Unveiling the comorbidity burden of male breast cancer.

Introduction

Male Breast cancer (MBC) is a rare condition, it accounts for less than 1% of all breast cancer in Spain and worldwide, as with Female Breast cancer (FBC) its incidence rate is steadily rising on an annual basis 1 – 3 . Due to its low prevalence, there is a lacking in prospective randomized clinical studies; historically male patients have been excluded from breast cancer clinical trials. Our current knowledge of MBC come from small retrospective studies, this is one of the reasons why MBC has been traditionally considered an analogous clinical entity to menopausal FBC 4 , 5 .

All the above has hampered to obtain useful and realistic knowledge regarding MBC characteristics and management, currently most treatment recommendations are extrapolated from FBC guidelines 6 . Nonetheless, there is an increasing evidence that MBC embodies its own distinct clinical identity, which requires its own particular considerations 4 , 5 , 7 . In fact, two specific histological subtypes have been described in MBC 8 , further supporting the aforementioned.

Most of the efforts for a better understanding of MBC have been focused to characterize sociodemographic, life-style and clinical differences between MBC and FBC patients and how those differences are associated to survivability and mortality. There are certain features of MBC well described in the literature. For instance, MBC patients tend to be diagnosed at older age, with a more advance tumour stage, with higher number of co-existing pathologies and with hormone-positive phenotype in comparison with their female counterparts. In reality, most of MBC patients are usually progesterone positive, estrogen positive and epidermal growth factor receptor negative. This hormone profile is associated with poorer prognosis 2 , 3 , 9 – 11 .

Breast cancer is a complex multifactorial disease, and as such, there seem to be genomic factors modulating its appearance and evolution. For instances, mutations in BRCA2 and BRCA1 are presented in around 16% of all MBC cases, increasing an 8% and a 2% respectively the risk of MBC development versus the general population with wild type genes with just 0.1%. There are other found genes that may influence appearance and evolution of breast cancer in a lighter way 12 . Other risk factor worthy to be mentioned are family history of breast cancer, strengthening the genomic background relevance; breast cancer in closed-degree relative has been associated with a high increased odds of MBC 13 .

Regarding treatment, MBC patients seem to mostly undergo mastectomy and they tend to be nonadherent to adjuvant endocrine therapy 14 , 15 . Nevertheless, it appears there are certain surgical treatments with better outcomes, but all of them have similar survival rates comparing with FBC once adjusted by treatment 9 , 10 , 16 , 17 .

On the other hand, available data of survivability in MBC patients suggest they have worse results than FBC in general, most likely due to the older age of diagnosis, the higher burden of multimorbidity and the advance tumour stage 18 – 20 . Remarkably, little is known about associated comorbidities to MBC, which may influence heavily survivability; and which ones differ from the general population or its female counterpart, information relevant enough to modulate the treatment itself of MBC patients. As far as we know up to the date, only Zoorob et al. (2019) have tried to elucidate this association and the differences between MBC and FBC patients in a set list of 20 chronic pathologies 21 . Other few studies have described the frequency of small fixed lists of chronic conditions without determining associations 3 , 9 , 22 , and lastly, in the vast majority of cases when talking about multimorbidity in MBC patients they choose some kind of index to assess disease number or multimorbidity burden without further disaggregation 8 , 9 , 14 , 16 , 17 , 20 , 23 – 26 . Despite the lack of knowledge in this matter, characterizing comorbidities associated to MBC patients is fundamental for a better management of their health and increasing chances of survival in their complex situation, as previous studies have widely seen that high multimorbidity burden leads to poorer cancer outcomes.

Bearing all above in mind, this study aimed to analyze the association of breast cancer with other comorbidities and to compare those associated comorbidities to those found in a general population of men without breast cancer and in a population of female breast cancer patients.

Methods

Study design and population

We conducted a retrospective, observational study in the EpiChron Cohort, which contains anonymized sociodemographic and clinical information of all users of the public health care system in the Spanish region of Aragon. Detailed description and data-linkage method of the EpiChron Cohort can be found elsewhere 27 . The total general population for this study comprised all individuals with at least one year of activity in the Health System and at least one chronic condition between 2010 and 2019 (1,136,624 individuals; 529,683 men and 606,941 women), almost 90% of the total population of Aragon region (1.3 M individuals).

For the breast cancer cohorts, all prevalent cases of breast cancer between 2010 and 2019 in men (105 men) and women (11,657 women) aged 18 years and older were selected. Patients with breast cancer were identified as those with an active diagnosis of breast cancer during the study period recorded in their primary or hospital electronic health records. All codes under the 24 code (Cancer of breast) of the Clinical Classification Software (CCS) were selected. Specifically, the following ICD9 diagnosis codes were considered by CCS: 174.0, 174.1, 174.2, 174.3, 174.4, 174.5, 174.6, 174.8, 174.9, 175.0, 175.9, 233.0 and V103. No other inclusion or exclusion criteria were applied.

Additionally, a small matched sample of male patients without breast cancer diagnosis (210 men) was selected to compare disease association.

Ethical considerations

The Clinical Research Ethics Committee of Aragón (CEICA) approved this study (PI17/0024). CEICA waived the need of obtaining the informed consent due to the use of anonymized data and the epidemiological approach used. This research was performed in accordance with the Declaration of Helsinki.

Study variables

For all MBC patients, we analysed age at breast cancer diagnosis, residency (urban/rural), all chronic diseases that the patient had registered in the studied period, number of chronic diseases at diagnosis and multimorbidity state (yes/no).

The diagnosis codes were originally coded according to the International Classification of Primary Care, 2nd edition (ICPC-2) or the International Classification of Diseases, 9th edition (ICD-9), depending on the source of the data (primary or hospital care). In order to reduce the number of different diagnosis codes, we transformed the ICPC-2 codes into ICD-9 codes using the conversion developed by the Navarra Institute of Public and Labour Health (8th edition) 28 , then we used the Agency for Healthcare Research and Quality’s Clinical Classification Software to group ICD-9 codes, particularly we used the single level category 29 . Then, we filtered out all non-chronic conditions using the Chronic Condition Indicator software tool, resulting in 161 chronic mutually exclusive categories 30 . Multimorbidity was defined as the presence of two or more chronic diseases after this reclassification process. For all populations, prevalence of the different CCS codes was analysed.

