Miao Mo

Long non-coding RNA metastasis associated in lung adenocarcinoma transcript 1 (MALAT1) interacts with estrogen receptor and predicted poor survival in breast cancer

Metastasis associated in lung adenocarcinoma transcript 1 (MALAT1), a lncRNA that was first recognized as a prognostic parameter for patient survival of stage I lung cancer, is up-regulated in multiple human malignancies, including breast cancer. However, the mechanism of its function remained elusive. In the current study, by examining MALAT1 expression on mRNA level, we demonstrated that compared with MCF10A, MALAT1 expression was up-regulated in the majority of breast cancer cell lines (9/12). In 26 pairs of estrogen receptor (ER)-positive breast cancer samples, MALAT1 expression was significantly up-regulated compared with adjacent normal tissues (P = 0.012). Furthermore, of 204 breast cancer patients, high MALAT1 expression was associated with positive ER (P = 0.023) and progesterone receptor (PR) (P = 0.024) status. Further analysis using TCGA database revealed that ER and its target genes PGR and CCND1, were overexpressed in MALAT1 altered group compared with unaltered group, both on the mRNA and protein level. Lastly, we verified MALAT1s prognostic value in breast cancer. At the cut-off value of 75%, MALAT1 was the only independent prognostic factor of recurrence-free survival (RFS) in ER-negative patients in a multivariate Cox regression model (hazard ratio [HR] = 2.83, 95% confidence interval [CI] 1.02–7.83). MALAT1 overexpression was also associated with poor RFS in tamoxifen treated ER-positive breast cancer patients, which might serve as a potential biomarker to predict endocrine treatment sensitivity.

Increased waist circumference and prevalence of type 2 diabetes and hypertension in Chinese adults: two population-based cross-sectional surveys in Shanghai, China

Objective To evaluate the changes in body mass index (BMI) and waist circumference (WC) and their associations with the prevalence of hypertension and type 2 diabetes mellitus (T2DM) in Chinese adults. Design 2 consecutive population-based cross-sectional surveys. Setting A total of 12 districts and seven counties in Shanghai, China. Participants 12 329 randomly selected participants of the survey in 2002–2003, and 7423 randomly selected participants of the survey in 2009. All participants were residents of Shanghai aged 35–74 years. Outcome measures Measured BMI and WC. Previously diagnosed and newly identified hypertension and T2DM by measured blood pressure, fasting and postload glucose. Results While the participants of the two surveys were comparable in BMI in each age group, the participants of the 2009 survey had significantly larger WC than those of the 2002–2003 survey, with an annual percentage change being higher among participants aged 45–49 years in men and women. The increase in prevalence of T2DM was observed in all age groups and also appeared more evident in participants aged 45–49 years. The prevalence of hypertension was observed to increase more rapidly in elderly men and middle-aged women. Obesity, both overt and central, was associated with the risk of the two diseases, but BMI was more strongly linked to hypertension while WC appeared more evidently related with T2DM. Conclusions The prevalence of central obesity and related chronic diseases has been increasing in Shanghai, China. Our findings provide useful information for the projection of the growing burden of T2DM and hypertension in Chinese adults.

18F-fluorodeoxyglucose (FDG) PET/CT after two cycles of neoadjuvant therapy may predict response in HER2-negative, but not in HER2-positive breast cancer.

The aim of this prospective study was to assess the ability of 18F-fluorodeoxyglucose (18FDG) positron emission tomography/computed tomography (PET/CT) scanning to predict pathological complete response (pCR) in breast cancer, and to investigate whether timing of the scan and trastuzumab treatment influence the accuracy of pCR prediction in human epidermal growth factor receptor 2 (HER2) positive breast cancer patients. We treated 81 locally advanced breast cancer patients with four cycles of neoadjuvant chemotherapy (NAC). HER2-negative breast cancer patients received NAC alone, while HER2-positive breast cancer patients received NAC plus trastuzumab. 18FDG PET/CT scans were scheduled at baseline and after the second cycle of NAC. Axillary lymph node (ALN) dissection was performed after the last cycle of neoadjuvant therapy. Relative changes in standardized uptake values (SUV) between the two PET/CT scans (ΔSUV) in primary tumors and ALN metastases were calculated. There were 75 patients with 150 PET/CT scans in the final analysis, including 41 HER2-negative and 34 HER2-positive cases. In the HER2-negative group, the ΔSUV predicted overall and ALN pCR; the receiver operating characteristics-areas under curve (ROC-AUC) were 0.87 and 0.80 (P = 0.0014 and 0.031, respectively) and the negative predictive values were 94% and 89% respectively. However, in the HER2-positive group, ΔSUV could predict neither overall nor ALN pCR; the ROC-AUCs were only 0.56 and 0.53, with P = 0.53 and 0.84, respectively. Hence, the ΔSUV after two cycles of neoadjuvant therapy could predict pCR in HER2-negative patients treated with NAC alone, but not in HER2-positive patients treated with NAC plus trastuzumab.

