Menopausal symptoms in relationship to breast cancer-specific quality of life after adjuvant cytotoxic treatment in young breast cancer survivors

Breast cancer is one of the most common female malignancies. In many parts of Asia, there has been an increasing trend in the incidence of breast cancer. The most recent data from the Hong Kong Cancer Registry have reported that more than 80% of newly diagnosed breast cancer patients have early stage disease [1]. Treatments for patients with early-stage breast cancer have curative intent. These mainly involve surgery followed by post-operative adjuvant therapies that may include chemotherapy, radiotherapy, endocrine therapy and/or targeted therapy. Although less than 15% of patients were reported to be diagnosed before age 40 [2], a higher proportion of these patients were subjected to adjuvant cytotoxic therapy [2].

Anti-neoplastic therapies, in particular those that involve cytotoxic agents, are associated with short- as well as long-term adverse effects [3‐13]. Particularly among premenopausal women, the drug’s effect on ovarian function could potentially lead to long-term menstrual disruptions. Our recent report on premenopausal young breast cancer survivors who were subjected to adjuvant cytotoxic therapy have noted that over 90% developed chemotherapy-related amenorrhea (CRA) within the first year of chemotherapy, with 50% developing chemotherapy-related menopause, in which over 60% reached menopause before aged 45 [14]. Patients who had undergone adjuvant chemotherapy have been reported to experience physical, emotional and social changes that may affect their quality of life (QoL) [15‐19]. Whilst earlier studies have suggested that the deterioration in QoL after chemotherapy may be associated with the transition of menopause [15, 16, 18], there has been limited data that demonstrate the association of menopausal symptoms on the overall QoL in young breast cancer survivors who have received adjuvant cytotoxic chemotherapy. Deciphering the relationship of menopausal symptoms and QoL may enable clinicians to better inform and advise patients prior to their anti-cancer therapies; furthermore, such knowledge is also valuable for researchers to explore potential interventions that could increase patients’ ability to cope with their symptoms and thereby improve their QoL.

In this study, young premenopausal Chinese breast cancer survivors who had undergone adjuvant chemotherapy were assessed. The objectives were to assess the symptoms related to menopause and the associated factors, as well as to determine the association of these symptoms with breast cancer-specific QoL during follow-up.

The study enrollment took place between September 2008 and February 2011 in the Department of Clinical Oncology of Prince of Wales Hospital, Hong Kong. Consecutive breast cancer patients attending the breast cancer follow-up clinics, who were identified to be eligible for the study, were invited to participate in the study. Inclusion criteria included premenopausal Chinese females who were diagnosed with early-stage (stage I to III) breast cancer at age 45 years or less and had received adjuvant chemotherapy. At study entry, these patients should have been between 3 and 10 years from their initial breast cancer diagnosis. Patients who had undertaken hysterectomy prior to breast cancer diagnosis and those who had undergone medical, surgical or radiation oophorectomies were excluded. The investigators obtained written informed consent from each individual prior to study entry. At study entry, patients were asked by a study nurse on the details of their menstruation history. Following this, patients filled in self-administered questionnaires to assess their menopausal-specific as well as breast cancer-specific QoL using Menopause-Specific Quality of Life Questionnaire (MENQOL) and Functional Assessment of Cancer Therapy–Breast (FACT-B + 4) questionnaires respectively. The study was approved by the Joint CUHK-NTEC Clinical Research Ethics Committee of the Hong Kong Hospital Authority and the Chinese University of Hong Kong.

Quality of life (QoL) among breast cancer survivors may be affected by the stage of the disease and the treatment required. It is well-acknowledged that breast cancer patients with metastatic disease suffer most from symptom burden and this is associated with worsening QoL [26]. On the other hand, it is also increasingly recognized that women with early-stage disease also experienced impairment in QoL [26]. Management of breast cancer patients have traditionally focused on effectiveness of anti-cancer treatment, such that in the case of patients with early disease, cure from breast cancer has been the key objective. With advances in adjuvant treatments, the survival of breast cancer patients has continuously improved during the past decades. However, with longer survival, side effects of anti-cancer treatments, especially those of long-term sequelae, have become increasingly apparent and this has been associated with adverse effects on QoL. In the present study on young Chinese breast cancer survivors who had previously undergone adjuvant chemotherapy, the objectives were to assess chemotherapy-associated symptoms that were related to long-term menstrual disturbances and to evaluate their effect on breast cancer-specific QoL. Findings from the current study revealed that five years after breast cancer diagnosis, women who had received taxanes and tamoxifen, those who were overweight/obese and those who utilized traditional Chinese medicine had worse menopausal symptoms. Further, patients who experienced worse menopausal symptoms were found to have worse breast cancer-specific QoL.

In premenopausal breast cancer patients who have received chemotherapy, endocrine changes may affect fertility and menstrual status, which in turn may have a detrimental effect on QoL [26‐28]. The decrease in estrogen secondary to ovarian failure is marked by a series of vasomotor symptoms including night sweats and hot flashes along with other symptoms such as vaginal dryness, dyspareunia and weight changes [28]. When compared to women who had undergone natural menopause, breast cancer patients who developed menopause following anti-cancer treatment have reported more severe menopausal symptoms [28].

