Evaluation and management of side effects of breast cancer treatment

Breast cancer is one of the most common malignant diseases. Adjuvant systemic therapies such as chemotherapy, immunotherapy and endocrine therapy play an important role in the treatment of breast cancer. These therapies reduce the risk of relapse of breast cancer and increase cure rates. However, these therapies are associated with short- and long-term side-effects. Sometimes these side-effects are irreversible and disabling, which may affect the quality of life, treatment continuation and treatment adherence. The research described in this thesis is focused on treatment of anti-cancer therapy induced menopausal symptoms and on trastuzumab-related cardiac dysfunction in women with early and advanced breast cancer. The aim was to investigate new treatment options for the management of hot flashes, and new modalities for the detection and prevention of trastuzumab-related cardiotoxicity. Results of a prospective randomized double blind three-armed trial comparing clonidine, venlafaxine and placebo in the management of hot flashes in women with a history of breast cancer are described. Venlafaxine treatment resulted in a more immediate reduction of hot-flash scores when compared with clonidine, however hot-flash scores at week 12 were lower in the clonidine group than in the venlafaxine group. The main conclusion of this study was that both drugs reduced the hot-flash scores in women after a diagnosis of breast cancer. However, since venlafaxine showed a better reduction of hot flashes score over the whole treatment period of 12 weeks, venlafaxine might be the preferred treatment. Several studies into the cardiac safety of trastuzumab treatment are described in this thesis. Trastuzumab is a humanized monoclonal antibody against the extracellular domain of HER2 and treatment with trastuzumab has resulted in clinical benefit in HER2 positive advanced breast cancer and improved disease-free and overall survival in combination with adjuvant chemotherapy in HER2 positive primary breast cancer. Overall trastuzumab treatment is well tolerated, however cardiac dysfunction is one of the clinically relevant side-effects of trastuzumab treatment manifested by left ventricular systolic dysfunction and in a small proportion of patients even in advanced congestive heart failure. Only prior or concomitant treatment with anthracyclines was identified as a significant predictive factor of cardiac dysfunction. However, no statistically significantly association was seen between potential risk factors for the development of cardiotoxicity, such as age, high body mass index and use of antihypertensive drug or co-morbidity and the incidence of cardiac events. Serum biomarkers such as NT-proBNP and the troponines were not statistically significantly related to trastuzumab-associated cardiotoxicity or recovery. Trastuzumab induced cardiac toxicity was partly reversible also in patients with a decreased left ventricular function prior to treatment with trastuzumab. The development of a pharmacokinetic-pharmacodynamic (PK-PD) model is described. This PK-PD model can be used to address clinical questions regarding optimal management of trastuzumab-associated cardiotoxicity and to develop monitoring strategies. The tentative blinded results of a prospective, placebo-controlled, pharmacological intervention study (CANDY) are described. In this study, patients were treated concurrently with adjuvant trastuzumab and an angiotensin II-receptor blocker (candesartan) for HER2 positive breast cancer. Currently, the effect of candesartan in the prevention of trastuzumab-associated cardiotoxicity can not be disclosed. In conclusion, longer follow-up studies in large patient populations are needed to evaluate long-term tolerability and cardiac safety of trastuzumab treatment. Unblinding and final results of the CANDY study are needed to evaluate the effect of candesartan in the prevention of trastuzumab-associated cardiotoxicity in early breast cancer patients.