Family history of breast cancer and breast cancer risk in Japan

Breast Cancer Vol. 3 No. 3 December 1996

Original Article

Family History of Breast Cancer and Breast Cancer Risk in Japan

M A S A O K A N A M O R I *~, T A K A S H I FUKUTOM1.2, M I N O R U SUGITA .1, A N D T A K A S H I IZUNO .1

We studied 132 families with a family history of breast cancer (familial aggregation cases, FA cases) to assess the breast cancer risk presented by such a family history. For comparison with these FA cases, we randomly selected 132 control families of sporadic cases (SP controls) by adjusting for the age of the proband at surgery. Information on family history was collected for all first-degree female relatives and maternal and paternal grandmothers. Japanese women with a first-degree relative affected by breast cancer were found to have an increased risk of the disease. The odds ratio (OR) for women with a family history of breast cancer was 1.99 (95% confidence interval [CII, 1.48-2.66). The OR for FA-case daughters of women with breast cancer was 1.54 (95% CI, 0.91-2.63). A higher risk was not observed if a woman's mother had breast cancer. If the proband had a sister with breast cancer, a slightly increased risk of other cancers of the proband was observed (OR, 1.85 [0.87- 3.921). These results suggest that a family history of breast cancer in Japanese women may affect their risk of developing cancer of the breast and other organs.

Breast Cancer 3.'161-165, 1996

Key words: Family history, Cancer risk, Odds ratio, Breast cancer

A family history of breast cancer reflects shared environmental and/or genetic factors. Com- plex segregation analysis of populat ion-based series of breast cancer patients has indicated that the risk of breast cancer among women inherit- ing susceptibility to the disease is extremely high 1). In 1994, Miki reported that the B R C A 1 gene is responsible for inherited predisposition to breast and ovarian cancer 2). According to recent results of epidemiologic studies, the estimated risk associated with a family history of breast cancer increases in combination with other risk factors 3-7). Furthermore, a case-control study assessing the impact of a family history of breast

*1Department of Environmental and Occupational Health, Toho University School of Medicine, and *2Department of Surgery, National Cancer Center Hospital. Reprint requests to Takashi Fukutomi, Department of Surgery, National Cancer Center Hospital, 5-1-1 Chuo-ku, Tokyo 104, Japan.

Abbreviations: OR, Odds ratio; FA, Familial aggregation case, SP, Sporadic control, CI, Confidence interval

Received April 3, 1996; accepted July 31, 1996

cancer on the risk of developing breast cancer in Utah, USA, found that women with such a family history, even if the nearest relative with breast cancer were a third-degree relative, have an increased risk of the disease 8~. We have previous- ly described the clinical and pathologic charac- teristics of Japanese breast cancer patients 9). The aim of this study was to assess the impact of such a family history on the risk of developing cancer.

Materials and Methods

We studied 132 families with a family history of breast cancer (familial aggregation cases, FA cases). We have used the epidemiologic method of the Utah report for this study. The family history was defined as positive if one or more members of the family within three generations, apart from the proband, had breast cancer. We randomly selected 132 control families of sporadic cases (SP controls) for comparison with the FA cases by adjusting for the age of the proband at the time of surgery. All patients were surgi-

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Kanamori M, et al Family History and Breast Cancer Risk

cally treated and diagnosed as having breast cancer between 1986 and 1991 at the National Cancer Center Hospital. Information on family history was collected for all first-degree female relatives as well as maternal and paternal grandmothers for both FA cases and SP controls. The number of maternal and paternal aunts with breast cancer was also detailed. Additional information collected for the FA cases and SP controls included clinical and pathologic characteris- tics, the occurrence of bilateral breast cancer, the prognosis, the age at the time of surgery, and social variables (marital status, business career and birth place). The data were considered in relation to the patient's age at surgery. The proportions of sisters of patients who also had breast cancer by 10-year age intervals were calculated using the computer program of SAS. The odds ratio (OR) was used to assess the relationship between a family history of breast cancer and having breast cancer. The OR indicates the likelihood of the proband of FA cases, compared with the likelihood of the proband of SP controls. The odds ratio and 95% likelihood- based confidence intervals (CIs) were calculated as follows:

OR- ad/ bc; CIs = exp Eln OR + 1.96s(L)] ;

s(L)= ~/ (1/a)+(1/b)+(1/c)+(1/d).

Where a and c are the number of sisters with and without breast cancer, respectively, of FA cases, and b and d are the number of sisters with and without breast cancer, respectively, of SP controls. The 10-year age class OR and 95% likelihood-based CIs were calculated. The adjusted OR was given by the Mantel-Haenszel method.

