T H E HEREDITARY ASPECT OF BREAST CANCER IN MOTHER AND DAUGHTER

DRYDEN PHELPS MORSE, M.D.

C ANCEK is now considered to develop under the twin influence of cornplex heredity and environmenml factors. Investigations of cancer in mice have clearly shown the role of heredity, but the evidence in man is less ob- vious. Breast cancer is perhaps the best form of cancel in man for analysis of the role of heredity, since it has been fairly accurately diagnosed in the past because of its external situation. It is preferable to cancer of the skin and lip, which are also easily diagnosed, be- cause i t has been shown that development of the latter is primarily under the influcnce of external carcinogens.

T o gain support for the fact that the tend- ency to develop breast cancer is hereditary, i t is necessary to take a close relative of the breast-cancer patient about whom the most information is available, and then to compare thc incidence of breast carcinoma in this per- son with the expected incidence based either on a control series or on mortality and morbid- ity figures.

T h e obvious clioicc for this analysis is the mother of the breast-cancer patient. The sister or daughter has not usually lived through thc cancer-developing age at the time the informa- tion is obtained. The grandmother is too distant for accurate recollection of facts. T h e aunt and cousin are not sufficiently close rela- tives for a complete or accurate survey. Figures for the incidence of cancer in the mothers of breast-cancer patients are therefore presented in ‘Table 1. ‘The table shows that cancer of the breast is found in approximately 6 per cent of the mothers of women with mammary cancers.

Three figures for comparison with Table 1 arc cited. Wainwright found only 1.1 per cent brcast cancer in the mothers of a control series of 576 patients dying at more than 40 years of age, one fourth as many as in his cancer series. Jacobsen found two cases in 200 controls, or 1 per cent. Busk calculated that according to the expected frequency of brcast-cancer cases from

From the Department of Surgery and the Laboratory of Surgical Pathology of the School of Medicine, Co- lumbia University, New York, New York.

Received for publication, January 15, 1951.

the mortality and morbidity figures for Den- mark there should ha\ c becn scvm cases aniong Jacobscn’s controls. l h e s e control fig- ures are also shown in Table 1.

Wainwright’s finding of 1.1 per cent in his control group is one fourth of the 4.8 per cent incidence in his breast-cancer group (Table 1). According to the highest estimate2 of the ex- pected incidence in control groups bascd on careful calculation from mortality and morbid- ity data in Denmark, the incidence of maternal breast cancer in the control series is one third of what i t is in the cancer series. Thus he found seven cases to be expected, where Jacob- sen discovered twenty one.

This implies that the daughter of a woman with breast cancer has about three times as much chance of developing breast cancer as a woman in the general population.

SPECIFIC INHERITANCE T h e evidence for the SPECIFIC inheritance of

breast cancer can be divided into two parts. The first is the increasing number of breast-

TABLE 1

INCIDENCE OF BREAST CANCER IN MOTHERS

Mothers with breast cancer

No. of Author cases No. %

Breast-Cancer Patients Antoine 8z Pfab, 1927 115 10 8.7 Wainwright, 1931 784* - 4.8 t Wassink, 1935 600 24 3.6 Jacobsen, 1946 200 21 10.5 Smithers, 1948 459 25 5.4 Penrose et al., 1947-49 510 31$ 6.1

TOTAL 1844 111 6.9 - - -

Control Patients Wainwright, 1931 576* - 1.1 Jacobsen, 1946 200 2 1.0 Busk, 1947-49 200 75 3.5 __ __ __

TOTAL 400 9 2.3

* Not included in totals. t Excluding those mothers who died at less than 40

$ Twenty-five dead; six under treatment. 0 Expected number calculated from morbidity and

years of age.

mortality data.

7463 CANCER July 1951

TABIE 2

GENETIC INHERITANCE OF CANCER OF THE BREAST AS OPPOSED T O CANCER O F OTHER SITES IN THE SUCCEEDING GENERATION O F RELATIVES OF BREAST-CANCER PATIENTS

~ ~~~~~ ~~

1st 2d generation generation

Moth- Fa- Sis- Broth- _____ -~~~

Typc of cancer ers thers ters ers ~~ ______ ~ ~ _ _

W’assznk460 cusps

Homotropic 21 - 43 - Heterotropic 40 54 16 23

Penrasp et al.-510 cares Homotropic 31 - 47 - Heterotropic 55 42 16 31

cancer cases in succccding generations of breast-cancer families, antl the second is the prcpondcrance of breast cancer aniong all the cancers of all relatives of breast-cancer patients.

IVassink found twenty-lour patients among 660 whose mothers had breast cancer, antl lorty whose mothers had cancer of other sites. It is interesting to comparc this with the num- ber of his cases whose sisters had breast in- volvement (forty three), as opposed to the number of cases whose sisters had carcinoma of other organs (sixteen), as shown in Table 2.

