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Background: Systemic cancer treatment is linked to reduced cardiorespiratory fitness (CRF), whereas poor CRF is associated with higher symptom burden and increased cardiovascular (CV) risk in cancer survivors. The magnitude of CRF impairment from systemic therapy, however, remains unclear. While exercise therapy may mitigate CRF decline during treatment and provide benefits in early survivorship, studies in short-term breast cancer survivors (BCSs) report only modest CRF improvements, suggesting potential treatment-related limitations in physiological adaption to exercise therapy. However, whether such blunted exercise response persists in long-term survivorship is unknown. Additionally, previous research reports that a high proportion of long-term BCSs experience a substantial symptom burden following treatment. However, while research shows beneficial effects of exercise therapy on overall health (e.g., fatigue) during and shortly after breast cancer treatment, the effects of exercise therapy on other late effects in long-term BCSs remain scarce. Aims: The main aims of this thesis were to: I) evaluate the effects of systemic anticancer treatment on CRF; II) evaluate the effects of aerobic exercise on CRF and CV risk factors in long-term BCSs, with comparisons to cancer naïve controls; and III) evaluate the impact of aerobic exercise on other late effects and health-related quality of life (HRQoL) in long-term BCSs. Design and participants: This thesis comprises three papers. Paper I is a systematic review and meta-analysis of studies involving adult cancer patients or adult childhood cancer survivors of any cancer diagnosis who had undergone systemic anticancer treatment, with peak oxygen consumption (VO2peak) directly measured before and after systemic therapy. Papers II and III are based on the two-armed randomized controlled trial the CAUSE (CArdiovascUlar Survivors Exercise). Eligible participants were female BCSs (stage II-III) diagnosed between 2008-2012, aged ≤60 years at diagnosis, and treated with Epirubicin. In Paper II, a non-cancer control group with similar-aged cancer naïve women free of malignancy diagnosis was included for comparison. Methods: For Paper I, a comprehensive literature search regarding systemic anticancer treatment and CRF was conducted in PubMed, EMBASE, CINAHL, SPORTDiscusTM, and the Cochrane Library. In Papers II and III, long-term BCSs were randomized to either supervised aerobic exercise consisting of thrice-weekly treadmill walking/running sessions for five months or to usual care. CRF was assessed as peak oxygen consumption (VO2peak) using cardiopulmonary exercise testing (CPET). CV risk factors included blood pressure, cardiometabolic blood biomarkers from blood samples, body composition measured from Dual X-ray Absorptiometry (DXA), and self-reported activity level from Godin Questionnaire. Patient-reported outcomes included the Subjective Vitality- and Satisfaction with Life Scale. Other late effects, including fatigue, breast cancer-specific symptoms, neuropathy, and HRQoL, were assessed by the Chalder Fatigue Questionnaire, the EORTC QLQ-BR23 Questionnaire, the EORTC QLQ-C30 Questionnaire, and the Scale for Chemotherapy-Induced Long-term Neurotoxicity Questionnaire. All assessments were measured at baseline and post-intervention, with additional questionnaires administered at one-year follow-up. Main results: I) Paper I indicated that 13 weeks of systemic anticancer treatment was associated with a significant decrease in VO2peak from pre- to post-systemic treatment. VO2peak remained significantly lower in cancer survivors a median time of two years (range: six weeks to 12 years) post-treatment compared to non-cancer controls. Lower arteriovenous oxygen difference (a-vO2 difference) was associated with lower VO2peak. II-III) Among the 140 longterm BCSs (aged 59.0±6.4 years, 11±1 years post-treatment) included in the CAUSE trial, exercise therapy led to significant improvements in VO2peak compared to usual care. The change in VO2peak from pre- to post-intervention was significantly less in the BCSs Exercise group compared to non-cancer controls (n=69, aged 57.8±4.9 years). No significant beneficial effects on CV risk factors were observed between groups. The BCSs Exercise group significantly improved subjective vitality and life satisfaction and improved fatigue, body image, and HRQoL compared to BCSs Usual care, with persistent improvements observed for mental fatigue and selected HRQoL domains at one-year follow-up. The effects of exercise therapy were most pronounced among BCSs with high symptom burden at baseline. Conclusion: Systemic anticancer therapy leads to significant and persistent CRF impairments. Aerobic exercise is well-tolerated and improves CRF, vitality, and life satisfaction in long-term BCSs, though the CRF responses were blunted compared to noncancer controls. Additionally, aerobic exercise improves fatigue, body image, and HRQoL compared to usual care, particularly for BCSs with high symptom burden at baseline. However, most of the observed exercise benefits returned towards baseline values at one-year follow-up.
