IGF-1 and Cancer Risk

The authors undertook a meta-analysis of 26 published (and closely scrutinized) data-sets examining the relationship between circulating concentrations of IGF-I and IGFBP-3 and the risk of developing prostatic, breast, colon, and lung cancer in adult men and women employing extremely strict, unified, and sensitive analytical methods. After stratification of the analyte levels, they compared the 75^th percentile of circulating protein concentration with the 25^th percentile and then calculated odds ratios for the development of cancer. There were significant associations between the concentration of IGF-I and development of premenopausal breast, prostatic, and colon cancer (odds ratios: 1.93, 1.83, and 1.58, respectively). There was no association between IGF-I values and risk of breast cancer in postmenopausal women or of lung cancer. The IGFBP-3 level was associated with an increased risk of development of breast cancer in premenopausal women (odds ratio 1.96) and possibly with a protective effect on development of lung cancer. The investigators concluded that because of the proliferative and anti-apoptotic effects of various IGFs, higher circulating concentrations of IGF-I are a risk factor for development of 3 non-smoking related common malignancies.

Renehan AG, Zwahlen M, Minder C, O'Dwyer ST, Shalet SM, Egger M. Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet 2004;363:1346-1353.

First Editor’s Comment: The association of hyper-somatotropism with increased risk for development of cancer of the colon is well known.¹ The present report concluded that higher IGF-I concentrations contributed to the development of several malignancies. The mechanism(s) by which IGF-I enhanced or facilitated neoplasia and the roles that IGFBPs and IGFBP proteases (such as prostate specific antigen) played in this process are not known with certainty.² The precise point at which a malignancy began and the corresponding IGF-I value is unknown. However, the association between IGF-I concentrations and malignancy should give one pause when recommending the use of growth hormone (GH) in short subjects without GH deficiency, particularly in the absence of data indicating that an increment in adult height of 2 or more inches results in greater academic, social, and economic well-being.

Allen W. Root, M.D

Second Editor’s Comment: The major lesson from the IGF/cancer association is to beware of over generalizations; this is a story of complicated nuances. Over 200,000 patient-years’ experience globally with recombinant human growth hormone (rhGH) therapy revealed a very strong safety profile. This safety profile may not hold as our use moves from purely physiologic replacement to increasingly pharmacologic use, in terms of both higher doses and newer indications. For example, increased mortality ensued when rhGH was administered to critically ill adults in an attempt to foster anabolism.³ Conversely, we cannot jump to the conclusion that IGF-1 (and GH) are necessarily harmful. While high IGF-1 levels have been associated with higher cancer risk, low IGF-1 levels have been associated with increased risk for age-related memory loss, Alzheimer’s dementia and diabetes-associated dementia.

The underlying science is also filled with nuances that likely contribute to the contradictory results found in the literature. The relative contributions of endocrine (circulating) versus autocrine or paracrine GH/IGF axis components to cancer progression remain unclear and technical issues, such as IGFBP interference with some IGF assays⁴ and interassay variations,⁵ can cloud the results. Due to its dynamic nature, measuring components of the IGF system may yield different results, ie a shift in the amount of free versus total IGF, the IGFBP profile, or the amount of intact versus proteolyzed IGFBP.

More research is needed, as in long-term surveillance of the rhGH recipients into late adulthood when the natural incidence of cancer increases. As a safety marker, IGF-1 levels should be closely monitored in all rhGH recipients to avoid supraphysiologic concentrations. Clinical nuances may also be explored regarding potential risk modulation by altering rhGH dose or duration of treatment.⁴ Ultimately, treatment should be individualized and tailored to the risk/benefit analysis for each patient. That includes appreciating the true benefit (or not) of height augmentation.

Adda Grimberg, MD

References - (linked to )

1. Wolk A. The growth hormone and insulin-like growth factor I axis, and cancer. Lancet 2004;363:1336-1337.
2. Grimberg A. Mechanisms by which IGF-I may promote cancer. Cancer Biol Ther. 2003 Nov-Dec;2(6):630-5
3. Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med. 1999 Sep 9;341(11):785-92
4. Grimberg A, Cohen P. Growth hormone and prostate cancer: guilty by association? J Endocrinol Invest. 1999;22(5 Suppl):64-73
5. Milani D, Carmichael JD, Welkowitz J, Ferris S, Reitz RE, Danoff A, Kleinberg DL. Variability and reliability of single serum IGF-I measurements: impact on determining predictability of risk ratios in disease development. J Clin Endocrinol Metab. 2004 May;89(5):2271-4.