The predictive and prognostic significance of pre- and post-treatment topoisomerase IIα in anthracycline-based neoadjuvant chemotherapy for local advanced breast cancer

Objective

To investigate the predictive and prognostic value of topoisomerase IIα (Topo IIα, Topo II) expression in the primary tumors and residual tumors of local advanced breast cancer (LABC) patients being treated with anthracycline-based neoadjuvant chemotherapy (NCT).

Methods

The data from 283 LABC patients who had been treated with anthracycline-based neoadjuvant chemotherapy were collected. The expression of Topo IIα, HER-2 and other biomarkers was determined via immunohistochemical analysis in pre- and post-chemotherapy specimens. The status of pre-treatment biomarkers was correlated with the clinical response determined by the RECIST 1.1 criteria, whereas the post-treatment biomarkers were studied for prognostic value using the Cox model.

Results

By analyzing the complete data from 99 patients, the co-expression of HER-2/Topo IIα was found to be significantly correlated with the clinical response to chemotherapy (Logistic regression P = 0.042). Notably, a 20% alteration in the Topo IIα status during neoadjuvant chemotherapy was found, which could also influence the sensitivity to treatment. With a survival analysis performed in 245 patients with residual tumors after NCT, node metastasis, HER-2 and Ki-67 were independent predictors of patient outcome. However, post-treatment Topo IIα expression demonstrated significant prognostic value in HER-2+ patients (P = 0.002). A relatively lower disease-free survival and overall survival was observed in HER-2+/Topo- patients (log rank P = 0.010 for DFS and P < 0.001 for OS).

Conclusion

Topo IIα, together with HER-2, might help to select for patients who could benefit from anthracycline-based neoadjuvant chemotherapy and identify non-complete responders at a higher risk of disease recurrence or death.     

A LONGITUDINAL STUDY OF CARDIAC FUNCTION IN CHILDREN WITH CANCER OVER 40 MONTHS

A previous study demonstrated impaired systolic function in 29% of patients treated with an thracycline as part of their therapy for malignant disease. A follow-up echocardiographic study was performed to determine whether there had been further deterioration of cardiac function. At least 40 months after the first study, those patients in whom abnormal systolic function had been detected and who had not received further anthracycline were studied by echocardiography using the same protocol as the initial study (group A). A second group of pediatric oncology patients who had not been given anthracycline but who had previously had cardiac assessment was selected as a control group (group N). The age and sex distributions of the two groups were comparable. Group A comprised 29 patients assessed on 2 occasions at mean times of 46 months and 89 months from the last dose of anthracycline. The mean dose of anthracycline received was 233 mg/m² (range 20-400). Nine of 16 patients and 4 of 5 patients who had abnormal ejection fraction (EF) and fractional shortening (FS) at first assessment had normal EF and FS at the second assessment. There were no significant changes in EF, FS, and left ventricular wall stress (LVWS) between the two examinations. In group N, 20 patients were assessed after a mean interval of 43 months. There were no significant changes in EF, FS, or LVWS between the two examinations. At the first but not the second examination there were significant differences in the left ventricular internal diameters, EF, FS, and LVWS between group A and group N. Mildly abnormal cardiac indices detected in children after cessation of treatment with anthracycline did not deteriorate in 3 to 4 years follow-up. A longer cardiac follow-up study is indicated to assess the late outcome.     

紫杉类药物用于可手术乳腺癌的辅助化疗

目的:蒽环类药物化疗方案中加入紫杉类药物能否提高可手术乳腺癌患者的生存获益.方法:选择2006年1月至2009年1月的初治乳腺癌患者391例,分为不含紫杉类药物组(CEF组138例,CTF组97例),含紫杉类药物组(TEC组98例,TTC组58例).以无病生存作为第一观察终点,以死亡作为第二观察终点.结果:中位随访47个月,不含紫杉类药物组患者中无病生存(DFS)占90.1％,总生存(0S)为97.7％,含紫杉类药物化疗组患者中DFS为90.0％,OS为97.6％,均无明显统计学意义.含紫杉类药物组有较高的Ⅲ度以上白细胞下降率和心脏损害发生率(P＜0.01).结论:蒽环类方案中加入紫杉类药物未显著改善患者DFS和OS.     

