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Community Medicine

UNILATERAL BREAST-FEEDING ANDBREAST CANCER

ROY ING J. H. C. HoNICHOLAS L. PETRAKIS

U.S. Public Health Service Hospital, Baltimore, Maryland,U.S.A., Medical and Health Department, Institute of

Radiology and Oncology, Queen Elizabeth Hospital, Kowloon,Hong Kong, and G. W. Hooper Foundation, University ofCalifornia, School of Medicine, San Francisco, California,

U.S.A.

Summary Women of fishing villages in Hong Kongby custom breast-feed with only the

right breast. The hypothesis that the unsuckled breastmay have an altered risk of cancer development was in-vestigated. Records of the radiotherapy divisions in

Hong Kong between 1958 and 1975 were searched, andbreast-cancer patients were interviewed for a detailedhistory of lactation. The overall left/right ratio of cancerin the breasts of 2372 women with unilateral breast car-cinoma was 0·97, indicating that breast cancer wasequally distributed between the two sides. Of 73 patientswith a history of exclusively one-sided breast-feeding, 27of 34 patients aged 55 or over (79·4%) and 19 of 39 pa-tients under age 55 (48·7%) had a carcinoma in the un-suckled breast. Comparisons of patients who had nursedunilaterally with nulliparous patients and with patientswho had borne children but had not breast-fed indicateda highly significantly increased risk of cancer in the un-suckled breast. No statistically significant differences inlaterality of breast cancer were found in 52 patients whohad for convenience nursed to a greater extent from oneside than the other. This study indicates that in post-menopausal women who have breast-fed unilaterally,the risk of cancer is significantly higher in the unsuckledbreast and that breast-feeding may help to protect thesuckled breast against cancer.

Introduction

THE Chinese Tanka (boat people) live on the coastalwaters and rivers of southern China, and their womenbreast-feed with only the right breast, probably for con-venience, the opening of the clothing being on the rightside.’ Non-Tanka Chinese women living on land havethe same style of clothing, but most of them breast-feedbilaterally. Multiparous Tanka women who nurse theirinfants with the right breast only have smaller, softerleft breasts,’ without signs of engorgement, mastitis, ormasses. Less than a millilitre of milk-like secretion canbe expressed from the unused left breast.

By comparing the laterality of breast cancer in Tankaand other Chinese patients in Hong Kong, we found asignificantly increased incidence of breast cancer in theunused breast in women who had breast-fed unilater-

ally. ’

Patients and Methods

Records of all breast-cancer patients treated at the radio-therapy divisions of Queen Mary Hospital, Hong Kong, and

Queen Elizabeth Hospital, Kowloon, Hong Kong, betweenJanuary, 1958, and August, 1975, were reviewed. Radicalmastectomy and postoperative radiotherapy have been theusual methods of treatment for breast cancer, and these twocentres did more than 95% of all radiation therapy in HongKong during this period. A search was made for breast-cancerpatients from the Tanka boat population and for any patientwith a history of breast-feeding more or exclusively on oneside. Information from the records included: age when firstseen at the radiotherapy division, place of origin, age at

menarche and natural menopause, marital status, age at mar-

riage, age at first pregnancy, number of full-term pregnancies,number of children breast-fed, average duration of nursing perchild, history of lactational mastitis or abscess, history of hypo-lactation (especially unilateral), relative use of the two breastsin lactation, and the side in which breast cancer initially devel-oped.Because some Tanka families have migrated to land, a pa-tient originally from the floating population might not be iden-tified in the record. For this reason, and to obtain a moredetailed history of lactation, breast-cancer patients being fol-lowed by the radiotherapy divisions were interviewed betweenJune and September, 1971, and in September, 1975. Ourresults represent all breast-cancer cases in Tanka women andin other patients with a history of breast-feeding unequallyfrom the two breasts.

Many studies of breast cancer have shown a slight prepon-derance in the left breast .2.3 For this reason, the relative fre-quency of left and right breast cancer in Hong Kong was stu-died. Again, the records of 2403 Chinese breast-cancer patientstreated at the radiotherapy divisions of the two hospitalsbetween January, 1958, and August, 1975, were used. Agewhen first seen at the radiotherapy division, parity, lactationalhistory, and the site of initial breast-cancer development wererecorded. Only patients presenting with carcinoma in bothbreasts simultaneously or consecutively within a few months ofinitial diagnosis are included in the category of bilateral breastcancer.

