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This article is part of our special October 2020 issue. Download the full issue here.
Relation
Tong Y, Wu J, Huang O, et al. IGF-1 interacted with adiposity in prognosis prediction in HER2-positive breast cancer patients.Front Onk. 2020;10:550.
Draft
Retrospective study
Objective
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
Participant
Researchers analyzed data from 679 Chinese breast cancer patients, all positive for human epidermal growth factor receptor 2 (HER2+), who were 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 older. There were 394 postmenopausal participants and 285 peri-/premenopausal participants. Almost all women had previously received chemotherapy (n=606). Of the 679 women, 209 had metabolic syndrome (MetS) according to American Heart Association (AHA) and National Heart, Lung, and Blood Institute (NHLBI) criteria. Overweight was defined by a body mass index (BMI) ≥ 24.0 kg/m2which is 1 BMI point lower than usual in most studies in the United States.
Target parameters
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 (HDL-C). Dense lipoprotein cholesterol (LDL-C). Researchers divided participants into 2 cohorts based on high or low IGF-1 levels.
Because tumor size, lymph node involvement, histologic grade, hormone receptor status, proliferation index, intrinsic HER2 enrichment subtype, and use of anti-HER2 therapy are known prognostic factors for HER2+ cancers, the researchers also tracked these parameters.
Key insights
The participants' mean IGF-1 level was 160.00 ng/ml, and the researchers used this midpoint as a dividing line between low and high IGF-1 levels. High IGF-1 (P<0.001) and high IGFBP-3 (P<0.001) were both more common in premenopausal and perimenopausal women. After a median follow-up of 3 years, 52 women experienced disease recurrence. IGF-1 levels were not associated with recurrence-free survival (RFS,P=0.620) in total (N=679).
However, when BMI was taken into account, RFS analysis showed a clear association between IGF-1 and RFS; BMI and IGF-1 interacted in predicting RFS (P=0.009). In non-obese patients, high IGF-1 levels were associated with superior 4-year RFS (91.1% vs. 85.0%; HR 0.53, 95% CI 0.27-1.00,P=0.049) compared to non-obese patients with low IGF-1 levels. In contrast, in obese patients, high IGF-1 was associated with impaired 4-year RFS (88.3% vs. 95.7%; HR 3.20, 95% CI 1.00-10.21,P=0.038) compared to overweight women with low IGF.
Overall, the IGF-1/IGFBP-3 ratio was much higher in the relapse patients than in the patients without relapse (45.14 vs. 40.53,P=0.030) regardless of BMI. Overall, relapsed 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 relapse and those without disease were the IGF-1/IGFBP-3 ratio and the amount of circulating C-peptide, 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) differed significantly by IGF-1 expression, but not when comparing the recurrent and non-recurrent groups.
Results for overall survival and IGF levels were also stratified by BMI. High IGF-1 was protective in non-obese 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 entire cohort (HR 0.26, 95% CI 0.08-0.82,P=0.044) and in the non-obese population (n=433; HR 0.15, 95% CI 0.03–0.68,P=0.005).
In obese women with a history of HER2+ breast cancer, lower than normal IGF-1 levels are preferred, but in women of healthy weight, elevated IGF-1 levels may be preferred.
Treatment with “targeted therapy” (trastuzumab [Herceptin]) did not significantly improve OS from 96.7% to 97.7% (P=0.149). Better 4-year OS was observed in the high IGF-1 group than in 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 (Pfor interaction=0.054). High IGF-1 levels were associated with improved OS in non-obese women (4-year OS 99.4% vs. 93.7%,P=0.005; HR 0.15, 95% CI 0.03–0.68), but not in obese women (4-year OS 98.7% vs. 98.9%,P=0.438; HR 2.51, 95% CI 0.23–27.63,Pfor interaction=0.054).
In lean patients with HER2+ disease, high IGF-1 was significantly associated with better overall survival (P=0.020). In patients receiving HER2-targeted therapy (trastuzumab), IGF-1 levels interacted with obesity; in patients with a BMI < 24.0 kg/m2who received adjuvant therapy, those with higher IGF-1 had significantly better OS than those with lower IGF-1 (P<0.001).
