Influence of Age on Health-Related Quality of Life of Women Diagnosed with Breast Cancer

Introduction: Women with breast cancer may have differences in health-related quality of life (HRQoL) at diagnosis by age. Objective : To analyze the influence of age on the HRQoL of women diagnosed with breast cancer. Method: Cross-sectional study was carried out with women diagnosed with breast cancer. HRQoL assessment was performed before starting cancer treatment, using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and its specific breast cancer module (BR-23). Association between age group and HRQoL was determined through multiple linear regression. Results: 961 women were included in the study, with a mean age of 54 (SD±11.7). Women aged ≥50 years displayed better emotional functioning (+7.6 points; p<0.001), and less fatigue (-4.4 points; p=0.014), pain (-4.7 points; p=0.033), nausea and vomiting (-2.3 points; p=0.030) and financial difficulties (-10.3 points; p<0.001) compared to younger women. Concerning the BR-23 module, these women displayed better body image scores (+3.6 points; p=0.029) and future perspective (+12.4 points; p<0.001), and worse sexual functioning (-19.9 points; p<0.001) and sexual enjoyment (-8.9 points; p=0.001), and on the symptom scale, less breast symptoms (-11.6 points; p<0.001) and arm symptoms (-3.5 points; p=0.047). Conclusion: Patients aged ≥50 years exhibited better HRQoL in all QLQ C-30 and BR-23 functioning scales and symptom scales, except for sexual functioning and sexual enjoyment.


INTRODUCTION
Breast cancer results in the highest incidence and mortality rates in the female population worldwide among the different types of cancer 1 . The diagnosis of a disease comprising a high risk of death can lead to psychological symptoms, anxiety and depression, negatively impacting the health-related quality of life (HRQoL) of this population [2][3][4][5] .
The HRQoL has been routinely applied as a health indicator due to its association with mortality, treatment effectiveness and survival of women with breast cancer [6][7][8] .
Breast cancer and age exhibit a well-established association in scientific studies. Aging is an inherent risk factor for the increased incidence and mortality of this disease 9 , and some authors also consider this variable as associated with worse HRQoL [10][11] . However, conflicting results have been reported by other authors, who observed that younger women diagnosed with breast cancer exhibit worse HRQoL 12 . In addition, younger patients more often report symptoms such as fear, anxiety, depression and problems with body self-image, which can interfere with their HRQoL 13,14 . A cross-sectional study conducted on breast cancer survivors indicates that cancer stage or treatments do not impact HRQoL in young women but instead, affect issues related to fertility, sexuality and professional reintegration 15 .
Faced with these controversial results, this study aims to analyze the influence of age on the HRQoL of women diagnosed with breast cancer. Based on the age of these women and their quality of life, it is possible to achieve better management of specific needs of each age group.

METHOD
A cross-sectional study was carried out with women diagnosed with breast cancer (ICD-10 C50) aged 18 or over undergoing curative-intent treatment (stages I, II and III) and enrolled at the Hospital do Câncer III (HCIII)/ Instituto Nacional de Câncer (INCA), Rio de Janeiro, Brazil, from April 4, 2016 to April 30, 2019. Women with a diagnosis of distant metastasis up to six months after recruitment, those that withdraw their Informed Consent Form and study inclusion failures were excluded from the evaluation ( Figure 1).
Patients were enrolled after admitted at the hospital, prior to beginning the cancer treatment, in the first appointment with the oncologist or in the preoperative period for breast cancer surgery. Eligible women were invited to participate in the study and were submitted to an interview, physical examination and application of HRQoL questionnaires after signing the consent form.
The main exposure in this study was age at recruitment, assessed in a dichotomous manner with a cutoff point set at 50 years of age, as this is the beginning of the age group at the highest risk for the disease in the country, reported as women aged between 50 and 69 years old.
The outcome (HRQoL) was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and its specific breast cancer module (BR-23), both translated and validated for the Brazilian population 16,17 .
The EORTC QLQ-C30 questionnaire comprises 30 questions that aim to assess HRQoL in the 7 days prior to its application. It is categorized into functional scale (physical functioning, role functioning, cognitive functioning, emotional functioning and social functioning) and symptoms/items scale (fatigue, pain, dyspnea, insomnia, appetite loss, nausea and vomiting, constipation, diarrhea and financial difficulties), with responses ranging from 1 to 4 (1 -not at all, 2 -a little, 3 -quite a bit, 4 -very much). It also presents a general health and global quality of life scale, with response options ranging from 1 to 7, with 1 being very poor and 7, excellent.
The EORTC QLQ-BR23 questionnaire comprises 23 questions and is also intended to assess HRQoL in the 7 days prior to its application. It is categorized into two dimensions, comprising a functional scale (body image, sexual functioning, sexual enjoyment and future perspective) and symptoms/items (systemic therapy side effects, breast symptoms, arm symptoms and upset by hair loss) scale, with response options ranging from 1 to 4 (1 -not at all, 2 -a little, 3 -quite a bit, 4 -very much).
At the study enrollment, sociodemographic and lifestyle covariates (race/skin color, marital status, education, alcohol use in the last 30 days and current tobacco use), clinical covariates (hypertension, status menopausal, body mass index) and tumor covariates (clinical stage, histological type) were obtained. The variables were collected through interviews and physical assessment, except for arterial hypertension, clinical stage

RESULTS
A total of 961 women were included in the study, with a mean age of 54 (SD±11.7) and median of 55 years old (range 23 to 86). Most women were Brown (40.8%), with over 8 years of education (69.0%). The predominant histological type was infiltrating ductal carcinoma (83.5%) and most patients (54.4%) were diagnosed with advanced clinical stage breast cancer (≥II B) ( Table 1).

