Cardiac Safety of Dual Anti-HER2 Therapy in the Neoadjuvant Setting for Treatment of HER2-Positive Breast Cancer

Oncologist. 2017 Jun;22(6):642-647. doi: 10.1634/theoncologist.2016-0406. Epub 2017 Mar 24.

Abstract

Background: Trastuzumab and pertuzumab are approved for the neoadjuvant treatment of human epidermal growth receptor 2 (HER2)-positive breast cancer, but cardiac safety data is limited. We report the cardiac safety of dose-dense doxorubicin and cyclophosphamide (AC) followed by paclitaxel, trastuzumab, and pertuzumab (THP) in the neoadjuvant setting followed by adjuvant trastuzumab-based therapy.

Methods: Fifty-seven patients treated with neoadjuvant dose-dense AC-THP followed by adjuvant trastuzumab-based therapy between September 1, 2013, and March 1, 2015, were identified. The primary outcome was cardiac event rate, defined by heart failure (New York Heart Association [NYHA] class III/IV) or cardiac death. Patients underwent left ventricular ejection fraction (LVEF) monitoring at baseline, after AC, and serially during 1 year of anti-HER2 therapy.

Results: The median age was 46 years (range 26-68). Two (3.5%) patients developed NYHA class III/IV heart failure 5 and 9 months after initiation of trastuzumab-based therapy, leading to permanent discontinuation of anti-HER2 treatment. Seven (12.3%) patients developed a significant LVEF decline (without NYHA class III/IV symptoms). The median LVEF was 65% (range 55%-75%) at baseline and 64% (range 53%-72%) after AC, and decreased to 60% (range 35%-70%), 60% (range 23%-73%), 61% (range 25%-73%), and 58% (range 28%-66%) after 3, 6, 9, and 12 months (± 6 weeks) of trastuzumab-based therapy.

Conclusion: The incidence of NYHA class III/IV heart failure after neoadjuvant AC-THP (followed by adjuvant trastuzumab-based therapy) is comparable to rates reported in trials of sequential doxorubicin and trastuzumab. Our findings do not suggest an increased risk of cardiotoxicity from trastuzumab plus pertuzumab following a doxorubicin-based regimen.

Implications for practice: Dual anti-human epidermal growth receptor 2 (HER2) therapy with trastuzumab and pertuzumab combined with standard chemotherapy has received accelerated approval for the neoadjuvant treatment of stage II-III HER2-positive breast cancer. Cardiac safety data for trastuzumab and pertuzumab in this setting are limited to clinical trials that utilized epirubicin-based chemotherapy. Formalized investigations into the cardiac safety of trastuzumab and pertuzumab with doxorubicin- (rather than epirubicin) based regimens are important because these regimens are widely used for the adjuvant and neoadjuvant treatment of breast cancer. The known role of HER2 signaling in the physiological adaptive responses of the heart provides further rationale for study on the potential cardiotoxicity of dual anti-HER2 blockade. Findings from this retrospective study provide favorable preliminary data on the cardiac safety of trastuzumab and pertuzumab in combination with a regimen of neoadjuvant doxorubicin and cyclophosphamide followed by paclitaxel, one of the preferred breast cancer treatment regimens, according to the National Comprehensive Cancer Network.

摘要

背景. 曲妥珠单抗和帕妥珠单抗已获批用于人类表皮生长因子受体2(HER2)阳性乳腺癌的新辅助治疗, 但心脏安全性数据有限。我们报告了患者依次使用多柔比星和环磷酰胺(AC)以及紫杉醇、曲妥珠单抗和帕妥珠单抗(THP)进行剂量密集型新辅助治疗, 随后接受以曲妥珠单抗为基础的辅助治疗时的心脏安全性。

方法. 共有57例患者于2013年9月1日至2015年3月1日期间接受剂量密集型AC‐THP新辅助治疗, 随后接受以曲妥珠单抗为基础的辅助治疗。主要结局为心脏事件的发生率, 定义为心力衰竭[纽约心脏协会(NYHA)III/IV级]或心源性死亡。在基线时、AC治疗后以及为期1年的抗HER2治疗期间连续监测患者的左心室射血分数(LVEF)。

结果. 患者的中位年龄为46岁(范围:26‐68岁)。2例(3.5%)患者分别在开始以曲妥珠单抗为基础的治疗后5个月和9个月出现NYHA III/IV级心力衰竭, 并因此永久性中止抗HER2治疗。7例(12.3%)患者的LVEF显著降低(不伴NYHA III/IV级症状)。基线时中位LVEF为65%(范围:55%‐75%), AC治疗后为64%(范围:53%‐72%), 以含曲妥珠单抗的方案治疗后3个月、6个月、9个月和12个月(± 6周)时分别降至60%(范围:35%‐70%)、60%(范围:23%‐73%)、61%(范围:25%‐73%)和58%(范围:28%‐66%)。

结论. AC‐THP新辅助治疗(随后进行以曲妥珠单抗为基础的辅助治疗)后NYHA III/IV级心力衰竭的发生率与多柔比星和曲妥珠单抗序贯治疗试验中报告的发生率相当。我们的结果显示, 在基于多柔比星的方案后以曲妥珠单抗联合帕妥珠单抗进行治疗时, 心脏毒性风险并未增加。The Oncologist 2017;22:642–647

对临床实践的提示:曲妥珠单抗和帕妥珠单抗双重抗HER2治疗联合标准化疗已获得加速审批, 用于II‐III期HER2阳性乳腺癌的新辅助治疗。曲妥珠单抗和帕妥珠单抗在此种条件下的心脏安全性数据仅来源于使用含表柔比星的化疗方案进行的临床试验。曲妥珠单抗和帕妥珠单抗联合基于多柔比星(而非表柔比星)的方案已广泛用于乳腺癌的辅助治疗和新辅助治疗, 因此有必要正式考察其心脏安全性。现已阐明HER2信号传导在心脏生理适应性反应中的作用, 这为抗HER2治疗双重阻滞的潜在心脏毒性提供了进一步的研究依据。本项回顾性研究的结果就曲妥珠单抗和帕妥珠单抗与由多柔比星和环磷酰胺及随后的紫杉醇组成的新辅助治疗方案(根据美国国家综合癌症网络, 此为乳腺癌首选治疗方案之一)联用时的心脏安全性提供了有利的初步数据。

Keywords: Cardiotoxicity; Heart failure; Pertuzumab; Trastuzumab.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Breast Neoplasms / complications
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology
  • Cardiotoxicity / physiopathology*
  • Cyclophosphamide / administration & dosage
  • Cyclophosphamide / adverse effects
  • Doxorubicin / administration & dosage
  • Doxorubicin / adverse effects
  • Female
  • Heart / drug effects
  • Heart / physiopathology*
  • Heart Failure / chemically induced
  • Heart Failure / physiopathology*
  • Humans
  • Middle Aged
  • Neoadjuvant Therapy / adverse effects
  • Paclitaxel / administration & dosage
  • Paclitaxel / adverse effects
  • Receptor, ErbB-2 / antagonists & inhibitors
  • Trastuzumab / administration & dosage
  • Trastuzumab / adverse effects
  • Ventricular Dysfunction, Left / chemically induced
  • Ventricular Dysfunction, Left / physiopathology*

Substances

  • Antibodies, Monoclonal, Humanized
  • Doxorubicin
  • Cyclophosphamide
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • pertuzumab
  • Trastuzumab
  • Paclitaxel