In the present study, the 5-year cumulative incidence of cardiovascular disease following diagnosis of breast cancer was 5.8% ([3.8–7.7] (CI 95%). Several factors influence the rising incidence of cardiovascular disease in survivors of breast cancer. These include competing risk of ageing, shared risk factors for both cardiovascular disease and breast cancer as well as smoking or obesity, and the impact of breast cancer treatments . Indeed, even if cardiovascular disease can be caused or accelerated by breast cancer treatments as for example heart failure caused by anthracycline chemotherapy and trastuzumab, it is the combination to direct cardiotoxic effects and indirect effects of cancer therapy, combined with patient factors such as pre-existing hypertension, diabetes, mellitus, dyslipidemia, or smoking that explains the growing burden of cardiovascular disease in breast cancer patients . In the present study, 50% of the patients had pre-existing risk factors for cardiovascular disease, hence the need of cardiovascular disease risk stratification at the time of breast cancer diagnosis for prophylactic strategies among patients at higher risk. Most of the cardiovascular disease events occurred within the first year after diagnosis, with a secondary increase between the 4th and 5th year of follow-up, highlighting two intervals of time at risk. Our results are relevant as the absolute risk of dying of CVD following breast cancer ranges from 1.6 to 10.4% . A recent study has pointed out that the cumulative incidence of CVD 20 years after breast cancer treatment was 11.3% for those who received radiotherapy with a cardiovascular risk factor at diagnosis, and it was higher if patients had received internal mammary chain irradiation .
According to the accumulated dose, the incidence of severe anthracycline-induced cardiotoxicity leading to systolic heart failure can be as high as 25% . As regards trastuzumab, cardiotoxicity was initially high when it was given concomitantly with anthracyclines, in trials of metastatic breast cancer. The administration of trastuzumab after anthracyclines substantially reduced the rate of clinical heart failure, with a rate of cardiac dysfunction in patients treated with anthracyclines and trastuzumab of 6.2 and 20.1% after 1 and 5 years respectively . The association between left-sided breast cancer and radiotherapy treatment with a higher risk of cardiovascular disease mortality has mainly been found in the early 1980’s as it usually involved higher doses on a large irradiation field. Risk of death from ischemic heart disease associated with radiation for breast cancer has substantially decreased over time .
This analysis suggests that patients with breast cancer have a higher risk of cardiovascular disease events, and may represent a perfect panel of ‘long-term survivors’ from cancer, for which dedicated preventive strategies should be elaborated. Garcia M et al. have highlighted emerging, non-traditional risk factors including breast cancer treatments that contribute to increase the risk of cardiovascular disease among women, claiming for aggressive prevention strategies . Indeed, patients with breast cancer who have received anthracycline-based therapy as well as mediastinal radiation therapy should be included in long-term cardiac surveillance programs. In the present study, factors associated with the occurrence of cardiovascular disease events are mainly patients with pre-existing cardiovascular disease risk factors as well as aggressive cancer factors such as the overexpression of HER2 and advanced stage of cancer. However, no multivariate analysis was done, because of the paucity of events. Hitherto, the only score developed to predict the risk of major adverse cardiovascular disease events among breast cancer patients mainly includes cardiovascular disease risk factors at the time of diagnosis. Specific breast cancer treatments associated with cardiovascular toxicity as well as relevant baseline variables such as tumor characteristics were not considered. Subsequently, our findings concerning the overexpression of HER2 and advanced stage of cancer that represent factors associated with the occurrence of cardiovascular disease may be implemented in such scores . Almost 90% of the patients were alive after a 5 years follow-up while 30 patients (4.4%) had a breast cancer relapse. The American Heart association underlines that breast cancer survivors who are 65 and older are more likely to die of cardiovascular disease events than breast cancer, breast cancer increasing the risk of cardiovascular disease at the same time, hence the interest of omics signatures for slowing the therapeutic armamentarium and to tailor the appropriate treatment to each patient, according to their accurate cancer’s risk recurrence, and subsequently spare the heart . Breast cancer survivors should be closely monitored as they may live long enough to be at risk for competing causes of death. In that regard, an effective screening tool for identifying cardiac damage in breast cancer survivors may not be too far off through the identification of bio markers that could lead to earlier detection of cardiac damage, subsequently allowing the instauration of cardioprotective therapies . Trials are currently exploring how effective it may be to give these agents during postoperative chemotherapy and radiotherapy [27, 28].
