Jiannan Wu

Plasma miR-221 as a Predictive Biomarker for Chemoresistance in Breast Cancer Patients who Previously Received Neoadjuvant Chemotherapy

Background: Neoadjuvant chemotherapy (NAC) is increasingly being used in breast cancer treatment. Research has revealed an elevated expression of miR-221 in adriamycinresistant MCF-7/ADR cells. This study aimed to explore the potential role of miR-221 as a biomarker for chemosensitivity in breast cancer patients who previously received NAC. Patients and Methods: The expression levels of circulating miR-221 in the plasma of 93 breast cancer patients who previously received NAC and in 32 healthy individuals were assessed. The correlations between miR-221 and clinicopathological features and chemosensitivity were also analysed. Results: The expression level of miR-221 was significantly associated with hormone receptor (HR) status (p = 0.008). Patients with higher plasma miR-221 levels tended to be HR-negative. Patients with different miR-221 levels had significant differences in the overall response rate (p = 0.044) but not in the pathologic complete response rate (p = 0.477). Conclusion: Our results indicate that plasma miR-221 may be a predictive biomarker for sensitivity to NAC in breast cancer patients.

The Peripheral Blood Neutrophil-To-Lymphocyte Ratio Is Superior to the Lymphocyte-To-Monocyte Ratio for Predicting the Long-Term Survival of Triple-Negative Breast Cancer Patients

Purpose The peripheral hematologic parameters of patients can be prognostic for many malignant tumors, including breast cancer, although their value has not been investigated among the different molecular subtypes of breast cancer. The purpose of this study was to examine the prognostic significance of the neutrophil-to-lymphocyte ratio (NLR) and the lymphocyte-to-monocyte ratio (LMR) in different molecular subtypes of breast cancer. Methods A retrospective cohort of 1570 operable breast cancer patients was recruited between January 2000 and December 2010. The counts of peripheral neutrophils, lymphocytes, monocytes and platelets were collected and applied to calculate the NLR and the LMR. Univariate and multivariate Cox proportional hazard analyses were used to assess the relationship of the NLR and the LMR with disease-free survival (DFS) and overall survival (OS) in all patients and triple negative breast cancer (TNBC) patients. Results Univariate analysis revealed that lower NLR (≤2.0) and higher LMR (>4.8) were significantly associated with superior DFS in all patients (NLR, P = 0.005; LMR, P = 0.041) and in TNBC patients (NLR, p = 0.007; LMR, P = 0.011). However, multivariate analysis revealed that only lower NLR was a significant independent predictor of superior DFS and OS in all breast cancer patients (DFS, HR = 1.50 95% CI: 1.14–1.97, P = 0.004; OS, HR = 1.63, 95% CI: 1.07–2.49, P = 0.022) and in TNBC patients (DFS, HR = 2.58, 95% CI: 1.23–5.42, P = 0.012; OS, HR = 3.05, 95% CI: 1.08–8.61, P = 0.035). Both univariate and multivariate analysis revealed that neither the NLR nor the LMR significantly predicted DFS and OS among the patients with other molecular subtypes of breast cancer. Conclusions A higher pretreatment peripheral NLR significantly and independently indicated a poor prognosis for breast cancer and TNBC, and this measurement exhibited greater prognostic value than a lower LMR. The NLR was not a prognostic factor for other breast cancer subtypes.

Reduced Let-7a Is Associated with Chemoresistance in Primary Breast Cancer

Chemotherapy resistance remains an important problem in the breast cancer clinic. The ability to predict the patients who would respond to a distinct therapy would help to optimize tailored treatment options. miRNAs can mediate a number of genes in response to drug-induced acute cellular stress. Several studies suggest that let-7 miRNA may be involved in the chemosensitivity of cancer cell lines in vitro. However, it is not known whether this phenomenon occurs in clinical breast tumors. The present study showed that lower let-7a expression was associated with epirubicin resistance in primary breast tumors. Moreover, upregulation of let-7a expression sensitized resistant breast tumor cell lines to epirubicin by enhancing cellular apoptosis in vitro. Collectively, these findings indicate that lower expression of let-7a miRNA can induce chemoresistance in breast cancer by enhancing cellular apoptosis and suggest that let-7a may be used as a therapeutic target to modulate epirubicin-based chemotherapy resistance.