Wassink points out that the number of “hornotropic” breast cancers in the sisters is double that in the mothers, while the number of cases with cancers of other sites, i.e., hetero- tropic, in sisters is not half that of the mothers. This also carries through for the male rela- tives. Table 2 shows that there is a specific tendency for cancer of the particular organ (the breast) to be inherited. T h e increase in the sister-breast-cancer incidence over thc mother- has been confirmed in other series, notably that of Penrose el al.

The second piece of evidence for the specific inheritance of breast cancer is to be found in Wassink’s data. I n his cases of breast cancer, 207 of 660 had one or niore relatives with can- cer of all sites. There were 301 relatives with cancer, of whom 192 were lemales and 109, males. In othcr words, thcrc were many more female, than male, relatives with cancer; whcreas, in thc general population, inale and female are about equal in developing tumors. Furthermore, this increased number of female relatives is found to have a preponderance of breast cancers (112, or 58 per cent). I n con- trast, breast cancer forms but 12 per cent of

the general female-canccr population in The Nctherlands.

AGE. OF O N 5 L l

Besides the evidence for the specific inherit- ance of breast cancer, a second point that has developed from the Scandinavian figures is that cancer of the breast generally appears at an earlier age in the daughter than in thc mother. Thus, Jacobsen quotes Lefkvre as showing that tumors in mice appearing after a cai ciriogenic influence has been brought to bear appear not only to be increased in inci- dence but also to be manifest at a younger age. \\Tarthin, in 1928, noticed that in families afnicted with a hereditary cancerous tendency the cancer occurred eailier than in those with-

TABLE 3

A COMPARISON O F T H E AGE, OF ONSET OF T H E TUMOR IN MOTHER AND DAUGHTER

~~

Age, yrs. ,- _ _ _ _ ~ _ _ _ _ _ _ -

Case Mother Daughter Difference - ~ _ _ _ ~ -

Jacobsm’s Serier 1 57 65 -8 2 72 45 27 3 40 40 0 4 63 58 5 5 61 38 23 6 38 47 -9 7 49 53 -4 8 45 55 -10 9 76 42 34

10 44 46 -2 11 70 51 19 12 52 35 17 13 65 40 25 14 79 72 7 15 51 46 5 16 49 44 5 17 55 66 -11 18 85 61 24 19 61 41 20 20 31 30 1 21 62 41 21

AVERAGE 57 48 9

M.B. 82 55 27 K.C. 62 58 4 F.H. 59 47 12 A T , . 42 40 2 M.L. 66 36 30 G.M. 68 42 26 A.O. 76 41 35 R.P. 43 36 7 C.R. 73 64 9

- - -

The Present Set ies

37 23 14 A.U. 66 66 0

AVERAGE 57.5 47 10.5 - - -

BREAST CANCER IN MOTHER AND DAUGHTER . Morse [747

out a caiicerous history. Smithcrs was unable t o confirin statistically Jacobsen’s finding that tho age 01’ onset ol the disease T.

t hosc with cancer in tlie laiiiily, although he gi \m in detail the pedigrcc of three cancer lamilies in which the age of onset is approxi- iii:itcly teii years younger in each succeeding geiieratioti. \\‘e analy~etl o w cases, therefore, to see i t the average age of the daughter was Ichs than that of the mother.

lktwecn 1916 and 1946, thirty-three breast- C;IIICC~ patients with maternal breast cancer

11 at the I’resbyterian Hospital. In only thirteen ol these was tlie age ol the mother at the onset of the disease obtainable from the records. Table 3 shows our thirteen patients and also Jacobsen’s inore complete scries.

Our average difference of ten and a half years is comparalde to Jacobscn’s difference of nine. Our series is lia1,le to Busk’s objection that older patients with breast carcinoma are less likely to remember their mothers’ disease ant1 age at diagnosis, and consequently the table tends to be filled by the younger women with breast cancer. This objection cannot be applied to Jacobsen’s material, since, in his series, the cause ol death, the date, and tlie age at death were checked in each instance against the death certificate of all 200 of the mothers, so that no selection of favorable cases was possible.

It might also be said that patients wliose mothers had had cancer would be more famil- iar with the symptoms of the disease and would, therefore, recognize the tumor at an (xi-licr age. This factor, however, would ac- count for only a small fraction of the tliffer- ence in years noted.

7’11iee of our series of thirty-three cases had bilateral heas t cancer at an early average age, as shown in Table 4.

The cai(iriomas on the first side were thus diagnosed at the aieiagc age o f 44 yeais, and on the second side, at 52. Engelbreth-Holm reported on cighty-seven cases of breast cancer associated with solme other malignant tumoi from the Radium Center in Copenhagen. The average age of these patients with multiple tumors was significantly less than that of the unselccted breast-cancer patient. Three fourths of the second carcinomas, or many more than

the expected a~i io i in~ , ivere in the other breast, utei‘lis, or ovary.