蒽环类药物及蒽环序贯紫杉类方案对乳腺癌辅助化疗后心脏毒性的影响

目的 研究蒽环类药物及蒽环序贯紫杉类两种化疗方案,对乳腺癌辅助化疗后引起的心脏毒性影响.方法 乳腺癌辅助化疗患者84例,根据化疗方案的不同,将其分为蒽环类组42例和蒽环序贯紫杉类组42例.蒽环类组患者接受蒽环类药物化疗方案治疗,而蒽环序贯紫杉类组则接受蒽环序贯紫杉类化疗方案治疗.试验过程中,分别于化疗前、首次化疗后及末次化疗次日3个实验时间点上,测定所有研究对象的静脉肌钙蛋白T和肌红蛋白含量,同时借助自制心脏毒性评级表评价患者心脏毒性级别,以评估上述两种化疗方案对患者引起的心脏毒性程度.结果 两种化疗方案组患者在进行辅助化疗后,静脉肌钙蛋白T含量均没有超出正常范围(P<0.1 ng/ml);在末次治疗后,蒽环序贯紫杉类组静脉肌钙蛋白T含量为(0.0210±0.0166)ng/ml,而另外一组为(0.0390±0.0168)ng/ml,前者低于后者,但无统计学意义(P>0.05);两组患者在3个实验时间点上的肌红蛋白含量均未发生明显变化,且均低于21 ng/ml;两组患者末次化疗后心脏毒性评级表情况,未出现明显差异.结论 蒽环序贯紫杉类化疗方案较蒽环类药物化疗方案,并没有引起患者心脏毒性的明显增大;静脉肌钙蛋白T含量及肌红蛋白含量在评估患者心脏毒性程度方面发挥一定的作用,但尚存在进一步优化之处.     

Effects of angiotensin II receptor blocker (candesartan) in daunorubicin-induced cardiomyopathic rats

BACKGROUND: Daunorubicin is an anthracycline anti-tumor agent; anthracycline chemotherapy in cancer can cause severe cardiomyopathy leading to a frequently fatal congestive heart failure; the first-line treatment is diuretics and digoxin. Recently, angiotensin-converting enzyme inhibitors have been shown to be effective in the treatment of such toxicity. The purpose of this study was to investigate the effects of angiotensin II type-1 receptor antagonist (candesartan) in a rat model of daunorubicin-induced cardiomyopathy. METHODS: Rats were treated with a cumulative dose of 9 mg/kg body weight daunorubicin (i.v.). 28 days later, after the development of cardiomyopathy, animals were randomly assigned to candesartan-treated (5 mg/kg/day, p.o.) or vehicle-treated groups; age-matched normal rats were used as the control group. Candesartan treatment was continued for 28 days. Hemodynamic and echocardiographic parameters were measured, cardiac protein and mRNA were analyzed, and histopathological analyses of myocardial fibrosis, cell size and apoptosis were conducted. RESULTS: Following cardiomyopathy, left ventricular end diastolic pressure and left ventricular systolic dimension were significantly elevated; while % fractional shortening and Doppler E/A ratio were significantly reduced. Cardiomyopathic hearts showed significant increases in % fibrosis, % apoptosis, and myocyte diameter/body weight ratio; candesartan treatment reversed these changes. Fas-L protein overexpression in myopathic hearts was significantly suppressed by treatment with candesartan. Moreover, SERCA2 mRNA and protein expression were both down-regulated in myopathic hearts and restored to normal by candesartan treatment, significantly. CONCLUSIONS: Our findings suggest that candesartan treatment significantly improved the left ventricular function and reversed the myocardial pathological changes investigated in this model of daunorubicin-induced cardiomyopathy; suggesting its potentials in limiting daunorubicin cardiotoxicity.     

Doxorubicin and cyclophosphamide followed by weekly docetaxel as neoadjuvant treatment of early breast cancer: analysis of biological markers in a GEICAM phase II study

Introduction  To evaluate the sequential administration of doxorubicin (A) and cyclophosphamide (C) followed by weekly docetaxel in women with stage II to IIIA breast cancer. Patients and methods  Patients received 60 mg/m² of A and 600 mg/m² of C every three weeks for four cycles followed by 12 infusions of weekly docetaxel at a dose of 36 mg/m² and with a 2-week resting period. Results  Sixty-three women were included. On an intentionto-treat basis, clinical response rate was 90% (95% CI: 83–98), with 46% complete responses. Breast-conserving surgery could be performed in 43 patients (68%). Complete pathological responses in the breast were confirmed in 17% of patients. No correlations between levels of expression of topoisomerase II alpha, survivin or p27 and the pathological response were detected. The study treatment was generally well tolerated. Conclusion  Neoadjuvant AC followed by weekly docetaxel is a feasible regimen for patients with early-stage breast cancer.     

