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Annals of Surgical Oncology 8:25-31 (2001)
© 2001 Society of Surgical Oncology

ORIGINAL ARTICLES

Effect of Breast Surgery on Serum Levels of Insulin-Like Growth Factors (IGF-I, IGF-II, and IGF Binding Protein-3) in Women With Benign and Malignant Breast Lesions

Ian M. Holdaway, MD, FRACP, Anne E. Lethaby, MA, Barbara H. Mason, BSc, Vijay Singh, BSc, John E. Harman, MBChB, FRACS, Murray MacCormick, MBChB, FRACS and Ian D. Civil, MBChB, FRACS

From the Department of Endocrinology (IMH, AEL, BHM, VS), School of Medicine, Auckland University; St. Mark’s Breast Centre (JEH); and Department of Surgery (MM, IDC), Auckland Hospital, Auckland, New Zealand.

Correspondence: Address correspondence and reprint requests to: Professor I. M. Holdaway, Department of Endocrinology, Auckland Hospital, Park Rd, Auckland, New Zealand; Fax: 64-9-307-4993.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
BACKGROUND: There is evidence that insulin-like growth factors play a role in the development of breast cancer. Antiestrogens reduce circulating levels of IGF-I, but the influence of other breast cancer treatments, including surgery, is unknown and is investigated in this study.

METHODS: Circulating serum concentrations of IGF-I, IGF-II, and IGF binding protein-3 (IGFBP-3) were measured before and after breast surgery in 31 patients with breast cancer and 12 controls with benign breast lesions. Serum albumin was measured as a marker of the nonspecific metabolic effect of surgery.

RESULTS: Serum IGF-I, IGF-II, IGFBP-3, and albumin fell 24 hours after surgery for breast cancer but largely normalized again over the next 7 days. The fall in IGF-I and IGFBP-3 was not significant when the change in serum albumin was used as a covariate, suggesting a nonspecific effect of surgery. However, the reduction in IGF-II remained significant when adjusted for albumin and was greater after lumpectomy of malignant tumors (-8 ± 2%) compared with benign disease (2 ± 2%, P = .001). The fall in IGF-II was significantly related to the size of the removed tumor.

CONCLUSIONS: Breast cancer may directly influence the serum concentration of IGF-II, possibly by direct tumor production.

Key Words: Breast neoplasms— • Breast dysplasia— • Surgery— • IGF-I— • IGF-II— • IGFBP-3.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The insulin-like growth factors and their binding proteins are known to be involved in the growth and maintenance of neoplastic breast tissue.1–8 Breast tumor cells possess receptors for both IGF-I and IGF-II.9,10 IGF-I is produced from stromal tissue adjacent to breast cancers,11 where it may act as a paracrine factor influencing tumor growth.12 IGF-II can act in a similar fashion and may, in some instances, be produced either from stromal tissue13 or directly from tumor tissue,14 where it could function as an autocrine growth factor. IGF binding proteins may also be produced in breast tissue3–8 and may modify the action of IGF at the cellular level.15

It is known that adjuvant therapy of early breast cancer with antiestrogens such as tamoxifen can modify the circulating concentrations of IGF-I.16 It is unclear whether this results from an effect of tamoxifen on lowering pituitary growth hormone secretion, with a resulting fall in circulating IGF-I, or whether this in some way reflects a direct effect of the agent of elaboration on IGF-I by breast tissue.17–19 As yet, there are few studies of circulating IGF and IGFBP levels in patients undergoing treatment for an existing breast tumor. We have, therefore, carried out a study measuring serum levels of IGF and IGFBP-3 before and after surgical removal of primary breast cancer, in order to determine whether excision induces a change in IGF concentrations and whether the extent of any change correlates with known tumor characteristics such as tumor size or receptor status.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects and Sampling
Blood samples for the measurement of IGF-I, IGF-II, IGFBP-3, and albumin were collected from 31 patients having surgery for malignant breast tumors and 12 patients having surgery for benign beast lesions. Five samples were collected from each patient: a basal level 1 day before or immediately before surgery, daily samples for the following 3 days, and a sample 1 week after surgery. The serum was frozen and stored at -20°C until analysis.

