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Oophorectomy for premenopausal breast cancer.

One-quarter of patients with breast cancer are diagnosed at a premenopausal age, and these young women may be directed to discuss oophorectomy with their ob.gyn. This may be because of the discovery of a deleterious BRCA gene mutation, which places them at increased risk for ovarian cancer, but oophorectomy may also be a therapeutic option for their breast cancer: 60% of premenopausal breast cancers are hormone receptor-positive. Ovarian ablation has been associated with improved overall survival and disease-free survival among these patients. (1)

Estrogen is an important promoter of breast cancer and is predominantly derived from ovarian tissue in premenopausal women. However, in postmenopausal women, the majority of estrogen is produced peripherally through the conversion of androgens to estrogen via the enzyme aromatase. Aromatase inhibitors, such as exemestane, anastrazole, and letrazole, are drugs which block this conversion in peripheral tissues. They are contraindicated in premenopausal women with intact ovarian function, because there is a reflex pituitary stimulation of ovarian estrogen release in response to suppression of peripheral conversion of androgens. For such patients, ovarian function must be ablated either with surgery or with gonadotropin-releasing hormone (GnRH) analogues such as leuprorelin and goserelin if aromatase inhibitors are desired.

Two major clinical trials, the SOFT and TEXT trials, explored the benefit of ovarian ablation in the adjuvant treatment of early stage premenopausal breast cancer. The SOFT trial included 3,066 women randomized to receive tamoxifen, tamoxifen with ovarian suppression, or an aromatase inhibitor with ovarian suppression. (2) In the TEXT trial, 2,672 patients were randomized to receive either an aromatase inhibitor with ovarian suppression or tamoxifen with ovarian suppression. (3) Results of the two trials showed that there was greatest treatment effect when ovarian suppression is added to tamoxifen, or in patients receiving an aromatase inhibitor with ovarian suppression. This effect appeared to be dominant among women who had received prior chemotherapy and were at higher risk for recurrence, and who remained premenopausal after completion of their primary therapy While ovarian suppression was associated with improved disease-free survival, it was not associated with an increased overall survival.

In these trials, ovarian ablation was achieved either reversibly with GnRH analogues or permanently and irreversibly with oophorectomy. No studies have compared the survival benefit of these two approaches; however, surgical ovarian ablation is immediate, reliable, and has been shown to be the most cost-effective method. (4) It is a good option for women who struggle with adherence to repeated appointments for injections. It also substantially reduces the risk for ovarian cancer, which is elevated among this population of patients, even among those without a deleterious BRCA gene mutation.

BRCA populations

For women with BRCA germline mutations and a history of breast cancer, oophorectomy is associated with a 70% risk of all-cause mortality, including a 60% reduction in breast cancer mortality. This effect is inclusive of patients with "triple-negative," hormone receptor-negative tumors. The positive effect on breast cancer mortality is predominantly seen among BRCA-1 mutation carriers, and if the oophorectomy is performed within 2 years of diagnosis. (5)

Technique

With oophorectomy either for breast cancer or because of a hereditary cancer syndrome such as BRCA mutation, it is important to ensure that the ovarian vessel pedicle is transected at least 2 cm from its insertion in the ovary. This prevents leaving a residual ovarian remnant. It may be necessary to skeletonize the ovarian vessels free from their physiological attachments to the sigmoid colon on the left, and terminal ileum and cecum on the right. It is also important to ensure that the ureter is not invested in this more proximal segment of ovarian vessels. To prevent this, the retroperitoneal space can be opened lateral to and parallel with the ovarian vessels, and the "medial leaf" of the broad ligament swept medially to expose the ureter as it crosses the bifurcation of the external and internal iliac arteries at the pelvic brim. With the ureter in view, a window can then be made in the "medial leaf" above the ureter and below the ovary and ovarian vessels, in doing so creating a skeletonized ovarian vessel segment which can be sealed and cut 2 cm or more from its insertion in the ovary.

The fallopian tubes should be removed with the ovarian specimens, with attention made to removing the fallopian tube at its junction with the uterine cornua. It should be noted that the majority of fallopian tube cancers arise in the fimbriated end of the tube, and cornual tubal malignancies are fairly uncommon.

