By Alexandra Samborski, MD
Adjunct Instructor, Department of Obstetrics & Gynecology, University of Rochester Medical Center, NY
SYNOPSIS: Risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) for patients at high risk of breast and ovarian cancer led to decreased cancer-related distress, unaffected health-related quality of life, poorer body image after RRM, and decreased sexual function and increased menopause symptoms after RRSO.
SOURCE: Wei X, Oxley S, Sideris M, et al. Quality of life after risk-reducing surgery for breast and ovarian cancer prevention: A systematic review and meta-analysis. Am J Obstet Gynecol 2023; Apr 12:S0002-9378(23)00240-5. doi: 10.1016/j.ajog.2023.03.045. [Online ahead of print].
With the increase in genetic testing, more patients with pathogenic variants in cancer susceptibility genes are being identified. Patients with increased risks of breast and ovarian cancer caused by genetic variants are important to identify, since this risk can be mitigated with increased screening, medical prevention, or risk-reducing surgery. Risk-reducing mastectomy (RRM) decreases the risk of breast cancer by up to 95%, and risk-reducing salpingo-oophorectomy (RRSO) decreases the risk of ovarian cancer by up to 90%.1,2
RRSO generally is performed before age 45 years, which causes surgical menopause and associated symptoms for these patients. Education regarding the cancer reduction benefits and quality of life (QoL) outcomes is crucial for patients who are making the decision of whether and when to proceed with surgery.
The primary aim of this review was to assess the effect of risk-reducing surgery on QoL. Secondary aims were to assess short- vs. long-term QoL, to assess the effect of hormone replacement therapy (HRT) use, and to assess whether a confirmed pathogenic variant vs. family history affected QoL.
This study is a systematic review and meta-analysis that searched MEDLINE, PubMed, Embase, and the Cochrane library from inception through February 2023 using predefined search terms. Studies involving women with an increased risk of breast cancer (greater than 30% to 40% lifetime risk) or ovarian cancer (greater than 5% lifetime risk) based on a known pathologic variant or family history and an intervention of RRM, RRSO, or risk-reducing early salpingectomy delayed oophorectomy (RRESDO) were included. Studies including patients undergoing RRM or RRSO for a personal history of cancer were excluded. QoL outcomes between those who underwent risk-reducing surgery and those who did not were compared over the short vs. long term, between those with pathogenic variants vs. a family history, between those who were premenopausal vs. postmenopausal, and between premenopausal patients with RRSO on HRT or not. Outcomes assessed included health-related QoL, sexual function, menopause symptoms, body image, cancer-related distress, and anxiety/depression. Multiple reviewers independently assessed each study for eligibility for inclusion and risk of bias. Summary estimates of QoL after risk-reducing surgery vs. no surgery were analyzed using a fixed-effects meta-analysis with 95% confidence intervals (CI). Heterogeneity was assessed using I2.
Thirty-four studies met eligibility criteria, with a total of 3,762 patients undergoing risk-reducing surgery and 3,002 patients without risk-reducing surgery. After RRM, the health-related QoL was unaffected in 12 studies and improved in one study. Sexual function worsened in four studies and was unchanged in eight studies. Women reported higher satisfaction with their body image after RRM with reconstruction or nipple- and areola-sparing RRM. Two studies reported decreased cancer-related distress after RRM, and two studies showed no appreciable difference. Cancer-related stress was higher for patients with a known breast cancer gene (BRCA) 1/2 pathogenic variant or a strong family history than for those with a limited family history. Two studies showed decreased anxiety after RRM, whereas three studies showed no difference in anxiety and six studies showed no difference in depression. One study showed increased rates of depression after long-term follow-up.
After RRSO, two studies showed improved health-related QoL and eight studies showed no change. Five of these studies showed short-term decreases in health-related QoL, which returned to baseline after six to 12 months. One study noted no change in health-related QoL for premenopausal patients specifically. In terms of sexual function, 13 studies showed decreased pleasure, decreased frequency, and increased discomfort after RRSO for pre- and postmenopausal women. Studies varied in whether these symptoms improved or worsened over long-term follow-up. Twelve studies showed an increase in menopausal symptoms after RRSO, and three studies demonstrated these symptoms could be mitigated by HRT. A decrease in cancer-related distress following RRSO was noted in six studies, and four studies showed that RRSO did not worsen anxiety or depression.
Two studies assessed early salpingectomy and delayed oophorectomy. In both studies, patients undergoing RRESDO had decreased cancer-related distress and did not change health-related QoL. One of the studies specifically noted increased menopausal symptoms and impairment in sexual function after RRSO as compared to early salpingectomy.