The probabilities of breast cancer in sisters of FA-case patients were calculated to estimate the expected probability of the proband's sister having breast cancer. The number of sisters with breast cancer was divided by the total number of sisters excluding the proband. The probabilities of cancer by 10-year intervals were calculated to assess the relationship between a family history of breast cancer and other cancers.

Results

Age Distribution and Family History of the Breast Cancer Patients

The age distribution of the study population is presented in Table 1 and shows that most FA cases and SP controls were 40 69 years of age at the time of surgery. The total number of sisters of FA cases was 243 and that of SP controls was 252. There was no significant difference between the number of sisters of FA cases and SP controls. The FA cases were grouped according to the type of transmission that had occurred over three generations (Table 2): 31 patients (23.5%) had a mother with breast cancer and 64 (48.5%) had one or more sisters with breast cancer. There were 24 FA-case patients (18.2%) with more than three relatives with breast cancer.

The mother, a sister and the proband had breast cancer in two instances (1.5%). In three other instances (2.3%), the maternal aunt and/or grandmother, mother and the proband had breast cancer. In ten instances, the familial group con- sisted of the maternal grandmother, a sister and the proband (7.6%), while in nine instances the paternal grandmother and/or aunt, a sister and the proband were affected (6.8%). Table 3 shows

Table 1. Distribution of Breast Cancer Patients according to Patient Age at Surgery

Age at Familial aggregation cases Sporadic controls

surgery Number of Number of Number of Number of (years) proband (%) sisters a) proband (%) sisters

20-29 1 (0.8) 0 1 (0.8) 2 30-39 10 (7.5) 9 10 (7.5) 13 40-49 45 (34.0) 80 45 (34.0) 79 50-59 36 (27.3) 69 36 (27.3) 83 60-69 27 (20.5) 55 27 (20.5) 49 70-79 12 (9.1) 29 12 (9.1) 25 80-89 1 (0.8) 1 1 (0.8) 1

Total 132 (100.0) 243 132 (100.0) 252

a~Number of proband's sisters excluding the proband.

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Table 2. Type of Transmission of Breast Cancer in Cases with a Family History of Breast Cancer

Aunt and/0r Bilateral Mother Sister Case (%)

grandmother case

Table 3. Proportion of Proband with a History of Cancers other than Breast Cancer

Proband's history Familial aggregation Sporadic of cancer case (%) control (%)

Af Af Un 2 (1.5%) 0 Uterus Af Un Af 3 (2.3%) 0 Stomach Af Un Un 26 (19.7%) 0 Ovary Un Af Af a> 10 (7.6%) 2 Liver Un Af Af b) 9 (6.8%) 2 Thyroid a) Un Af Un 43 (32.6%) 0 Lung Un Un Af 39 (29.5%) 1 Bone b>

None Af, Affected cases with breast cancer; Un, Unaffected cases

including the case who have no sisters. a)Mother's aunt; b)Father's aunt.

0 0 0

121

4 3.0%) 3 2.3%) 3 2.3%) 1 0.8%)

0.0%) 0.0%)

(91.6%)

4 3.0%) 1 0.8%) 0 o.o%) 0 o.o%) 3 2.3%) 1 0.8%) 1 0.8%)

122 (92.4%)

~)Including benign tumor; b)Sarcoma.

Table 4. Proportion of Sisters with Breast Cancer according to Patient Age at Surgery

Age at surgery Proportion of sisters with breast cancer a)

(years) Familial aggregation case Sporadic control Odds ratio (95% CI)

20-29 1.000 (1/1) 0.333 (1/3) 30-39 0.579 (11/19) 0.435 (10/23) 1.79 (0.52-6.11) 40-49 0.528 (66/125) 0.363 (45/124) 1.96 (1.18-3.24) 50-59 0.476 (50/125) 0.303 (36/119) 2.10 (1.21-3.63) 60-69 0.500 (41/82) 0.355 (27/76) 1.82 (0.96-3.44) 70-79 0.512 (21/41) 0.324 (12/37) 2.19 (0.87-5.50) 80-89 0.500 (1/2) 0.500 (1/2) 1.00 (0.02-50.4)

Total 0.509 (191/375) 0.344 (132/384) 1.98 (1.48-2.65) b)

a>Proportion of sisters with breast cancer: Number of affected with breast cancer divided by number of sisters of patients.

b)Adjusted odds ratio was 1.99 (1.48-2.66), calculated by Mantel-Haenszel method (Breslow- Day test for homogeneity of odds ratio, ,g~-1.09, df=6, p-0.982).

CI, Confidence intervaI.

