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Tong Y, Wu J, Huang O, et al. IGF-1 interacted with obesity in prognosis prediction in HER2-positive breast cancer patients. Front Oncol. 2020;10:550.
To evaluate the prognostic value (recurrence and mortality) of insulin-like growth factor 1 (IGF-1) and metabolic abnormalities in women with a history of HER2+ breast cancer
Researchers analyzed data from 679 Chinese breast cancer patients, all of whom were positive for human epidermal growth factor receptor 2 (HER2+) and who had been treated at Ruijin Hospital in Shanghai, China, between November 2012 and June 2017. There were 299 women whose tumors were estrogen receptor (ER) positive and 380 who had ER-negative tumors. There were 244 women under 50 years of age and 435 women 50 years of age or more. There were 394 postmenopausal participants and 285 peri/premenopausal participants. Nearly all of the women had received prior chemotherapy (n=606). Of the 679 women, 209 had metabolic syndrome (MetS) as defined by the criteria of the American Heart Association (AHA) and the National Heart, Lung, and Blood Institute (NHLBI). Being overweight was defined by body mass index (BMI) ≥ 24.0 kg/m2, which is 1 BMI point lower than is customary in most studies in the United States.
Researchers calculated recurrence-free survival (RFS) from the date of surgery to the first recurrent event or death from any cause. Parameters measured included BMI, fasting glucose, IGF-1, IGF binding protein 3 (IGFBP-3), insulin, C-peptide, triglycerides, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). Researchers divided the participants into 2 cohorts based on high or low IGF-1 levels.
As tumor size, node involvement, histological grade, hormone receptor status, proliferation index, HER2-enrichment intrinsic subtype, and anti-HER2 therapy application are known prognostic factors for HER2+ cancers, the researchers tracked these parameters as well.
The median IGF-1 of the participants was 160.00 ng/mL, and the researchers used this midpoint as the dividing line between low or high IGF-1. High IGF-1 (P<0.001) and high IGFBP-3 (P<0.001) were both more common in pre- and perimenopausal women. After a median of 3 years follow-up, 52 women had disease recurrence. IGF-1 levels were not associated with recurrence-free survival (RFS, P=0.620) overall (N=679).
However, when BMI was taken into account, RFS analysis revealed a clear association between IGF-1 and RFS; BMI and IGF-1 interacted in predicting RFS (P=0.009). For non-overweight patients, high IGF-1 levels were associated with a superior 4-year RFS (91.1% vs 85.0%; HR 0.53, 95% CI 0.27–1.00, P=0.049) compared with non-overweight patients with low IGF-1 levels. In contrast, for overweight patients, high IGF-1 was associated with an impaired 4-years RFS (88.3% vs 95.7%; HR 3.20, 95% CI 1.00–10.21, P=0.038) versus overweight women with low IGF.
Overall, the IGF-1/IGFBP-3 ratio was much higher in the recurrent patients compared to those without recurrence (45.14 vs 40.53, P=0.030) regardless of BMI. Overall, recurrent patients also had higher C-peptide levels (2.24 vs 2.04, P=0.045).
Again, the only metabolic variables that differed between those with recurrence and those disease-free were the IGF-1/IGFBP-3 ratio and circulating C-peptide level unless the groups were divided by BMI. Blood pressure (P<0.001), IGFBP-3 (P<0.001), insulin (P<0.001), C-peptide (P=0.001), and the number of MetS components (P=0.033) significantly differed by IGF-1 expression, but not when comparing recurrent and nonrecurrent groups.
The results for overall survival and IGF levels were also stratified by BMI. High IGF-1 was protective in non-overweight patients but appeared to be a risk factor for those who were overweight. High IGF-1 levels were independently associated with better overall survival (OS) in the whole cohort (HR 0.26, 95% CI 0.08–0.82, P=0.044) as well as in the non-overweight population (n=433; HR 0.15, 95% CI 0.03–0.68, P=0.005).
For women with a history of HER2+ breast cancer who are overweight, preference is for below-average IGF-1 levels, but for those who are at a healthy weight, elevated IGF-1 levels might be preferred.
Treatment with “targeted therapy” (trastuzumab [Herceptin]) non-significantly improved OS from 96.7% to 97.7% (P=0.149). Better 4-year OS was observed in the high IGF-1 group compared to the low IGF-1 group (99.2% vs 95.8%, P=0.044). Subgroup analysis showed a modest but insignificant interaction of IGF-1 and BMI in predicting OS (P for interaction=0.054). High IGF-1 levels were associated with improved OS in non-overweight women (4-years OS 99.4% vs 93.7%, P=0.005; HR 0.15, 95% CI 0.03–0.68), but not in overweight women (4-years OS 98.7% vs 98.9%, P=0.438; HR 2.51, 95% CI 0.23–27.63, P for interaction=0.054).
For lean patients with HER2+ disease, high IGF-1 was significantly associated with better OS (P =0.020). For patients who received HER2 targeted therapy (trastuzumab), IGF-1 levels interacted with obesity; in patients with BMI < 24.0 kg/m2 who received adjuvant therapy, those with higher IGF-1 had significantly superior OS than those with lower IGF-1 (P<0.001).
This is the largest study to date that looks at the relationship between IGF-1 and HER2+ breast cancer, and the first to report a significant interaction between IGF-1, BMI, and outcomes.
The reported conclusions stand in contrast to what many of us would have predicted and require our careful attention as these findings may influence the interventions that we suggest to some breast cancer patients who are HER2+.
