Abstract
Objectives:
This study aimed to assess the association between hormone replacement therapy and the incidence of subsequent malignancies in patients who underwent risk-reducing salpingo-oophorectomy and had mutations predisposing them to Müllerian cancers.
Methods:
This Institutional Review Board-approved retrospective study was performed at five academic institutions. Women were included if they were age 18-51 years, had one or more confirmed germline highly penetrant pathogenic variants, and underwent risk-reducing salpingo-oophorectomy. Patients with a prior malignancy were excluded. Clinicodemographic data were collected by chart review. Patients with no documented contact for one year prior to study termination were called to confirm duration of hormone use and occurrence of secondary outcomes. Hormone replacement therapy included any combination of estrogen or progesterone.
Results:
Data were analyzed for 159 women, of which 82 received hormone replacement therapy and 77 did not. In both groups an average of 6 years since risk reduction had passed. The patients treated with hormone replacement therapy did not have a higher risk of subsequent malignancy than those not treated with hormone replacement therapy (6 out of 82 vs. 7 out of 77, P=0.68). Patients who received hormone replacement therapy were younger than those who did not receive hormone replacement therapy (39.0 vs. 43.9 years, P<0.01) and were more likely to have undergone other risk reductive procedures including mastectomy and/or hysterectomy, though this difference was not statistically significant (69.5% vs. 55.8%, P=0.07).
Conclusions:
In this multi-institution retrospective study of data from patients with high-risk variant carriers who underwent risk-reducing salpingo-oophorectomy, there was no statistically significant difference in the incidence of malignancy between women who did and did not receive hormone replacement therapy.
Introduction
Women who carry pathogenic variants predisposing them to Müllerian cancers1-3 are counseled to consider a risk-reducing bilateral salpingo-oophorectomy (RRSO) after they complete child bearing or by their mid-forties. However, because this procedure leads to premature menopause, it is important to determine whether this is the best prevention strategy, especially as many patients undergo this procedure prior to age 40. An international trial (GOG-0199) comparing RRSO to longitudinal screening has completed accrual and will hopefully clarify risks of Müllerian cancer development in both groups as well as the appropriate screening frequency in those known to carry a BRCA mutation and in those with a greater than 20% chance of being a carrier4. Additionally, this trial should provide information regarding the non-oncological outcomes of RRSO (e.g., heart disease and osteoporosis) in this population. Kwon et al. created a model to compare costs and benefits of RRSO vs. salpingectomy at age 40 with delayed oophorectomy at age 50 in BRCA1 and BRCA2 mutation carriers5. RRSO at age 40 was less costly and led to longer overall life expectancy, but the salpingectomy and delayed oophorectomy group had the highest quality-adjusted life expectancy 5. This finding suggests that the increased length of ovarian hormonal exposure in the delayed oophorectomy group contributed to quality of life, though the model assumed that the RRSO group did not receive any hormone replacement therapy (HRT).
An important concern with HRT is that it could increase the risk of cancers. Most notably, the Women’s Health Initiative study reported that women who used combination estrogen and progesterone HRT for more than five years had a higher risk of breast cancer than those who did not receive HRT; however, this was not seen in the estrogen only arm. Moreover, this study did not assess mutation status, and the women were not premenopausal, which limits the applicability of the findings in younger patients undergoing RRSO.6
The majority of studies that have focused on the risks of subsequent malignancy and reception of hormonal medications have studied the incidence of breast cancer. A prior case-control study from 2008 reviewing BRCA1 carriers specifically found that the risk of breast cancer was actually lower in those who received estrogen only supplementation from surgical or natural menopause 7. A more recent prospective, longitudinal study followed 872 patients with BRCA1 mutations who underwent RRSO. HRT (combined or estrogen only) users (n=377) did not have a higher risk of developing breast cancer than did the nonusers (n=495)8. A systematic literature review reported that BRCA mutation carriers treated with hormonal therapies likely benefited symptomatically and did not have a higher breast cancer incidence than those who did not receive hormonal therapy. However, the authors emphasized the need for additional studies assessing Müllerian adenocarcinoma risk9 . Another study concluded that a short HRT course, avoiding progestins whenever possible in those with native breast tissue, was reasonable in BRCA mutation carriers10.