COMMENTARY
Risk-reducing surgery, including RRM and RRSO, is an important aspect of care for patients with strong family histories of breast or ovarian cancer or known pathogenic variants in cancer susceptibility genes. Although the oncologic benefits of surgery are well established, there are less data and understanding of the other endocrine effects and QoL after risk-reducing surgery, especially RRSO. These aspects of surgical management for these high-risk patients are important to delineate so that clinicians can thoroughly counsel patients and patients can make appropriately informed decisions.
As more genetic testing is being performed and more cancer susceptibility genes are being identified, the number of patients eligible for risk-reducing surgery is likely to increase. The benefit of risk-reducing surgery in high-penetrance genes is well known, but for moderate- or low-penetrance genes, the role of risk-reducing surgery is less clear. One guide reviewed the risks of ovarian cancer for various genes and provides recommendations for whether RRSO is beneficial, and, if so, when it should be performed.3 Additionally, risk prediction models for both breast and ovarian cancer are available to provide personalized risk levels for patients based on genetic factors and family history.4,5 These tools can help both patients and clinicians understand the oncologic risks and benefits of undergoing risk-reducing surgery, but understanding the non-oncologic outcomes of surgery and what patients can expect post-operatively also is critical for patients in making decisions on whether to proceed with surgery.
This systematic review showed that patients undergoing RRM in general had a minimal effect in health-related QoL. There may be a decrease in sexual function and body image depending on whether reconstruction is performed, and there may be a slight decrease in cancer-related distress and anxiety. Patients undergoing RRSO had a minimal change in health-related QoL in the long term, decreased sexual function, more menopause symptoms, and less cancer-related distress without worsening anxiety or depression. Although not currently the standard of care, RRESDO may help with decreasing menopausal symptoms for these patients while still decreasing cancer-related distress. This approach does not reduce the risk of cancer to the extent that bilateral salpingo-oophorectomy does, but for patients who are concerned about the effects of early oophorectomy, this may be a more acceptable option. Patients with BRCA2 have the added benefit of decreasing their breast cancer risk with a bilateral oophorectomy, so the benefits of this procedure need to be weighed as well, particularly for patients who have not undergone RRM. Clinical trials currently are ongoing, and as we collect more data, we will be able to better counsel patients regarding the risks and benefits of this approach.6
Another approach to mitigate some of the effects of early oophorectomy in premenopausal patients is treatment with HRT. There is concern about the increased risk of breast cancer with HRT in patients with BRCA pathologic variants, but one meta-analysis showed no difference in breast cancer risk with HRT after RRSO.7 Estrogen alone for patients who have undergone hysterectomy may confer lower risk than estrogen plus progesterone. This systematic review did not evaluate other effects of early surgical menopause, such as osteoporosis risk, cardiovascular risk, and risk of cognitive decline. HRT theoretically could improve these as well, but data are lacking to support this definitively. Ultimately, the decision to undergo RRS is personal for each patient based on their cancer risk, surgical risk, and acceptability of long-term effects. Continued collection of data will allow more thorough counseling so that patients can fully weigh the risks and benefits to determine if, and when, this is an appropriate step for them.
REFERENCES
- Rebbeck TR, Friebel T, Lynch HT, et al. Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: The PROSE Study Group. J Clin Oncol 2004;22:1055-1062.
- Eleje GU, Eke AC, Ezebialu IU, et al. Risk-reducing bilateral salpingo-oophorectomy in women with BRCA1 or BRCA2 mutations. Cochrane Database Syst Rev 2018;8:CD012464.
- Liu YL, Breen K, Catchings A, et al. Risk-reducing bilateral salpingo-oophorectomy for ovarian cancer: A review and clinical guide for hereditary predisposition genes. JCO Oncol Pract 2022;18:201-209.
- Lee A, Yang X, Tyrer J, et al. Comprehensive epithelial tubo-ovarian cancer risk prediction model incorporating genetic and epidemiological risk factors. J Med Genet 2022;59:632-643.
- Lee A, Mavaddat N, Wilcox AN, et al. BOADICEA: A comprehensive breast cancer risk prediction model incorporating genetic and nongenetic risk factors. Genet Med 2019;21:1708-1718.
- Daly MB, Pal T, Berry MP, et al. Genetic/familial high-risk assessment: Breast, ovarian, and pancreatic, version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2021;19:77-102.
- Marchetti C, De Felice F, Boccia S, et al. Hormone replacement therapy after prophylactic risk-reducing salpingo-oophorectomy and breast cancer risk in BRCA1 and BRCA2 mutation carriers: A meta-analysis. Crit Rev Oncol Hematol 2018;132:111-115.
Risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) for patients at high risk of breast and ovarian cancer led to decreased cancer-related distress, unaffected health-related quality of life, poorer body image after RRM, and decreased sexual function and increased menopause symptoms after RRSO.
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