Jun Jie Li

TIEG1 induces apoptosis through mitochondrial apoptotic pathway and promotes apoptosis induced by homoharringtonine and velcade

Overexpression of TGFβ inducible early gene (TIEG1) mimics TGFβ action and induces apoptosis. In this study, we found that TIEG1 was significantly up‐regulated during apoptosis induced by homoharringtonine or velcade. Overexpression of TIEG1 could induce apoptosis in K562 cells and promote apoptosis induced by HHT or velcade. TIEG1‐induced apoptosis was shown to involve Bax and Bim up‐regulation, Bcl‐2 and Bcl‐XL down‐regulation, release of cytochrome c from mitochondria into the cytosol, activation of caspase 3 and disruption of the mitochondrial membrane potential (ΔΨm). We concluded that TIEG1 is a key regulator which induces and promotes apoptosis through the mitochondrial apoptotic pathway.

UHRF1 inhibits MDR1 gene transcription and sensitizes breast cancer cells to anticancer drugs.

Overexpression of MDR1 in breast cancer remains a major cause for the failure of chemotherapy. In the present report, we find UHRF1 plays an important role in inhibiting MDR1 promoter activity by directly binding to the MDR1 promoter. Knockdown of UHRF1 activates MDR1 promoter activity and expression, attenuates the binding of UHRF1 and HDAC1 to the MDR1 promoter. Overexpression of UHRF1 in NCI/ADR-RES cells can induce deacetylation of histones H3 and H4 on the MDR1 promoter, which is facilitated by recruitment of HDAC1 to the MDR1 promoter. Loss of histone acetylation is accompanied by loss of binding of the key transcription factor, MyoD, CBP and p300, locking in marked suppression of MDR1, increasing sensitivity of MDR cancer cells to cytotoxic drugs that are transported by P-glycoprotein (P-gp). The inhibition of MDR1 expression by UHRF1 may provide potential ways to overcome multidrug resistance (MDR) in breast cancer treatment.

The role of mammographic calcification in the neoadjuvant therapy of breast cancer imaging evaluation.

Introduction Investigate the patterns of mammographically detected calcifications before and after neoadjuvant chemotherapy (NACT) to determine their value for efficacy evaluation and surgical decision making. Methods 187 patients with malignant mammographic calcifications were followed to record the appearances and changes in the calcifications and to analyze their responses to NACT. Results Patients with calcifications had higher rates of hormonal receptor (HR) positive tumors (74.3% versus 64.6%) and HER2 positive tumors (51.3% versus 33.4%, p = 0.004) and a similar pathologic complete response (pCR) rate compared to patients without calcifications (35.4% versus 29.8%). After NACT, the range of calcification decreased in 40% of patients, increased in 7.5% and remained stable in 52.5%; the calcification density decreased in 15% of patients, increased in 7.5% and remained stable in 77.5%; none of these change patterns were related to tumor response rate. No significant correlation was observed between the calcification appearance (morphology, distribution, range, diameter or density) and tumor subtypes or pCR rates. Among patients with malignant calcifications, 54 showed calcifications alone, 40 occurred with an architectural distortion (AD) and 93 with a mass. Calcifications were observed inside the tumor in 44% of patients and outside in 56%, with similar pCR rates and patterns of change. Conclusions Calcification appearance did not clearly change after NACT, and calcification patterns were not related to pCR rate, suggesting that mammogram may not accurate to evaluate tumor response changes. Microcalcifications visible after NACT is essential for determining the extent of excision, patients with calcifications that occurred outside of the mass still had the opportunity for breast conservation.

A Straightforward but Not Piecewise Relationship between Age and Lymph Node Status in Chinese Breast Cancer Patients

Purpose To investigate the relationship between age and axillary lymph node (LN) involvement in Chinese breast cancer patients, and to replicate a recently identified piecewise relationship between age and LN involvement. Methods A dataset, consisting of 3,715 patients (with complete information on study variables) with operable breast cancer consecutively surgically treated between 1996 and 2006, was derived from the database of Shanghai Cancer Hospital. Univariate and multivariate logistic regression were employed to analyze the relationship between age and LN. We subsequently performed a similar analysis on another dataset including 1,832 consecutive patients treated between 2007 and 2008 to replicate our findings in the first dataset. Results A U-shaped relationship (previously observed in two European populations) between age and LN status failed to be replicated in our dataset of Chinese patients. Instead, we observed a linear rather than piecewise relationship. After multivariate adjustment, the linear relationship was still present. Moreover, the interaction between age and LN involvement was not modified by tumor size. The odds of LN involvement decreased by 1.5% for each year increase in age (OR 0.985, 95% CI 0.979–0.991, P<0.001). Breast cancer subtypes were also associated with LN status. Proportions of basal-like and ERBB2+ subtypes decreased with increasing age. The observations in the first dataset were successfully replicated in a second independent dataset. Conclusion We confirmed a straightforward but not piecewise relationship between age and LN status in Chinese patients. The different pattern between Chinese and European elderly patients should be considered when making clinical decisions.

