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Tamoxifen treatment for breast cancer was associated with an increased risk of endometrial cancer
GY N EC O L OG I C AL O N C O LO G Y
Tamoxifen treatment for breast cancer was associated with an increased risk of endometrial cancer Mignotte H, Lasset C, Bonadona V et al. Iatrogenic risks of endometrial carcinoma after treatment for breast cancer in a large French case-control study. Int J Cancer 1998; 76: 325d330
OBJECTIVE To determine the risk of endometrial cancer in women who received tamoxifen and other treatments for breast cancer. DESIGN Case-control study. SETTING 14 cancer centres in France. SUBJECTS Cases were 135 women who were diagnosed with breast cancer between 1976 and 1994 and with invasive endometrial cancer at least 6 months later. Controls were 487 women with breast cancer matched to cases for date of birth, date of breast cancer diagnosis, hospital and survival with an intact uterus. All women had a follow-up hospital visit at least once per year. Median age at breast cancer diagnosis was 58 (range 33–79) years. INTERVENTION Information on the breast cancer and its treatment, endometrial cancer and survival was obtained from medical records. The diagnosis of endometrial cancer was confirmed by a pathologist. MAIN OUTCOME MEASURES Relative risk (RR) for endometrial cancer in women who received tamoxifen, compared to women who did not. Odds ratio (OR) for endometrial cancer in women who received treatment for breast cancer, compared to women who did not, adjusted for other treatments and risk factors.
Commentary The risk of endometrial cancer associated with tamoxifen therapy for breast cancer was first reported in the mid-1980s. The present paper is one of several subsequent reports confirming this risk, and is notable because it includes a larger number of endometrial cancer cases, provides an assessment of the dosedresponse effect and includes some assessment of the possible factors that may confound the association between tamoxifen and endometrial cancer. The results reported provide useful information regarding the magnitude and duration of endometrial cancer risk associated with tamoxifen therapy. The individuals included in this case-control study were patients with breast cancer, who had had at least one visit per year during the course of follow-up. Thus, the findings may not be generalizable to a larger population, although this restriction should not cause a bias in the estimates of the effect of tamoxifen. Two important confounding factors in assessing the risk of endometrial cancer are history of estrogen replacement therapy (ERT) and body mass index. The authors of the present study did not consider these factors. Thus, their estimate of the relative risk associated with tamoxifen is probably an overestimate for a woman who has never used ERT, particularly if she is not overweight. Bernstein et al1 provided estimates of relative risk adjusted for estrogen use and body mass index, and showed that the tamoxifen dosedresponse effects were substantially more pronounced in women with previous ERT exposure and higher body mass index than in women without these factors. Although the findings from this restrospective study suggest that women with endometrial cancer after treatment with tamoxifen have a poorer prognosis, several prospective studies indicate that this inference may not be correct. For example, the recently completed
^ 1999 Harcourt Publishers Ltd
MAIN RESULTS The median time between diagnosis of breast cancer and diagnosis of endometrial cancer was 55 (range 7–221) months. The cases were more likely to have had stage III or IV breast cancer and to have had involvement of '3 axillary nodes, 67% of cases and 39% of controls received tamoxifen treatment ( p(0.001). 24% of cases and 12% of controls received pelvic radiotherapy to suppress ovarian function ( p(0.001). The matched RR for endometrial cancer was 4.9 (95% CI 3.4–7.1) in women who used tamoxifen and was similar for current and past use. The baseline OR for women who used tamoxifen at a dose of 20 mg daily for 436 months was 4.5 (CI 1.8–11.0); this risk was not increased by higher doses up to 40 mg, but was increased with longer use (OR compared to baseline 3.9, CI 1.2–12.7, for 37–48 months of use and 7.0, CI 3.0–16.7, for '48 months of use). Women who had used tamoxifen were more likely to have tumours of FIGO stage 52 (28 vs 7%, p"0.006). The OR for endometrial cancer with pelvic radiotherapy was 3.2 (CI 1.3–7.4), with chemotherapy was 1.6 (CI 1.0–2.6) and with loco-regional radiotherapy was 1.5 (CI 0.9–2.4). CONCLUSION In women with breast cancer, tamoxifen use was associated with a 5-fold increased risk of endometrial cancer, which was strongly related to duration of treatment. Pelvic radiotherapy also increased the risk of endometrial cancer.