Most patients who had breast-fed unilaterally had done sofor convenience or custom. They had had no abnormalities ofthe breasts or nipples and no problems with milk secretion.None of these women had developed bilateral primary breastcancer. 30 women had breast-fed from one breast only forother reasons, including inverted nipples, mastitis, hypolac-tation, and infant preference. Because such abnormalities

might reflect a possible predisposition to breast disease, thesewomen are not included in the analyses. Segi and Kurihara’reported that breast cancer was more common in breasts witha history of hypolactation and mastitis. Goldsmith5,6 describedthe "milk-rejection sign" in 5 cases of breast cancer that devel-oped during lactation. The infants had suddenly refused tonurse from the breast which was later found to contain cancer.

Patients were arbitrarily separated into "premenopausal"and "postmenopausal" groups at age 55. For Tanka and otherwomen having nursed only with the right breast, the left/right(L/R) ratio of breast cancer is a direct measure of the relativerisk of cancer development in the unused breast. In additionto L/R ratios, the percentage of left-breast cancer was calcu-lated. Standard tests of statistical significance were used.

Results

Distribution of Right, Left, and Bilateral Breast CancerTable i summarises the laterality of 2403 cases of

breast carcinoma among Chinese women in Hong Kong.Percentages of right, left, and bilateral breast cancer are50.1%, 48.6%, and 1.3%, respectively. The overall L/Rratio for 2372 patients with unilateral breast carcinomais 0 - 9 7. The left side appears to be afflicted slightly moreoften only among parous women who did not breast-feedtheir children; all other groups have a slight preponder-

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TABLE I-LATERALITY OF 2403 CASES OF FEMALE BREAST CARCINOMA, 1958-75

R right, L =left, B=bilateral, u=unilateral.

ance of cancer on the right side. These differences arenot statistically significant. Among parous patients whobreast-fed, the L/R ratio for 800 patients under 55 is

0.94, whereas for 627 patients aged 55 and over it is1.06. Included in this group are Tanka women andother patients who breast-fed with only the right breast.Although many other reports note a slight excess ofbreast cancer on the left side, none has studied the L/Rratio in relationship to parity and lactational history.Lactation status was either not recorded or not availablefor 58 parous patients, and no parity data could beobtained for 57 other patients.Of 1312 women under 55, 16 (1.23%) had bilateral

breast cancer, as did 15 of 1091 (1-39%) women aged 55or older. This difference is not statistically significant,but the number of bilateral cases is relatively small.

Unilateral Breast-feeding and Site of Breast Cancer

Among the 43 Tanka women for whom case-historieswere found, 6 were single or nulliparous, 1 was parousbut did not breast-feed, and 2 were parous but the lacta-tional history was incomplete. These 9 have been omit-ted from the analysis. Of the remaining 34 patients, 22had breast-fed on the right side only. 10 had histories ofpregnancy and lactation, but the side used for breast-

fABLE II—LATERALITY OF BREAST CANCER IN 32 TANKA WOMENWHO BREAST-FED EXCLUSIVELY FROM THE RIGHT BREAST

TABLE III-LATERALITY OF BREAST CANCER IN 73 PATIENTS WHOHAD BREAST-FED EXCLUSIVELY FROM ONE BREAST BECAUSE OF

CUSTOM OR CONVENIENCE

x2= 6.0 (Yates); P=0.02.u=breast cancer developing in unsuckled breast. s=breast cancerdeveloping in suckled breast.

feeding was not recorded. They are assumed to havebreast-fed on the right side-only, since unilateral breast-feeding is customary among Tanka women. 2 women

reported that they had breast-fed initially with the rightbreast only but had also used the left breast when milkproduction from the right breast was inadequate: bothdeveloped cancer on the left side.

