There are several million breast cancer survivors worldwide. In the United States, 180,000 women were diagnosed with breast cancer in 1997, and approximately 97,000 of these women have an extremely low chance of suffering a recurrence of their cancer. With an average age at diagnosis of 60 years and a 25-year expected duration of survival, the current number of breast cancer survivors in the United States may approach 2.5 million women. Since breast cancer is now being detected at an earlier stage than previously and since adjuvant chemotherapy may cause ovarian failure, an increasing number of women are becoming postmenopausal at a younger age after breast cancer treatment. This conference was convened in September 1997 to consider how menopausal breast cancer survivors should be treated at the present time and what future studies are needed to develop improved therapeutic strategies. A total of 47 breast cancer experts and 13 patient advocates participated. The proceedings of the conference are being published in six installments in successive issues of oncology. This fourth part focuses on the treatment of urogenital atrophy, vasomotor instability, sleep disorders, and other related symptoms. [ONCOLOGY 13(4):551-575,1999]
Proceedings of a Conference, Held at the Boar's Head Inn, Charlottesville,Virginia, September 21-23, 1997
Patricia Ganz, MD: I will discuss two different studies focusing on the frequency of vasomotor symptoms and urogenital atrophy, respectively, in women surviving breast cancer. One study involved breast cancer patients recruited from the Los Angeles community and followed longitudinally during the first year after diagnosis. The second study, conducted in Washington, DC, and Los Angeles, was a large, cross-sectional survey of breast cancer patients who were disease-free between 1 and 5 years after diagnosis.
In the first study, the average age of patients was 55 years; most had partners and were very well educated; and their ethnic distribution was representative of the breast cancer population in Los Angeles. Patients were interviewed at 1, 4, 7, and 13 months after diagnosis regarding their symptoms related to the climacteric.
For the purpose of this presentation, I have divided the sample into three age groups: women < 50 years; those 50 to 59 years old; and those ³ 60 years old. In women < 50 years of age, there was a relatively low rate of hot flashes at 1 month after diagnosis, with an increase to 45% at 7 months and a slight decline by 13 months. These findings likely represent the effect of chemotherapy in inducing premature menopause in these younger women.
The severity of hot flashes increased in women under age 50 as a function of time since surgery. For women over 50 years old, hot flash severity remained stable over the course of the 1 year of observation. These findings suggest that breast cancer treatment has an impact on ovarian function in younger women, but no hormonal changes probably occur in the older group.
It is likely that most women 50 to 59 years old had already entered menopause at the time of their breast cancer diagnosis. Many of these women could have been receiving hormone replacement therapy (HRT) at the time of diagnosis and stopped it thereafter. Some of these women (35%) were already experiencing vasomotor symptoms at 1 month after surgery; these symptoms increased in frequency at 7 months (60%) and persisted over the course of 1 year (55%).
Symptoms due to vaginal lubrication problems were available from sexually active women only. High rates of these problems were reported 1 month after surgery for all women independent of age (< 50 years old, 50%; 50 to 59 years old, 52%; ³ 60 years old, 57%), and these high rates persisted for up to 1 year. Since many of these women were postmenopausal at diagnosis, one cannot conclude that the therapy initiated for breast cancer treatment was causative. This finding led to more detailed studies focused on sexuality and intimacy in breast cancer survivors. The older women stated that the severity of sexual problems was greatest early after diagnosis, with an improvement during the year of follow-up. Regardless of age, all women reported nearly the same severity of symptoms (hot flashes, lubrication problems) when evaluated at 1 year.
In additional analyses of the same study sample, we used the Cancer Rehabilitation Evaluation System (CARES) Sexual Functioning Scale (an 8-item measure) to assess sexual functioning. The youngest women reported the most disruption in sexual functioning initially after surgery; this improved somewhat over time but was still a persistent problem at 1 year. In the women 50 to 59 years old, sexual functioning scores at 1 month after surgery were intermediate between the youngest and oldest women, and their functioning did not change over time. In contrast, women over 60 years of age reported better sexual functioning initially (many were not sexually active with a partner), and this did not change over time.
These findings suggest that sexual functioning is disrupted to the greatest extent in the younger women, and that the reported dysfunction does not seem to recover after the breast cancer experience (ie, it does not improve with time since diagnosis).
Sexuality and Intimacy in Breast Cancer Survivors
In the second cross-sectional study, our research group addressed the question of sexuality and intimacy in breast cancer survivors, with a special focus on whether sexual functioning would improve somewhat later after the breast cancer diagnosis. We reported on data from a large cross-section of disease-free patients living in Los Angeles and Washington, DC (N = 864). On average, these women completed the survey 3 years after their breast cancer diagnosis. The women in this sample were similar medically and demographically to those in the first study.
One issue that was addressed in this survey was the frequency of menstruation after breast cancer and the history of use of HRT. Only a small number of women continued to menstruate after their breast cancer diagnosis, and many (36%) had used HRT before being diagnosed. There was a divergence in HRT use between women living on the East and West coasts; a larger proportion of Los Angelean women reported a history of HRT use.
