Upsala J Med Sci 84: 228-234, 1979 

Thyroid Function in Breast Cancer Patients before 
and up to Two Years after Mastectomy 

Hans-Olov Adam?, Jorgen Hansenz, Ake Rimsten' and Leif Wide3 
From the Departments of Surgery', Oncologyz and Clinical Chemistry3, University 

Hospital, Uppsalu, Sweden 

ABSTRACT 

In 41 women newly diagnosed as having breast cancer the thyroid function was 

assessed by determination of the serum TSH, tririodothyronine (T3), reverse tri- 

iodothyronine (rT3), thyroxine (T4), T3-resin uptake and free T4-index. Blood 

samples were drawn before the primary treatment and at follow-up after 1 - 2 0  

months. There was no significant change in any of these variables during the 

period of observation. Nor was there any difference between the values of the 
patients who developed recurrent disease and of those who did not. 

These results contradict previously proposed hypotheses of a progressive de- 

crease in thyroid function after primary treatment and of a relation between the 

clinical course and the thyroid function in breast cancer patients. 

INTRODUCTION 

The hypothesis that breast cancer and thyroid function are related to each 

other has been discussed from different viewpoints ever since Beatson in 1896 

(4) suggested thyroid as a treatment in advanced breast cancer. 

In a previous study ( 2 )  we analyzed the possible role of thyroid disease or 

dysfunction as an etiologic factor in breast cancer. A comparison with non-hos- 

pitalized controls revealed that the patient group had a slightly but signifi- 

cantly higher mean serum concentration of TSH, rT3 and T3-resin uptake and a 

lower T3 than the control group. These findings were considered inconsistent 

with a hypothyroidism, which has repeatedly been suggested as increasing the 

risk for breast cancer (cf 2, 1 7 ) .  The same pattern of changes have, however, 

recently been reported to be secondary to a number of non-thyroidal diseases ( 5 )  

and we concluded that the results of our study could not support the concept 

that a thyroid dysfunction is an etiologic factor in breast cancer. 

In a subsequent study (1) further support for this conclusion was obtained 

when the thyroid function was assessed before, during and at different times 

after mastectomy in breast cancer patients and compared with that of women 

undergoing a cholecystectomy. There were no significant differences in TSH or 

228 



thyroid hormone levels between the two groups. Both groups showed changes after 

surgical trauma which were in close agreement with those previously noticed as 

an unspecific reaction to illness. 

The aim of the present study was to find out whether there is a progressive 

change in thyroid function and if so, whether this is in any way related to the 

course of the disease as repeatedly reported in earlier (6, 7, 1 0 )  and also in 

Some recent (3, 11) studies. 

METHODS 

Thyrotropin (TSH) in the serum was assayed by a radioimmunosorbent technique 

using indirectly coupled antibodies (13, 16). The results were expressed in mU/1 

with the MRC preparation 68/38 used as a reference standard. The incubations 

were performed overnight at room temperature and the limit of sensitivity was 

about 0.5 mU/1 of serum. 

Triiodothyronine (T3) in the serum was measured by solid phase radioimmuno- 

assay with antibodies coupled directly to microcrystalline cellulosa particles 

activated with cyanogen bromide (15). Incubations were performed at 6OoC for two 

hours and overnight at room temperature in 0.5% polysorbate-20 (Tween-20), in a 

0.05 M phosphate-buffered saline, pH 7.4. 

Reverse triiodothyronine (rT3) was measured by a radioimmunoassay using poly- 

ethylenglycol for separation of bound and free rT3. The reagents were obtained 

from Biodata (Rome, Italy). 

Thyroxine (T4) in the serum was determined according to the Bio-Rad thyroxine 

column test (Bio-RAD Laboratories, Richmond, California). 
R The T3-resin uptake test was performed with Sephadex -G-25 (Pharmacia, Upp- 

sala, Sweden) as a resin and the results were expressed as a percentage of the 

mean of healthy controls. The value for free T4-index (FT4 I) was calculated by 

multiplying the value for T4 with the value for T3-resin uptake test divided 

by 100. 

The limits of the reference range, defined as a mean * 2 S.D. of values for 
healthy controls, were in this laboratory for TSH 0.5-6 mU/1, for T3 1.3-3.2 

nmol/l, for rT3 0.13-0.44 nmol/l, for T4 65-165 nmol/l and for T3-resin uptake 

75-115. 

MATERIAL 

The study comprises 41 women without thyroid substitution therapy. Only one 

of the patients had a history of thyroid disease. She was operated in 1942 due 

to a diffuse toxic goitre but euthyroid at the time of this investigation. All 

patients had a newly diagnosed breast cancer without known distant metastases. 