Table 5. Odds Ratio of Breast Cancer for Daughters of Women with or without Breast Cancer in Familial Aggre- gation Cases

Table 6. Probabili ty of Breast Cancers in Sisters of Probands with a Family History of Disease according to Patient Age at Surgery

Age Odds ratio (95% confidence interval) Age at Number of Number of Probabili ty (years) Daughters of women Daughters of women surgery (Sisters with

without breast cancer with breast cancer (years) proband sisters breast cancer)

30- - 0.98 (0.26-3.73) 20-29 1 0 - 40- 2.05 (1.20-3.51) 1.61 (0.66-3.94) 30-39 10 9 0.111 (1) 50- 2.20 (1.24 3.92) 1.68 (0.62 4.52) 40-49 45 80 0.263 (21) 60- 1.86 (0.97-3.58) 1.36 (0.28-6.54) 50-59 36 69 0.202 (14) 70- 2.20 (0.86 5.65) 2.08 (0.26-16.6) 60-69 27 55 0.254 (14) 80- 1.00 (0.02-50.4) 70-79 12 29 0.313 (9)

Total 2.08 (1.53-2.83) a) 1.60 (0.95-2.70) b> 80-89 1 1 0.000 (0)

")Age adjusted odds ratio was 2.14 (1.57-2.93) (X2=3.09, dr= 5, p = 0.686 by Breslow-Day test).

~>Age adjusted odds ratio was 1.54 (0.91 2.63) (x2-1.55, dr - 5, p =0.907 by Breslow-Day test).

the proportions of probands with a history of other cancers apart from breast cancer: three (2.3%) had a history of gastric cancer; three had a history of ovarian cancer; and four (3.0%) had a history of uterine cancer in FA cases.

Total 132 243 0.243 (59)

Breast Cancer Risk The proportions of sisters of FA case and SP

controls with breast cancer are shown in Table 4. The cumulative proportion of breast cancer for FA cases was 0.509, showing a tendency to be higher than that for SP controls, which was 0.344. The pattern of breast cancer incidence among

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Kanamori M, et al Family History and Breast Cancer Risk

Table 7. Probabil i ty and Odds Ratio of Cancers other than Breast Cancer in Sisters of Patients according to Patient Age at Surgery

Age at surgery Probability of other cancers in sisters ")

(years) Familial aggregation case Sporadic control Odds ratio (95% CI)

20-29 0.500 (1/2) - 30-39 0.000 (0/9) 0.000 (0/13) - 40-49 0.063 (5/80) 0.051 (4/79) 1.25 (0.32- 4.84) 50-59 0.072 (5/69) 0.024 (2/83) 3.16 (0.59-16.85) 60-69 0.109 (6/55) 0.082 (4/49) 1.38 (0.37- 5.20) 70-79 0.137 (4/29) 0.040 (1/25) 3.84 (0.40-36.86) 80-89 0.000 (0/1) 0.000 (0/1) -

Tota l 0.082 (20/243) 0.048 (12/252) 1.79 (0.86-3.75) b>

a)Probability of other cancers in sisters: Number of sisters with cancer divided by number of sisters.

b)Age adjusted odds ratio was 1.85 (0.87-3.92), calculated by Mantel-Haenszel method (Breslow-Day test for homogeneity of odds ratio, ,~2= 1.34, df= 3, p =0.721).

CI, Confidence interval.

FA cases was consistent with Mendelian transmission of an autosomal dominantly inherited factor. An increase in risk, estimated by the OR of breast cancer, was observed among the FA cases compared with the SP controls. The OR for women with a family history of breast cancer was 1.99 (95% CI, 1.48-2.66). The OR did not increase with increasing age. Sisters with more than two relatives with breast cancer among third-degree relatives had a 2.0-fold higher risk of developing breast cancer than the sisters of SP controls. The proportions of sisters of patients with breast cancer in relation to whether their mother had the disease are shown in Table 5. For FA cases, the OR for daughters of women with breast cancer was 1.54 (95% CI, 0.91-2.63) and that for daughters of women who did not have breast cancer was 2.14 (95% CI, 1.57-2.93). A greater risk was therefore not observed for FA cases who were daughters of women with breast cancer. The probabilities of sisters of FA case patients having breast cancer are shown in Table 6 in relation to the patient 's age at surgery. The probabili ty of distribution shows two peaks in the eighth and fifth decades. The probabili ty for all ages was 0.243 (95% CI, 0.193-0.298). One of every four sisters of the proband would be expected to have breast cancer.

Cancer Risk The probabilit ies of other cancers apart from

breast cancer for sisters of patients showed a slightly higher risk for other cancers for FA cases than for SP controls (Table 7). The probabili t iy among all ages for sisters of patients was 0.082 (95% CI, 0.048-0.116), and 0.048 (95%

CI, 0.022-0.074) for FA cases and SP controls, respectively. The OR, for FA cases was slightly elevated (OR, 1.85 E0.87-3.92]), but the difference between FA cases and SP controls was not statis- tically significant. These results suggest that a family history of breast cancer may affect the risk of cancer in Japanese women.

