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I am writing in response to the article “Gynaecological effects of tamoxifen” by Sezgin M Ismail.1 The article reviews the current knowledge on gynaecological side effects by summarising studies measuring cervical, endometrial, uterine, and ovarian effects in women taking tamoxifen.
Ismail cites a small study of 16 women and implies a relation between ovarian cancer and tamoxifen use. In fact, the literature suggests that the incidence of ovarian cancer in women on tamoxifen is not increased and might even be lower than in women not on tamoxifen.2–6 In the national surgical adjuvant breast and bowel project P-1 (NSABP P-1) trial, there were 11 ovarian cancers in the placebo arm and 10 ovarian cancers in the tamoxifen arm.7
The author states that there is still uncertainty with regard to the aggressiveness of endometrial cancers that develop in women on tamoxifen. Reviewing three small studies (n = 15, n = 6 and n = 15), Ismail notes that a significant proportion of women taking tamoxifen were diagnosed with endometrial cancers that carried a poor prognosis. In fact, the author goes on to note that a larger case control study that noted an “excess of well differentiated tumors in tamoxifen users”, and to mention that two other sizable studies support this claim. The bulk of the evidence points to uterine cancers seen in women on tamoxifen being early stage, well differentiated, and highly curable.8
Furthermore, the author comments that the “tamoxifen treated endometrium is notoriously hard to biopsy” and suggests that tamoxifen exposure complicates the biopsy procedure.
Although tamoxifen is associated with endometrial thickening, it is not associated with difficulties in sampling the uterine cavity. Tamoxifen does not obscure or complicate sampling the uterine cavity, and neither does it obscure the pathologist's interpretation of the specimen.
To suggest that tamoxifen is related to ovarian cancer or an aggressive subtype of endometrial cancer in the absence of new data is incorrect, and will only confuse and concern women who are taking tamoxifen for legitimate medical reasons.
The author replies
I am pleased at the interest shown by Jerry P Lewis in my recent article and regret that I must refute all the points he has raised.
Tamoxifen and ovarian cancer: far from implying a relation between ovarian cancer and tamoxifen use, my article emphasises that the study cited is small, that women with breast cancer might have a familial predisposition to ovarian cancer, and that the link between tamoxifen and ovarian tumorigenesis is by no means established. The study cited, although small, was of interest to the readership of this journal because it listed the pathological types of ovarian neoplasms that occurred in association with tamoxifen, whereas other available literature is pathologically imprecise.
Tamoxifen and endometrial cancer: I would reiterate my statement that “there is still some uncertainty about the pathological features of tamoxifen associated endometrial cancer”. As clearly stated in my article, a number of sizeable studies have been unable to show a definite association between tamoxifen and poorly differentiated or aggressive endometrial carcinomas, but a number of small studies have raised this possibility. Once raised, this possibility cannot be ignored, however inconvenient it might be for Zeneca Pharmaceuticals. The uncertainty raised by these small studies can only be settled by a large, well designed, long term, prospective study such as the American breast cancer prevention study had it not been terminated prematurely.
Biopsy of tamoxifen treated endometrium: I disagree with Dr Lewis's assertion that tamoxifen is not associated with difficulties in sampling the uterine cavity. As mentioned in my article, Cohen and colleagues1 were able to obtain adequate endometrial tissue in only 29% of tamoxifen treated breast cancer patients even though 99% of the women had ultrasonographically thickened endometrium. The findings of these authors accord well with our own experience here in Cardiff.
There is no doubt that tamoxifen is an effective drug that is immensely useful in the setting of breast cancer. Like all effective drugs, however, it has important side effects. In the interests of the patients I challenge the manufacturers of tamoxifen to consider financing independent research into these side effects.