Issue: December 2020
Disclosures: Biro reports no relevant financial disclosures.
October 21, 2020
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Longitudinal study reveals mechanism of early puberty as a driver of breast cancer risk

Issue: December 2020
Disclosures: Biro reports no relevant financial disclosures.
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Early-onset of puberty and other pubertal parameters have been linked to a significantly increased risk for developing breast cancer later in life.

The mechanism of this association was the focus of a longitudinal study conducted by researchers at Cincinnati Children’s Hospital Medical Center and University of Cincinnati. The results, published in Journal of Adolescent Health, identified higher insulin-like growth factor-1 (IGF-1) levels, greater lifelong estrogen exposure and longer pubertal growth period as factors driving this correlation.

Frank M. Biro, MD, faculty member in the division of adolescent and transition medicine at Cincinnati Children’s Hospital Medical Center and professor in the department of pediatrics at University of Cincinnati College of Medicine.

The researchers evaluated pubertal maturation of 183 girls recruited at ages 6 or 7 years and followed between 2004 and 2018 as part of the “Growing Up Female” study conducted by the Breast Cancer and the Environment Research Program.

According to lead researcher Frank M. Biro, MD, faculty member in the division of adolescent and transition medicine at Cincinnati Children’s Hospital Medical Center and professor in the department of pediatrics at University of Cincinnati College of Medicine, the study was prompted in part by the activism of women with breast cancer.

“Women with breast cancer went to Capitol Hill and said, ‘We’ve found that there are neighborhoods where several of us developed breast cancer at young ages,’” Biro told Healio. “They voiced their concerns and asked for a longitudinal study that investigates risk [for] breast cancer and the environment.”

Biro spoke with Healio about the relationship between early puberty and breast cancer risk, environmental factors that may induce earlier onset of puberty, and a proposed unifying hypothesis that emerged from the study.

Question: How did the Breast Cancer and the Environment Research Program originate?

Answer: The program was initiated by a group of women with breast cancer trying to understand the role of environmental factors in breast cancer risk. Our study examined factors associated with puberty that are impacted by the environment and sought to relate these factors to pubertal markers specifically to age of menarche. Studies have demonstrated that for every year that menarche is delayed, the risk for premenopausal breast cancer decreases by 9% and the risk for postmenopausal breast cancer decreases by 4%.

Q: Why does later menarche decrease breast cancer risk?

A: An earlier age of menarche is associated with a higher number of menstrual cycles. So, I started doing the math. If a girl has her first menarche at age 14.5 years instead of age 12.5 years, that somehow reduces her risk for premenopausal breast cancer by 15% to 18%. How can 2 years account for 18%? The math doesn’t work.

That suggested there is something else different about a girl with earlier menarche. That something is probably the hormonal milieu, identified in the study.

Here’s another part of this issue: girls who mature earlier have a greater peak height velocity, but who wind up the same height or a little bit shorter than their on-time peers. That means women who mature earlier have a higher risk for breast cancer and a higher peak height velocity, but they are shorter. This seem inconsistent with other findings that women who are taller have higher risk for breast cancer.

It could make sense, though. The early maturing girls have a higher peak/height velocity and tall women tend to have pubertal growth velocities in the higher percentiles. Their growth per year is at the higher end of the range all the time. IGF-1 could do both. IGF-1 is related to breast development, breast density and breast cancer risk.

I also recalled a paper published several decades ago that suggested you could estimate the activity of how the adrenal androgen androstenedione was converted to estrogen. I hypothesized these earlier-maturing or later-maturing kids handle the androgen/estrogen milieu differently.

So, I looked not only at estrogen levels, but also the ratio of estrogen to androstenedione. It turned out that IGF-1 and the estrone-to-androstenedione ratio are both associated with those pubertal marker risks.

A couple of papers published about 15 to 20 years ago looked at other pubertal parameters. Ahlgren and colleagues found that when you start incorporating growth parameters into breast cancer risk, it knocks out age of menarche. Another study, by Li and colleagues, applied those growth parameters to a different group of women and found age of menarche remained a breast cancer risk factor. The growth parameters identified the risk for the more aggressive cancers, the ones spurred by hormones.

The women in our study are now in their early 20s and, fortunately, none of them has developed breast cancer.

Q: Is age of menarche what drives the association with breast cancer or is it environmental factors?

A: Environmental factors slightly influenced the age of onset of some of these pubertal parameters. There were differences by race and ethnicity, too, but BMI was a more important factor. So, one of the approaches at a public health level that might help would be to lower BMI. I am not talking about encouraging a society of women with eating disorders. However, we noticed that healthier eating habits tended to delay pubertal parameters a bit. The girls in our study whose families had higher consumption of phytoestrogens tended to have later onset of breast development and menarche. We also found that greater phthalate exposure was modestly associated with some of the measures of increased central adiposity, but that’s been demonstrated in the adult literature. Still, it seems worthwhile to limit exposure to phthalates in these kids. Living a little greener is not a bad thing.

Q: How has the age of menarche changed over the years?

A: Age of menarche has decreased only modestly, but the age of breast development has gone down more dramatically. That is not necessarily a good thing because it essentially increases the duration of puberty.

Another reason we looked at puberty is that several people — including Jose Russo, MD, FACP, director of the Irma H. Russo, MD, Breast Cancer Research Lab at Fox Chase Cancer Center — have proposed that puberty represents a window of susceptibility for breast cancer risk. Girls with earlier breast development have a longer duration of puberty, which potentially would increase risk for breast cancer because of the changes within the breast tissue during puberty. The breast goes from a small group of dedicated cells beneath the areola to an expansion of cells that become palpable breast tissue. Cells that are actively dividing and proliferating are always at greater risk for any kind of environmental exposures, and for cancer.

A retrospective study by Land and colleagues, as well as similar papers, examined breast cancer rates in the context of Nagasaki and Hiroshima. Girls who were in their teen years when exposed to the atomic bombs had higher dose-specific excess relative risk for cancer. So, we know radiation is a factor for breast cancer risk, and growing, maturing breast tissue during puberty is at greater risk for these environmental factors. When you expand that window, you enhance the risk. The factors we identified as playing a role in this expanded interval of puberty in our paper include IGF-1 and estrone-to-androstenedione ratio. This ratio is considered a surrogate for aromatase activity and estrogen exposure.

Q: What does the future hold for this research?

A: Susan Pinney, PhD, FACE, at University of Cincinnati, and I are leading a separate study of how some of the environmental factors impact specific hormone levels. We are trying to explore the mechanisms, especially those associated with these environmental exposures.

References:

For more information:

Frank M. Biro, MD, can be reached at Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229; email: frank.biro@cchmc.org