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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 8 2711-2716
Copyright © 1998 by The Endocrine Society

Original Studies

Serum Thyroid Peroxidase Autoantibodies, Thyroid Volume, and Outcome in Breast Carcinoma1

P. P. A. Smyth, S. G. Shering, M. T. Kilbane, M. J. Murray, E. W. M. McDermott, D. F. Smith and N. J. O’Higgins

Endocrine Laboratory, Department of Medicine and Therapeutics and Department of Surgery, St. Vincent’s Hospital and University College Dublin, Dublin 4, Ireland

Address all correspondence and requests for reprints to: Dr. P. P. A. Smyth, Endocrine Laboratory, Department of Medicine and Therapeutics, Woodview, University College Dublin, Dublin 4, Ireland. E-mail: ppa.smyth{at}ucd.ie


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The prevalence of thyroid peroxidase autoantibodies (TPO.Ab) was assessed in patients with either breast carcinoma or benign breast disease, and its association with disease outcome in breast carcinoma was studied. TPO.Ab were detected by direct RIA in serum from 121/356 (34.0%) of patients with breast carcinoma, compared with 36/194 (18.5%) of controls (P < 0.001); and in 31/108 (28.7%) with benign breast disease, compared with 12/88 (13.6%) of controls (P < 0.05). Survival analysis in a group of 142 women with breast carcinoma demonstrated that TPO.Ab titres >= 0.3 U/mL were associated with a significantly better disease-free [relative risk (RR) = 1.84, P < 0.05] and overall survival (RR = 3.46, P < 0.02), compared with those who were TPO.Ab-negative. Better outcome associated with higher TPO.Ab titres was confined to those who had thyroid volumes within the intermediate range (10.1–18.8 mL) and did not further enhance the good outcome recorded when volumes were <= 10.0 mL or > 18.8 mL. Multivariate survival analysis showed that both TPO.Ab and thyroid volume were independently associated with prognosis in breast carcinoma and that RRs for disease-free survival were of a similar order of magnitude to well-established prognostic indices such as axillary nodal status or tumor size. These findings supply evidence that manifestations of thyroid autoimmunity are associated with a beneficial effect on disease outcome in breast carcinoma and provide the strongest evidence to date of a biological link between breast carcinoma and thyroid disease.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
RECENT REPORTS have refocused attention on the long-debated question of possible links between diseases of the thyroid and breast. One of these reports from our laboratory demonstrated a direct relationship between thyroid enlargement and breast carcinoma (1). We have recently shown better disease-free and overall survival in patients with breast carcinoma having smaller or larger thyroid volumes (2). An association between autoimmune thyroid disease and breast carcinoma has been reported (3, 4), but this was not confirmed (5). Higher frequency of thyroid peroxidase antibodies (TPO.Ab) in breast carcinoma patients, compared with controls, has been reported (6); and, more recently, it has been demonstrated (7) that there was an overall increased prevalence of both thyroid disorders and TPO.Ab in patients with breast carcinoma.

The objective of the present study was to investigate TPO.Ab, using a direct RIA, in sera from patients who had either breast carcinoma or benign breast disease (BBD), with or without coincident thyroid enlargement, and to examine whether the presence of TPO.Ab contributed to the outcome in breast carcinoma. \.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Breast carcinoma

The breast carcinoma group consisted of 356 women, 32–81 yr old (median, 57), with a histological diagnosis of invasive breast carcinoma, who were attending a single specialist clinic. Patients who had undergone therapy for thyroid disease were excluded from the study. Only those patients whose breast carcinoma was first diagnosed during the period of the study were included. Survival analysis was restricted to a group of 142 women in whom a first potentially curable invasive breast carcinoma was diagnosed during the period of this study and whose thyroid volume and TPO.Ab status were determined during potentially curative treatment for their breast carcinoma. Clinical, pathological, and follow-up data were recorded prospectively, using a computerized database. The median time between diagnosis and thyroid volume/serum TPO.Ab estimation was 5 months.

