Arch. Gyn~ik. 220, 73-81 {1975) 9 by I. F. Bergmann, Mfinchea 1975

Cancer of the Breast, Diabetes and Pathological Glucose Tolerance B. R. Muck, S. T r o f n o w and G. H o m m e l Frauenklinik der Universit/it Erlangen-Niirnberg (Dir.: Prof. Dr. K. G. Ober) und Institut ffir Medizinische Statistik und Dokumentation der Universit~t Erlangen-Nfirnberg (Dir.: Prof. Dr. L. Horbach) Received May 5, 1975

Summary. In a prospective study at the Department of Obstetrics and Gynecology, University Erlangen-Nfirnberg, covering the period from January 1st 1971 til December 3!st 1973 the incidence of pathological glucose tolerance was examined in 837 women with breast cancer, benign tumours and conditions requiring excision or air cystography and/or mammography because of suspicion of tumour. The glucose tolerance was tested in all patients by oral ingestion with 100 g glucose or i.v. by means of intravenous injection of 0.33 g glucose/kg body weight. The results in 327 women with breast cancer were compared with those in 510 women with benign breast affections. Using matched pairs, the evaluation was done with an electronic data processing system. Diabetogenic factors like age and body weight were thus allowed for. In the total coIlective 22.30/o out of 327 women with breast cancer were manifestly and 6.7~ subclinically diabetic. Our findings allow the following conclusions. 1. Manifest diabetes mellitus is found twice as frequently in women with breast cancer compared to women with benign breast affections. 2. In the collective of pairs matched according to age, height and weight (n = 217} 21~ of the women with breast cancer have a pathological glucose tolerance, compared with 10% of the women with benign breast affections. 3. Only 25 out of 73 manifestly diabetic women with breast cancer were aware of their metabolic disorder before admission to hospital, whereas 75% of the diabetic women with benign histological findings did know of it. M a m m a c a r c i n o m , Diabetes u n d pathologische G l u c o s e t o l e r a n z

Zusammenfassung. In einer prospektiven Studie yam 1.1. I971 bis zum 31.12. :1973 wurde an der Erlanger Universit~its-Frauenklinik bei 837 Frauen mit Mammacarcinom, gutartigen Tumoren und Erkrankungen, die unter Tumorverdacht Anlal] zur Excision waren, die Htiufigkeit pathologischer Glucosetoleranz bestimmt. Die Glucosetoleranz wurde bei allen Patienten durch eine orale Belastung mit 100 g Glucose oder eine i.v. Belastung C0,33 g Glucose/kg K6rpergewicht} fiberprfiff. Die Ergebnisse bei 327 Frauen mit Mammacarcinom wurden denen bei 510 Frauen mit einer gutartigen Brusterkrankung gegenfibergestellt. Die Auswertung erfolgte mit einer elektronischen Informationsverarbeitungsanlage durch Bildung yon ,,matched pairs". Diabetogene Faktoren wie Alter und KSrpergewicht wurden somit beriicksichtigt. Im Gesamtkollektiv waren Frauen mit Brustkrebs (I1 = 327} zu 22,3% manifest und zu 6,7% subklinisch diabetisch. Unsere Ergebnisse lassen folgende Aussagen zu: 1. Manifester Diabetes mellitus finder sich bei Frauen mit Brustkrebs gut zweimal so h~ufig wie bei Frauen mit einer gutartigen Brusterkrankung.

74

B.R. Muck et al.

