Journal of Surgical Oncology 11: 129-133 (1979)
Serum Immunoglobulins in Breast Cancer ..................................................................................... ..................................................................................... ELIAS A. K.ALSABTI, MD Eighty-one women admitted for breast tumor biopsy have been followed sequentially for 12 months. Thirty-one women had clinical stage I and I1 breast cancer and 50 had benign breast disease. All these women had serum immunoglobulin IgA, IgC, IgM and IgE levels measured by immunodiffusion and radioimmunoassay preoperatively, two weeks postoperatively, then three months, six months, nine months and twelve months postoperatively. Significant differences were found in IgA and IgG levels preoperatively in the cancer group while no differences were found in IgM or IgE levels a t any time. There was positive correlation between the extent of metastatic breast cancer and IgA level. There was negative correlation between the extent of metastatic breast cancer and IgM levels. These findings raise the value of measuring t h e levels of immunoglobulins in patients with breast cancer as a guide t o subclinical spread of the disease. The results may also support the hypothesis of the role of early immune defect in immunoglobulin metabolism in the pathogenesis of breast cancer.
.................................................................................... .................................................................................... Key words: breast cancer, IgG, IgA, IgM, IgE, immunodiffusion, radioimmunoassay
INTRODUCTION Serum immunoglobulin levels may be useful in the management of cancer patients as diagnostic indicators, tumor spread indicators or as indicators of immunosuppression in the pathogenesis o f cancer. Hughes [I9711 found that serum levels of IgG, IgA and IgM were altered in various nonhematopoietic cancers. Elevated IgG and IgA were found in patients with skin and lung cancer whereas patients with intestinal tumors or uterine tumors had increased IgA only. Serum IgM was elevated in sarcoma and melanoma (one male and one female respectively). Rowinska-Zakerwska et a1 [ 19701;and Roberts et a1 [ 19751 reported elevated IgA levels in breast cancer.
From the Royal Scientific Society, Amman, Jordan.
Address reprint requests to Elias Alsabti, MD, c/o Mrs. W. Aljaff, Flat #5,8 Norfolk Terrace, Brighton, BN1 3AD, England.
0022-4790/79/1102-Ol29$01.40 @ 1979 Alan R. Liss, Inc.
130
Alsabti
Meyer et a1 [1973] suggested that patients with breast cancer who have increased IgA level before mastectomy have an improved prognosis. MacKay [ 19661 reported that cases with breast cancer suffer less from allergic disease, and this observation raised the hypothesis of atopic subjects are higher responders [Platts-Mills et al, 19761 . The objective of this study was to determine whether serum levels of IgG, IgA, IgM and IgE changed in early breast cancer compared to non-malignant breast disease and whether these changes could be correlated with the spread of tumors and t o what degree of accuracy one can depend on immunoglobulin levels in the management of breast cancer. MATERIALS AND METHODS Eighty-one women admitted to the Main Royal Hospital for breast tumor biopsy have been studied. Thirty-one of these women were found t o have malignant breast disease and 50 nonmalignant breast disease. Their ages ranged between 49-68 years. All had breast lumps less than five cm in diameter, with or without palpable axillary lymph nodes. Therefore, those with breast cancer had tumors which fell into clinical stage I or I1 of the Manchester classification [Wise et al, 19711, and had no evidence of metastasis clinically as shown by chest x-ray, normal liver function tests, normal bone scanning and normal serum chemistry. Venous blood was taken on the day of admission, the day before surgery and two weeks postoperatively. Subsequently, they have had further samples taken three months postoperatively. Correlation between the immunoglobulin levels and the extent of the cancer was performed by quantifying the tumor mass in each patient which will produce the clinical score. The scoring was based upon the diameter of the tumor postoperatively and extra points were given for histopathological metastasis to skin, lymph nodes or muscles. The local score usually subtracted from the total score postoperatively. The score was the same for each confirmed systemic spread whether by biopsy, radiology or cytology and was hgher than that for suspected symptoms. Details of our scoring is shown in Figure 1. Radial immunodiffusion on tripartigen plates (obtained from Behringwerke Inst., West Germany) were used for the estimations of IgC, IgM, IgA and IgE. Radioimmunoassay was used to measure total serum IgE levels as described by Merrett et a1 [ 19751.