In the 22 Tanka women with a confirmed history and

TABLE IV—66) BREAST-CANCER PATIENTS COMPARED BY HISTORYOF PARITY AND BREAST-FEEDING

(comparisons: -

A1 vs. A2, 2 -0-04N.s. Bl vs. B2,y2 =10.0 (Yates) P=0.01.A 1 vs. A3, y2=0.43 N.S Bl vs. B3, y2=6.11 (Yates) p=0.02.A vs. A4, y2=0.04 N.S. Bl vs. B4, y2=13.5 (Yates) P=0.001.* Right-sided nursing by custom or convenience.N.S. not significant.

10 with an assumed history of breast-feeding on theright side only, cancer developed in the left breast in 21and in the right breast in 1 1-an L/R ratio of 1-90. Thedifference is greater among the older patients: 13 of 17patients aged 55 or over (compared with 8 of 15 patientsunder 55) developed cancer on the left side (table n).

Apart from the Tanka women, 41 other Chinese pa-tients had breast-fed for custom or convenience exclus-

ively with one breast. Among 34 who had nursed withthe right breast only, 8 of 17 under 55 and 14 of 17 aged55 or over had cancer of the left side. 7 patients, all pre-menopausal, had nursed exclusively with the left breast:3 had cancers in the right breast and 4 in the left.

Table m shows the laterality of breast cancer in bothTanka and non-Tanka Chinese patients who for customor convenience had used only one breast. Among post-menopausal women, 79.4% had cancer in the unsuckledbreast, whereas in premenopausal women there was nounilateral dominance. The ratio of cancers in the un-suckled/suckled side was 0-95 in patients under 55 and3-86 in those aged 55 and over. In the postmenopausalwomen, 7 cancers occurred in the breast used for nurs-

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TABLE V-LATERALITY OF BREAST CANCER IN 52 PATIENTS WHOBREAST-FED MORE, BUT NOT EXCLUSIVELY, FROM THE RIGHT

BREAST

ing and 27 in the unused breast, whereas 17 cancerswould be expected on each side. The probability that theobserved findings or an even more skewed distribution oflaterality would occur by chance is less than 1/1000.

(0 = observed, E = expected)The patients wno for convenience had nursed exclus-ively with the right breast were compared with the sub-sets of (1) parous patients who lactated, (2) parouspatients with no history of lactation, and (3) nulliparouspatients, taken from columns a, b, and c in table I. Theunilateral lactators were subtracted from subset 1.For clarity, the data in the tables show only thosepatients who’ had nursed exclusively with the rightbreast and do not include the 7 women who nursed ex-

clusively with the left breast. A significant preponder-ance of breast cancer in the left (non-suckled) breast wasfound among postmenopausal right-sided lactators, com-pared with the nearly equal L/R distribution of breastcancer in premenopausal nulliparous patients and inparous patients with and without a history of lactation(table IV).

Some patients used both breasts but nursed morefrom one side-52 more from the right and 9 more fromthe left. Of those who used mainly the right breast, 13of 30 patients under 55 and 10 of 22 over 55 developedcancer in the less-suckled breast (table v). There was noapparent relationship between the breast that had beensuckled less and the site of breast cancer development inthese patients. The L/R ratios were 1 3 for premenopau-sal women and 1-2 for postmenopausal patients. Theseratios, though higher than those in nulliparous women,were not significantly different.

Except for age at first pregnancy, the menstrual andreproductive characteristics of the patients did not differsignificantly between those who had developed cancer inthe suckled versus the unsuckled breast, or between pa-tients who nursed more, but not exclusively, on one sideand those who had breast-fed unilaterally. Median ageswere: 15-16 at menarche; 19-20 at marriage; and

TABLE VI-MENSTRUAL AND REPRODUCTIVE CHARACTERISTICS (MEDIAN AND RANGE) OF PATIENTS WHO BREAST-FED EXCLUSIVELY ORMOSTLY FROM ONE BREAST

a

*P,0.05, Kolmogorov-Smirnov two-sample test.taverage duration of lactation for each child.n=number of patients with sufficient information. Total numbers of patients are 108 in under-55 age-group and 83 aged 55 and over.

21-23 at first pregnancy. The patients had an averageof four full-term pregnancies and a lactational periodlasting one year per child.

Patients aged 55 or over had a median age at first

pregnancy of 21, compared with 23 for those under 55(table VI). 92.7% of the children of patients under 55were breast-fed, compared with 89.6% for the offspringof women over 55. More than 96% of the patients aged55 or older had had a natural menopause, comparedwith 27% of the patients under 55.