Statistical analysis

For the descriptive analysis, we presented continuous data by their mean and standard deviation and categorical data by their frequency and proportion.

For the characterization of comorbidities, firstly no matching by age was performed in the comparison with the FBC population, so odds ratios (OR) were calculated by using the whole population without breast cancer for their respective sex, the comorbidity results were compared between MBC and FBC. For the second comparison, a matching procedure was performed in a ratio 1:2, using birth year as matching variable, MBC patients were matched with male patients without breast cancer, a small population of 315 individuals in total. Conditional logistic regression models were used to calculate OR and their confidence interval of prevalence for each comorbidity according to the presence or absence of breast cancer in each population. OR were adjusted by age. All p-values were two-sided and adjusted by age, results with adjusted p-values < 0.05 were considered statistically significant. All the analysis was made in STATA 12.0.

Data visualization was performed using Microsoft Excel version 1808; for the frequency tables and using ggplot2 v3.4.2 in R v4.3.0; for the bar plots.

Results

Characteristics of male breast cancer patients

Between 2010 and 2019, 105 MBC patients were identified in EpiChron Cohort, their mean age at diagnosis was 65.62 ± 12.02 years [Mean ± Standard deviation]. Half of all MBC patients had died during the study period and 60 of them (57.14%) lived in an urban area. Almost all of them (more than 90%) were over 45 years old and with multimorbidity. Notoriously, more than half of all MBC patients (52.38%) had six or more chronic conditions at breast cancer diagnosis time and, in general, the mean number of chronic diseases presented in the population was 5.7 ± 3.17, without considering breast cancer diagnosis (Table 1 ).

Table 1 Socio-demographic and clinical characteristics of men with cancer of breast between 2010 and 2019 from the EpiChron Cohort. Characteristics Total N (%) 105 (100) Mean age, years (SD 1 ) 65.62 (12.02) Age interval, years (n, %) < 44 5 (4.76) 45–64 46 (43.81) 65-84 49 (46.67) > 85 5 (4.76) Residence, urban 2 (n,%) 60 (57.14) All-cause mortality 53 (50.48) Chronic diseases Mean (SD) 5.70 (3.17) Number of diseases (n, %) 1 7 (6.67) 2 11 (10.48) 3 11 (10.48) 4 9 (8.57) 5 10 (9.52) > 6 55 (52.38) Multimorbidity, yes (n, %) 96 (91.43) 1 Standard deviation; 2 Versus rural.

Most frequent comorbidities in breast cancer patients

The most frequent comorbidities for breast cancer patients are shown in Fig. 1 . “Hypertension”, “Genitourinary symptoms and ill-defined conditions” and “Delirium, dementia, and amnestic and other cognitive disorders” were shared similarly in proportion between male and female breast cancer populations. Nevertheless, in MBC patients there were some pathologies more frequently presented, such as “Disorders of lipid metabolism”, “Other nutritional, endocrine, and metabolic disorders”, “Diabetes Mellitus”, “Cardiac dysrhythmia”, “Other ear and sense organ disorders”, “Coagulation and haemorrhagic disorders” and “Acute myocardial infraction”. On the other hand, FBC patients tended to suffer more “Anxiety disorders”, “Osteoarthritis”, “Thyroid disorders”, “Depression and mood disorders”, “Osteoporosis”, “Headache; including migraine”, “Spondylosis; intervertebral disc disorders; other back problems” and “Menopausal disorders”. Around 15% of MBC cases suffered from “Hyperplasia of prostate” (all prevalences can be found in Table 2 ).

Fig. 1 Most frequent comorbidities in prevalent male breast cancer (MBC) and female breast cancer (FBC) patients older than 18 years old between 2010 and 2019. Results expressed as percentage of the total population of MBC patients (105 cases) and FBC patients (11,657 cases).

