Emond JA, Pierce JP, Natarajan L, et al. Risk of breast cancer recurrence associated with carbohydrate intake and tissue expression of IGFI receptor. Cancer Epidemiol Biomarkers Prev. 2014;23(7):1273-1279. Epub 2014 Apr 22.
Nested, case control study designed to determine associations between insulin-like growth factor 1 receptor (IGF-1R) expression of the primary tumor, postdiagnosis changes in carbohydrate intake, and breast cancer recurrence
Data on 265 postmenopausal women with a diagnosis of breast cancer recurrence were extracted from the Women’s Healthy Eating and Living (WHEL) Study. Controls were also from the WHEL study, matched for age, stage of primary tumor (I-III), and time from diagnosis to enrollment in study. There were 91 cases matched to 174 controls. The average age was 57 years, average body mass index was 28.7 kg/m2, and the majority of participants had received chemotherapy, radiation therapy, and/or tamoxifen. Median time of follow-up was 7.3 years from start of the WHEL study.
IGF-1R expression on the primary tumor was given a rating of 0 to 3, based on total membrane staining and intensity for IGF-1 receptors. Any expression (1-3) was considered “positive” of IGF-1R, and those with a score of 0 were considered negative. Changes in carbohydrate consumption from year 1 vs baseline were divided into 3 categories: decreased (<26.8 g/d), stable (26.8 g/d-22.2 g/d), and increased (>22.2 g/d). To preserve meaningful statistical power for analysis, the stable and increased intake groups were combined into 1 group.
The number of primary tumors from women varied by ethnicity, with non-Hispanic whites having a lower rate of IGF-1R expression (47.5%) vs Hispanics (57.9%) and African Americans (91.7%). The difference between ethnicities reached statistical significance (P=0.074). IGF-1R positivity, without consideration for carbohydrate intake, was associated with greater risk of recurrence (hazard ratio [HR]: 1.7; 95% confidence interval [CI]: 1.2-2.5). In the group who had IGF 1R–positive tumors, those with stable or increasing intake of carbohydrates had twice the risk of recurrence (HR: 2.0; 95% CI: 1.3-5.0) vs those in that group who decreased intake. The effect of stable or increased carbohydrate intake was dramatically higher in women with IGF-1R positivity (HR: 5.5; 95% CI: 1.8-16.3) vs those who were receptor negative. This variation in recurrence with increased/stable carbohydrate intake between those with IGF 1R–positive tumors vs those who had negative tumors reached borderline significance (P=0.11).
This is the first study to assess whether dietary changes postdiagnosis affect recurrence relative to expression levels of IGF-1R on the original tumor. The WHEL study, from which these cases and controls were drawn, was designed as a prospective interventional trial. Half of the WHEL participants were assigned a diet high in fruits, vegetables, and fiber and low in total fat, and half were simply given a printed copy of US Department of Agriculture dietary guidelines. The study found there was no difference in recurrence rates between the 2 groups.1 The current study suggests that the effects of dietary changes may be influenced by specifics of the tumor biology.
What is interesting in this particular study is that it was a very modest reduction in carbohydrate intake that had a measurable effect on risk.
The concept that IGF-1R expression confers a poorer prognosis in breast cancer is not new.2-4 IGF-1 is a well-known mitogen and can act on cells alone or in concert with insulin, another well-defined growth promoter. What is interesting in this particular study is that it was a very modest reduction in carbohydrate intake (26 g/d or more) that had a measurable effect on risk. The baseline average intake of carbohydrates across all participants was 243 g/d, so a mere reduction of just over 10% rendered significant differences in recurrence. It is essential to note that while the effect of carbohydrate restriction was most dramatic in the IGF 1R–positive group vs the IGF 1R–negative group, all women showed a trend for benefit from decreased carbohydrate intake.
IGF-1 binds with its receptor IGF-1R, and this binds with another IGF-1R or an insulin receptor to trigger cellular signaling involved in proliferation, antiapoptosis, proangiogenesis, and migration.5 The simplest explanation for an increased risk of recurrence in those with increased carbohydrate intake is that higher carbohydrates result in higher circulating insulin and IGF-1, which bind their respective receptors and induce the cellular changes leading to growth. This alone is sufficient explanation for the observed increased rates of recurrence in this study. However, it is also possible there is something more insidious going on.
Studies suggest that the intracellular changes induced by IGF-1R activation may undermine treatment efficacy. For example, radiation is used to lessen risk of local recurrence in the majority of women with breast cancer. Overexpression of IGF-1R is associated with resistance to the cytotoxic effects of radiation.6 Further, IGF-1R activation has been shown to decrease the cytotoxicity of chemotherapy and monoclonal antibodies such as trastuzumab (Herceptin).7,8 Last, there is evidence that IGF-1R pathway activation on cells that are estrogen receptor–positive may contribute to the endocrine-resistant disease that develops in a subset of these women.9 Any or all of these interferences with the cytotoxic effects of adjuvant treatments may contribute to the higher risk of recurrence in those with denser concentrations of IFG-1R in their tumors.
Again, restriction of carbohydrate intake appears to confer benefit to all women in the current study. While not statistically significant, women in the IGF 1R–negative group still had a reduction in recurrence with decreased carbohydrate intake postdiagnosis (HR: 0.7) vs the women who had stable/increased intake in that group. In short, it’s a no-lose proposition to cut carbohydrates. Given the underlying tumor biology, some women will derive greater benefit than others, but there is essentially no risk to this intervention.
