Long-term cardiovascular outcomes and overall survival of early-stage breast cancer patients with early discontinuation of trastuzumab: a population-based study.
We critically examined long-term cardiovascular (CV) outcomes and overall survival (OS) of breast cancer (BC) patients who had cardiotoxicity during adjuvant trastuzumab treatment requiring discontinuation in a population-based sample. This was a retrospective cohort of early-stage BC patients diagnosed before 2010 and treated with trastuzumab in Ontario. Patients were stratified based on trastuzumab doses received: 1-8, 9-15, ≥16 (therapy completion). Time-dependent multivariable Cox models were used to analyze primary endpoint OS, and the following composite endpoints: hospitalization/emergency room visit for heart failure (HF) or death; non-HF CV (myocardial infarction, stroke) or death; and clinically significant relapse (palliative systemic therapy initiation >90 days after last trastuzumab dose) or death. Of the 3134 women, 6, 10, and 85 % received 1-8, 9-15, and ≥16 doses, respectively. Over 5-year median follow-up, early trastuzumab discontinuation was associated with more HF/death [1-8 doses hazard ratio (HR) 4.0, 95 % confidence interval (CI) 2.7-6.0; 9-15 doses HR 2.97, 95 % CI 2.1-4.3], non-HF/death (1-8 doses HR 4.3, 95 % CI 3.0-6.1; 9-15 doses HR 3.1, 95 % CI 2.2-4.4), clinically significant relapse/death (1-8 doses HR 3.1, 95 % CI 2.2-4.4; 9-15 doses HR 2.4, 95 % CI 1.8-3.3), and importantly lower OS (77, 80, 93 %; P < 0.001). Early discontinuation (1-8 doses HR 2.41, 95 % CI 1.5-3.8; 9-15 doses HR 2.9, 95 % CI 2.0-4.1) and clinically significant relapse (HR 34.0, 95 % CI 24.9-46.6) were both independent predictors of mortality. Of note, early discontinuation remained a critical independent predictor of OS even after adjusting for incident HF. Early trastuzumab discontinuation is a powerful independent predictor of cardiac events and clinically significant relapse, and both may contribute to poor survival. Both adequate cancer control and optimal CV management are required to improve long-term outcomes.
University of Toronto, Toronto, ON, Canada.
Inna Y
IY
Gong
University of Toronto, Toronto, ON, Canada.|Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
Sunil
S
Verma
University of Toronto, Toronto, ON, Canada.|St. Michael's Hospital, Toronto, ON, Canada.
Andrew T
AT
Yan
University of Toronto, Toronto, ON, Canada.|Sunnybrook Health Sciences Centre, Toronto, ON, Canada.|Institute for Clinical Evaluative Sciences, Toronto, ON, Canada.
Dennis T
DT
Ko
University of Toronto, Toronto, ON, Canada.|Sunnybrook Health Sciences Centre, Toronto, ON, Canada.|Institute for Clinical Evaluative Sciences, Toronto, ON, Canada.|Ontario Institute for Cancer Research, Toronto, ON, Canada.
Craig C
CC
Earle
University of Toronto, Toronto, ON, Canada.|University Health Network, Toronto, ON, Canada.
George A
GA
Tomlinson
University of Toronto, Toronto, ON, Canada.|Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
Maureen E
ME
Trudeau
University of Toronto, Toronto, ON, Canada.|Toronto Health Economics and Health Assessment, Toronto, ON, Canada.
Murray D
MD
Krahn
University of Toronto, Toronto, ON, Canada.|Institute for Clinical Evaluative Sciences, Toronto, ON, Canada.|University Health Network, Toronto, ON, Canada.
Monika K
MK
Krzyzanowska
University of Toronto, Toronto, ON, Canada.|St. Michael's Hospital, Toronto, ON, Canada.
Christine B
CB
Brezden-Masley
Cancer Care Ontario, Toronto, ON, Canada.
Scott
S
Gavura
British Columbia Cancer Agency, Vancouver, BC, Canada.|Canadian Center for Applied Research in Cancer Control, Canada.
Stuart
S
Peacock
University of Toronto, Toronto, ON, Canada. kelvin.chan@sunnybrook.ca.|Sunnybrook Health Sciences Centre, Toronto, ON, Canada. kelvin.chan@sunnybrook.ca.|Cancer Care Ontario, Toronto, ON, Canada. kelvin.chan@sunnybrook.ca.|Canadian Center for Applied Research in Cancer Control, Canada, . kelvin.chan@sunnybrook.ca.
Kelvin K W
KK
Chan
D000328:Adult; D000368:Aged; D000074322:Antineoplastic Agents, Immunological / Q000008:administration & dosage / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017024:Chemotherapy, Adjuvant / Q000009:adverse effects; D005260:Female; D006331:Heart Diseases / Q000139:chemically induced* / Q000401:mortality; D006760:Hospitalization; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D009864:Ontario; D012189:Retrospective Studies; D016019:Survival Analysis; D000068878:Trastuzumab / Q000008:administration & dosage / Q000009:adverse effects*; D016896:Treatment Outcome
D000074322:Antineoplastic Agents, Immunological; D000068878:Trastuzumab
Cardiovascular outcomes; Disease relapse; HER2; Overall survival; Trastuzumab; Trastuzumab-related cardiotoxicity