Jinghong Guan

Expression of ALDH1 in breast invasive ductal carcinoma: an independent predictor of early tumor relapse

BackgroundThe specific mechanism underlying the contribution of the Aldehyde dehydrogenase 1 (ALDH1) phenotype to metastatic behavior and early tumor relapse in breast cancer is currently unclear.Methods147 randomly selected invasive ductal carcinoma samples were assayed for expression of ALDH1A1, NOTCH1, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2), and association of the ALDH1A1 phenotype with clinic pathological features was further evaluated.ResultsALDH1A1-positive cells were detected in 63.3% (93 of 147) of tumors. 80.0% (32 of 40) of tumors with strong ALDH1A1 staining displayed early recurrence, compared with 20.0% (8 of 40) of tumors negative for ALDH1A1 expression (P = 0.027). ALDH1A1 status was significantly correlated with strong malignant proliferative marker Ki67 staining (P = 0.001), and no significantly different expression of ALDH1A1 across the subtypes of ER, PR, and HER2 expression and triple negative features of tumor tissue. Multivariate regression analysis demonstrated that elevated ALDH1A1 expression is an independent predictor of recurrence-free survival and distant metastasis-free survival. Notably, breast cancer tissue strong for ALDH1A1 expression displayed weak NOTCH1 staining compared to ALDH1A1 weak tumor tissue (P = 0.002), and the relationship between ALDH1A1 and NOTCH1 mRNA positivity was significant (Pearson correlation - 0.337, P = 0.014; Spearman’s rho - 0.376, P = 0.006). Elevated NOTCH1 mRNA level (using a cut-off value based on the median ALDH1A1 2-△△C T value) was associated with reduction of ALDH1A1 mRNA level (P = 0.001).ConclusionsThe ALDH1A1 phenotype is an independent predictor of early tumor relapse characteristic (specifically, incidence of early local recurrence and distant metastasis) of invasive ductal carcinoma. The NOTCH1 signaling pathway is possibly involved in the negative association of the ALDH1A1 phenotype with early malignant relapse in invasive ductal carcinoma.

Diagnostic Performance of Indocyanine Green-Guided Sentinel Lymph Node Biopsy in Breast Cancer: A Meta-Analysis.

Background The diagnostic performance of indocyanine green (ICG) fluorescence-guided sentinel lymph node biopsy (SLNB) for the presence of metastases in breast cancer remains unclear. Objective We performed a meta-analysis to investigate the diagnostic performance of ICG-guided SLNB. Methods Eligible studies were identified from searches of the databases PubMed and EMBASE up to September 2015. Studies that reported the detection rate of ICG fluorescence-guided SLNB with full axillary lymph node dissection and histological or immunohistochemical examinations were included. A meta-analysis was performed to generate pooled detection rate, sensitivity, specificity, false negative rate, diagnostic odds ratio (DOR) and a summary receiver operator characteristic curve (SROC). Results Nineteen published studies were included to generate a pooled detection rate, comprising 2594 patients. The pooled detection rate was 0.98 (95% confidence interval [CI], 0.96–0.99). Six studies finally met the criteria for meta-analysis, which yielded a pooled sensitivity of 0.92 (95% CI, 0.85–0.96), specificity 1 (95% CI, 0.97–1), and DOR 311.47 (95% CI, 84.11–1153.39). The area under the SROC was 0.9758. No publication bias was found. Conclusion ICG fluorescence-guided SLNB is viable for detection of lymph node metastases in breast cancer. Large-scale randomized multi-center trials are necessary to confirm our results.

Pure mucinous carcinoma of the breast: a clinicopathologic analysis with 56 patients.

