Jianrong He

Knocking down cyclin D1b inhibits breast cancer cell growth and suppresses tumor development in a breast cancer model

Cyclin D1 is aberrantly expressed in many types of cancers, including breast cancer. High levels of cyclin D1b, the truncated isoform of cyclin D1, have been reported to be associated with a poor prognosis for breast cancer patients. In the present study, we used siRNA to target cyclin D1b overexpression and assessed its ability to suppress breast cancer growth in nude mice. Cyclin D1b siRNA effectively inhibited overexpression of cyclin D1b. Depletion of cyclin D1b promoted apoptosis of cyclin D1b‐overexpressing cells and blocked their proliferation and transformation phenotypes. Notably, cyclin D1b overexpression is correlated with triple‐negative basal‐like breast cancers, which lack specific therapeutic targets. Administration of cyclin D1b siRNA inhibited breast tumor growth in nude mice and cyclin D1b siRNA synergistically enhanced the cell killing effects of doxorubicin in cell culture, with this combination significantly suppressing tumor growth in the mouse model. In conclusion, the results indicate that cyclin D1b, which is overexpressed in breast cancer, may serve as a novel and effective therapeutic target. More importantly, the present study clearly demonstrated a very promising therapeutic potential for cyclin D1b siRNA in the treatment of cyclin D1b‐overexpressing breast cancers, including the very malignant triple‐negative breast cancers. (Cancer Sci 2011; 102: 1537–1544)

Progesterone receptor status and Ki-67 index may predict early relapse in luminal B/HER2 negative breast cancer patients: a retrospective study.

Purpose Few studies has documented early relapse in luminal B/HER2-negative breast cancer. We examined prognostic factors for early relapse among these patients to improve treatment decision-making. Patients and Methods A total 398 patients with luminal B/HER2-negative breast cancer were included. Kaplan-Meier curves were applied to estimate disease-free survival and Cox regression to identify prognostic factors. Results Progesterone receptor (PR) negative expression was associated with higher tumor grade (p<.001) and higher Ki-67 index (p = .010). PR-negative patients received more chemotherapy than the PR-positive group (p = .009). After a median follow-up of 28 months, 17 patients (4.3%) had early relapses and 8 patients (2.0%) died of breast cancer. The 2-year disease-free survival was 97.7% in the PR-positive and 90.4% in the PR-negative groups (Log-rank p = .002). Also, patients with a high Ki-67 index (defined as >30%) had a reduced disease-free survival (DFS) when compared with low Ki-67 index group (≤30%) (98.0% vs 92.4%, respectively, Log-rank p = .013). In multivariate analysis, PR negativity was significantly associated with a reduced DFS (HR = 3.91, 95% CI 1.29–11.88, p = .016). Conclusion In this study, PR negativity was a prognostic factor for early relapse in luminal B/HER2-negative breast cancer, while a high Ki-67 index suggested a higher risk of early relapse.

Prognostic and predictive value of Ki-67 in triple-negative breast cancer

This study was to investigate the prognostic role of Ki-67 in further classification of triple negative breast cancer (TNBC), and to test whether high expression level of Ki67 can predict benefit from carboplatin. From January 2004 to December 2012, 363 patients operated for TNBC were identified through the institutional clinical database. After a median follow-up time of 34 months (5.2–120.0 months), 62 patients (17.1%) had relapses and 33 patients (9.1%) died of breast cancer. In univariate analysis, high Ki-67 index as well as larger tumor size and lymph node involvement was associated with shorter disease-free survival (DFS) and overall survival (OS). In multivariate analysis, high Ki-67 is an independent risk factor for DFS (Risk Ratio, RR: 2.835, 95% confidence interval, 95% CI: 1.586–5.068, P < 0.001) and OS (RR: 3.180, 95% CI: 1.488–6.793, P = 0.003). When analyzing the 3-year DFS by Ki-67 distribution, Subpopulation Treatment Effect Pattern Plot analysis showed a beneficial effect of carboplatin in patients with high Ki-67 index. In conclusion, TNBC is probably a heterogeneous disease with different characteristics and prognosis, and may be further subdivided according to the Ki-67 expression levels. Patients in the high Ki- 67 group seem to benefit more from treatment with carboplatin, but this needs to be further verified.