They were classified according to a combined clinical and histopathological 

staging (12). Twentysix patients had no axillary metastases, two had a locally 

229 



Table 1. Staging according to a combined clinical and histopathological 
classification. 

Stage Definition Number % 

0 In situ carcinoma 

I No local tumour complications, 
no axillary metastases 

I1 No local tumour complications 

a Axillary metastases 

b As IIa but perinodal tumour 
growth and/or involvement of 
apical nodes 

I11 Locally advanced tumour 

2 5 

24 59 

3 7 

10 24 

41 100 

advanced tumour but nobody had known distant metastasis at the time of primary 

treatment (Table 1 ) .  The mean age at diagnosis was 60.2 years (range 30-80 

years). 

All patients were treated by a total mastectomy. An axillary dissection was 

done in all cases where a peroperative histological examination of axillary node 

biopsies revealed metastases. Postoperative irradiation was given against the 

supraclavicular and parasternal region to patients with medially or centrally 

located cancers in stage I or IIa. All 12 patients with cancers in stage IIb or 

I11 in addition got postoperative irradiation against the axilla. 

The first serum sample was obtained after the initial hospital admission but 

before surgery. All patients were postoperatively followed regularly at the 

Department of Oncology where a second serum sample was drawn after an observa- 

tion time varying between 7 and 27 months with a mean of 18 months. The period 

of observation was for one group of 12 women 7-13 months (mean 9.4) and for 

another of 29 women 19-27 months (mean 22.2). All sera were stored at -2OOC 

until they were concomitantly analyzed. 

RESULTS 

The mean values before treatment and at follow-up are shown in Table 2 for 

the whole group and after subdivision into one group with a shorter (n = 12) and 

one with a longer (n = 29) observation time. The differences between the first 

and the second sample were very small, were not more pronounced in those fol- 

lowed for a longer period and were all insignificant (p > 0.05, t-test). Five 

patients had developed distant metastases during the observation period. There 

were no significant differences (p > 0.05, t-test) between any of the mean 

values for this group and for the whole group, neither before treatment nor at 

the follow-up (Table 2). 

230 



T
a
b
l
e
 2
. 

Th
yr
oi
d 
f
u
n
c
t
i
o
n
 b
ef
or
e 
tr
ea
tm
en
t 

(
I
)
 a
nd
 a
t
 f
ol
lo
w-
up
 
(1
1)
 i
n 
th
e 
wh
ol
e 
m
a
t
e
r
i
a
l
,
 i
n 
s
u
b
g
r
o
u
p
s
 w
it
h 
a
 s
ho
rt
er
 

an
d 
a
 l
o
n
g
e
r
 o
b
s
e
r
v
a
t
i
o
n
 t
im
e 
an
d 
in
 p
at
ie
nt
s 
wi
th
 
re
cu
rr
en
t 
di
se
as
e.
 

Me
an
 

2
 
S.
D.
 

Al
l 
p
a
t
i
e
n
t
s
 

P
a
t
i
e
n
t
s
 
wi
th
 o
b
s
e
r
v
a
-
 

P
a
t
i
e
n
t
s
 w
it
h 
o
b
s
e
r
v
a
-
 

P
a
t
i
e
n
t
s
 w
it
h 
me
ta
st
at
ic
 

ti
on
 t
im
e 
7
-
1
3
 m
o
n
t
h
s
 

ti
on
 t
im
e 
19
-2
7 
mo
nt
hs
 

di
se
as
e 

T
e
s
t
 

n
 =

 
41
 

n
 =

 
12
 

n
 =

 
29
 

n
=

5
 

I
 

I
1
 

I
 

I
1
 

I 
I1
 

I
 

I1
 

T
S
H
 

mU
/l
 

2.
45
t1
.3
4 

3.
99
+8
.4
O1
) 

2.
75
21
 .
06
 

2.
95
k1
.1
9 

2.
32
k1
.4
4 

4.
42
+1
0.
00
2)
 

2.
16
k0
.4
0 

2.
56
20
.4
2 

T
3
 
nm
ol
/l
 

1.
79
f0
 -
3
5
 

1.
93
t0
.3
4 

1.
87
kO
 .