Few studies have formally assessed menopausal symptoms in relation to quality of life after adjuvant cytotoxic chemotherapy. An Australian study that involved 843 breast cancer survivors had assessed menopausal symptoms using MENQOL during follow-up of up to 5 years after initial diagnosis. The result revealed that, in comparison to women enrolled from the community who did not have history of breast cancer, breast cancer survivors had significantly worse scores for vasomotor and sexual domains. The impact on QoL may differ according to pre-treatment menopausal status. In the Australian study, breast cancer survivors who were postmenopausal were more likely to report on vasomotor and sexual symptoms than their premenopausal counterpart. However, findings from this study was limited by a low representation of premenopausal women, with pre- or peri- menopausal patients accounting for only 7% of the whole studied population, and assessment on menopausal symptoms in relation to chemotherapy was only confined to 40% of the overall studied population who had undergone adjuvant chemotherapy [29]. In another study that was conducted in Korea, which addressed issues on menopausal symptoms among premenopausal patients who had undergone chemotherapy, MENQOL was reported to be persistently worse after adjuvant chemotherapy; however, any changes beyond the first year were not assessed [30]. Risk analysis revealed that older age was associated with worse symptoms in all the four (vasomotor, psychosocial, physical and sexual) domains, tamoxifen usage was associated with worse symptoms in vasomotor, physical and sexual domains, while a BMI of >/= 23 kg/m² was associated with worse physical symptoms [30].

The present study was undertaken to specifically assess a homogenous group of young premenopausal Chinese young breast cancer patients who had received adjuvant chemotherapy; with their endocrine-related symptoms and the associated factors were investigated, while long-term breast cancer-specific QoL issues in relation to menopausal symptoms were evaluated. Data from the present study highlights that patients who underwent taxane-containing chemotherapy and those who received tamoxifen had worse vasomotor symptoms. Tamoxifen has been well-associated with vasomotor adverse effects, while taxane-containing regimen has been reported in a number of studies to be associated with increased incidences of chemotherapy-related amenorrhea [8, 10‐12, 30]. However, as taxanes are often given following anthracycline and cyclophosphamide-containing chemotherapy, it is difficult to ascertain whether the agents per se, or whether the extended duration of cytotoxic regimens that involve taxanes, leads to the higher incidence of amenorrhea [9], which in turn, could lead to increased vasomotor symptoms. Sexual symptoms were worse among patients who became peri- or post-menopausal after chemotherapy. This lends support to findings from previous studies that assessed premenopausal breast cancer patients, where sexual interest and functioning were noted to be worst among those who received chemotherapy and subsequently became amenorrheic after treatment [31]. Patients who utilized TCM also scored worse for vasomotor, psychosocial and physical domains. The causal relationship of TCM with menopausal symptoms remains to be clarified. TCM is often adopted among Chinese patients in an attempt to alleviate menopausal symptoms. Indeed, interventional studies have suggested the potential efficacy of pharmacological and non-pharmacological maneuvers as well as complementary medicine in relieving side effects including that of vasomotor symptoms due to anti-cancer therapy [33‐34]. When MENQOL was assessed together with outcomes of FACT-B + 4, patients who had worse menopausal symptoms were associated with poorer breast cancer-specific QoL in all aspects, reflecting a wide dimension of QoL impairment with the occurrence of menopausal symptoms.

Findings from the present study are limited by the fact that menopausal symptoms and QoL assessments were only conducted at one time-point without longitudinal follow-up and that the patient number was limited. Another limitation of the study was the lack of exploration of the effect of potential confounding factors on the reported associations by the construction of a linear regression model. Nonetheless, the current study provides a snapshot into the close association between endocrine-related symptoms and breast cancer-specific QoL experienced by young Chinese breast cancer survivors after adjuvant chemotherapy. With increasing knowledge on long-term adverse effects of cytotoxic chemotherapy, clinicians could potentially support patients by better preparing them for their anti-cancer therapies. At the same time, researches into interventional therapies that tackle specific menopausal symptoms which are bothering and affecting the QoL of patients are needed. Interventions that have been advocated include pharmacological as well as non-pharmacological means [35]. However, it has to be noted that to date, interventional therapies that have been suggested have not been confirmed to be effective in large scale clinical trials. As such, high quality interventional studies with a focus on young breast cancer patients are required to provide evidence-based clinical recommendations to clinicians, so that appropriate and efficacious management for menopausal symptoms can be offered in order to make a positive impact on their QoL.

In this study among premenopausal Chinese women with breast cancer who had undergone adjuvant chemotherapy, having received taxanes or tamoxifen, being overweight/obese and having utilized TCM were associated with more severe menopausal symptoms. The current study demonstrates that the multifactorial nature of menopausal symptoms has an impact on QoL. Further studies using serial assessments in a larger sample of patients would enable a better understanding of the dynamic changes of these aspects in relation to timing of chemotherapy and other adjuvant therapies.