Table 2 Prevalence of chronic comorbidities in men with cancer of breast between 2010 and 2019 from the EpiChron Cohort ( n =105). Comorbidity Men Women n % n % Disorders of lipid metabolism 58 55.24% 5062 43.40% Hypertension 52 49.52% 5811 49.80% Other nutritional; endocrine; and metabolic disorders 34 32.38% 3088 26.50% Diabetes Mellitus 30 28.57% 1809 15.50% Anxiety disorders 22 20.95% 3136 26.90% Osteoarthritis 21 20.00% 3076 26.40% Genitourinary symptoms and ill-defined conditions 21 20.00% 2089 17.90% Cardiac dysrhythmias 21 20.00% 1137 9.80% Cataract 17 16.19% 1911 16.40% Obesity 17 16.19% 1568 13.50% Hyperplasia of prostate 16 15.24% Other ear and sense organ disorders 14 13.33% 1185 10.20% Coagulation and hemorrhagic disorders 13 12.38% 712 6.10% Depression and mood disorders 12 11.43% 3242 27.80% Thyroid disorders 12 11.43% 2344 20.10% Acute myocardial infarction 12 11.43% 409 3.50% Osteoporosis 10 9.52% 2931 25.10% Delirium, dementia, and amnestic and other cognitive disorders 10 9.52% 1275 10.90% Glaucoma 10 9.52% 965 8.30% Chronic obstructive pulmonary disease and bronchiectasis 10 9.52% 352 3.00% Chronic kidney disease 9 8.57% 763 6.50% Spondylosis; intervertebral disc disorders; other back problems 8 7.62% 1470 12.60% Blindness and vision defects 8 7.62% 1088 9.30% Other upper respiratory disease 8 7.62% 995 8.50% Congestive heart failure; nonhypertensive 8 7.62% 648 5.60% Gout and other crystal arthropathies 8 7.62% 123 1.10% Asthma 7 6.67% 760 6.50% Chronic ulcer of skin 7 6.67% 566 4.90% Diverticulosis and diverticulitis 6 5.71% 426 3.70% Heart valve disorders 6 5.71% 247 2.10% Headache; including migraine 5 4.76% 1686 14.50% Miscellaneous mental health disorders 5 4.76% 469 4.00% Other diseases of veins and lymphatics 4 3.81% 590 5.10% Esophageal disorders 4 3.81% 495 4.20% Acute cerebrovascular disease 4 3.81% 452 3.90% Other inflammatory condition of skin 4 3.81% 420 3.60% Retinal detachments; defects; vascular occlusion; and retinopathy 4 3.81% 284 2.40% Epilepsy; convulsions 4 3.81% 143 1.20% Residual codes; unclassified 4 3.81% 141 1.20% Cancer of bronchus; lung 4 3.81% 52 0.40% Peripheral and visceral atherosclerosis 4 3.81% 40 0.30% Aortic; peripheral; and visceral artery aneurysms 4 3.81% 9 0.10% Cancer of prostate 4 3.81% Other nervous system disorders 3 2.86% 724 6.20% Transient cerebral ischemia 3 2.86% 365 3.10% Other liver diseases 3 2.86% 260 2.20% Peri-; endo-; and myocarditis; cardiomyopathy (except that caused by tuberculosis or sexually transmitted disease) 3 2.86% 101 0.90% Other endocrine disorders 3 2.86% 83 0.70% Alcohol-related disorders 3 2.86% 48 0.40% Acquired foot deformities 2 1.90% 746 6.40% Other gastrointestinal disorders 2 1.90% 361 3.10% Other non-traumatic joint disorders 2 1.90% 200 1.70% Parkinson`s disease 2 1.90% 136 1.20% Cancer of colon 2 1.90% 106 0.90% Attention-deficit, conduct, and disruptive behavior disorders 2 1.90% 56 0.50% Other microcrystalline arthritis 2 1.90% 41 0.40% Cancer of pancreas 2 1.90% 19 0.20% Cancer of bladder 2 1.90% 12 0.10% Cancer of kidney and renal pelvis 2 1.90% 12 0.10% Other male genital disorders 2 1.90% 1 0.00% Inflammatory conditions of male genital organs 2 1.90% Menopausal disorders 1 0.95% 1172 10.10% Menstrual disorders 1 0.95% 980 8.40% Adjustment disorders 1 0.95% 350 3.00% Other eye disorders 1 0.95% 336 2.90% Nonmalignant breast conditions 1 0.95% 308 2.60% Allergic reactions 1 0.95% 298 2.60% Other acquired deformities 1 0.95% 185 1.60% Conduction disorders 1 0.95% 181 1.60% Rheumatoid arthritis and related disease 1 0.95% 172 1.50% Endometriosis 1 0.95% 155 1.30% Joint disorders and dislocations; trauma-related 1 0.95% 141 1.20% Urinary tract infections 1 0.95% 82 0.70% Hepatitis 1 0.95% 74 0.60% Other bone disease and musculoskeletal deformities 1 0.95% 61 0.50% Other and ill-defined heart disease 1 0.95% 60 0.50% Other connective tissue disease 1 0.95% 60 0.50% Pancreatic disorders (not diabetes) 1 0.95% 50 0.40% Paralysis 1 0.95% 50 0.40% Female infertility 1 0.95% 47 0.40% Multiple myeloma 1 0.95% 38 0.30% Melanomas of skin 1 0.95% 35 0.30% Sleeping disorders 1 0.95% 31 0.30% Nutritional deficiencies 1 0.95% 25 0.20% Aortic and peripheral arterial embolism or thrombosis 1 0.95% 21 0.20% Malignant neoplasm without specification of site 1 0.95% 20 0.20% Sexual disorders 1 0.95% 17 0.10% Cancer of head and neck 1 0.95% 9 0.10% Cancer of other female genital organs 1 0.95% Prolapse of female genital organs 413 3.50% Diseases of white blood cells 159 1.40% Other hereditary and degenerative nervous system conditions 136 1.20% Other circulatory disease 127 1.10% Secondary malignancies 98 0.80% Schizophrenia and other psychotic disorders 90 0.80% Cancer of uterus 84 0.70% Systemic lupus erythematosus and connective tissue disorders 83 0.70% Other female genital disorders 76 0.70% Other congenital anomalies 71 0.60% Cancer of cervix 51 0.40% Regional enteritis and ulcerative colitis 50 0.40% Cancer of ovary 45 0.40% Disorders usually diagnosed in infancy, childhood, or adolescence 44 0.40% Other and unspecified benign neoplasm 40 0.30% Other and ill-defined cerebrovascular disease 37 0.30% Conditions associated with dizziness or vertigo 33 0.30% Infective arthritis and osteomyelitis (except that caused by tuberculosis or sexually transmitted disease) 32 0.30% Leukemias 32 0.30% Other diseases of bladder and urethra 32 0.30% Cancer of rectum and anus 30 0.30% Genitourinary congenital anomalies 28 0.20% Other lower respiratory disease 27 0.20% Hodgkin`s disease 26 0.20% Personality disorders 25 0.20% Pulmonary heart disease 25 0.20% Developmental disorders 20 0.20% Cancer of thyroid 19 0.20% Non-Hodgkin`s lymphoma 19 0.20% Deficiency and other anemia 18 0.20% Biliary tract disease 17 0.10% Multiple sclerosis 17 0.10% Eating disorders 16 0.10% Inflammation; infection of eye (except that caused by tuberculosis or sexually transmitteddisease) 16 0.10% Nervous system congenital anomalies 16 0.10% Substance-related disorders 16 0.10% Viral infection 16 0.10% Cancer of brain and nervous system 15 0.10% Cancer of other GI organs; peritoneum 15 0.10% Cancer of stomach 15 0.10% Malaise and fatigue 13 0.10% Immunity disorders 11 0.10% Cancer of bone and connective tissue 9 0.10% Other CNS infection and poliomyelitis 8 0.10% Other infections; including parasitic 8 0.10% HIV infection 7 0.10% Cardiac and circulatory congenital anomalies 6 0.10% Lymphadenitis 6 0.10% Somatization and hypochondria disorders 6 0.10% Digestive congenital anomalies 4 0.00% Nephritis; nephrosis; renal sclerosis 4 0.00% Cystic fibrosis 3 0.00% Cancer of other urinary organs 2 0.00% Cancer; other and unspecified primary 1 0.00% Cancer; other respiratory and intrathoracic 1 0.00% Lung disease due to external agents 1 0.00% Sickle cell anemia 1 0.00% Spinal cord injury 1 0.00%