Distribution patterns of 21-gene recurrence score in 980 Chinese estrogen receptor-positive, HER2-negative early breast cancer patients

Aim The current study aimed to explore the distribution patterns of 21-gene recurrence score (RS) assay in Chinese early breast cancer patients. Methods Nine hundred and eighty consecutive estrogen receptor(ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer patients treated at Ruijin Hospital, Shanghai Jiaotong University, School of Medicine from 2009 to 2016 were retrospectively recruited. Reverse transcriptase-polymerase chain reaction (RT-PCR) assay of 21 genes were conducted in paraffin-embedded tumor tissue to calculate the RS. Co-relations of RS and clinico-pathologic factors were evaluated. Concordances of RT-PCR and immunohistochemistry (IHC) tests were measured. Logistic regression were applied to determine independent variables associated with RS. Results The median RS of 980 patients was 23(0~90), and the proportions of patients categorized as having a low, intermediate, or high risk were 26.1%, 49.3% and 24.6%. The distribution of RS varied significantly according to different tumor grade, T stage, progesterone receptor(PR) status, Ki67 index and molecular subtypes (p<0.05). Grade, PR status and Ki67 index were identified as independent variables associated with RS. The concordance rates between RT-PCR and IHC test were 98.8% and 88.3% for ER and PR status, and there were weak to moderate correlation between IHC and RT-PCR tests for ER, PR expression and Ki67 index. Conclusions RS correlated significantly with grade, T stage, PR status, Ki67 index and molecular subtypes in Chinese early breast cancer patients. Grade, PR status and Ki67 index could independently predict RS. ER, PR status and Ki67 index between RT-PCR and IHC test had remarkable concordance.

Presence of CHD1L Over-Expression Is Associated with Aggressive Tumor Biology and Is a Novel Prognostic Biomarker for Patient Survival in Human Breast Cancer

Background The chromodomain helicase/adenosine triphosphatase DNA binding protein 1–like gene (CHD1L) is a recently identified oncogene localized at 1q21. CHD1L protein over-expression in primary hepatocellular carcinoma is correlated with enhanced apoptosis inhibition, reduced chemosensitivity and shortened patient survival. However, CHD1L protein status or mRNA expression in breast cancer and its clinical significance remain obscure. Material and Methods In this study, immunohistochemical staining for CHD1L expression was performed on tissue microarrays containing 179 primary invasive breast cancers and 65 matched normal breast tissue specimens. Clinico-pathological features were collected and compared between different CHD1L statuses. Kaplan-Meier curves were applied to estimate disease-free survival (DFS) and overall survival (OS). Cox regression was used to identify independent prognostic factors. Also, quantitative real-time polymerase chain reaction (QRT-PCR) was employed to evaluate the mRNA level expression of CHD1L in six breast cancer cell lines. Results Presence of CHD1L over-expression was observed in 87 of the 179 patients (48.6%), which associated with a younger age (P = 0.011), higher grade (P = 0.004), higher Ki-67 index (P = 0.018) and HER2 over-expression/amplification (P = 0.037). After a median follow-up of 55 months, patients with presence of CHD1L over-expression had significantly poorer DFS (82.6% Vs 76.3%, P = 0.035), but not OS (87.0% Vs 94.9%, P = 0.439). In multivariate analysis, CHD1L status (HR = 2.169, [95%CI, 1.029–4.573], P = 0.042), triple negative subtype (HR = 2.809, [95%CI 1.086–7.264], P = 0.033) and HER2 positive subtype (HR = 5.221, [95%CI 1.788–15.240], P = 0.002) were identified as independent prognostic factors for DFS. In vitro study indicated that relative mRNA expression level of CHD1L was higher in breast cancer cell lines, especially in MDA-MB-231 and LM2-4175, when compared to normal breast epithelial cell line. Conclusions Presence of CHD1L over-expression is probably associated with aggressive tumor biology in breast cancer. CHD1L status might be a novel prognostic biomarker for patients with breast cancer.

Distribution and Clinical Utility of the 21-gene Recurrence Score in Pure Mucinous Breast Cancer Patients: a case-control study

