Extended Tamoxifen May Double Endometrial Cancer Risk

KeepHealthCare.ORG – Extended Tamoxifen May Double Endometrial Cancer Risk

There was a twofold increase in the risk of endometrial cancer following extended versus standard adjuvant tamoxifen therapy in patients with breast cancer, a meta-analysis found.

The systematic review of four randomized controlled trials showed that the absolute risk of endometrial cancer in patients receiving adjuvant tamoxifen for 10 years was 3.2% compared with 1.5% in patients receiving 5-year standard therapy (cumulative risk ratio [RR] 2.29, 1.60 to 3.28, P<0.001), reported Christina A. Fleming, MBBCh, of St. Vincent’s Hospital Group in Dublin, and colleagues.

Most tamoxifen-related uterine cancers occurred in patients who were postmenopausal and symptomatic, but diagnosed at an early stage and with a low grade, and carried a mortality risk of less than 1%, the authors wrote in the British Journal of Surgery.

“There is a paucity of clear evidence on how we should best manage endometrial cancer risk in extended tamoxifen therapy,” said Fleming in a statement. “This is a research area that requires immediate focus with expansion of extended tamoxifen therapy regimes.”

Few studies have data on endometrial surveillance in patients on adjuvant tamoxifen, the most recent of which (2003) was part of this review and did not find any benefit for routine endometrial surveillance in patients receiving tamoxifen for 5 years. Guidelines published by the American College of Obstetricians and Gynecologists, plus those from the Australian and New Zealand group do not recommend routine surveillance in asymptomatic patients receiving tamoxifen.

“Although it is difficult to make clear evidence-based recommendations on endometrial surveillance in the setting of extended therapy because of the sparsity of robust results, a practical approach may be to screen all patients using endometrial ultrasonography after 5 years on tamoxifen,” they wrote. “The validity of this approach should be assessed prospectively.”

Regarding breast cancer outcomes, Fleming’s group observed a non-significant reduction in breast cancer-specific mortality in patients receiving tamoxifen for 10 years, from 11.6% to 10.1% (RR 0.94, P=0.58). Likewise, the overall reduction in local recurrence, from 19.1% to 17.1% (RR 1.03, P = 0.76), and 1.7% reduction in overall mortality with 10-year tamoxifen were not significant (RR 0.93, P = 0.14).

These data would not preclude the use of extended tamoxifen in women who are deemed appropriate, Hatem Soliman, MD, of H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, told MedPage Today. He added that there are “many factors to consider in choosing endocrine therapy,” including menopausal status, risk of breast cancer recurrence, bone health, other comorbid conditions, and tolerance of estrogen deprivation.

Soliman, who was not affiliated with the study, noted that the absolute increase in endometrial cancer rates was very small. Also, it was seen predominantly in postmenopausal women who had baseline endometrial abnormalities. “The majority of these endometrial cancers are treatable if patients are followed and counseled appropriately,” he pointed out.

“In general, higher risk women who are or have become postmenopausal during their first 5 years of tamoxifen should be counseled to try switching to an aromatase inhibitor if they have no contraindications to doing so,” advised Soliman.

When asked to comment, Marissa Weiss, MD, of Lankenau Medical Center in Philadelphia, told MedPage Today: “There are a lot of issues here that impact clinical practice, including compliance.”

Weiss, who was not affiliated with the research, noted that in one study in the meta-analysis, 17% of patients randomized to extended tamoxifen therapy didn’t finish the first 5 years, while in a second study, 40% didn’t complete extended tamoxifen therapy. Even in patients randomized to standard treatment, there was a fall-off in the number who continued taking adjuvant tamoxifen because of side effects such as vaginal bleeding.

The study confirms that premenopausal women with serious disease still derive the most benefit from taking tamoxifen for an extended period of time, Weiss said. Like Soliman, she emphasized that patients need to be assessed individually, and said the pros and cons of adjuvant tamoxifen therapy must be discussed regularly.

“This is not just one conversation,” she said. “At the time of prescription renewal, you always have a repeat conversation about tamoxifen therapy and ask the patient how it’s going.” This is also the time to revisit the increased risk of endometrial cancer and to ask your patient about signs of abnormal bleeding and so on, Weiss said.

The four randomized controlled trials included in the meta-analysis enrolled 21,361 patients from 1978 to 2005. Of these, 7,652 (35.8%) received 10 years of 20-mg oral tamoxifen daily. Follow-up ranged from a median of 7 to 10 years.

Three studies compared 10 years of adjuvant tamoxifen therapy in patients with estrogen receptor–positive breast cancer with standard 5-year therapy with or without placebo.

In the first, the National Surgical Adjuvant Breast and Bowel Project (NSABP) trial, the RR of endometrial malignancy was 6.84. However, 75% of participants in that trial were postmenopausal, with most endometrial cancers stage I with good to moderate histological grade, the study authors noted.

Both the 2012 ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) trial, and the 2013 aTTom (Adjuvant Tamoxifen: To Offer More?) trial showed that younger patients with high-risk disease benefitted most from extended tamoxifen therapy.

ATLAS showed that extending tamoxifen to 10 years was associated with a twofold increase in the 15-year endometrial cancer risk and a 0.4% absolute increase in mortality. This was seen almost exclusively in postmenopausal patients. Similar observations were reported in aTTom (RR 2.28) and in the 2001 Scottish trial of adjuvant tamoxifen (RR 3.42).

None of the surveillance studies compared the benefit of routine endometrial surveillance with no surveillance in similar or matched cohorts of patients receiving tamoxifen. “This greatly limits the conclusions that can be drawn from the included studies,” the investigators wrote.

Fleming and co-authors reported having no conflicts of interest.

Weiss is the founder of Breastcancer.org.

2018-07-10T16:00:00-0400

Source: https://www.medpagetoday.com/hematologyoncology/breastcancer/73949

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