BBD

This group consisted of 122 patients, 16–50 yr old (median, 36) with clinical or histological evidence of fibrocystic breast disease or fibroadenoma.

Controls

Control groups (A and B) consisted of women recruited from the same geographical area who had no clinical evidence of breast disease and who had a similar age distribution to those of the breast carcinoma and BBD patients, respectively [group A: age range, 32–84 yr (median 55); group B: age range, 18–45 yr (median 34)].

The study populations (patients and controls) were restricted to persons who had no history of overt thyroid disease.

Thyroid function tests

Serum TT4 and TSH were estimated by immunoassay using an IMX analyzer (Abbott laboratories, Diagnostic Division, Ireland Ltd). The TSH assay was second generation, with a functional sensitivity of 0.05 mU/L.

Serum TPO. Ab were measured using a highly sensitive direct RIA (RSR, Cardiff, UK). TPO. Ab titres were recorded as U/mL Medical Research Council Standard 66/387. The upper limit of the reference range was 0.3 U/mL (8).

Thyroid volume was measured by ultrasound using a 7.5-mHz linear transducer. The volume of each lobe was calculated using the formula: width x depth x length x 0.479 (9). Volumes more than 18.0 mL were termed: enlarged (10).

Statistics

Statistical analysis was performed using the {chi}-square, Mann-Whitney U and Krushkal-Wallis tests. The relationship between TPO.Ab and patient outcome was studied using the recursive partitioning technique (11), the Mantel-Haensel log-rank test (12), and the Cox proportional hazards model (13). Survival curves were constructed using the Kaplan-Meier method (14).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Findings for serum total thyroxine (TT4) and TSH (median and range) in patient and control groups are shown in Table 1Go. Although there was no significant difference in either index between any of the 4 groups studied, the distribution of individual serum TSH values in breast carcinoma patients was skewed to the right, compared with older controls. Serum TSH values were above the upper limit of the reference range (>4.0 mU/L) in 10.5% of breast carcinoma patients, compared with 2.7% for group A controls (P < 0.01). Differences in serum TSH distribution between patients with BBD and group B controls were not significant (serum TSH values > 4.0 mU/L were 4.0% and 6.7%, respectively). The distribution of individual values for TPO.Ab in the patient and control groups are shown in scattergraph form in Fig. 1Go. Using 0.3 U/mL as the upper limit of the normal reference range, 121/356 (34.0%) of patients with breast carcinoma were TPO.Ab-positive, compared with 36/194 (18.5%) of group A controls (P < 0.001). TPO.Ab more than 0.3 U/mL were observed in 75.0% of breast carcinoma patients who had serum TSH more than 4.0 mU/L, compared with 30.2% less than 4.0 mU/L (P < 0.01). Of patients with BBD, 31/108 (28.7%) were TPO.Ab-positive, compared with 12/88 (13.6%) in group B controls (P < 0.05). The frequency of TPO.Ab more than 0.3 U/mL was not related to serum TSH levels in the BBD group.


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  		Table 1. Serum TT4 and TSH (median and range) in groups of patients with breast disease and appropriate controls

 


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  		Figure 1. TPO.Ab prevalence in breast carcinoma, BBD, and control groups (group A, older; group B, younger).

 
The relationship between TPO.Ab positivity and ultrasound-measured thyroid volume in the 356 breast carcinoma patients and 122 patients with BBD, subdivided into 2 groups, on the basis of normal (<=18.0 mL) or enlarged (>18.0 mL) thyroid volumes, is shown in Table 2Go. The findings demonstrate that patients with breast carcinoma having enlarged thyroid volumes were not significantly more likely to have higher TPO.Ab titres (39.3%) than those having volumes <= 18.0 mL (30.8%, P > 0.05). In contrast, the prevalence of TPO.Ab more than 0.3 U/mL in BBD was significantly greater (50.0%) when thyroid volume was more than 18.0 mL than when it was <= 18.0 mL (22.6%, P < 0.05). Comparison of TPO.Ab titres, between breast carcinoma and BBD groups, showed that breast carcinoma patients were no more likely to have higher TPO.Ab titres than those with BBD (P > 0.05).