No similar prospective studies have yet been conducted to assess outcomes in patients carrying other mutations that increase Müllerian risk, such as Lynch syndrome mutations or mutations in the RAD50 family or PALB2. A recent paper did discuss the difficulties women with Lynch syndrome face with prophylactic procedures and some of the included women did vocalize concerns with the lack of counseling regarding surgically induced menopause and options for post-surgical management11. Thus, additional studies are needed to guide long-term care and counseling of all high-risk patients after RRSO. Here, we aimed to determine whether exposure to HRT after RRSO increased the risk of any malignancy in patients with any high-risk variant predisposing to Müllerian carcinomas.
Materials and Methods
This was a retrospective cohort study of patient data from five large academic institutions: Washington University in St. Louis; University of North Carolina, Chapel Hill; The Ohio State University; The Mayo Clinic; and The University of South Florida/Moffitt Cancer Center. The Institutional Review Board of Washington University initially approved the study protocol as the coordinating center; the other sites subsequently obtained local Institutional Review Board approval before data abstraction and transmission. Data were abstracted from each institution's electronic medical records and entered into the secure, web-based remote Research Electronic Data Capture (REDCap) electronic data capture tool hosted through Washington University.
Female patients were included if they were age 18-51 years, confirmed carriers of a high-risk mutation for development of Müllerian carcinomas, and underwent a risk-reduction procedure including at least removal of the fallopian tubes and ovaries between January 1991 and December 2016. Patients were excluded if no mutation could be confirmed, if they had a history of any malignancy before the risk-reductive procedure, or if inadequate follow-up data were available. The following data were abstracted: age at time of procedure, race, body mass index, type of mutation, years since risk-reduction procedure, history of mastectomy and/or hysterectomy, type and years of HRT used, and occurrence of malignancy and type. Data on secondary outcomes included menopausal symptoms, osteoporosis, stroke, myocardial infarction, venous thromboembolism, and death. If patients had not followed up within the last year of study cessation, up to three phone call attempts were made to reach the patient to collect data. No minimum or maximum number of follow up visits were required for enrollment.
The primary outcome was incidence of any subsequent malignancy after risk-reductive procedures. Secondary outcomes included menopausal symptoms, osteoporosis, stroke, myocardial infarction, venous thromboembolism, and death.
. We attempted to enroll patients from a national cohort of 10 academic centers; however only five of the ten cites were able to submit patients. Therefore, final accrual reached only 159 patients, which yielded a 57% power. For all analyses, P < .05 was considered significant. Continuous variables were analyzed with a student’s t-test or Mann Whitney U Test, and categorical variables were analyzed with the chi-square or Fisher’s exact test. SAS version 9.4 (SAS Inc., Cary, NC) was used for all analyses.
Results
A total of 159 patients were identified with overall follow up of 5.11± 6.24 years. Baseline demographics are included in Table 1. Patients who received HRT were significantly younger than those who did not receive HRT (39.0 vs. 43.9 years, P<0.01) and were more likely to have undergone other risk-reductive procedures including mastectomy and/or hysterectomy, though this association was not significant (69.5% vs. 55.8%, P=0.07). A higher percentage of those receiving HRT had BRCA1 mutations, whereas a higher percentage of those not receiving HRT had BRCA2 mutations or Lynch mutations, though these differences were not significant (P=0.07). Obesity, concomitant hysterectomy at time of RRSO, and duration of follow-up after RRSO were not significantly different between groups. Women were noted to receive HRT for 5.13±4.65 years.