The patients studied included 12 women who had excision biopsies for breast lesions that later were shown to be benign on histology and 31 women who had breast surgery for malignancies, of whom 16 women had wide local excision, 10 women had mastectomy, and 5 women had mastectomy with immediate reconstruction. Women in the benign group were significantly younger than women in the malignant groups (mean ages 37 and 47 years, respectively) but were comparable by other patient characteristics, including weight, height, and body mass index. The protocol was approved by the North Health Medical Ethics Committee.

Measurements
Serum insulin-like growth factor-I (IGF-I) was measured by radioimmunoassay.20 The assay sensitivity was 2 µg/L, and the intra- and interassay coefficients of variation (CV) were 5% and 7%, respectively, with a normal range of 90 to 300 µg/L. IGFBP-3 was measured using a commercial kit (Bioclone Australia Pty Ltd, Sydney, Australia). The sensitivity of the assay was 0.7 mg/L, and the intra- and interassay CVs were 5% and 6%, respectively. The normal range was 2.2 to 5.6 mg/L, with a mean value of 4 mg/L. Insulin-like growth factor-II was separated from binding proteins using Sephacryl (Pharmacia, Uppsala, Sweden) extraction and measured by radioimmunoassay as previously described.21 The assay sensitivity was 36 µg/L and the intra- and interassay variation were 5% and 12%, respectively, with a normal range of 490 to 1056 µg/L. Albumin was measured by a commercial kit (Boehringer Mannheim, Mannheim, Germany). The interassay variation was 1.5%, and the detection limit was 2 g/L, with a normal range of 35 to 50 g/L.

The stromal content of the breast tumors was graded according to the method of Bertin et al.22

Statistical Analysis
The difference between change over time in the surgical groups was assessed by repeated measures analysis of variance using age and change in albumin over 24 hours as covariates. The statistic of interest was the interaction of surgical group with time. Analysis was performed using SAS software.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Mean levels of insulin-like growth factors, IGFBP-3, and albumin before and for 7 days following surgery in the benign and malignant groups are shown in Table 1. The mean percentage change over time of serum IGF-I, IGF-II, and IGFBP-3 concentration in the benign and malignant groups is shown in Fig. 1. Marked differences in the extent of fall in IGF and IGFBP-3 levels were noted between the groups, but it was unclear whether this simply represented the extent of surgery involved. To investigate this further, the mean percentage change over time of serum albumin concentration with surgery was assessed as shown in Fig. 1D. Because serum levels of IGF-I and IGFBP-3 are negatively correlated with age,20,21 comparisons were made between the benign and malignant groups, allowing for age as a confounding variable and using the change in serum albumin with surgery as a nonspecific marker of the metabolic impact of surgery. When assessed using repeated measures analysis of variance there was no significant difference in change of IGF-I or IGFBP-3 levels over the 7 days of measurement in the groups studied (benign lesions, malignant disease treated by local excision, malignant disease treated by mastectomy, and mastectomy with reconstruction). However there was a significant difference in change in the levels of IGF-II between the benign group and three cancer groups over the 7 days of the study (P = .0008,) and there was a similar result using only age as a covariate. Within the cancer group there was a significant difference over the 7 days in the level of IGF-II between patients who had local excision of tumor and those treated by mastectomy (P = .03). The greatest differences were at the 24-hour timepoint.


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  		Table 1. Mean IGF and albumin levels before and after surgery for malignant and benign breast lesions
 


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  		FIG. 1. The mean percentage change in insulin-like growth factors IGF-I (A) and IGF-II (B), IGFBP-3 (C), and albumin (D) before and after surgery for benign (solid line) and malignant (dotted line) lesions. * in part B indicates significant difference in change over time between groups, controlling for age and serum albumin, P = .0008.

