Forty years ago, Helene Glaser received a letter in the mail from Harvard epidemiologist Frank E. Speizer, MD. The letter invited Glaser, a 31-year-old nurse at the Lown Cardiovascular Group just outside of Boston, to participate in “a study of a major public health issue.”
This was 1976, more than 15 years after the birth control pill came on the market. But “there was no one who was looking at potential long-term consequences of oral contraceptives,” Speizer, now the Edward H. Kass Distinguished Professor of Medicine at Harvard Medical School (HMS) and professor of environmental science at the Harvard T.H. Chan School of Public Health, said in an interview.
Scientists suspected the pill would have some undesired health effects. Breast cancer was at the top of the list. Knowing that the disease is influenced by hormones, “there was real concern that this might be a time bomb ticking and the consequence might be a huge epidemic of breast cancer,” said Walter Willett, MD, DrPH, professor of epidemiology and nutrition and chairman of the department of nutrition at Harvard Chan School.
Speizer and his coinvestigators chose to study the long-term health effects of the pill on nurses, surveying them every 2 years. Glaser was 1 of 121 700 married registered nurses aged 30 to 55 years who enrolled that year in the landmark prospective Nurses’ Health Study (NHS)—today the largest, longest-running investigation of women’s health with repeated measures.
The researchers assumed this group of medical professionals would have a better response rate and would give more accurate answers to their health questions than other populations. In fact, the nurses’ loyalty has been unprecedented. After accounting for deaths, the response rate of the original NHS cohort is still more than 90%. Around 80 000 nurses—some of them in their 90s—continue to diligently report in on their health 4 decades after the survey began.
The breast cancer epidemic, fortunately, did not transpire. Starting with a 1986 article in JAMA, NHS research suggests that current and recent users of oral contraceptives have only a moderate increased risk of breast cancer; that higher risk disappears after women stop taking the pill.
The lifetime risk of breast cancer for women born in the United States is 12.4%, according to the National Cancer Institute. The disease is still relatively rare in younger women, and NHS researchers have estimated that current oral contraceptive use accounts for just 1.8% of all breast cancer cases.
Because of the NHS findings, women can worry less about trading their breast health for the benefits of family planning. “I think we allayed the fears of a lot of people by showing the magnitude of the risk being as small as it was,” Speizer said.
Investigating the pill and breast cancer risk was the beginning of a wildly ambitious study of women’s health. The scope of the NHS has expanded to examine the effects of exposures including exogenous and endogenous hormones, smoking, dietary factors, physical activity, weight, sleep, and shift work on more than 30 diseases ranging from cardiovascular disease to colorectal cancer to kidney stones.
JoAnn Manson, MD, DrPH, chief of preventive medicine at Brigham and Women’s Hospital and a professor of medicine at HMS, said the study is “a treasure trove of information” about the benefits and risks of oral contraceptives and postmenopausal hormone therapy on a wide range of outcomes, including cardiovascular disease, cancer, diabetes, autoimmune diseases, and cognitive function.
The study’s repeated assessments, combined with biosamples—blood, urine, toenail clippings, tissue samples, and DNA from cheek cells—collected in substudies over the years, have “enabled us to study things that just wouldn’t be possible without that wealth of data,” said Meir Stampfer, MD, DrPH, professor of medicine at HMS and of epidemiology and nutrition at Harvard Chan School and current NHS principal investigator.
Glaser, now 71 and still working at the same heart clinic outside of Boston, steadfastly completes her survey when it arrives in the mail. “It does make you feel good that you’re contributing something to someone,” she said.
In fact, the contributions of the original NHS cohort—and of the more than 116 000 nurses who enrolled in the follow-up NHS-II, which Willett launched in 1989 with younger women—have critically advanced the contemporary understanding of the role of diet, exercise, and other lifestyle factors on health.
“It’s one of the major cohorts in the nation and the world that has generated a broad range of risk-factor epidemiology findings, especially on chronic disease,” said Ross L. Prentice, PhD, a professor in the public health sciences division at the Fred Hutchinson Cancer Research Center and a founder of the Clinical Coordinating Center for the Women’s Health Initiative (WHI).
Some of the biggest successes of the NHS have been in identifying modifiable risk factors of cardiovascular disease and diabetes. Articles by NHS investigators published in The New England Journal of Medicine in 2000 and 2001 suggest that 82% of coronary events and 91% of type 2 diabetes cases could be prevented with diet and lifestyle changes. “That’s staggering,” said Manson, who leads arms of both the NHS and the WHI.
Since the introduction of the Harvard Semiquantitative Food Frequency Questionnaire, developed by Willett and added to the survey in 1980, NHS data have provided evidence for the role of dietary factors such as polyunsaturated fats, nuts, alcohol, and fiber in lowering heart disease risk and have contributed to the understanding that not all fat is “bad.”
“The quality of their results [and] the importance of their results … showed that epidemiology was able to contribute to public health recommendations,” said Loic Le Marchand, MD, PhD, a professor in the epidemiology program at the University of Hawaii Cancer Center. “Government agencies started to look at the results coming out of our field as crucial in terms of making those recommendations.”
Perhaps most notably, research from the NHS and the Health Professionals Follow-Up Study of men, launched in 1986, was critical to the US Food and Drug Administration ban on trans fat in the food supply for the prevention of heart disease.
Although NHS researchers have made significant strides in identifying modifiable risk factors for breast cancer beyond oral contraceptive use, such as a sedentary lifestyle, alcohol consumption, and postmenopausal weight gain and hormone replacement therapy, they say that much more needs to be learned to lower incidence of the disease.