Focus on AF
Considering AF, the cumulative incidence was 1.1% [0.1–2.1] (CI 95%). Epidemiological evidence of AF in cancer patients, which has been initially mostly explored in colorectal and lung cancers through case-control studies, found prevalence rates of AF after cancer diagnosis ranging from 0.59 to 5.2% [29,30,31]. According to Guzetti et al.,the relation between AF and cancer does not seem to be restricted to particular cancer location, suggesting that cancer could lead to AF through a systemic inflammatory state . A cohort study of 269,742 patients based on Danish registry data displayed that the relative risk of cancer diagnosis was high for all types of cancer within 3 months after AF diagnosis but especially pronounced for lung, kidney and colon cancers. Similarly, in a long-term prospective cohort study of 34,691 patients, the risk of incident AF after cancer diagnosis was 20% higher in the first 3 months and especially for colon cancer [32, 33]. Beyond systemic inflammation, AF may complicate the course of breast cancer, notably through local factors including thoracic radiation . The development of AF also possibly represents a complication of medical breast cancer therapy as several chemotherapeutic agents are associated with AF arrhytmiogenesis . Further research is needed to explore such hypotheses . Nevertheless, even though breast cancer doesn’t seem to be the first provider of AF, as illustrated by our figure analysis, it should not be considered as an epiphenomenon, particularly in view of therapeutic issues.
Therapeutic features of AF in breast cancer patients
Important dilemmas remain in the treatment of patients with new-onset AF occurring during cancer course concerning both antithrombotic and antiarrhythmic therapy. One major unresolved concern is the consideration of AF occurring during cancer course as a classical AF that would lead to the same conventional treatment. The present study showed that patients with AF were allocated treatments with either direct oral anticoagulants (DOACs) or low molecular weight heparins (LMWH). This reflects the fact that no clinical guidelines in the management of AF following cancer diagnosis are currently available, notably when antithrombotic treatment is chosen, the same for antiarrhythmic strategy. If DOACs are being increasingly prescribed for patients with AF in common population, data concerning DOACs in patients with AF and active cancer are scarce [36, 37]. The large clinical trials of dabigatran, apixaban, and rivaroxaban for stroke prevention in AF have excluded patients with active cancer [36, 38, 39]. If DOACs are non-inferior to LMWH for the treatment of venous thromboembolism in cancer patients, there is however a higher risk of major bleeding associated to their use [40, 41]. LMWH may be used preferentially, even if no sufficient data support the relevance of such therapeutic management. Indeed, the 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with AF has addressed the scope of the issue and suggests a dedicated interdisciplinary team approach for assessing the accurate anticoagulant treatment in cancer patients with AF since further data are still required . Trials are currently ongoing to notably demonstrate the efficacy and safety of apixaban in comparison to LMWH for treating venous thromboembolism among patients with cancer . Finally, there is still no strong evidence to guide practice despite the fact that both AF and breast cancer have growing incidences.
In the interpretation of our findings, some strengths and limitations deserve to be taken into account. The major strength of our study is of methodological nature. All patients from the area were treated in the same center, so we feel confident that any patient with diagnosed breast cancer has been screened and included in our analysis. Since the first national “Plan Cancer” promoted by Président Jacques CHIRAC in 2003, the management of patients with cancer has been devoted to the corresponding oncologist. Thereby, the risk of missing information due to the retrospective may be low. Moreover, existence of missing information would have increased the rate of cardiovascular disease events. So, we feel confident that the incidence of cardiovascular disease events after breast cancer diagnosis is at least 5.8% [3.8;7.7] 95%CI. Besides, as regards cardiovascular disease events, we had an access to cardiology files of Saint-Etienne University hospital center where patients are usually admitted for cardiovascular disease events. The occurrence of other cardiovascular disease events which could have been passed under silence was sought by calls to each patient’s general practitioner. The same process was used to collect pre-existing cardiovascular disease. Because of the retrospective collection of information, we then decided to proceed solely to an univariate analysis.