Surgical management of breast cancer in China: A 15-year single-center retrospective study of 18,502 patients

AbstractThe aim of the study was to review the surgical trends in breast cancer treatment in China over the past 15 years and to explore the possible factors related to the choice of surgical modality.The medical records of 18,502 patients with unilateral early stage breast cancer who underwent surgery from January 1999 to December 2013 at our institute were retrospectively reviewed. The utilization of different surgical modalities and the associated clinicopathological factors were analyzed. Furthermore, the prognostic role of surgical modality was also evaluated.The median patient age was 50.0 years. According to the pTNM staging system, 12.5% of the patients were classified as stage 0; 30.2% as stage I; 40.0% as stage II; and 17.3% as stage III. In total, 9.3% of the patients could not be staged. Overall, 67.1% of the breast cancer cases were estrogen receptor (ER) positive. The pattern of breast cancer surgery has changed tremendously over the past 15 years (P < 0.001). The pattern of mastectomy has shifted from radical mastectomy to modified radical mastectomy and simple mastectomy + sentinel lymph node biopsy. A total of 81.7% of the patients underwent mastectomy without immediate reconstruction, 15.2% underwent breast-conserving surgery (BCS), and 3.7% received immediate breast reconstruction after mastectomy. Age, TNM staging, and pathological characteristics greatly affected the choice of surgical modality. The 5-year recurrence-free survival (RFS) rates for the mastectomy, BCS, and reconstruction groups were 87.6%, 93.2%, and 91.7%, respectively (P < 0.001); the RFS rate was likely affected by distant recurrence instead of loco-regional recurrence. We also identified improved RFS over time, stratified by surgical modality and tumor stage. Multivariate Cox-regression analysis revealed that time of treatment, tumor stage, tumor grade, LVI status, and ER status were independent prognostic factors for RFS in our cohort, whereas surgical modality was not.Mastectomy remains the most prevalent surgical modality used to manage early stage breast cancer in China, although the utilization of BCS has increased in the past decade. However, surgical management was not a prognostic factor for RFS. The selection of appropriate patients depended on the assessment of multiple clinicopathological factors, which is essential for making surgical decisions.

Abstract P1-12-02: Effect of using LHRH analog during chemotherapy (CT) on premature ovarian failure and prognosis in premenopausal patients with early-stage, hormone receptor-positive breast cancer: The primary analysis of a randomized controlled phase III trial

Background: Whether administration of LHRH analog during CT in premenopausal patients with early-stage, hormone receptor-positive disease would reduce CT-induced premature ovarian failure (POF) is still controversial. Moreover, whether LHRH analog would influence the prognosis of patients is unknown yet. This randomized study is to evaluate whether administration of LHRH analog during CT would reduce POF and effect the prognosis of breast cancer. Methods: This is arandomized, controlled phase III clinical trial. Premenopausal patients age Results: Between 2/09 and 5/13, the trial has finished enrollment, 216 patients were enrolled. The median age were 37.5 in combined arm (n=108) and 39 in sequential arm (n=108), respectively. The median follow-up time was 27.4 months and 25.7 months, respectively. 15 patients and 21 patients received neoadjuvant CT, respectively. There were no significant difference in age, tumor stage and CT regimens (p>.05). The median cycles of GN were 25, respectively. 47% had complete primary endpoint data. POF rate were 5/42 (11.9%) in the combined arm and 16/60 (26.7%) in the sequential arm. POF rate (and post-menopausal FSH) rate were 1/42 (2.4%) in the combined arm and 8/60 (13.3%) in the sequential arm. In neoadjuvant CT subgroup, each has 1 patient achieved pathological complete remission, and there was no significant difference in objective clinical response. There were 9 patients in the combined arm and 3 patients in the sequential arm had occured RFS events (including 2 and 0 deaths, respectively, OR=3.18, 95%CI:0.84-12.09, P=.075). Conclusions:LHRH analog administration with CT might be associated with less POF and did not affect the efficacy of neoadjuvant CT, however, had no RFS benefit, it may need longer follow-up. We will conduct an interim analysis in November 2014. Clinicaltrials.gov Registry Number: NCT01712893. Citation Format: Jian-Wei Li, Guang-yu Liu, Ke-Da Yu, Ya-jie Ji, Miao Mo, Li Lei, Jiong Wu, Gen-hong Di, Yi-feng Hou, Zhen Hu, Can-ming Chen, Zhen-Zhou Shen, Zhi-Ming Shao. Effect of using LHRH analog during chemotherapy (CT) on premature ovarian failure and prognosis in premenopausal patients with early-stage, hormone receptor-positive breast cancer: The primary analysis of a randomized controlled phase III trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-12-02.

