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Abstract
Radiotherapy, endocrine therapy, chemotherapy and targeted therapy adjunct to surgery have a critical role in the management of early breast cancer for outcome improvement. Anthracycline containing chemotherapy reduces 10-year incidence of breast cancer mortality by an absolute 6.5% compared to no adjuvant chemotherapy and addition of taxanes to anthracycline regimes leads to additional gain of 2.8% in 8-years breast cancer mortality. Dose dense chemotherapy improves breast cancer mortality by an estimated relativereduction of 40%. Trastuzumab, the first anti-HER2 agent among plenty, administered for one year, led to a paradigm shift in the management of HER2 positive breast cancer and significantly altered prognosis. Adjuvant trastuzumab improves disease free survival by are lative risk reduction of 40%. Despite beneficial effect of chemotherapy and anti-HER2targeted therapy, acute or late toxicity can be dose limiting and even influence patients quality of life during treatment and long time after it is completed. Given the good prognosis of breast cancer and the millions of breast cancer survivors, therapy related toxicity affects a considerable number of women. Efforts to escalate or de-escalate treatment are ongoing and potential trade-offs in safety are monitored, resulting at best to improved benefit-risk balance.
The aim of the current thesis was to examine heart failure outcomes and management after breast cancer diagnosis compared to a population of women with heart failure and toxicity out comes related to tailored dose dense chemotherapy namely, cardiotoxicity after combination with trastuzumab, neutropenia related events and premature ovarian in sufficiency.
The Swedish Registry for heart failure (Swede HF) and the national health care registries were utilised for the purposes of Paper I. Patients enrolled in the Swede HF registry between 2008and 2013 were included and followed for a median period of two years. Patients with breast cancer history, identified through the National Cancer Registry, and age-matched controls(1:5) were investigated. Heart failure related baseline characteristics and outcomes did not differ amid presence of breast cancer history among women registered in the Swede HF registry with incident heart failure. Differences in the history of myocardial infarction, administration of aspirin and device therapy were observed among women with prevalent heart failure, depending on previous breast cancer history. Breast cancer history did not alter heart failure outcomes but time from heart failure diagnosis did; women with prevalent heart failure had worse survival than those with incident heart failure.
Papers II-IV investigated different toxicity aspects related to the population enrolled and treated in the PANTHER phase III study comparing tailored (protocol predefined dose escalation or de-escalation) and dose dense (every two weeks) chemotherapy to standard dose three weekly chemotherapy. Paper II, investigated if tailored dose dense chemotherapy can further improve trastuzumab efficacy, compared to combination with standard chemotherapy and whether this combination would jeopardise cardiac safety; both parts of the study were predefined. The trastuzumab and tailored dose dense group demonstrated a 32% relative improvement in risk for breast cancer relapse but the results did not reach formal statisticalsignificance. Despite small reductions of left ventricular ejection fraction at four- and sixyears follow-up, no clinically meaningful difference in the risk for cardiotoxicity was demonstrated between tailored dose dense chemotherapy and standard chemotherapy compared as administration per HER2 treatment or as per chemotherapy group.
