madman
Super Moderator
Abstract
Background: Metformin has been associated with lower breast cancer (BC) risk and improved outcomes in observational studies. Multiple biologic mechanisms have been proposed, including a recent report of altered sex hormones. We evaluated the effect of metformin on sex hormones in MA.32, a phase III trial of nondiabetic BC subjects who were randomly assigned to metformin or placebo.
Methods: We studied the subgroup of postmenopausal hormone receptor-negative BC subjects not receiving endocrine treatment who provided fasting blood at baseline and at 6 months after being randomly assigned. Sex hormone-binding globulin, bioavailable testosterone, and estradiol levels were assayed using electrochemiluminescence immunoassay. Change from baseline to 6 months between study arms was compared using Wilcoxon sum rank tests and regression models.
Results: 312 women were eligible (141 metformin vs 171 placebo); the majority of subjects in each arm had T1/2, N0, HER2-negative BC and had received (neo)adjuvant chemotherapy. Mean age was 58.1 (SD=6.9) vs 57.5 (SD=7.9) years, mean body mass index (BMI) was 27.3 (SD=5.5) vs 28.9 (SD=6.4) kg/m2 for metformin vs placebo, respectively. Median estradiol decreased between baseline and 6 months on metformin vs placebo (5.7 vs 0 pmol/L; P < .001) in univariable analysis and after controlling for baseline BMI and BMI change (P < .001). There was no change in sex hormone-binding globulin or bioavailable testosterone.
Conclusion: Metformin lowered estradiol levels, independent of BMI. This observation suggests a new metformin effect that has potential relevance to estrogen-sensitive cancers.
Metformin has garnered attention as a potential anticancer agent across a range of cancers, including breast cancer (BC); potential effects on BC outcomes are being studied in the Canadian Cancer Trials Group MA.32, an ongoing phase 3 an adjuvant trial comparing metformin 850 mg twice a day vs placebo twice a day (each given for 5 years) in subjects receiving standard breast cancer therapy (1). It has been postulated that metformin may impact BC directly (eg, via intratumoral LKB1-mediated AMP-activated protein kinase leading to suppression of mTORC1 signaling) and/or indirectly (eg, via inhibition of hepatic gluconeogenesis with a subsequent reduction in circulating insulin levels, reducing PI3K/Akt/mTOR signaling in cancer cells expressing the insulin receptor) (2). Data from neoadjuvant clinical trials have provided some support for both direct and indirect mechanisms (3,4). Recent research has suggested metformin may also act indirectly via an effect on sex hormones (SHs), although findings have been inconsistent (5–8).
Discussion
Our observation of a statistically significant decrease in estradiol between baseline and month 6 in the metformin arm as compared with placebo is consistent with the work published by Campagnoli et al. (5, 6), who studied a selected postmenopausal nondiabetic BC population (50% of whom were receiving tamoxifen) who were required to have high baseline testosterone levels. In that study, a decrease in estradiol (38%; P < .02) and in testosterone (29%; P < .02) was seen in those receiving metformin 1500 mg/day (close to the 1700 mg/day administered in MA.32) vs metformin 1000 mg/day. The 30% reduction in estradiol we identified was similar to that seen by Campagnoli et al. Our population differs from the studies by Campagnoli et al. in that our subjects were not selected for high baseline levels of testosterone; this difference in entry criteria may account for our failure to identify changes in SHBG or BT with metformin. These observations suggest that the estradiol change we observed is independent of testosterone or of a potential effect of metformin on the liver synthesis of SHBG.
Patterson et al. (7) reported reductions in estradiol, testosterone, and SHBG in overweight or obese BC patients receiving metformin; however, it was not clear whether the small reductions in estradiol that were observed (-10%, 95% CI ¼ -18.5% to - 1.5%) in those receiving metformin were due to coadministration of the lifestyle-based weight loss intervention. Small changes were also seen in testosterone and SHBG. As noted previously, metformin had no impact on SHBG, estradiol, testosterone, and dehydroepiandrosterone in 382 overweight, glucose-intolerant patients enrolled into the Diabetes Prevention Program (13).
Our study is the first to report the independent effect of metformin on estradiol in a placebo-controlled trial without cointervention (tamoxifen or lifestyle intervention). The reduction we observed (approximately 30%) is substantial and of potential clinical relevance in breast cancer and possibly in women with hormone receptor-positive BC, although we did not study whether similar effects would have occurred in women receiving hormonal therapies for their BC. Our findings are also potentially relevant to other estrogen-sensitive cancers, notably endometrial cancer for which observational data suggest strong associations of metformin with both risk and prognosis. Should beneficial effects of metformin be seen in our primary efficacy analysis in hormone receptor-positive BC, we plan to investigate the effects of metformin on SHs, including estradiol, in this population. The independence of the observed reduction in estradiol from baseline BMI, BMI change, and insulin change suggest it did not occur as a result of a loss of fat mass, nor is it associated with an insulin effect.
The mechanism by which metformin lowered estradiol remains unclear. Preclinical data have suggested that metformin may inhibit aromatase activity, potentially accounting for our observed reduction and also suggesting an additional mechanism of anticancer action of metformin. Both ER-positive breast cancer cells and breast adipose stromal cells exhibited reductions in aromatase mRNA levels in response to metformin treatment via mechanisms involving the suppression of promoter (PII) and P1.3-specific transcripts as well as activation of AMPK (18, 19).
In conclusion, metformin lowered estradiol levels, independent of BMI and insulin in nondiabetic, postmenopausal women with ER- and PR-negative BC enrolled onto MA.32 trial. This observation suggests a new mechanism of metformin action that may be relevant in breast and other estrogen-mediated cancers.
