Original Study
Modification of Abdominal Fat Distribution After Aromatase Inhibitor Therapy in Breast Cancer Patients Visualized Using 3-D Computed Tomography Volumetry Sofia Battisti,1 Francesco Maria Guida,2 Federica Coppa,1 Donata M. Vaccaro,1 Daniele Santini,2 Giuseppe Tonini,2 Bruno B. Zobel,1 Richard C. Semelka3 Abstract The pattern of abdominal fat distribution is hormone linked and it can affect or be predictive of various diseases, in particular metabolic syndrome is associated with an increase amount of visceral adipose tissue. After system therapy with aromatase inhibitor in breast cancer patients, we found a relative increase of visceral adipose tissue regardless of whether they gained or lost weight after therapy. Introduction/Background: The purpose of this study was to describe modification of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) distributions in breast cancer patients after aromatase inhibitor (AI) therapy using computed tomography (CT) volumetric measurement of abdominal body fat distribution. Patients and Methods: Sixty-four consecutive patients who were receiving adjuvant AI therapy were included in this study. Patients were evaluated using CT before and after at least 6 months of AI therapy with imaging follow-up of 4.3 2.2 years. Abdominal fat distribution was automatically calculated using a workstation that obtained total abdominal adipose tissue (TAAT) area (mm3). SAT was manually segmented and VAT was determined as TAAT SAT. Percentages were calculated for change of TAAT, VAT, and SAT. VAT/SAT ratio was calculated. Results: Percentage of TAAT after AI therapy was increased by a mean of 9.1% from baseline (16,280.3 6953.3 mm3) to (17,763.6 6850.8 mm3). Two groups of patients were observed; those with an increase in TAAT and those with a decrease. Modification of VAT/SAT ratio was observed (from 1.38 to 1.69) in all subjects, reflecting a relative increased volume of VAT (mean, 18%) and slight mean reduction of SAT (mean 1.9%). Conclusion: In our study, therapy with AI in breast cancer patients was accompanied with a change in fat distribution to relatively greater VAT/SAT ratio in patients, regardless of whether they gained or lost weight after therapy. Because this pattern of fat distribution is associated with metabolic disorders, attention must be paid to these clinical manifestations in patients during their follow-up management. Clinical Breast Cancer, Vol. -, No. -, --- ª 2014 Elsevier Inc. All rights reserved. Keywords: Aromatase inhibitor therapy, Breast cancer, CT, Subcutaneous fat, Visceral fat
Introduction Breast cancer is the most common malignancy in women, represents 18% of all female cancers, and there are > 100,000 new 1
Department of Radiology, Campus Bio-Medico University of Rome, Rome, Italy Department of Medical Oncology, Campus Bio-Medico University of Rome, Rome, Italy 3 Department of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 2
Submitted: Oct 23, 2013; Revised: Feb 7, 2014; Accepted: Feb 12, 2014 Address for correspondence: Sofia Battisti, MD, Department of Radiology, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 200, Rome 00128, Italy Fax: þ39-06-225411633; e-mail contact: sofi[email protected]
1526-8209/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2014.02.003
cases of hormone receptor-positive breast cancers per year in the United States.1 To reduce the risk of recurrence in postmenopausal women with hormone receptor-positive breast cancer, aromatase inhibitor (AI) therapy is currently recommended for 5 years and has become the standard of care because of their superior reduction of breast cancer recurrence compared with estrogen receptor agonists and antagonists.2 It is well known that estrogen plays an important role in initiating and promoting breast cancer.3 Because of this recognition, hormone therapy plays an important role in the treatment of breast cancer, in fact, AIs are drugs that inhibit the aromatase-mediated synthesis of estrogens in peripheral tissues, with the effect of decreasing body estrogen level. The AIs may be
Clinical Breast Cancer Month 2014
-1
Modification of Abdominal Fat Distribution After AI Therapy
2
-
nonsteroidal, such as the triazole derivatives, anastrozole and letrozole, or steroidal, such as exemestane.4 In postmenopausal women the dominant source of estrogens is the peripheral conversion from androgens, which is catalyzed by aromatase, an enzyme of the cytochrome P450 subfamily, mediated by the CYP19A1 gene. Aromatase enzymes in premenopausal women are highly expressed in placenta and in granulose cells of ovarian follicles.5 Additionally, aromatases are present, at lower levels, in several nonglandular tissues including subcutaneous fat, liver, muscle, brain, normal breast, and breast cancer tissue.6 Estrogen production after menopause is solely from nonglandular sources, in particular from subcutaneous fat.7 Recent studies have observed that that treatment with AIs might be associated with an increase of cardiovascular diseases.8,9 Amir et al8 reported in their metaanalysis that longer duration of AI use was associated with an increased odds ratio of cardiovascular disease. During menopause, androstenedione produced in the adrenal glands, and, to a lesser extent, testosterone produced in the ovaries, are released into the circulation, and then sequestered to nonglandular tissues such as liver and breast, where they are converted to estrone and estradiol, respectively, by aromatase enzymes located in nonglandular tissues, especially subcutaneous fat.6 Body fat mass and its distribution in men and women is determined by both sex steroids, androgens and estrogens, which play important roles, and their effect results in different patterns of total abdominal adipose tissue (TAAT) distribution. The male pattern of fat distribution is termed “android,” which is characterized by a high amount of visceral adipose tissue (VAT), and the female pattern is termed “gynoid,” which is characterized by peripheral or gluteofemoral fat distribution with a greater amount of subcutaneous adipose tissue (SAT). SAT of the abdomen is defined as the fat tissue located between the skin and abdominal musculature, and VAT is the fat tissue present within the abdominal cavity. VAT tissue contains adipocytes that are more metabolically active, and are linked to a series of disease processes involving the cardiovascular systems10 and also carcinogenesis.11 Different fat compartments are thereby associated with differential metabolic risks.12 Previous studies on the risk of developing metabolic diseases have shown that the VAT compartment might possess unique pathogenic properties13 that can influence the risk of developing metabolic diseases.14 Visceral adipose obesity is well known be associated with adverse metabolic effects and increased cardiovascular risk, and a prominent aspect of this tissue is a predominance of androgen action over that of estrogen.15,16 In fact, circulating androgen levels are greater in women with central obesity compared with nonobese women.17 Previous reports indicate that aromatase deficiency in humans18 and in mice19 results in a predominance of androgens over estrogens, abdominal obesity, and insulin resistance.20 A prolonged period of estrogen suppression, such as occurs during AI therapy, results in relative hyperandrogenemia,21 that might induce major alterations in body composition that might be more extensive than those induced by menopause.22 Quantification of abdominal adipose tissue can be performed using several methods. In clinical practice, measurement of body mass index (BMI) is commonly performed, however, this approach does not evaluate an increase in visceral fat,23 and similarly limited are surface measurements such as the circumference of the hip, the waist to hip circumference ratio, or abdominal sagittal diameter, which also do not separate VAT from
Clinical Breast Cancer Month 2014
SAT with any reliability.24 The most accurate and reproducible methods are computed tomography (CT)- or magnetic resonance images, which allow visualization of the body compartments.25 In the current medical literature, there are many studies that describe the measurement of abdominal fat tissue using imaging with the intent to understand the relationship between VAT and the metabolic syndrome.26 To the best of our knowledge, no previous study has used objective quantification of VAT and SAT with crosssectional imaging to evaluate the potential modification of fat compartment distribution in women taking AIs for the treatment of breast cancer. The purpose of our study was to determined the presence of anthropometric modification using CT volumetry of abdominal body fat distribution in patients with previous breast cancer who are taking AI therapy.