Our basic understanding of insulin-like growth factor is that it is critical to the growth, development, and maintenance of many tissues in the human body.1 IGF-1 is especially important during neonatal and pubertal growth and acts by stimulating cell proliferation and interrupting programmed cell death.2 IGF-1 is of particular importance in breast tissue development. Binding of IGF-1 to its receptor (IGF-1R) stimulates activation of the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways that cause cell proliferation. There are a half dozen IGF binding proteins that moderate IGF bioavailability and half-life, although in vivo the majority of IGF binds to IGFBP-3.
IGF-1 signaling is involved in 87% of invasive breast cancers.4 For several years we have relied on a hypothesis that cross-talk exists between the IGF-1 pathway, insulin, and the epidermal growth factor receptor family. Given our current understanding and hypothesis, increased IGF signaling should lead to progression of breast cancer and metastatic invasion, and promote resistance to therapies such as chemotherapy and radiotherapy.4,5 Elevated insulin levels bind to certain IGF-1 receptors on breast cancer cells and stimulate proliferation.6 This has been our rationale for encouraging women with a history of breast cancer to reduce excess carbohydrate consumption, as this might lower insulin production. In keeping with this line of thought, an increase in IGF is expected to lead to a decrease in breast cancer survival7 and an increased all-cause mortality in HER2+ patients.8 Or at least this has been our rationale and approach to date.
This study amends this thinking and suggests that a benefit from lowering IGF-1 only occurs in women who are overweight. In healthy weight women, it appears higher levels of IGF-1 are associated with possible benefit against recurrence and that strategies for lowering IGF-1 might be counterproductive, at least in those who had HER2+ tumors.
Fasting and fasting-mimicking diets reliably lower IGF-1 levels, and this effect has been used to explain the benefits of these diets on limiting cancer growth and improving survival. Stefanie de Groot et al reported in Nature Communications earlier this year that in a randomized trial of 131 HER2-negative breast cancer patients who either followed a fasting-mimicking diet or their regular diet for 3 days prior to and during chemotherapy, that a complete or partial response to treatment occurred more often in those following the fasting-mimicking diet, presumably because they had lowered their IGF-1 levels.9
Thus, we are left with seemingly conflicting data. Fasting, which lowers IGF-1, seems helpful for breast cancer patients in general, but lower IGF-1 levels are associated with a worse prognosis in women with HER2+ breast cancer—unless the patients are overweight, with a BMI ≥ 24.0 kg/m2, and then lower IGF levels are a possible advantage. We must remember that this was a retrospective study, and the associations reported should not be interpreted as causative. We should note that this isn’t the first report that differentiates the effect of IGF-1 in women with a history of breast cancer based on BMI. In 2013, Catherine Duggan et al reported that increased IGF-1 levels were associated with an approximately 2-fold greater risk of breast cancer-specific mortality in participants with a BMI > 25 kg/m2, but not in lean women. On the other hand, they also found that high serum levels of IGF-1 and the IGF-1/IGFBP-3 ratio were associated with increased risk of all-cause mortality in women with breast cancer.8 Duggan’s study participants were not limited by HER2 status, and their findings suggest that a similar division by BMI might apply to a broader range of breast cancer patients.
Clearly something else is at play in the high BMI subgroup of women with HER2+ breast cancer and also possibly with other breast cancer subtypes. The authors have not offered a theory to explain their results.
For HER2+ patients, if this study is to be relied upon, assessment of both IGF-1 levels and BMI become crucial in making our therapeutic suggestions. For women with a history of HER2+ breast cancer who are overweight, preference is for below-average IGF-1 levels, but for those who are at a healthy weight, elevated IGF-1 levels might be preferred.
These findings may influence our general recommendations regarding fasting. We may reconsider the general dietary suggestions we have made aimed at impacting IGF-1 levels. High animal-protein diets raise IGF-1 levels while low animal-protein diets are associated with decreased IGF-1. Thus, in HER2+ breast cancer, we may even want to fine-tune diet recommendations based on BMI and IGF-1 levels. For normal-weight women, a diet high in animal protein, associated with elevated IGF, might be advantageous compared to a vegan diet that will lower IGF. For overweight women, the opposite recommendation might be appropriate.
- LeRoith D, Roberts CT Jr. The insulin-like growth factor system and cancer. Cancer Lett. 2003;195:127-137.
- Vincent AM, Feldman EL. Control of cell survival by IGF signaling pathways. Growth Horm IGF Res. 2002;12:193-197.
- Christopoulos PF, Msaouel P, Koutsilieris M. The role of the insulin-like growth factor-1 system in breast cancer. Mol Cancer. 2015;14:43.
- Denduluri SK, Idowu O, Wang Z, et al. Insulin-like growth factor (IGF) signaling in tumorigenesis and the development of cancer drug resistance. Genes Dis. 2015;2:13-25.
- Nahta R. Pharmacological strategies to overcome HER2 cross-talk and trastuzumab resistance. Curr Med Chem. 2012;19:1065-1075.
- Lanzino M, Morelli C, Garofalo C, et al. Interaction between estrogen receptor alpha and insulin/IGF signaling in breast cancer. Curr Cancer Drug Targets. 2008;8(7):597-610.
- Yerushalmi R, Gelmon KA, Leung S, et al. Insulin-like growth factor receptor (IGF-1R) in breast cancer subtypes. Breast Cancer Res Treat. 2012;132:131-142.
- Duggan C, Wang CY, Neuhouser ML, et al. Associations of insulin-like growth factor and insulin-like growth factor binding protein-3 with mortality in women with breast cancer. Int J Cancer. 2013;132:1191-1200.
- de Groot S, Lugtenberg RT, Cohen D, et al. Fasting mimicking diet as an adjunct to neoadjuvant chemotherapy for breast cancer in the multicentre randomized phase 2 DIRECT trial. Nat Commun. 2020;11(1):3083.