Breast Cancer Prevention Trial (BCPT)2 confirmed that the risk of endometrial cancer was significantly elevated in women in the tamoxifen group, but found no difference between groups in terms of the prognosis of the cases. In fact, all cases of endometrial cancer in the tamoxifen group and all but one case in the placebo group were diagnosed as FIGO stage I. In this trial, women in both treatment groups were screened by annual gynecological examinations and any abnormal bleeding or other symptoms were evaluated thoroughly, which was probably not the case for most women in the present study. The evidence from Bernstein et al, the BCPT, the present study and other reports is clear. Tamoxifen treatment results in an increased risk of endometrial cancer. Women who are being treated with tamoxifen should receive annual gynecological examinations and should be advised to report any occurrence of abnormal bleeding. Women treated with tamoxifen who are taking ERT are at a particularly high risk for endometrial cancer; therefore, such therapy should not be given concomitantly with tamoxifen. Joseph P. Costantino, PhD and Samuel Wieand, PhD University of Pittsburgh, Pittsburgh, PA, USA
Literature cited 1. Bernstein L, Deapen D, Cerhan JR et al. Tamoxifen therapy for breast cancer and endometrial cancer risk. J Natl Cancer Inst 1999; 91: 1654d1662 2. Fisher B, Costantino JP, Wickerham DL et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998; 90: 1371d1388
Evidence-based Obstetrics and Gynecology (1999) 1, 117
117117
Tamoxifen treatment for breast cancer was associated with an increased risk of endometrial cancer Mignotte H, Lasset C, Bonadona V et al. Iatrogenic risks of endometrial carcinoma after treatment for breast cancer in a large French case-control study. Int J Cancer 1998; 76: 325d330
OBJECTIVE To determine the risk of endometrial cancer in women who received tamoxifen and other treatments for breast cancer. DESIGN Case-control study. SETTING 14 cancer centres in France. SUBJECTS Cases were 135 women who were diagnosed with breast cancer between 1976 and 1994 and with invasive endometrial cancer at least 6 months later. Controls were 487 women with breast cancer matched to cases for date of birth, date of breast cancer diagnosis, hospital and survival with an intact uterus. All women had a follow-up hospital visit at least once per year. Median age at breast cancer diagnosis was 58 (range 33–79) years. INTERVENTION Information on the breast cancer and its treatment, endometrial cancer and survival was obtained from medical records. The diagnosis of endometrial cancer was confirmed by a pathologist. MAIN OUTCOME MEASURES Relative risk (RR) for endometrial cancer in women who received tamoxifen, compared to women who did not. Odds ratio (OR) for endometrial cancer in women who received treatment for breast cancer, compared to women who did not, adjusted for other treatments and risk factors.
Commentary The risk of endometrial cancer associated with tamoxifen therapy for breast cancer was first reported in the mid-1980s. The present paper is one of several subsequent reports confirming this risk, and is notable because it includes a larger number of endometrial cancer cases, provides an assessment of the dosedresponse effect and includes some assessment of the possible factors that may confound the association between tamoxifen and endometrial cancer. The results reported provide useful information regarding the magnitude and duration of endometrial cancer risk associated with tamoxifen therapy. The individuals included in this case-control study were patients with breast cancer, who had had at least one visit per year during the course of follow-up. Thus, the findings may not be generalizable to a larger population, although this restriction should not cause a bias in the estimates of the effect of tamoxifen. Two important confounding factors in assessing the risk of endometrial cancer are history of estrogen replacement therapy (ERT) and body mass index. The authors of the present study did not consider these factors. Thus, their estimate of the relative risk associated with tamoxifen is probably an overestimate for a woman who has never used ERT, particularly if she is not overweight. Bernstein et al1 provided estimates of relative risk adjusted for estrogen use and body mass index, and showed that the tamoxifen dosedresponse effects were substantially more pronounced in women with previous ERT exposure and higher body mass index than in women without these factors. Although the findings from this restrospective study suggest that women with endometrial cancer after treatment with tamoxifen have a poorer prognosis, several prospective studies indicate that this inference may not be correct. For example, the recently completed
^ 1999 Harcourt Publishers Ltd
MAIN RESULTS The median time between diagnosis of breast cancer and diagnosis of endometrial cancer was 55 (range 7–221) months. The cases were more likely to have had stage III or IV breast cancer and to have had involvement of '3 axillary nodes, 67% of cases and 39% of controls received tamoxifen treatment ( p(0.001). 24% of cases and 12% of controls received pelvic radiotherapy to suppress ovarian function ( p(0.001). The matched RR for endometrial cancer was 4.9 (95% CI 3.4–7.1) in women who used tamoxifen and was similar for current and past use. The baseline OR for women who used tamoxifen at a dose of 20 mg daily for 436 months was 4.5 (CI 1.8–11.0); this risk was not increased by higher doses up to 40 mg, but was increased with longer use (OR compared to baseline 3.9, CI 1.2–12.7, for 37–48 months of use and 7.0, CI 3.0–16.7, for '48 months of use). Women who had used tamoxifen were more likely to have tumours of FIGO stage 52 (28 vs 7%, p"0.006). The OR for endometrial cancer with pelvic radiotherapy was 3.2 (CI 1.3–7.4), with chemotherapy was 1.6 (CI 1.0–2.6) and with loco-regional radiotherapy was 1.5 (CI 0.9–2.4). CONCLUSION In women with breast cancer, tamoxifen use was associated with a 5-fold increased risk of endometrial cancer, which was strongly related to duration of treatment. Pelvic radiotherapy also increased the risk of endometrial cancer.
Breast Cancer Prevention Trial (BCPT)2 confirmed that the risk of endometrial cancer was significantly elevated in women in the tamoxifen group, but found no difference between groups in terms of the prognosis of the cases. In fact, all cases of endometrial cancer in the tamoxifen group and all but one case in the placebo group were diagnosed as FIGO stage I. In this trial, women in both treatment groups were screened by annual gynecological examinations and any abnormal bleeding or other symptoms were evaluated thoroughly, which was probably not the case for most women in the present study. The evidence from Bernstein et al, the BCPT, the present study and other reports is clear. Tamoxifen treatment results in an increased risk of endometrial cancer. Women who are being treated with tamoxifen should receive annual gynecological examinations and should be advised to report any occurrence of abnormal bleeding. Women treated with tamoxifen who are taking ERT are at a particularly high risk for endometrial cancer; therefore, such therapy should not be given concomitantly with tamoxifen. Joseph P. Costantino, PhD and Samuel Wieand, PhD University of Pittsburgh, Pittsburgh, PA, USA
Literature cited 1. Bernstein L, Deapen D, Cerhan JR et al. Tamoxifen therapy for breast cancer and endometrial cancer risk. J Natl Cancer Inst 1999; 91: 1654d1662 2. Fisher B, Costantino JP, Wickerham DL et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998; 90: 1371d1388
Evidence-based Obstetrics and Gynecology (1999) 1, 117
117117