Annals of Oncology Advance Access originally published online on September 13, 2006
Annals of Oncology 2006 17(12):1777-1782; doi:10.1093/annonc/mdl299
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© 2006 European Society for Medical Oncology
breast cancer |
Menopausal-type symptoms in young breast cancer survivors
1 Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, MA, USA
2 Harvard Medical School, Boston, MA, USA
3 Beth Israel Deaconess Medical Center, Boston, MA, USA
4 Young Survival Coalition, New York, USA
* Correspondence to: Dr A. H. Partridge, Dana-Farber Cancer Institute, 44 Binney Street, D1210, Boston, MA 02115, USA. Tel: +1(617) 632-3800; Fax: +1(617) 632-1930; E-mail: ahpartridge{at}partners.org
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Abstract |
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 Top Abstract introductionpatients and methodsresultsdiscussionReferences |
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Background: There has been little previous information available about menopausal-type symptoms in very young breast cancer survivors.
Methods: In collaboration with the Young Survival Coalition, we conducted an Internet-based survey of women with a history of breast cancer diagnosed at age 40 years or younger using items derived from the Breast Cancer Prevention Trial symptom checklist.
Results: A total of 371 respondents were eligible for analysis. Mean age at diagnosis was 32.8 years and mean age at follow-up 36.2 years; 89% of women received chemotherapy, 49% tamoxifen, 15% ovarian suppression, 4% aromatase inhibitors. At the time of survey, 37% were taking tamoxifen and 9% ovarian suppression. Excluding women on ovarian suppression, 77% of women were premenopausal at follow-up. Many women reported bothersome menopausal-type symptoms. In particular, 46% of women reported hot flashes and 39% reported dyspareunia. In a linear regression model of symptom scores, current ovarian suppression, postmenopausal status, baseline anxiety before the diagnosis, pregnancy after the diagnosis, prior chemotherapy, and lower perceived financial status were associated with more bothersome symptoms.
Conclusion: A substantial number of young breast cancer survivors experience bothersome menopausal symptoms. While the women who responded to our survey may represent a select group of survivors, these findings may have important implications for treatment decision making and long-term quality of life of young women with breast cancer.
Key words: breast cancer, menopausal symptoms, quality of life, young women
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introduction |
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Menopausal-type symptoms are a common problem for breast cancer survivors. Fifty percent or more of breast cancer survivors report symptoms, including hot flashes, early awakening, forgetfulness, and breast sensitivity and >40% report weight gain, vaginal dryness, and night sweats [1]. Women with a history of breast cancer are approximately five times more likely to report menopausal-type symptoms than controls in the general population [2].
The risk of menopausal-type symptoms appears to be related to the treatment received and to experience of a menopausal transition with therapy [1, 3]. Women who experience menopausal-type symptoms during breast cancer therapy report more severe symptoms than population-based controls [2, 4]. Symptoms may be particularly severe among younger women who undergo chemotherapy-induced ovarian failure, likely because of the rapid change in menopausal status [3, 4]. Previous studies evaluating menopausal-type symptoms in women with breast cancer have defined young women as those 50 years of age or younger. As a result, findings have been generalized to all premenopausal women, but the majority of information has come from women over the age of 40 years at diagnosis. Little information is available regarding menopausal-type symptoms in very young women—those who are 40 years or younger at diagnosis. Although breast cancer in women who are 40 years or younger is not common, representing only 
5%–6% of women diagnosed with breast cancer, there are >14 000 women aged 40 years or younger diagnosed with breast cancer each year in the United States alone [5].
We conducted a study to characterize menopausal-type symptoms in young breast cancer survivors. The primary objectives of the study were to determine the prevalence and severity of menopausal-type symptoms in these women, the incidence of specific symptoms in women receiving common long-term hormonal treatments, and the factors associated with severe menopausal-type symptoms.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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We evaluated menopausal-type symptoms as part of a large cross-sectional survey of fertility and related issues among young women with a history of breast cancer. The survey was conducted in collaboration with the Young Survival Coalition (YSC), an international nonprofit advocacy group for young women with breast cancer. The details of the survey methods have been previously reported [6]. All registered YSC members were informed by e-mail about the Web-based survey, and eligible members were encouraged to participate, with e-mail reminders used to maximize the response rate. Our local institutional review board approved the research, and each participant provided Web-based informed consent before responding to the survey.
The criteria for eligibility were an age of 40 years or younger and premenopausal status at diagnosis (defined as at least one menstrual period within 6 months before the diagnosis). For this analysis, we also required an interval of at least 1 year between the diagnosis and participation in the survey. Women who were pregnant or who had a history of recurrent or contralateral disease at the time of the survey were excluded.