Table 1. Demographics.
| HRT (n=82) |
No HRT (n=77) |
P-valuea | |
|---|---|---|---|
| Age at RRSO, mean ± std. dev. | 38.95 ± 6.24 | 43.92 ± 6.98 | <0.01b |
| Race, n (%) | 0.28 | ||
| Caucasian | 80 (97.56) | 71 (92.21) | |
| Black | 0 (0.00) | 2 (2.60) | |
| Asian | 0 (0.00) | 1 (1.30) | |
| Other | 2 (2.44) | 3 (3.90) | |
| Weight (kg), mean ± std. dev. | 71.76 ± 13.57 | 74.75 ± 18.92 | 0.26 b |
| BMI, mean ± std. dev. | 26.20 ± 5.36 | 27.34 ± 6.31 | 0.23 b |
| Obese (≥30 kg/m2), n (%) | 15 (18.29) | 23 (29.87) | 0.09 |
| Mutation, n (%) | 0.07 | ||
| BRCA1 | 53 (64.63) | 40 (51.95) | |
| BRCA2 | 28 (34.15) | 34 (44.16) | |
| BRCA1 & BRCA2 | 0 (0.00) | 0 (0.00) | |
| Lynch Family | 0 (0.00) | 3 (3.90) | |
| RAD51C/D | 1 (1.22) | 0 (0.00) | |
| Years of HRT, mean ± std. dev. | 5.13±4.65 | --- | <0.01b |
| Hysterectomy at RRSO, n (%) | 50 (60.98) | 50 (64.94) | 0.61 |
| Years since RRSO, median (range) | 6.00 (4.00, 10.00) | 6.00 (4.00, 9.00) | 0.67c |
| Other Risk Reduction Surgery d, n (%) | 57 (69.51) | 43 (55.84) | 0.07 |
BMI, body mass index; HRT, hormone-replacement therapy; RRSO, risk-reducing salpingo-oophorectomy.
except where noted, P-values calculated by chi-square or Fisher’s exact test, as appropriate.
student t-test.
Kruskal-Wallis Test.
Includes hysterectomy or mastectomy
Table 2 shows data regarding both the primary and secondary outcomes. The primary outcome, incidence of any subsequent malignancy, did not differ between those who did and did not receive HRT after RRSO (6 out of 82 vs. 7 out of 77, P=0.68). Subsequent malignancies in the entire cohort included malignant melanoma, basal and squamous cell skin carcinomas, gastrointestinal carcinoma, lymphoma, and breast carcinomas. 5 patients were diagnosed with subsequent breast cancers, of which only 1 patient had previously also received a risk reduction mastectomy (Table 6). That same patient (#1), who did not receive HRT, unfortunately went on to develop acute myeloid leukemia at a later time and had demised at last follow up date. No Müllerian carcinomas were identified. In addition, the two groups showed no differences in rates of menopausal symptoms, osteoporosis, stroke, myocardial infarction, venous thromboembolism, or death. An adjusted odds ratio was performed controlling for age and having undergone an additional risk reduction procedure for malignancy, osteoporosis and menopausal symptoms, and in all cases, no significant effect was noted.
Table 2. Outcomes by HRT status.
| HRT (n=82) |
No HRT (n=77) |
P- Valuea |
OR (95% CI) |
aOR (95% CI)c |
|
|---|---|---|---|---|---|
| Malignancyb | 6 (7.32) | 7 (9.09) | 0.68 | 0.79 (0.25, 2.46) | 1.15 (0.34, 3.92) |
| Menopausal Symptoms | 27 (32.93) | 27 (35.06) | 0.78 | 0.91 (0.47, 1.75) | 0.89 (0.44, 1.81) |
| Osteoporosis | 3 (3.66) | 5 (6.49) | 0.49 | 0.55 (0.13, 2.37) | 0.60 (0.12, 2.92) |
| Stroke | 0 (0.00) | 0 (0.00) | -- | -- | |
| Myocardial Infarction | 0 (0.00) | 1 (1.30) | 0.48 | -- | |
| Venous Thromboembolism | 1 (1.22) | 0 (0.00) | 1.00 | -- | |
| Death | 0 (0.00) | 3 (3.90) | 0.11 | -- |
All numbers reported as n (%). HRT, hormone-replacement therapy; OR, odds ratio.