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  		Table 2. Relationship of TPO.Ab positivity to thyroid volume in patients with breast carcinoma or BBD

 
Using recursive partioning, it was found that the TPO.Ab titre that produced the maximum separation of patients, according to disease-free or overall survival, was 0.3 U/mL.

The effect of TPO.Ab titres on survival in the 142 patients with breast carcinoma using this threshold is shown in Fig. 2Go. As shown in Fig. 2aGo, the 2 survival curves diverge with TPO.Ab >= 0.3 U/mL (upper curve) being associated with better disease-free survival, compared with values less than 0.3 U/mL [73%, compared with 56% at 5 yr, relative risk (RR) = 1.84, P = 0.047]. Similarly, in Fig. 2bGo, overall survival was significantly better when TPO.Ab were >= 0.3 U/mL (upper curve). Five-year survival was 91% when TPO.Ab were >= 0.3 U/mL, compared with 80% (TPO.Ab < 0.3 U/mL; RR = 3.46, P = 0.0160).



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  		Figure 2. Survival curves (a, disease-free survival; b, overall survival) in breast carcinoma subgroups defined by TPO.Ab using a cutoff (0.3 U/mL) determined by recursive partitioning.

 
Table 3Go summarizes the results of multivariate survival analysis using the Cox proportional hazards model. In this analysis, patients were given a thyroid score in a way that reflected the association of thyroid volume with worsening outcome. Those patients with thyroid volumes <= 10.0 mL were assigned a thyroid volume score of 0, patients with thyroid volumes more than 18.8 mL were assigned a thyroid volume score of 1, and patients with intermediate thyroid volumes (10.1–18.8 mL) were given a score of 2. Similarly, patients with TPO.Ab >= 0.3 U/mL were given a TPO.Ab score of 0, whereas those with volumes less than 0.3 U/mL were given a score of 1. In this analysis, both thyroid volume and TPO.Ab status emerged as significant independent prognostic factors for disease-free survival (RR being 2.210 and 2.315, respectively; P = 0.003 and 0.011). The comparable RRs for axillary nodal status and tumor size were 2.336 and 1.829; P = 0.003 and 0.001, respectively. The RR for overall survival associated with TPO.Ab less than 0.3 U/mL (3.424) was similar to that associated with being axillary node-positive (3.031), P = 0.043 and 0.026, respectively. In the current study, tumor size and thyroid volume were not significantly associated with disease outcome, as measured by overall survival in multivariate analysis, and are therefore not included in the results presented in the table.


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  		Table 3. Results of multivariate survival analysis using the Cox proportional hazards model based on 139 patients in whom nodal status and tumor size are known

 
Because both thyroid volume and TPO.Ab had been shown to be significantly associated with outcome in breast carcinoma, the data were examined to determine whether the two effects were additive. The effects, on both disease-free and overall survival in the 142 patients with breast carcinoma, of combining TPO.Ab positivity with ultrasound measured thyroid volume are shown in Figs. 3Go and 4Go. The thyroid volume intervals selected were those previously reported by our group (<10.0 mL and >18.8 mL) as providing maximum separation of patients according to disease-free or overall survival. As shown in Fig. 3aGo, disease-free survival in patients with breast carcinoma having thyroid volumes <= 10.0 mL was unaffected by the level of TPO.Ab (RR = 1.18, P = 0.892). Survival curves were superimposed. However, it should be noted that numbers of patients with volumes in this category were relatively low (8 TPO.Ab-negative and 14 TPO.Ab-positive). Similarly, as shown in the lower graph (Fig. 3cGo), when thyroid volumes were more than 18.8 mL, disease-free survival curves were not significantly different (RR = 1.10, P = 0.878).