A similar increase iii uteiiiic and ovarian c;~iicer was lountl b y Wassink in the relatives ol’ bi-east-cancer patients. This fiiitling inay be important as evidence that part o f the inhcr- itcd tendency to cancer is caused by a n ovarian hormonal iiiibalance. In o ~ i r series Irom Pres- byterian Hospital, evidence of noncancerous ovarian disease was found in two of the breast- cancer cases that had a maternal history of breast cancer. ‘l’hc first, whose sister died of cancer of the breast at 29 years, hat1 operative

tic left o \wy and puncture o f lit o\ary a t 26 years of age.

Three years later, at 29 years, she developed bilateral intlepeiiden t carcinomas, both pri- marily intraductal in type. The second patient, whose mother had a carcinoma of tlie uterus as well as of tlie breast, had had an ovarian cyst removed sixteen years before. Her breast carcinoma was primarily intraductal, and sec- tion of the other breast showed no carcinoma but “intense glandular activity with niany small intraductal papillary growths.”

PATHOLOGICAL FINDINGS

T h e pathological reports in eight of our cases revealed that tlie carcinoma was of the ~ ~ ~ e l l - d i ~ e ~ - e n t i a t e ~ l intraductal type. T h e sig- nificance ot this high incidence of wcll-differ- entiated carcinoma is not clear.

BREAST FEEDING

No discussion of heredity and breast cancer can omit mention of tlie role of breast feeding, although satislactory evidence on this in tlie human is lacking. I n the present series of cases no data bearing on this point was lound in the records. Penrose et al. found that slightly more patients with familial breast cancer were breast fed than an unselected group: Of seventy-one breast-cancer cases with a familial

TABLE 4

BILATERAL CANCER ~~~~~~~~ ~ ~-

~

Age of onset, yrs. __ ~~ ~~ Survival

1st 2d from Patient 1st side side side 1st ca., yrs.

C.P. Right 38 47 12 (living) H.S. Concomitant 29 29 13 (living) F.Ta. Right 66 79 13 (died postop.,

~~~~~~ ~~~ ~ ~ ~

not of ca.)

7481 CANCER July 1951

breast-cancer history, 93 per cent were breast fed; o f 360 unselectetl breast-cancer cases, 87 per cent were breast led. It can be seen Irorn these da ta that the results are patently equiv- ocal.

SUMMARY

A special study of the hereditary aspect oi bieast cancer in mother and daughter has

1.

been made. I t has been shown that cancer oE the breast has a specific lieieditai y tcntlency.

Cancer of the breast is moie common in the daughters of women with breast cancer than in the general population by about three to one.

3. Cancer of the breast develops approxi- mately ten years eal lier in the daughter than in the mother.

2.

REFERENCES

1. ANTOINE, T. , and PFAR, n.: Einiges uber das Mammakarzinom. Dezilsche Ztschr. f. Chi?. 201: 99- 109, 1927.

2. BUSK, T.: Some observations on heredity in breast cancer and leukemia. Ann. Eugenics 14: 213-229, 1947- 49.

3. CLEkfiuEsEN, ,J.: The status of genetical studies in human cancer. Brit. 3. Cancer 3: 474-484, 1949.

beltsidig Brystkraeft og om Brystkraeftens Sammen- traef med andre Kraeftformer. Ugesk. f. laeger 104: 456-461, 1942.

5. JACOBSEN, 0.: Heredity in breast cancer: a genetic and clinical study of two hundred probands. (Transl. by Robert Frascr.) Opera ex Doino Riologiae Heredi- ta7-iae Hurnnnne UnCuersitatis Hnfniensis 11: 1-306, 1946; Also London. H . K. Lewis & Co., Ltd.

6. LEF~VRE, H.: Acceleration of the development of spontaneous tumours in mice. (Studies on the accelera- tion of the development of spontaneous tumours in mice following painting with the carcinogenic hydro-

4. ENCEIBRETH-HOLM, J.: Om Hyppigheden af dob-

carbons 9: 10-dimethyl- 1 :2 henzanthracene and meth- ylcholanthrene in benzene.) (Transl. by Anna la Cour.) [Thesis.] Copenhagen. Thaning & Appels Forlag. 1915.

7. PENROSE, L. S.; MACKENZIE, HI. J., and KARN, M. N.: A genetical study of human mammary cancer. A n n . Eugenics 14: 234-266, 1947-49.

8. SMITIIERS, D. W.: Family histories or 459 patients with cancer of the breast. Brit. 3. Cancer 2: 163-167, 1948.

9. WAALER, G . H. M.: Uber die Erblichkeit des Krebses. Beurteilt nach dem vom norwegischcn Krebs- komitee gesammelteii Material. Skriftcr utgitt av det Norske Videnskaps-Akademi i Oslo. I. Mat.-natnrv. KI., 1931, 2. Oslo. Jacob Dyhwad. 1931: Reviewed by GREENWOOD, M., Cancer Rev . 7: 464-470, 1932.

10. WAINWRIGHT, J. M.: A comparison of conditions associated with breast cancer in Great Britain and America. Am. 7. Cancer 15: 2610-2645, 1931.

11. WASSINK, W. F.: Cancer et hkrkditk. Genetica 17: 103-144, 1935.