRR. METHODS: We reviewed the data of 208 patients with LRR as the first event after primary surgery for breast cancer at our institution between 1997 and 2010, to identify significant factors associated with DM. Subsequently, Kaplan-Meier curves and the Cox regression method were used to analyze the correlation between clinical factors and survival. RESULTS: DM occurred in 33.2% (68/208) of LRR patients. The median DM-free interval was 23 months. Some clinical factors were associated with DM in univariate analysis, including the type of primary surgery (p=0.026), tumor size (p=0.005), nodal status (p=0.011), and administration of initial adjuvant chemotherapy (p=0.001). In addition, regional rather than local recurrence and a disease-free interval (DFI; duration between primary surgery and LRR) < or =30 months were also significant (p<0.001 for both). However, only a shorter DFI reached significance in multiple logistic regression analysis. Cox regression analysis of DM-free survival showed that both a shorter DFI and regional recurrence were significant factors with hazard ratios of 2.1 (95% confidence interval [CI], 1.21-3.65) and 1.85 (95% CI, 1.04-3.28), respectively. CONCLUSION: DFI was the most important factor associated with subsequent DM in patients with LRR as a first event of failure.

Predictive Significance of p53, Ki-67, and Bcl-2 Expression for Pathologic Complete Response after Neoadjuvant Chemotherapy for Triple-Negative Breast Cancer / 한국유방암학회지

PURPOSE: Patients with triple-negative breast cancer (TNBC) with pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) have superior survival outcomes compared to those with residual disease after NAC. This study investigated the value of three biomarkers, p53, Ki-67, and Bcl-2 for predicting pCR in NAC-treated patients with TNBC. METHODS: Between 2003 and 2012, 198 patients with pathologically confirmed primary TNBC were treated with two different taxane-based chemotherapeutic regimens prior to surgery. Before NAC, expression of p53 (cutoff 25%), Ki-67 (cutoff 10%), and Bcl-2 (cutoff 10%) was assessed immunohistochemically in core biopsy specimens. The incidence of pCR was correlated with the expression of these biomarkers. RESULTS: Overall, pCR occurred in 37 of the 198 patients (18.7%). A significant association was observed between the pCR rate and overexpression of the p53 and Ki-67 biomarkers. Multivariate analysis showed that only p53 expression was independently associated with pCR to NAC (odds ratio, 3.961; p=0.003). The sensitivity, specificity, positive predictive value, and negative predictive value of p53 expression for predicting pCR were 77.8%, 50.3%, 26.2%, and 90.9%, respectively. The pCR rate was the lowest (5.2%) in patients with low expression of both p53 and Ki-67, and it was the highest (25.8%) when both biomarkers showed high expression. CONCLUSION: Expression of p53 was significantly associated with pCR after NAC in patients with TNBC, suggesting that this biomarker might be particularly valuable in identifying TNBC patients prone to have residual disease after NAC.

Nomogram for Predicting Breast Conservation after Neoadjuvant Chemotherapy / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The ability to accurately predict the likelihood of achieving breast conservation surgery (BCS) after neoadjuvant chemotherapy (NCT) is important in deciding whether NCT or surgery should be the first-line treatment in patients with operable breast cancers. MATERIALS AND METHODS: We reviewed the data of 513 women, who had stage II or III breast cancer and received NCT and surgery from a single institution. The ability of various clinicopathologic factors to predict the achievement of BCS and tumor size reduction to < or = 3 cm was assessed. Nomograms were built and validated in an independent cohort. RESULTS: BCS was performed in 50.1% of patients, with 42.2% of tumors reduced to < or = 3 cm after NCT. A multivariate logistic regression analysis showed that smaller initial tumor size, longer distance between the lesion and the nipple, absence of suspicious calcifications on mammography, and a single tumor were associated with BCS rather than mastectomy (p < 0.05). Negative estrogen receptor, smaller initial tumor size, higher Ki-67 level, and absence of in situ component were associated with residual tumor size < or = 3 cm (p < 0.05). Two nomograms were developed using these factors. The areas under the receiver operating characteristic curves for nomograms predicting BCS and residual tumor < or = 3 cm were 0.800 and 0.777, respectively. The calibration plots showed good agreement between the predicted and actual probabilities. CONCLUSION: We have established a model with novel factors that predicts BCS and residual tumor size after NCT. This model can help in making treatment decisions for patients who are candidates for NCT.

Postoperative Complications of Laparoscopy-assisted Gastrectomy in Early Gastric Cancer: The Importance of Precise Preoperative Staging

PURPOSE: Although laparoscopy-assisted gastrectomy (LAG) has become a popular treatment option for early gastric cancer, information about postoperative complications is limited in the literature and their risk factors vary among investigators. We analyzed the complications and their risk factors of LAG. METHODS: We performed LAGs in 92 gastric cancer patients from July 2006 to December 2009. LAG indication was gastric cancer preoperatively diagnosed as cT1N0. Clinical and operative data and perioperative complications were retrospectively reviewed. According to the surgical experience, cases were divided into early (1~40) and late (41~92) groups because operative times stabilized after the 40th case. RESULTS: There were no open conversion or mortality cases. Complications occurred in 11 patients. Two of them were non-surgical complications: postoperative delirium and cerebral infarction. Surgical complications were ischemic necrosis of transverse colon, duodenal stump leakage, anastomotic bleeding, leakage and stenosis. Univariate analysis proved that lymph node metastasis, and comorbidities were related to complication rate (P=0.000, P=0.032). Multivariate analysis proved that lymph node metastasis was the most important risk factor of complication (P=0.001). Surgical experience was not related to complication rate (12.5% in early period and 11.5% in late period, P=1.000). CONCLUSION: Complication rate of LAG was acceptable (11.9%). According to this study, unexpected lymph node metastasis is thought to be the most important risk factor for complications of LAG. Therefore, it is possible to accomplish lower complication rates in this procedure with careful patient selection through accurate preoperative evaluation.