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  		Figure 3. Effect of TPO.Ab titre on disease-free survival in breast carcinoma subgroups divided on the basis of thyroid volume (a, <=10.0 mL; b, 10.1–18.8 mL; c, >18.8 mL). RR, Relative risk.

 


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  		Figure 4. Effect of TPO.Ab titre on overall survival in breast carcinoma subgroups divided on the basis of thyroid volume (a, <=10.0 mL; b, 10.1–18.8 mL; c, >18.8 mL). RR, Relative risk.

 
In contrast, when thyroid volumes were in the intermediate range (10.1–18.8 mL), as shown in the centre graph (Fig. 3bGo), the survival curves diverged. The finding of TPO.Ab >= 0.3 U/mL was associated with a significantly better disease-free survival (RR = 2.41, P = 0.019). Survival at 5 yr was 65%, compared with 40% when TPO.Ab was less than 0.3 U/mL. Overall survival curves for breast carcinoma patients, grouped on the basis of both TPO.Ab titre and thyroid volume, are shown in Fig. 4Go. The upper and lower graphs (Fig. 4Go, a and c) showed significant overlap for TPO.Ab less than 0.3 U/mL and >= 0.3 U/mL, respectively. The level of TPO.Ab was not significantly associated with survival when thyroid volumes were less than 10.0 mL (RR = 1.57, P = 0.747) or more than 18.8 mL (RR = 1.81, P = 0.601). In contrast, when thyroid volume was in the intermediate range (10.0–18.8 mL), as shown in Fig. 4bGo, the finding of TPO.Ab >= 0.3 U/mL was associated with a significantly better survival, compared with breast carcinoma patients whose TPO.Ab were less than 0.3 U/mL (RR = 14.14, P = 0.0004). In this intermediate thyroid volume category, the 5-yr overall survival of 55%, when TPO.Ab was less than 0.3 U/mL, increased to 95% when TPO.Ab was >= 0.3 U/mL; and the difference increased with increasing time.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The above findings demonstrate that a highly sensitive direct RIA revealed greater TPO.Ab positivity (34.0%) in 356 patients with breast carcinoma, compared with 18.5% in appropriate female controls. Similarly, the prevalence of TPO.Ab in patients with BBD (28.7%) was higher than that encountered in controls (13.6%). The association between TPO.Ab positivity and breast disease, particularly breast carcinoma, suggests the presence of subclinical autoimmune thyroid disease in a proportion of patients with breast carcinoma.

The finding of higher serum TSH values, even within the reference range, together with the presence of TPO.Ab, may indicate susceptibility to future hypothyroidism (15). The tendency towards thyroid hypofunction, evident in the skewed distribution of serum TSH values in breast carcinoma patients associated with TPO.Ab positivity, is consistent with previous reports showing an association between thyroid disease and breast carcinoma, in which hypothyroidism was the most frequently observed finding (16, 17).

The findings in the present study confirm recent reports of higher TPO.Ab positivity in women with breast carcinoma (6, 7). They also demonstrate an increased prevalence of TPO.Ab positivity in BBD and are in agreement with the earlier finding of a higher prevalence of Hashimoto’s thyroiditis in Japanese women with breast carcinoma (3).

TPO.Ab positivity was associated with a better disease outcome in the 142 patients with breast carcinoma who had TPO.Ab values >= 0.3 U/mL, compared with those with values less than 0.3 U/mL. The potential importance of the association between TPO.Ab, thyroid volume, and outcome in breast carcinoma was emphasized by the finding that the magnitude of the prognostic effect for disease-free survival of thyroid volume and TPO.Ab (RR = 2.21 and 2.31, respectively) was comparable to that for axillary nodal status and tumor size, often regarded as the most important prognostic characteristic of women with breast carcinoma. Similarly, nodal status and TPO.Ab had comparable RRs for overall survival (3.03 and 3.42, respectively). Because the prognostic significance of both thyroid volume and TPO.Ab were independent of and additional to the information provided by established risk factors, they therefore cannot be attributed to an association with such factors.