In Tables 3 and 4 the results for men and women of the conditional logistic model after adjusting by age can be checked, nine pathologies showed modified risk chances in MBC patients in comparison to the general male population. MBC patients had less risk of “Hypertension” [0.62 (0.41–0.93)] [OR (95% CI)]. In contrast, these patients had more risk than male population of “Anxiety disorders” [1.65 (1.03–2.65)], “Asthma” [2.66 (1.23–5.77)], “Heart valve disorders” [2.99 (1.31–6.85)], “Aortic; peripheral; and visceral artery aneurysms” [3.39 (1.24–9.28)], “Epilepsy; convulsions” [3.43 (1.26–9.31)], “Osteoporosis” [4.26 (2.2–8.24)], “Other endocrine disorders” [7.77 (2.46–24.58)] and “Other diseases of veins and lymphatics” [23.12 (8.45–63.25)] (Tables 3 and 4 ). Women with FBC also had less risk of “Hypertension”, but this risk also decreased with other comorbidities like “Genitourinary symptoms and ill-defined conditions”, “Headache; including migraine” or “Congestive heart failure; nonhypertensive”.

Table 3 Logistic regression models were used to calculate odds ratios (OR) of prevalence for each comorbidity (dependent variable) according to the presence or absence of breast cancer in men (independent variable). Comorbidity Prevalence Crude OR Adjusted OR 1 p -value 2 (n, %) (95% CI) (95% CI) Disorders of lipid metabolism 58 (55.24) 2.46 (1.67-3.62) 1.38 (0.94-2.04) 0.104 Hypertension 52 (49.52) 1.91 (1.30-2.79) 0.62 (0.41-0.93) 0.019* Other nutritional; endocrine; and metabolic disorders 34 (32.38) 1.87 (1.24-2.82) 1.15 (0.76-1.73) 0.509 Diabetes Mellitus 30 (28.57) 2.6 (1.70-3.98) 1.26 (0.81-1.93) 0.303 Anxiety disorders 22 (20.95) 1.66 (1.04-2.66) 1.65 (1.03-2.65) 0.036* Cardiac dysrhythmias 21 (20.00) 3.25 (2.02-5.25) 1.43 (0.88-2.34) 0.150 Genitourinary symptoms and ill-defined conditions 21 (20.00) 3.98 (2.47-6.42) 1.48 (0.89-2.44) 0.129 Osteoarthritis 21 (20.00) 2.36 (1.46-3.80) 1.01 (0.62-1.64) 0.982 Cataract 17 (16.19) 2.15 (1.28-3.61) 0.80 (0.47-1.37) 0.415 Obesity 17 (16.19) 1.75 (1.04-2.94) 1.48 (0.88-2.49) 0.141 Hyperplasia of prostate 16 (15.24) 1.78 (1.05-3.03) 0.65 (0.37-1.12) 0.119 Other ear and sense organ disorders 14 (13.33) 1.62 (0.92-2.85) 1.14 (0.65-2.00) 0.652 Coagulation and hemorrhagic disorders 13 (12.38) 2.83 (1.58-5.05) 1.25 (0.69-2.25) 0.462 Thyroid disorders 12 (11.43) 2.42 (1.33-4.41) 1.81 (0.99-3.31) 0.053 Acute myocardial infarction 12 (11.43) 2.5 (1.37-4.56) 1.13 (0.61-2.08) 0.695 Depression and mood disorders 12 (11.43) 1.21 (0.66-2.20) 0.86 (0.47-1.57) 0.621 Glaucoma 10 (9.52) 2.04 (1.06-3.92) 0.95 (0.49-1.83) 0.876 Chronic obstructive pulmonary disease and bronchiectasis 10 (9.52) 1.76 (0.92-3.38) 0.73 (0.37-1.41) 0.342 Osteoporosis 10 (9.52) 9.08 (4.73-17.42) 4.26 (2.2-8.24) 0.000* Delirium, dementia, and amnestic and other cognitive disorders 10 (9.52) 1.82 (0.95-3.50) 0.82 (0.42-1.58) 0.550 Chronic kidney disease 9 (8.57) 2.11 (1.07-4.18) 0.82 (0.41-1.65) 0.582 Gout and other crystal arthropathies 8 (7.62) 1.63 (0.79-3.34) 0.85 (0.41-1.75) 0.656 Blindness and vision defects 8 (7.62) 0.92 (0.45-1.90) 1.10 (0.53-2.26) 0.797 Congestive heart failure; nonhypertensive 8 (7.62) 2.75 (1.34-5.66) 0.98 (0.47-2.05) 0.954 Other upper respiratory disease 8 (7.62) 0.65 (0.32-1.34) 1.21 (0.59-2.49) 0.608 Spondylosis; intervertebral disc disorders; other back problems 8 (7.62) 1.21 (0.59-2.49) 0.72 (0.35-1.49) 0.376 Asthma 7 (6.67) 0.9 (0.42-1.95) 2.66 (1.23-5.77) 0.013* Chronic ulcer of skin 7 (6.67) 2.54 (1.18-5.48) 0.93 (0.43-2.04) 0.857 Heart valve disorders 6 (5.71) 5.95 (2.61-13.56) 2.99 (1.31-6.85) 0.010* Diverticulosis and diverticulitis 6 (5.71) 3.48 (1.52-7.92) 1.83 (0.79-4.18) 0.154 Headache; including migraine 5 (4.76) 0.38 (0.16-0.93) 0.65 (0.26-1.60) 0.350 Miscellaneous mental health disorders 5 (4.76) 0.76 (0.31-1.87) 0.81 (0.33-2.00) 0.655 Cancer of bronchus; lung 4 (3.81) 5.18 (1.91-14.07) 2.38 (0.87-6.51) 0.090 Cancer of prostate 4 (3.81) 2.07 (0.76-5.63) 0.81 (0.29-2.24) 0.691 Epilepsy; convulsions 4 (3.81) 3.06 (1.13-8.31) 3.43 (1.26-9.31) 0.016* Retinal detachments; defects; vascular occlusion; and retinopathy 4 (3.81) 2.88 (1.06-7.82) 1.54 (0.56-4.19) 0.398 Acute cerebrovascular disease 4 (3.81) 1.26 (0.46-3.42) 0.48 (0.18-1.34) 0.163 Peripheral and visceral atherosclerosis 4 (3.81) 2.36 (0.87-6.42) 1.09 (0.40-2.99) 0.857 Aortic; peripheral; and visceral artery aneurysms 4 (3.81) 7.58 (2.79-20.6) 3.39 (1.24-9.28) 0.017* Other diseases of veins and lymphatics 4 (3.81) 38.23 (14.03-104.21) 23.12 (8.45-63.25) 0.000* Esophageal disorders 4 (3.81) 1.18 (0.43-3.21) 0.99 (0.36-2.69) 0.985 Other inflammatory condition of skin 4 (3.81) 1.00 (0.37-2.72) 0.88 (0.33-2.41) 0.813 Residual codes; unclassified 4 (3.81) 1.12 (0.41-3.05) 0.89 (0.33-2.42) 0.823 Other endocrine disorders 3 (2.86) 12.37 (3.92-39.05) 7.77 (2.46-24.58) 0.000* Other nervous system disorders 3 (2.86) 1.06 (0.34-3.34) 0.79 (0.25-2.49) 0.689 Peri-; endo-; and myocarditis; cardiomyopathy (except that caused by tuberculosis or sexually transmitted disease) 3 (2.86) 3.82 (1.21-12.05) 2.25 (0.71-7.11) 0.167 Transient cerebral ischemia 3 (2.86) 1.45 (0.46-4.56) 0.55 (0.17-1.74) 0.307 Other liver diseases 3 (2.86) 1.23 (0.39-3.89) 0.88 (0.28-2.80) 0.840 Alcohol-related disorders 3 (2.86) 1.07 (0.34-3.39) 0.95 (0.30-3.01) 0.937 1 odds ratios adjusted by age; 2 p-values for the adjusted OR; * p <0.05.