Patients and Methods Patients This study was approved by our institutional ethics committee with written informed consent. This retrospective study included 64 consecutive Caucasian female patients (mean age, 55.8 11.7 years; age range, 36-77 years), who underwent CT scanning between September 2005 and December 2012. Selection criteria were: histologically confirmed breast cancer after radical mastectomy, postmenopausal status, AI adjuvant therapy for at least 6 months before CT restaging, no recurrence of breast cancer, and no other substantial disease over the follow-up period (average, 4.3 2.2 years). Clinical characteristics of the subjects are summarized in Table 1. Table 1 Clinical Characteristics of the Study Sample (n [ 64 Patients) Characteristic Age, Years
Value 55.9 11.7
Aromatase Inhibitor Anastrozolo
n ¼ 33/64
Letrozolo
n ¼ 31/64
Stage, % Ia
4
Ib
4
IIa
21
IIb
23
IIIa
6
IIIb
1
IIIc
5
Anthracycline-Based Adjuvant Chemotherapy, % No
9
Yes
55
Histology, n ER status (positive)
63/64
PR status (positive)
60/64
c-erb-B2 status (triple positive)
6/64
Grading, % 1
7
2
32
3
25
Sofia Battisti et al CT Analysis Subjects underwent CT examination with Somaton, Sensation 64 CT scanners (Siemens, Forcheim, Germany). CT studies were performed before and after the initiation of AI therapy. TAAT, VAT, and SAT were determined in the CT study before initiation of AI therapy, and in the study after the last oncological restaging. CT measurements of fat tissue were assessed using 3-mm slice thickness images, which were acquired of the entire abdomen and pelvis during the venous phase in postcontrast images. Abdominal adipose tissue measurements were quantified semiautomatically using a dedicated workstation (Leonardo, Siemens). TAAT was automatically generated by the workstation. SAT was generated by manual tracing from the skin surface to the outer surface of the abdominal musculature. VAT was generated using the formula, TAAT SAT.
Statistical Analysis Percentages were calculated for the increase of TAAT, VAT, and SAT. The VAT/SAT ratio was calculated. Two groups were created: group A, who experienced an increase in TAAT, and group B, who experienced a decrease. A pairwise Student t test was used to compare TAAT, VAT, and SAT before and after AI therapy for both groups. Spearman rank correlation between weight and BMI TAAT before and after therapy was performed to evaluate the relationship between various weight estimation tools and TAAT, as indices of fat. Spearman rank correlation was used for AI and age comparisons with TAAT, VAT, and SAT as variables, before and after AI, for both groups.
Results The anthropometrical characteristic of the entire study population and the percentage distribution of TAAT, VAT, and SAT are summarized in Table 2. The volumetric 3-D CT analysis showed a mean increase of 9.1% of TAAT volume for all subjects after at least 6 months of AI therapy, from the baseline mean of 16,280.3 6953.3 mm3 to 17,763.6 6850.8 mm3. The pattern of fat distribution was characterized by a modification of VAT/ SAT ratio (from 1.38 SD to 1.69 SD), reflecting a relative increased volume of VAT (mean 18% SD) and slight reduction of SAT (mean 1.9% SD). Mean patient BMI at baseline was 26.3 4.2 with 11% of subjects considered obese (BMI 30). After AI therapy, based on TAAT, 2 groups of patients were observed; those with an increase (group A, 43 patients) and those with a decrease (group B, 21 patients) (Figs. 1 and 2). At the baseline time point, group A had a BMI of 25.5 4, and BMI for group B was 27.9 4.2. The body fat distribution of the 2 groups was analyzed using a t test to compare the difference before and after AI therapy. The result are shown in Table 3, which
demonstrates a significant difference in the increase of TAAT and VAT after therapy in group A (P < .0001), and in the TAAT decrease in group B (P < .0001). In both groups, a modification of VAT/SAT ratio was observed (from 1.38 to 1.69), reflecting a relative increased volume of VAT (mean, 18%) and slight reduction of SAT (mean, 1.9%). The difference in the fat distribution, based on CT calculations before and after hormone therapy in the 2 patient groups is shown in Table 3. Group A included patients who showed an increase in TAAT after therapy. Group B included patients who showed a decrease in TAAT. In an unpaired t test, the difference in TAAT between the 2 groups before therapy was significant (P ¼ .0031). After hormone therapy there was not a significant difference in the final TAAT in the 2 groups. The data demonstrate that patients in group A experienced an increase of TAAT, and those in group B a reduction. A different pattern of body fat distribution was apparent between the groups. Group A had an increase of VAT after hormone therapy, with a significant increase of TAAT (mean, 24.9% increase), and an even greater increase in VAT (mean, 37.9%). Group B had a significant reduction of TAAT (mean, 14.5%). Before the hormone therapy group A had a lower TAAT compared with group B. The difference of TAAT between the 2 groups before the therapy was significant (P ¼ .0031), and after hormone therapy there was not a significant difference in the final TAAT between the 2 groups. A fair correlation between weight and TAAT at baseline (r ¼ 0.66; P < .0001) and good correlation between BMI and TAAT (r ¼ 0.71; P < .0001) was observed. There was no correlation between the type of AI drug used and the changes in TAAT, VAT, and SAT.
Discussion Over the past decade, several authors have shown the relationship between VAT and various adverse outcomes, including: obesity, hypertension, noneinsulin-dependent diabetes mellitus, dyslipidemia, and cardiovascular disease,27 with collectively these conditions referred to as the metabolic syndrome. The greatest metabolic risks associated with obesity have been correlated with the presence of excess VAT, appearing as central or abdominal fat, termed android distribution, rather than a peripheral or gluteofemoral fat pattern, termed gynoid distribution. The well recognized complications of obesity that have been attributed to increases in VAT, have been recently postulated to reflect an associated increase in portal vein free fatty acid levels.28 Marked differences in the amount and distribution of body fat tissue between men and women have been understood for millennia, however, the understanding of the biochemical nature of these differences and that it reflects differences in the whole-body lipid metabolism is relatively new.29 In
Table 2 Three-Dimensional Volumetry Computed Tomography Imaging Characteristics of the Study Sample (n [ 64 Patients) Adipose Tissue Type 3
Total Abdominal Adipose Tissue, mm Abdominal Visceral Adipose Tissue, mm3 Abdominal Subcutaneous Adipose Tissue, mm3
Before Therapy
After Therapy
Outcome
16,280.3 6953.3 9024.4 4630.0 7255.8 3376.6
17,763.6 6850.8 10,651.9 4371.7 7111.6 3372.0
Increased 9.1% Increased 18 % Decreased 1.9%
All values are mean SD.