The decision about whether or not to perform hysterectomy at the time of salpingo-oophorectomy is complex. In patients without hereditary cancer syndromes, such as BRCA or Lynch syndrome, hysterectomy likely offers no benefit to the patient who is undergoing a procedure for the purpose of ovarian ablation. An argument has been made that hysterectomy can eliminate the increased endometrial cancer risk associated with tamoxifen. However, given the previously discussed data, after oophorectomy, aromatase inhibitors are the preferred treatment option, and tamoxifen can be avoided. If a patient has unrelated underlying uterine pathology a hysterectomy might be indicated. Women with BRCA germline mutations, particularly women with BRCA-1 mutations, may be at increased risk for uterine serous carcinoma, and in these patients, hysterectomy at the time of oophorectomy can be discussed and offered, though as yet, it is not a guideline recommendation for all patients. (6) Patients who ask to "just take everything out while you are there" without a clear indication for hysterectomy should be counseled that hysterectomy is associated with increased risk, recovery, and cost, compared with bilateral salpingo-oo phorectomy. Among patients with elevated surgical risk (such as morbid obesity, known adhesive disease, increased venous thromboembolism risk, diabetes, and so on) it may not always be appropriate to extend the complexity of the procedure given the limited benefit.

Consequences of ovarian ablation

It should be noted that ovarian ablation in the TEXT and SOFT trials was not associated with an increase in overall survival for women with premenopausal breast cancer. Alternatively, large, observational studies such as the Nurses' Health Study have shown that premenopausal oophorectomy without hormone replacement therapy is associated with increased all-cause mortality. This is primarily driven by the increased cardiopulmonary risk (heart attack and stroke), deaths after osteoporotic hip fractures, and the increased risk for lung and colon cancer. (7,8)

It is normal for young patients to have heightened concerns regarding their risk of recurrence from their cancer, and less concerned by threats to their health in decades to come. However, it is important to discuss these data with the patient and allow for her to make an informed decision about her immediate versus future risks. If she determines that she is not interested in permanent ovarian ablation with oophorectomy because of either surgical risks, concerns regarding permanent infertility, or increased all-cause mortality, she still has an option for medical ovarian ablation with GnRH analogues in the treatment of her breast cancer.

Hormone replacement therapy postoperatively

Women who undergo oophorectomy for the treatment of breast cancer should not be offered hormone replacement therapy. This is true even for "triple-negative" or hormone receptor-negative breast cancers as there is still some observed benefit I of ovarian ablation, and risk from exogenous hormone administration in these women. Alternatively, postoperative hormone replacement therapy remains safe until the age of natural menopause among premenopausal patients with BRCA germline mutations without a preceding breast cancer diagnosis.

Surgical ovarian ablation with bilateral salpingo-oophorectomy is a valuable strategy in the adjuvant therapy of premenopausal breast cancer, particularly among BRCA mutation carriers and women with hormone receptor-positive disease, or among women who find adherence to medical ablation difficult. Patients should be carefully counseled that this may introduce increased long-term cardiovascular risks for them.

References

(1.) Early Breast Cancer Trialists' Collaborative Group. Lancet. 1996 Nov 2;348:1189-96.

(2.) Pagani O et al. N EnglJ Med. 2014 Jul 10;371(12):107-18.

(3.) Francis PA et al. N EnglJ Med. 2015Jan 29;372(5):436-46.

(4.) Ferrandina G et al. Clin Drug Investig. 2017 Nov;37(ll): 1093-102.

(5.) Finch AP et al. J Clin Oncol. 2014 May 20;32(15):1547-53.

(6.) Shu CA et al. JAMA Oncol. 2016 Nov 1;2(11): 1434-40.

(7.) Parker WH et al. Obstet Gynecol. 2013 Apr;121(4):709-16.

(8.) Rivera CM et al. Menopause. 2009JanFeb;16:15-23.

BY EMMA ROSSI, MD

Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.
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Title Annotation:Gynecologic Oncology Consult
Author:Rossi, Emma
Publication:OB GYN News
Date:Jun 1, 2018
Words:1414
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