P-values calculated by chi-square or Fisher’s exact test, as appropriate.
Malignancies include melanoma (1), basal and squamous cell skin carcinomas (5), gastrointestinal carcinoma (1), and breast carcinoma(6).
Adjusted for age and other risk reduction surgery
Table 6. Characterization of Patients who Developed Breast Cancer.
| Hormonal Exposure (Y/N) |
Type of Hormone Received (E+P, E, VE) |
Prior Hysterectomy for Any Indication (Y/N) |
Prior Risk Reduction Mastectomy (Y/N) |
Vital Status | |
|---|---|---|---|---|---|
| 1 | N | None | N | Y | Dead |
| 2 | N | None | Y | N | Alive |
| 3 | Y | E+P | N | N | Alive |
| 4 | Y | E+P | N | N | Alive |
| 5 | N | None | N | N | Alive |
E+P = Systemic Estrogen + Progesterone, E= Systemic Estrogen, VE=Vaginal Estrogen
We examined the types of hormones used in the 82 patients in the HRT group (Table 3), which included systemic combination therapy, systemic estrogen only therapy and local vaginal therapy. No progesterone only therapy was given to any patients. No sub-group had a higher rate of malignancy than the others (P=1.0). However, the groups significantly differed in their rates of menopausal symptoms, and all patients receiving vaginal estrogen reported menopausal symptoms (100%, P=0.01).
Table 3. Outcomes by HRT type.
| E + P (n=34) |
E Only (n=43) |
P Only (n=0) |
Vaginal Estrogen (n=5) |
No HRT (n=77) |
P- value |
|
|---|---|---|---|---|---|---|
| Malignancy | 3 (8.82) | 3 (6.98) | 0 (0.00) | 0 (0.00) | 7 (9.09) | 1.00 |
| Menopausal Symptoms | 12 (35.29) | 10 (23.26) | 0 (0.00) | 5 (100.00) | 27 (35.06) | 0.01 |
| Osteoporosis | 1 (2.94) | 1 (2.33) | 0 (0.00) | 1 (20.00) | 5 (6.49) | 0.28 |
| Stroke | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | -- |
| Myocardial Infarction | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 1 (1.30) | 1.00 |
| Venous Thromboembolism | 1 (2.94) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0.25 |
| Death | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | 3 (3.90) | 0.49 |
All numbers reported as n (%). E, oral estrogen; HRT, hormone-replacement therapy; P, oral progesterone.
P-values calculated by chi-square or Fisher’s exact test, as appropriate.
Next, we stratified the patients according to the number of years since undergoing RRSO, with the median, 6, as the cut-off (Table 4). Those that were less than 6 years after RRSO did not have a higher incidence of malignancy than those that were greater than or equal to 6 years after RRSO (4 out of 64 vs. 9 out of 95, P=0.56). However, those that were greater than or equal to 6 years after RRSO had a lower incidence of menopausal symptoms (24/95 vs. 30/64, P<0.01, OR 0.38, CI: 0.20-0.75) and a higher incidence of osteoporosis (8.4% vs. 0%, P=0.02). An adjusted odds ratio was also performed for both malignancy and menopausal symptoms, which demonstrated no significant increase in malignancy between groups and confirmed the increased rate of menopausal symptoms in those 6 years or more since undergoing RRSO.
