Ning Liao

HER2-positive status is an independent predictor for coexisting invasion of ductal carcinoma in situ of the breast presenting extensive DCIS component

DCIS of the breast with coexisting invasion is commonly seen, and no consensus on any biomarker capable of discriminating this subgroup has been reached yet. We retrospectively examined the receptor status and the histological grade in Chinese DCIS patients to identify any independent predictor in order to discriminate a subgroup with coexisting invasion from pure DCIS patients. A consecutive Chinese DCIS patient cohort registered at a single institution was included for ER, PR, and HER2 status, as well as for evaluation of the histological grade. Patients with invasion foci >1cm in diameter were excluded. The HER2 gene amplification status was further examined by FISH when the IHC result was HER2 (2+). Molecular subtypes were also profiled. Age, histological grade, ER, PR, and HER2 status were included in association analyses. In total, 183 patients were included. A hundred and forty patients had pure DCIS, and 43 patients had DCIS with invasion. The luminal A subtype accounted for 49.7% of all cases, the HER2-positive subtype for 27.9%, and only 10.4% and 12.0% represented the luminal B and basal-like subtypes, respectively. Univariate analyses showed that histological Grade 2, Grade 3, and HER2-positive status were associated with DCIS with invasion, odds ratios 5.1 (P = 0.017), 5.2 (P = 0.01) and 3.34 (P = 0.001), respectively. However, only the HER2-positive status was of statistical significance in the multivariate logistic regression analyses after adjustment for other markers, odds ratio 3.8 (95%CI 1.4-10, P = 0.008). The 43 cases with invasion were further stratified into extensive or small DCIS components according to the percentage of DCIS to total tumor area using 25% as the cutoff point. Multinomial logistic regression with pure DCIS cases as reference showed that the HER2-positive status was associated only with the group showing an extensive DCIS component, odds ratio 6.2 (95%CI 1.8-21, P = 0.003), but not with the group having a small DCIS component. Our study demonstrates that HER2-positive status is an independent predictor for DCIS, with invasion presenting an extensive DCIS component, and favors the hypothesis that HER2 overexpression or gene amplification is involved in the transition from DCIS to invasive disease.

Guidelines on the diagnosis and treatment of breast cancer (2011 edition)

As the most common malignancy among women, breast cancer seriously endangers the physical and mental health of women. So far, the application of multidisciplinary treatment has made breast cancer one of the most treatment-responsive solid tumors.

Efficacy of intraoperative GeneSearch Breast Lymph Node (BLN) Assay for breast cancer metastasis detection in sentinel lymph node in Chinese patients

Although intraoperative assessment of the sentinel lymph node (SLN) is useful, it has not gained popularity in China as it involves a heavy workload for pathologists. We conducted a prospective clinical feasibility study of the GeneSearch Breast Lymph Node (BLN) Assay performed in 158 SLNs from 97 patients by comparison with postoperative permanent section histopathology, to validate its potential usefulness in China. Every SLN was cut into alternating 1.5 to 3.0 mm slabs. The BLN assay processed 50% of the fresh alternating slabs to detect the presence of cytokeratin 19 and mammaglobin mRNA. Assay results were compared with those for permanent section histopathology and intraoperative imprint cytology. Slides for imprint cytology were prepared from the BLN assay node tissue before it was processed. Full axillary lymph node (ALN) dissections were performed on some patients after a SLN biopsy. The BLN assay was successfully performed on 158 SLNs from 97 patients. Overall performance of the BLN assay compared with permanent section histopathology was sensitivity 83.9% (26/31), specificity 95.5% (63/66), positive predictive value 89.7% (26/29), negative predictive value 92.6% (63/68), and overall agreement 91.8% (89/97). The BLN assay detected about 25% more metastases than imprint cytology. Moreover, the BLN assay correctly identified most of the additional non‐sentinel ALNs metastases (P = 0.005). Our results from a large series of Chinese patients with breast cancer indicate that the BLN assay may be a viable alternative for the standard intraoperative procedures used for metastases detection, especially in early stage breast cancer patients. Name of the trial register: GeneSearch Breast Lymph Node (BLN) Assay China Registration Study. Clinical trial registration number: NCT00869674. (Cancer Sci 2010)

National consensus in China on diagnosis and treatment of patients with advanced breast cancer

The recently available guidelines on the management of advanced breast cancer (ABC) organized by Chinese Anti-Cancer Association, Committee of Breast Cancer Society (CACA-CBCS) do not elucidate ABC in details. To instruct clinicians in treatment of ABC, a Chinese expert consensus meeting on diagnosis and treatment of ABC was held in June 2014 and a consensus is developed. The following consensus provides the level of evidence and supporting documents for each recommendation, and introduces research topics to be urgently addressed. Notably, the consensus on diagnosis and treatment of ABC in China is developed to be applied nationwide. In different areas, multidisciplinary treatment (MDT) tailored to the each patient and the disease itself should be applied based on the basic principles of modern oncology.

