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



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.



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.



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.



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.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA yua3@mskcc.org.|Department of Cardiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Anthony F
AF
Yu
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Department of Breast Medicine Services, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Jasmeet C
JC
Singh
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Department of Breast Medicine Services, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Rui
R
Wang
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Department of Cardiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Jennifer E
JE
Liu
Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Anne
A
Eaton
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Division of Survivorship and Supportive Care, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Kevin C
KC
Oeffinger
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Department of Cardiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Richard M
RM
Steingart
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Department of Breast Medicine Services, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Clifford A
CA
Hudis
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Department of Breast Medicine Services, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Chau T
CT
Dang
D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D001943:Breast Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D066126:Cardiotoxicity / Q000503:physiopathology*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006333:Heart Failure / Q000139:chemically induced / Q000503:physiopathology*; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000009:adverse effects; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D000068878:Trastuzumab / Q000008:administration & dosage / Q000009:adverse effects; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000503:physiopathology*
D061067:Antibodies, Monoclonal, Humanized; D003520:Cyclophosphamide; D004317:Doxorubicin; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C485206:pertuzumab
Cardiotoxicity; Heart failure; Pertuzumab; Trastuzumab