Clinical Breast Cancer Month 2014
-3
Modification of Abdominal Fat Distribution After AI Therapy Figure 1 A 42-Year-Old Woman From Group A With Previous Breast Cancer Before and After 2 Years of AI Therapy, who Experienced an Increase of TAAT. (A) Axial CT Image at the Umbilical Level. SAT Is Determined (Colored Green in A and B). (B) In the Same Patient After 2 Years of AI, the SAT Volume Is Increased. (C) Axial CT Image at the Level of the Celiac Axis. VAT Is Shown (Colored Red in C and D). (D) The Same Patient After 2 Years of AI Therapy Shows That VAT Volume has Increased
Abbreviations: AI ¼ aromatase inhibitor; CT ¼ computed tomography; SAT ¼ subcutaneous adipose tissue; TAAT ¼ total abdominal adipose tissue; VAT ¼ visceral adipose tissue.
women, a greater amount of fat tissue is stored in the lower body gluteal region, and in men most fat is stored in an upper abdominal distribution. This sex difference in the amount and distribution
of body fat provides clear evidence of sex-related differences in whole-body lipid metabolism,30 which reflects differing susceptibilities to disease processes. In general, women store greater
Figure 2 A-53-Year Old Woman From Group B With Previous Breast Cancer Before and After 3 Years of AI Therapy, who has a Decreased TAAT. (A) CT Axial Image at the Level of the Iliac Crest. The SAT Is Shown (Colored Green in A and B). (B) The Same Patient After 3 Years of AI Therapy Shows That SAT Is Decreased. (C) CT Axial Image at the Level of the Celiac Axis Shows the VAT Distribution (Colored Red in C and D). (D) The Same Patient After 3 Years of AI Therapy Shows That VAT Is Increased, and the VAT/SAT Ratio Is Also Increased
4
-
Abbreviations: AI ¼ aromatase inhibitor; CT ¼ computed tomography; SAT ¼ subcutaneous adipose tissue; TAAT ¼ total abdominal adipose tissue; VAT ¼ visceral adipose tissue.
Clinical Breast Cancer Month 2014
Sofia Battisti et al Table 3 The Difference in Fat Distribution Before and After Hormone Therapy in the 2 Patient Groups, Based on Computed Tomography Calculations Tissue Type
Before Therapy
After Therapy
Adipose Volume
Paired Student t Test
Group A (n [ 43) 14,526.3 6425.1
18,143.3 7053.9
Increased 24.9%
P < .0001
SAT
6634.4 3149.8
7259.5 3343.4
Increased 9.4%
P ¼ .033
VAT
7891.9 3827.0
10,889.8 4272.3
Increased 37.9%
P < .0001
TAAT
Group B (n [ 21) TAAT SAT VAT
19,871.8 6741.5 8528.3 3542.3 11,343.5 5326
16,973.7 6509.87
Decreased 14.5%
P < .0001
6808.9 3492.6
Decreased 20.1%
P ¼ .033
10,164.8 4636.9
Decreased 10.3%
P ¼ .148
Total VAT/SAT Ratio
1.38 0.9
1.69 0.83
VAT/SAT Ratio Group A
1.34 0.9
1.65 0.7
Increased 25.3%
e
e
VAT/SAT Ratio Group B
1.46 0.9
1.75 0.9
Increased 19.6%
e
Increased 21.8%
All values are mean SD. Group A includes patients who showed an increase in TAAT after therapy. Group B includes patients who showed a decrease in TAAT. Abbreviations: SAT ¼ subcutaneous adipose tissue; TAAT ¼ total abdominal adipose tissue; VAT ¼ visceral adipose tissue.
amounts of fat subcutaneously, whereas in men fat storage occurs more substantially around the organs in the abdominal cavity, referred to as VAT fat.31 Among the deleterious effects of VAT is an association with chronic inflammation and with an increased circulating proinflammatory cytokine level involved with cardiovascular and oncological diseases.27,32 After menopause, the concentrations of circulating lipoproteins and body fat distribution shift toward a more male pattern, reflecting the actions of sex steroids in their metabolism. Previous studies33 demonstrated that total aromatase expression was significantly greater in omental fat tissue compared with subcutaneous fat in pregnant women, and this pattern was reversed in obese women. This difference supports the theory that fat depots are derived from different cell lineages, and that a promoter-derived aromatase translation varies according to physiologic and pathophysiologic status. During menopause, the aromatase translation is more expressed in SAT than in VAT tissue. In our results, in group A, a decrease of SAT compared with VAT was observed, which might be due to the effects of AI therapy, which results in an android pattern of fat distribution. After menopause, a woman’s risk of cardiovascular disease is increased.34 An important aspect of this increased risk is because of changes in plasma lipid lipoprotein levels that occur secondary to estrogen deficiency, and this condition is improved by the use of AIs.35 An accumulation of fat tissue in the abdominal cavity occurs with aging in men and women. In our study, we observed that with the use of AI therapy in postmenopausal women that the proportion of VAT increased regardless of whether the patients gained or lost weight. The development of increased VAT compared with the baseline level in an established postmenopausal state in all of these women suggests that this accumulation is much more pronounced than simple aging alone would incur. VAT is associated with chronic inflammation and an increased level of circulating proinflammatory cytokines (interleukin [IL]-1, IL-6, and tumor necrosis factor-a), which are involved in cardiovascular diseases. SAT has aromatase enzymes, which during menopause produce estrone and estradiol, which are the targets of AI therapies. Primary limitations of our study include that clinical
follow-up of patients in our study was not sufficiently long, and the number of patients sufficiently large to determine if an increased incidence of cardiovascular disease was present in patients with greater relative increases in VAT. A major limitation in our study was the absence of a control group with similar clinical features; further study including a control group who do not receive AI therapy is needed. Our findings suggest that more studies should be performed on body fat distribution in oncology patients, and whether changes in therapy or modifications of diet or behavior should be emphasized in patients who experience the greatest increases of VAT. It might be that clinicians should pay attention to changes in fat distribution in patients undergoing therapies, to anticipate and prevent the development of disease processes that arise from an increasing VAT/ SAT ratio. It is also conceivable that psychiatric distress that arises in women after mastectomy, might not only reflect the changes from breast removal, but also the changing fat distribution into a more androgenic pattern. Addressing this latter component might further help the confidence of these patients.36 An important risk factor for breast cancer is patient BMI.37,38 At present, the importance of a particular distribution of fat for cancer risk has not been established. It might be that a greater proportion of VAT is the important aspect of the risk that an increased BMI represents. Furthermore, to extend beyond the findings of our study, women that show accumulation of VAT during AI therapy might experience a higher long-term risk of cardiovascular diseases, metabolic syndrome, and diabetes.39 Our observations of increased VAT, and the known association between increased VAT and the metabolic syndrome and cardiovascular disease, provide underlying explanatory evidence to reports in the literature that describe increased cardiovascular disease in women taking AIs.40 In our study we used CT imaging to measure fat and the distribution of fat. In the literature, CT and magnetic resonance imaging have been described as accurate and reliable methods to measure fat.41 Because our practice in the clinical management of patients with breast cancer is to use CT imaging as a method of disease follow-up, we used CT imaging in our study, to avoid duplicate imaging examinations.
Clinical Breast Cancer Month 2014
-5
Modification of Abdominal Fat Distribution After AI Therapy Conclusion We observed a relative increase in the proportion of VAT tissue in postmenopausal women with breast cancer treated with AI therapy, regardless of whether women gained or lost weight. The implications of increased VAT include a host of deleterious disease processes collectively referred to as the metabolic syndrome. Attention to changes in fat distribution might become an important part of future assessment and management of cancer patients using this type of therapy.
