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Gynecologic conditions in participants in the NSABP breast cancer prevention study of tamoxifen and raloxifene (STAR)

  • Carolyn D. Runowicz
    Correspondence
    Reprints: Carolyn D. Runowicz, MD, Florida International University, Herbert Wertheim College of Medicine, 11200 S.W. 8th St., AHC 6963, Miami, FL 33199
    Affiliations
    National Surgical Adjuvant Breast and Bowel Project (NSABP), National Cancer Institute, Pittsburgh, PA

    Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut Health Center, University of Connecticut School of Medicine, Farmington, CT
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  • Joseph P. Costantino
    Affiliations
    National Surgical Adjuvant Breast and Bowel Project (NSABP), National Cancer Institute, Pittsburgh, PA

    NSABP Biostatistical Center, and the Department of Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA
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  • D. Lawrence Wickerham
    Affiliations
    National Surgical Adjuvant Breast and Bowel Project (NSABP), National Cancer Institute, Pittsburgh, PA

    Department of Human Oncology, Allegheny General Hospital, Pittsburgh, PA
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  • Reena S. Cecchini
    Affiliations
    National Surgical Adjuvant Breast and Bowel Project (NSABP), National Cancer Institute, Pittsburgh, PA

    NSABP Biostatistical Center, and the Department of Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA
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  • Walter M. Cronin
    Affiliations
    National Surgical Adjuvant Breast and Bowel Project (NSABP), National Cancer Institute, Pittsburgh, PA

    NSABP Biostatistical Center, and the Department of Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA
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  • Leslie G. Ford
    Affiliations
    National Surgical Adjuvant Breast and Bowel Project (NSABP), National Cancer Institute, Pittsburgh, PA

    Division of Cancer Prevention, National Cancer Institute/National Institutes of Health, Bethesda, MD
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  • Victor G. Vogel
    Affiliations
    National Surgical Adjuvant Breast and Bowel Project (NSABP), National Cancer Institute, Pittsburgh, PA

    Geisinger Health System, Danville, PA
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  • Norman Wolmark
    Affiliations
    National Surgical Adjuvant Breast and Bowel Project (NSABP), National Cancer Institute, Pittsburgh, PA

    Department of Human Oncology, Allegheny General Hospital, Pittsburgh, PA
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      Objective

      This study reports the gynecologic conditions in postmenopausal women (intact uterus on enrollment) in the National Surgical Adjuvant Breast and Bowel Project (NSABP) study of tamoxifen and raloxifene (STAR)/P-2 trial.

      Study Design

      This study, with a median follow-up period of 81 months, evaluated the incidence rates/risks of gynecologic conditions among women who were treated with tamoxifen and raloxifene.

      Results

      Compared with women who received tamoxifen therapy, women who received raloxifene therapy had a lower incidence of uterine cancer (relative risk, 0.55)/endometrial hyperplasia (relative risk, 0.19), leiomyomas (relative risk, 0.55), ovarian cysts (relative risk, 0.60), and endometrial polyps (relative risk, 0.30) and had fewer procedures performed. Women receiving tamoxifen therapy had more hot flashes (P < .0001), vaginal discharge (P < .0001), and vaginal bleeding (P < .0001).

      Conclusion

      Our results suggest that tamoxifen has more of an estrogenic effect on the gynecologic reproductive organs. These effects should be considered in counseling women on options for breast cancer prevention.

      Key words

      Breast cancer represents a major health hazard for women in the United States. Findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial (P-1) resulted in tamoxifen's approval by the US Food and Drug Administration for the prevention of breast cancer in high-risk women.
      • Fisher B.
      • Costantino J.P.
      • Wickerham D.L.
      • et al.
      Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study.
      Studies that evaluated raloxifene in postmenopausal women with osteoporosis demonstrated a reduction in invasive breast cancer in postmenopausal women. These studies concluded that the risk of estrogen receptor–positive invasive breast cancer was decreased by 72% and 66% with 4 and 8 years, respectively, of raloxifene treatment.
      • Cummings S.R.
      • Eckert S.
      • Krueger K.A.
      • et al.
      The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial: Multiple Outcomes of Raloxifene Evaluation.
      • Martino S.
      • Cauley J.A.
      • Barrett-Connor E.
      • et al.
      Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene.
      The NSABP P-2 trial, known as the Study of Tamoxifen and Raloxifene (STAR), was launched to directly compare tamoxifen with raloxifene. The STAR/P-2 trial was a prospective, double-blind, randomized clinical trial of 19,747 healthy postmenopausal women who were at an increased risk of breast cancer. The STAR/P-2 trial resulted in raloxifene's approval by the Food and Drug Administration for the prevention of breast cancer in high-risk women.
      • Vogel V.G.
      • Costantino J.P.
      • Wickerham D.L.
      • et al.
      Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial.
      • Vogel V.G.
      • Costantino J.P.
      • Wickerham D.L.
      • et al.
      Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: preventing breast cancer.
      For Editors' Commentary, see Table of Contents
      See related editorial, page 511
      This assessment was undertaken to report in detail on the gynecologic conditions that occurred among postmenopausal women with an intact uterus on enrollment in the STAR/P-2 trial.