One question that arises is whether more restriction is better. There is no way to determine this from the current study, but certainly studies looking at caloric restriction and/or intermittent fasting are intriguing. Interestingly, while carbohydrate restriction would be expected to lower insulin and IGF, data suggest that protein restriction and/or calorie restriction is more effective at lowering circulating IGF and increasing its binding proteins.10,11 Data also suggest that intermittent fasting may increase the cytotoxic effects of chemotherapeutics to cancerous cells while preserving normal cells.12 There is also good justification for caloric restriction during radiation treatment in an effort to lessen stimulation of IGF-1R, thus reducing radioresistance.13
An incidental finding in this study is the ethnic discrepancy in IGF-1R concentrations of the tumor. As the authors note, this was a small sample, and such findings need to be validated in larger studies. However, the implications are intriguing. African American women overall have a poorer prognosis than any other ethnic group. While access to care has long influenced this discrepancy, with African Americans having a greater likelihood of being diagnosed with later stages of disease, this study suggests that distinct molecular characteristics may lead to a more aggressive phenotype. This is in keeping with other studies showing the biology of the tumor is distinctly more aggressive in those of African descent. Certainly, we as practitioners should keep this finding in mind for our patients within the African diaspora.
In case there was any question about the integral role the IGF 1R–stimulated pathways play in tumor promotion, there are many pharmaceutical agents in various stages of development aimed at blocking its activation.13-16 While these drugs will take years to pan out, they can serve to underscore our rationale for targeting the pathway today.
This study provides further confirmation that dietary changes may have a profound effect on one’s risk of cancer recurrence. Whether you are a patient or practitioner, the operative question is not “Why?” but “Why not?” At the very least, a 10% restriction in carbohydrate intake sets a very doable goal for nearly anyone.
- Pierce JP, Natarajan L, Caan BJ, et al. Influence of a diet very high in vegetables, fruit, and fiber and low in fat on prognosis following treatment for breast cancer: the Women's Healthy Eating and Living (WHEL) randomized trial. JAMA. 2007;298(3):289-298.
- Railo MJ, von Smitten K, Pekonen F. The prognostic value of insulin-like growth factor-I in breast cancer patients. Results of a follow-up study on 126 patients. Eur J Cancer. 1994;30(3):307-311.
- Nielsen TO, Andrews HN, Cheang M, et al. Expression of the insulin-like growth factor I receptor and urokinase plasminogen activator in breast cancer is associated with poor survival: potential for intervention with 17-allylamino geldanamycin. Cancer Res. 2004;64(1):286-291.
- Peiró G, Adrover E, Sánchez-Tejada L, et al. Increased insulin-like growth factor-1 receptor mRNA expression predicts poor survival in immunophenotypes of early breast carcinoma. Mod Pathol. 2010;24(2):201-208.
- 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(9418):1346-1353.
- Turner BC, Haffty BG, Narayanan L, et al. Insulin-like growth factor-I receptor overexpression mediates cellular radioresistance and local breast cancer recurrence after lumpectomy and radiation. Cancer Res. 1997;57(15):3079-3083.
- Gooch JL, Van Den Berg CL, Yee D. Insulin-like growth factor (IGF)-I rescues breast cancer cells from chemotherapy-induced cell death–proliferative and anti-apoptotic effects. Breast Cancer Res Treat. 1999;56(1):1-10.
- Lu Y, Zi X, Zhao Y, Mascarenhas D, Pollak M. Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J Natl Cancer Inst. 2001;93(24):1852-1857.
- Fox EM, Kuba MG, Miller TW, Davies BR, Arteaga CL. Autocrine IGF-I/insulin receptor axis compensates for inhibition of AKT in ER-positive breast cancer cells with resistance to estrogen deprivation. Breast Cancer Res. 2013;15(4):R55.
- Fontana L, Weiss EP, Villareal DT, Klein S, Holloszy JO. Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans. Aging Cell. 2008;7(5):681-687.
- Longo VD, Fontana L. Calorie restriction and cancer prevention: metabolic and molecular mechanisms. Trends Pharmacol Sci. 2010;31(2):89-98.
- Lee C, Safdie FM, Raffaghello L, et al. Reduced levels of IGF-I mediate differential protection of normal and cancer cells in response to fasting and improve chemotherapeutic index. Cancer Res. 2010;70(4):1564-1572.
- Champ CE, Baserga R, Mishra MV, et al. Nutrient restriction and radiation therapy for cancer treatment: when less is more. Oncologist. 2013;18(1):97-103.
- Ma CX, Suman VJ, Goetz M, et al. A phase I trial of the IGF-1R antibody Cixutumumab in combination with temsirolimus in patients with metastatic breast cancer. Breast Cancer Res Treat. 2013;139(1):145-153.
- Mahadevan D, Sutton GR, Arteta-Bulos R, et al. Phase 1b study of safety, tolerability and efficacy of R1507, a monoclonal antibody to IGF-1R in combination with multiple standard oncology regimens in patients with advanced solid malignancies. Cancer Chemother Pharmacol. 2014;73(3):467-473.
- Rosen LS, Puzanov I, Friberg G, et al. Safety and pharmacokinetics of ganitumab (AMG 479) combined with sorafenib, panitumumab, erlotinib, or gemcitabine in patients with advanced solid tumors. Clinical Cancer Res. 2012;18(12):3414-3427.