We evaluated menopausal-type symptoms using 16 questions derived from the BCPT symptom checklist, a list of 43 commonly reported physical and emotional symptoms associated with menopause and use of endocrine therapy for breast cancer [7]. Survey participants were asked how bothersome each symptom had been within the previous 4 weeks. They rated the degree of bothersomeness on the basis of a five-point Likert scale with the following response categories: ‘not at all’, ‘slightly’, ‘moderately’, ‘quite a bit’, and ‘extremely’. We also included questions from two previously validated questionnaires: the Lasry Fear of Recurrence Scale [8] for recall from the time of diagnosis and the Hospitalized Anxiety and Depression Scale (HADS) [9] for recall from the period before diagnosis. A score >10 on the anxiety subscale was considered exhibiting severe anxiety and a score >10 on the depression subscale was considered exhibiting severe depressive symptoms.
statistical analysis
We used a linear regression model predicting a weighted summary score of symptom prevalence and degree of bothersomeness to determine the association of symptoms with patient and disease characteristics and with treatments received. To determine whether the severity of symptoms was associated with menopausal status or treatment, we dichotomized the bothersomeness ratings as ‘not at all’ or ‘slightly’ versus ‘moderately’, ‘quite a bit’, or ‘extremely’, with the latter three ratings defined as indicating moderate to severe symptoms. We used the chi-square test to evaluate associations with Bonferroni adjustment for multiple comparisons, with P values of <0.003 indicating statistical significance.
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results |
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Of the 1702 registered YSC members, 860 women gave electronic informed consent and responded to the survey (Figure 1). A total of 489 women were excluded from the analysis for the following reasons: no history of breast cancer (eight), completion of only a small portion of the survey (120), a history of hysterectomy and/or bilateral oophorectomy (84), age >40 years (15), postmenopausal status (13), or stage IV disease (nine) at the time of diagnosis; recurrent or contralateral disease (23), a period of <1 year since the diagnosis (206), or pregnancy (11) at the time of the survey. Thus, 371 women were evaluated as part of this cohort. However, one eligible woman did not respond to any of the menopausal symptom items of our survey, leaving a total of 370 women included in the analysis.
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characteristics of the survey respondents
The characteristics of the women who participated in the survey and were eligible for our cohort are presented in Table 1. The mean age at the time of the survey was 36.2 years. Eighty-nine percent of the respondents were Caucasian, and only 2% were African American. Overall, the women were well educated, with 77% reporting having graduated from college. The majority of respondents were financially secure; 65% were working full time at diagnosis, and 60% reported that they were able to afford ‘special things’. Only 3% reported difficulty with paying bills. Most women were married or had a partner (70%); 7% were divorced or separated at the time of diagnosis. Ninety-one percent of women reported no major comorbid conditions at the time of the survey.
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The women were asked to recall their emotional state in the month before the diagnosis. Twenty percent of women reported having experienced severe anxiety (a score >10 on the HADS anxiety subscale), and 3% reported having had severe depressive symptoms (a score >10 on the HADS depression subscale).
breast cancer and treatment history
The mean age at the time of the diagnosis of breast cancer was 32.8 years. Most of the women (51%) were diagnosed with stage II disease; 7% had stage 0 disease, 26% stage I, and 13% stage III, and 3% were missing information about stage. Fifty-eight percent of the women reported having had a mastectomy (all but one woman reported having had breast surgery, either lumpectomy or mastectomy), and 66% had received adjuvant radiation therapy. Eighty-nine percent of women had received chemotherapy and 49% had received tamoxifen. Smaller proportions of women had been treated with ovarian suppression (15%) or aromatase inhibitors (AIs) (4%). At the time of the survey, 53% of women were 1–2 years from diagnosis. Thirty-seven percent of the women were being treated with tamoxifen, 9% with ovarian suppression, and 3% with AIs at the time of the survey. We grouped the 33 women receiving ovarian suppression therapy at the time of the survey separately. Of these patients, 22 were also on tamoxifen and seven were on an AI, with four on ovarian suppression alone. No patients reported currently taking both an AI and a tamoxifen.
menstrual history
All women included in this analysis were premenopausal at diagnosis: 96% reported that they had been menstruating once a month, 2% once in every 2 months, and 1% every 2–6 months; <1% had two menstrual periods per month. Among the 338 women who were not being treated with ovarian suppression, 77% reported menses within 6 months preceding the survey and were defined as premenopausal at the time of the survey.
