曲妥珠单抗增加乳腺癌患者心衰风险的新证据

一项以人群为基础的大规模回顾性队列研究表明，无论是否与蒽环类化疗药物联用，曲妥珠单抗均与乳腺癌治疗患者心衰(HF)和心肌症(CM)风险显著增加相关(J. Natl. Cancer Inst. 2012 Aug. 30 [doi:10.1093/jnci/djs317])。

西雅图群体健康研究所(GHRI)的Erin J. Aiello Bowles及其同事完成的这项旨在考察实际临床实践中曲妥珠单抗治疗与患者HF/CM风险相关性的研究表明，单纯接受曲妥珠单抗(赫赛汀)治疗的患者，校正后HF/CM风险比未接受化疗者增加4倍，而接受蒽环类+曲妥珠单抗治疗的患者风险增加7倍。年龄<65岁的女性患者与蒽环类相关的HF/CM风险与随机临床试验结果相似，但无论单纯应用还是与蒽环类联用，与曲妥珠单抗相关风险与既往报告相比增加显著。

研究者指出，随机试验通常排除老龄和主要共病患者，因此对上述两种药物与这类人群HF/CM风险相关性的了解并不充分。他们利用健康维护组织(HMO)癌症研究网络数据，纳入8家综合性癌症研究网络健康系统1999年1月~2007年12月确诊的12,500例浸润性乳腺癌女性患者，并排除了乳腺癌确诊前HF/CM患者或已接受化疗的患者。平均年龄60岁(22~99岁)，85.8%为白人。在中位时间为4.4年的随访期间，近半数(46.5%)患者未接受化疗，1/3(29.6%)患者单纯接受以蒽环类为基础的化疗，0.9%患者接受单纯曲妥珠单抗治疗，3.5%患者接受蒽环类+曲妥珠单抗治疗，而19.5%患者接受其他化疗。

结果显示，与接受其他化疗或未接受化疗的患者相比，单纯接受蒽环类或蒽环类+曲妥珠单抗治疗的患者较为年轻、多为晚期患者、共病较少且接受放疗比例稍多。这一结果表明“在社区临床实践中，大量患者因年龄和共病情况不同而采取个性化辅助性化疗。”

所有接受化疗的患者HF/CM发病率均随随访时间延长而增加，但曲妥珠单抗治疗患者增加程度更为明显。蒽环类化疗患者HF/CM累积发病率由第1年的1.2%增加至第5年的4.3%，与其他化疗患者发病率增加情况相似(1.3%~4.5%)。未接受化疗患者累积发病率由0.9%增加至3.1%，而蒽环类+曲妥珠单抗化疗患者累积发病率由6.2%增加至20.1%。

与未接受化疗的患者相比，所有化疗患者的HF/CM发病风险均呈显著增加。单纯蒽环类、单纯曲妥珠单抗、蒽环类+曲妥珠单抗以及其他化疗患者校正后风险比(HR)分别为1.40、4.21、7.19和1.49。

对于年龄较大患者，与各种化疗相关的HF/CM 5年累计发病率相对较高，但与化疗相关的HF/CM风险比随着患者年龄增加而降低。例如，单纯接受蒽环类化疗的<55岁患者HF/心肌症风险比(HR，2.52)具有统计学意义，但55~64岁(HR，1.61)或以上患者则无统计学意义。

研究者认为，该研究表明安全性和有效性观察性对比研究对于补充临床试验结果具有重要意义。“观察性研究可评估社区医疗患者的风险与受益，而这些患者可能不符合临床试验纳入标准。临床试验对于符合纳入标准的患者可提供更为准确的评估，但许多未能纳入临床试验的患者在社区医疗机构也接受相关药物治疗。”

该研究由美国国立癌症研究所资助。Bowles女士报告无利益冲突，共同作者Larry A. Allen博士报告接受安进公司、杨森科学事务公司和Robert Wood Johnson基金会的咨询费用。