 
Repeated measures analysis of variance controlling for age and change in albumin showed that the change from baseline to 24 hours in IGF-II levels differed significantly between those with benign lesions and those having surgery for malignancy (P = .004) The IGF-II levels also differed significantly between the benign group and the three groups having surgery for malignancy (P = .001, P = .0001, and P = .0001, respectively) ( Fig. 2). It is apparent from Fig. 2 that there was a decline in IGF-II levels according to extent of surgery in those with malignancy.



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  		FIG. 2. The mean (±SEM) percentage change in IGF-II 24 hours following breast surgery by groups according to type of surgery, analyzed after allowing for the effects of age and parallel changes in serum albumin. *, benign compared to wide local excision, P = .001; **, benign compared to mastectomy, P = .0001; t, benign compared to mastectomy with reconstruction, P = .0001.

 
The change in serum IGF-II concentration was assessed according to the variation in tumor size, the amount of tissue removed at surgery, and the type of operation performed. There was a significant positive relationship between the fall in IGF-II and tumor size ( Fig. 3).



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  		FIG. 3. Association between percentage change in serum IGF-II levels 24 hours after removal of breast cancer with clinical size of the excised tumor. R = -0.53, P = .004.

 
Because mRNA for IGF-I and IGF-II is dominantly expressed in stromal tissue around breast tumors,12,13 the amount of fibrous desmoplastic reaction in the breast tissue was correlated with the changes in IGF-I, IGF-II, and serum albumin. No correlation was observed between the grade of desmoplastic reaction and serum levels, nor was there a relationship with weight of tissue removed at surgery.

The mean change in serum IGF concentrations over 24 hours following surgery was compared within the combined cancer group according to nodal and receptor status, tumor grade, and tumor size. Any differences in the percentage change in growth factor levels according to these factors were largely related to the influence of age and extent of surgery. However, the change in IGF-I over 24 hours differed significantly according to progesterone receptor status, even after allowance for age, with the fall being greater in those with PR- tumors ( Table 2). The difference in mean IGF-I levels in those with differing progesterone receptor status persisted over the 7 days of sampling ( Fig. 4), although this was of borderline significance (P < .10 comparing PR+ and PR- groups). In comparison with the PR data, IGF-I levels tended to be lower in those with ER+ tumors, although the difference compared with the ER- group was not significant.


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  		Table 2. Change in mean serum IGF and IGFBP-3 levels 24 hours following breast cancer surgery, according to estrogen and progesterone receptor status
 


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  		FIG. 4. The mean (±SEM) percentage change in serum IGF-I levels after breast surgery in progesterone receptor-positive (solid line) and negative (dotted line) patients. P = NS.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study shows that serum levels of IGF-I, IGF-II, and IGFBP-3 fell by 20–30% in the 24 hours following surgery for malignant breast tumors, whereas they remained relatively unchanged following removal of benign breast lesions. Serum levels in those with malignant disease tended to return toward preoperative levels by 7 days following surgery, and in the case of IGF-II rose above the mean preoperative level 1 week after surgery (Fig. 1B). Because there was a difference in age between the groups any comparison between benign and malignant groups required adjustment for the effect of age on IGF levels.23,24 Circulating levels of IGF and IGFBP-3 also are strongly influenced by nutrition25,26 and by the catabolic stress that may accompany major surgery or trauma.27–29 A fall in IGF levels following surgery might thus have been expected in the present study in response to surgical stress and calorie withdrawal over the time of surgery. The change in serum albumin thus was used as a measure of the extent of metabolic stress with surgery, and it was noted that the greatest fall in albumin levels also was seen in those undergoing more extensive surgery (Fig. 1D), with serum concentrations remaining low for up to 7 days after operation (Table 1, Fig. 1D). When the data were age-adjusted and allowance made for the change in serum albumin, only the change in IGF-II over 7 days was significantly different among the benign and malignant groups. When the fall in serum IGF-II was evaluated by extent of surgery, significant differences were observed, with greater reduction in those having surgery for malignancy compared with removal of benign lesions, and a significant difference between those having local excision of benign disease compared with equivalent surgery for malignant growths.