Thus, both the presence of TPO.Ab positivity, as shown in this study, and of smaller (<=10.0 mL) and larger (>18.8 mL) thyroid volumes previously demonstrated (2) are associated with a better outcome in breast carcinoma. Indirect support for these findings was provided by reports that suggested that patients with breast carcinoma and coincidental thyroid disease may have a good outcome (18, 19, 20). The better outcome associated with higher TPO.Ab titres was not additive to that associated with smaller or larger thyroid volumes. This finding is supported by the absence of an association between TPO.Ab positivity and increased thyroid volume in patients with breast carcinoma investigated in this study.

The mechanisms through which TPO.Ab positivity or reduced/enlarged thyroid volumes might influence breast carcinoma progression remain a matter of conjecture. Because the association of TPO.Ab positivity with improved outcome was only observed when thyroid volume was in the intermediate range (10.1–18.8 mL), it would seem that thyroidal involvement, whether in terms of volume or antibody positivity, was effected via different pathways. TPO.Ab positivity has been shown to be an important factor in antibody-dependent cell cytotoxicity in the thyroid (21), although no such evidence exists for the breast. A factor that can result in either a smaller or larger thyroid gland is the presence of thyrotrophin receptor antibodies (TRAb), which have been shown to both stimulate and impede thyroidal growth (22, 23, 24). Although extrathyroidal expression of thyrotrophin receptors has been recently demonstrated (25, 26), they have not, as yet, been located in mammary tissues. Whether these antibodies could interact with receptors on breast tumors is unknown but is the subject of further study. Although we do not yet have a definitive explanation for our findings, they do provide the strongest evidence to date of a biological link between breast carcinoma and thyroid disease.


   Acknowledgments
 
The authors gratefully acknowledge the contribution, in making this work possible, of: Nurse F. Hanley (for expert phlebotomy), Sr. Josepha, Nurse K. Murray, and the staff of St. Anthony’s Rehabilitation Center.


   Footnotes
 
1 The financial support of the Health Research Board is gratefully acknowledged. Informed consent was obtained from patients and controls participating in the study. Back

Received March 5, 1998.

Revised May 4, 1998.