      Materials and Methods

      This trial was approved by local human investigations committees or institutional review boards in accordance with assurances filed with and approved by the Department of Health and Human Services. Written informed consent was required for participation in this trial.
      To be eligible, women had to be postmenopausal, be at least 35 years old, and have a 5-year predicted risk for breast cancer of at least 1.66%. Breast cancer risk was determined with the Gail model, as modified and applied in the Breast Cancer Prevention Trial (P-1).
      • Costantino J.P.
      • Gail M.H.
      • Pee D.
      • et al.
      Validation studies for models to project the risk of invasive and total breast cancer incidence.
      The details of the STAR/P-2 methodology are described in the initial report of the study.
      • Vogel V.G.
      • Costantino J.P.
      • Wickerham D.L.
      • et al.
      Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial.
      The participants were assigned randomly to receive either 20 mg/d of tamoxifen plus placebo (9736 women) or 60 mg/d of raloxifene plus placebo (9754 women) for 5 years. Because the formulations of tamoxifen and raloxifene tablets were dissimilar, it was necessary to use placebo tablets to maintain the double blinding of treatment assignment. The enrollment period began on June 1, 1999, and ended on November 4, 2004. This report is based on a cutoff date of March 31, 2009.
      On enrollment in the NSABP STAR/P-2 trial, the study population consisted of 9456 postmenopausal women with an intact uterus. As in the Breast Cancer Prevention Trial trial,
      • Fisher B.
      • Costantino J.P.
      • Wickerham D.L.
      • et al.
      Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study.
      • Chalas E.
      • Costantino J.P.
      • Wickerham D.L.
      • et al.
      Benign gynecologic conditions among participants in the Breast Cancer Prevention Trial.
      women were monitored for symptoms of hot flashes, vaginal discharge, vaginal dryness, and abnormal vaginal bleeding; the occurrence of numerous gynecologic conditions that were diagnosed during the study period were reported and included endometrial adenocarcinomas, endometrial hyperplasia, leiomyomas, polyps, endometritis, endometriosis, and ovarian cysts. Surgical interventions (such as dilation and curettage, hysteroscopy, laparoscopy, oophorectomy, and hysterectomy) similarly were recorded in the study database.
      The χ2 test was used to compare the raloxifene and tamoxifen groups with regard to age, parity, history of oral contraceptive use, history of estrogen therapy, number of relatives with breast cancer, history of diabetes mellitus and hypertension, smoking status, and body mass index. The χ2 test also was used to compare treatment groups by distribution of severity of self-reported symptoms. The analyses of the incidence of gynecologic conditions and surgical procedures mentioned earlier were performed to evaluate the differences between treatment groups. These analyses were based on the determination of risk ratios (RRs) of the incidence rates by treatment group (raloxifene compared with tamoxifen) and the 95% confidence intervals (CIs) on the RR. The incidence rates were calculated as the number of events divided by the person-years at risk. The 95% CIs were determined by the exact method, assuming that the events followed a Poisson distribution, on the condition of the total number of events and person-years at risk.
      Results were considered to be statistically significant if the probability value was < .05 or when the 95% CI for the RR did not include 1.00. The date file cutoff that was used for this analysis of March 31, 2009, was chosen to be consistent with that used for the update report of the main findings.
      • Vogel V.G.
      • Costantino J.P.
      • Wickerham D.L.
      • et al.
      Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: preventing breast cancer.