Practice implications
This is the largest study to date looking 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 are contrary to what many of us would have predicted and require our careful attention because these results may influence the interventions we suggest to some HER2+ breast cancer patients.
Our basic understanding of insulin-like growth factor is that it is critical for the growth, development and maintenance of many tissues in the human body.1IGF-1 is particularly important during neonatal and pubertal growth and works by stimulating cell proliferation and interrupting programmed cell death.2IGF-1 is of particular importance in the development of breast tissue. The binding of IGF-1 to its receptor (IGF-1R) stimulates the activation of the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways, which cause cell proliferation. However, there are half a dozen IGF-binding proteins that moderate the bioavailability and half-life of IGFin vivothe majority of IGF binds to IGFBP-3.
IGF-1 signaling is involved in 87% of invasive breast cancers.4For several years we have relied on a hypothesis that there is an interaction between the IGF-1 signaling pathway, insulin and the epidermal growth factor receptor family. Given our current understanding and hypothesis, increased IGF signaling should lead to breast cancer progression and metastatic invasion and promote resistance to therapies such as chemotherapy and radiotherapy.4.5Elevated insulin levels bind to certain IGF-1 receptors on breast cancer cells and stimulate proliferation.6For this reason, we have encouraged women with a history of breast cancer to reduce excessive carbohydrate consumption as this may reduce insulin production. Consistent with this line of thought, an increase in IGF is expected to result in a decrease in breast cancer survival7and increased all-cause mortality in HER2+ patients.8At least that was our previous reasoning and approach.
This study changes that thinking and suggests that benefit from lowering IGF-1 occurs only in overweight women. In women of healthy weight, higher IGF-1 levels appear to be associated with a possible benefit against recurrence, and strategies to lower IGF-1 may be counterproductive, at least in women with HER2+ tumors.
Fasting and fasting-mimicking diets reliably reduce IGF-1 levels, and this effect has been used to explain the benefits of these diets in limiting cancer growth and improving survival. Stefanie de Groot et al reported inNature communicationEarlier this year, it emerged that in a randomized trial of 131 HER2-negative breast cancer patients who followed either a fasting-like diet or their regular diet for 3 days before and during chemotherapy, these patients were more likely to have a complete or partial response to treatment after the fasting-like diet, presumably because they had lowered their IGF-1 levels.9
This leaves us with seemingly contradictory data. Fasting, which lowers IGF-1, appears to be helpful for breast cancer patients in general, but lower IGF-1 levels are associated with a worse prognosis in women with HER2-positive breast cancer - unless patients are overweight and have a BMI ≥ 24.0 kg/m2, and then lower IGF levels are a possible benefit. We must remember that this was a retrospective study and the reported associations should not be interpreted as causal. We should note that this is not the first report to differentiate the effect of IGF-1 in women with a history of breast cancer based on BMI. In 2013, Catherine Duggan et al reported that elevated IGF-1 levels were associated with an approximately 2-fold higher risk of breast cancer-specific mortality in participants with a BMI >25 kg/m2, but not in slim women. On the other hand, they also found that high serum IGF-1 levels and IGF-1/IGFBP-3 ratio were associated with an increased risk of all-cause mortality in women with breast cancer.8Duggan's study participants were not limited by HER2 status, and their results suggest that a similar classification by BMI could 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 possibly other breast cancer subtypes. The authors did not offer any theory to explain their results.
If this study is to be relied upon, for HER2+ patients, assessment of both IGF-1 levels and BMI is critical to our therapeutic suggestions. In obese women with a history of HER2+ breast cancer, lower than normal IGF-1 levels are preferred, but in women of healthy weight, elevated IGF-1 levels may be preferred.
These findings may influence our general fasting recommendations. We can reconsider the general dietary suggestions we have made for influencing IGF-1 levels. Diets high in animal protein increase IGF-1 levels, while diets low in animal protein are associated with decreased IGF-1. Therefore, for HER2+ breast cancer, we may even want to fine-tune dietary recommendations based on BMI and IGF-1 levels. For normal-weight women, a diet high in animal protein, associated with increased IGF, may be beneficial compared to a vegan diet that lowers IGF. For overweight women, the reverse recommendation may be appropriate.