Adjuvant chemotherapy increases the prevalence of fat necrosis in immediate free abdominal flap breast reconstruction

BACKGROUND Fat necrosis is one of the most common complications following free flap breast reconstruction. Although a minor complication, fat necrosis can compromise esthetic results and confuse with cancer recurrence. Perfusion-related factors and post-operative radiotherapy are the known risks. However, the influence of adjuvant chemotherapy on fat necrosis prevalence remains unknown. METHODS Our initial experience of 88 consecutive breast reconstructions with free abdominal flaps was reviewed. The prevalence of fat necrosis was recorded and the risk factors were analyzed using univariate and multivariate logistic regression models. RESULTS The overall prevalence of fat necrosis was 36.4% in this series. In a multivariate logistic regression model, adjuvant chemotherapy significantly increased the risk of fat necrosis. The relative risk was 4.762 (95% confidence interval (CI), 1.767-12.831; p = 0.002). There was no evidence of a specific chemotherapeutic agent causing fat necrosis. The first cycle of adjuvant chemotherapy was frequently delivered earlier in patients with fat necrosis than those without fat necrosis, although this tendency was not statistically significant. CONCLUSIONS Our initial experience with free flap breast reconstruction seems to suggest that chemotherapy may increase the risk of fat necrosis following immediate breast reconstruction. Patients should be fully informed, and the initiation of post-operative chemotherapy may be adjusted accordingly.

Adjuvant Therapy of Breast Cancer with Pirarubicin Versus Epirubicin in Combination with Cyclophosphamide and 5-fluorouracil

Abstract:  We performed a retrospective study of 856 breast cancer patients in our hospital, to compare the therapeutic effect of pirarubicin with cyclophosphamide and 5‐fluorouracil (CPF) with the standard epirubicin‐based regimen (CEF) in adjuvant treatment of breast cancer. Patients were given cyclophosphamide and 5‐fluorouracil 500 mg/m2 each, and either pirarubicin 40 mg/m2 or epirubicin 75–100 mg/m2, every 3 weeks, six cycles. A total of 233 patients used CPF and 623 patients used CEF regimen. The clinical and pathologic characteristics were well balanced between the two groups. The median follow‐up time was 41 months, relapse‐free survival (RFS) and overall survival (OS) were similar in both groups, p = 0.561 and p = 0.783, respectively. No treatment‐related congestive heart failure or death was observed in either group. Regardless of chemotherapy regimens, only tumor size, lymph node status, and ER status were predictive factors in multivariate survival analysis. In stratified analysis, the total hazard ratio estimate for RFS was 0.876 (95% CI 0.561–1.369; p = 0.562), not in favor of either regimen, and no significant difference was observed in any subgroups between the two treatment arms. Our study verified that 3 weekly CPF gives the same efficacy and safety as the standard CEF; both CPF and CEF are the effective regimens that can be used in adjuvant chemotherapy of breast cancer.

Pathological complete response as a surrogate for relapse-free survival in patients with triple negative breast cancer after neoadjuvant chemotherapy

We retrospective analyzed triple negative breast cancer (TNBC) patients who received either taxane-based or anthracycline-based neoadjuvant chemotherapy, evaluated whether pathological complete response (pCR) is a surrogate endpoint for relapse free survival (RFS) in TNBC and explored which subgroup of patients benefits more from superior treatment regimen. 186 patients received taxane-based (Group A) or anthracycline-based (Group B) neoadjuvant chemotherapy, median follow-up was 48.1 months. 42 patients received total pCR (ypT0/is ypN0), 34 in Group A and 8 in Group B, p < 0.001. Patients who achieved pCR had an increased RFS when compared with non-pCR patients, p = 0.043. Patients in Group A had a better RFS, p = 0.025, after adjusting for tumor size and clinical lymph node status before neoadjuvant therapy. Only patients sensitive to neoadjuvant chemotherapy exhibited RFS benefit from taxane-based treatment, and those who were treatment insensitive had similar RFS between both groups. Our analysis showed Taxane-based regimen had higher pCR rate and could predict improved RFS in TNBC, and the prognostic value was greater in treatment sensitive patients. This retrospective analysis supports the use of pCR as a surrogate endpoint for RFS in TNBC.