Local recurrence following mastectomy and autologous breast reconstruction: incidence, risk factors, and management.

Background Breast reconstruction (BR), including autologous breast reconstruction (ABR) after mastectomy (MST), has been gaining popularity all around the world, especially in the People’s Republic of China during the past decade. However, there is a small proportion, but a significant number, of patients who develop local recurrence (LR) of breast cancer postoperatively. The purpose of this study is to examine the incidence of LR, discuss risk factors associated with LR, and management of LR following MST and ABR. Methods A total of 397 patients who underwent MST and ABR after diagnosis of breast cancer were included in this retrospective study. Data were analyzed by the Kaplan–Meier method, the log-rank statistical test, and Cox proportional hazards model. Results From January 1999 to December 2011, 400 ABRs were performed in 397 patients in Fudan University Shanghai Cancer Center. The median follow-up time in the study was 3.6 years. LR occurred in 11 of 397 patients, with a median time to LR of 2.9 years. In univariate and multivariate analyses, tumor stage, hormonal therapy (yes or no), and tumor type (multifocal or nonmultifocal) were significantly associated with LR after ABR following MST. Conclusion ABR is an oncologically safe surgical procedure with an acceptable LR rate of 2.8%. Risk factors associated with high rate of LR were higher tumor stage, absence of hormonal therapy, and multifocal tumor type.

Indispensability of Chemotherapy in Estrogen Receptor-Negative Early Breast Cancer in Elderly Women with Diabetes Mellitus

To evaluate whether chemotherapy is indispensable in elderly patients with early estrogen receptor (ER)-negative breast cancer and diabetes mellitus (DM), the data on 112 patients, ≥70 years of age, with early, operable ER-negative breast cancer who were treated at the Cancer Hospital of Fudan University, Shanghai, China, between 2000 and 2010, were analyzed. The overall survival (OS), disease-free survival (DFS), and breast cancer-specific survival (BCS) were compared. Survival analysis was performed using the Kaplan-Meier method. The Cox proportional hazards model was used to evaluate the prognostic value of DM and chemotherapy for OS, DFS, and BCS. The univariate Cox regression analysis revealed that DM at diagnosis, the number of positive lymph nodes, and radiotherapy were associated with OS, the number of positive lymph nodes, human epidermal growth factor 2 (HER2/neu) status, and radiotherapy were associated with DFS, and the number of positive lymph nodes, tumor size, HER2/neu status, chemotherapy, and radiotherapy were associated with BCS. The subsequent multivariate analysis identified DM at diagnosis (hazard ratio [HR]=3.797; 95% confidence interval [CI], 1.515-9.520; P=0.004) as an independent prognostic factor for OS (with the addition of chemotherapy regimen). Chemotherapy was not an independent prognostic factor for either OS (HR=1.275; 95% CI, 0.614-2.646; P=0.515) or DFS (HR=0.849; 95% CI, 0.445-1.619; P=0.619) when other possible factors that may affect the results were adjusted. In conclusion, chemotherapy was not found to be indispensable for elderly (≥70 years of age) female patients with early ER-negative breast cancer with DM because, particularly in such patients, the treatment of DM may be more important compared with chemotherapy.

Serum tumor marker levels might have little significance in evaluating neoadjuvant treatment response in locally advanced breast cancer