RESULTS The serum levels of IgA and IgG in breast cancer patients were significantly different from the levels in patients with benign breast disease preoperatively (Table I). IgM and IgE levels were not significantly different in both groups, either preoperatively or at any of the postoperative follow-up times. The clinical scores of cancer patients at various follow-up times is shown in Table 11. There is a correlation between serum immunoglobulin levels and the clinical score of each patient. Six cases from the original 31 had developed definite clinical evidence of metastatic disease and 2 patients had died of breast cancer. There was positive correlation with IgA at 6 months (Pearson Coefficient, = 0.32, P 0.05) and at 9 months ( = 0.3). There was also a significant negative correlation with IgM at 3 months ( = 0.31, P 0.05) (Table 111). One can conclude that the rise of IgG and IgA was seen in the majority of patients (four out of six) before the clinical appearance of their metastasis. The preoperative elevation of IgG (1.95 gm/100 ml) was associated with early metastasis (313 patients), and serum IgA level (0.5 gm/100 ml) was associated with late metastasis (?4patients), particularly if serum level raised progressively.
Serum Immunoglobulins in Breast Cancer I. Preoperative
Score
a) Locai Tumor specimen diameter in cm Histopathological evidence of deep or superficial involvement Histological node involvement b) Systemic Confirmed by biopsy, radiology or cytology in any organ Suspected clinically or by non-specific investigations like scanning in any organ Any unexplained chemical findings include elevated enzymes General symptoms 11. Postoperative
+1 per cm
+1 +1 for each +3 +2 +1 +I
a) Local Persistence, recurrence in node or scar b) Systemic as above 111. At each assessment a) b) c) d) e)
131
.+2
Confirmed new system involvement Suspected new system involvement Increased size of existing lesion Decreased size of existing lesion No change in size ~
+3 +2 +1 -1 0
~~
~
~~
Fig. 1. Clinical scoring in breast cancer.
TABLE I. Serum Immunoglobulin Levels in Malignant and Benign Breast Disease
IgA Preoperative 3 months 6 months 9 months 12 months
Cancer
Benign
Mean f SD
Mean f SD
342.2 f 0.22 170.9 f 0.29 185.8 f 0.33 190.1 f 0.29 197.1 f 0.33
160.1 f 0.31 Significant 168.2 f 0.25 185.0 f 0.21 201.2 f 0.29 199.7 f 0.31
90.7 f 0.25 101.3 f 0.29 109.1 f 0.25 109.9 f 0.33 101.7 f 0.27
100.3 f 0.24 99.9 f 0.30 103.2 f 0.25 104.3 f0.31 107.2 k0.28
fgM
Preoperative 3 months 6 months 9 months 12 months
kc Preoperative 3 months 6 months 9 months 12 months IgE Preoperative 3 months 6 months 9 months 12 months
2,071.3 r0.34 1,890.2 i 0.28 1,799.3 f 0.30 1,810.9 0.21 1,905.3 0.24
* *
29.5 f 0.84 30.2 f 0.76 28.5 f 0.71 25.1 f0.69 27.7 f 0.84
1,680.9 i 0.44 Significant 1,795.9 i 0.27 1,770.2 f 0.32 1,800.5 2 0.26 1,889.2 f 0.25 31.2 f 0.78 28.9 f 0.71 27.1 fO.51 20.0 f 0.81 22.8 f 0.69
132
Alsabti
TABLE 11. Clinical Scores Among Breast Carcinoma Cases at Different Times Time of scoring
Score
1. Preoperative
No. of cases
0-3 3-6 6-10
19 10 2 0 29
10 + 0- 3
11. 3 months postoperative
2
3- 6 6-10 10 + 0- 3 3-6
111. 6 months postoperative
0
0 27 2 2 0 22 4 4 0 21 2 5 1
6-10 10 + 0-3 3-6 6-10 10 + 0- 3 3-6 6-10 10 +
IV. 9 months postoperative
V. 12 months postoperative
TABLE 111. Pearson Coefficient ( ) for Correlation Between Serum Immunoglobulins and Clinical Scores in Breast Cancer Cases ~-
Prcoperative correlation IgA
0.09
IgC IgE IgM
0.12 0.15 0.05
-
3 Months postoperative correlation 0.18 - 0.20 -
0.21 0.31 (SS)
6 Months
postoperative correlation 0.32 ( S S ) 0.20 0.1 1 0.09
9 Months postoperative correlation
12 Months postoperative correlation
0.30 ( S S ) 0.24 0.14 0.10
0.28 0.14 0.19 0.13
P = 0.05 SS = statistically significant correlation.