Background: Metformin has been associated with lower breast cancer (BC) risk and improved outcomes in observational studies. Multiple biologic mechanisms have been proposed, including a recent report of altered sex hormones. We evaluated the effect of metformin on sex hormones in MA.32, a phase III trial of nondiabetic BC subjects who were randomly assigned to metformin or placebo.
Methods: We studied the subgroup of postmenopausal hormone receptor-negative BC subjects not receiving endocrine treatment who provided fasting blood at baseline and at 6 months after being randomly assigned. Sex hormone-binding globulin, bioavailable testosterone, and estradiol levels were assayed using electrochemiluminescence immunoassay. Change from baseline to 6 months between study arms was compared using Wilcoxon sum rank tests and regression models.
Results: 312 women were eligible (141 metformin vs 171 placebo); the majority of subjects in each arm had T1/2, N0, HER2-negative BC and had received (neo)adjuvant chemotherapy. Mean age was 58.1 (SD=6.9) vs 57.5 (SD=7.9) years, mean body mass index (BMI) was 27.3 (SD=5.5) vs 28.9 (SD=6.4) kg/m2 for metformin vs placebo, respectively. Median estradiol decreased between baseline and 6 months on metformin vs placebo (5.7 vs 0 pmol/L; P < .001) in univariable analysis and after controlling for baseline BMI and BMI change (P < .001). There was no change in sex hormone-binding globulin or bioavailable testosterone.
Conclusion: Metformin lowered estradiol levels, independent of BMI. This observation suggests a new metformin effect that has potential relevance to estrogen-sensitive cancers.
Metformin has garnered attention as a potential anticancer agent across a range of cancers, including breast cancer (BC); potential effects on BC outcomes are being studied in the Canadian Cancer Trials Group MA.32, an ongoing phase 3 an adjuvant trial comparing metformin 850 mg twice a day vs placebo twice a day (each given for 5 years) in subjects receiving standard breast cancer therapy (1). It has been postulated that metformin may impact BC directly (eg, via intratumoral LKB1-mediated AMP-activated protein kinase leading to suppression of mTORC1 signaling) and/or indirectly (eg, via inhibition of hepatic gluconeogenesis with a subsequent reduction in circulating insulin levels, reducing PI3K/Akt/mTOR signaling in cancer cells expressing the insulin receptor) (2). Data from neoadjuvant clinical trials have provided some support for both direct and indirect mechanisms (3,4). Recent research has suggested metformin may also act indirectly via an effect on sex hormones (SHs), although findings have been inconsistent (5–8).
Discussion
Our observation of a statistically significant decrease in estradiol between baseline and month 6 in the metformin arm as compared with placebo is consistent with the work published by Campagnoli et al. (5, 6), who studied a selected postmenopausal nondiabetic BC population (50% of whom were receiving tamoxifen) who were required to have high baseline testosterone levels. In that study, a decrease in estradiol (38%; P < .02) and in testosterone (29%; P < .02) was seen in those receiving metformin 1500 mg/day (close to the 1700 mg/day administered in MA.32) vs metformin 1000 mg/day. The 30% reduction in estradiol we identified was similar to that seen by Campagnoli et al. Our population differs from the studies by Campagnoli et al. in that our subjects were not selected for high baseline levels of testosterone; this difference in entry criteria may account for our failure to identify changes in SHBG or BT with metformin. These observations suggest that the estradiol change we observed is independent of testosterone or of a potential effect of metformin on the liver synthesis of SHBG.
Patterson et al. (7) reported reductions in estradiol, testosterone, and SHBG in overweight or obese BC patients receiving metformin; however, it was not clear whether the small reductions in estradiol that were observed (-10%, 95% CI ¼ -18.5% to - 1.5%) in those receiving metformin were due to coadministration of the lifestyle-based weight loss intervention. Small changes were also seen in testosterone and SHBG. As noted previously, metformin had no impact on SHBG, estradiol, testosterone, and dehydroepiandrosterone in 382 overweight, glucose-intolerant patients enrolled into the Diabetes Prevention Program (13).
Our study is the first to report the independent effect of metformin on estradiol in a placebo-controlled trial without cointervention (tamoxifen or lifestyle intervention). The reduction we observed (approximately 30%) is substantial and of potential clinical relevance in breast cancer and possibly in women with hormone receptor-positive BC, although we did not study whether similar effects would have occurred in women receiving hormonal therapies for their BC. Our findings are also potentially relevant to other estrogen-sensitive cancers, notably endometrial cancer for which observational data suggest strong associations of metformin with both risk and prognosis. Should beneficial effects of metformin be seen in our primary efficacy analysis in hormone receptor-positive BC, we plan to investigate the effects of metformin on SHs, including estradiol, in this population. The independence of the observed reduction in estradiol from baseline BMI, BMI change, and insulin change suggest it did not occur as a result of a loss of fat mass, nor is it associated with an insulin effect.
The mechanism by which metformin lowered estradiol remains unclear. Preclinical data have suggested that metformin may inhibit aromatase activity, potentially accounting for our observed reduction and also suggesting an additional mechanism of anticancer action of metformin. Both ER-positive breast cancer cells and breast adipose stromal cells exhibited reductions in aromatase mRNA levels in response to metformin treatment via mechanisms involving the suppression of promoter (PII) and P1.3-specific transcripts as well as activation of AMPK (18, 19).
In conclusion, metformin lowered estradiol levels, independent of BMI and insulin in nondiabetic, postmenopausal women with ER- and PR-negative BC enrolled onto MA.32 trial. This observation suggests a new mechanism of metformin action that may be relevant in breast and other estrogen-mediated cancers.