OBJECTIVE To assess recent trends and prognostic features in the treatment of pure mucinous carcinoma (PMC) of the breast. METHODS Fifty-six patients diagnosed with PMC of the breast in our hospital from December 1982 to June 2008 were included. We evaluated the general information and tumor characteristics of the patients, examined the relationship between these factors and prognosis. Fishers exact test was applied to analyze tumor characteristics. RESULTS The mean age of the patients was 53.7 years. The majority of the patients presented with early stage disease. Tumor size was found not a significant prognostic factor in this study. Mean follow-up period was 39 months and no breast cancer-related deaths were identified in the patient cohort. CONCLUSIONS PMC of the breast has a favorable prognosis. Tumor size does not appear to significantly impact survival.

Ultrasound-Assisted Thoracic Paravertebral Block Reduces Intraoperative Opioid Requirement and Improves Analgesia after Breast Cancer Surgery: A Randomized, Controlled, Single-Center Trial.

Objectives The contribution of ultrasound-assisted thoracic paravertebral block to postoperative analgesia remains unclear. We compared the effect of a combination of ultrasound assisted-thoracic paravertebral block and propofol general anesthesia with opioid and sevoflurane general anesthesia on volatile anesthetic, propofol and opioid consumption, and postoperative pain in patients having breast cancer surgery. Methods Patients undergoing breast cancer surgery were randomly assigned to ultrasound-assisted paravertebral block with propofol general anesthesia (PPA group, n = 121) or fentanyl with sevoflurane general anesthesia (GA group, n = 126). Volatile anesthetic, propofol and opioid consumption, and postoperative pain intensity were compared between the groups using noninferiority and superiority tests. Results Patients in the PPA group required less sevoflurane than those in the GA group (median [interquartile range] of 0 [0, 0] vs. 0.4 [0.3, 0.6] minimum alveolar concentration [MAC]-hours), less intraoperative fentanyl requirements (100 [50, 100] vs. 250 [200, 300]μg,), less intense postoperative pain (median visual analog scale score 2 [1, 3.5] vs. 3 [2, 4.5]), but more propofol (median 529 [424, 672] vs. 100 [100, 130] mg). Noninferiority was detected for all four outcomes; one-tailed superiority tests for each outcome were highly significant at P<0.001 in the expected directions. Conclusions The combination of propofol anesthesia with ultrasound-assisted paravertebral block reduces intraoperative volatile anesthetic and opioid requirements, and results in less post operative pain in patients undergoing breast cancer surgery. Trial Registration ClinicalTrial.gov NCT00418457

Diabetic Mastopathy Mimicking Breast Cancer: Two Case Reports

Diabetic mastopathy (DMP) is a benign fibrous disease of the breast. DMP is closely associated with along-standing history of insulin-dependent diabetes mellitus and often demonstrates a palpable, hard, and nontender mass similar to breast cancer. In our study, excisional biopsy was performed for diagnosis in both patients. DMP is an uncommon benign fibrous disease of the breast that is difficult to differentiate from breast cancer by clinical examination. Breast ultrasonography and mammography are recommended. Core biopsy should be performed if the lesions become clinically or radiologically suspicious. Excisional biopsy should be performed if malignancy cannot be excluded. Regarding mastectomy, we think that the patients preference is very important; physicians can never make decisions for patients no matter how certain we are about nonmalignancy.