Discussion

Lactation was formerly thought to protect againstbreast cancer, because of the low rates among Orientalwomen who practised prolonged breast-feeding and

among women of high parity and low social class whonursed their children. The notion that a breast whichhas lactated differs from one which has not is biologi-cally plausible; but international studies in populationsof high, low, and intermediate risks indicated that lac-tation does not protect against breast cancer.7 Our find-ings, on the other hand, suggest that lactation does in-fluence the occurrence of breast cancer.Our "natural experiment", in a population of women

who nurse from the right breast only, approaches therigour of a laboratory experiment in which the fre-

quency of cancer development in the suckled rightbreast is compared with that in the unsuckled left one.Although retrospective, this study is more akin to the"historical prospective" approach,8 without many pos-sible sources of bias inherent in most retrospective case-control studies.9-11 As nursing with the right breast onlyis customary among Tanka women, their reported lacta-tional history should be very reliable. The distributionof the laterality of breast cancer among the rest of theChinese patients who breast-fed on one side only is simi-lar to that observed in the Tanka women: therefore theirlactational history would also be expected to be reliable.It is inconceivable that the side on which breast cancer

develops should influence a patient’s likelihood of seek-ing medical attention or of being referred for radiationtherapy. Sources of systematic bias should be manifestedin patients of all age-groups, and they seem unlikely tobe present here, since the unsuckled breast in unilateralbreast-feeding has a fourfold increase in cancer risk

apparent only among older patients. Bias, if any, is pre-sumably most likely to occur in a patient’s report thatone breast was suckled more than the other in bilateralbreast-feeding. Indeed, the lack of association betweenthe reportedly less-suckled breast and site of cancer

(table v) argues against this potentially serious source ofbias. To our knowledge there is no general preconcep-

127

tion among these patients in Hong Kong that breast-feeding is in any way related to breast-cancer develop-ment.

Most other series show a higher frequency of breastcancer on the left side, although some report a slightexcess in the right breast.2.3 We have found a few morecases of right-sided breast cancer among Chinese womenin Hong Kong and a slight preponderance of left-sidedbreast cancer among parous patients who had not lac-tated and parous women aged 55 and over who hadnursed their children.Our data show a threefold to fourfold increase in risk

of cancer in the unsuckled breast only for patients aged55 and over (table IV). Although this could represent ageneration cohort effect, we have not noted any strikingdifferences in the reported lactational history betweenyounger and older patients, and the numbers and agesof Tanka and non-Tanka unilateral lactators were uni-

formly distributed over the 18-year period of the study.The menstrual and reproductive characteristics of thepatients shown in table vi are designed to describe thepatient population under study and are not intended asa comparison of risk factors between younger and olderwomen. Patients over 55 were younger at first preg-nancy than those under 55. This could represent eithera real difference between premenopausal and postmeno-pausal patients or merely a general trend towards laterchildbearing.

The increased risk of cancer in the unsuckled breastfor patients who breast-fed on one side only is strikingin that this difference in found only among patients aged55 and over. Breast cancer of early and late onset mayhave different aaiologies and/or mechanisms of develop-ment, and perhaps an "incubation period" of severaldecades may elapse before the excess cancer risk is mani-fested in the unilaterally weaned breast. Possibly a

sudden change in hormonal status during the meno-pause may inhibit tumour growth in incipient breastcarcinomas that are hormonally dependent and thusdelay the onset until a few years after the menopause.

Animal models have been reported which are some-what analogous to unilateral lactation as practised bythe Tanka and some other Hong Kong women. Liga-tion, cauterisation, or excision of nipples on one side ofbreeding and lactating mice has been reported to pro-duce more tumours in the blocked glands. This has beenobserved in different inbred strains of mice both withand without mammary-tumour virus. 12-14 In more

recent studies Marchant,15-17 Biancifiori, 18 andothers 19,20 have studied chemical induction of breasttumours by 3-methylcholanthrene following unilateralexcision of the nipples in pseudopregnant and lactatingmice. Significantly more tumours were found in nipple-excised than normal breasts. Biancifiori and associatesI8found that the carcinogen is secreted into both sides butthat obstruction of the nipple results in prolonged expo-sure of the epithelium to the carcinogen. On the suckledside the carcinogen is excreted in the milk. Petrakis andothers21,22 have found that exogenous chemicals are se-creted into the breast ducts of adult non-lactatingwomen, suggesting that normal physiological secretoryactivity may result in exposure of breast epithelium toingested or inhaled environmental carcinogens. The sus-tained presence and accumulation of harmful chemicalsand their metabolic activation by breast tissue may lead

to initiation and promotion of breast cancer. These clini-cal studies, when viewed in the light of the mouse experi-ments, may explain our observations in Hong Kongwomen.