Clinical Practice Points A modification of body fat distribution is possible after AI
therapies, and attention must be paid in patients during their clinical follow-up management. A correct lifestyle and diet should always be recommended to these patients. Studies are needed on this topic to clarify the association between abdominal fat tissue distribution and the risk of cardiovascular disease in these patients.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Daudt A, Alberg AJ, Helzlsouer KJ. Epidemiology, prevention, and early detection of breast cancer. Curr Opin Oncol 1996; 8:455-61. 2. Dowsett M, Cuzick J, Ingle J, et al. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol 2010; 28: 509-18. 3. Russo J, Russo IH. The role of estrogen in the initiation of breast cancer. J Steroid Biochem Mol Biol 2006; 102:89-96. 4. Rieber AG, Theriault RL. Aromatase inhibitors in postmenopausal breast cancer patients. J Natl Compr Canc Netw 2005; 3:309-14. 5. Labrie F, Simard J, Luu-The V, Pelletier G, Belghmi K, Belanger A. Structure, regulation and role of 3 beta-hydroxysteroid dehydrogenase, 17 betahydroxysteroid dehydrogenase and aromatase enzymes in the formation of sex steroids in classical and peripheral intracrine tissues. Baillieres Clin Endocrinol Metab 1994; 8:451-74. 6. Labrie F, Luu-The V, Labrie C, et al. Endocrine and intracrine sources of androgens in women: inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone. Endocr Rev 2003; 24:152-82. 7. Desta Z, Nguyen A, Flockhart D, et al. Antiestrogen pathway (aromatase inhibitor). Pharmacogenet Genomics 2009; 19:554-5. 8. Amir E, Seruga B, Niraula S, Carlsson L, Ocana A. Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and metaanalysis. J Natl Cancer Inst 2011; 103:1299-309. 9. Burstein HJ, Prestrud AA, Seidenfeld J, et al. American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol 2010; 28: 3784-96. 10. Fair AM, Montgomery K. Energy balance, physical activity, and cancer risk. Methods Mol Biol 2009; 472:57-88. 11. Ibrahim MM. Subcutaneous and visceral adipose tissue: structural and functional differences. Obes Rev 2010; 11:11-8. 12. Klein S. The case of visceral fat: argument for the defense. J Clin Invest 2004; 113: 1530-2. 13. Matsuzawa Y. Therapy insight: adipocytokines in metabolic syndrome and related cardiovascular disease. Nat Clin Pract Cardiovasc Med 2006; 3:35-42. 14. Wajchenberg BL. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev 2000; 21:697-738.
6
-
Clinical Breast Cancer Month 2014
15. Wajchenberg BL, Giannella-Neto D, da Silva ME, Santos RF. Depot-specific hormonal characteristics of subcutaneous and visceral adipose tissue and their relation to the metabolic syndrome. Horm Metab Res 2002; 34:616-21. 16. Korhonen S, Hippelainen M, Vanhala M, Heinonen S, Niskanen L. The androgenic sex hormone profile is an essential feature of metabolic syndrome in premenopausal women: a controlled community-based study. Fertil Steril 2003; 79: 1327-34. 17. Kirschner MA, Samojlik E, Drejka M, Szmal E, Schneider G, Ertel N. Androgenestrogen metabolism in women with upper body versus lower body obesity. J Clin Endocrinol Metab 1990; 70:473-9. 18. Simpson ER. Genetic mutations resulting in loss of aromatase activity in humans and mice. J Soc Gynecol Investig 2000; 7(suppl 1):S18-21. 19. Jones ME, Thorburn AW, Britt KL, et al. Aromatase-deficient (ArKO) mice accumulate excess adipose tissue. J Steroid Biochem Mol Biol 2001; 79:3-9. 20. Jones ME, Thorburn AW, Britt KL, et al. Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity. Proc Natl Acad Sci U S A 2000; 97:12735-40. 21. Blanchette S, Blouin K, Richard C, Dupont P, Luu-The V, Tchernof A. Expression and activity of 20alpha-hydroxysteroid dehydrogenase (AKR1C1) in abdominal subcutaneous and omental adipose tissue in women. J Clin Endocrinol Metab 2005; 90:264-70. 22. Carr MC. The emergence of the metabolic syndrome with menopause. J Clin Endocrinol Metab 2003; 88:2404-11. 23. Hirooka M, Kumagi T, Kurose K, et al. A technique for the measurement of visceral fat by ultrasonography: comparison of measurements by ultrasonography and computed tomography. Intern Med 2005; 44:794-9. 24. Yoshizumi T, Nakamura T, Yamane M, et al. Abdominal fat: standardized technique for measurement at CT. Radiology 1999; 211:283-6. 25. Kuk JL, Church TS, Blair SN, Ross R. Does measurement site for visceral and abdominal subcutaneous adipose tissue alter associations with the metabolic syndrome? Diabetes Care 2006; 29:679-84. 26. Borkan GA, Gerzof SG, Robbins AH, Hults DE, Silbert CK, Silbert JE. Assessment of abdominal fat content by computed tomography. Am J Clin Nutr 1982; 36:172-7. 27. Vague J. Sexual differentiation. A determinant factor of the forms of obesity. 1947. Obes Res 1996; 4:201-3. 28. Bjorntorp P. “Portal” adipose tissue as a generator of risk factors for cardiovascular disease and diabetes. Arteriosclerosis 1990; 10:493-6. 29. Bjorntorp P. Regional patterns of fat distribution. Ann Int Med 1985; 103:994-5. 30. Ley CJ, Lees B, Stevenson JC. Sex- and menopause-associated changes in body-fat distribution. Am J Clin Nutr 1992; 55:950-4. 31. Kotani K, Tokunaga K, Fujioka S, et al. Sexual dimorphism of age-related changes in whole-body fat distribution in the obese. Int J Obes Relat Metab Disord 1994; 18:207-2. 32. Artac M, Bozcuk H, Afacan B, Ozdogan M, Samur M. The impact of waist-to-hip ratio on clinical outcomes in metastatic breast cancer patients treated with aromatase inhibitors. Breast 2008; 17:418-22. 33. Rice S, Patel B, Bano G, Ugwumadu A, Whitehead SA. Aromatase expression in abdominal omental/visceral and subcutaneous fat depots: a comparison of pregnant and obese women. Fertil Steril 2012; 97:1460-1466.e1. 34. Poehlman ET. Re: Tchernof, A. and Poehlman E., Effects of the menopause transition on body fatness and body fat distribution, Obesity Research vol. 6, No. 3 (May):246-254 1998. Obes Res 2005; 13:1300. 35. Engan T, Krane J, Johannessen DC, Lonning PE, Kvinnsland S. Plasma changes in breast cancer patients during endocrine therapyelipid measurements and nuclear magnetic resonance (NMR) spectroscopy. Breast Cancer Res Treat 1995; 36: 287-97. 36. Kim KR, Chung HC, Lee E, Kim SJ, Namkoong K. Body image, sexual function and depression in Korean patients with breast cancer: modification by 5-HTT polymorphism. Support Care Cancer 2012; 20:2177-82. 37. Cleary MP, Grossmann ME. Minireview: obesity and breast cancer: the estrogen connection. Endocrinology 2009; 150:2537-42. 38. Santen RJ. Assessing individual risk for breast cancer: role of oestrogens and androgens. Breast Cancer Res 2008; 10(suppl 4):S10. 39. Lapauw B, T’Sjoen G, Mahmoud A, Kaufman JM, Ruige JB. Short-term aromatase inhibition: effects on glucose metabolism and serum leptin levels in young and elderly men. Eur J Endocrinol 2009; 160:397-402. 40. Winer EP, Hudis C, Burstein HJ, et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol 2005; 23:619-29. 41. Noone TC, Semelka RC, Chaney DM, Reinhold C. Abdominal imaging studies: comparison of diagnostic accuracies resulting from ultrasound, computed tomography, and magnetic resonance imaging in the same individual. Magn Reson Imaging 2004; 22:19-24.