Table 4. Outcomes by years since RRSO (Median: 6 years).
| ≥6 Years Since RRSO (n=95) |
<6 Years Since RRSO (n=64) |
P-value | OR (95% CI) | aOR (95% CI)a |
|
|---|---|---|---|---|---|
| Malignancy | 9 (9.47) | 4 (6.25) | 0.56 | 1.57(0.46, 5.33) | 2.12 (0.59, 7.67) |
| Menopausal Symptoms | 24 (25.26) | 30 (46.88) | <0.01 | 0.38 (0.20, 0.75) | 0.39 (0.19, 0.76) |
| Osteoporosis | 8 (8.42) | 0 (0.00) | 0.02 | -- | |
| Stroke | 0 (0.00) | 0 (0.00) | -- | -- | |
| Myocardial Infarction | 1 (1.05) | 0 (0.00) | 1.00 | -- | |
| Venous Thromboembolism | 1 (1.05) | 0 (0.00) | 1.00 | -- | |
| Death | 3 (3.16) | 0 (0.00) | 0.27 | -- |
All numbers reported as n (%). OR, odds ratio; RRSO, risk-reducing salpingo-oophorectomy
P-values calculated by chi-square or Fisher’s exact test, as appropriate
Adjusted for age and other risk reduction surgery
Finally, we stratified the patients according to whether or not they had undergone additional risk-reductive procedures including mastectomy or hysterectomy (Table 5). Risk of malignancy was greater in those who had not undergone an additional risk-reductive procedure, but this difference was not statistically significant (8 out of 59 vs. 5 out of 100, P=0.06). These groups did not differ in the rates of any secondary outcomes. Adjusted odds ratios were performed for incidence of malignancy, menopausal symptoms and osteoporosis, as well, without significant findings.
Table 5. Outcomes by other Risk Reductive Procedure status.
| Other RR (n=100) |
No Other RR (n=59) |
P-value | OR (95% CI) |
aOR (95% CI)a |
|
|---|---|---|---|---|---|
| Malignancy | 5 (5.00) | 8 (13.56) | 0.06 | 0.34 (0.10, 1.08) | 0.36 (0.11, 1.17) |
| Menopausal Symptoms | 32 (32.00) | 22 (37.29) | 0.50 | 0.79 (0.40, 1.55) | 0.78 (0.40, 1.54) |
| Osteoporosis | 6 (6.00) | 2 (3.39) | 0.71 | 1.82 (0.36, 9.32) | 2.00 (0.38, 10.50) |
| Stroke | 0 (0.00) | 0 (0.00) | -- | -- | |
| Myocardial Infarction | 0 (0.00) | 1 (1.69) | 0.37 | -- | |
| Venous Thromboembolism | 1 (1.00) | 0 (0.00) | 1.00 | -- | |
| Death | 3 (3.00) | 0 (0.00) | 0.(30) | -- |
All numbers reported as n (%). OR, odds ratio; RRO, risk-reducing operation
P-values calculated by chi-square or Fisher’s exact test, as appropriate
Adjusted for age
Discussion
Consistent with previous studies7,8,10,12, the results from this multi-institutional retrospective study suggest that HRT use does not increase the risk of malignancy in women with high-risk Müllerian mutations who undergo RRSO. Our data suggest that HRT is safe when used in a patient population such as this. Additionally, we found no relationship between the type of HRT and incidence of subsequent malignancy.
When considering whether or not to offer HRT to mutation carriers after RRSO, providers consider the risks of several cancers, most frequently, of the breast. Because breast cancers with BRCA2 mutations are more likely to express hormone receptors, and breast cancers with BRCA1 mutations are less likely to express hormone receptors13, BRCA1 and BRCA2 mutation status may affect providers' decisions about offering HRT. Although we found that patients with BRCA1 mutations were more likely to receive HRT than were patients with BRCA2 mutations, this difference was not statistically significant. In addition, the study was not designed to examine why providers did or did not prescribe HRT.