随刊述评：未见HF发病率达到平台期的迹象

威克森林大学公共健康科学部的ANN M. GEIGER博士评论指出，曲妥珠单抗开发用于治疗人体表皮生长因子受体2(HER2)阳性的非转移性侵润性乳腺癌肿瘤是个体化治疗领域非常重要的一步。多项试验已经证实，与其他化疗药物相比，曲妥珠单抗等辅助治疗可显著改善患者临床及总体和无病生存时间。不同于大多数癌症化疗药物，曲妥珠单抗用于早期HER2阳性乳腺癌治疗还具有成本效益(ANN. PHARMACOTHER. 2009;43:296-303)。然而，其受益因安全性担忧而有所折扣。对早期乳腺癌试验汇聚分析表明，曲妥珠单抗治疗患者充血性心衰风险比未接受治疗者增加5倍，并且在不同的治疗方案中该结果相似(COCHRANE DATABASE SYST. REV. 2012;4:CD006243)。

本项研究较既往试验随访时间延长1年，并且显示充血性心衰发病率持续增加，未见达到平台期，这也证明了对曲妥珠单抗治疗患者进行长期充血性心衰监测以及延长受试者随访时间的合理性。

虽然在既往随机临床试验中，无论治疗组还是对照组大多包括了蒽环类治疗患者，但该项观察性研究发现，在实际临床实践中约40%的化疗患者方案中并不包括蒽环类药物，部分原因可能是相对于临床试验受试者而言，患者年龄较大和共病负担较高。

最后，根据该研究结果，令人担忧的是在相关随机对照试验结果发表之前，仅有大约1/4的曲妥珠单抗辅助治疗患者得到了良好治疗。临床医生的治疗方案可能是基于针对转移性乳腺癌患者试验结果以及早期乳腺癌试验初步结果，然而这些来自随访时间较短的中期结果，不能说明早期乳腺癌患者生命预期长于转移性乳腺癌患者。许多实例已经表明，一些新药根据其初期获益报告而得到广泛应用，但在后续安全性数据出来后却被撤市。患者、医生以及研究人员应该对癌症新药获益的热情有所节制，不能仅仅依据对某些临床试验受试患者的短期观察结果来判断不良事件长期风险。

GEIGER博士报告无相关利益冲突。

爱思唯尔版权所有  未经授权请勿转载

By: MIRIAM E. TUCKER, Cardiology News Digital Network

Trastuzumab, whether given with or without anthracyline-based chemotherapy, was associated with significant increases in heart failure and cardiomyopathy in a large population-based, retrospective cohort study of women treated for breast cancer.

In the "real world" study, which used data from the health maintenance organization Cancer Research Network, the adjusted risk of heart failure (HF) and/or cardiomyopathy increased fourfold among women who received trastuzumab (Herceptin) alone and sevenfold in those who received anthracycline plus trastuzumab, compared with women who received no chemotherapy.

In all, the risk of anthracycline-associated HF/cardiomyopathy among women younger than 65 years was similar to results from randomized clinical trials, while the trastuzumab-associated HF/cardiomyopathy risk – whether administered alone or following an anthracycline – was greater than that previously reported.

"Our results highlight the importance of generalizability in applying clinical trial findings to community settings; although similar to clinical trial results, these population-based results cannot be attributed to any single patient in clinical practice," wrote Erin J. Aiello Bowles of Group Health Research Institute, Seattle, and her associates.

Randomized trials have typically excluded older women and those with major comorbidities, and therefore the association between the two agents and HF/cardiomyopathy in this population is not well understood, Ms. Bowles and her associates noted (J. Natl. Cancer Inst. 2012 Aug. 30 [doi:10.1093/jnci/djs317]).

The current study population comprised 12,500 women diagnosed with incident, invasive breast cancer from Jan. 1, 1999, through Dec. 31, 2007, at eight integrated Cancer Research Network health systems. Women diagnosed with HF/cardiomyopathy prior to breast cancer diagnosis or initiation of chemotherapy were excluded. They had a mean age of 60 years (range, 22-99), and 85.8% were white.

In a median follow-up of 4.4 years, nearly half (46.5%) had received no chemotherapy. Just under a third, 29.6%, had received anthracycline-based chemotherapy alone, 0.9% received trastuzumab-based therapy without anthracycline, 3.5% received anthracycline plus trastuzumab, and 19.5% received other chemotherapy.

Compared with the women who received other chemotherapy or no chemotherapy, the women who received anthracycline alone or anthracycline plus trastuzumab were younger, diagnosed at later stages, had fewer comorbidities, and were slightly more likely to receive radiation therapy. These findings "suggest substantial individualization of adjuvant chemotherapy administration by age and comorbidity in community practice," Ms. Bowles and her associates wrote.