      Results

      A total 4739 women who received tamoxifen and 4717 women who received raloxifene had an intact uterus on entry (Figure). The characteristics of the participants who were included in the current analysis are shown in Table 1. The groups were similar in baseline characteristics, which included age, parity, body mass index, history of oral contraceptive or estrogen use, family history of breast cancer, diabetes mellitus, hypertension, and smoking status. At a median follow-up period of 81 months, significant differences existed in self-reported bothersome hot flashes (P < .0001), vaginal discharge (P < .0001), and vaginal bleeding (P < .0001) in patients who received tamoxifen, compared with raloxifene (Table 2). Vaginal dryness was more common in patients who received raloxifene (P < .0001).
      Figure thumbnail gr1
      FIGURECONSORT diagram: National Surgical Adjuvant Breast and Bowel Project P-2
      The asterisk indicates that 2 women with bilateral mastectomy before entry and 1 woman with a diagnosis of breast cancer before entry were discovered after random assignment.
      Runowicz. Gynecologic conditions in STAR/P-2 trial participants. Am J Obstet Gynecol 2011.
      TABLE 1Baseline characteristics for women with an intact uterus
      CharacteristicTamoxifen (n = 4739)Raloxifene (n = 4717)P value
      N%n%
      Age, y
      Mean age for the tamoxifen group: 58.8 ± 6.8 years; mean age for the raloxifene group: 58.8 ± 6.8 years;
       ≤492375.02334.9.99
       50-59259254.7258454.8
       60-69151632.0151532.1
       ≥703948.33858.2
      Parity, n
       ≤1125226.4121125.7.41
       ≥2348773.6350674.3
      History of oral contraceptive use
       No150131.7154032.6.31
       Yes323868.3317767.4
      History of estrogen therapy
       No176337.2182338.6.15
       Yes297662.8289461.4
      Relatives with breast cancer, n
       0148931.4144630.7.22
       1239950.6240451.0
       271015.075215.9
       ≥31413.01152.4
      History of diabetes mellitus
       Yes2415.12274.8.54
       No449894.9449095.2
      History of hypertension
       Yes141729.9138329.3.54
       No332270.1333470.7
      Smoking status
       Never241450.9244851.9.29
       Former186039.2178037.7
       Current4439.34589.7
       Unknown220.5310.7
      Body mass index, kg/m2
      Unavailable for 1 person in the tamoxifen group and 1 person in the raloxifene group; mean age for the tamoxifen group: 28.1 ± 6.0 years; mean age for the raloxifene group: 28.2 ± 6.1 years.
       <25.0161934.2157633.4.74
       25.0-29.9163834.6164634.9
       ≥30148131.3149431.7
      Runowicz. Gynecologic conditions in STAR/P-2 trial participants. Am J Obstet Gynecol 2011.
      a Mean age for the tamoxifen group: 58.8 ± 6.8 years; mean age for the raloxifene group: 58.8 ± 6.8 years;
      b Unavailable for 1 person in the tamoxifen group and 1 person in the raloxifene group; mean age for the tamoxifen group: 28.1 ± 6.0 years; mean age for the raloxifene group: 28.2 ± 6.1 years.
      TABLE 2Highest level of self-reported symptoms disclosed by participants with an intact uterus
      Symptom/severity levelTamoxifen (n = 4693)
      Forty-six women in the tamoxifen group and 48 women in the raloxifene group opted not to complete follow-up quality-of-life questionnaires.
      Raloxifene (n = 4669)
      Forty-six women in the tamoxifen group and 48 women in the raloxifene group opted not to complete follow-up quality-of-life questionnaires.
      P value
      N%n%
      Hot flashes bothersome
       No67014.377416.6< .0001
       Slightly69214.791219.5
       Moderately102021.7103122.1
       Quite a bit133928.5121526.0
       Extremely97220.773715.8
      Vaginal discharge bothersome
       No176537.6267357.2< .0001
       Slightly127627.2119425.6
       Moderately83817.948410.4
       Quite a bit55111.72345.0
       Extremely2635.6841.8
      Vaginal dryness bothersome
       No143230.5131528.2< .0001
       Slightly92419.789319.1
       Moderately91519.582217.6
       Quite a bit80217.192419.8
       Extremely62013.271515.3
      Vaginal bleeding
       No354875.6404286.6< .0001
       Slightly66614.24439.5
       Moderately2335.01002.1
       Quite a bit1533.3531.1
       Extremely932.0310.7
      Runowicz. Gynecologic conditions in STAR/P-2 trial participants. Am J Obstet Gynecol 2011.
      a Forty-six women in the tamoxifen group and 48 women in the raloxifene group opted not to complete follow-up quality-of-life questionnaires.
      The average annual rates of invasive uterine cancer, hyperplasia (with and without atypia), and hysterectomy during the follow-up period are shown in Table 3. The incidence of invasive cancer was 45% lower in the raloxifene group, compared with the tamoxifen group (RR, 0.55; 95% CI, 0.36–0.83). The risk of endometrial hyperplasia was almost 80% higher among women in the tamoxifen group, compared with women in the raloxifene group (RR, 0.19; 95% CI, 0.12–0.29). Of the women with hyperplasia, 82.5% had hyperplasia without atypia. The rate of hysterectomy for conditions other than invasive cancer in the tamoxifen group was more than twice that in the raloxifene group (RR, 0.45; 95% CI, 0.37–0.54), which suggests that the rates of invasive cancer and hyperplasia in the tamoxifen group would have been higher than actually observed if there were no differential in the rates of hysterectomy.
      TABLE 3Average annual rates of uterine disease
      Type of uterine diseaseEvents, nRate per 1000 womenRisk ratio
      Risk ratio for women in the raloxifene group compared with women in the tamoxifen group;
      95% CI
      TamoxifenRaloxifeneTamoxifenRaloxifeneDifference
      Rate in the tamoxifen group minus rate in the raloxifene group;
      Invasive cancer65372.251.231.020.550.36–0.83
      Hyperplasia126254.400.843.560.190.12–0.29
       Without atypia104213.630.702.930.190.11–0.31
       With atypia2240.770.130.640.170.04–0.51
      Hysterectomy during follow-up period
      For conditions other than invasive cancer.
      34916212.085.416.670.450.37–0.54
      CI, confidence interval.
      Runowicz. Gynecologic conditions in STAR/P-2 trial participants. Am J Obstet Gynecol 2011.
      a Rate in the tamoxifen group minus rate in the raloxifene group;
      b Risk ratio for women in the raloxifene group compared with women in the tamoxifen group;
      c For conditions other than invasive cancer.
      Women were also evaluated for other gynecologic conditions and surgical procedures (Table 4). Women who received raloxifene had a decreased incidence of leiomyoma (RR, 0.55; 95% CI, 0.49–0.62), ovarian cysts (RR, 0.60; CI, 0.49–0.74), polyps (RR, 0.30; 95% CI, 0.250.35), and endometriosis (RR, 0.32; 95% CI, 0.24–0.43). They were also less likely to undergo dilation and curettage (RR, 0.30; 95% CI, 0.26–0.35), hysteroscopy (RR, 0.29; 95% CI, 0.24–0.35), and bilateral salpingo-oophorectomy or oophorectomy (RR, 0.50; 95% CI, 0.42–0.60).
      TABLE 4Average annual rates of gynecological conditions and procedures by treatment group
      VariableEvents, nRate per 1000 womenRisk ratio
      Risk ratio for women in the raloxifene group compared with women in the tamoxifen group.
      95% CI
      TamoxifenRaloxifeneTamoxifenRaloxifeneDifference
      Rate in the tamoxifen group minus rate in the raloxifene group;
      Condition
       Leiomyomas75744328.4015.5612.840.550.49–0.62
       Ovarian cysts2361478.325.013.310.600.49–0.74
       Polyps57518521.066.2814.780.300.25–0.35
       Endometriosis190646.602.144.460.320.24–0.43
      Procedure
       Dilation and curettage67321824.307.3216.980.300.26–0.35
       Bilateral oophorectomy37119212.806.466.340.500.42–0.60
       Laparoscopy1440.460.130.330.280.07–0.90
       Hysteroscopy49315117.325.0312.290.290.24–0.35
      CI, confidence interval.
      Runowicz. Gynecologic conditions in STAR/P-2 trial participants. Am J Obstet Gynecol 2011.
      a Rate in the tamoxifen group minus rate in the raloxifene group;
      b Risk ratio for women in the raloxifene group compared with women in the tamoxifen group.