3
2

 
1.
97
20
.2
4 

1.
76
f0
.3
6 

1.
92
f0
.3
8 

1.
83
k0
.1
1 

1.
92
f0
.2
2 

rT
3

 n
mo
l/
l 

0.
34
20
.1
0 

0.
32
k0
.1
1 

0.
37
20
.0
8 

0.
37
20
.1
2 

0.
3O
tO
.1
0 

0.
34
20
.1
0 

0.
34
f0
.0
6 

0.
25
kO
.0
4 

T
4
 
nm
ol
/l
 

10
8f
31
 

1
1
 15
27
 

12
6f
28
 

T
3
-
r
e
s
i
n
 

9
5
2
1
4
 

9
1
t
9
 

8
8
2
9
 

up
ta
ke
 

%
 

11
 1k
13
 

2
4
2
2
2
 

10
6k
29
 

10
82
31
 

10
82
14
 

9
 2k
8 

9
1
2
9
 

9
5
2
1
4
 

9
4
2
7
 

9
7
2
1
3
 

10
.4
f0
.7
 

11
.1
22
.1
 

F
T
4
I
 

9.
62
2.
7 

10
.3
f2
.4
 

11
.O
f1
.9
 

11
.3
22
.0
 

9.
9k
2.
4 

9.
62
2.
7 

’)
 

2
, 

Af
te
r 
th
e 
e
x
c
l
u
s
i
o
n
 o
f
 o
n
e
 w
o
m
a
n
 w
h
o
 d
ev
el
op
ed
 o
v
e
r
t
 h
yp
ot
hy
ro
id
is
m 
th
e 
co
rr
es
po
nd
in
g 
va
lu
es
 w
er
e 

2.
69
21
.3
0 

an
d 

2.
58
f0
.3
5.
 



O u r  results were also analyzed after subdivision of the material according to 

the clinical and histopathological classification. This analyses did not reveal 

any significant differences between the stages, which is in accordance with our 

previous findings ( 2 )  , and no significant changes in thyroid function in any of 
the stages during this observational period. 

One 7 8  year old woman developed an overt hypothyroidism during an observation 

time of two years with an increase in TSH from 3.0 to 56 mU/1 with a concomi- 

tantly subnormal T3, rT3 and T4 value. Except for this woman only one had a 

TSH-value slightly exceeding the upper limit of the reference range. The T3- 

values were normal in all other women before treatment as well as at the time of 

follow-up . 

DISCUSSION 

A thyroid dysfunction might be involved in breast cancer disease both by in- 

fluencing the etiologic process and the progress of the disease. It might be 

reasonable then to assume that such a dysfunction should take the form of a 

hypothyroidism or a hyperthyroidism. The hypothesis of hypothyroidism as a risk 

factor has at the present time been supported by the uniform finding of a higher 

mean TSH-concentration in breast cancer women at the time of diagnosis than in 

comparable controls ( 2 ,  9, 1 1 ,  14). Values exceeding the upper limit of the 

reference ragne were in these studies found in 8.5% (2) - 36% (3) of the pa- 
tients. A concomitantly exaggerated TSH-response to TRH-stimulation was also 

shown in some of the patients (3, 9, 14). Women with breast cancer were there- 

fore considered to have an increased frequency of hypothyroidism - usually sub- 
clinic (9, 11). These findings were suggested to reflect subnormal thyroid hor- 

mone levels by Mittra (9). He also proposed - with support from experimental 
research ( 8 )  - that low thyroid hormone levels render the breast epithelium more 
sensitive to prolactin stimulation and hypothyroidism thereby to be involved in 

the etiologic process. 

The later finding of normal plasma TI-levels ( 2 ,  3, 14) and also a normal 

free T4-index ( 2 )  appears to invalidate this hypothesis although one recent 

study in fact showed a slightly decreased free T4-index ( 1 1 ) .  The whole concept 

of hypothyroidism was questioned when thyroid function was more completely as- 

sessed by the concomitant determination of TSH, T3, rT3, T4 and T3-resin uptake 

(2). The pattern of differences between patients and controls was then con- 

sidered inconsistent with a hypothyroidism but in agreement with that found in 

many non-thyroidal diseases (2, 5 ) .  

The concept that slight changes in thyroid hormone metabolism are secondary 

to stress and disease in women with breast cancer might also explain why a sig- 

nificant increase in TSH was restricted to (14) or more pronounced in (9) women 

with an advanced disease. 

232 



The present study was primarily aimed at evaluating the hypothesis of pro- 

gressive changes in thyroid function after the primary treatment which made a 

control group superfluous. The study has however further confirmed our previous 

finding of euthyroidism in breast cancer patients. 

