Obesity and Breast Cancer: Narrowing the Focus.

In large part, obesity represents the end result of excess calorie consumption.1 Because overweight or obesity has always been an issue, somemay ask whywe are focusing on it now.2 A unique change is occurring on a global scale.3 Overweight and obesity are more prevalent than ever in recorded history, rates have been rising in almost every society inwhichmedical recordsareavailable, and thenumberof individualswhoareoverweight or obese is at an all-time high. What is causing this unprecedented global phenomenon?Thesimpleanswer is thatmorepeopleare ingestingmore calories thantheyneed.Withoutdwellingonagriculturepolicy orgovernmentsupport for farming,wecanmarvel at theglobal calorie production and distribution machine that feeds and overfeeds so many of Earth’s citizens. (That is not to deny or ignore realpocketsofdeprivationandstarvation,butmanyare the consequence of war, cruelty, and corruption rather than production deficiencies.) Themeasurable result is pretty clear. The Centers for Disease Control and Prevention reported the prevalence of overweight and obesity at the state level, showing that the numberofAmericans in thehighestweight categoryhas risen from 10% to 14% tomore than 30% inmany regions of the country since 1990.4 It ispredicted thatmore than60%of theadult citizensofmanystateswillbe in thehighestbodymass index(BMI) category by 2030.5 Therearemanyconsequencesofbeingoverweightorobese inadulthood, including increased risksof type2diabetesmellitus, cardiovasculardiseases,arthritis, anddiminishedqualityof life, among many others. A specific issue is the risk of cancer, and an evenmore specific one is the risk of individual cancers or subtypes. These increased risks of cancer have been largely unknownto thegeneralpublic.6However, it is increasinglyevident that a variety of commonmalignant neoplasms are associated with obesity, and a recent National Cancer Institute projection7 suggests that increased BMIwill replace tobacco as the leadingmodifiable risk factor foradults in thecomingyears. This suggests a need for both public awareness and action. To identify themost effective potential interventions we would need to understand both how overweight and obesity cause (not “are associated with”) malignant diseases (or specificmalignantneoplasms)but alsowhichactions—weight loss through diet and calorie restriction being just 1 of many possible ones—are effective at lowering risk. The danger of inaction is before us—a growing public health burden in the form of cancer and other ailments—but which action to take remains far from clear. The article by Neuhouser et al8 in this issue of JAMA Oncology is an important contribution. It extends and refines our understanding of one of the risks of overweight and obesity: increased incidence of the most common manifestation of breast cancer (postmenopausal, hormone receptor–positive disease). This team of investigators used data from the Women’s Health Initiative clinical trials (WHI) drawn frommore than 67 000women older than 50 years (but <80 years) from 1993 to 1998whowere followed at 40US centers for amedian of 13 years. They adjudicated all cases of new primary breast cancer (detectedclinicallyor through theuseof regular screening mammography) and examined the risks for overweight, obese, andveryobesewomencomparedwith thosewhowere in thenormalweight category. In addition to identifying an increased risk forwomenwhoareoverweightorobese, theirdata suggest a dose-response relationshipwithhigherBMI categories associatedwithgreater relative risk. The collectionofWHI clinical trials includes some in which estrogen supplementation (aloneorwithprogesterone)was tested, but theynoteno significant modification of risk with the use of hormone replacement therapy.Finally, theydidnotdetect a change in risk forhormonereceptor–negativebreastcancers.Consideringearlier observations suggesting a protective effect for obesity among premenopausal women, Neuhouser et al8 help refine our understanding of the risk of overweight and obesity; it is a particular concern for themost common formof breast cancer, hormone receptor–positive postmenopausal disease. These investigators8 also made a frustrating observation with regard to weight loss: it was not protective, whereas weight gain (amongwomenwhowere in the nonoverweight/ nonobese category at baseline) raised risk. This challenges the simple suggestion that patients who are overweight or obese should just loseweight to reduce their cancer risk.Weight control (when achieved) may be very effective for many weightassociated illnesses andailments, but thedata suggesting that itwill reduce an already elevated risk of breast cancer are limited.We need clinical trials to determinewhetherweight loss andbody composition changes in overweight andobesitywill reduce breast cancer risk. The article by Neuhouser et al,8 along with other data, is a call for action on several fronts. First, we need to refine our understandingof thewhyoverweightandobesity raise therisks of somecancers. Classically, clear cell endometrial cancer, but also a large number of others, including a range of gastrointestinal primary, prostate, and breast cancers, has been associated with overweight and obesity, but recently so has nonHodgkin lymphoma.9Ourgrouphas focusedonthe importance of subclinicalwhite adipose tissue inflammationand itsdownstream consequences including induction of aromatase (and henceestrogen synthesis).7 Changes in levels ofnumerous cirAuthor Audio Interview at jamaoncology.com