The Natural History of Mammary Carcinoma

IAN MACDONALD, M.D.,* Los Angeles, California

From the Department of Surgery, University of Southern California School of Medicine, and the Tumor Surgery Service, Los Angeles County Hospital, Los Angeles, California.

C ONTRIBUTIONS by surgeons to the medical literature on carcinoma of the breast ex-

ceed by a considerable margin their writings on any other single organ-site of cancer. Such an interest is a reflection of a number of features which characterize mammary carcinoma. I t is the most common form of cancer in American and European women. I t has its origin in a superficially located organ which is readily ac- cessible to clinical examination, and this accessi- bility produced the concept of periodic self- examination some fifteen years ago. Its primary site and its regional, axillary metastatic deposits are ideally suited to the principles of en bloc resection, at least in theory, as exemplified in the Halsted-NIeyer operation employed during this century.

Actually, the use of this operative form of t reatment did not become widespread until the opportunity for graduate training in surgery produced a sufficient number of competent surgeons. The number of centers for sound graduate training increased slowly after the first quarter of this century. Since World War II, graduate training in all of the medical spe- cialties has had a phenomenal expansion in the United States, unparalleled in the annals of higher education. For more than a decade the availability of competent surgical t reatment of breast cancer has been so widespread that, with modern ease of transportation, women in the smallest hamlet may obtain a quality of sur- gical care formerly enjoyed only by those who could reach centers of medical education. This is not to say that surgical management of breast

cancer is assigned generally to surgeons; un- happily, the economic aspects of surgical ther- apy prevent some proportion of patients from securing the best available care. Nevertheless, the relative number of women with mammary carcinoma treated by competent surgeons has increased constantly and significantly in the past twenty years.

Coincident with the increased application of the classical surgical t reatment of carcinoma of the breast, modifications of the Halsted-lV[eyer operation have engaged the interest of many clinical investigators. Some have applied exten- sions of the conventional operation, mainly to neighboring anatomic areas of lymphnodal. drainage in substernal and supraelavicular sites. The notion that an induced change in the pa- tient's hormonal milieu might be of value has led some surgeons to use ovarian ablation ad- junctive to radical masteetomy. Other varia- tions have been in the direction of a contraction of the extirpative effort: simple mastectomy with or without some degree of axillary dissec- tion, the use of irradiation after a limited opera- tion, and even excision of the primary tumor without masteetomy. Still another modification is concerned with a limitation of radical mastee- tomy to the most favorable candidates by pre- operative biopsy of apical axillary, internal mammary, and supraelavicular nodes; with histologie demonstration of metastasis in any of these nodes, the patient is declared inoper- able and treated by irradiation.

All of these diverse modifications of conven- tional surgical therapy are reflections of justifi- able discontent with end results. A look at the trends of incidence and mortal i ty of mammary carcinoma leaves no reason for clinical com- placency. Shown in Figure 1 is the experience

* Clinical Professor of Surgery, University of Southern California School of Medicine; Senior Attending Surgeon, Los Angeles County Hospital.

Vol. 111, March 1966 435

436 M a c d o n a l d

7°i ~° £ 5o] ~-~---'j . . . . ! /

0~30 -x--- ...... ~"

z 194k 4'2 43 44 45 4t 47 & 49 50 51 5} 5'3 54 CALENDAR YEAR

F IG . 1. G r a p h i c r e p r e s e n t a t i o n o f i n c i d e n c e a n d m o r -

t a l i t y o f c a n c e r o f t h e b r e a s t i n w o m e n i n t h e s t a t e o f

Connecticut (adjustment has been made for age). (Data taken from Griswold [1]. Reproduced from: Management of the Patient with Cancer. Edited by Thomas F. Nealon, Jr. Philadelphia, 1965. W. B. Saunders Co.)