Table 4 Logistic regression models were used to calculate odds ratios (OR) of prevalence for each comorbidity (dependent variable) according to the presence or absence of breast cancer in women (independent variable). Comorbidity Prevalence Crude OR Adjusted OR 1 p -value 2 (n, %) (95% CI) (95% CI) Hypertension 5811 (49,85) 2.08 (2.00-2.15) 0.88 (0.85-0.92) 0.000* Disorders of lipid metabolism 5062 (43,42) 1.76 (1.69-1.82) 1.07 (1.03-1.11) 0.001* Depression and mood disorders 3242 (27,81) 1.55 (1.49-1.62) 1.16 (1.11-1.21) 0.000* Anxiety disorders 3136 (26,9) 1.10 (1.06-1.15) 1.08 (1.04-1.13) 0.000* Other nutritional; endocrine; and metabolic disorders 3088 (26,49) 1.49 (1.43-1.56) 1.06 (1.02-1.11) 0.006* Osteoarthritis 3076 (26,39) 1.79 (1.72-1.87) 0.98 (0.94-1.02) 0.344 Osteoporosis 2931 (25,14) 2.48 (2.37-2.58) 1.45 (1.39-1.52) 0.000* Thyroid disorders 2344 (20,11) 1.15 (1.1-1.21) 0.98 (0.94-1.03) 0.375 Genitourinary symptoms and ill-defined conditions 2089 (17,92) 1.54 (1.47-1.62) 0.77 (0.73-0.81) 0.000* Cataract 1911 (16,39) 1.87 (1.78-1.96) 0.99 (0.94-1.04) 0.676 Diabetes Mellitus 1809 (15,52) 1.77 (1.68-1.86) 1.04 (0.98-1.09) 0.168 Headache; including migraine 1686 (14,46) 0.67 (0.63-0.7) 0.94 (0.89-0.99) 0.021* Obesity 1568 (13,45) 1.16 (1.09-1.22) 1.00 (0.95-1.06) 0.940 Spondylosis; intervertebral disc disorders; other back problems 1470 (12,61) 1.58 (1.49-1.67) 1.08 (1.02-1.14) 0.007* Delirium , dementia , and amnestic and other cognitive disorders 1275 (10,94) 1.40 (1.32-1.49) 0.72 (0.68-0.77) 0.000* Other ear and sense organ disorders 1185 (10,16) 1.34 (1.26-1.42) 1.01 (0.95-1.07) 0.866 Menopausal disorders 1172 (10,05) 1.14 (1.08-1.22) 0.94 (0.89-1.00) 0.069 Cardiac dysrhythmias 1137 (9,75) 1.72 (1.62-1.83) 0.98 (0.92-1.04) 0.452 Blindness and vision defects 1088 (9,33) 0.97 (0.91-1.03) 1.14 (1.07-1.21) 0.000* Other upper respiratory disease 995 (8,54) 0.67 (0.63-0.72) 1.01 (0.95-1.08) 0.718 Menstrual disorders 980 (8,41) 0.38 (0.35-0.40) 0.72 (0.67-0.77) 0.000* Glaucoma 965 (8,28) 1.64 (1.53-1.75) 0.98 (0.91-1.05) 0.544 Chronic kidney disease 763 (6,55) 1.58 (1.47-1.71) 0.83 (0.77-0.90) 0.000* Asthma 760 (6,52) 0.75 (0.70-0.81) 0.98 (0.91-1.05) 0.536 Acquired foot deformities 746 (6,4) 1.43 (1.32-1.54) 1.10 (1.02-1.19) 0.010* Other nervous system disorders 724 (6,21) 1.12 (1.03-1.20) 1.00 (0.92-1.08) 0.948 Coagulation and hemorrhagic disorders 712 (6,11) 1.60 (1.48-1.73) 0.94 (0.87-1.02) 0.141 Congestive heart failure; nonhypertensive 648 (5,56) 1.73 (1.59-1.87) 0.85 (0.78-0.92) 0.000* Other diseases of veins and lymphatics 590 (5,06) 15.05 (13.71-16.52) 10.74 (9.76-11.81) 0.000* Chronic ulcer of skin 566 (4,86) 1.44 (1.32-1.57) 0.68 (0.62-0.74) 0.000* Esophageal disorders 495 (4,25) 1.22 (1.11-1.33) 1.05 (0.95-1.15) 0.341 Miscellaneous mental health disorders 469 (4,02) 0.64 (0.58-0.70) 0.82 (0.75-0.90) 0.000* Acute cerebrovascular disease 452 (3,88) 1.53 (1.39-1.68) 0.79 (0.71-0.87) 0.000* Diverticulosis and diverticulitis 426 (3,65) 1.82 (1.65-2.00) 1.12 (1.02-1.24) 0.024* Other inflammatory condition of skin 420 (3,6) 1.08 (0.98-1.19) 1.11 (1.01-1.23) 0.031* Prolapse of female genital organs 413 (3,54) 1.50 (1.36-1.66) 1.02 (0.92-1.12) 0.758 Acute myocardial infarction 409 (3,51) 1.66 (1.50-1.84) 0.91 (0.82-1.01) 0.078 Transient cerebral ischemia 365 (3,13) 1.53 (1.37-1.70) 0.79 (0.71-0.88) 0.000* Other gastrointestinal disorders 361 (3,10) 1.21 (1.09-1.35) 1.14 (1.02-1.26) 0.019* Chronic obstructive pulmonary disease and bronchiectasis 352 (3,02) 1.49 (1.34-1.66) 0.92 (0.82-1.02) 0.113 Adjustment disorders 350 (3,00) 1.32 (1.18-1.47) 1.04 (0.94-1.16) 0.440 Other eye disorders 336 (2,88) 1.37 (1.23-1.53) 1.18 (1.06-1.32) 0.003* Nonmalignant breast conditions 308 (2,64) 1.00 (0.89-1.12) 1.21 (1.08-1.36) 0.001* Allergic reactions 298 (2,55) 0.36 (0.32-0.4) 1.79 (1.59-2.01) 0.000* Retinal detachments; defects; vascular occlusion; and retinopathy 284 (2,44) 1.64 (1.45-1.85) 1.02 (0.9-1.15) 0.768 Other liver diseases 260 (2,23) 1.66 (1.46-1.88) 1.28 (1.13-1.45) 0.000* Heart valve disorders 247 (2,12) 1.90 (1.67-2.16) 1.18 (1.04-1.34) 0.013* Other non-traumatic joint disorders 200 (1,72) 1.08 (0.94-1.25) 0.99 (0.86-1.14) 0.907 Other acquired deformities 185 (1,59) 0.53 (0.46-0.62) 0.97 (0.84-1.13) 0.716 Conduction disorders 181 (1,55) 1.64 (1.41-1.90) 1.04 (0.89-1.20) 0.648 Rheumatoid arthritis and related disease 172 (1,48) 1.24 (1.07-1.45) 0.92 (0.79-1.07) 0.285 Diseases of white blood cells 159 (1,36) 0.85 (0.73-1.00) 0.93 (0.79-1.09) 0.364 Endometriosis 155 (1,33) 1.71 (1.46-2.01) 2.12 (1.80-2.49) 0.000* Epilepsy; convulsions 143 (1,23) 1.13 (0.96-1.34) 1.16 (0.98-1.38) 0.078 Joint disorders and dislocations; trauma-related 141 (1,21) 0.98 (0.83-1.16) 1.20 (1.01-1.42) 0.035* Residual codes; unclassified 141 (1,21) 1.22 (1.03-1.44) 1.07 (0.90-1.26) 0.456 Parkinson`s disease 136 (1,17) 1.49 (1.25-1.76) 0.78 (0.65-0.93) 0.004* Other hereditary and degenerative nervous system conditions 136 (1,17) 1.42 (1.20-1.68) 1.02 (0.86-1.22) 0.794 Other circulatory disease 127 (1,09) 0.92 (0.77-1.10) 0.75 (0.63-0.90) 0.001* Gout and other crystal arthropathies 123 (1,06) 1.51 (1.26-1.81) 0.89 (0.74-1.07) 0.214 1 odds ratios adjusted by age; 2 p-values for the adjusted OR; * p <0.05.