Breast cancer-specific mortality pattern and its changing feature according to estrogen receptor status in two time periods

Purpose To determine whether and how the patterns of breast cancer-specific mortality (BCSM) changed along with time periods. Methods We used the Surveillance, Epidemiology and End Results registry to identify 228209 female patients diagnosed with invasive breast cancer between 1990 and 2000 (cohort 1 [C1], 112981) and between 2001 and 2005 (cohort 2 [C2], 115228). BCSM was compared in two cohorts using Cox proportional hazard regression models. We analysed the relative hazard ratios (HRs) and absolute BCSM rates by flexible parametric survival modelling. Results The patterns of BCSM were similar between the two cohorts, with the peak of mortality presenting in the first 2–3 years after diagnosis, and mortality rate significantly decreased in C2 in all cases. In C2, the annual BCSM rate of all cases was 9.64 (per 1000 persons per year) in year 10 with a peak rate of 23.34 in year 2. In ER-negative and high-risk patients, marked survival improvements were achieved mostly in the first 5 years, while in ER-positive and low-risk patients, survival improvements were less but constant up to 10 years. Conclusion There has been a significant improvement of BCSM with substantially decreased mortality within 5 years. The current pattern of BCSM and its changing feature differs according to ER status. Our findings have some clinical implications both for treatment decisions and adjuvant treatment trial design.

Outcome of Elderly Breast Cancer Patients in China: The Influence of Prognostic Factors and Adjuvant Systemic Therapies

To the Editor: Age is the greatest risk factors for the development of new breast cancer, and the incidence increases with age: 1 in 50 by age 50, 1 in 14 by age 70 and 1 in 9 by age 85 (1). Elderly breast cancer patients have more comorbid diseases (2), often been excluded from large randomized controlled trials (3,4). The optimal managements are still uncertain, but median life expectancy is as long as 14.8 years for women of 70 years, and still 8.4 years for women of 80 years, even though it is often underestimated by clinicians (5). Tumor features, as well as the influence of prognostic factors and adjuvant systemic therapies on survival, of elderly breast cancer in the Chinese population are still not reported. Furthermore, time distribution of tumor recurrence or mortality hazard in the elderly were still unknown. So this retrospective study was performed to analyze the outcome and survival pattern of elderly breast cancer patients in China, and to determine the influence of prognostic factors on survival and the efficiency of adjuvant systemic therapy. Between August 1991 and October 2006, 594 breast cancer patients over 70 years, were treated surgically in our institute. Data recorded on the database included age at diagnosis, date of diagnosis, clinical stage, histopathology features (pathology subtype, lymph node status, tumor size, estrogen ⁄ progesterone receptor [ER ⁄ PgR], Her-2), treatment details (surgery and adjuvant therapy) and survival status. Follow-up information was obtained from hospital and office records and from the patients and their families. Overall survival (OS) and disease-free survival (DFS) were evaluated using Kaplan–Meier curves and the curves were compared by a log rank test. Multivariate analysis was carried out to assess the major significant prognostic factors on DFS and OS, by using the Cox proportional hazards regression model. p < 0.05 was considered statistically significant. The median age at diagnosis was 75.2 ± 4.4 years (range: 70–92 years); 86.7% had infiltrative carcinomas, 22.5% were lymph node positive and 13.2% had tumor larger than 5 cm. The ER, PgR, and Her-2 positive rate were 64.7%, 58%, and 10.4%, respectively. The median follow-up time was 45.5 months. At the time of analysis, 19.3% patients had relapsed and 13.4% died. As shown in Figure 1a, 5 years DFS and OS was 77% and 82%. Figure 1b indicated that both the recurrence and mortality hazard curves for elderly patients showed double-peaked patterns. The first major recurrence surge reaching the maximum was near the 30th month after surgery and the second peak was near the 62th month. The mortality hazard curve reached the early peak at the 36th month, with the late peak near the 65th month. Multivariate analysis showed lymph node, estrogen receptor, chemotherapy and endocrine therapy were independent prognostic factors for DFS and OS (Table 1). Lymph node positive was connected with a higher recurrence risk (hazard ratio, hr: 2.22; 95%CI: 1.34–3.82). ER positive decreased recurrence risk by 41%. Patients received chemotherapy still had a higher relapse risk (hr: 1.66; 95%CI: 1.06–2.74), while receiving endocrine therapy may decrease the relapse risk by 34%. These four factors could also predict overall survival. Node positive diseases presented a 2.53-fold mortality risk compared to node negative, while ER positive diseases showed a better outcome (hr: 0.59; 95%CI: 0.32–0.98). Receiving endocrine therapy may reduce the mortality risk by 43%, while chemotherapy showed no benefit to elderly patients, with a 1.87-fold higher mortality risk. We also analyzed whether lymph node and hormone receptor (HR) status had effect on recurrence time by hazard estimate curves. As shown in Figure 1c, Address correspondence and reprint requests to: Zhi-Min Shao, MD, Department of Breast Surgery, Cancer Hospital ⁄ Cancer Institute, Fudan University; and Department of Oncology, Shanghai Medical College, Fudan University, 399 Ling-Ling Road, Shanghai 200032, China, or e-mail: zhiming shao@yahoo.com.