CONNECTICUT CALl FORNIA

7( PERIOD 2 6( PERIOD I PERIOD 2 PERIOD I

5c 2c

3 Io ~ o

TOTAL CASES 5658 5052 5176 8987

m 5 YEAR RELATIVE SURVIVAL RATES FOR FEMALE PATIENTS BREAST CANCER : CONNECTICUT : PERIOD I ... 1941-1951 CALIFORNIA: PERIOD I..t942-I949

PERIOD 2 1950-1956 PERIOD 2_ 1950-1957

FIG. 2. Five year relative survival rates for two com- parable periods in two states, Connecticut and Cali- fornia, in female patients with carcinoma of the breast. (Reproduced from: Management of the Patient with Cancer. Edited by Thomas F. Nealon, Jr. Philadelphia, 1965. W. B. Saunders Co.)

of one state, Connecticut, with total data on the incidence of breast cancer as well as on mortal- i ty for over two decades [1 ]. Despite a highly organized program of cancer control and all which this term implies, there is no suggestion of any improvement. In terms of survival after diagnosis, Figure 2 provides information for two separate periods for two states, Connecticut and California, on significantly large samples of patients [2]. Again, in the more recent inter- vals, no evidence of any improvement is appar- ent in comparison with earlier end results.

These fixed rates of incidence, mortali ty, and survival after diagnosis permit but one conclu- sion: m a m m a r y carcinoma presents a biologic complex which has been entirely resistant to all of the massive effort which has been directed against it. Neither early diagnosis, small size of the pr imary lesion, long, meticulous, or ex- tended operations, nor adjunctive use of radia- tion therapy have been of any value in this form of cancer.

To many assiduous students of the surgical literature, such a conclusion may seem unwar- ranted. Unhappily, a major i ty of the articles on breast cancer by surgeons are of limited value for two reasons: (1) The sample of experience is too small to permit conclusions of significance. (2) The sample is selected rather than represen- ta t ive of the total experience.

The biologic variabil i ty of m a m m a r y car- cinoma is such tha t valid reporting on its pri- mary t rea tment demands large samples.

The factor of selection is automatic if a surgeon is reporting only operable cases. Ob-

viously, patients with more ominous examples of the disease have excluded themselves by the development of signs of inoperability, even with the most liberal interpretation of "operabil i ty." Furthermore, surgeons differ in their criteria of operability. As indicated earlier, a surgeon who practices preoperative "triple biopsy" has a highly selected, favorable sample of operable candidates.

Whether the criteria of operability are strin- gent or liberal, samples of experience which include only those women treated by definitive surgery are necessarily unrepresentat ive of breast cancer in general. Only the total experi- ence of the individual surgeon or institution is representative, and even this is variable. I t is necessary only to compare the end results from institutions with patient-populations of dis- parate economic circumstances for demonstra- tion of differences in total experience. Two examples of extremes can be cited: the Los Angeles County Hospital and the Mayo Clinic. The former is the largest teaching hospital in the United States, and its patients are almost exclusively indigent, either in a socioeconomic or medical sense. Furthermore, its female pa- tients are nearly two decades older on the aver- age than those in the private, voluntary hospi- tals of the Los Angeles area. Hence, the Los Angeles County Hospital sample of m a m m a r y carcinoma is atypical; the patients are largely in their postmenopausal years and the disease is anatomically much more advanced than tha t in pr ivate patients. The patients at the Mayo Clinic are in sharp contrast to the sample of

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patients in a charity hospital [3 ]. Patients must travel to the Institution, of ten from some con- siderable distance; their economic circum- stances are distinctly superior; women with advanced disease are much less apt to seek a distant place for treatment, with or without the necessary economic resources. Thus, it is no surprise to find that, with roughly comparable criteria of operability, 97.8 per cent (9,437 of 9,649) of women were classed as operable at the Mayo Clinic, less than half as many at the Los Angeles County Hospital. In a recent period at the latter institution, only 52 of 130 patients with primary (previously untreated) cancer were deemed operable. Moreover, the number of women with recurrent disease after t reatment elsewhere almost equals the number of primary cases.