DISCUSSION The study has demonstrated an alteration in tlie levels of serum immunoglobulins IgG and IgA in patients with breast cancer when followed prospectively for the first year. The results confirmed tlie findings of Rowinska-Zakrewska et a1 [ 19701 and Roberts et a1 [ 19751. The measurement of serum immunoglobulin levels in breast cancer patients is of value as an indicator of the disease spread. There is positive correlation between IgA level and the advancement of metastatic breast cancer, as quantified by the clinical score. Analysis of individuals who have subsequently developed metastasis confirms that large rises in serum IgG and IgA may antedate the detection o f metastases.
Serum Immunoglobulins in Breast Cancer
133
The findings suggest a secondary defense mechanism against the increasing tumor load which might be responsible for these abnormalities but nevertheless, it does not support the theory of early immune defect in immunoglobulin metabolism in the pathogenesis of breast cancer.
ACKNOWLEDGMENTS Many thanks t o His Royal Highness Crown Prince Hassan for his financial support and encouragement. I would like to thank Prof, H. Menduke (Thomas Jefferson Hospital) for his help with evaluating the statistical analysis.
REFERENCES Hughes NR: J NatlCanc lnst 46:1015,1971. Mac Kay WD: Brit J Cancer 20:434,1966. Merrett TG. Pantin CFA: Clin Chem Acta 65: 131, 1975. Meyer KK, Mackler GL, Beck WC: Arch Surg 107: 159, 1973. Platts-Mills TAE, Von Maur RK, lshizakz K. Norman PS, Lichtenstein LM: J CIin Invest 57: 1041, 1976. Roberts MM, Bathgate EM, Stevenson A: Cancer 36:221, 1975. Rowinska-Zakerwska E, Lazar P, Burtin P: Ann lnst Pasteur 119:621, 1970. Wise L, Mason AY, Ackerman LV: Ann Surg 174:392, 1971.
Serum Immunoglobulins in Breast Cancer ..................................................................................... ..................................................................................... ELIAS A. K.ALSABTI, MD Eighty-one women admitted for breast tumor biopsy have been followed sequentially for 12 months. Thirty-one women had clinical stage I and I1 breast cancer and 50 had benign breast disease. All these women had serum immunoglobulin IgA, IgC, IgM and IgE levels measured by immunodiffusion and radioimmunoassay preoperatively, two weeks postoperatively, then three months, six months, nine months and twelve months postoperatively. Significant differences were found in IgA and IgG levels preoperatively in the cancer group while no differences were found in IgM or IgE levels a t any time. There was positive correlation between the extent of metastatic breast cancer and IgA level. There was negative correlation between the extent of metastatic breast cancer and IgM levels. These findings raise the value of measuring t h e levels of immunoglobulins in patients with breast cancer as a guide t o subclinical spread of the disease. The results may also support the hypothesis of the role of early immune defect in immunoglobulin metabolism in the pathogenesis of breast cancer.
.................................................................................... .................................................................................... Key words: breast cancer, IgG, IgA, IgM, IgE, immunodiffusion, radioimmunoassay
INTRODUCTION Serum immunoglobulin levels may be useful in the management of cancer patients as diagnostic indicators, tumor spread indicators or as indicators of immunosuppression in the pathogenesis o f cancer. Hughes [I9711 found that serum levels of IgG, IgA and IgM were altered in various nonhematopoietic cancers. Elevated IgG and IgA were found in patients with skin and lung cancer whereas patients with intestinal tumors or uterine tumors had increased IgA only. Serum IgM was elevated in sarcoma and melanoma (one male and one female respectively). Rowinska-Zakerwska et a1 [ 19701;and Roberts et a1 [ 19751 reported elevated IgA levels in breast cancer.
From the Royal Scientific Society, Amman, Jordan.
Address reprint requests to Elias Alsabti, MD, c/o Mrs. W. Aljaff, Flat #5,8 Norfolk Terrace, Brighton, BN1 3AD, England.
