跨线曲妥珠单抗联合不同化疗方案治疗HER2阳性晚期乳腺癌的临床研究

目的 观察跨线曲妥珠单抗联合不同化疗方案治疗人表皮生因子受体2（human epidermal growth factor receptor 2, HER2）阳性晚期乳腺癌的疗效、不良反应和生存期。方法 收集2009年1月至2014年6月间应用跨线曲妥珠单抗（H）联合不同化疗方案治疗HER2阳性的晚期乳腺癌患者71例,均完成一线H治疗,30例患者疾病进展后继续二线H治疗,19例患者疾病再次进展后继续三线H治疗,主要观察疗效、不良反应、生存情况及预后分析。结果 一、二、三线治疗中,曲妥珠单抗联合紫杉类方案和联合非紫杉类方案相比在有效率（RR）和临床获益率（clinical benefit rate, CBR）方面差异均无统计学意义（P＞0.05）。一、二、三线治疗的中位无进展生存时间（PFS）和中位总生存时间（OS）分别为14、9、4月和26、39、53月,总的中位PFS为11月,总的中位OS为36月。一线治疗的PFS较二、三线治疗明显延长（P=0.000）,曲妥珠单抗持续应用至三线的中位OS较仅一线治疗的有延长（P=0.008）。全组患者的1、2、3年生存率分别为88%、66%、39%。71例患者中14例出现了17次心脏相关事件,1例患者因左心室射血分数（LVEF）下降至48%停止曲妥珠单抗治疗,无治疗相关性死亡发生。在OS的Log rank单因素分析中,术后淋巴结转移的个数、有无脑转移、治疗线数、一线治疗的PFS时间与OS有关（P=0.026, P=0.042, P=0.028, P=0.005）。在OS的多因素Cox比例风险模型分析中,治疗线数、有无脑转移、DFS和一线PFS时间为对OS有影响的独立因素（P=0.004,P=0.021, P=0.018, P=0.000）。结论 在HER-2阳性晚期乳腺癌治疗中,疾病进展后跨线曲妥珠单抗联合化疗的疗效优于未继续使用曲妥珠单抗的方案,曲妥珠单抗的跨线使用可以使患者持续获益,跨线曲妥珠单抗联合化疗的方案疗效确切,不良反应可以耐受,值得进一步研究。     

Role of cardioprotective therapy for prevention of cardiotoxicity with chemotherapy: A systematic review and meta-analysis

BackgroundCardiotoxicity is a well-recognised complication of chemotherapy with anthracycline and/or trastuzumab, and its prevention remains an important challenge in cancer survivorship. Several successful preventative strategies have been identified in animal trials. We sought to assemble the clinical evidence that prophylactic pharmacological interventions could prevent left ventricular (LV) dysfunction and heart failure in patients undergoing chemotherapy.MethodsWe undertook a systemic review of the evidence from randomised trials and observational studies where a prophylactic intervention was compared with a control arm in patients with a normal ejection fraction and no past history of heart failure. The primary outcome was development of heart failure (HF), a drop in ejection fraction (EF) or both. A random-effects model was used to combine relative risks (RR) and 95% confidence intervals (CIs), and a meta-regression was undertaken to assess the impact of potential covariates.FindingsData were collated from 14 published articles (n = 2015 paediatric and adult patients) comprising 12 randomised controlled trials and two observational studies. The most studied chemotherapeutic agents were anthracyclines, and prophylactic agents included dexrazoxane, statins, beta-blocker and angiotensin antagonists. There were 304 cardiac events in the control arm compared to 83 in the prophylaxis arm (RR = 0.31 [95% CI: 0.25–0.39], p < 0.00001). Cardiac events were reduced with dexrazoxane (RR = 0.35 [95% CI 0.27–0.45], p < 0.00001), beta-blockade (RR = 0.31 [95% CI 0.16–0.63], p = 0.001), statin (RR = 0.31 [95% CI 0.13–0.77], p = 0.01) and angiotensin antagonists (RR = 0.11 [95% CI 0.04–0.29], p < 0.0001).InterpretationProphylactic treatment with dexrazoxane, beta-blocker, statin or angiotensin antagonists appear to have similar efficacy for reducing cardiotoxicity.     

Cardiac Tolerability of Pertuzumab Plus Trastuzumab Plus Docetaxel in Patients With HER2‐Positive Metastatic Breast Cancer in CLEOPATRA: A Randomized,Double‐Blind,Placebo‐Controlled Phase III Study

Introduction.

We report cardiac tolerability of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel observed in the phase III study CLEOPATRA in patients with HER2-positive first-line metastatic breast cancer (MBC).

Patients and Methods.

Left ventricular ejection fraction (LVEF) ≥50% and ECOG performance status of 0 or 1 were required for study entry. During the study, LVEF assessments took place every 9 weeks. Pertuzumab/placebo was given at 840 mg, then 420 mg q3w; trastuzumab was administered at 8 mg/kg, then 6 mg/kg q3w, and docetaxel was initiated at 75 mg/m² q3w.

