Objective
To investigate the prevalence of urogenital symptoms and vaginal atrophy in postmenopausal breast cancer patients on adjuvant endocrine therapy.
Study Design
A population-based, cross-sectional study on postmenopausal breast cancer patients on adjuvant endocrine treatment and age-matched control subjects. Vaginal atrophy was assessed by gynecologic examination and atrophy-related symptoms by validated questionnaires.
Results
In all, 57.6% of aromatase inhibitor-treated and 32.4% of tamoxifen-treated breast cancer patients rated at least 1 vaginal atrophy symptom as moderate/severe, which was significantly more common than in control subjects ( P < .01). Aromatase inhibitor-treated patients more often had moderate or severe vaginal atrophy ( P < .05), a more atrophic cytohormonal evaluation, and significantly higher vaginal pH ( P < .05) than all control subjects, irrespective of hormonal use.
Conclusion
Our findings indicate that the frequency of vaginal atrophy symptoms, particularly in aromatase inhibitor-treated women, might have been underestimated in previous clinical trials.
In developed countries approximately 75% of all breast cancers occur in postmenopausal women, and 80% of these cancers are hormone receptor positive. Adjuvant endocrine treatments are all primarily directed to induce estrogen deprivation, either at the estrogen receptor level (tamoxifen), or by inhibiting estrogen biosynthesis (aromatase inhibitors). In women with hormone receptor-positive tumors, administration of tamoxifen for 5 years has been shown to reduce breast cancer recurrence by 41% and mortality by 34% compared with placebo. Third-generation aromatase inhibitors (AIs), such as anastrozole, letrozole, and exemestane, have been shown to further improve disease-free survival, although a significant reduction in overall survival for AIs compared with tamoxifen has not yet been proven.
The use of both tamoxifen and AIs has, however, been associated with gynecologic side effects and worsening of menopausal symptoms. Tamoxifen has been shown to increase the risk for endometrial cancer compared with placebo. In comparison to tamoxifen, treatment with AIs is associated with lower endometrial thickness, fewer cases of vaginal bleeding, possibly fewer cases of endometrial pathologies, and fewer systemic menopausal symptoms such as hot flushes and night sweats.
Urogenital symptoms are strongly associated with low endogenous estrogen levels and are common in postmenopausal women. Vaginal dryness, irritation, discharge, and dyspareunia are frequently reported adverse symptoms in clinical trials with adjuvant endocrine therapy, but urogenital symptoms have otherwise not been extensively studied in patients with breast cancer. Because no comparative studies have been conducted, it is unknown whether urogenital symptoms in fact are more common in breast cancer patients than in healthy women. With more women receiving adjuvant endocrine therapy after primary therapy for breast cancer, and more women surviving breast cancer, any increase in the frequency of urogenital symptoms represents a clinical challenge, especially because there is now a lack of effective treatment options. Use of systemic hormone replacement therapy in women with a history of breast cancer is generally advised against because of the increased risk of breast cancer recurrence. Until recently, vaginally administered low-dose estrogen for the treatment of urogenital symptoms has been considered safe, because the systemic absorption of such preparations has been found to be low and within the normal postmenopausal range. However, a recent small study of the systemic absorption of vaginally administered estradiol in patients with adjuvant AI treatment after early breast cancer found a significant increase in systemic levels of estradiol. Because the goal of AI treatment is to eliminate the circulating levels of estrogen, professional organizations have concluded that also topical vaginal estrogen treatment should be avoided in women on AI treatment. As for nonhormonal interventions, although commonly recommended, the efficacy and tolerability remain to be established.
The aim of the current study was to investigate the prevalence and degree of urogenital symptoms and vaginal atrophy in postmenopausal breast cancer patients on adjuvant endocrine therapy with tamoxifen or AIs compared with age-matched women with or without estrogen therapy.
Materials and Methods
Patients
Eligible patients were identified in the Swedish Cancer Registry in the Uppsala/Örebro Region, Sweden, a population-based register that covers more than 96% of breast cancer cases. Inclusion criteria were being postmenopausal, residing in the county of Uppsala or Örebro, and being 55 to 70 years old, with estrogen receptor-positive breast cancer diagnosed between 2003 and 2006. Patients still undergoing primary therapy (radiation or chemotherapy) and patients with recurrent cancer were excluded. Patients with other severe diseases that potentially could interfere with sexual functioning or be bothersome for the gynecologic evaluation were excluded. Hence, women with neurologic or rheumatoid disorders associated with impaired mobility (paraplegia, prior stroke with hemiplegia, multiple sclerosis, and severe rheumatoid or musculoskeletal disorders), women hospitalized for depression or psychosis, and women with severe cancer (other than breast cancer) were excluded. Information derived from the Cancer Registry, including TNM classification, was checked with the medical reports of each invited patient. Patients were invited by letter.
Age-matched control subjects were selected from the Swedish Population Registry and invited by letter. For each breast cancer patient, 3 control subjects residing in the same county and born during the same year and month as the index patients were randomly selected and invited in turn until 1 agreed to take part. Postmenopausal status, defined as 12 months of amenorrhea after the last bleeding event, was ensured before inclusion, and controls with previous breast cancer or other severe diseases (similar as for breast cancer patients) were excluded.
All participants gave written informed consent, and the Independent Ethical Review Board at Uppsala University, Sweden, approved the study.