Outcomes of re-treatment with first-line trastuzumab plus a taxane in HER2 positive metastatic breast cancer patients after (neo)adjuvant trastuzumab: A prospective multicenter study

Trastuzumab is the backbone of HER2-positive early breast cancer (eBC) and metastatic breast cancer (mBC) treatment, but limited data exist as to re-treatment in relapsed patients. In this prospective, single arm, multicenter trial, we assessed efficacy and safety of trastuzumab and taxane combination in Chinese patients with HER2-positive mBC relapsed after prior (neo)adjuvant trastuzumab. Patients with previous (neo)adjuvant trastuzumab treatment for≥9 weeks and a relapse-free interval ≥6 months were assigned to trastuzumab treatment with paclitaxel or docetaxel. The primary endpoint was progression free survival (PFS). Secondary endpoints included overall response rate (ORR), clinical benefit rate (CBR), duration of response (DOR), time to progression (TTP), overall survival (OS) and safety profile. Thirty-two patients were enrolled and treated for a median duration of 33.5 weeks. The median PFS was 9.9 months (95% CI, 6.28 - 13.63 months). The ORR was 81.3% (95% CI, 63.6% - 92.8%) and CBR (CR+PR+SD≥6months) was 81.3% (95% CI, 63.6% - 92.8%). The median DOR was 9.8 months (95% CI, 5.82 - 11.60 months) and median TTP was 9.9 months (95% CI, 6.28-13.63 months). OS median follow-up time was 20.1 months and 25% OS time was 25.5 months. The safety profile was acceptable with common adverse events including leukopenia (59.4%), neutropenia (56.3%), hypoaesthesia (34.4%) and granulocytopenia (31.3%). In conclusion, re-treatment with trastuzumab plus a taxane as first-line therapy is an effective regimen for patients with HER2-positive mBC relapsed after (neo)adjuvant trastuzumab. The safety profile was good and the adverse reactions were tolerable and manageable.

Presence of circulating tumor cells is associated with metabolic-related variables in postoperative patients with early-stage breast cancer

Objective Although circulating tumor cells (CTCs) have been well-established as promising prognostic biomarkers in both early breast cancer and metastatic settings, little is known regarding the prognostic relevance of CTCs in the long-term postoperative monitoring of patients with non-metastatic breast cancer (non-MBC). In this study, we investigated the associations of CTCs with clinicopathological features and metabolic-related variables, such as obesity and hyperglycemia. Methods In this retrospective study, we recruited 264 patients with postoperative stage I-III breast cancer at Guangdong General Hospital from January 2009 to December 2015. The prevalence and number of CTCs were assessed using the CellSearch System at a median time of 19.0 months [interquartile range (IQR), 7.8-33.0] after surgery. The CTC assay results were correlated with the clinicopathological features and metabolic-related variables. A multivariate logistic regression analysis was performed to further determine the independent predictors of CTCs. Results CTCs were detected in 10.6% of all patients. The positive rate of CTCs in patients with infiltrating ductal carcinoma was lower than that in patients with other pathological types (9.0% vs. 28.6%, P=0.020). More importantly, the presence of CTCs was correlated with blood glucose level (P=0.015) and high-density lipoprotein level (P=0.030). The multivariate logistic regression analysis showed that the pathological type [odds ratio (OR): 1.757, 95% CI: 1.021-3.023; P=0.042] and blood glucose level (OR: 1.218, 95% CI: 1.014-1.465; P=0.035) were independent predictors of the presence of CTCs. Conclusions This study revealed potential associations between CTCs and metabolic-related factors in Chinese patients with non-MBC and supports the hypothesis that metabolic dysfunction in breast cancer patients might influence the biological activity of metastatic breast cancer, leading to a higher prevalence of CTCs.

Abstract P1-01-17: Characterization of novel ESR1 (c.749T>C; p.Met250Thr) mutation in enhancing cellular invasiveness of breast cancer