      Comment

      Although gynecologic conditions were not considered the primary endpoint of the NSABP STAR/P-2 study, interesting data have emerged from careful follow-up evaluation of these women during the study period. Although there are some limitations to the generalization of the findings (almost all of the STAR/P-2 participants [93.5%] were white, and the average Gail score [4.03%] was very high), the findings provide very important unbiased comparisons of the relative efficacy and toxicity of tamoxifen and raloxifene.
      Our study findings support that tamoxifen has more of an estrogenic effect on the gynecologic reproductive tract organs than does raloxifene. These findings include an increased risk of (1) invasive endometrial cancer, (2) endometrial hyperplasia both with and without atypia, and (3) leiomyomas, polyps, and endometriosis. Our findings also support that tamoxifen has more effect on the ovaries with an increased incidence of ovarian cysts, which may be reflective of the chemical structure of tamoxifen and its similarity to clomiphene.
      • Williamson J.G.
      • Ellis J.D.
      The induction of ovulation by tamoxifen.
      In addition to increasing the risk of gynecologic conditions, the differential effects of tamoxifen and raloxifene also resulted in more procedures performed in the tamoxifen group, which included hysterectomy, salpingo-oophorectomy, oophorectomy, hysteroscopy, and laparoscopy. With the average annual rate of hysterectomy for reasons other than uterine cancer in the tamoxifen group (12.08/1000 women) being more than double than that found in the raloxifene group (5.41/1000 women), the increased risk of invasive uterine cancer that is associated with tamoxifen is likely higher than was actually observed.
      Raloxifene and tamoxifen are good preventive choices for higher risk postmenopausal women who are at risk for breast cancer, and there are differing gynecologic effects with each, respectively. These differing gynecologic effects should be considered when women with an intact uterus are being counseled on options for breast cancer prevention.

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