Comparison of ER/PR and HER2 statuses in primary and paired liver metastatic sites of breast carcinoma in patients with or without treatment

PurposeThe aim of this study was to determine whether estrogen receptor (ER)/progesterone receptor (PR) and human epidermal growth factor receptor type 2 (HER2) statuses between primary tumors and paired liver metastatic localizations of breast carcinoma were modified by treatment or during the natural metastatic process.MethodsER, PR, and HER2 expressions were analyzed on paired tissue specimens taken from the primary and the liver metastatic tumors in breast cancer patients. The first group included 46 women who presented with T1–T4, N0–N3, M0 breast carcinoma when first diagnosed and were treated by neoadjuvant therapy or directly underwent surgery, then received postoperative treatment and developed liver metastasis several months/years later. The second group included 12 patients with liver metastatic breast carcinoma when first diagnosed for breast cancer. HER2 status was determined by immunohistochemistry as well as fluorescence in situ hybridization.ResultsAmong the 46 patients in the first group, the ER/PR and HER2 statuses (when considered as a whole histological subtype) were changed between primary tumor and liver metastatic lesions in 12 patients (26.1%). While ER and PR status were modified in 14 (30.4%) and 25 (54.3%) patients, respectively, there were only 5 (10.9%) cases showed a discrepancy in the HER2 status. In the second group, the ER/PR and HER2 statuses (when considered as a whole subtype) were consistent between primary and liver metastatic tumor in 10 of 12 (83.3%) patients. ER, PR, and HER2 statuses were modified in 0 of 12 (0%), 4 of 12 (33.3%), and 1 of 12 (8.3%) cases, respectively.ConclusionsER/PR and HER2 statuses between primary and liver metastatic lesions of breast carcinoma can be modified after treatment but are stable in most cases during the natural metastatic process.

A comparison of survival outcomes and side effects of toremifene or tamoxifen therapy in premenopausal estrogen and progesterone receptor positive breast cancer patients: a retrospective cohort study.

BackgroundIn premenopausal women, endocrine adjuvant therapy for breast cancer primarily consists of tamoxifen alone or with ovarian suppressive strategies. Toremifene is a chlorinated derivative of tamoxifen, but with a superior risk-benefit profile. In this retrospective study, we sought to establish the role of toremifene as an endocrine therapy for premenopausal patients with estrogen and/or progesterone receptor positive breast cancer besides tamoxifen.MethodsPatients with early invasive breast cancer were selected from the breast tumor registries at the Sun Yat-Sen Memorial Hospital (China). Premenopausal patients with endocrine responsive breast cancer who underwent standard therapy and adjuvant therapy with toremifene or tamoxifen were considered eligible. Patients with breast sarcoma, carcinosarcoma, concurrent contralateral primary breast cancer, or with distant metastases at diagnosis, or those who had not undergone surgery and endocrine therapy were ineligible. Overall survival and recurrence-free survival were the primary outcomes measured. Toxicity data was also collected and compared between the two groups.ResultsOf the 810 patients reviewed, 452 patients were analyzed in the study: 240 received tamoxifen and 212 received toremifene. The median and mean follow up times were 50.8 and 57.3 months, respectively. Toremifene and tamoxifen yielded similar overall survival values, with 5-year overall survival rates of 100% and 98.4%, respectively (p = 0.087). However, recurrence-free survival was significantly better in the toremifene group than in the tamoxifen group (p = 0.022). Multivariate analysis showed that recurrence-free survival improved independently with toremifene (HR = 0.385, 95% CI = 0.154-0.961; p = 0.041). Toxicity was similar in the two treatment groups with no women experiencing severe complications, other than hot flashes, which was more frequent in the toremifene patients (p = 0.049). No patients developed endometrial cancer.ConclusionToremifene may be a valid and safe alternative to tamoxifen in premenopausal women with endocrine-responsive breast cancer.