menopausal-type symptoms and associated concerns
Table 2 presents the percentages of the 371 respondents who reported experiencing slightly bothersome or more severe symptoms. The majority of respondents reported some degree of breast sensitivity (52%), vaginal dryness (51%), and vaginal discharge (54%). Forty-six percent were bothered by hot flashes, 46% by night sweats, and 39% by dyspareunia. Sixty percent of the women were bothered by a tendency to take naps or stay in bed and 52% reported early awakening. Difficulty in concentrating, distractibility, and forgetfulness were also reported by large proportions of the women (72%, 71%, and 81%, respectively). In addition, 79% reported being bothered by their physical appearance and 62% by weight gain.
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Figure 2 shows the prevalence of moderate to severe symptoms (those rated by the survey participants as moderately to extremely bothersome) among women grouped according to menopausal status and treatment at the time of the survey including premenopausal women not on current treatment, premenopausal women on tamoxifen, postmenopausal women not on current treatment, postmenopausal women on tamoxifen, all women on ovarian suppression therapy. The 1% of women who were on AI-only therapy at the time of the survey were excluded from this analysis. Differences between groups were significant by chi-square analyses for five of the 16 symptoms: hot flashes (P < 0.0001), night sweats (P < 0.0001), dyspareunia (P < 0.0001), vaginal dryness (P < 0.0001), and weight gain (P = 0.0029). In general, women who were postmenopausal, or on tamoxifen or ovarian suppression at the time of the survey were more likely to report moderate to severe menopausal-type symptoms. Moderate to severe hot flashes and night sweats were least common among premenopausal women not on tamoxifen (9% and 15%, respectively) and were most common among postmenopausal women on tamoxifen (61% and 45%, respectively) and women in the ovarian suppression group (79% and 64%, respectively). Moderate to severe weight gain was also least common among premenopausal women not on tamoxifen (35%); 42% of both premenopausal women on tamoxifen and postmenopausal women not on tamoxifen, 61% of postmenopausal women on tamoxifen, and 70% of women being treated with ovarian suppression reported moderate to severe weight gain. At least 50% of women in each group reported moderate to severe unhappiness with body appearance, with no statistically significant differences among the groups.
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Moderate to severe genitourinary symptoms were also associated with menopausal status and treatment. Dyspareunia was reported by 11% of premenopausal women not on tamoxifen and 21% of premenopausal women on tamoxifen. Postmenopausal women not on tamoxifen were more likely to report moderate or severe dyspareunia (42%) than were postmenopausal women on tamoxifen (34%), and moderate to severe dyspareunia was most common in the ovarian suppression group (48%). Following a similar trend, moderate to severe vaginal dryness was least common in premenopausal women not on tamoxifen (17%) and premenopausal women on tamoxifen (22%). Moderate to severe vaginal dryness was more common among postmenopausal women not on tamoxifen (49%) than among postmenopausal women on tamoxifen (39%) and was most common in the group of women being treated with ovarian suppression (59%). Moderate to severe vaginal discharge was reported by 23% of premenopausal women not on tamoxifen, 38% of premenopausal women on tamoxifen, 19% of postmenopausal women not on tamoxifen, 32% of postmenopausal women on tamoxifen, and 13% of women being treated with ovarian suppression; there were no statistically significant differences among these groups. Moderate to severe genital irritation or itching and loss of bladder control were less prevalent and were similar among the groups.
Moderate to severe distractibility, difficulty with concentration, and forgetfulness were reported by at least 40% of women in each group, with no statistically significant differences among the groups. Moderate to severe early awakening and fatigue were also common and did not differ significantly among the groups.
We used a stepwise selection to build a linear regression model of symptom scores, predicting the presence and severity of symptoms or symptom bothersomeness. In this model, more bothersome symptoms were significantly associated with current ovarian suppression (P < 0.0001), postmenopausal status (P < 0.0001), baseline anxiety before the diagnosis (P = 0.02), pregnancy after the diagnosis (P = 0.0005), prior chemotherapy (P = 0.009), and lower perceived financial status (P = 0.0001). Covariates that were not significant in univariate models and were not selected by the stepwise model selection included race, education, marital status, employment status, presence or absence of comorbid conditions, severe depressive symptoms before diagnosis, fear of recurrence, history of irregular menses, radiation therapy or mastectomy, fertility history, age, and cancer stage at diagnosis, time since diagnosis, current age, and tamoxifen use (either before or at the time of the survey).