The very close agreement between the values from the first and the second 

sampling period is in disagreement with the findings that the thyroid function 

is, for one reason or another, continuously decreasing after the initial treat- 

ment as reported by Perry et al. (11). This study showed a significant decrease 

in free TI-index at a follow-up after 6 months. The follow-up was, however, 

incomplete and included only 29 of 40 patients. The concomitant increase in TSH 

was also insignificant. We have therefore condluded from o u r  study - based on a 
more extensive assessment of thyroid function, a longer observation time and a 

complete follow-up - that there is no systematic change in thyroid function 
after the primary treatment. 

The thyroid function in patients who developed distant metastases and there- 

fore ultimately will die due to the disease, has to be interpreted with caution 

due to the small number of patients. There is no indication from our results 

that recurrent disease is proceded or accompanied by a decreased thyroid func- 

tion as previously suggested. 

1. 

2. 

3. 

4 .  

5. 

6. 

7 .  

8. 

9. 

10. 

11. 

REFERENCES 

Adami, H.-O., Johansson, H., Thorh, L., Wide, L. & Akerstrom, G.: Serum 
levels of TSH, T3, rT3, T4 and T3-resin uptake in surgical trauma. 
Acta Endocrinol 88:482-489, 1978. 
Adami, H.-O., Rimsten, A . ,  Thorhn, L., Vegelius, J. & Wide, L.: Thyroid dis- 
ease and function in breast cancer patients and non-hospitalized controls 
evaluated by determination of TSH, T3, rT3 and T4 levels in serum. 
Acta Chir Scand 144:89-97, 1978. 
Aldinger, K., Schultz, P.N., Blumenschein, G.R. & Samaan, N.A.: Thyroid- 
-,timulating hormone and prolactin levels in breast cancer. Arch Intern 
Med 138:1638-1641, 1978. 
Beatson, G.T.: On the treatment of inoperable cases of carcinoma of the 
mama: Suggestions for a new method of treatment, with illustrative cases. 
Lancet I, 104-107, 1896. 
Bermudez, F., Surks, M.I. & Oppenheimer, J.H.: High incidence of decreased 
serum triiodothyronine concentration in patients with nonthyroidal disease. 
J Clin Endocrinol Metab 41:27-40, 1975. 
Carter, A.C.: Levels of serum protein-bound iodine in patients with meta- 
static carcinoma of the breast. J Clin Endocrinol Metab 20:477-479, 1960. 
Edelstyn, G.A.: Thyroid function in patients with mammary cancer. 
Lancet I, 670-671, 1958. 
Mittra, I.: Mammotropic effect of prolactin enhanced by thyroidectomy. 
Nature 248: 525-526 r 1974. 
Mittra, I. & Hayward, J.L.: Hypothalamic-pituitary-thyroid axis in breast 
cancer. Lancet I, 885-889, 1974. 
Myhill, J., Reeve, T.S. & Hales, I.B.: Thyroid function in breast cancer. 
Acta Endocrinol 51:290-300, 1966. 
Perry, M., Goldie, D.J. & Self, M.: Thyroid function in patients with breast 
cancer. Ann R Coll Surg Engl 60:290-293, 1978. 

233 



12. 

13. 

1 4 .  

15. 

16. 

17. 

Rimsten, A . ,  Johansson, H., Stenkvist, B. & Thelin, A.-M.: Axillary recur- 
rences after selective treatment of the axillary nodes in cancer of the 
breast. Clin Oncol 2: 357-364 , 1976. 
Roos, P., Jacobson, G. & Wide, L.: Isolation of five active TSH components 
from the human pituitary glands. Biochim Biophys Acta 379:247-261, 1975. 
Rose, D.P. & Davis, T.E.: Plasma thyroid-stimulating hormone and thyroxine 
concentrations in breast cancer. Cancer 41:666-669, 1 9 7 8 .  
Wide, L.: Radioimmunoassays employing immunosorbents. In: Immunoassay of 
Gonadotropins (ed. E. Diczfalusy) . Acta Endocrinol [Suppl] 142: 207-218,1969. 
Wide, L., Nillius, S . J . ,  Gemzell, C. & ROOS, P.: Radioimmunosorbent assay 
of follicle-stimulating hormone and luteinizing hormone in serum and urine 
from men and women. Acta Endocrinol [Suppl] 73:174:1-60, 1 9 7 3 .  

Vorherr, H.: Thyroid disease in relation to breast cancer. Klin Wochenschr 
5 6 ~ 1 1 3 9 - 1 1 4 5 ,  1 9 7 8 .  

Accepted June 1 , 1 9 7 9  

Address for reprints: 
Hans-Olov Adami, M.D. 
Department of Surgery 
University Hospital 
5 - 7 5 0  14 Uppsala 
Sweden 

234