0022-4790/79/1102-Ol29$01.40 @ 1979 Alan R. Liss, Inc.
130
Alsabti
Meyer et a1 [1973] suggested that patients with breast cancer who have increased IgA level before mastectomy have an improved prognosis. MacKay [ 19661 reported that cases with breast cancer suffer less from allergic disease, and this observation raised the hypothesis of atopic subjects are higher responders [Platts-Mills et al, 19761 . The objective of this study was to determine whether serum levels of IgG, IgA, IgM and IgE changed in early breast cancer compared to non-malignant breast disease and whether these changes could be correlated with the spread of tumors and t o what degree of accuracy one can depend on immunoglobulin levels in the management of breast cancer. MATERIALS AND METHODS Eighty-one women admitted to the Main Royal Hospital for breast tumor biopsy have been studied. Thirty-one of these women were found t o have malignant breast disease and 50 nonmalignant breast disease. Their ages ranged between 49-68 years. All had breast lumps less than five cm in diameter, with or without palpable axillary lymph nodes. Therefore, those with breast cancer had tumors which fell into clinical stage I or I1 of the Manchester classification [Wise et al, 19711, and had no evidence of metastasis clinically as shown by chest x-ray, normal liver function tests, normal bone scanning and normal serum chemistry. Venous blood was taken on the day of admission, the day before surgery and two weeks postoperatively. Subsequently, they have had further samples taken three months postoperatively. Correlation between the immunoglobulin levels and the extent of the cancer was performed by quantifying the tumor mass in each patient which will produce the clinical score. The scoring was based upon the diameter of the tumor postoperatively and extra points were given for histopathological metastasis to skin, lymph nodes or muscles. The local score usually subtracted from the total score postoperatively. The score was the same for each confirmed systemic spread whether by biopsy, radiology or cytology and was hgher than that for suspected symptoms. Details of our scoring is shown in Figure 1. Radial immunodiffusion on tripartigen plates (obtained from Behringwerke Inst., West Germany) were used for the estimations of IgC, IgM, IgA and IgE. Radioimmunoassay was used to measure total serum IgE levels as described by Merrett et a1 [ 19751.
RESULTS The serum levels of IgA and IgG in breast cancer patients were significantly different from the levels in patients with benign breast disease preoperatively (Table I). IgM and IgE levels were not significantly different in both groups, either preoperatively or at any of the postoperative follow-up times. The clinical scores of cancer patients at various follow-up times is shown in Table 11. There is a correlation between serum immunoglobulin levels and the clinical score of each patient. Six cases from the original 31 had developed definite clinical evidence of metastatic disease and 2 patients had died of breast cancer. There was positive correlation with IgA at 6 months (Pearson Coefficient, = 0.32, P 0.05) and at 9 months ( = 0.3). There was also a significant negative correlation with IgM at 3 months ( = 0.31, P 0.05) (Table 111). One can conclude that the rise of IgG and IgA was seen in the majority of patients (four out of six) before the clinical appearance of their metastasis. The preoperative elevation of IgG (1.95 gm/100 ml) was associated with early metastasis (313 patients), and serum IgA level (0.5 gm/100 ml) was associated with late metastasis (?4patients), particularly if serum level raised progressively.
Serum Immunoglobulins in Breast Cancer I. Preoperative
Score
a) Locai Tumor specimen diameter in cm Histopathological evidence of deep or superficial involvement Histological node involvement b) Systemic Confirmed by biopsy, radiology or cytology in any organ Suspected clinically or by non-specific investigations like scanning in any organ Any unexplained chemical findings include elevated enzymes General symptoms 11. Postoperative
+1 per cm
+1 +1 for each +3 +2 +1 +I
a) Local Persistence, recurrence in node or scar b) Systemic as above 111. At each assessment a) b) c) d) e)
131
.+2
Confirmed new system involvement Suspected new system involvement Increased size of existing lesion Decreased size of existing lesion No change in size ~
+3 +2 +1 -1 0
~~
~
~~
Fig. 1. Clinical scoring in breast cancer.