Expression and function of MutT homolog 1 in distinct subtypes of breast cancer

Human MutT homolog 1 (MTH1) detoxifies the oxidized DNA precursor 8-oxo-2′-deoxyguanosine-5′-triphosphate and serves a tumor suppressive role in distinct types of cancer. In the present study, the expression of MTH1 was examined in various subtypes of breast cancer, and the effect of its suppression on breast cancer growth was characterized in vitro and in vivo. MTH1 mRNA and protein levels were assessed using the reverse transcription-quantitative polymerase chain reaction and immunohistochemistry. The effect of MTH1 expression on the proliferation of breast cancer cells was investigated in vitro using Cell Counting Kit-8 and colony formation assays, and in vivo using breast cancer cell line xenografts in mice. The toxicity of the MTH1 inhibitor TH588 was investigated in nude mice. A marked increase in MTH1 protein and mRNA levels was demonstrated in breast cancer tissues compared with the non-cancerous control. However, no apparent differences in MTH1 expression were observed between distinct molecular subtypes of breast cancer. MTH1 overexpression was demonstrated to be independent of patient age, tumor size and lymph node metastasis. Inhibition of MTH1 decreased cancer cell viability and the clonogenic potential of cancer cells in a dose-dependent manner. These results were confirmed by decreased in vivo proliferation of MCF7, MDA-MB-231 and MDA-MB-453 cancer cell lines, representing distinct subtypes of breast cancer. Although inhibition of MTH1 activity decreased xenograft growth in mice, no major adverse effects of TH588 were detected on the basis of blood biochemistry, and liver and kidney function. The results of the present study suggested that MTH1 is overexpressed in the majority of breast cancers, independent of the molecular identity and clinicopathological features of the tumor, including patient age, tumor size and lymph node metastasis. Inhibition of MTH1 activity suppressed the growth of three subtypes of breast cancer, including luminal, basal-like and human epidermal growth factor receptor 2-positive, in vitro and in vivo. Treatment with the MTH1 inhibitor appears to be safe; however, further studies are required prior to the clinical use of MTH1 inhibitors.

Abstract P6-05-12: Prognosis of subtypes of the mucinous breast carcinoma in Chinese women: A population-based study of 32-year experience (1983-2014)

Background: The heterogeneous nature of the mucinous breast cancer (MBC), with its subtypes of pure (PMBC) and mixed carcinoma (MMBC), calls for more precise individualized prognosis assessment. PMBC showed favorable prognosis in both Chinese and Caucasian women, with nodal status and TNM stage as the prognostic predictors [PMID: 18026874, 22451233]. However, few studies had investigated tumor biology and prognosis of MMBC in Chinese population, especially with respect to the different co-existing cancer components. Methods: From January 1983 to December 2014, 197 consecutive MBC patients, including 117 PMBC and 80 MMBC, received breast cancer surgery in Peking Union Medical College Hospital. The clinicopathological characteristics, treatment choice, disease-free survival (DFS) and overall survival (OS) were compared both between PMBC vs MMBC, and among subgroups of MMBC according to the mixed entities, including 24 women with ductal caricinoma in situ (DCIS) and 45 with IDC. Univariate and Cox multivariate analyses were performed to identify the prognostic factors. Results: The 197 MBC comprised 1.9% of contemporary 10,192 breast cancer (BC). Compared to PMBC, MMBC had significantly more lymph node metastasis (p=0.038), Her2 positivity (p=0.036), high Ki-67 index (defined as >20%, p=0.026) and anti-Her2 targeted therapy (p=0.006). All these differences remained significant when the comparison were performed among PMBC, MBC+DCIS and MBC+IDC, and additional significant difference were identified in tumor size (p=0.036), pTNM stage (p=0.003) and chemotherapy (p=0.003). However, no significant difference was found in DFS or OS between any two subtypes/subgroups of MBC, including PMBC, MMBC, MBC+DCIS and MBC+IDC. High Ki-67 index (p=0.046) appeared to be the significant DFS related prognostic factor for PMBC, whereas estrogen receptor (ER) status (univariate p=0.000, multivariate p=0.062) and immunophenotype (luminal, her2, or triple-negative, univariate p=0.000, multivariate p=0.079) might be the potential DFS predictors for MMBC. None of the above-mentioned clinicopathological factors could serve as OS predictors for MBC. Conclusion: This population-based study showed that there were significant difference in nodal status, Ki-67, Her2 positivity and targeted therapy between PMBC and MMBC, and furthermore in tumor size, stage and chemotherapy among PMBC and subgroups of MMBC such as MBC+DCIS and MBC+IDC. However, survival outcomes were similar between these clinical entities and subgroups, suggesting the intra-tumoral heterogeneity might not interfere with survival outcomes of MBC in Chinese woman. High Ki-67 index was identified as the significant DFS related prognostic factor for PMBC, whereas ER status and immunophenotype as the potential DFS predictors for MMBC. Citation Format: Yao R, Pan B, Sun Q, Zhou Y, Mao F, Lin Y, Guan J, Wang X, Zhang Y, Zhang X, Shen S, Zhong Y, Xu Y, Shi J, Zhu Q, Cai F, Liang Z. Prognosis of subtypes of the mucinous breast carcinoma in Chinese women: A population-based study of 32-year experience (1983-2014). [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 P6-05-12.