2. In dem Kollektiv der ,,matched pairs" nach Alter, GrSl~e und Gewicht (n = 217} haben 21~ der Frauen mit Brustkrebs gegenfiber 10% der Frauen mit einer gutartigen Brusterkrankung eine pathologische Glucosetoleranz. 3. Nut 25 von 73 manifest diabetischen Frauen mit Brustkrebs kannten bereits ihre StoffwechselstSrung vor dem Klinikaufenthalt, w~hrend dieser Befund 3/4 der diabetischen Frauen mit gutartigen Excisionsbefunden bekannt war. The i n c r e a s e in n e w cases of b r e a s t a n d e n d o m e t r i a l c a n c e r is d e m o n s t r a b l e [3, 9]. In the r e l a t i v e d i s t r i b u t i o n of c a r c i n o m a I o c a l i s a t i o n s in w o m e n , c a n c e r of the b r e a s t at p r e s e n t o c c u p i e s first place, w h i l e in the p a s t c e r v i c a l c a n c e r w a s the m o s t c o m m o n [4]. A n y u n i f o r m e n d o c r i n e h o r m o n e c o n s t e l l a t i o n g e n e r a l l y a p p l i c a b l e to b r e a s t c a n c e r o b v i o u s l y d o e s n o t exist [9, 12, 13, 14]. P o s s i b l y w o m e n affected b e f o r e the m e n o p a u s e m u s t be a s s e s s e d differently f r o m t h o s e of h i g h e r age g r o u p s [16]. W e n o t i c e d a c e r t a i n s i m i l a r i t y b e t w e e n w o m e n w i t h b r e a s t c a n c e r a n d t h o s e w i t h e n d o m e t r i a l cancer, e s p e c i a l l y in elder w o m e n . The c h a r a c t e r i s t i c s of the l a t t e r l a r g e l y c o n f o r m w i t h t h o s e in w o m e n w i t h c a n c e r of the e n d o m e t r i u m w h e r e the c o n s t i t u t i o n a l t y p e w i t h obesity, h y p e r t e n s i o n a n d p a t h o l o g i c a l glucose t o l e r a n c e is p a r t i c u l a r l y affected [10]. I n v e s t i g a t i n g the e p i d e m i o l o g y of b r e a s t c a n c e r it is n e c e s s a r y to define " r i s k f a c t o r s " [15]. High r i s k w o m e n can t h e n be o b s e r v e d m o r e c a r e f u l l y [5, 8]. N e a r l y 5 0 % of the w o m e n w i t h e n d o m e t r i a l c a n c e r in the E r l a n g e n series of 1971--1973 h a d p a t h o l o g i c a l glucose tolerance, a n d n e a r l y 75o/o w e r e m o r e t h a n 1 0 % overw e i g h t [6, 11]. T h e c o i n c i d e n c e of b r e a s t c a n c e r a n d p a t h o l o g i c a l glucose tolerance w a s e x a m i n e d in a p r o s p e c t i v e study. The c o n t r o l group c o n s i s t e d of 459 p a t i e n t s w h o d u r i n g the s a m e p e r i o d h a d biopsies, that m e a n s the c o m p l e t e r e m o v e m e n t of t u m o u r or b r e a s t affections s u s p i c i o u s of tumour. 31 p a t i e n t s h a d an air c y s t o g r a p h y ( P n e u m o c y s t o g r a p h y ) . a n d the m a m m o g r a p h i c findings of a f u r t h e r 20 p a t i e n t s w e r e not s u s p e c t of tumour, so that a b i o p s y d i d n o t s e e m to be necessary. This series contains, b e s i d e s b e n i g n t u m o u r s (e.g. fibroadenoma}, all d i s e a s e s f r o m m a s t o p a t h y to fibrosing a d e n o s i s to i n t r a c a n a l i c u l a r p r o l i f e r a t i o n s of v a r i o u s t y p e a n d extent. It w a s e s s e n t i a l to f o r m s t a t i s t i c a l pairs, a l l o w i n g for the v a r i a b l e s of age, h e i g h t a n d weight. The m a t e r i a l w a s e v a l u a t e d b y m e a n s of e l e c t r o n i c d a t a p r o c e s s i n g . The p r o g r a m m e is c a l l e d E x h o m m 11.

Material and Methods From January 1st 1971 til December 31st 1973 a total of 837 breast cases were histologically examined, respectively by puncture and/or mammography in 7~ of the cases. 327 women had a cancer, and 510 a benign condition with clinical and/or mammographic turnout findings. The glucose tolerance of all patients was examined. We preferred, according to the recommendations of the "Deutsche Gesellschaft ffir Diabetes", the oral tolerance test with 100 g glucose ("Boehringer Gluco-Probetruuk", Dextro OGT) [17, 18]. In the rare case of intolerance towards the above test, 0.33 g glucose per kg body weight was given intravenously. The criteria for diagnosis of diabetes are shown in Tables I and 2. As baseline we used the blood glucose concentration 2 hrs after ingestion of 100 g glucose. If the concentration was above 130 mg/100 ml the tolerance test was repeated. The blood glucose concentrations evaluated 120 and 180 min after glucose ingestion must be regarded as the main diagnostic criteria. 120 rain after administrating the glucose, it's concentration in the capillary blood should be below 120 mg/10O ml (Hexokinase test) [19]. If the concentration lies above 140 mg/100 ml most authors consider a diabetic

Cancer of the Breast

75

Table 1. Criteria of 100 g oral glucose tolerance test. Blood glucose concentration in mg/100 ml (capillary blood}

1. 2-hr value 2. maximal value

normal (mg/100ml)

doubtfully pathological (mg/100ml)

pathological (mg/100ml)

120 160

121-140 161-180

140 180

The 2-hr value is more important than the maximal value. Control examination of spontaneous urine after ingestion is not recommended. (From: Mehnert, H. and H. FTrster: Stoffwechselkrankheiten. Thieme, Stuttgart 1970, p. 218.)