Comparison with age-matched population

The aforementioned relationships were checked in a case-control sample to confirm their validity and reduce biases. For that purpose, a matched-by-birth-year population of male breast patients without breast cancer diagnoses were selected. Only four diseases remained associated in this scenario, two of them not previously associated, “Disorder of lipid metabolism” [1.65 (1.03–2.64)] and “Genitourinary symptoms and ill-defined conditions” [2.03 (1.07–3.87)]; and the other two had been already associated, “Anxiety disorders” [2.05 (1.09–3.87)] and “Osteoporosis” [3.58 (1.26–10.14)] (Table 5 ).

Table 5 Logistic regression models results for male breast cancer (MBC) patients in the year-of-birth matched cohort. Comorbidity Prevalence Crude OR p -value ( n , %) (95% CI) Disorders of lipid metabolism 58 (55.24) 1.65 (1.03-2.64) 0.039* Hypertension 52 (49.52) 0.71 (0.44-1.13) 0.150 Other nutritional; endocrine; and metabolic disorders 34 (32.38) 1.14 (0.69-1.89) 0.604 Diabetes Mellitus 30 (28.57) 0.95 (0.57-1.60) 0.861 Anxiety disorders 22 (20.95) 2.05 (1.09-3.87) 0.026* Cardiac dysrhythmias 21 (20.00) 1.63 (0.87-3.03) 0.126 Genitourinary symptoms and ill-defined conditions 21 (20.00) 2.03 (1.07-3.87) 0.031* Osteoarthritis 21 (20.00) 0.89 (0.5-1.59) 0.697 Cataract 17 (16.19) 0.85 (0.45-1.58) 0.603 Obesity 17 (16.19) 1.26 (0.65-2.42) 0.495 Hyperplasia of prostate 16 (15.24) 0.93 (0.49-1.78) 0.827 Other ear and sense organ disorders 14 (13.33) 0.96 (0.48-1.91) 0.908 Coagulation and hemorrhagic disorders 13 (12.38) 1.15 (0.56-2.37) 0.707 Thyroid disorders 12 (11.43) 1.68 (0.76-3.73) 0.204 Acute myocardial infarction 12 (11.43) 1.96 (0.86-4.45) 0.110 Depression and mood disorders 12 (11.43) 0.95 (0.46-1.99) 0.902 Glaucoma 10 (9.52) 0.86 (0.39-1.87) 0.697 Chronic obstructive pulmonary disease and bronchiectasis 10 (9.52) 0.82 (0.37-1.78) 0.608 Osteoporosis 10 (9.52) 3.58 (1.26-10.14) 0.016* Delirium, dementia, and amnestic and other cognitive disorders 10 (9.52) 0.86 (0.39-1.87) 0.697 Chronic kidney disease 9 (8.57) 1.14 (0.48-2.67) 0.768 Gout and other crystal arthropathies 8 (7.62) 0.70 (0.30-1.64) 0.417 Blindness and vision defects 8 (7.62) 0.83 (0.35-1.96) 0.670 Congestive heart failure; nonhypertensive 8 (7.62) 1.84 (0.69-4.92) 0.223 Other upper respiratory disease 8 (7.62) 1.65 (0.63-4.31) 0.307 Spondylosis; intervertebral disc disorders; other back problems 8 (7.62) 0.70 (0.30-1.64) 0.417 Asthma 7 (6.67) 1.60 (0.58-4.41) 0.368 Chronic ulcer of skin 7 (6.67) 1.60 (0.58-4.41) 0.368 Heart valve disorders 6 (5.71) 1.53 (0.52-4.53) 0.442 Diverticulosis and diverticulitis 6 (5.71) 2.48 (0.74-8.34) 0.141 Headache; including migraine 5 (4.76) 0.53 (0.19-1.48) 0.227 Miscellaneous mental health disorders 5 (4.76) 0.83 (0.28-2.41) 0.725 Cancer of bronchus; lung 4 (3.81) 8.28 (0.91-75.01) 0.060 Cancer of prostate 4 (3.81) 0.48 (0.16-1.47) 0.200 Epilepsy; convulsions 4 (3.81) 2.73 (0.6-12.44) 0.194 Retinal detachments; defects; vascular occlusion; and retinopathy 4 (3.81) 1.62 (0.43-6.18) 0.477 Acute cerebrovascular disease 4 (3.81) 0.60 (0.19-1.89) 0.383 Peripheral and visceral atherosclerosis 4 (3.81) 1.35 (0.37-4.88) 0.651 Aortic; peripheral; and visceral artery aneurysms 4 (3.81) 8.28 (0.91-75.01) 0.060 Other diseases of veins and lymphatics 4 (3.81) omitted Esophageal disorders 4 (3.81) 0.88 (0.27-2.94) 0.841 Other inflammatory condition of skin 4 (3.81) 1.35 (0.37-4.88) 0.651 Residual codes; unclassified 4 (3.81) 0.79 (0.24-2.59) 0.700 Other endocrine disorders 3 (2.86) omitted Other nervous system disorders 3 (2.86) 2.03 (0.4-10.23) 0.391 Peri-; endo-; and myocarditis; cardiomyopathy (except that caused by tuberculosis or sexually transmitted disease) 3 (2.86) 2.03 (0.4-10.23) 0.391 Transient cerebral ischemia 3 (2.86) 0.66 (0.17-2.48) 0.535 Other liver diseases 3 (2.86) 1.00 (0.25-4.08) 1.000 Alcohol-related disorders 3 (2.86) 0.74 (0.19-2.86) 0.665 * p <0.05. Associated in Table 3 in italic. Associated in Table 4 in bold.