TABLE I. Serum Immunoglobulin Levels in Malignant and Benign Breast Disease
IgA Preoperative 3 months 6 months 9 months 12 months
Cancer
Benign
Mean f SD
Mean f SD
342.2 f 0.22 170.9 f 0.29 185.8 f 0.33 190.1 f 0.29 197.1 f 0.33
160.1 f 0.31 Significant 168.2 f 0.25 185.0 f 0.21 201.2 f 0.29 199.7 f 0.31
90.7 f 0.25 101.3 f 0.29 109.1 f 0.25 109.9 f 0.33 101.7 f 0.27
100.3 f 0.24 99.9 f 0.30 103.2 f 0.25 104.3 f0.31 107.2 k0.28
fgM
Preoperative 3 months 6 months 9 months 12 months
kc Preoperative 3 months 6 months 9 months 12 months IgE Preoperative 3 months 6 months 9 months 12 months
2,071.3 r0.34 1,890.2 i 0.28 1,799.3 f 0.30 1,810.9 0.21 1,905.3 0.24
* *
29.5 f 0.84 30.2 f 0.76 28.5 f 0.71 25.1 f0.69 27.7 f 0.84
1,680.9 i 0.44 Significant 1,795.9 i 0.27 1,770.2 f 0.32 1,800.5 2 0.26 1,889.2 f 0.25 31.2 f 0.78 28.9 f 0.71 27.1 fO.51 20.0 f 0.81 22.8 f 0.69
132
Alsabti
TABLE 11. Clinical Scores Among Breast Carcinoma Cases at Different Times Time of scoring
Score
1. Preoperative
No. of cases
0-3 3-6 6-10
19 10 2 0 29
10 + 0- 3
11. 3 months postoperative
2
3- 6 6-10 10 + 0- 3 3-6
111. 6 months postoperative
0
0 27 2 2 0 22 4 4 0 21 2 5 1
6-10 10 + 0-3 3-6 6-10 10 + 0- 3 3-6 6-10 10 +
IV. 9 months postoperative
V. 12 months postoperative
TABLE 111. Pearson Coefficient ( ) for Correlation Between Serum Immunoglobulins and Clinical Scores in Breast Cancer Cases ~-
Prcoperative correlation IgA
0.09
IgC IgE IgM
0.12 0.15 0.05
-
3 Months postoperative correlation 0.18 - 0.20 -
0.21 0.31 (SS)
6 Months
postoperative correlation 0.32 ( S S ) 0.20 0.1 1 0.09
9 Months postoperative correlation
12 Months postoperative correlation
0.30 ( S S ) 0.24 0.14 0.10
0.28 0.14 0.19 0.13
P = 0.05 SS = statistically significant correlation.
DISCUSSION The study has demonstrated an alteration in tlie levels of serum immunoglobulins IgG and IgA in patients with breast cancer when followed prospectively for the first year. The results confirmed tlie findings of Rowinska-Zakrewska et a1 [ 19701 and Roberts et a1 [ 19751. The measurement of serum immunoglobulin levels in breast cancer patients is of value as an indicator of the disease spread. There is positive correlation between IgA level and the advancement of metastatic breast cancer, as quantified by the clinical score. Analysis of individuals who have subsequently developed metastasis confirms that large rises in serum IgG and IgA may antedate the detection o f metastases.
Serum Immunoglobulins in Breast Cancer
133
The findings suggest a secondary defense mechanism against the increasing tumor load which might be responsible for these abnormalities but nevertheless, it does not support the theory of early immune defect in immunoglobulin metabolism in the pathogenesis of breast cancer.
ACKNOWLEDGMENTS Many thanks t o His Royal Highness Crown Prince Hassan for his financial support and encouragement. I would like to thank Prof, H. Menduke (Thomas Jefferson Hospital) for his help with evaluating the statistical analysis.
REFERENCES Hughes NR: J NatlCanc lnst 46:1015,1971. Mac Kay WD: Brit J Cancer 20:434,1966. Merrett TG. Pantin CFA: Clin Chem Acta 65: 131, 1975. Meyer KK, Mackler GL, Beck WC: Arch Surg 107: 159, 1973. Platts-Mills TAE, Von Maur RK, lshizakz K. Norman PS, Lichtenstein LM: J CIin Invest 57: 1041, 1976. Roberts MM, Bathgate EM, Stevenson A: Cancer 36:221, 1975. Rowinska-Zakerwska E, Lazar P, Burtin P: Ann lnst Pasteur 119:621, 1970. Wise L, Mason AY, Ackerman LV: Ann Surg 174:392, 1971.
