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Long-term cardiovascular outcomes and overall survival of early-stage breast cancer patients with early discontinuation of trastuzumab: a population-based study

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Abstract

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.

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Funding

This work was supported by the Canadian Cancer Society (Grant #700839). This research was supported through provision of data by ICES and Cancer Care Ontario (CCO) and through funding support to ICES from an Annual Grant by the Ministry of Health and Long-Term Care (MOHLTC) and the Ontario Institute for Cancer Research (OICR). The opinions, results, and conclusions reported in this paper are those of the authors and are independent from the funding sources. No endorsement by ICES, CCO, OICR or the Government of Ontario is intended or should be inferred.

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Authors and Affiliations

  1. University of Toronto, Toronto, ON, Canada

    Inna Y. Gong, Sunil Verma, Andrew T. Yan, Dennis T. Ko, Craig C. Earle, George A. Tomlinson, Maureen E. Trudeau, Murray D. Krahn, Monika K. Krzyzanowska, Christine B. Brezden-Masley & Kelvin K. W. Chan

  2. Sunnybrook Health Sciences Centre, Toronto, ON, Canada

    Sunil Verma, Dennis T. Ko, Craig C. Earle, Maureen E. Trudeau & Kelvin K. W. Chan

  3. St. Michael’s Hospital, Toronto, ON, Canada

    Andrew T. Yan & Christine B. Brezden-Masley

  4. Institute for Clinical Evaluative Sciences, Toronto, ON, Canada

    Dennis T. Ko, Craig C. Earle & Monika K. Krzyzanowska

  5. Ontario Institute for Cancer Research, Toronto, ON, Canada

    Craig C. Earle

  6. University Health Network, Toronto, ON, Canada

    George A. Tomlinson & Monika K. Krzyzanowska

  7. Toronto Health Economics and Health Assessment, Toronto, ON, Canada

    Murray D. Krahn

  8. Cancer Care Ontario, Toronto, ON, Canada

    Scott Gavura & Kelvin K. W. Chan

  9. British Columbia Cancer Agency, Vancouver, BC, Canada

    Stuart Peacock

  10. Canadian Center for Applied Research in Cancer Control, Canada http://cc-arcc.ca/

    Stuart Peacock & Kelvin K. W. Chan

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  1. Inna Y. Gong
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  2. Sunil Verma
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  10. Christine B. Brezden-Masley
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Correspondence to Kelvin K. W. Chan.

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Gong, I.Y., Verma, S., Yan, A.T. et al. Long-term cardiovascular outcomes and overall survival of early-stage breast cancer patients with early discontinuation of trastuzumab: a population-based study. Breast Cancer Res Treat 157, 535–544 (2016). https://doi.org/10.1007/s10549-016-3823-y

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