乳腺癌晚期的化疗药物研究

目的探讨乳腺癌晚期患者的化疗治疗方案。方法对乳腺癌晚期的常用化疗药物进行研究。结果目前乳腺癌晚期患者进行全面的医治效果不佳,应用诺维本、蒽环类、紫杉类以及吉西他滨药物治疗乳腺癌疗效较高。结论诺维本、蒽环类、紫杉类以及吉西他滨药物治疗乳腺癌晚期患者安全可靠,单用、并用均可。     

A murine experimental anthracycline extravasation model: Pathology and study of the involvement of topoisomerase II alpha and iron in the mechanism of tissue damage

The bisdioxopiperazine topoisomerase II catalytic inhibitor dexrazoxane has successfully been introduced into the clinic as an antidote to accidental anthracycline extravasation based on our preclinical mouse studies. The histology of this mouse extravasation model was investigated and found to be similar to findings in humans: massive necrosis in the subcutis, dermis and epidermis followed by sequestration and healing with granulation tissue, and a graft-versus-host-like reaction with hyperkeratotic and acanthotic keratinocytes, occasional apoptoses, epidermal invasion by lymphocytes and healing with dense dermal connective tissue. The extension of this fibrosis was quantified, and dexrazoxane intervention resulted in a statistically significant decrease in fibrosis extension, as also observed in the clinic. Several mechanisms have been proposed in anthracycline extravasation cytotoxicity, and we tested two major hypotheses: (1) interaction with topoisomerase II alpha and (2) the formation of tissue damaging reactive oxygen species following redox cycling of an anthracycline Fe²⁺ complex. Dexrazoxane could minimise skin damage via both mechanisms, as it stops the catalytic activity of topoisomerase II alpha and thereby prevents access of anthracycline to the enzyme and thus cytotoxicity, and also acts as a strong iron chelator following opening of its two bisdioxopiperazine rings. Using the model of extravasation in a dexrazoxane-resistant transgenic mouse with a heterozygous mutation in the topoisomerase II alpha gene (Top2a^Y165S/+), we found that dexrazoxane provided a protection against anthracycline-induced skin wounds that was indistinguishable from that found in wildtype mice. Thus, interaction with topoisomerase II alpha is not central in the pathogenesis of anthracycline-induced skin damage. In contrast to dexrazoxane, the iron-chelating bisdioxopiperazine ICRF-161 do not inhibit the catalytic cycle of topoisomerase II alpha. This compound was used to isolate and test the importance of iron in the wound pathogenesis. ICRF-161 was found ineffective in the treatment of anthracycline-induced skin damage, suggesting that iron does not play a dominant role in the genesis of wounds.     

Cardiac safety of pegylated liposomal doxorubicin (Doxil/Caelyx) demonstrated by endomyocardial biopsy in patients with advanced malignancies

Although conventional doxorubicin demonstrates broad activity, its clinical use is limited by cardiotoxicity. A more recent analysis suggests conventional doxorubicin-related cardiotoxicity occurs more frequently and at lower cumulative doses than previously reported. Pegylated liposomal doxorubicin, designed to maintain or improve conventional doxorubicin activity while reducing toxicities, has demonstrated improved cardiac safety versus conventional doxorubicin. In this prospective study, we evaluated endomyocardial biopsies to determine the cardiac effects of pegylated liposomal doxorubicin in patients with advanced malignancies receiving doxorubicin-equivalent doses ≥ 550 mg/m² (including pegylated liposomal doxorubicin) or ≥ 400 mg/m² pegylated liposomal doxorubicin alone. Eight patients were enrolled, and 10 biopsy scores were obtained (two patients had two biopsies). Median biopsy score (Billingham scale) was 0.75 (range, 0-1.5) after a median pegylated liposomal doxorubicin dose of 707.5 mg/m² and median total anthracycline exposure of 908.5 mg/m². These results suggest that pegylated liposomal doxorubicin minimizes doxorubicin-related cardiotoxicity, even at doses exceeding the recommended lifetime cumulative conventional dose (450-550 mg/m²).