The strong association between breast cancer risk and serum IGF-1 has prompted clinical drug trials to use serum IGF-1 as a surrogate endpoint biomarker for predicting risk of developing primary breast carcinogenesis. In this way, circulating IGF-1 could be a cofactor in the development of breast cancer or it may be a by product of other processes that lead to carcinogenesis. As mentioned previously, several case-control studies have shown that serum IGF-1 in premenopausal women could potentially be used to predict risk of developing breast cancer later in life. In the clinical setting, serum IGF-1 could be used as a risk biomarker that could allow evaluation of risk of breast cancer in the general population or at least in groups of patients with high risk of developing early breast cancer such as BRCA1 and BRCA-2 gene mutation carriers or patients on exogenous oestrogen treatment.
Another use of serum IGF-1 is its use as a response biomarker in testing chemopreventive drugs. Chemoprevention has been defined as the prevention of cancer by the use of pharmacological agents that inhibit or reverse the process of carcinogenesis. It aims to treat premalig-nant cells thereby disrupting the series of events involved in carcino-genesis which would promote their progression to neoplastic disease. Traditionally, many drug chemoprevention trials recruited early-stage breast cancer patients who had completed breast cancer treatment, and then prospectively looked at their risk of developing either contralateral or ipsilateral breast cancer in another quadrant as an end-point (64). Response biomarkers allow breast cancer risk to be evaluated before the incident occurs which can play a very important role in chemo-prevention trials. In addition to this, once the biomarker has been validated to be a consistent predictor of risk, it can also be utilised outside trial settings to help patients and physicians make decisions regarding initiation or continuation of chemoprevention drug treatment. To date serum IGF-1 and serum IGFBP-3 has been shown been one of the most widely used biomarkers of response used in chemoprevention trials in addition to Ki-67, breast intraepithelial neoplasia morphology by FNA, nipple aspiration or biopsy, and mammographic density (65).
Many early studies have shown that adjuvant tamoxifen treatment of breast cancer patients led to a reduction in serum IGF-1 (66-68) which suggests that oestrogen stimulation may be required in order to produce IGF-1 in circulation. The National Surgical Adjuvant Breast Project (NSABP) trial showed that women with a high Gail-risk of 1.7% or higher who were randomised to a 5-year treatment of tamoxifen enjoyed a 50% reduction in breast cancer risk incidence relative to those who received placebo (69). Likewise, chemopreventive trials involving Tamoxifen treatment of normal women showed a reduction of levels of biomarkers including serum IGF-1 (70). However, whether tamoxifen lowers breast cancer risk directly or via modulation of serum IGF-1 levels still remains to be validated and further drug trial studies are required before we can confidently use serums IGF-1 as a response biomarker.
This effect was investigated further in a phase III drug trial using fenretinide (a synthetic retinoid). The trial looked at whether the administration of the drug could reduce the risk of contralateral and recurrent ipsilateral breast cancer in treated breast cancer patients between ages 30 and 70. Fenretinide which inhibits cell growth and induces apoptosis was shown to reduce the risk of secondary breast malignancy in premenopausal women by 35%. Incidentally, this reduction in risk corresponded to a reduction in circulating IGF-1 which was observed one year after drug administration only in premenopausal women but not in postmenopausal women (51). The observed modulation of IGF-1 by Fenretinide together with its clinical effects of secondary cancer risk suggests that a decline in IGF-1 levels may at least partially account for its chemopreventive activity. A 2 * 2 randomised trial of fenretinide and low dose tamoxifen and another randomised trial involving fenretinide and women on hormone replacement therapy are currently underway and aim to measure the change in serums IGF-1 levels to clarify the role of IGF-1 as a response biomarker of carcinogenesis (70).