A symptom checklist was used to assess menopausal symptoms in this study sample. As shown in Figure 1, the prevalence and severity of hot flashes increased with age, and these symptoms were more frequent in the breast cancer survivors than in healthy volunteers participating in the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial (baseline data obtained prior to randomization to tamoxifen [Nolvadex] or no tamoxifen).
The breast cancer survivors who were < 60 years old appeared to show the greatest differences from the healthy comparison group. Hot flashes were less of a problem in women over 60 years old, but their severity was greater in the women with breast cancer than in controls. Although hot flashes were reported more frequently in breast cancer survivors, they were not extraordinarily severe.
With respect to urinary incontinence, the frequency of this complaint increased with increasing age (< 50 years old, 16%; 50 to 59 years old, 35%; ³ 60 years old, 40%). In both normal healthy women and those treated for breast cancer, these symptoms were not extremely severe.
When asked about vaginal dryness, only 20% of younger (35- to 49-year-old) healthy women reported this problem vs 45% of younger breast cancer survivors. The same trend was seen in older women, with breast cancer survivors reporting this problem more frequently.
Similar trends were noted with respect to pain during intercourse; younger healthy women reported less pain than did age-matched women surviving breast cancer. This symptom increased with age in both the healthy women and breast cancer survivors.
Sexual Functioning andQuality of Life
There is a similarity between our findings on sexual functioning in breast cancer survivors and data obtained from the Postmenopausal Estrogen/Progestin Intervention (PEPI) trial in healthy postmenopausal women. When comparing our database with the PEPI data, age-matched scoring of sexual dysfunction scales did not differ between the two groups. Both groups experienced a decline in sexual functioning with age.
Based on this finding, it is difficult to attribute most sexual dysfunction to therapy for breast cancer, as opposed to the normal effects of aging. This must be taken into account when conducting studies of sexual functioning in breast cancer survivors.
In addition, quality-of-life scores of breast cancer survivors on the Medical Outcomes Study, Short Form-36 (MOS SF-36) were equal to or better than scores of healthy, age-matched, control women. These observations suggest that although breast cancer has an important effect on women’s lives, it does not translate into apparent decrements in their quality of life, as measured by standardized instruments.
Using data from this large cross-sectional sample, our group developed a model for examining sexual functioning that takes into account factors affecting women with breast cancer (eg, type of surgery, body image, chemotherapy, use of tamoxifen). In this multivariate model, the use of chemotherapy, discomfort with body image, and the presence of hot flashes predicted for poorer sexual functioning. Tamoxifen use was not associated with worse sexual functioning.
1. Ganz PA, Schag CAC, Lee JJ, et al: Breast conservation versus mastectomy: Is there a difference in psychological adjustment or quality of life in the year after surgery? Cancer 69:1729-1738, 1992.
2. Ganz PA et al: Life after breast cancer: Understanding women’s health-related quality of life and sexual functioning. J Clin Oncol 16:501-514, 1998.
3. Ganz PA, Day R, Ware JE Jr, et al: Base-line quality-of-life assessment in the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial. J Natl Cancer Inst 87:1372-1382, 1995.
3a. Powles T, Eeles R, Ashley S, et al: Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomized chemoprevention trial. Lancet 352:98-101, 1998.
4. Greendale GA, Hogan P, Shumaker S, for the Postmenopausal Estrogen/Progestins Intervention trial (PEPI) investigators: Sexual functioning in postmenopausal women: The Postmenopausal Estrogen/Progestins Intervention (PEPI) trial. J Womens Health 5:445-458, 1996.
5. Mandel F, Geola F, Meldrum D, et al: Biological effects of various doses of vaginally administered conjugated equine estrogens in postmenopausal women. J Clin Endocrinol Metab 57:133, 1983.
6. Nachtigall LE, Nachtigall LB: The menopause, in Conn’s Current Therapy, p 1085. Philadelphia, WB Saunders, 1991.
7. Deutsch S. Ossowski R, Benjamin I: Comparison between degree of systemic absorption of vaginally and orally administered estrogens at different dose levels in postmenopausal women. Am J Obstet Gynecol 139:967-968, 1981.
8. Bachmann G, Notelovitz L, Birgerson L: A comparative study of low-dose estradiol vaginal ring and conjugated estrogen cream for postmenopausal urogenital atrophy. Prim Care Update Ob/Gyn 4:109-115, 1997.
9. Bachmann G: The clinical platform for the 17b-estradiol vaginal releasing ring. Am J Obstet Gynecol 178:5, 1998.
10. Holmgren PA, Lindskog M, von Schoultz B: Vaginal rings for continuous low-dose release of oestradiol in the treatment of urogenital atrophy. Maturitas 11:55-63, 1989.