Discussion

Our MBC population is mostly old with high number of chronic conditions, which is in accordance with previously seen in the literature, independently if we are referring to a Western or Eastern country 3 , 5 , 10 , 11 , 14 , 18 , 20 , 21 , 23 , 26 , 31 . The fact that they have a greater number of comorbidities is a factor to be taken into account, since a greater number of comorbidities has been related to a worse prognosis 14 , along with other factors like poor access to health care, older age and black race 11 , 18 , 19 .

The difference in the prevalence of comorbidities between MBC and FBC was observed previously 3 , 11 , 22 . Men are described to have more comorbidities than women 3 , 11 , 21 , and some diseases like diabetes, chronic obstructive pulmonary disease (COPD), chronic kidney disease and liver cirrhosis are more frequent in men, whereas female patients are more likely to suffer from autoimmune diseases 22 . The higher rate of comorbidities in MBC cases may be associated to the higher median age of MBC cases comparing with FBC 3 .

Between 2010 and 2019, the five most prevalent comorbidities in men in our cohort were “Disorders of lipid metabolism”, “Hypertension”, “Other nutritional; endocrine; and metabolic disorders”, “Depression and mood disorders”, “Diabetes Mellitus” and “Anxiety disorders”, Shimomura et al. observed similar results to us, with more prevalence of diabetes and cardiovascular disease 3 . Furthermore, our results seem to be in accordance with those from Zoorob et al. Despite using only a set of 20 chronic conditions; their top five most prevalent comorbidities were the same as ours, except for the presence of “Arrythmia” instead of “Other nutritional disorders” 21 .

From this descriptive analysis, there seem to be a difference at least in the nature of the most frequent diseases between MBC and FBC; MBC patients tend to suffer more of cardiometabolic diseases in contrast with FBC patients who presented more hormone-, bone- and mental comorbidities. It might be useful for a proper management of their diseases to act in tailored manner regarding the most common MBC patient’s comorbidities, as they are thought to impact the overall risk of developing second primary cancer 22 .

Regarding the association analysis, initially nine diseases were linked to MBC. Nevertheless, most of them are presented in a very low number of MBC patients. “Hypertension”, “Anxiety disorder” and “Osteoporosis” account for 58, 22 and 10 cases respectively, greater MBC cohort numbers are needed to confirm these findings. Furthermore, after matching by year of birth, only four of those associations remained. “Disorder of lipid metabolism” and “Genitourinary symptoms and ill-defined conditions” were added to the before mentioned associations.

Firstly, “Hypertension” [0.62 (0.41–0.93)] was the only disease to have a negative association, this finding should be taken with special care, as to the low quantity of cases, lack of specific MBC literature and mix results of this association in FBC patients 3 , 21 , 32 increases its uncertainty of an actual association. In fact, in our case once we matched by age, this association disappeared. The mechanisms proposed for the relationship between hypertension and breast cancer risk are the common pathophysiological pathway mediated by adipose tissue, which could cause chronic inflammation, the modification in the apoptosis caused by hypertension, and the use of calcium channel blockers 32 .