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Women who undergo breast cancer therapy are at higher risk for menopausal-type symptoms than population-based controls [1, 2, 7]. Ganz et al. [10] compared menopausal-type symptoms in breast cancer survivors by age group and found that the frequency of several reported symptoms, including hot flashes, night sweats, vaginal dryness, dyspareunia, and loss of bladder control, increased with age. Similar findings were reported recently by Avis et al. [11]. To date, there has been little information available regarding menopausal-type symptoms in very young breast cancer survivors. Women who experience menopausal-type symptoms at an early age may be at increased risk for associated stressors, including sexual dysfunction, problems with body image, psychological distress, and infertility [10–13].
A considerable number of young breast cancer survivors in our survey reported bothersome menopausal-type symptoms. Postmenopausal status at the time of the survey was a significant predictor of moderate to severe menopausal-type symptoms. All the women included in this study were premenopausal and aged 40 years or younger at the time of the diagnosis, and the vast majority (86%) had been diagnosed within 5 years of the survey. Thus, recognizing that the median age of natural menopause in the Western world is 51 years, most of the women who were postmenopausal at the time of survey had experienced a menopausal transition with treatment. Our finding that these women were more likely to have substantial bothersome symptoms supports prior research suggesting that women who experience a rapid change in menopausal status from chemotherapy-induced ovarian failure are at greater risk for severe menopausal-type symptoms [3, 4]. Further, this finding in conjunction with the finding that women receiving ovarian suppression therapy were most likely to have moderate or severe menopausal-type symptoms may have important implications as oncologists increasingly use ovarian suppression to treat premenopausal patients [14–16]. It should be noted, however, that the number of women in this study who were being treated with ovarian suppression was small, and some of these women were also receiving tamoxifen or an AI.
In our study, tamoxifen therapy was not a significant predictor of menopausal-type symptoms and premenopausal women on tamoxifen reported relatively few moderate to severe symptoms. The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial found that tamoxifen use was associated with an increase in the mean number of reported menopausal-type symptoms compared with placebo [17]. In particular, tamoxifen recipients reported significantly more night sweats, hot flashes, vaginal discharge, and genital itching than the placebo group; the frequency of several other reported symptoms was dependent on age and menopausal status. In contrast to our study population, the mean age of the participants in the NSABP P-1 trial was 53.8 years (range 35–79 years), 66% were postmenopausal, 33% had used hormone replacement therapy, and 15% had a history of bilateral oophorectomy at the time of enrollment. In addition, none of the women in P-1 trial had a history of breast cancer or chemotherapy use. These differences in the study populations may account for the discrepancy between the results of the NSABP P-1 trial and our findings with respect to tamoxifen.
This study has several limitations. Selection and nonresponder bias should be considered in evaluating the results. Our cohort included predominantly well-educated, financially secure, Caucasian women who were members of the YSC and were motivated to respond to an Internet-based survey regarding fertility and menopausal issues. Therefore, our study results may not be generalizable to all young breast cancer survivors. In particular, women who were suffering from more symptoms may have been more likely to respond to the menopausal symptom questions in our survey, although only one of the 371 participants who were eligible for this analysis did not respond to the menopausal symptoms items. Recall bias must also be considered; recalled anxiety, depression, and fear of recurrence, as measured by the HADS and the Lasry Fear of Recurrence Scale, may be distorted by responses to subsequent events [18]. In addition, we relied on patient self-report of important variables and this may have resulted in some inaccuracies, especially with regard to history of breast cancer stage and treatment. Further, analyses in this study were limited by the small number of women who were being treated with an AI or ovarian suppression. As the optimal adjuvant endocrine therapy in the treatment of premenopausal women with breast cancer continues to be defined, ongoing studies will further characterize menopausal-type symptoms associated with AI, ovarian suppression, and tamoxifen use.
Our study, the largest to date to characterize menopausal-type symptoms among very young breast cancer survivors, identified a high prevalence of bothersome menopausal-type symptoms in these women and the substantial impact of becoming postmenopausal with chemotherapy, receiving ovarian suppression or tamoxifen use on the severity of symptoms. These results may have implications both for young women who are making decisions about adjuvant therapy and for the long-term quality of life of young survivors. Health care providers and young women with breast cancer can use these results to discuss risks, manage expectations, and potentially guide therapeutic interventions. Furthermore, these findings highlight the need for future research in this area including prospective evaluation of menopausal symptoms and the study of interventions to ameliorate symptoms in young breast cancer survivors.
Received for publication April 6, 2006. Revision received July 7, 2006. Accepted for publication July 10, 2006.
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