Discussion

This study was based on data on women with breast cancer with a family history of breast cancer affecting sisters and mothers. The family history reflects shared genes as well as a shared environment. A combination of genetic and environmental factors may play a role in the develop- ment of breast cancer in both FA cases and the SP controls. Our hypothesis was that genetic factors play a more significant role in FA cases than in the SP controls. The present study revealed that the OR for women with a family history of breast cancer was 1.99. Using logistic regression analysis, Miura et al reported that a family history of breast cancer is a risk factor for developing breast cancer in Japan 1~ Using the Utah Population Database, Slattery reported that the OR for women with a first-degree relative with breast cancer was 2.45. A slightly higher risk was observed if the first-degree relative was the woman's mother (OR, 2.44) rather than a sister (OR, 2.01) 8). However, in our study, a higher risk was not observed if a woman's mother had breast cancer. Approximately 1 7 % - 1 9 % of breast cancer in the Utah population could be attributed to family history 8). Although there is no family population database on breast cancer

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in Japan, we es t imate tha t the p ropor t ion of b reas t cancer in the Japanese popula t ion at t r ibut- able to a fami ly h i s to ry might be smal le r than tha t of the Utah popula t ion 9'11). We previous ly repor ted tha t only about 10~o of Japanese b reas t cancer famil ies can be l inked to the B R C A 1

gene 11'12). T h e r e is a s t rong possibi l i ty tha t this lower gene f requency as well as env i ronmenta l f ac to r s might account for the lower incidence of b reas t cancer in Japan. We think tha t genet ic he te rogene i ty of breas t cancer exis ts be tween Caucas ians and Japanese women. In the present study, the sisters of p robands with a posi t ive fami ly h i s to ry of b reas t cancer had an increased r isk of the disease. It is t he re fo re impor t an t for such sisters to assess their individual r isks and to wa tch for any signs of the cancer .

Our paper is the first s tudy of fami ly members of pa t ien ts wi th b reas t cancer to r epo r t tha t Japanese women with a fami ly h i s to ry of b reas t cance r have an increased r isk of the disease. It is now necessary to inves t iga te the B R C A 1 gene based ep idemiology in Japanese women to assess the individual r isks and fac to r s for developing b reas t cance r so tha t the tumor can be detec ted at an ea r ly stage.

References

1) Newman B, Austin MA, Lee M, et al: Inheritance of human breast cancer; Evidence for autosomal domi- nant transmission in high risk families. Proc Natl Acad Sci 85:3044-3048, 1988.

2) Miki Y, Swensen J, Futreal PA, et al: A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266:66-71, 1994.

3) Bryne C, Brinton LA, Haile RW, et al: Heterogeneity of the effect of family history on breast cancer risk. Epidemiology 2:276-284, 1991.

4) Mettlin C, Croghan I, Natarajan N, et al: The associa- tion of age and familial risk in a case-control study of breast cancer. Am ] Epidemiol 131:973-983, 1990.

5) Sellers TA, Kishi LH, Potter JD: Effect of family history, body-fat distribution and reproductive factors on the risk of postmenopausal breast cancer. N Engl ] Med 326:1323-1329, 1992.

6) Harris JR, Lippman ME, Veronesi U, et al: Breast cancer. N Engl J Med 327:319-328, 1992.

7) Parazzini F, LaVecchia C, Negri E, et al: Menstrual and reproductive factors and breast cancer in women with family history of the disease. Int ] Cancer 51: 677-681, 1992.

8) Slattery ML, Kerber RA: A comprehensive evaluation of family history and breast cancer risk. JAMA 270: 1563-1568, 1993.

9) Fukutomi T, Kobayashi Y, Nanasawa T, et al: A clinicopathological analysis of breast cancer in patients with a family history. Surg Today 23:849-854, 1993.

10) Miura S, Kasumi F, Iwase T, et al: Familial aggregation of breast cancer among Japanese. Jpn ] Breast Cancer 7:237-247, 1992 (in Japanese with English summary).

11) Inoue R, Fukutomi T, Ushijima T, et al: Linkage analysis of BRCA1 in Japanese breast cancer families. ]pn J Cancer Res 85:1233-1239, 1994.

12) Inoue R, Fukutomi T, Ushijima T, et al: Germline mutation of BRCA1 in Japanese breast cancer families. Cancer Res 55: 3521-3524, 1995.

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Family history of breast cancer and breast cancer risk in Japan