The incidence of HF/cardiomyopathy increased with increasing follow-up time for all of the chemotherapy types, but to a greater degree with trastuzumab. The cumulative HF/cardiomyopathy incidence increased from 1.2% at year 1 to 4.3% at year 5 for the anthracycline recipients, which was similar to the increase from 1.3% to 4.5% for those on other chemotherapies. For those with no chemotherapy, the cumulative incidence rose from 0.9% to 3.1%.

In contrast, the cumulative HF/cardiomyopathy incidence among recipients of anthracycline plus trastuzumab was 6.2% after 1 year of follow-up and continued to increase to 20.1% by 5 years.

Compared with no chemotherapy, the risk of incident HF/cardiomyopathy among all women was statistically significantly increased for anthracycline alone (adjusted hazard ratio, 1.40), trastuzumab without anthracycline (HR, 4.12), anthracycline plus trastuzumab (HR, 7.19), and other chemotherapy (HR, 1.49), the investigators said.

The 5-year cumulative incidence for HF/cardiomyopathy associated with each of the chemotherapies was greater in the older age groups, but the hazard ratios for HF/cardiomyopathy associated with chemotherapy use decreased with increasing age. For example, the hazard ratio for HF/cardiomyopathy associated with anthracycline use alone was statistically significant among women younger than 55 years (HR, 2.52) but not among women 55-64 years (HR, 1.61) or older.

According to Ms. Bowles and her associates, this study demonstrates the importance of observational comparative safety and effectiveness studies in providing complementary data to those obtained in clinical trials. "Observational studies allow for estimation of risks and benefits in community practice, which includes patients who may not be eligible for clinical trials. Clinical trials may provide more relevant estimates for patients who are eligible candidates, but many people are not and still receive these treatments in community practice," they wrote.

This work was supported by the National Cancer Institute through an administrative supplement to the Cancer Research Network. Ms. Bowles did not report any financial disclosures, but one of her coauthors, Dr. Larry A. Allen, has received consulting fees from Amgen, Janssen Scientific Affairs, and the Robert Wood Johnson Foundation.

View on The News
No Indication of a Plateau

The development of trastuzumab for the treatment of nonmetastatic invasive breast cancer tumors expressing human epidermal growth factor receptor 2 has been an important step in the field of personalized medicine.

Multiple trials have documented clinically and statistically significant improvements in overall and disease-free survival for women receiving adjuvant treatment including trastuzumab, compared with those receiving other chemotherapy agents. Unlike most new cancer chemotherapies, trastuzumab’s use in early-stage HER2-positive breast cancer also appears to be cost effective (Ann. Pharmacother. 2009;43:296-303).

This benefit, however, has been offset by safety concerns, with a pooled analysis of the early breast cancer trials suggesting a fivefold increase in risk of congestive heart failure for women who receive trastuzumab versus those who do not, with consistent results across varying treatment regimens (Cochrane Database Syst. Rev. 2012;4:CD006243).

The current study adds an additional year of follow-up to previous trials, during which the incidence of congestive heart failure continues to increase with no indication of a plateau. This justifies long-term surveillance for congestive heart failure in women who have received trastuzumab, as well as extended follow-up of women enrolled in trials.

Although most previous randomized clinical trials have included anthracycline in both treatment and comparison arms, the current observational study found that, in real life, about 40% of women undergoing chemotherapy received regimens excluding anthracycline, probably due in part to the older age and higher comorbidity burden relative to participants in clinical trials.

Finally, this study raises concern in that roughly a quarter of the women who received adjuvant trastuzumab had been treated well before the publication of peer-reviewed results of relevant randomized controlled trials. Clinicians may have been basing their decision on findings from trials in women with metastatic breast cancer and preliminary data from the early breast cancer trials. The interim findings, however, were based on follow-up periods too short to account for the longer life expectancy of women with early breast cancer relative to women with metastatic disease.

There have been many instances in which new treatments disseminate based on preliminary reports of benefit, only to be withdrawn after additional safety data become available. Patients, clinicians, and researchers must temper their enthusiasm about the benefits of new cancer therapies with the recognition that estimates of the long-term risk of adverse events are based on short-term observations among carefully selected clinical trial participants.

ANN M. GEIGER, PH.D., is with the division of public health sciences at Wake Forest University, Winston Salem, N.C. She said that she has no conflicts of interest.