Another malignancy that providers consider as a risk in mutation carriers is endometrial cancer. The reported incidences of endometrial cancer in BRCA mutation carriers14-16 are variable. However, data suggesting that BRCA1 mutation carriers have an increased risk for serous histology uterine cancers may affect counseling regarding concomitant hysterectomy at time of RRSO17. The clinical scenario favoring concomitant hysterectomy is clearest with Lynch syndrome mutations, as a patient with certain Lynch syndrome variants has a 40% to 60% lifetime risk of developing endometrial cancer18,19. The risk of endometrial cancer in carriers of other high-risk Müllerian mutations is less clear. Therefore, a provider's decision about offering HRT may depend on whether or not other risk-reductive procedures such as mastectomy and/or hysterectomy have been done, especially since in women with a uterus who receive HRT, as it is usually given in a combination formulation to avoid constant estrogen-driven endometrium stimulation. Personalized patient counseling should drive the decision regarding concomitant hysterectomy at the time of RRSO, keeping in mind the subsequent plans for HRT regimens and dosing. In our cohort, women receiving versus not receiving HRT had similar rates of hysterectomy at the time of RRSO. Those who received HRT were more likely than those who did not receive HRT to have undergone other risk-reductive surgeries at some time, but this difference was not significant.
Surgical intervention is indicated to reduce the risk of Müllerian carcinoma in high-risk variant carriers, but we need firm data regarding timing and the possibility of delayed interval or “staged” procedures to improve the quality of management and counseling available to these patients. The ongoing prospective observational Women Choosing Surgical Prevention trial (WISP; NCT02760849) will include patients with mutations in BRCA1, BRCA2, BRIP1, PALB2, RAD51C, RAD51D, BARD1, MSH2, MSH6, MLH1, PMS2, and EPCAM. This study’s primary outcomes include sexual function, menopausal symptoms, quality of life, and mental health outcomes in a group of women who choose interval salpingectomy followed by delayed oophorectomy (ISDO) compared to a group of women who choose standard-of-care RRSO. However, secondary outcomes of cancer risk and risk-reduction effectiveness are not expected to be mature until 204120. A recently published pilot study evaluating ISDO versus immediate RRSO versus screening only showed patients in the ISDO arm experienced an overall safe and satisfactory procedure that improved cancer related anxiety similar to the RRSO arm and a trend towards preservation of sexual function21. In addition, the European TUBA trial is examining a similar interval procedure in BRCA1 and BRCA2 mutation carriers only, but this study is not expected to have mature cancer risk and risk-reduction data until 203522. While interim analyses have indicated no increased risk of cancer in the setting of ISDO, ISDO remains experimental and should only be offered in a clinical trial setting without careful discussion with patients.
The strengths of this study include the multi-center nature, inclusion of multiple mutation types, and focus on a rare but significant outcome. The largest weakness of this study was the smaller than anticipated sample size, which resulted in an overall low power. In addition, given the retrospective nature of this study, we could not ensure that all medications were used as prescribed, and the study was not designed to examine the many variations in HRT dosage or compliance in administration. This study was also subject to the usual limitations of retrospective studies including data abstraction errors and failure to identify biases. Lastly, the majority of patients in this study carried high risk BRCA1 or BRCA2 variants, limiting our ability to assess risks for patients with other types of high risk mutations. While this limits our conclusions in this cohort specifically, as minimal data is available in non-BRCA patients, we opted to include them in our final analysis in hopes of driving further investigative interest in these groups. In addition, the overall age of this cohort was young with a short follow up time, which limits our ability to comment on life-long risk.
This study adds to the growing data available regarding the safety of HRT after RRSO for high-risk variant carriers, but larger datasets are needed, especially for patients with non BRCA variants. Next steps might include prospective studies that allow patients to select whether or not to receive HRT, or double-blind randomized controlled trials to assess the impact of HRT on risk of malignancy.
Highlights.
Multi-institutional study of high risk variant carriers after risk reducing procedure
Receiving hormonal therapy after a risk reductive procedure was not associated with increased risk of malignancy
There were no subsequent gynecologic carcinomas identified in either group
Being younger and undergoing other risk reductive procedures increased use of hormonal therapy
Acknowledgements
The authors thank Deborah Frank, PhD, for the scientific editing of this manuscript.
Grant support: REDCap: Supported by Clinical and Translational Science Award (CTSA) Grant [UL1 TR000448] and Siteman Comprehensive Cancer Center and NCI Cancer Center Support Grant P30 CA091842.
Footnotes
Conflict of Interest:
The authors of this manuscript certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.
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