Modification of Abdominal Fat Distribution After Aromatase Inhibitor Therapy in Breast Cancer Patients Visualized Using 3-D Computed Tomography Volumetry Sofia Battisti,1 Francesco Maria Guida,2 Federica Coppa,1 Donata M. Vaccaro,1 Daniele Santini,2 Giuseppe Tonini,2 Bruno B. Zobel,1 Richard C. Semelka3 Abstract The pattern of abdominal fat distribution is hormone linked and it can affect or be predictive of various diseases, in particular metabolic syndrome is associated with an increase amount of visceral adipose tissue. After system therapy with aromatase inhibitor in breast cancer patients, we found a relative increase of visceral adipose tissue regardless of whether they gained or lost weight after therapy. Introduction/Background: The purpose of this study was to describe modification of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) distributions in breast cancer patients after aromatase inhibitor (AI) therapy using computed tomography (CT) volumetric measurement of abdominal body fat distribution. Patients and Methods: Sixty-four consecutive patients who were receiving adjuvant AI therapy were included in this study. Patients were evaluated using CT before and after at least 6 months of AI therapy with imaging follow-up of 4.3 2.2 years. Abdominal fat distribution was automatically calculated using a workstation that obtained total abdominal adipose tissue (TAAT) area (mm3). SAT was manually segmented and VAT was determined as TAAT SAT. Percentages were calculated for change of TAAT, VAT, and SAT. VAT/SAT ratio was calculated. Results: Percentage of TAAT after AI therapy was increased by a mean of 9.1% from baseline (16,280.3 6953.3 mm3) to (17,763.6 6850.8 mm3). Two groups of patients were observed; those with an increase in TAAT and those with a decrease. Modification of VAT/SAT ratio was observed (from 1.38 to 1.69) in all subjects, reflecting a relative increased volume of VAT (mean, 18%) and slight mean reduction of SAT (mean 1.9%). Conclusion: In our study, therapy with AI in breast cancer patients was accompanied with a change in fat distribution to relatively greater VAT/SAT ratio in patients, regardless of whether they gained or lost weight after therapy. Because this pattern of fat distribution is associated with metabolic disorders, attention must be paid to these clinical manifestations in patients during their follow-up management. Clinical Breast Cancer, Vol. -, No. -, --- ª 2014 Elsevier Inc. All rights reserved. Keywords: Aromatase inhibitor therapy, Breast cancer, CT, Subcutaneous fat, Visceral fat
Introduction Breast cancer is the most common malignancy in women, represents 18% of all female cancers, and there are > 100,000 new 1
Department of Radiology, Campus Bio-Medico University of Rome, Rome, Italy Department of Medical Oncology, Campus Bio-Medico University of Rome, Rome, Italy 3 Department of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 2
Submitted: Oct 23, 2013; Revised: Feb 7, 2014; Accepted: Feb 12, 2014 Address for correspondence: Sofia Battisti, MD, Department of Radiology, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 200, Rome 00128, Italy Fax: þ39-06-225411633; e-mail contact: sofi[email protected]
1526-8209/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2014.02.003
cases of hormone receptor-positive breast cancers per year in the United States.1 To reduce the risk of recurrence in postmenopausal women with hormone receptor-positive breast cancer, aromatase inhibitor (AI) therapy is currently recommended for 5 years and has become the standard of care because of their superior reduction of breast cancer recurrence compared with estrogen receptor agonists and antagonists.2 It is well known that estrogen plays an important role in initiating and promoting breast cancer.3 Because of this recognition, hormone therapy plays an important role in the treatment of breast cancer, in fact, AIs are drugs that inhibit the aromatase-mediated synthesis of estrogens in peripheral tissues, with the effect of decreasing body estrogen level. The AIs may be
Clinical Breast Cancer Month 2014
-1
Modification of Abdominal Fat Distribution After AI Therapy
2
-
nonsteroidal, such as the triazole derivatives, anastrozole and letrozole, or steroidal, such as exemestane.4 In postmenopausal women the dominant source of estrogens is the peripheral conversion from androgens, which is catalyzed by aromatase, an enzyme of the cytochrome P450 subfamily, mediated by the CYP19A1 gene. Aromatase enzymes in premenopausal women are highly expressed in placenta and in granulose cells of ovarian follicles.5 Additionally, aromatases are present, at lower levels, in several nonglandular tissues including subcutaneous fat, liver, muscle, brain, normal breast, and breast cancer tissue.6 Estrogen production after menopause is solely from nonglandular sources, in particular from subcutaneous fat.7 Recent studies have observed that that treatment with AIs might be associated with an increase of cardiovascular diseases.8,9 Amir et al8 reported in their metaanalysis that longer duration of AI use was associated with an increased odds ratio of cardiovascular disease. During menopause, androstenedione produced in the adrenal glands, and, to a lesser extent, testosterone produced in the ovaries, are released into the circulation, and then sequestered to nonglandular tissues such as liver and breast, where they are converted to estrone and estradiol, respectively, by aromatase enzymes located in nonglandular tissues, especially subcutaneous fat.6 Body fat mass and its distribution in men and women is determined by both sex steroids, androgens and estrogens, which play important roles, and their effect results in different patterns of total abdominal adipose tissue (TAAT) distribution. The male pattern of fat distribution is termed “android,” which is characterized by a high amount of visceral adipose tissue (VAT), and the female pattern is termed “gynoid,” which is characterized by peripheral or gluteofemoral fat distribution with a greater amount of subcutaneous adipose tissue (SAT). SAT of the abdomen is defined as the fat tissue located between the skin and abdominal musculature, and VAT is the fat tissue present within the abdominal cavity. VAT tissue contains adipocytes that are more metabolically active, and are linked to a series of disease processes involving the cardiovascular systems10 and also carcinogenesis.11 Different fat compartments are thereby associated with differential metabolic risks.12 Previous studies on the risk of developing metabolic diseases have shown that the VAT compartment might possess unique pathogenic properties13 that can influence the risk of developing metabolic diseases.14 Visceral adipose obesity is well known be associated with adverse metabolic effects and increased cardiovascular risk, and a prominent aspect of this tissue is a predominance of androgen action over that of estrogen.15,16 In fact, circulating androgen levels are greater in women with central obesity compared with nonobese women.17 Previous reports indicate that aromatase deficiency in humans18 and in mice19 results in a predominance of androgens over estrogens, abdominal obesity, and insulin resistance.20 A prolonged period of estrogen suppression, such as occurs during AI therapy, results in relative hyperandrogenemia,21 that might induce major alterations in body composition that might be more extensive than those induced by menopause.22 Quantification of abdominal adipose tissue can be performed using several methods. In clinical practice, measurement of body mass index (BMI) is commonly performed, however, this approach does not evaluate an increase in visceral fat,23 and similarly limited are surface measurements such as the circumference of the hip, the waist to hip circumference ratio, or abdominal sagittal diameter, which also do not separate VAT from
Clinical Breast Cancer Month 2014
SAT with any reliability.24 The most accurate and reproducible methods are computed tomography (CT)- or magnetic resonance images, which allow visualization of the body compartments.25 In the current medical literature, there are many studies that describe the measurement of abdominal fat tissue using imaging with the intent to understand the relationship between VAT and the metabolic syndrome.26 To the best of our knowledge, no previous study has used objective quantification of VAT and SAT with crosssectional imaging to evaluate the potential modification of fat compartment distribution in women taking AIs for the treatment of breast cancer. The purpose of our study was to determined the presence of anthropometric modification using CT volumetry of abdominal body fat distribution in patients with previous breast cancer who are taking AI therapy.
