Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial.
OBJECTIVE
To assess cardiac safety and potential cardiac risk factors associated with trastuzumab in the NCCTG N9831 Intergroup adjuvant breast cancer trial.


METHODS
Patients with HER2-positive operable breast cancer were randomly assigned to doxorubicin plus cyclophosphamide (AC) followed by either weekly paclitaxel (arm A); paclitaxel then trastuzumab (arm B); or paclitaxel plus trastuzumab then trastuzumab alone (arm C). Left ventricular ejection fraction (LVEF) was evaluated at registration and 3, 6, 9, and 18 to 21 months.


RESULTS
Of 2,992 patients completing AC, 5.0% had LVEF decreases disallowing trastuzumab (decrease below normal: 2.4%, decrease > 15%: 2.6%). There were 1,944 patients with satisfactory or no LVEF evaluation who proceeded to post-AC therapy. Cardiac events (congestive heart failure [CHF] or cardiac death [CD]): arm A, n = 3 (2 CHF, 1 CD); arm B, n = 19 (18 CHF, 1 CD); arm C, n = 19 (all CHF); 3-year cumulative incidence: 0.3%, 2.8%, and 3.3%, respectively. Cardiac function improved in most CHF cases following trastuzumab discontinuation and cardiac medication. Factors associated with increased risk of a cardiac event in arms B and C: older age (P < .003), prior/current antihypertensive agents (P = .005), and lower registration LVEF (P = .033). Incidence of asymptomatic LVEF decreases requiring holding trastuzumab was 8% to 10%; LVEF recovered and trastuzumab was restarted in approximately 50%.


CONCLUSIONS
The cumulative incidence of post-AC cardiac events at 3 years was higher in the trastuzumab-containing arms versus the control arm, but by less than 4%. Older age, lower registration LVEF, and antihypertensive medications are associated with increased risk of cardiac dysfunction in patients receiving trastuzumab following AC.
Perez
Edith A
EA
Division of Hematology/Oncology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224, USA. perez.edith@mayo.edu
Suman
Vera J
VJ
Davidson
Nancy E
NE
Sledge
George W
GW
Kaufman
Peter A
PA
Hudis
Clifford A
CA
Martino
Silvana
S
Gralow
Julie R
JR
Dakhil
Shaker R
SR
Ingle
James N
JN
Winer
Eric P
EP
Gelmon
Karen A
KA
Gersh
Bernard J
BJ
Jaffe
Allan S
AS
Rodeheffer
Richard J
RJ
D000293:Adolescent; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000150:complications / Q000188:drug therapy*; D003520:Cyclophosphamide / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006321:Heart / Q000187:drug effects*; D006333:Heart Failure / Q000139:chemically induced* / Q000188:drug therapy; D006801:Humans; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012307:Risk Factors; D015996:Survival Rate; D013629:Tamoxifen / Q000008:administration & dosage; D000068878:Trastuzumab; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003520:Cyclophosphamide; D004317:Doxorubicin; D005472:Fluorouracil; D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen; D000068878:Trastuzumab