Menopausal hormone therapy (MHT) did not increase breast cancer risk in women with BRCA mutations, according to a study reported here.
In fact, women who used estrogen-only MHT had a significantly lower risk of breast cancer compared with a matched cohort of women who did not use MHT (42.% vs 24.9%). An analysis of different types of estrogen showed either a lower risk of breast cancer or no effect. MHT that included estrogen and progesterone had no effect on breast cancer risk.
The findings added to a growing body of literature showing the safety of MHT, reported Joanne Kotsopoulos, PhD, of Women's College Hospital and the University of Toronto, at the San Antonio Breast Cancer Symposium (SABCS).
"We have over 19,000 women that we study, and about 6,000 had undergone oophorectomy and did not have breast cancer, but only 37% of them had ever taken a hormone," she added. "I think that just shows that we can do better, that we can safely use hormones when it's indicated for this population... . I think with longer follow-up, we'll be able to show not only the impact on cancer risk, but potentially how we're doing with respect to managing comorbidities in these women."
An unidentified European clinician at the meeting pointed out that a current trend in Europe is to perform salpingectomy without removing the ovaries.
"I think we have to be cautious with that," said Kotsopoulos. "We're still awaiting data that's looking at not only at quality of life but also cancer risks. Until we have that data, I think I agree with the NCCN [National Comprehensive Cancer Network] guidelines and other guidelines. Ovarian cancer has no screening opportunity. Once ovarian cancer is diagnosed, we know the outcomes are horrible, so I think as long as women who are enrolled in these trials of salpingectomy alone are returning for ovary removal at the recommended time, I think that's okay. Salpingectomy instead of oophorectomy, we're definitely not there yet."
An SABCS virtual attendee referenced the increased breast cancer risk associated with combined hormonal therapy in the Women's Health Initiative (WHI) and asked Kotsopoulos to comment on the differences between the WHI results and the results from her group.
"Our population is already at higher risk of cancer because of their gene mutation," she said. "We did not see a harmful effect of [combination therapy], which is discordant with other trials. There's more to understand, as we evaluate risk factors and prognostic factors, and finding that perhaps there is less and less of a role of these traditional hormones and rather other pathways involved in the development of cancer."
During a press briefing prior to the presentation, Kotsopoulos was asked whether duration of MHT had an effect on breast cancer risk.
"The signal was similar, for example, when we looked at women who used it for less than 5 years or longer," she said. "In fact, the association was even stronger with longer duration of use."
BRCA and Cancer Risk
Kotsopoulos noted that BRCA carriers have a substantially increased lifetime risk of breast and ovarian cancer. Management of high-risk women is a balancing act, reducing cancer risk while mitigating short- and long-term impacts of early menopause in women and improve their quality of life.
In the general population, combined MHT is associated with an increased risk of breast cancer, but limited data exist regarding MHT and breast cancer risk in BRCA carriers. To address the issue, investigators in the Hereditary Breast and Ovarian Cancer Clinical Study Group performed a matched-cohort analysis to gain insights into the relationship between MHT and breast cancer in BRCA carriers and whether the relationship varies by gene mutation and hormonal formulation.
From an eligible cohort of 3,086 patients, investigators assembled two cohorts of 676 patients each (MHT and no MHT), matched for type of gene mutation (BRCA 1 or 2), birth year, baseline age, age at menopause, oophorectomy status, and age at oophorectomy.
The two cohorts had a mean age of 43.8, BRCA1 in 81% of cases, 84-88% with parity, 71-81% with preventive mastectomy (higher in MHT cohort, P<0.0001), and bilateral oophorectomy in 94.8%. The MHT users had a mean age of 43.2 at first use and a mean duration of 5.7 years.
Key Findings
The results showed an absolute 18.4% lower incidence of breast cancer in the MHT group during follow-up to 15 years. Subsequent analyses showed a 52% reduction in breast cancer risk for any MHT use (95% CI 0.36-0.83, P<0.0001), 63% lower for estrogen only (95% CI 0.24-0.57, P<0.0001), and a non-significant 6% lower risk associated with combination MHT (95% CI 0.54-1.63).
For estrogen-only MHT, matching showed statistically significant reductions in breast cancer risk for any use (n=291 per cohort, HR 0.37, P<0.0001) and transdermal estradiol (n=169, HR 0.48, P=0.008). The analysis yielded non-significant trends favoring oral estradiol (n=60, HR 0.57, 95% CI 0.20-1.62), oral conjugated equine estrogen (n=69, HR 0.40, 95% CI 0.11-1.55), and oral synthetic estrogen (n=36, HR 0.32, 95% CI 0.04-2.38).
Analyses of combined MHT formulations yielded no statistically significant differences.
Investigators noted that they were intrigued by results of an analysis of use versus non-use of conjugated estrogen plus bazedoxifene (CE/BZA, Duavee), which women with an intact uterus take to reduce menopausal symptoms and bone mineral loss. None of the 43 users developed breast cancer versus three cases in the matched non-users.
A randomized study of CE/BZA reported earlier this year showed that women with ductal carcinoma in situ had a significant reduction in the proliferation marker Ki-67, consistent with preclinical studies showing CE/BZA reduced mammary ductal proliferation and increased expression of anti-tumorigenic markers in breast stroma.
"I think this is a really exciting area, when we think about managing [menopausal] symptoms but also potentially impacting breast cancer risk," said Kotsopoulos.
Disclosures
Kotsopoulos disclosed no relationships with industry.
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