When are risk factors good for identifying women at high risk of cancer

Media coverage this week draws attention to a well-known fact in epidemiologic research. A risk factor alone does not always identify the top stratum of risk for a disease. Kerlikowske and colleagues from the NCI-funded breast cancer surveillance consortium draw on prospective data to demonstrate for women that a mammographic report of dense breasts is not sufficient on its own to identify woman at high risk for breast cancer (see the story). This principle applies to heart disease, cancer and other illnesses. Professor Wald wrote eloquently on this more than a decade ago when he showed that the relative risk for any risk factor had to be huge to on its own identify a stratum at very high risk of disease.(1) A detailed presentation is available at the British Medical Journal. If we use a risk factor as a screening test to classify those who will get disease and those who will not, we may need a large relative risk. For example, using 2.8 as the relative risk (comparable to the top 10% of women scored on the Gail model in the Nurses’ Health Study), we will detect or predict only 15% of cancers.(2) To detect more than 50% of cancers with less than 5% false positive rate, we need a relative risk of more than 100. This is beyond the ability of lifestyle and genomic risk factors combined for most of our common major illnesses. Even women with BRCA 1 or 2 have only about 50% chance of developing breast cancer in their lifetime.

We might remember that many risk factors combine to increase (or decrease) risk of disease. Holding age constant (since we cannot change our age at any given time), we can see that for breast cancer several common risk factors such as family history may double a woman’s risk. Never having children increases risk compared to women who have one or more children. A history of dense breasts (see recent media coverage) may increase risk 3-fold compared to those with the extreme of no dense breast tissue on mammography. This increase in risk is about the same as that seen in the subset of women with benign breast disease. For women with benign breast disease (BBD) confirmed by breast biopsy and whose pathology review (under the microscope) shows proliferative changes that include cells with atypia, the relative risk is 4 to 5 when their risk is compared to that of a women who has not had benign breast disease.(3-5)

To summarize risk, we multiply out the risk (increase or decrease) for each factor. In the Nurses’ Heath Study when we do this, we see that women in the top 10% of risk have more than 6 times the rate of breast cancer of those in the lowest 10 percent of risk.(6) This is true in each 5-year age group. Importantly, 25% of all breast cancers are diagnosed among the women in the top 10% of risk. Hence this group may be a subset of women for women prevention strategies should be emphasized. Our model for calculating breast cancer risk, validated in independent prospective data, outperforms the commonly used Gail model (7). This is in part because it includes several risk factors omitted from the Gail model – such as later age at menopause, use of postmenopausal hormones, alcohol, and obesity – all well known causes of breast cancer. (8-10)

What does this mean?

Being smart about how to interpret studies is important. Living a healthy lifestyle is the best insurance against getting cancer, heart disease diabetes, and other major illnesses. In fact, women who followed the American Cancer Society diet and physical activity guidelines (11) had significantly lower risk of cancer and all cause mortality during following than those who did not. Women in the lowest category of risk, following all the guidelines, had more than a 20% reduction in their risk of breast cancer over 12 years and more than 50% reduction in their risk of colorectal cancer. Put simply, during 12 years of follow-up, women who maintained a healthy weight, were physically active, consumed a diet with emphasis on plant sources, and limited alcohol to 1 drink or less per day, had significantly lower cancer risk compared to those who did not follow the guidelines.(12)

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1. Wald NJ, Hackshaw AK, Frost CD. When can a risk factor be used as a worthwhile screening test? BMJ. 1999;319(7224):1562-5.
2. Rockhill B, Spiegelman D, Byrne C, Hunter DJ, Colditz GA. Validation of the Gail et al. model of breast cancer risk prediction and implications for chemoprevention. Journal of the National Cancer Institute. 2001;93(5):358-66. Epub 2001/03/10. PubMed PMID: 11238697.
3. London SJ, Connolly JL, Schnitt SJ, Colditz GA. A prospective study of benign breast disease and the risk of breast cancer. JAMA. 1992;267(7):941-4. Epub 1992/02/19. PubMed PMID: 1734106.
4. Marshall LM, Hunter DJ, Connolly JL, Schnitt SJ, Byrne C, London SJ, Colditz GA. Risk of breast cancer associated with atypical hyperplasia of lobular and ductal types. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 1997;6(5):297-301. Epub 1997/05/01. PubMed PMID: 9149887.
5. Dyrstad SW, Yan Y, Fowler AM, Colditz GA. Breast cancer risk associated with benign breast disease: systematic review and meta-analysis. Breast cancer research and treatment. 2015;149(3):569-75. doi: 10.1007/s10549-014-3254-6. PubMed PMID: 25636589.
6. Chen WY, Rosner B, Colditz GA. Moving forward with breast cancer prevention. Cancer. 2007;109(12):2387-91. PubMed PMID: 17464950.
7. Rosner BA, Colditz GA, Hankinson SE, Sullivan-Halley J, Lacey JV, Jr., Bernstein L. Validation of Rosner-Colditz breast cancer incidence model using an independent data set, the California Teachers Study. Breast cancer research and treatment. 2013;142(1):187-202. doi: 10.1007/s10549-013-2719-3. PubMed PMID: 24158759.
8. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (2007: Lyon France). Alcohol consumption and ethyl carbamate. Lyon, France: International Agency for Research on Cancer; Distributed by WHO Press; 2010.
9. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans., World Health Organization. IAfRoC. Combined estrogen-progestogen contraceptives and combined estrogen-progestogen menopausal therapy. Lyon, France. Geneva: International Agency for Research on Cancer ; Distributed by WHO Press; 2007. ix, 528 p. p.
10. International Agency for Research on Cancer. Weight Control and Physical Activity. Lyon: International Agency for Research on Cancer; 2002. 315 p.
11. Kushi LH, Doyle C, McCullough M, Rock CL, Demark-Wahnefried W, Bandera EV, Gapstur S, Patel AV, Andrews K, Gansler T, American Cancer Society N, Physical Activity Guidelines Advisory C. American Cancer Society Guidelines on nutrition and physical activity for cancer prevention: reducing the risk of cancer with healthy food choices and physical activity. CA Cancer J Clin. 2012;62(1):30-67. doi: 10.3322/caac.20140. PubMed PMID: 22237782.
12. Thomson CA, McCullough ML, Wertheim BC, Chlebowski RT, Martinez ME, Stefanick ML, Rohan TE, Manson JE, Tindle HA, Ockene J, Vitolins MZ, Wactawski-Wende J, Sarto GE, Lane DS, Neuhouser ML. Nutrition and Physical Activity Cancer Prevention Guidelines, Cancer Risk, and Mortality in the Women’s Health Initiative. Cancer Prev Res (Phila). 2014;7(1):42-53. doi: 10.1158/1940-6207.CAPR-13-0258. PubMed PMID: 24403289.

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