Secondly, breast cancer is well documented to generate psychological distress to female patients, depending on several factors, such as prognosis, tumour state, patient’s personal circumstance; their mental health might worsen in a lighter or heavier manner. A positive association of MBC with “Anxiety disorder” seems more than plausible and clear 33 . In addition, a study in the United States observed that the prevalence of depression was higher in MBC and FBC patients than in the general population, with a greater gradient between number of comorbidities and the odds of depression 21 . Nevertheless, FBC and MBC patients might react different to the psychological distress, as FBC patients appear to suffer less from “Anxiety disorders” and more from “Depression and mood disorders” than MBC patients, further concise research is needed.

Thirdly, bone health has been described to be negatively affected by endocrine therapy and adjuvant settings in certain cases in FBC and male prostate cancer patients with similar treatments, it is plausible that these increased chances of “Osteoporosis” in our MBC and FBC cohorts are cancer treatment-related comorbidity 34 , thus, actually associated, even though there is no possibility to determine if it is due to the disease or the treatment effect.

Fourthly, dyslipidaemia was more frequent in MBC patients, and it is important to control this disease properly because deregulation of lipid metabolism has been seen to increase proliferation, chemoresistance and invasiveness of breast cancer, leading to worsen outcomes and complications 35 – 37 . In addition, this deregulation generates an enhancing microenvironment for BC tumours proliferation and selection of chemoresistant cells 35 , 37 .

Lastly, “Genitourinary symptoms and ill-defined conditions” refers to a broad group of events related to the urinary tract, as with the case of “Osteoporosis” it might be related to BC medication and the older age of this kind of patients. The higher risk of genitourinary symptoms and MBC may be related to the associated risk between cancers of the breast and prostate, because BCRA2 mutations and estrogen treatment used in the prostate cancer 38 . Also, it has been showed that the incidence of urinary symptoms, like urinary incontinence, in patients with early-stage breast cancer may be higher than in the general population related to endocrine adjuvant therapy, and is questioned if the risk factors of developing urinary incontinence and breast cancer overlap 39 .

When compared to the age-matched population, the MBC cohort exhibited a similar pattern of comorbidities. This finding suggests that, from a comorbidity perspective, MBC patients may resemble to their non-cancerous counterparts of a similar age group. However, the presence of breast cancer itself may interact with these pre-existing conditions, potentially influencing treatment decisions and overall prognosis. Regarding prognosis, it is well-known that MBC patients have higher risk of cancer recurrence and similar overall survival than FBC patients, at least in later tumour stages 40 , 41 . Nevertheless, once comorbidities are taken into account, the recurrence, overall survival and breast-cancer specific mortality seems to worsen in FBC patients with high comorbidity burden, it is plausible this issue affect similarly to MBC patients 42 . Furthermore, it appears that specific comorbidities, such as anxiety and depression, are associated with poorer prognosis in all aspects (recurrence, overall survival and cancer-specific mortality) 43 . In regards of treatment, FBC patients with high comorbidity were associated with reduced usage of different treatments (mastectomy, lumpectomy + radiation, and chemotherapy) in regards of their tumour stage 44 . Additionally, pre-existing conditions not only might affect breast cancer treatment decision, but also the concomitant medication of those comorbidities might influence positively or negatively the prognosis of breast cancer 45 .

All these findings highlight the distinct characteristics of the MBC patient population, particularly regarding their high burden of comorbidities. The traditional approach of extrapolating treatment guidelines from FBC to MBC may not be optimal, given the differences in the associated comorbidity profiles. Our study underscores the need for a more tailored approach to managing MBC, considering the unique challenges posed by co-existing chronic conditions. Future research should focus on developing evidence-based treatment strategies that address the specific needs of the MBC population while accounting for their complex comorbidity landscape.

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Acknowledgements

This research was funded by the Carlos III Institute of Health, Ministry of Science and Innovation (Spain), through the Network for Research on Chronicity, Primary Care, and Health Promotion (RICAPPS), awarded for the call for the creation of Health Outcomes-Oriented Cooperative Research Networks (grant number RD21/0016/0019). This research was also funded by Gobierno de Aragón (grant number B01_23R) and funded by European Union’s Next Generation EU funds.

Limitations

As with the majority of secondary-use clinical real-world-data based studies, our results are subjected to several limitations. The data used are extracted from the daily clinical practice, some level of inconsistency and low reliability in the diagnosis may be possible. The small sample size of male breast cancer patients, due to its rareness, may decrease the observed differences, but show the differences between patient profiles. In addition, there is a lack of potential explanatory variables not considered by this research, like lifestyle habits that could influence in the prevalence of some comorbidities or cancer prognosis that is related to mental health disorders. Lastly, the gap in knowledge of the literature hinders comparability with previous studies. Studies with bigger sample sizes of male patients with breast cancer are needed to strengthen our knowledge in this matter. These studies should also take into account and analyse the role of potential influencing and confounding socio-demographic and clinical factors such as socioeconomic status, lifestyle habits, environmental factors, tumour characteristics, or genetic factors. Future studies analysing the differences in the comorbidity profile and survival between MBC and FBC are encouraged to improve our knowledge about this clinical entity and to identify potential differences between men and women that could justify the revision and adaptation of the clinical practice guidelines currently available for this condition. The ultimate goal of all this would be to adopt a person-centred care approach to improve the treatment, care, prognosis and quality of life of these patients.

Author contributions

Conceptualization: A.S.M. , D.A.L., M.C.C.F., R.I.C.; Data curation and Formal Analysis: C.L.B; Methodology: B.P.P., C.L.B; Project Administration: A.G.M.; Visualization: A.S.M.; Writing – original draft: A.S.M.; Writing – review & editing: A.S.M., A.M.J., C.L.B., D.A.L., M.C.C.F., R.I.C.

Data availability

The data used in this study cannot be publicly shared because of restrictions imposed by the data owner (i.e., Aragon Health Sciences Institute—IACS) due to the existence of potentially identifying patient information. This restriction has been asserted by the Clinical Research Ethics Committee of Aragón (CEICA). The authors who accessed the data belong to the EpiChron Research Group of IACS and received permission from IACS to utilise the data for this specific study. The EpiChron Group can establish future collaborations with other groups based on the same data. However, each new project based on these data must be previously submitted to the CEICA to obtain the respective mandatory approval. Potential collaborations should be addressed to the Principal Investigator of the EpiChron Research Group at agimenomi.iacs@aragon.es.

Declarations

Competing interests

The authors declare no competing interests.

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