Results.

The incidence of cardiac adverse events (all grades) was 16.4% in the placebo arm and 14.5% in the pertuzumab arm, with left ventricular systolic dysfunction (LVSD, all grades) being the most frequently reported event (8.3% versus 4.4% in the placebo and pertuzumab arm). Declines in LVEF by ≥10% points from baseline and to <50% were reported in 6.6% and 3.8% of patients in the placebo and pertuzumab arm, respectively. Seventy-two percent (placebo arm) and 86.7% (pertuzumab arm) of those patients recovered to a value ≥50%. The incidence of symptomatic LVSD was low, occurring in 1.8% (n = 7) versus 1.0% (n = 4) of patients in the placebo and pertuzumab arm. In 8/11 patients, the symptomatic LVSD had resolved at data cutoff.

Conclusion.

The combination of pertuzumab plus trastuzumab plus docetaxel did not increase the incidence of cardiac adverse events, including LVSD, compared with the control arm in HER2-positive MBC. The majority of cardiac adverse events were reversible.     

Trastuzumab‐Related Cardiotoxicity in Early Breast Cancer: A Cohort Study

Background.

Concerns have been raised about the cardiac safety profile of trastuzumab for the adjuvant treatment of early stage breast cancer in clinical practice. We assessed trastuzumab-related cardiotoxicity and its predictors in a large cohort of Italian women.

Methods.

Through a record linkage between four regional health care databases, we identified the rate of severe cardiac adverse events among women treated with trastuzumab for early breast cancer in Lombardy. The cumulative risk of cardiotoxicity was estimated using the Kaplan-Meier method, and independent predictors were assessed using the Cox model.

Results.

Of 2,046 trastuzumab users, 53 (2.6%) experienced at least one hospitalization for a cardiac event, and there were two cardiac deaths. The cumulative risk of cardiotoxicity increased up to 2 years after starting treatment, reaching a plateau at 2.8%. The risk was low (0.2%) among young women, whereas the incidence was approximately 10% in women aged ≥70 years, irrespective of cardiovascular risk factors. Age and history of cardiac disease were strong predictors of cardiotoxicity, with a hazard ratio of 11.3 (95% confidence interval [CI]: 3.5–36.6) for women aged ≥70 years as compared with those <50 years of age. Hazard ratio was 4.4 (95% CI: 2.1–9.5) for women with a history of cardiac disease compared with those without a history of cardiac disease.

Conclusions.

Cardiotoxicity of trastuzumab varies considerably across subgroups of patients. The long-term safety profile was less favorable than in the largest clinical trial. Strategies to reduce cardiotoxicity in high-risk women should be investigated.     

曲妥珠单抗联合多西紫杉醇治疗Her-2阳性乳腺癌的临床研究

目的探析注射用曲妥珠单抗联合多西紫杉醇注射液治疗人类表皮生长因子受体2(Her-2)阳性乳腺癌的临床疗效。方法选取黄石市中心医院(普爱院区)2011年2月—2015年2月收治的乳腺癌患者86例作为研究对象,所有患者按照就诊顺序编号分为对照组和治疗组,每组各43例。对照组静脉滴注多西紫杉醇注射液75 mg/m2,1 h内滴完,间隔21 d重复给药,共给药4次。治疗组在对照组的基础上静脉滴注注射用曲妥珠单抗,将曲妥珠单抗溶于250 mL生理盐水中,首次剂量4 mg/kg,90 min内滴完,之后维持2 mg/kg,1次/周。观察两组的客观有效率、疾病控制率,同时比较治疗前后Her-2表达、细胞凋亡相关因子水平和不良反应发生情况。结果治疗后,对照组、治疗组的客观有效率、疾病控制率分别为60.5%、81.4%,70.0%、88.4%,两组比较差异有统计学意义(P0.05)。治疗后,两组患者Her-2(++)、(+++)比例显著降低,同组治疗前后差异有统计学意义(P0.05);且治疗组指标的降低程度优于对照组,两组比较差异有统计学意义(P0.05)。治疗后两组Caspase-3、DcR3、COX-2水平均显著降低,同组治疗前后差异有统计学意义(P0.05);且治疗组这些观察指标的降低程度优于对照组,两组比较差异有统计学意义(P0.05)。两组不良反应均以胃肠道反应、皮疹、白细胞减少、疲倦、心脏毒性等为主,但各种不良反应发生率的差异无统计学意义。结论注射用曲妥珠单抗联合多西紫杉醇注射液治疗Her-2阳性乳腺癌具有较好的临床疗效,可有效弱化Her-2表达,降低细胞凋亡相关因子水平,安全性佳,值得推广应用。     