The reason for the fall in IGF and IGFBP-3 levels in these patients remains uncertain. In the case of IGF-I and IGFBP-3, it seems likely that the fall results from the changes occurring as a metabolic response to the stress of surgery, with changes being greater in those having more extensive surgery and paralleling the changes seen in serum albumin. Provisional reports suggest that down-regulation of the hepatic growth hormone receptor following surgery may contribute to these changes.30 In the case of IGF-II, however, the fall was greater in those having surgery for malignant compared to benign disease, and could not be explained by the metabolic response to surgery as assessed by change in serum albumin. It is possible that the response of IGF-II to surgical trauma differs from that of IGF-I, IGFBP-3, or albumin, and that the present results still reflect the metabolic events surrounding surgery. However, most studies of trauma and surgery have shown mainly effects on IGF-I metabolism with much lesser effects on IGF-II, which makes surgical trauma an unlikely explanation for the present results. It thus remains possible that breast cancer itself may directly influence IGF-II levels. Tumor tissue and/or stroma may contribute specifically to the circulating pool of IGF-II, or, alternatively, breast tumors may influence systemic production of IGF-II from other tissues such as liver, modulated, for example, by tumor synthesis of cytokines or IGFBPs. The possibility that the tumor itself contributes to IGF-II production is supported by the observation that the fall in IGF-II was greater following removal of larger tumors (mastectomy) than of smaller lesions (wide local excision) (Fig. 2) and that removal of similar amounts of benign and malignant tissue by local excision led to a fall in IGF-II only in the malignant group. In addition, there was a significant direct correlation between the size of the removed tumor and the extent of the fall in IGF-II following surgery.

Because IGF-I and IGF-II can be produced by fibrous tissue adjacent to breast cancer,12,13 the change in IGF following surgery was correlated with the extent of stromal fibrous reaction in the removed samples. There was no significant correlation between the fall in IGF and the desmoplastic tumor reactions graded by standard means.22

Within the limitation of small numbers in some subgroups, there did not appear to be a difference in the extent of change in IGF levels between patients according to tumor markers such as tumor grade and receptor status, except for a greater fall in IGF-I after surgery in women with progesterone receptor negative (PR-) compared with PR positive (PR+) tumors. This finding is of interest in view of the observation that IGF-I can increase expression of PR in cultured mammary tumor cells.31 However, serum IGF-I levels were not found to differ between patients with PR+ compared with PR- ovarian cancer.32 A number of studies report that mRNA for IGFBP-3 is increased in ER- breast cancer,33–36 but serum IGFBP-3 levels from this study in groups divided by ER status were significantly different only in women age < 50 years (data not shown).

This study thus demonstrates that circulating serum concentrations of IGF-I, IGF-II, and IGFBP-3 fall acutely following removal of a primary breast tumor, but largely recover by 1 week after surgery. In the case of IGF-I and IGFBP-3, the fall can be explained by the metabolic stress of surgery, as demonstrated by parallel changes in serum albumin. The change in serum IGF-II levels, however, appears to relate directly to tumor removal ,and is more marked with excision of larger tumors and less apparent with local excision of benign lesions compared with equivalent excision of malignant tumors. The significance of this finding remains uncertain. It could be due to an influence of breast cancer on production of IGF-II in normal tissues, or it could indicate a component of direct release of IGF-II by breast tumor tissue as previously indicated by in vitro studies.2–4


   Acknowledgments
 
This research was supported by a grant from the Cancer Society of New Zealand. The authors are indebted to Mrs J. Stewart for biostatistical advice and to Dr T. Bierre for histopathology review.

Received for publication July 7, 1999. Accepted for publication August 8, 2000.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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