11. Nachtigall LE: Comparative study: Replens versus local estrogen in menopausal women. Fertil Steril 61:178-180, 1994.
12. Klein KO, Demers LM, Santner SJ, et al: Use of ultrasensitive recombinant cell bioassay to measure estrogen levels in women with breast cancer receiving the aromatase inhibitor, letrozole. J Clin Endocrinol Metab 80:2658-2660, 1995.
13. Loprinzi CL, Michalak JC, Quella SK, et al: Megestrol acetate for the prevention of hot flashes. N Engl J Med 331:347-52, 1994.
14. Goldberg RM, Loprinzi CL, O’Fallon JR, et al: Transdermal clonidine for ameliorating tamoxifen-induced hot flashes. J Clin Oncol 12:155-158, 1994.
15. Barton DL, Loprinzi CL, Quella SK, et al: Prospective evaluation of vitamin E for hot flashes in breast cancer survivors. J Clin Oncol 16(2):495-500, 1998.
16. Fioretti P, Cagnacci A, Paoletti AM, et al: Effects of the antidopaminergic drug veralipride on LH and PRL secretion in postmenopausal women. J Endocrinol Invest 12(5):295-301, 1989.
17. Melis GB, Gambacciani M, Cagnacci A, et al: Effects of the dopamine antagonists veralipride on hot flushes and luteinizing hormone secretion in postmenopausal women. Obstet Gynecol 72(5):688-692, 1988.
18. Boulot P, Viala JL: A multicenter comparison of veralipride versus placebo in the vasomotor flushes of menopause: An evaluation of the prolonged effect. Rev Francaise de Gynecologie et d Obstetrique 83(12):823-827, 1988.
19. Verbeke K, Dhont M, Vandekerckhove D: Clinical and hormonal effects of long-term veralipride treatment in postmenopausal women. Maturitas 10(3):225-230, 1988.
20. Loprinzi CL, Pisansky TM, Fonseca R, et al: Pilot evaluation of venlafaxine hydrochloride for the therapy of hot flashes in cancer survivors. J Clin Oncol 16:2377-2381, 1998.
21. Merchenthaler I, Funkhouser JM, Carven JM, et al: The effect of estrogens and antiestrogens in a rat model for hot flush. Maturitas 30(3):307-316, 1998.
22. Hirata JD, Swiersz LM, Zell B, et al: Does Dong Quai have estrogenic effects in postmenopausal women? A double-blind, placebo-controlled trial. Fertil Steril 68(6):981-986, 1997.
23. Koff RS: Herbal hepatotoxicity: Revisiting a dangerous alternative. JAMA 73(6):502-503, 1995.
24. Sheikh NM, Philen RM, Love LA: Chaparral-associated hepatotoxicity. Arch Intern Med 157(8)913-919, 1997.
25. Tyler V: What pharmacists should know about herbal remedies. J Am Pharm Assoc NS36:29-37, 1996.
26. Arjmandi BH, Alekel L, Hollis BW, et al: Dietary soybean protein prevents bone loss in ovariectomized rat model of osteroporosis. J Nutr 126:161-167, 1996..
27. Lien LL, Lien EJ: Hormone therapy and phytoestrogens. J Clin Pharm Ther 21(2):101, 1996.
28. Anthony MS, Clarkson TB, Hughes CL, et al: Soybean isoflavones improve coronary heart disease risk factors without affecting the reproductive system of peripubertal rhesus monkeys. J Nutr 126:43-50, 1996.
29. Anderson J, Johnstone B, Cook-Newell M: Meta-analysis of the effects of soy protein intake on serum lipids. N Engl J Med 333:276-282, 1995.
30. Bundred NJ, Harding C, McMichael Phillips D, et al: Serum phytoestrogen concentrations in British women with breast cancer and controls. Am J Clin Nutr 68(6;suppl):1529S, 1998.
31. Petrakis NL, Barnes S: Stimulatory effects of soy protein isolates on breast fluid secretion (abstract). Am J Clin Nutr 68(6;suppl):1530S, 1998.
32. Peterson TG, Kim H, Barnes S: Genistein may inhibit the growth of human mammary epithelial (HLE) cells by augmenting transforming growth factor beta (TGFb) signaling (abstract). Am J Clin Nutr 68(6;suppl):1527S, 1998.
33. Ito A, Goto T, Yamanda K, et al: Primary prevention of cancers by miso, soybeans and biochanin A on rodent tumors (abstract). Am J Clin Nutr 68(6;suppl): 1525S, 1988.
34. Korzenik JR, Barnes S, Coward L, et al: Possible efficacy of isolated soy protein in treatment of hereditary hemorrhagic telangiectasia-associated epistaxis, gastrointestinal hemorrhage, and migraine: A pilot study (abstract). Am J Clin Nutr 68(6;suppl):1530, 1998.
35. Albertazzi P, Pansini F, Bonaccorsi G, et al: The effect of dietary soy supplementation on hot flushes. Obstet Gynecol 91(1):6-11, 1998.
36. Murkies AL, Wilcox G, Davis SR: Phytoestrogens. J Clin Endocrinol Metab 83:297-303, 1998.