The 21-gene recurrence score (RS) is increasingly being used for patients with early stage, hormone receptor-positive, Her-2-negative breast cancer. However, these results are largely from populations with infiltrating ductal carcinoma (IDC). The clinical value of RS testing in mucinous carcinoma has not been well investigated. Pure mucinous breast cancer (PMBC) and paired pure IDC patients who underwent 21-gene RS were retrospectively reviewed and matched with tumor stage and molecular subtype. Clinic-pathological factors, treatment strategies, and RS distribution were compared between the PMBC and IDC patients. A total of 35 PMBC and 70 IDC patients were included. We found that RS was lower in the PMBC as compared with the IDC group: 21.26 vs. 24.40 (P=0.037). Regarding RS categories, PMBC patients had a relatively lower percentage of high RS patients than the IDC group: 8.57% vs. 22.86% (P = 0.048). Multivariate analysis showed that histologic type was an independent factor predicting RS distribution: IDC patients were associated with a higher RS as compared with PMBC patients (OR: 1.27, 95% CI: 1.03-2.13; P=0.014). Among genes in 21-gene RS testing, HER2, STMY3, STK15, and BAG1 were significantly different between the PMBC and IDC groups (P < 0.05). Two patients (5.71%) in the PMBC group, both with high RS, were recommended to receive adjuvant chemotherapy, much lower than patients with IDC (57.14%, P < 0.001). In multivariate analysis, histologic type of IDC was an independent factor for chemotherapy recommendation (OR = 22.00, 95% CI: 4.89-98.97, P<0.001). With a medium follow-up time of 24 months, one IDC patient had ipsilateral axillary lymph nodes recurrence and one PMBC patient had contralateral breast cancer. In conclusion, PMBC patients, mostly classified with low or intermediate RS category, were associated with lower RS as compared with IDC patients. PMBC and IDC had different genes expression patterns. Patients with high RS in the PMBC group might be recommended to receive adjuvant chemotherapy, which deserves further clinical evaluation.

A nomogram to predict adjuvant chemotherapy recommendation in breast cancer patients with intermediate recurrence score

Objective The indication of adjuvant chemotherapy recommendation (ACR) in breast cancer patients with intermediate recurrence score (RS) is controversial. This study investigated the relationship between routine clinicopathological indicators and ACR, and established a nomogram for predicting the probability of ACR in this subset of patients. Methods Data for a total of 504 consecutive patients with intermediate RS from January 2014 to December 2016 were retrospectively reviewed. A nomogram was constructed using a multivariate logistic regression model based on data from a training set (378 cases) and validated in an independent validation set (126 cases). A Youden-derived cut-off value was assigned to the nomogram for accuracy evaluation. Results The multivariate logistic regression analysis identified that age, histological grade, tumor size, lymph node (LN) status, molecular subtype, and RS were independent predictors of ACR. A nomogram based on these predictors performed well. The P value of the Hosmer-Lemeshow test for the prediction model was 0.286. The area under the curve (AUC) values were 0.905 [95% confidence interval (95% CI): 0.876-0.934] and 0.883 (95% CI: 0.824-0.942) in the training and validation sets, respectively. The accuracies of the nomogram for ACR were 84.4% in the training set and 82.1% in the validation set. Conclusions We developed a nomogram to predict the probability of ACR in breast cancer patients with intermediate RS. This model may aid the individual risk assessment and guide treatment decisions in clinical practice.

Danggui Buxue Decoction, a Classical Formula of Traditional Chinese Medicine, Fails to Prevent Myelosuppression in Breast Cancer Patients Treated With Adjuvant Chemotherapy: A Prospective Study:

Danggui Buxue Decoction (DBD), a classical formula of traditional Chinese medicine (TCM), has an impact on promoting hematopoiesis. The aim of our study was to determine whether DBD can prevent myelosuppression in breast cancer patients treated with adjuvant chemotherapy. We conducted a phase II randomized prospective controlled clinical study. From December 2013 to February 2015, 106 patients were enrolled and randomly assigned (1:1) to the TCM group and control group. The primary end point was incidence of grade 3-4 neutropenia. The secondary end points included incidence of grade 3-4 neutropenia in each cycle, incidence of anemia, and incidence of thrombopenia during 4 cycles. Seventeen patients withdrew from this study, and 89 patients were included in the final analysis. Incidences of grade 3-4 neutropenia during 4 cycles were 57.1% in the TCM group and 59.6% in the control group, and there was no significant difference (P = .816). Similarly, no significant differences were observed between the 2 groups for incidence of grade 3-4 neutropenia in each cycle. While incidences of anemia were 54.8% and 66.6% for the TCM group and control group, respectively (P = .280), incidences of thrombopenia were 11.9% for the TCM group and 4.3% for the control group (P = .248). No significant differences were observed for the incidence of other nonhematological toxicities between the 2 groups. DBD failed to prevent myelosuppression in breast cancer patients treated with adjuvant chemotherapy. Further studies are warranted to validate the efficacy of DBD in selected patients.