Materials and methods
All participants attended a health examination at the Department of Women’s and Children’s Health, Uppsala University Hospital, or the Department of Obstetrics and Gynecology, Örebro University Hospital, from November 2008 to March 2009. One experienced gynecologist at each department performed all examinations, which included medical history (with the exception of questions concerning breast cancer or breast cancer treatment), a gynecologic examination, and a transvaginal ultrasound evaluation. Each examiner saw a similar proportion of patients and controls. As many women revealed their breast cancer diagnosis to the examiner, blinding of patient/control status was imperfect. Otherwise, all laboratory analyses were made by staff that was blinded to patient/control status.
Breast cancer history, including previous and current adjuvant endocrine therapy, was taken from the medical records in addition to information obtained directly from the patients (questionnaire). Medical history, including demographic variables and information on reproductive health, previous and ongoing diseases, drug therapy, and previous and current hormonal treatment, was requested. Weight and height were measured in a standardized manner, and body mass index was calculated.
The degree of vaginal atrophy was judged by assessing the epithelium according to thickness, color, fluor, and presence of petechial bleeding. A 4-grade scale was used for classification purposes (0 = none, 1 = mild, 2 = moderate, 3 = severe). Vaginal pH was measured using a paper indicator (Machery-Nagel, Düren, Germany) that was placed in the lateral wall of the vagina. Vaginal cytologic smears were obtained from the junction of the upper and middle part of the lateral vaginal wall using a brush (Cytobrush; Medscand, Berlin, Germany). Smears were fixed in 95% alcohol and stained according to Papanicolaou. The Maturation Index, ie, the percentage proportion of parabasal, intermediate, and superficial vaginal epithelial cells was calculated on 300 cells by 1 cytotechnologist at the Department of Clinical Pathology, Örebro University Hospital. Vaginal ultrasound examination was done with a 7-MHz transvaginal probe. The measurements were obtained in real time according to a standardized protocol, with examination of the endometrium performed under the highest possible magnification.
Subjective endocrine symptoms were assessed by the Endocrine Subscale-FACT-B, a validated 5-point response scale (not at all/a little bit/somewhat/quite a bit/very much) developed for breast cancer research. Only items reflecting systemic and local estrogen deficiency symptoms were included. Vaginal atrophy symptoms consisted of vaginal itching or irritation, vaginal dryness, and pain or discomfort with intercourse.
Urinary incontinence was evaluated with the Incontinence Impact Questionnaire short form (IIQ-7) and the Urogenital Distress Inventory short form (UDI-6), a validated questionnaire using a 4-point response scale (not at all/slightly/moderately/greatly).
Statistical methods
All values are displayed as mean ± standard deviation (SD). For comparison between breast cancer patients and control subjects independent t tests or Mann-Whitney U tests were performed, depending on whether the variable was normally distributed. Frequencies were compared between groups by χ 2 test.
For clinical presentation and subjective reports of vaginal atrophy symptoms, 4 distinct groups of women were used: (1) control subjects without local or systemic estrogen treatment, (2) control subjects with local or systemic estrogen treatment, (3) tamoxifen-treated breast cancer patients without local or systemic estrogen treatment, and (4) AI-treated breast cancer patients without local or systemic estrogen treatment. Because of the small numbers, breast cancer patients with ongoing local/systemic estrogen use and breast cancer patients without adjuvant endocrine therapy were excluded from these analyses. Mean values were compared by 1-way analysis of variance (ANOVA) or Kruskal-Wallis test, depending on normal distribution. In cases when the ANOVA or Kruskal-Wallis test was significant, post hoc tests (Tukey HSD) were made for normally distributed variables and Mann-Whitney U test for skewed data.
Subjective symptoms assessed by the ES-FACT-B questionnaire were categorized as light (not at all/a little bit) and moderate/severe (somewhat/quite a bit/very much), respectively. Symptoms of the IIQ-7 and UDI-6 questionnaire were also categorized as light (not at all/ slightly) and moderate/severe (moderately/greatly), respectively.
The SPSS statistical package version 15.0 was used for all analyses (SPSS, Inc, Chicago, IL). A P value less than .05 was considered significant.
Results
Study population
In all, 233 breast cancer patients fulfilled the inclusion/exclusion criteria for the study and were invited. Among these, 97 agreed to participate. There were no systematic differences in terms of age, TNM classification, and use of adjuvant endocrine treatment between breast cancer patients who participated and those who declined participation (data not shown). In all, 493 control subjects were invited to the study. Of these, 107 accepted the invitation and 2 were excluded because of previous breast cancer. Hence, the final study sample consisted of 97 breast cancer patients and 105 controls. One control subject did not fill out the questionnaires and has been included in analyses of clinical outcomes only.
Demographic data and clinical characteristics of the study population are displayed in Table 1 . There were no clinically relevant differences between the 2 groups, except the use of local or systemic estrogen, which was significantly more common among control subjects. One breast cancer patient who had discontinued adjuvant endocrine therapy was currently on systemic estrogen treatment, and 18 (18.6%) breast cancer patients had local estrogen therapy. Tumor characteristics of breast cancer patients are shown in Table 2 . Among patients treated with AIs, 24 were on anastrozole, 10 on exemestane, and 1 on letrozole. Between the review of the medical records and the clinical examination, 8 (8.2%) breast cancer patients had discontinued endocrine therapy and 7 (7.2%) had not had any endocrine therapy at all, based on low tumor grade.