This work was supported in part by Public Health Service grantCA-13556 from the National Cancer Institute and by a gift from MrsViola K. Schroeder.

Requests for reprints should be addressed to R. I., c/o G. W. HooperFoundation, 1699 HSW, University of California, San Francisco,California 94143, U.S.A.

REFERENCES

1. Ing, R., Petrakis, N. L., Ho, J. H. C. Unpublished.2. Garfinkel, L., Craig, L., Seidman, H. J. natn. Cancer Inst. 1959, 23, 617.3. Busk, T., Clemmesen, J. Br. J. Cancer, 1947, 1, 345.4. Segi, M., Kurihara, M. Tohoku J. exp. Med. 1960, 72, 169.5. Goldsmith, H. S. Cancer, N.Y. 1966, 19, 1185.6. Goldsmith, H. S. Am. J. Surg. 1974, 127, 280.7. MacMahon, B., Lin, T. M., Lowe, C. R., et al. Bull. Wld Hlth Org. 1970,

42, 185.8. Mausner, J. S., Bahn, A. K. Epidemiology; p. 325. Philadelphia, 1974.9. Dorn, H. F. New Engl. J. Med. 1959, 261, 571.

10. Cornfield, J., Haenszel, W.J. chron. Dis. 1960, 11, 523.11. Sartwell, P. E. Ann. intern. Med. 1974, 81, 381.12. Bagg, H. J. J. Cancer Res. 1925, 9, 498.13. Bogen, E. Am. J. publ. Hlth 1935, 25, 245.14. Fekete, E., Green, C. V. Am. J. Cancer, 1936, 27, 513.15. Marchant, J. Nature, 1959, 183, 629.16. Marchant, J. Br.J. Cancer, 1961,15, 568.17. Marchant, J. Acta Un. int. Cancr. 1964, 20, 1443.18. Biancifiori, C., Bonser, G. M., Caschera, F. Br. J. Cancer, 1962, 16, 232.19. Mühlbock, O., van Ebbenhorst Tengbergen, W. Acta Un. int. Cancr. 1961,

17, 88.20. Zeilmaker, G. H. Int. J. Cancer, 1968, 3, 291.21. Petrakis, N. L., Mason, L., Lee, R., Sugimoto, B., Pawson, S., Catchpool,

F.J. natn. Cancer Inst. 1975, 54, 829.22. Petrakis, N. L. in Genetics of Human Cancer (edited by J. J. Mulvihill); p.

297. New York, 1977.

Occasional Survey

SPLENECTOMY AND SUBSEQUENTMORTALITY IN VETERANS OF THE 1939-45

WAR

C. DENNIS ROBINETTE

Medical Follow-up Agency, National Academy ofSciences-National Research Council, 2101 Constitution

Avenue, N. W., Washington, D.C. 20418, U.S.A.

JOSEPH F. FRAUMENI, JR.

Environmental Epidemiology Branch, National CancerInstitute, Bethesda, Maryland 20014, U.S.A.

Summary A long-term follow-up of 740 Americanservicemen splenectomised because of

trauma during the 1939-45 war showed a significantexcess mortality from pneumonia and ischæmic heart-disease. Mortality from cirrhosis was also increased, butnot significantly. The findings confirm that the risk offatal infections is increased by asplenia; however, the riskof cancer was not increased, as it is in some other im-

munodeficiency states. Post-splenectomy thrombocytosisand hypercoagulability may account for the increasedrisk of fatal myocardial ischæmia in this group.

INTRODUCTION

THE function of the human spleen is poorly under-stood. However, clues have come from the few and oftentransient effects of splenectomy, including immunologi-