8. THE RELATIONSHIP BETWEEN IGF-1 PHENOTYPE, SERUM IGF-1, AND RISK OF EARLY BREAST CANCER
There is evidence that serum IGF-1 levels vary considerably between healthy adults. Twin studies show that 50% of the inter-individual variability of circulating IGF-1 is genetically determined (71, 72). Some studies have suggested that this variablility may be due to an inheritable polymorphism of the IGF-1 gene which in turn may be due to the alleic variations upstream to the IGF-1 gene that lead to changes in the promoter region (73). The promoter region in the IGF-1 gene contains a CA-repeat sequence which ranges from 12 to 23 repeats (74). There is wide variation in the frequency of the 19-repeat allele between ethnic groups. The absence of a common 19-repeat allele in the IGF-1 gene is associated with high levels of serum IGF-1 during oral contraceptive (OC) use in nulliparous women (75). The risk of early-onset breast cancer after teenage OC use also varies considerably between ethnic groups, and this appears to correlate with the relative frequencies of the absence of this 19-repeat allele (76). Jernstrom et al. found that the absence of the IGF-1 19-repeat allele was more common in premenopausal women with breast cancer than those without breast cancer. Even though this IGF-1 polymorphism did not have any effect on serum IGF-1 in nulliparous non-OC users, women with absent 19-repeat alleles demonstrated higher levels of IGF-1 during OC use. This study suggested that there was an increased risk of breast cancer after hormonal exposure especially in teenage OC use or pregnancy in women who lack the 19-repeat allele (75). In addition, this study showed the absence of the 19-repeat allele was more common in BRCA1 mutation carriers than other women, and that these women were more prone to develop early-onset breast cancer than BRCA1 carriers who expressed the 19-repeat allele. As with circulating IGF-1, the IGF-1 genotype did not seem to affect the risk of breast cancer in postmeno-pausal women (75).
Several studies have suggested an association between breast volumes/density and risk of breast cancer (77). Measurement of breast densities using computer-assisted analysis of mammograms has shown a consistent association between high breast density and breast cancer risk. IGF-1 stimulates cell proliferation, reduces apoptosis, and is associated with larger breast volumes (78, 79). Hartmann et al. showed that in women who underwent hormonal breast augmentation, only women who lacked the 19-repeat allele demonstrated a substantial increase in breast volume (81) whilst other studies studies noted that larger breasts may be associated with higher risk of breast cancer (82). Jernstrom et al. showed that OC users with absent 19-repeat alleles had larger body-weight adjusted breast volumes than those with at least one copy of the 19-repeat allele (80). These findings suggest that the IGF-1 genotype may play an important role in early breast cancer and its effect on serum IGF-1 and breast cancer risk may rely on the availability of high levels of endogenous and exogenous oestrogen. A consequence to this interaction may be an effect on proliferation of normal breast epithelia which leads to larger breasts and also an increased risk of breast cancer. In future, gene testing on the presence or absence of the 19-repeat allele may be useful in determining risk of breast cancer in high risk premenopausal women such as those with family history breast cancer and those on oral contraceptives.
9. HOW CAN IGF-1 MEASUREMENT BE USED IN THE FUTURE?
Of all the components in the IGF-1 system, serum IGF-1 (and IGFBP-3-not elaborated in this review) has shown promise in the clinical management of breast cancer (53). Measuring serum IGF-1 may be used to predict breast cancer risk in premenopausal women which is especially useful in high-risk women such as those with strong familial breast cancer histories, young oral contraceptive users, and gene mutation carriers. Even though many studies have shown a strong association between serum IGF-1 and the risk of recurrent new primary or contralateral breast cancers, further studies are needed to validate this. We look forward to results of chemopreventive drug trials which use serum IGF-1 as a response biomarker and further reinforce serum IGF-1 as a useful biomarker of measuring drug efficacy rather than using just clinical outcome as the end-point. So far, studies looking at IGF-1 expression in normal and malignant breast tissue and its prognostic value in breast cancer patients have been inconsistent but this may be limited by the relatively few studies performed on this subject. Consistently, research has shown that the IGF-1 system and oestrogen hormone system interact substantially in stimulating breast cancer and that IGF-1 may be the key step between oestrogen stimulation and breast cancer carcinogenesis. If these results are borne out by further studies, inhibiting the action of IGF-1 systemically or locally at breast tissue level by growth factor-targeted therapy may be the next step in IGF-1 research.
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