DISCUSSION
In the present study, most women were diagnosed at advanced breast cancer stages (≥IIB), with a mean age of 54. Before beginning cancer treatment, patients aged ≥50 years exhibited better emotional function, body image and future perspectives and worse sexual function and sexual satisfaction compared to younger patients. Women aged ≥50 years exhibited less fatigue, pain, nausea and vomiting, financial difficulties, breast and arm symptoms.
A study carried out with Vietnamese women, with an age cutoff of 45 years concluded that younger women exhibited better HRQoL 19 . Another study with 1,498 breast cancer patients analyzed the HRQoL as a function of different stages and age groups and demonstrated that women in the initial stage aged 50 or less exhibited worse overall quality of life scores, as well as in other five domains, when compared to other age groups (p<0.05) 20 . The Carolina Breast Cancer Study (a study about the causes, treatments and personal experience of North Carolina women diagnosed with breast cancer) with 2,142 women with breast cancer analyzed the profiles of qualityof-life and 5 and 25 months after the diagnosis. Younger women at the diagnosis (OR 0.95; 95% CI 0.93-0.96) 21 exhibited the worst quality of life in all domains.
A systematic review 22 revealed that younger women treated for breast cancer displayed psychological impacts, weight gain and physical inactivity during treatment, in addition to anxiety and depression, contributing to compromised quality of life. Leinert et al. 23 found a higher frequency of fatigue in patients over 60 years of age and a higher prevalence of symptoms such as nausea and vomiting in younger women. It is possible that younger women, while faced with a diagnosis that can bring disabilities or uncertainties about the maintenance of their role in society, feel more threatened compared to older women, who display greater stability for being older, as observed in the present study, where younger women exhibited worse HRQoL for most domains, except sexual function and sexual satisfaction.
A French study also stratified by age group, found that older ages are more associated with economic deprivation or unsatisfactory financial situation, as well as less social support for this population 24 . In Brazil, a recent study revealed that most younger 25

women diagnosed with
Santos LN, Aguiar SS, Rodrigues GM, Thuler LCS, Bergmann A Influence of Age on Health-Related Quality of Life breast cancer who were employed and/or actively working and more financially independent, may become more emotionally vulnerable when temporary discontinuation of their labor activities may occur due to cancer treatment compared to older women who are less economically active or who do not work full time.
A Saudi Arabian study applied the EORTC instrument to evaluate 284 women already treated for breast cancer, with an average age over 50, and revealed worse HRQoL in relation to the symptom scale 26 of sexual function, as the results reported herein have also shown. In addition to hormonal changes resulting from age, a breast cancer diagnosis reduces the rate of female sexual function 27 . In fact, younger women are often more sexually active than older women, and hormonal factors hold a direct influence on sexual behavior. Thus, younger patients tend to display better sexual function and sexual satisfaction.
Although some differences are noted in the population, age stratification and types of questionnaires used in some studies, most of them report that younger women with Santos LN, Aguiar SS, Rodrigues GM, Thuler LCS, Bergmann A breast cancer exhibit a worse quality of life in several domains.
The results presented herein must be considered under the perspective of the study's strengths and weaknesses which was carried out in a public breast cancer treatment reference hospital in the state of Rio de Janeiro, Brazil, including a high number of patients treated free of charge by the National Health System (SUS). To carry out the interviews, the research team was periodically trained, and questionnaires translated and validated for the Brazilian population were used. Among the limitations of the study is the non-inclusion of important variables as the relationship between age and quality of life, other comorbidities and physical activity. However, the extrapolation of the results to other populations should be done cautiously, considering that the reality of patients treated at a reference center may not reflect the HRQoL profile of women treated at other centers.
This study calls for better evaluation of the sexuality of women diagnosed with breast cancer aged ≥50, with specific quality of life questionnaires, and an investigation on their function and sexual satisfaction for possible treatment and potential improvement in these domains because of the worst scores found in comparison with younger women.

CONCLUSION
Women diagnosed with breast cancer aged ≥50, despite exhibiting worse sexual functioning and sexual enjoyment, presented better emotional functioning, body image and future perspectives, in addition to less pain, fatigue, nausea and vomiting, financial difficulties and breast and arm symptoms.
The differences observed by age group (<50 and >50) indicate the domains in each population requiring interventions to improve the HRQoL of these women, preventing negative physical and mental health effects during all cancer care stages.

CONTRIBUTIONS
Larissa Nascimento dos Santos contributed to the investigation, data curation, formal analysis and wording of the original draft. Suzana Sales de Aguiar contributed to the investigation, project administration and data curation. Graziele Marques Rodrigues contributed to the investigation, data curation, formal analysis. Luiz Claudio Santos Thuler and Anke Bergmann contributed to the study design, methodology, validation, formal analysis, wording, review, editing and supervision. All the authors approved the final version for publication.

DECLARATION OF CONFLICT OF INTERESTS
The author Anke Bergmann declares potential conflict of interests due to its position as Scientific-Editor of INCA's Revista Brasileira de Cancerologia. The other authors have no conflict of interests to declare