Accepted May 12, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Smyth PPA, Smith DF, McDermott EWM, Murray MJ, Geraghty JG, O’Higgins NJ. 1996 A direct relationship between thyroid enlargement and breast carcinoma. J Clin Endocrinol Metab. 81:937–941.[Abstract]
  2. Shering S, Zbar A, McDermott E, O’Higgins N, Smyth P. 1996 Significance of thyroid enlargement in breast carcinoma. J Endocrinol. 148:269.
  3. Itoh K, Maruchi N. 1975 Breast carcinoma in patients with Hashimoto’s thyroiditis. Lancet. ii:1119–1121.
  4. Mittra I, Perrin J, Kumaoka S. 1976 Thyroid and other autoantibodies in British and Japanese women: an epidemiological study of breast carcinoma. Br Med J. i:257–259.
  5. Maruchi N, Annegers JF, Kurland LT. 1976 Hashimoto’s thyroiditis and breast carcinoma. Mayo Clin Proc. 51:263–265.[Medline]
  6. Rasmusson B, Feldt-Rasmussen U, Hegedüs L, Perrild H, Bech K, Hoier-Madsen M. 1987 Thyroid function in patients with breast carcinoma. Eur J Cancer Clin Oncol. 23:553–556.[CrossRef][Medline]
  7. Giani C, Fierabracci P, Bonacci R, et al. 1996 Relationship between breast carcinoma and thyroid disease: relevance of autoimmune thyroid disorders in breast malignancy. J Clin Endocrinol Metab. 81:990–994.[Abstract]
  8. Beever K, Bradbury K, Phillips D, et al. 1989 Highly sensitive assays of autoantibodies to thyroglobulin and to thyroid peroxidase. Clin Chem. 35:1945–1954.[Abstract/Free Full Text]
  9. Brunn J, Block U, Ruf G, Bos I, Kunze WP, Scriba PC. 1981 Volumetric der Schilddrusnelappen mittels real-time-Sonographie. Dtsch Med Wochenschr. 106:1338–1340.[Medline]
  10. Gutekunst R, Martin-Teichert H. 1993 Requirements for goitre surveys and the determination of goitre size. In: Delange F, Dunnand JT, Glinoer D, eds. Iodine deficiency in Europe; a continuing concern. New York: Plenum Press: 109–118.
  11. Segal M. 1988 Regression trees for censored data. Biometrics. 44:35–47.
  12. Mantel N. 1966 Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep. 50:163.[Medline]
  13. Cox D. 1972 Regression models and life tables. J R Stat Soc Series B. 34:187–202.
  14. Kaplan EL, Meir P. 1958 Nonparametric estimation from incomplete observations. J Am Stat Assoc. 53:457–481.[CrossRef]
  15. Vanderpump MP, Tunbridge WM, French JM, et al. 1995 The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham survey. Clin Endocrinol. 43:55–68.[Medline]
  16. Stoll BA. 1965 Breast carcinoma and hypothyroidism. Carcinoma. 18:1431–1436.
  17. Takatani O, Okumoto T, Kosano H, et al. 1989 Relationship between the levels of serum thyroid hormones or estrogen status and the risk of breast carcinoma genesis in Japanese women. Cancer Res. 9:3109–3112.
  18. Humphrey LMS. 1964 The relationship of breast disease to thyroid disease. Carcinoma. 17:1170–1173.
  19. Fukutomi T, Nanasawa J, Yamamoto H. 1989 Influences from the treatment of thyroid disease and diabetes mellitus on breast carcinoma prognosis. Gan No Rinsho. 35:575–579.[Medline]
  20. Hercbergs AJ, Werner A, Brenner HJ, Sheba C. 1988 Does hypothyroidism favour the response to therapy in metastatic breast carcinoma. Proc Am Soc Clin Oncol. 7:2.
  21. Rodien PM, Madec AM, Ruf J, et al. 1996 Antibody dependent cell-mediated cytotoxicity in autoimmune thyroid disease: relationship to antithyroperoxidase antibodies. J Clin Endocrinol Metab. 81:2595–2600.[Abstract]
  22. Rieu M, Portos CLC, Laplanche S, Sambor B, Berrod JL, Fombeur JP. 1996 Relationship of antibodies to thyrotrophin receptors and to thyroid ultrasonographic volume in euthyroid and hypothyroid patients with autoimmune thyroiditis. J Clin Endocrinol Metab. 80:641–645.[CrossRef]
  23. Miyamoto S, Kasagi K, Alam MS, Takashi M, Lida Y, Konishi J. 1997 Assessment of thyroid growth stimulating activity of immunoglobulins from patients with autoimmune thyroid disease by cytokinesis arrest assay. Eur J Endocrinol. 136:499–507.[Abstract/Free Full Text]
  24. Drexhage HA. 1996 Autoimmunity and thyroid growth. Where do we stand? Eur J Endocrinol. 135:39–45.[Abstract/Free Full Text]
  25. Drvota V, Janson A, Norman C, et al. 1995 Evidence for the presence of functional thyrotropin receptor in cardiac muscle. Biochem Biophys Res Commun. 211:426–431.[CrossRef][Medline]
  26. Dutton CM, Joba W, Spitzweg C, Heufelder AE, Bahn RS. 1997 Thyrotropin receptor expression in adrenal, kidney and thymus. Thyroid. 7:879–884.[Medline]



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