ENDOMETRIAL CANCER IN A WOMAN ON LONG TERM TAMOXIFEN THERAPY
Satish R Rao*, Raja S Rao**
*Clinical Assistant; **Consultant Surgeon, Department of Surgery, Shushrusha Citizen’s Co-operative Hospital, Ranade Road, Shivaji Park, Mumbai 400 028.
We report a case of postmenopausal woman, who underwent a modified radical mastectomy for carcinoma breast. She was subsequently put on tamoxifen 20 mg a day. She developed carcinoma of the endometrium, two years after initiation of tamoxifen therapy.
Tamoxifen is a non-steroidal substance which is widely used in the treatment of breast cancer. Worldwide, about seven million women are taking tamoxifen. It is a safe drug with no side effects. However it has the potential to induce endometrial carcinoma. The incidence of endometrial carcinoma in women, who are on tamoxifen, is estimated to be 1.4/1000 women as compared to .7/1000 in the general population.
A fifty year old woman presented with a painless lump in the right breast of one month’s duration. She had two children, and had attained menopause two years ago. She had no gynaecological symptoms. On clinical examination, she had a lump in the upper and outer quadrant of the right breast. Its size was 5 cm. by 3 cm. It was hard in consistency, and free from the overlying skin and underlying pectoralis major. There were no palpable lymph nodes in the axilla. A fine needle aspiration cytology (FNAC) was performed; it was reported as carcinoma. She underwent a modified radical mastectomy. The final histopathology report was “Infiltrating duct carcinoma grade 1. The axillary lymph nodes do not show any metastases”. The tumour was oestrogen receptor negative (ER-ve) and progesterone receptor negative (PR-ve). Post operatively, she was put on tamoxifen tablets 10 mg. twice a day; which she took for two years. Pre-operative ultrasound examination had revealed a uterus of normal size with endometrial thickness of 7 mm. She was followed up regularly at three monthly intervals.
Two years following surgery, she complained of vaginal bleeding. The endometrium was reported to be 20 mm in thickness by the sonologist. The patient underwent a curettage followed by a panhysterectomy. Histopathology was reported as adenocarcinoma of the endometrium grade 1, with superficial invasion of the myometrium. At present, she is asymptomatic, six months after hysterectomy.
Tamoxifen is an oestrogen antagonist at some sites and oestrogen agonists at other sites. It is anti-oestrogenic in the breast. It does not cause any osteoporosis or alteration in lipid metabolism. It causes proliferation of the endometrium. Women on long term tamoxifen therapy are at risk of developing endometrial cancer. This has been a cause for widespread concern.
There is evidence to show that rats on tamoxifen develop hepatocellular carcinoma. However this is species specific. There is no scientific basis to extrapolate this data to women on tamoxifen therapy. Shibutani has detected DNA adducts from endometrium of women who are on tamoxifen. DNA adducts are substances which indicate the carcinogenic action of a drug in a particular species. These tamoxifen-DNA adducts serve as bio-markers for investigation of the carcinogenic potential of this drug.
Several large scale prospective randomised controlled trials have been conducted using tamoxifen as an adjuvant therapy. A study of these trials gives us an idea of the risk of endometrial cancer in these women. In the Stockholm trial, there was six fold increase in endometrial cancer in the tamoxifen arm as compared to the control arm (n=2729 p < 0.001). In the National Surgical Adjuvant Breast and Bowel project trial (NSABP B-14), conducted by Fisher et al, 2843 women, node negative and ER+ve, were entered into a randomised trial to receive tamoxifen or placebo. 15 women in the test arm developed endometrial cancer as compared with 2 in the control arm. However, in other well documented trials viz. National adjuvant tamoxifen organisation trial, a multicentric study, (n=1129), the Scottish trial (n=1312) and the Christie Hospital trial (n=961), there was no increased incidence of endometrial cancer in the test arm. Creaseman reviewed 15 tamoxifen related trials including those mentioned above. He found no relationship in 12 trials, increased incidence of endometrial cancer in two trials and decreased incidence in one trial. He concluded that when one considers the increased incidence of endometrial cancer in breast cancer patients, potential surveillance and detection bias, latency and occult endometrial cancer; there is a very small, if any, association between tamoxifen and endometrial cancer. Macmahon reviewed several of these randomised trials, case studies and cohort studies. He concluded that there is an association between tamoxifen and endometrial cancer; but the evidence was inconclusive and incomplete to label tamoxifen as a causative agent. He observed that confounding factors, like previous hysterectomy and hormonal replacement therapy prior to entry into the trial, had not been addressed in these trials.
One thing that comes out consistently in all the trials is the immense benefit, women derive from tamoxifen. In a meta analysis of 29892 cases, there was 17% decrease in overall mortality and 39% decrease in the incidence of cancer in the contralateral breast. The benefits were seen in all subsets, premenopausal, post menopausal, node +ve, node -ve, ER+ve and ER-ve. The benefits were more marked in post menopausal, ER+ve group. These results have stimulated further trials of tamoxifen as a chemopreventive agent in women deemed to be at high risk for breast cancer.
The current recommendation is that women on chronic tamoxifen therapy should undergo an annual clinical gynaecological checkup. Ultrasound examination gives an indication of the thickness of the endometrium. However it should be interpreted cautiously. Should a woman be symptomatic, e.g. postmenopausal bleeding, further investigation like curettage must be done. If indicated, a panhysterectomy should be done.
Efforts are on to find new drugs which have no action on the endometrium. Raloxifen is one such drug which prevents osteoporosis and which has no agonist action on the endometrium. However its role in treatment of carcinoma breast is yet to be defined.
The benefits of tamoxifen for patients with breast cancer far outweigh its side effects. Women on tamoxifen therapy should have annual gynaecological checkup. Efforts are on to synthesize a drug which is anti-oestrogenic in breast tissues and has no agonistic action on the endometrium.
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