Science: Krebs und Stoffwechsel

Aerobic glycolysis, the Warburg effect, describes tumor cells consuming glucose at high rates and producing lactate despite adequate oxygen, whereas most normal cells reserve fermentation for low-oxygen conditions. The modern interpretation is that a rapidly dividing cell needs biosynthetic precursors (carbon and nitrogen for membranes, nucleotides and proteins) as much as it needs ATP, and running glucose partway through glycolysis leaves those intermediates available. It is understood as the metabolism of a cell committed to growth, not as evidence of mitochondrial failure.

The 2011 hallmarks-of-cancer update added reprogramming of energy metabolism (deregulated cellular energetics) to the set of capabilities a cancer acquires as it develops. This situates the metabolic changes this page describes within the dominant genetic model of cancer: mutations in growth-controlling genes are treated as the driving events, and metabolic reprogramming is one of the enabling capabilities that follows and interacts with them. It is a framework statement, not a single experimental result.

The International Agency for Research on Cancer convened a Working Group that reviewed over a thousand studies and concluded the evidence was sufficient for a cancer-preventive effect of the absence of excess body fatness for thirteen cancer types: colon and rectum, esophagus (adenocarcinoma), gastric cardia, liver, gallbladder, pancreas, postmenopausal breast, corpus uteri (endometrium), ovary, kidney (renal cell), meningioma, thyroid and multiple myeloma. This expanded the list of five cancers identified in the agency's earlier 2002 evaluation.

The MA.32 randomized controlled trial assigned 3,649 patients with high-risk, non-metastatic breast cancer and no diabetes to metformin or placebo alongside standard therapy. In the hormone-receptor-positive subset the primary endpoint of invasive disease-free survival showed no benefit (HR 1.01, 95% CI 0.84-1.21; P=0.93), and overall survival was likewise unaffected (HR 1.10, 95% CI 0.86-1.41; P=0.47). It is the most rigorous test to date of the widely repeated idea, drawn from observational data, that a diabetes drug treats cancer, and it was null for the main outcomes.

A pooled analysis of 12 prospective cohorts (1.44 million participants, 186,932 cancers) compared high versus low leisure-time physical activity and found lower risk for 13 of 26 cancer types, including esophageal, liver, lung (HR 0.74), kidney, gastric cardia, endometrial, colon (HR 0.84) and breast (HR 0.90). Most associations persisted after adjustment for body mass index and smoking. Activity was associated with higher risk of malignant melanoma (HR 1.27), likely reflecting sun exposure during outdoor activity.

A joint consensus report from the American Diabetes Association and the American Cancer Society reviewed the association between diabetes and cancer. It reported type 2 diabetes associated with roughly a twofold higher risk of cancers of the liver, pancreas and endometrium, and a 1.2 to 1.5 fold higher risk of cancers of the colon and rectum, breast and bladder, while risk of prostate cancer was lower in men with diabetes. The report stressed the difficulty of separating the effect of diabetes from the shared upstream risk factors of obesity, aging, physical inactivity and diet.

The SPLENDID matched-cohort study followed 5,053 adults with obesity who underwent bariatric surgery and 25,265 matched non-surgical patients (median follow-up 6.1 years). Obesity-related cancer incidence at 10 years was 2.9% with surgery versus 4.9% without (adjusted HR 0.68, 95% CI 0.53-0.87), and cancer-related mortality was 0.8% versus 1.4% (adjusted HR 0.52, 95% CI 0.31-0.88). This is evidence that substantial intentional weight loss tracks with lower cancer risk, from surgery, not diet.

A 2021 systematic review and meta-analysis of low-carbohydrate ketogenic diets as adjuvant cancer therapy found inadequate evidence to support beneficial antitumor effects; body weight, total cholesterol and fasting glucose did not shift meaningfully, and only ketosis achievement, satisfaction and a fall in the PSA marker reached significance. A 2017 systematic review of isocaloric ketogenic regimes reached the same conclusion, that evidence supporting effects on tumor development or progression is absent and more robust clinical data are needed before the diet can be recommended for any cancer. Trials were small, short and heterogeneous, and strict ketogenic adherence during treatment is difficult.

The phase 2 DIRECT trial randomized 131 patients with HER2-negative stage II/III breast cancer to a fasting-mimicking diet or a regular diet around neoadjuvant chemotherapy. Toxicity did not differ between the groups. The radiological response was better with the diet in the intention-to-treat and multivariable-adjusted analyzes (OR 3.2, P=0.039), while the pathological response defined as 90-100% tumor cell loss reached significance only in the per-protocol analysis (OR 4.1, P=0.016), and the diet reduced chemotherapy-induced DNA damage in T-lymphocytes. As a small phase 2 trial whose pathological signal rests on per-protocol analysis, it is a hypothesis for larger trials to test, not evidence that diet treats cancer.