BACKGROUND To determine the potential value of serum tumor markers in predicting pCR (pathological complete response) during neoadjuvant chemotherapy. MATERIALS AND METHODS We retrospectively monitored the pro-, mid-, and post- neoadjuvant treatment serum tumor marker concentrations in patients with locally advanced breast cancer (stage II-III) who accepted pre-surgical chemotherapy or chemotherapy in combination with targeted therapy at Fudan University Shanghai Cancer Center between September 2011 and January 2014 and investigated the association of serum tumor marker levels with therapeutic effect. Core needle biopsy samples were assessed using immunohistochemistry (IHC) prior to neoadjuvant treatment to determine hormone receptor, human epidermal growth factor receptor 2(HER2), and proliferation index Ki67 values. In our study, therapeutic response was evaluated by pCR, defined as the disappearance of all invasive cancer cells from excised tissue (including primary lesion and axillary lymph nodes) after completion of chemotherapy. Analysis of variance of repeated measures and receiver operating characteristic (ROC) curves were employed for statistical analysis of the data. RESULTS A total of 348 patients were recruited in our study after excluding patients with incomplete clinical information. Of these, 106 patients were observed to have acquired pCR status after treatment completion, accounting for approximately 30.5% of study individuals. In addition, 147patients were determined to be Her-2 positive, among whom the pCR rate was 45.6% (69 patients). General linear model analysis (repeated measures analysis of variance) showed that the concentration of cancer antigen (CA) 15-3 increased after neoadjuvant chemotherapy in both pCR and non-pCR groups, and that there were significant differences between the two groups (P=0.008). The areas under the ROC curves (AUCs) of pre-, mid-, and post-treatment CA15-3 concentrations demonstrated low-level predictive value (AUC=0.594, 0.644, 0.621, respectively). No significant differences in carcinoembryonic antigen (CEA) or CA12-5 serum levels were observed between the pCR and non-pCR groups (P=0.196 and 0.693, respectively). No efficient AUC of CEA or CA12-5 concentrations were observed to predict patient response toward neoadjuvant treatment (both less than 0.7), nor were differences between the two groups observed at different time points. We then analyzed the Her-2 positive subset of our cohort. Significant differences in CEA concentrations were identified between the pCR and non-pCR groups (P=0.039), but not in CA15-3 or CA12-5 levels (p=0.092 and 0.89, respectively). None of the ROC curves showed underlying prognostic value, as the AUCs of these three markers were less than 0.7. The ROC-AUCs for the CA12-5 concentrations of inter-and post-neoadjuvant chemotherapy in the estrogen receptor negative HER2 positive subgroup were 0.735 and 0.767, respectively. However, the specificity and sensitivity values were at odds with each other which meant that improving either the sensitivity or specificity would impair the efficiency of the other. CONCLUSIONS Serum tumor markers CA15-3, CA12-5, and CEA might have little clinical significance in predicting neoadjuvant treatment response in locally advanced breast cancer.

Accumulation of p53 is prognostic for aromatase inhibitor resistance in early-stage postmenopausal patients with ER-positive breast cancer.

Objective Studies have indicated that p53 protein accumulation exerts an adverse effect on the survival of breast cancer patients; however, the prognostic value of p53 protein accumulation for aromatase inhibitor (AI) resistance in ER-positive breast cancer is uncertain. Methods The expression level of p53 protein was detected by immunohistochemistry in primary early-stage ER-positive breast tumor specimens from 293 postmenopausal breast cancer patients who received first-line AI treatment (letrozole, anastrozole, or exemestane) until relapse, and analysis was performed to determine whether expression of p53 protein affected the response to endocrine therapy. Results Of the 293 invasive ductal carcinomas, 65.4% were positive for p53 protein expression. All patients received AI therapy as first-line treatment until relapse. The 5-year disease-free survival rates in p53-positive and p53-negative patients were 78% and 89%, respectively. Patients with primary breast tumors that had p53 protein accumulation showed significantly more resistance to AI treatment (hazard ratio=1.729, 95% confidence interval=1.038–2.880, P=0.035). Conclusion This study demonstrated that p53 protein accumulation was helpful in choosing patients who may benefit from AI treatment and is a prognostic marker in ER-positive early-stage breast cancer.

Low rate of positive margins and re-excision after partial mastectomy in highly selected breast cancer patients: A Chinese single-institution experience

A recent randomized controlled trial firstly demonstrated that cavity shaving significantly decreased the rate of positive margins and re-excision among partial mastectomy (PM) patients. However, it remains unknown whether cavity shaving should be routinely applied to Chinese breast cancer patients undergoing PM. A total of 408 PM patients undergoing 410 PMs among 1796 surgically treated breast cancer patients at Fudan University Shanghai Cancer Centre from January 2015 to June 2015 were included in our study. Data were analysed with univariate or multivariate analysis. Overall, 11 of 410 cases (2.7%) had positive margins postoperatively. Moreover, only 24.6% of the cases (P<0.05) presented with ductal carcinoma in situ (DCIS), among whom 10.0% obtained positive margins. In multivariate logistic regression analysis, presence of mammographic calcifications was significantly associated with margin positivity (P<0.05, OR=6.06, 95% CI: 1.53-23.91). In conclusion, cavity shaving during PM should not be routinely performed in Chinese breast cancer patients, particularly in highly selected cases with a low prevalence of DCIS. PM patients with preoperative mammographic calcifications were more likely to have positive margins and might benefit more from cavity shaving.