HER-2 positive breast cancer is associated with an increased risk of positive cavity margins after initial lumpectomy

BackgroundThe effect of breast cancer subtype on margin status after lumpectomy remains unclear. This study aims to determine whether approximated breast cancer subtype is associated with positive margins after lumpectomy, which could be used to determine if there is an increased risk of developing local recurrence (LR) following breast-conserving surgery.MethodsWe studied 1,032 consecutive patients with invasive cancer who received lumpectomies and cavity margin (CM) assessments from January 2003 to November 2012. The following data were collected: patient age, cT stage, pT stage, grade, status of CM, lymph node status, menopausal status, ER, PR, HER-2, and Ki67, as well as the presence of extensive intraductal component (EIC) and lymphovascular invasion (LVI). A χ2 test was used to compare categorical baseline characteristics. Univariate and multivariate logistic regression analyses were performed to evaluate associations between pathologic features of CM status. Kaplan-Meier actuarial cumulative rates of LR (ipsilateral in-breast) were calculated.ResultsA total of 7,884 pieces of marginal tissue were collected from 1,032 patients, and 209 patients had positive CMs. Of the patients tested, 52.3% had luminal A subtype, 14.9% were luminal B, 12.8% were luminal-HER-2, 8.1% were HER-2 enriched, and 11.8% were triple negative. Univariate analysis showed that EIC (P <0.001), LVI (P = 0.026), pN stage (N1 vs. N0: P = 0.018; N3 vs. N0: P <0.001), and luminal B (P = 0.001) and HER-2 (P <0.001) subtypes were associated with positive CMs. Multivariable analysis indicated that only EIC (P <0.001), pN stage (P = 0.003), and HER-2 subtype (P <0.001) were significantly correlated with positive CMs. On multivariable analysis, HER-2 subtype was an independent prognostic factor in LR (P = 0.031).ConclusionsThe HER-2 subtype was the predictive factor most associated with positive CMs and an independent prognostic factor for LR. This result suggests that the increased risk of LR in HER-2 breast cancer is due to an increased microscopic invasive tumor burden, which is indicated by margin status after lumpectomy.

Clinical outcomes of 1,578 Chinese patients with breast benign diseases after ultrasound-guided vacuum-assisted excision: recurrence and the risk factors

BACKGROUND The aim of this study was to evaluate the clinical outcomes of 1,578 patients with breast benign diseases after excisions and the risk factors. METHODS AND RESULTS With a median follow-up of 34 months, 69 patients were identified to have recurrence (local recurrence: 45; new lesion: 24). Univariate and multivariate analyses revealed that multiple lesions, a larger lesion size, and a hematoma were independent risk factors for recurrence. Patients with in situ recurrence tended to have fewer lesions and more samples taken per lesion. Patients with new lesions tended to have multiple lesions. After re-excisions, there was no second recurrence events observed in the patients with local recurrence (0/30), whereas 5 patients with new lesions (5/14) were noted to have second recurrence events. CONCLUSIONS Ultrasound-guided vacuum-assisted biopsy for the complete excision of breast benign diseases is safe and effective. Local recurrence and new lesions may have different clinicopathological features and underlying mechanisms. Different management might be given to patients with a different pattern of recurrence.

Significance of Tumor-Infiltrating Lymphocytes and the Expression of Topoisomerase IIα in the Prediction of the Clinical Outcome of Patients with Triple-Negative Breast Cancer after Taxane-Anthracycline-Based Neoadjuvant Chemotherapy

Purpose: The aim of this study was to determine factors able to predict chemotherapeutic responses and clinical outcomes in patients with triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC). Methods: Fifty-two TNBC patients on taxane-anthracycline-based NAC were included. The expression of Ki67, topoisomerase IIα (TOPOIIα), and p53, as well as the presence of CD4+ tumor-infiltrating lymphocytes (TILs) and CD8+ TILs were evaluated in biopsy specimens by immunohistochemistry. The expression of Ki67, TOPOIIα, and p53, as well as CD4 and CD8 in TILs was calculated according to the pathological response to NAC, disease-free survival (DFS), and overall survival (OS). Results: Fourteen (26.9%) TNBC patients demonstrated a pathological complete response (pCR). According to univariate analyses, significant factors associated with pCR were high infiltration of CD4+ TILs (p = 0.004), high infiltration of CD8+ TILs (p = 0.010), and high expression of topoisomerase IIα (TOPOIIα) (p = 0.006). CD4+ TILs and TOPOIIα were significantly positively correlated with CD8+ TILs. Multivariate analyses indicated that TOPOIIα was an independent predictor of pCR. Although TNBC patients with high infiltration of CD4+ TILs, CD8+ TILs, or with high expression of TOPOIIα exhibited a significantly good 5-year DFS, only TNBC patients with a high infiltration of CD8+ TILs exhibited significantly positive 5-year OS probabilities. Conclusion: Our study demonstrated that CD4+ TILs and TOPOIIα in pretreated cancer tissues were significantly correlated with CD8+ TILs. CD4+ TILs, CD8+ TILs, and TOPOIIα expression were predictors of pCR and 5-year DFS of TNBC patients who were treated with NAC, and TOPOIIα was an independent predictor of pCR. CD8+ TILs were a key factor in the prediction of good 5-year OS rates of TNBC patients after taxane-anthracycline-based NAC.