Abstract P5-18-06: Trastuzumab can be safely administered concurrently with anthracycline for adjuvant treatment of HER2-positive breast cancer

Background Anthracycline and trastuzumab are the preferential choices in the treatment of HER2-positive breast cancer. Due to the unacceptably high rates of cardiotoxicity observed in the metastatic breast cancer, concurrent administration of anthracycline and trastuzumab (A+H) is contraindicated. However, in the neoadjuvant setting, A+H has shown high rates of pathological complete response and very low cardiotoxicity. So far, all the large adjuvant trials have only evaluated the sequential strategy of administration anthracycline and trastuzumab (A-H), whereas the safety and efficacy of A+H has never been evaluated prospectively. Thus, we conducted a prospective study to evaluate the cardiac safety and efficacy of A+H regimen in the adjuvant treatment of HER2-positive breast cancer. Methods This is a prospective, randomized and controlled trial. Participants, with HER2-positive, operable breast cancer, but without previous neoadjuvant treatment, were randomized to receive adjuvant A+H or A-H. If anthracycline was administered alone or sequentially to taxane, the dose of doxorubicin and epirubicin was 60mg/m 2 and 90-100mg/m 2 , respectively. If anthracycline was given concurrently with taxane, the dose of doxorubicin and epirubicin was 50mg/m 2 and 75mg/m 2 , respectively. Trastuzumab was given every 3 weeks (loading dose of 8mg/kg, followed by 6mg/kg) for one year. Left ventricular ejection fraction (LVEF) was monitored by echocardiogram (ECHO) at baseline (before chemotherapy) and 3, 6, 9, 12 and 24 months after the initial dose of trastuzumab. The primary endpoint was cardiac safety. The second endpoints were disease-free survival (DFS) and overall survival. ClinicalTrials.gov ID: NCT01413828. Results Between August 2011 and March 2014, 196 HER2-postive breast cancer patients (98 in the A+H group and 98 in the A-H group) were enrolled and randomized. Women in the two groups had similar baseline characteristics including age, tumor stage, hormonal receptor status, chemotherapy regimen, radiation therapy and endocrine therapy. Trastuzumab was well-tolerated in both groups and the primary cardiac event was asymptomatic decrease in LVEF. In the A+H group, there were 11 (11.2%) patients showed more than 10% but less than 20% reduction in LVEF (NCI-CTC Grade I). In the A-H group, there were 14 (14.3%) patients showed NCI-CTC Grade I LVEF reduction and 1 (1.0%) patient showed more than 20% reduction in LVEF (NCI-CTC Grade II). There was no case of congestive heart failure. The difference of the rates of cardiac events between the two groups was not significant ( P =0.400). The mean LVEF of the baseline and 3, 6, 9, 12 and 24 months after initial dose of trastuzumab also showed no difference between the two groups. Patients in both groups had excellent disease control at a median follow up of 16 months. There were numerically more DFS events in the A-H group (6/98, 6.1%) than the A+H group (10/98, 10.2%), but the difference of DFS did not reach the statistical significance ( P =0.485). There was no death in both groups. Conclusions Trastuzumab administered concurrently with anthracycline is a safe adjuvant regimen and might improve the survival of patients with HER2-positvie breast cancer. Citation Format: Songjie Shen, Qiang Sun, Ying Xu, Yidong Zhou, Jinghong Guan, Feng Mao, Yan Lin, Xuejing Wang. Trastuzumab can be safely administered concurrently with anthracycline for adjuvant treatment of HER2-positive breast cancer [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 P5-18-06.