Emerging evidence has revealed that the mutations in estrogen receptor alpha (ERα) gene (ESR1) is frequently observed in ER+ metastatic breast cancer, and is associated with the aggressively invasive and metastatic phenotype in advanced breast cancer due to the resistance of endocrine therapy. In our previous study, we have identified three novel mutations of ESR1, including ESR1 G74R, D230H and M250T, in the untreated patients with early breast cancer. However, the functional roles for these novel mutations in the cellular biology of breast cancer remain to be elucidated. In this study, we described the molecular mechanism underlying potential roles for the novel mutation ESR1 p.Met250Thr (c.749T>C) in regulating the cellular invasiveness of breast cancer. Firstly, we found, as compared with wild-type (WT) HA-ESR1, forced expression of HA-ESR1 M250T enhanced the invasive capacity of breast cancer MCF-7 cells by using Transwell assay. Moreover, we found that the levels of miR-190 were significantly up-regulated in the MCF-7 (HA-ESR1 M250T) cells, and further verified that miR-190 played an important role in ESR1 M250T-mediated induction of cellular invasiveness by using specific shRNA to knock down miR-190 levels in MCF-7 (HA-ESR1 M250T) cells. Further bioinformatics analysis showed that there were several half Estrogen Response Elements (EREs) in the promoter region of Talin-2, as the host gene of miR-190. Talin-2-driven luciferase reporter assay indicated ESR1 M250T resulted in a higher increase in the luciferase activity than ESR1 WT. Chromatin-immunoprecipitation (ChIP) assay identified a higher binding ability with Talin-2 promoter for ESR1 M250T than ESR1 WT. Collectively, our mechanistic study revealed that the ESR1 M250T mutation, located in the DNA-binding domain, increased the invasive capacity of breast cancer cells via the transcriptional induction of Talin-2 and miR-190. The potential role for ESR1 M250T in affecting the efficacy of endocrine therapy has been under the investigation in our laboratory, and the result from which will help us better elucidate the clinical relevance for novel ESR1 mutations in affecting the sensitivity of endocrine therapy. This study was supported in part by National Natural Science Foundation of China (8160111571) and Guangdong Natural Science Foundation (2016A030313768). Citation Format: Liao N, Zhang G-C, Wang Y, Cao L, Li K, Ren C-Y, Wen L-Z, Shi Y, Zhu W, Chen X. Characterization of novel ESR1 (c.749T>C; p.Met250Thr) mutation in enhancing cellular invasiveness of breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-01-17.

Reply to Span et al.: Mammaglobin RT‐qPCR for breast cancer metastasis detection in sentinel lymph nodes

(Cancer Sci 2010; 101: 2502)

Abstract P1-15-05: HER2 Positivity Correlates to Coexisting Invasion in Ductal Carcinoma In Situ of the Breast

Background: Ductal carcinoma in situ (DCIS) of the breast with coexisting invasion is commonly seen and no consensus on any biomarkers capable of discriminating this subgroup is reached yet. We therefore carried out a retrospective study to investigate the receptor status and histological grade in Chinese DCIS patients aiming to identify if there is any independent predictor that could discriminate the subgroup of DCIS with coexisting invasion from pure DCIS patients. Methods: A Consecutive Chinese DCIS patient cohort in a single institution was included for ER, PR and HER2 status and histological grade evaluation. Patients with invasion foci greater than 1cm in diameter were excluded. For HER2 (2+) cancers by IHC, fluorescence in situ hybridization was performed to examine HER2 gene amplification status. HER2 positive was defined as HER2 (3+) by IHC or HER2 gene amplified. Histological grading was performed only for DCIS component using Van Nuys classification system. Molecular subtypes were also profiled using the following criteria: ER and/or PR positive and HER2 negative as luminal A, ER or PR positive and HER2 positive as luminal B, ER and PR negative while HER2 positive as HER2-positive and ER, PR, HER2 negative as basal-like. Age, histological grade, ER, PR, and HER2 status were included in association analyses using appropriate statistical methods to test if any of these markers independently correlates to DCIS with invasion. Results: Our study included 183 patients in total. Among these patients, 140 had pure DCIS and 43 had DCIS with invasion. Luminal A subtype accounted for 49.7% of all cases, HER2-positive subtype for 27.9% and only 10.4% and 12.0% were luminal B and basal-like subtypes, respectively. Univariate analyses showed that histological grade 2, grade 3 and HER2 positive status were associated with DCIS with invasion, odds ratios 5.1(95%CI 1.3-19, P=0.017), 5.2 (95%CI 1.5-18, P=0.01) and 3.34 (95%CI 1.6 −6.8, P=0.001), respectively. Nonetheless, after adjusting for other markers, only HER2 positivity independently correlates to DCIS with invasion, odds ratio 3.8 (95%CI 1.4 to 10, P=0.008). Consistently, luminal B and HER2-positive subtypes were also correlated to DCIS with invasion and the odds ratio was 3.0 (95%CI 1.0-8.7, P=0.045) and 3.0 (95%CI 1.4-6.6, P=0.005), respectively when compared to luminal A subtype. Basal-like subtype was not correlated to DCIS with invasion, odds ratio 0.50(95%CI 0.11-2.4, P=0.384). Conclusions: Our study suggests that HER2 positivity rather than higher histological grade is the independent predictor for coexisting invasion. ER/PR status and age do not correlate to coexisting invasion. Molecular subtype classification for treatment guidance especially HER2 targeted therapy in DCIS deserves further exploration. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-15-05.