Patients and Methods Patients This study was approved by our institutional ethics committee with written informed consent. This retrospective study included 64 consecutive Caucasian female patients (mean age, 55.8 11.7 years; age range, 36-77 years), who underwent CT scanning between September 2005 and December 2012. Selection criteria were: histologically confirmed breast cancer after radical mastectomy, postmenopausal status, AI adjuvant therapy for at least 6 months before CT restaging, no recurrence of breast cancer, and no other substantial disease over the follow-up period (average, 4.3 2.2 years). Clinical characteristics of the subjects are summarized in Table 1. Table 1 Clinical Characteristics of the Study Sample (n [ 64 Patients) Characteristic Age, Years
Value 55.9 11.7
Aromatase Inhibitor Anastrozolo
n ¼ 33/64
Letrozolo
n ¼ 31/64
Stage, % Ia
4
Ib
4
IIa
21
IIb
23
IIIa
6
IIIb
1
IIIc
5
Anthracycline-Based Adjuvant Chemotherapy, % No
9
Yes
55
Histology, n ER status (positive)
63/64
PR status (positive)
60/64
c-erb-B2 status (triple positive)
6/64
Grading, % 1
7
2
32
3
25
Sofia Battisti et al CT Analysis Subjects underwent CT examination with Somaton, Sensation 64 CT scanners (Siemens, Forcheim, Germany). CT studies were performed before and after the initiation of AI therapy. TAAT, VAT, and SAT were determined in the CT study before initiation of AI therapy, and in the study after the last oncological restaging. CT measurements of fat tissue were assessed using 3-mm slice thickness images, which were acquired of the entire abdomen and pelvis during the venous phase in postcontrast images. Abdominal adipose tissue measurements were quantified semiautomatically using a dedicated workstation (Leonardo, Siemens). TAAT was automatically generated by the workstation. SAT was generated by manual tracing from the skin surface to the outer surface of the abdominal musculature. VAT was generated using the formula, TAAT SAT.
Statistical Analysis Percentages were calculated for the increase of TAAT, VAT, and SAT. The VAT/SAT ratio was calculated. Two groups were created: group A, who experienced an increase in TAAT, and group B, who experienced a decrease. A pairwise Student t test was used to compare TAAT, VAT, and SAT before and after AI therapy for both groups. Spearman rank correlation between weight and BMI TAAT before and after therapy was performed to evaluate the relationship between various weight estimation tools and TAAT, as indices of fat. Spearman rank correlation was used for AI and age comparisons with TAAT, VAT, and SAT as variables, before and after AI, for both groups.
Results The anthropometrical characteristic of the entire study population and the percentage distribution of TAAT, VAT, and SAT are summarized in Table 2. The volumetric 3-D CT analysis showed a mean increase of 9.1% of TAAT volume for all subjects after at least 6 months of AI therapy, from the baseline mean of 16,280.3 6953.3 mm3 to 17,763.6 6850.8 mm3. The pattern of fat distribution was characterized by a modification of VAT/ SAT ratio (from 1.38 SD to 1.69 SD), reflecting a relative increased volume of VAT (mean 18% SD) and slight reduction of SAT (mean 1.9% SD). Mean patient BMI at baseline was 26.3 4.2 with 11% of subjects considered obese (BMI 30). After AI therapy, based on TAAT, 2 groups of patients were observed; those with an increase (group A, 43 patients) and those with a decrease (group B, 21 patients) (Figs. 1 and 2). At the baseline time point, group A had a BMI of 25.5 4, and BMI for group B was 27.9 4.2. The body fat distribution of the 2 groups was analyzed using a t test to compare the difference before and after AI therapy. The result are shown in Table 3, which
demonstrates a significant difference in the increase of TAAT and VAT after therapy in group A (P < .0001), and in the TAAT decrease in group B (P < .0001). In both groups, a modification of VAT/SAT ratio was observed (from 1.38 to 1.69), reflecting a relative increased volume of VAT (mean, 18%) and slight reduction of SAT (mean, 1.9%). The difference in the fat distribution, based on CT calculations before and after hormone therapy in the 2 patient groups is shown in Table 3. Group A included patients who showed an increase in TAAT after therapy. Group B included patients who showed a decrease in TAAT. In an unpaired t test, the difference in TAAT between the 2 groups before therapy was significant (P ¼ .0031). After hormone therapy there was not a significant difference in the final TAAT in the 2 groups. The data demonstrate that patients in group A experienced an increase of TAAT, and those in group B a reduction. A different pattern of body fat distribution was apparent between the groups. Group A had an increase of VAT after hormone therapy, with a significant increase of TAAT (mean, 24.9% increase), and an even greater increase in VAT (mean, 37.9%). Group B had a significant reduction of TAAT (mean, 14.5%). Before the hormone therapy group A had a lower TAAT compared with group B. The difference of TAAT between the 2 groups before the therapy was significant (P ¼ .0031), and after hormone therapy there was not a significant difference in the final TAAT between the 2 groups. A fair correlation between weight and TAAT at baseline (r ¼ 0.66; P < .0001) and good correlation between BMI and TAAT (r ¼ 0.71; P < .0001) was observed. There was no correlation between the type of AI drug used and the changes in TAAT, VAT, and SAT.
Discussion Over the past decade, several authors have shown the relationship between VAT and various adverse outcomes, including: obesity, hypertension, noneinsulin-dependent diabetes mellitus, dyslipidemia, and cardiovascular disease,27 with collectively these conditions referred to as the metabolic syndrome. The greatest metabolic risks associated with obesity have been correlated with the presence of excess VAT, appearing as central or abdominal fat, termed android distribution, rather than a peripheral or gluteofemoral fat pattern, termed gynoid distribution. The well recognized complications of obesity that have been attributed to increases in VAT, have been recently postulated to reflect an associated increase in portal vein free fatty acid levels.28 Marked differences in the amount and distribution of body fat tissue between men and women have been understood for millennia, however, the understanding of the biochemical nature of these differences and that it reflects differences in the whole-body lipid metabolism is relatively new.29 In
Table 2 Three-Dimensional Volumetry Computed Tomography Imaging Characteristics of the Study Sample (n [ 64 Patients) Adipose Tissue Type 3
Total Abdominal Adipose Tissue, mm Abdominal Visceral Adipose Tissue, mm3 Abdominal Subcutaneous Adipose Tissue, mm3
Before Therapy
After Therapy
Outcome
16,280.3 6953.3 9024.4 4630.0 7255.8 3376.6
17,763.6 6850.8 10,651.9 4371.7 7111.6 3372.0
Increased 9.1% Increased 18 % Decreased 1.9%
All values are mean SD.