Impact of Breast Cancer Subtype Defined by Immunohistochemistry Hormone Receptor and HER2 Status on the Incidence of Immediate Postmastectomy Reconstruction

Abstract Immediate postmastectomy reconstruction has become an increasingly popular choice for breast cancer patients recently. However, whether molecular subtype of cancer impacts the incidence of breast reconstruction is unclear. We aimed to investigate the association between breast cancer subtype defined by immunohistochemistry hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status and recent rates of immediate postmastectomy reconstruction in the United States. The National Cancer Institutes Surveillance, Epidemiology, and End Results (SEER) database was used to evaluate stage I–III breast cancer patients with different subtypes who underwent either mastectomy alone or mastectomy plus reconstruction between 2010 and 2012. Univariate and multivariate analyses were conducted to identify factors influencing the incidence of immediate reconstruction. Of 47,123 women included, 33.1% (10,712/32,376) of HR+/HER2−, 33.1% (1912/5768) of HR+/HER2+, 29.6% (850/2875) of HR−/HER2+, and 27.7% (1689/6104) of triple negative breast cancer patients received immediate breast reconstruction (chi-square test, P < 0.001), respectively. Thus, HER2-overexpressing and triple negative breast cancer patients received significantly less breast reconstruction. After adjusting for demographic, socioeconomic, geographic, or clinicopathologic factors, HER2-overexpressing (OR 0.896, 95% CI 0.817–0.984) and triple negative (OR 0.806, 95% CI 0.751–0.866) breast cancer patients remained less likely to undergo immediate postmastectomy reconstruction compared with HR+/HER2− or HR+/HER2+ patients. No significant difference was found in the type of reconstruction among different subtypes. Subgroup analysis showed that the difference of breast reconstruction rates among distinct subtypes varied with different grade and stage groups, and the association between breast cancer subtype and the reconstruction rate was not significant in low grade and early stage patients. This population-based study determined that breast cancer subtype was an independent predictor for the utilization of immediate postmastectomy reconstruction. Patients with HER2-overexpressing or triple negative breast cancer subtype that has relatively higher risk of local recurrence, were less likely to receive immediate breast reconstruction than those with luminal tumors. Further studies are needed to disclose more underlying reasons of different reconstruction incidences for distinct subtypes of breast cancer.

Combined Let-7a and H19 Signature: A Prognostic Index of Progression-Free Survival in Primary Breast Cancer Patients

Purpose The long non-coding RNA H19, a conservatively imprinted gene, acts as a molecular sponge for the let-7 family, which has been identified as a set of tumor suppressors. However, the combined prognostic value of H19 and let-7a signature in breast cancer patients remains unclear. Methods In this research we assessed the prognostic value of the combined H19 and let-7a signature in breast cancer patients by retrospectively reviewing that data of 79 patients who underwent neoadjuvant chemotherapy; we also investigated the expression and function of H19 in breast cancer cell lines in vitro. Survival data were calculated using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate survival analyses were conducted using the Cox proportional hazards regression method. As determined using X-tile, the optimal cutoff value for the risk score to assess progression-free survival (PFS) based on the combined signature was –0.1. Results Patients with an overall positive treatment response had higher let-7a and lower H19 levels. In addition, let-7a expression was negatively correlated with H19 expression. Patients with a risk score of >–0.1 had shorter overall survival and PFS. In vitro data showed that chemoresistant cell lines exhibit higher H19 and lower let-7a levels and knockdown H19 restores paclitaxel sensitivity. Conclusion Our results suggest that the combined let-7a and H19 signature is a novel prognostic factor for breast cancer patients treated with neoadjuvant chemotherapy.