metabolic disorder to be present [18]. The 3-hour value should be reduced to the initial (fasting) value. Least reliable are the so-called maximal values, i.e. the highest blood sugar values found at any time (30, 60 or 90 min after glucose ingestion). None of these should be above 180 mg/100 ml and all should be below 160 mg/100 ml. In the not uncommon cases of maximal values being above 180 or 200 rag/100 ml, however, diabetes should certainly not be diagnosed if the 2 oder 3-hour value turns out to be perfectly normal. If owing to oral intolerance we had to resort to intravenous application, the patient was injected with 0.33 g glucose per kg body weight within a period of 3 minutes. The blood was taken from the cubital vein before injection (the patient having fasted for at least six hours), and then the procedure was repeated every ten minutes for one hour. The calculations were determined according to Konard {Tab. 2). We speak of a pathological tolerance, in the sense of manifest diabetes, if the glucose elimination coefficient is below 1.0. With a coefficient of 1.0-1.2 we call the glucose tolerance doubtfully pathological. The breast turnout or suspect area of tissue was removed under intubation anaesthesia after previous clinical assessment, mammography or xeroradiography, and, if

Table 2. Criteria of intravenous glucose tolerance test. Glucose values determined in venous blood Calculated acc. to K -----

log BGo - log BGt] 9 In 10

BGo = Blood glucose value at start of test period. BGt = Blood glucose value after any period t, counted from 0.

KG-value

normal

doubtfully pathological

pathological

1,2-2,2

1,0--1,2

1,0

The test period is optional but it is advisable not to start measurements earlier than 10-20 min after injection because at the start the glucose distribution space is being filled up. Estimations are therefore commonly made after 20 and 40 rain. (From: Mehnert, H. and H. FTrster: Stoffwechselkrankheiten. Thleme, Stuttgart 1970, p. 142.)

76

B.R. Muck et aJ.

%

%

20-

-20

15-

-15

10-

-10

-5

manifest

subclinical

cancer n=327

benign findings n=510

Fig. 1. Incidence of diabetes in w o m e n w i t h benign and malignant breast diseases. UFK Erlangen 1971-1973

necessary, galactography, and " T h e r m o g r a p h i e en plaque". In 6o/0 of the cases air cystography and/or m a m m o g r a p h y w e r e considered sufficient to exclude malignant breast diseases without biopsy. The complete histological processing evaluation took place in our histological department.

Results

I. Incidence Rate of Pathological Glucose Tolerance Fig. I shows the incidence of diabetes in all patients examined. 73 (22.3~ out of 327 women with cancer suffered from manifest diabetes, and 22 (6.7%}

Table 3. Glucose tolerance in w o m e n w i t h benign and malignant breast diseases Tumour (Morphology)

manifest diabetes

subclinical diabetes

232 (71,0~

73 (22,30/0)

22 (6,7~

481 (94,3~

16 (3,2o/0)

13 (2,5~

179 (77,8~

36 (15,7~

15 (6,5~

209 (91,0s/s}

13 (5,6%)

n = 226

181 [80,1s/o)

31 (13,7~

benign n = 226

206 (91,2~

13 (5,7a/ol

malignant n = 217

172 (79,3~

28 (12,9~

benign n = 217

194 (89,4~

14 (6,5~/o)

total collective

malignant n = 327 benign n = 510

matched pairs acc. to age

malignant n = 230 benign n = 230

matched pairs acc. to age, weight

matched pairs acc. to age, weight, height

Glucose tolerance normal

malignant

8(3,4% ) 14 (6,2~ 7 (3,1~ 17 (7,8~ 9 (4,2~

Cancer of the Breast

~

77

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0 ~J o

~

o

v~ 0

0

v~

O v~

2

v~

v~

i ~

0 0

I]

~ ]I ~ II

~

78

B.R. Muck et al.

matched

age pairs acc. to age,weight age,height,weight

manifest

n=230 n=226 n=217

~

manifest

subclinical

~'o 2b

subclinical

lg

lb

5

I

0

5

lb

15 20 %

b e n i g n findings

cancer

Fig. 2. Incidence of diabetes in women with benign and malignant breast diseases

from subclinical diabetes. Contrary to this the diabetes incidence in women with benign "tumour" was 3.20/0 (n --- 16}. Further 13 w o m e n (2.50/0) suffered from a subclinical diabetes. Diabetogenic factors like age and body weight were taken into account in the formation of statistical pairs. A first collective of matched pairs allows for the criteria age (+- 2.5 years} (230 pairs}, a second for the age plus weight criteria (226 pairs} and a third for age, height and weight (217 pairs}. As can be seen in Fig. 2 and Table 3, here too, a significantly higher incidence rate of diabetes is demonstrated in w o m e n with breast cancer. Especially in the collective of matched pairs for the criteria of age, height and weight, manifest diabetes (13g/0) as well as subclinical diabetes {80/0) is found twice as frequently in cancer patients.

217matchedpairs acc. cancer

to

benign

age,height,weight cancer

findings

benign findings

%

%

100"

100

75.

75

50

.50

25

-25 normalweightn=121 diabetic

~

overweightn=96 normalGTT

Fig. 3. G l u c o s e t o l e r a n c e i n w o m e n w i t h b e n i g n a n d m a l i g n a n t b r e a s t d i s e a s e s

Cancer of the Breast

79

%

o---o

c a n c e r (n = 3 2 7 )

25-

9- - .

benign findings (n = 510)

20. IS.

9/ "

I1~

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