Clinical Breast Cancer Month 2014
-3
Modification of Abdominal Fat Distribution After AI Therapy Figure 1 A 42-Year-Old Woman From Group A With Previous Breast Cancer Before and After 2 Years of AI Therapy, who Experienced an Increase of TAAT. (A) Axial CT Image at the Umbilical Level. SAT Is Determined (Colored Green in A and B). (B) In the Same Patient After 2 Years of AI, the SAT Volume Is Increased. (C) Axial CT Image at the Level of the Celiac Axis. VAT Is Shown (Colored Red in C and D). (D) The Same Patient After 2 Years of AI Therapy Shows That VAT Volume has Increased
Abbreviations: AI ¼ aromatase inhibitor; CT ¼ computed tomography; SAT ¼ subcutaneous adipose tissue; TAAT ¼ total abdominal adipose tissue; VAT ¼ visceral adipose tissue.
women, a greater amount of fat tissue is stored in the lower body gluteal region, and in men most fat is stored in an upper abdominal distribution. This sex difference in the amount and distribution
of body fat provides clear evidence of sex-related differences in whole-body lipid metabolism,30 which reflects differing susceptibilities to disease processes. In general, women store greater
Figure 2 A-53-Year Old Woman From Group B With Previous Breast Cancer Before and After 3 Years of AI Therapy, who has a Decreased TAAT. (A) CT Axial Image at the Level of the Iliac Crest. The SAT Is Shown (Colored Green in A and B). (B) The Same Patient After 3 Years of AI Therapy Shows That SAT Is Decreased. (C) CT Axial Image at the Level of the Celiac Axis Shows the VAT Distribution (Colored Red in C and D). (D) The Same Patient After 3 Years of AI Therapy Shows That VAT Is Increased, and the VAT/SAT Ratio Is Also Increased
4
-
Abbreviations: AI ¼ aromatase inhibitor; CT ¼ computed tomography; SAT ¼ subcutaneous adipose tissue; TAAT ¼ total abdominal adipose tissue; VAT ¼ visceral adipose tissue.
Clinical Breast Cancer Month 2014
Sofia Battisti et al Table 3 The Difference in Fat Distribution Before and After Hormone Therapy in the 2 Patient Groups, Based on Computed Tomography Calculations Tissue Type
Before Therapy
After Therapy
Adipose Volume
Paired Student t Test
Group A (n [ 43) 14,526.3 6425.1
18,143.3 7053.9
Increased 24.9%
P < .0001
SAT
6634.4 3149.8
7259.5 3343.4
Increased 9.4%
P ¼ .033
VAT
7891.9 3827.0
10,889.8 4272.3
Increased 37.9%
P < .0001
TAAT
Group B (n [ 21) TAAT SAT VAT
19,871.8 6741.5 8528.3 3542.3 11,343.5 5326
16,973.7 6509.87
Decreased 14.5%
P < .0001
6808.9 3492.6
Decreased 20.1%
P ¼ .033
10,164.8 4636.9
Decreased 10.3%
P ¼ .148
Total VAT/SAT Ratio
1.38 0.9
1.69 0.83
VAT/SAT Ratio Group A
1.34 0.9
1.65 0.7
Increased 25.3%
e
e
VAT/SAT Ratio Group B
1.46 0.9
1.75 0.9
Increased 19.6%
e
Increased 21.8%
All values are mean SD. Group A includes patients who showed an increase in TAAT after therapy. Group B includes patients who showed a decrease in TAAT. Abbreviations: SAT ¼ subcutaneous adipose tissue; TAAT ¼ total abdominal adipose tissue; VAT ¼ visceral adipose tissue.
amounts of fat subcutaneously, whereas in men fat storage occurs more substantially around the organs in the abdominal cavity, referred to as VAT fat.31 Among the deleterious effects of VAT is an association with chronic inflammation and with an increased circulating proinflammatory cytokine level involved with cardiovascular and oncological diseases.27,32 After menopause, the concentrations of circulating lipoproteins and body fat distribution shift toward a more male pattern, reflecting the actions of sex steroids in their metabolism. Previous studies33 demonstrated that total aromatase expression was significantly greater in omental fat tissue compared with subcutaneous fat in pregnant women, and this pattern was reversed in obese women. This difference supports the theory that fat depots are derived from different cell lineages, and that a promoter-derived aromatase translation varies according to physiologic and pathophysiologic status. During menopause, the aromatase translation is more expressed in SAT than in VAT tissue. In our results, in group A, a decrease of SAT compared with VAT was observed, which might be due to the effects of AI therapy, which results in an android pattern of fat distribution. After menopause, a woman’s risk of cardiovascular disease is increased.34 An important aspect of this increased risk is because of changes in plasma lipid lipoprotein levels that occur secondary to estrogen deficiency, and this condition is improved by the use of AIs.35 An accumulation of fat tissue in the abdominal cavity occurs with aging in men and women. In our study, we observed that with the use of AI therapy in postmenopausal women that the proportion of VAT increased regardless of whether the patients gained or lost weight. The development of increased VAT compared with the baseline level in an established postmenopausal state in all of these women suggests that this accumulation is much more pronounced than simple aging alone would incur. VAT is associated with chronic inflammation and an increased level of circulating proinflammatory cytokines (interleukin [IL]-1, IL-6, and tumor necrosis factor-a), which are involved in cardiovascular diseases. SAT has aromatase enzymes, which during menopause produce estrone and estradiol, which are the targets of AI therapies. Primary limitations of our study include that clinical
follow-up of patients in our study was not sufficiently long, and the number of patients sufficiently large to determine if an increased incidence of cardiovascular disease was present in patients with greater relative increases in VAT. A major limitation in our study was the absence of a control group with similar clinical features; further study including a control group who do not receive AI therapy is needed. Our findings suggest that more studies should be performed on body fat distribution in oncology patients, and whether changes in therapy or modifications of diet or behavior should be emphasized in patients who experience the greatest increases of VAT. It might be that clinicians should pay attention to changes in fat distribution in patients undergoing therapies, to anticipate and prevent the development of disease processes that arise from an increasing VAT/ SAT ratio. It is also conceivable that psychiatric distress that arises in women after mastectomy, might not only reflect the changes from breast removal, but also the changing fat distribution into a more androgenic pattern. Addressing this latter component might further help the confidence of these patients.36 An important risk factor for breast cancer is patient BMI.37,38 At present, the importance of a particular distribution of fat for cancer risk has not been established. It might be that a greater proportion of VAT is the important aspect of the risk that an increased BMI represents. Furthermore, to extend beyond the findings of our study, women that show accumulation of VAT during AI therapy might experience a higher long-term risk of cardiovascular diseases, metabolic syndrome, and diabetes.39 Our observations of increased VAT, and the known association between increased VAT and the metabolic syndrome and cardiovascular disease, provide underlying explanatory evidence to reports in the literature that describe increased cardiovascular disease in women taking AIs.40 In our study we used CT imaging to measure fat and the distribution of fat. In the literature, CT and magnetic resonance imaging have been described as accurate and reliable methods to measure fat.41 Because our practice in the clinical management of patients with breast cancer is to use CT imaging as a method of disease follow-up, we used CT imaging in our study, to avoid duplicate imaging examinations.
Clinical Breast Cancer Month 2014
-5
Modification of Abdominal Fat Distribution After AI Therapy Conclusion We observed a relative increase in the proportion of VAT tissue in postmenopausal women with breast cancer treated with AI therapy, regardless of whether women gained or lost weight. The implications of increased VAT include a host of deleterious disease processes collectively referred to as the metabolic syndrome. Attention to changes in fat distribution might become an important part of future assessment and management of cancer patients using this type of therapy.