“For cardiovascular disease, colon cancer, and diabetes, we have gotten to the point where most cases are potentially preventable,” Stampfer said. But “for breast cancer, applying the best knowledge—much of which comes from NHS—we could prevent a substantial portion but not as much as those other diseases.”
The difficulties arise at least in part from the nature of the disease itself. It’s now understood that breast cancer risk accrues over a woman’s lifespan and that important determinants may occur early in life, Stampfer said. Although the original NHS cohort provided “a very good first look at oral contraceptives and breast cancer,” Willett said, it didn’t provide the full picture because the pill wasn’t yet available when the nurses were adolescents and teenagers.
Insights that have emerged from the NHS and other studies have been hampered by another major snag: “Some of the things we learned about breast cancer don’t lend themselves well to interventions,” Stampfer said. “We learned that early pregnancy is protective, but that’s not a very good intervention. And being leaner is actually a risk factor for premenopausal breast cancer, so that’s another risk factor that doesn’t have a public health intervention.” Delaying the start of menstruation with poor nutrition is also associated with lower breast cancer rates, according to Willett. But interventions like these simply aren’t practical, he said: “[C]learly we value not having teenage pregnancy, having girls educated, and having active lives.”
Today, armed with new knowledge about the disease and with new cohorts and technologies at their disposal, NHS investigators are hoping to make a more profound impact on breast cancer prediction and prevention.
Within the first decade of the study, the researchers realized they needed to start studying women earlier in life. This was a major aim of NHS-II, which enrolled women aged 25 to 42 years. The NHS3, which launched in 2010 and is just beginning to produce results, starts even younger: nurses and student nurses as young as 19 years can sign up for the study.
One of the primary aims of NHS3 is to deduce how lifestyle factors and environmental exposures before or during a woman’s first pregnancy may affect her breast cancer risk later in life. “We wanted to capture a cohort of younger women … who ideally would be recruited before their first pregnancy, since this appears to be the time when most breast cancer risk accrues,” said Jorge Chavarro, MD, associate professor of nutrition and epidemiology at Harvard Chan School and principal investigator of NHS3.
Chavarro’s group is particularly interested in dietary exposures, physical activity, and geographically determined environmental exposures. They will rely more heavily on wearable devices and smartphone-based technologies to produce objective data on these exposures, he said. Pending funding approval from the National Institutes of Health, biospecimens and biomarkers will also figure heavily into the research.
Prentice emphasized the importance of such improvements to exposure assessments: “Bringing in objective measures at specific time points is a major research pathway that hasn’t been very fully utilized,” he said.
NHS3 updates the study design in several additional ways. The survey is delivered via email, with questionnaires sent every 6 months instead of 2 years. Among other benefits, this allows investigators to capture perinatal exposures more reliably. Male nurses are also welcome to join so researchers can learn more about their chronic disease risk factors.
Some of the changes help to address criticism that NHS and NHS-II are not sufficiently racially and ethnically diverse. Chavarro is working to recruit a more heterogeneous sampling of nurses to make the data more generalizable. For the first time, enrollment is open to licensed practical nurses and licensed vocational nurses in addition to registered nurses, with the goal of increasing the cohort’s diversity. Geographic diversity has also been expanded in NHS3, with better representation in rural areas and the inclusion of Canadian nurses.
Meanwhile, since 1996 the Growing Up Today Study (GUTS) has tracked NHS-II participants’ children, who are now in their 20s and 30s. Investigators are studying how psychosocial factors lead to cancer-associated behaviors in this group, like smoking and alcohol consumption, and how intermediate end points such as benign breast disease may contribute to breast cancer down the line, said GUTS Director and NHS investigator Rulla M. Tamimi, ScD, an associate professor of medicine at HMS.
The NHS and GUTS researchers are also working to unravel the biological mechanisms behind breast cancer risk factors across the life course. “Maybe if we better understood what the mechanism was, we could still target those pathways [without] recommending that women have their children when they’re in their teens,” Tamimi said.
In the nearer term, Tamimi and other NHS investigators are working on integrating discoveries of risk factors into improved breast cancer risk prediction modelling for clinical use. Preliminary research from an NHS substudy presented at the American Association for Cancer Research annual meeting in April 2016 suggests that updating commonly used prediction models to incorporate a genetic risk score, mammographic density, and postmenopausal endogenous hormone levels could improve risk prediction.
“I do think we are really getting to that point where we will be able to more accurately bin women into high, medium, [or] low risk, and I think that’s what’s needed to change the way that we either screen or do targeted prevention,” Tamimi said.
Today, NHS investigators attribute much of the success of their historic study to the nurse participants. “They’re such an exceptional group,” Stampfer said. “A very high fraction responds right away to the very first mailing of questionnaires. I think many of them really feel like they’re part of a community.”
Of course, there’s a limitation to this cohort, which NHS investigators freely acknowledge: a group of health professionals may not be fully representative of the general population. But the tradeoff was worth it, said Le Marchand, a principal investigator on the Multiethnic Cohort Study, which investigates cancer risk factors in diverse populations. “Everything we do has a limitation,” he said. “They chose to focus on a population that was very compliant, [and] who were very knowledgeable about health, so that was a way to get good participation and very high-quality data.”
For her part, Glaser was matter of fact about her role in one of the most influential studies of women’s health ever conducted: “I thought it would be worthwhile. They were going to study nurses, and I thought we were a good group to follow.”
Time, it would seem, has proven her right.
Correction: This article was corrected online December 6, 2016, to correct the number of enrollees in 1976 and 1989 reported in the Figure.
Note: The print version excludes source references. Please go online to jama.com.
Abbasi J. The Nurses’ Health Study Takes Fresh Aim at Breast Cancer as It Heads Into Decade Five. JAMA. Published online November 23, 2016. doi:10.1001/jama.2016.15976