HER2 aberrations in cancer: Implications for therapy

Although anti-HER2 (human epidermal growth factor receptor 2) therapy is currently approved for breast, gastric, and gastroesophageal cancers overexpressing the HER2 protein or amplified for the HER2 gene, HER2 aberrations (gene amplification, gene mutations, and protein overexpression) are reported in other diverse malignancies. Indeed, about 1–37% of tumors of the following types harbor HER2 aberrations: bladder, cervix, colon, endometrium, germ cell, glioblastoma, head and neck, liver, lung, ovarian, pancreas, and salivary duct. Four HER2-targeted therapies have been approved for HER2-positive breast cancer: two antibodies (trastuzumab and pertuzumab), an antibody-drug conjugate (ado-trastuzumab emtansine), and a small molecule kinase inhibitor (lapatinib). In addition, afatinib, a small molecule kinase inhibitor that causes irreversible inhibition of EGFR (epidermal growth factor receptor) and HER2, was recently approved for EGFR-mutated non-small cell lung cancer. A large number of novel HER2-targeted agents are also in clinical trials. Herein we discuss the state of the art in understanding and targeting HER2 across anatomic tumor types.     

A case of HER2-positive male breast cancer with lung metastases showing a good response to trastuzumab and paclitaxel treatment

We present a case of advanced HER2-positive male breast cancer, which showed a good response to a combined treatment of trastuzumab and paclitaxel. A 78-year-old man was diagnosed with invasive ductal carcinoma (T4d N3 M1, stage IV). He had advanced breast cancer consisting of multiple tumors with skin involvement and redness over the entire left chest region. A computed tomography (CT) scan of the chest revealed a metastatic tumor in the left lung. Histologically, both the primary breast cancer and the metastatic lung tumor were identified as invasive ductal carcinoma that was estrogen receptor-negative (ER)(−) and progesterone receptor-negative (PgR)(−), with a HER2 score of 3+ (IHC). The patient received a combination chemotherapy using trastuzumab and paclitaxel. Two months later, a follow-up chest CT scan showed that the left lung tumor had disappeared, suggesting a good response to trastuzumab and paclitaxel. During trastuzumab treatment, no severe adverse events above grade 3 were observed. This is the first reported case of advanced HER2-positive male breast cancer in which a good response to trastuzumab and paclitaxel was demonstrated at both primary breast cancer and metastatic sites.     

Brain metastases in patients who receive trastuzumab-containing chemotherapy for HER2-overexpressing metastatic breast cancer

Background  Recently, a high rate of brain metastases has been reported among patients with human epidermal growth factor receptor (HER2)-overexpressing metastatic breast cancer who were treated with trastuzumab. The present study examined risk factors for the development of brain metastasis in patients with HER2-overexpressing breast cancer who were treated with trastuzumab. Methods  We retrospectively reviewed 204 patients with HER-2-overexpressing breast cancer who were treated with a trastuzumab-containing regimen between 1999 and 2006. Patients with clinical symptoms were diagnosed as having brain metastases when brain magnetic resonance imaging (MRI) or a computed tomography (CT) scan revealed positive findings for brain metastases. The median follow-up time of this cohort was 53.6 months. Results  Among the patients who received a trastuzumabcontaining regimen, 74 patients (36.3%) developed brain metastases. The median survival from the diagnosis of brain metastases was 13.5 months (95% confidence interval [CI], 12.2–14.7 months). The median time interval between the beginning of trastuzumab treatment and the diagnosis of brain metastases was 13.6 months (range, 0.0–45.8 months). Among patients with brain metastases, the median overall survival period was 39 months. A multivariate logistic regression analysis showed that age (≤50 years), recurrent breast cancer, and liver metastases were significant risk factors for the development of brain metastases. Conclusion  Patients with HER2-overexpressing breast cancer treated with trastuzumab had a high incidence of brain metastases (36.3%). Routine screening for brain metastases 1 year after the start of trastuzumab treatment, may be warranted in younger patients (≤50 years) who had recurrent breast cancer with liver metastases.     

Trastuzumab mediated cardiotoxicity in the setting of adjuvant chemotherapy for breast cancer: a retrospective study

Background The incidence and management of trastuzumab-mediated cardiotoxicity outside of clinical trials has not been well described. Objective and methods The aim of the study was to retrospectively evaluate the incidence of cardiac dysfunction, characterize its natural history, and identify the degree of reversibility using cardiac MRI, in a population of HER-2 positive breast cancer patients receiving trastuzumab in the adjuvant setting. Results Out of 152 patients (mean age 52 ± 10 years), 36 (24%) developed trastuzumab mediated cardiomyopathy, the majority asymptomatic. Factors that predicted the development of trastuzumab mediated cardiac dysfunction were a pre-existing history of hypertension, smoking history, and a family history of coronary artery disease. Within 3 months of treatment with trastuzumab, there was a difference in LVEF between the normal cohort and those patients who developed LV systolic dysfunction (61 ± 5% vs. 51 ± 8%, P < 0.01). During the 6-month-followup, 34/36 patients demonstrated subepicardial linear delayed enhancement of the lateral wall of the left ventricle on cardiac MRI, suggesting trastuzumab induced myocarditis. Conclusion Approximately 1 in 4 women may develop LV systolic dysfunction after treatment with adjuvant trastuzumab, necessitating careful patient selection and close serial monitoring using noninvasive cardiac imaging.