The average human lifespan increased dramatically during the 20^th century, driven largely by advances in public health, nutrition, and effective treatment for a growing list of infectious diseases. Building on that progress will require more effective approaches to deal with chronic conditions such as cardiovascular disease and cancer.

“Prevention is better than therapy in cancer,” said Adriana Albini, PhD, Fondaziona MultiMedican Onlus. “Both cardiovascular disease and cancer have risk factors including diet, weight, physical activity, and smoking, that we can modify. You can do something to prevent cancer even if you have started with bad habits. If you are overweight, you can lose weight and change your diet habits. And chemoprevention is very real.”

Albini moderated the session Molecular Targets of Precision Prevention and Interception and a related live panel discussion. Annual Meeting registrants can watch a replay of them through June 21, 2021.

Targeted prevention could change the course of a rising epidemic of early death in women linked to a combination of poor diet and low levels of physical activity. Obesity is the obvious culprit, particularly in the development of estrogen receptor positive (ER+) breast cancer.

There is a clear connection between obesity, inflammation, and breast cancer. Obesity triggers estrogen synthesis, insulin resistance, and altered adipokine and cytokine production, all linked to angiogenesis, cell proliferation, and cell survival in breast cancer.

“Obesity causes an inflammatory state of crown-like structures (CLS) in adipose tissue made up of hypertrophic adipocytes surrounded by macrophages,” said Andrew J. Dannenberg, MD, Weill Cornell Medical College. “CLSs and breast white adipose tissue inflammation are common in the breasts of overweight and obese women. This subclinical inflammation is associated with changes in gene expression, and elevation of insulin is linked to the pathogenesis of ER+ breast cancer.”

The same pathophysiology can be seen in about a third of normal-weight women, he added. An analysis of Women’s Health Initiative data found that elevated truncal fat, even in women with normal BMI, carries similar cancer risk.

Dannenberg said that a lifestyle intervention trial to improve body composition in women with normal BMI, originally planned for 2020, will begin after the COVID-19 pandemic ends.

Adipose tissue is an obvious culprit in breast cancer, but insulin resistance and insulin-driven cancer biology are the real problems, said Victoria Seewaldt, MD, City of Hope Comprehensive Cancer Center.

“Insulin is upstream of several pathways that contribute to breast cancer,” Seewaldt said. “And in normal-weight women, Insulin resistance is driven by more aggressive cancer biology.”

Insulin resistance activates aggressive Wnt/EZH2 and pAKT signaling pathways that can promote genomic instability and encourage tumor growth.

Blocking insulin resistance could interfere with cancer-promoting pathways, Seewaldt said. A 12-month, multicenter study of metformin in premenopausal women with mammary atypia is ongoing.

Prostate cancer is more puzzling. Many men are diagnosed with indolent disease that is unlikely to be lethal.

“A minority of men will progress to metastatic cancer,” said Cory Abate-Shen, PhD. “The challenge is to identify those few men who require aggressive intervention in the form of prevention at an early stage.”

Abate-Shen, Herbert Irving Comprehensive Cancer Center, Molecular Pharmacology & Therapeutics, Columbia University Irving Medical School, identified dysregulation of the homeobox gene NKX3.1 as a vital step in the development and progression of prostatic intraepithelial neoplasia (PIN).

NKX3.1 protects against inflammation, oxidative stress, and DNA damage, she said. Loss or reduction leads to defects in differentiation, cellular senescence, and cancer initiation. It is commonly present in the nucleus and migrates to the mitochondria in response to oxidative stress.

At least two polymorphisms in NKX3.1 are incapable of protecting against oxidative stress and are associated with increased risk of aggressive cancer types.

“Monitoring NKX3.1 status in men on active surveillance would provide a great opportunity for precision prevention and to identify men at the highest risk for progression,” she said.