Clinical Practice Points A modification of body fat distribution is possible after AI
therapies, and attention must be paid in patients during their clinical follow-up management. A correct lifestyle and diet should always be recommended to these patients. Studies are needed on this topic to clarify the association between abdominal fat tissue distribution and the risk of cardiovascular disease in these patients.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Daudt A, Alberg AJ, Helzlsouer KJ. Epidemiology, prevention, and early detection of breast cancer. Curr Opin Oncol 1996; 8:455-61. 2. Dowsett M, Cuzick J, Ingle J, et al. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol 2010; 28: 509-18. 3. Russo J, Russo IH. The role of estrogen in the initiation of breast cancer. J Steroid Biochem Mol Biol 2006; 102:89-96. 4. Rieber AG, Theriault RL. Aromatase inhibitors in postmenopausal breast cancer patients. J Natl Compr Canc Netw 2005; 3:309-14. 5. Labrie F, Simard J, Luu-The V, Pelletier G, Belghmi K, Belanger A. Structure, regulation and role of 3 beta-hydroxysteroid dehydrogenase, 17 betahydroxysteroid dehydrogenase and aromatase enzymes in the formation of sex steroids in classical and peripheral intracrine tissues. Baillieres Clin Endocrinol Metab 1994; 8:451-74. 6. Labrie F, Luu-The V, Labrie C, et al. Endocrine and intracrine sources of androgens in women: inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone. Endocr Rev 2003; 24:152-82. 7. Desta Z, Nguyen A, Flockhart D, et al. Antiestrogen pathway (aromatase inhibitor). Pharmacogenet Genomics 2009; 19:554-5. 8. Amir E, Seruga B, Niraula S, Carlsson L, Ocana A. Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and metaanalysis. J Natl Cancer Inst 2011; 103:1299-309. 9. Burstein HJ, Prestrud AA, Seidenfeld J, et al. American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol 2010; 28: 3784-96. 10. Fair AM, Montgomery K. Energy balance, physical activity, and cancer risk. Methods Mol Biol 2009; 472:57-88. 11. Ibrahim MM. Subcutaneous and visceral adipose tissue: structural and functional differences. Obes Rev 2010; 11:11-8. 12. Klein S. The case of visceral fat: argument for the defense. J Clin Invest 2004; 113: 1530-2. 13. Matsuzawa Y. Therapy insight: adipocytokines in metabolic syndrome and related cardiovascular disease. Nat Clin Pract Cardiovasc Med 2006; 3:35-42. 14. Wajchenberg BL. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev 2000; 21:697-738.
6
-
Clinical Breast Cancer Month 2014
15. Wajchenberg BL, Giannella-Neto D, da Silva ME, Santos RF. Depot-specific hormonal characteristics of subcutaneous and visceral adipose tissue and their relation to the metabolic syndrome. Horm Metab Res 2002; 34:616-21. 16. Korhonen S, Hippelainen M, Vanhala M, Heinonen S, Niskanen L. The androgenic sex hormone profile is an essential feature of metabolic syndrome in premenopausal women: a controlled community-based study. Fertil Steril 2003; 79: 1327-34. 17. Kirschner MA, Samojlik E, Drejka M, Szmal E, Schneider G, Ertel N. Androgenestrogen metabolism in women with upper body versus lower body obesity. J Clin Endocrinol Metab 1990; 70:473-9. 18. Simpson ER. Genetic mutations resulting in loss of aromatase activity in humans and mice. J Soc Gynecol Investig 2000; 7(suppl 1):S18-21. 19. Jones ME, Thorburn AW, Britt KL, et al. Aromatase-deficient (ArKO) mice accumulate excess adipose tissue. J Steroid Biochem Mol Biol 2001; 79:3-9. 20. Jones ME, Thorburn AW, Britt KL, et al. Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity. Proc Natl Acad Sci U S A 2000; 97:12735-40. 21. Blanchette S, Blouin K, Richard C, Dupont P, Luu-The V, Tchernof A. Expression and activity of 20alpha-hydroxysteroid dehydrogenase (AKR1C1) in abdominal subcutaneous and omental adipose tissue in women. J Clin Endocrinol Metab 2005; 90:264-70. 22. Carr MC. The emergence of the metabolic syndrome with menopause. J Clin Endocrinol Metab 2003; 88:2404-11. 23. Hirooka M, Kumagi T, Kurose K, et al. A technique for the measurement of visceral fat by ultrasonography: comparison of measurements by ultrasonography and computed tomography. Intern Med 2005; 44:794-9. 24. Yoshizumi T, Nakamura T, Yamane M, et al. Abdominal fat: standardized technique for measurement at CT. Radiology 1999; 211:283-6. 25. Kuk JL, Church TS, Blair SN, Ross R. Does measurement site for visceral and abdominal subcutaneous adipose tissue alter associations with the metabolic syndrome? Diabetes Care 2006; 29:679-84. 26. Borkan GA, Gerzof SG, Robbins AH, Hults DE, Silbert CK, Silbert JE. Assessment of abdominal fat content by computed tomography. Am J Clin Nutr 1982; 36:172-7. 27. Vague J. Sexual differentiation. A determinant factor of the forms of obesity. 1947. Obes Res 1996; 4:201-3. 28. Bjorntorp P. “Portal” adipose tissue as a generator of risk factors for cardiovascular disease and diabetes. Arteriosclerosis 1990; 10:493-6. 29. Bjorntorp P. Regional patterns of fat distribution. Ann Int Med 1985; 103:994-5. 30. Ley CJ, Lees B, Stevenson JC. Sex- and menopause-associated changes in body-fat distribution. Am J Clin Nutr 1992; 55:950-4. 31. Kotani K, Tokunaga K, Fujioka S, et al. Sexual dimorphism of age-related changes in whole-body fat distribution in the obese. Int J Obes Relat Metab Disord 1994; 18:207-2. 32. Artac M, Bozcuk H, Afacan B, Ozdogan M, Samur M. The impact of waist-to-hip ratio on clinical outcomes in metastatic breast cancer patients treated with aromatase inhibitors. Breast 2008; 17:418-22. 33. Rice S, Patel B, Bano G, Ugwumadu A, Whitehead SA. Aromatase expression in abdominal omental/visceral and subcutaneous fat depots: a comparison of pregnant and obese women. Fertil Steril 2012; 97:1460-1466.e1. 34. Poehlman ET. Re: Tchernof, A. and Poehlman E., Effects of the menopause transition on body fatness and body fat distribution, Obesity Research vol. 6, No. 3 (May):246-254 1998. Obes Res 2005; 13:1300. 35. Engan T, Krane J, Johannessen DC, Lonning PE, Kvinnsland S. Plasma changes in breast cancer patients during endocrine therapyelipid measurements and nuclear magnetic resonance (NMR) spectroscopy. Breast Cancer Res Treat 1995; 36: 287-97. 36. Kim KR, Chung HC, Lee E, Kim SJ, Namkoong K. Body image, sexual function and depression in Korean patients with breast cancer: modification by 5-HTT polymorphism. Support Care Cancer 2012; 20:2177-82. 37. Cleary MP, Grossmann ME. Minireview: obesity and breast cancer: the estrogen connection. Endocrinology 2009; 150:2537-42. 38. Santen RJ. Assessing individual risk for breast cancer: role of oestrogens and androgens. Breast Cancer Res 2008; 10(suppl 4):S10. 39. Lapauw B, T’Sjoen G, Mahmoud A, Kaufman JM, Ruige JB. Short-term aromatase inhibition: effects on glucose metabolism and serum leptin levels in young and elderly men. Eur J Endocrinol 2009; 160:397-402. 40. Winer EP, Hudis C, Burstein HJ, et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol 2005; 23:619-29. 41. Noone TC, Semelka RC, Chaney DM, Reinhold C. Abdominal imaging studies: comparison of diagnostic accuracies resulting from ultrasound, computed tomography, and magnetic resonance imaging in the same individual. Magn Reson Imaging 2004; 22:19-24.
