Introduction
Breast cancer is the most common cancer diagnosed among women worldwide, with 80–90% of patients surviving more than 5 years after diagnosis [
1]. Breast cancer patients have an increased risk of recurrences, early side effects, and with increasing survival, late adverse health effects related to both the disease and therapy. Previous studies on diseases associated with breast cancer have focused on a limited number of diseases [
2‐
4]. Available evidence regarding the incidence of, and mortality due to, other diseases after breast cancer diagnosis is limited by small sample sizes, limited number of diseases selected, and/or short-term follow-up [
5‐
8]. As a result, the global spectrum of diseases and mortality among breast cancer patients has not been thoroughly addressed.
Since the effectiveness of clinical care for breast cancer patients depends on early detection and intervention for adverse outcomes, analyzing sequential patterns of disease occurrence (disease trajectories) may help identify key diagnoses to mitigate the risk of future poor outcomes. While disease trajectories are commonly identified in the general population [
9,
10], to date no study has been conducted among breast cancer patients, specifically studying the sequential associations between early treatment-related side effects and later life-threatening outcomes.
This study comprehensively investigated disease progression by (i) assessing the risk of disease incidence and mortality among breast cancer patients, compared to the general population, and (ii) analyzing disease trajectories in breast cancer patients to identify targets for early preventive interventions.
Discussion
A systemic attempt to elucidate the risk profile for all other diseases after breast cancer diagnosis has previously not been performed. In this study, we found increased incidence of many infectious and non-communicable diseases after breast cancer diagnosis (see Fig.
1), confirming previous findings [
2,
15‐
17]. We also identified several diseases of previously unknown risk among breast cancer patients, such as larynx diseases and several gynecological disorders. Since larynx disorders are associated with external hormones (e.g., oral contraceptives) [
18], it is possible that this increased risk is a result of hormone therapy in breast cancer patients. Another novel finding was an increased risk of several non-inflammatory gynecological disorders, such as hyperplasia, cysts, and polyps of the female genital tract (Additional file
1: Table S1). Since tamoxifen has a known influence on the female genital tract [
19], it is therefore not surprising to find an increased risk of such gynecological disorders among breast cancer patients.
Despite the increased risk of many diseases, we observed increased mortality only for other cancers (Table
2), suggesting that the lethality of diseases diagnosed among breast cancer patients was the same as in the general population. The increased incidence of and mortality due to other cancers among breast cancer patients has been reported previously with similar estimates [
20,
21]. Since younger age at diagnosis and family history of breast cancer are both associated with an increased risk of other cancers after breast cancer diagnosis [
22], shared genetic factors among different types of cancers might contribute to this increased risk. Moreover, treatments for breast cancer may also be carcinogenic and increase the risk of other cancers; the risk of lung cancer is increased after radiotherapy for breast cancer [
23], while hormonal treatments may increase the risk of endometrial cancer [
24].
The disease trajectory analysis in our study indicated several sequential associations for side effects of chemotherapy and hormone therapy among breast cancer patients (see Fig.
2). The risk of depression, anxiety, dermatitis, and osteoporosis was associated with a diagnosis of neutropenia, with all of these diseases being toxic side effects of chemotherapy [
25‐
28]. These sequential associations also suggest that neutropenia is an early and instant sign for chemotherapy toxicity among breast cancer patients. It is therefore necessary to provide targeted interventions for this patient group (such as granulocyte colony-stimulating factors), in order to reduce side effects and promote treatment adherence. Other diseases identified in the overall trajectories are mainly associated with tamoxifen use, considering its effect on ovarian cysts and endometrial tumorigenesis [
24,
29,
30].
Among the trajectories leading to breast cancer mortality, a diagnosis of neutropenia was also associated with increased mortality due to breast cancer (see Fig.
3a). Since neutropenia is a side effect of chemotherapy, and chemotherapy is usually given to patients with advanced tumors, it is reasonable to believe that neutropenia is associated with breast cancer mortality. We also found that dorsalgia and anxiety were associated with breast cancer mortality. Dorsalgia is long identified as a sign of bone metastasis [
31], while the risk of anxiety is increased after chemotherapy and is associated with advanced tumor characteristics [
27]. Indeed, all these three diseases/disorders are indicators of aggressive breast cancer tumor characteristics and consequently are associated with a worse disease prognosis. Our finding also suggests that clinicians (particularly general practitioners) and patients should pay special attention to dorsalgia symptoms, considering it is associated with bone metastasis.
In the disease trajectories leading to other cancer mortality, we found an increased incidence of menopausal disorders among breast cancer patients; these disorders are associated with the incidence of other cancers, ileus, and finally other cancer mortality (see Fig.
3b). Menopausal disorders are common side effects of hormone therapy, with a prevalence of more than 10% among breast cancer patients in the studied cohort. Symptoms in menopausal disorders such as uterine bleeding are established predictors for endometrial cancer [
24], while ileus is a complication after gynecological surgery [
32]. Since the risk of endometrial cancers is increased after tamoxifen treatment [
33], but not aromatase inhibitors [
34], a genital tract examination should be recommended during follow-ups for breast cancer patients being treated with tamoxifen.
There are several key strengths of our study. The large sample size of breast cancer patients and matched individuals retrieved from the Swedish national health registries provided a unique opportunity to detect a comprehensive spectrum of diseases with increased risk among patients in the real world, with an accurate estimation of HRs. The use of national registries also minimizes selection and information bias. In addition, analysis of disease trajectories allowed us to reveal key diagnostic indicators for poor survival.
However, we also acknowledge several limitations of this study. Although validity of the ICD codes used for disease diagnoses in the Swedish Inpatient Registry is about 85–95% [
12], diagnoses from the outpatient registry have not as yet been validated. This could possibly result in disease misclassification, particularly for those diseases with slight to moderate symptoms and those defined by contributory diagnostic codes. Such misclassification should not have influenced our main findings, since the majority of our results relate to life-threatening diseases among breast cancer patients, and sensitivity analyses focusing on the main diagnosis did not differ greatly from the presented results (Additional file
1: Table S3, 80% of the significant point estimates had a difference of less than 10%). We were also limited by using the patient registry, which does not include diseases diagnosed and treated in a primary care setting and therefore the disease trajectories identified represent only severe cases. Furthermore, due to increased medical surveillance for breast cancer patients, these women may have been diagnosed with a disease that would continue to be undiagnosed in matched healthy individuals. Despite this, those diseases with an extremely high HR or with a long-term increased risk could not be solely explained by this possible surveillance bias. We have also endeavored to minimize this influence by starting the follow-up time from 2 months after cancer diagnosis. Finally, tumor characteristics and treatment data for both breast cancer and other diseases were not available, and consequently, we were not able to study the specific effects of disease treatments. Further studies are also needed to test and validate the identified disease trajectories in other settings and populations.
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