The most consistent defect in U. S. literature on breast cancer is the lack of statistical con- firmation of clinical judgment. Whether the samples of clinical experience to be compared are large or small, apparent differences should be subjected to testing for : (1) validity: the two samples should have comparable prediction of outcome, before the "experimental" influence is applied; (2) the influence of sample heterogeneity as occurs in a T test.

When the problem concerns primary defini- tive t reatment of breast cancer, the one hope of acquiring comparable populations is large sam- ple size. The larger the samples, the more likely it becomes that unusual variants of the neo- plasm will occur with representative frequency.

There seems to be considerable distrust of statistical methods among U. S. clinicians and clinical investigators; yet the comparison of sets of data is meaningless unless statistical valida- tion of methods and endorsement of conclusions are provided. At the same time, the most sophisticated technics, unless tempered by sound clinical knowledge of biologic variables, may lead to egregious errors. Evaluation of statistical testing in the framework of biologic problems constitutes the area of biometrics, which is in par t art, in part science.

Statistical testing is essentially numerical estimation of probabilities which permits an expression of the degree of confidence which one may have in concluding that observed differ- ences or similarities are meaningful. When numerical or percentile differences between two sets of data are observed, the application of sta- tistical testing will reflect one of two situations :

(1) The disparity is as likely to have bee~ the result of chance as of therapeutic design and is thus of no significance. (2) The observed differ- ence is more likely a reflection of difference in therapeutics, and probably is of significance. Also, by statistical methods, degrees of probable confidence can be measured.

In biologic problems, variable factors of con- siderable complexity often are present, the necessary consideration of which distinguishes biometry from statistology. Mammary carci- noma is an outstanding example of an anatomic site in human beings of cancer with a highly variable natural history; its extremes in growth rates and metastatic patterns, for example, are so disparate as to suggest tha t it may represent a number of pathologic entities masquerading under terminologic singleness. In primary un- treated patients, we lack the necessary criteria of biologic behavior which would permit some rough segregation into groups of comparable natural history. Thus, the one hope of acquiring comparable populations is large sample size.

In carcinoma of the breast which is recurrent or metastatic after definitive treatment, indica- tions of natural history are available by which relatively small groups of patients may be com- pared to determine their degree of biologic homogeneity. The most important of such cri- teria seems to be the average "free interval," tha t is, the interval between definitive treat- ment and the diagnosis of metastatic disease as derived from mean age at diagnosis of metas- tasis. The average interval between confirma- tion of metastasis and institution of palliative t reatment may be a reflection of host-tumor relationship. Other indications of biologic po- tential include the extent of axillary disease in the operative specimen, by histologic examina- tion; the microscopic grading of the neoplasm; local signs of preoperative invasiveness; the interval between first recognition of the primary tumor and definitive treatment.

These are the principal measures for estima- tion of biologic balance between host and neo- plasm in patients requiring palliative treat- ment. Their application permits the comparison of small groups of patients in the evaluation of palliative treatments, but only if a preliminary analysis demonstrates a reasonable degree of biologic homogeneity.

An example will serve to emphasize the im- portance of sample size in any comparison of primary surgical t reatment of mammary car-

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438 M a c d o n a l d

T A B L E I

YEARLY DECREMENT OF SURVIVORS AFTER SIMPLR AND

RADICAL MASTECTOMY

Years of M a s t e c t o m y - - ~ X2 Survival Simple Radical

1 64/79 58/62 4.68 2 57/69 49/62 0.27 3 53/69 42/62 1.35 4 46/69 38/62 0.41 5 44/69 36/62 0.45 6 42/69 35/62 0.23 7 38/69 30/62 0.58

cinoma. A recent publication [4] purports to show tha t simple mas tee tomy is more effective than radical mas tec tomy in the management of the neoplasm. The two groups of patients under comparison are seventy-nine women treated by simple mas tec tomy and sixty-two treated by the conventional procedure. The patients indi- cated as having "simple" mastectomies in- eluded some patients in whom only the pr imary tumor was excised. On the basis of a seven year follow-up study, a case was made for the superi- ority of the less extensive procedures, with support provided by the following percentile values: for "simple" mastectomy, thirty-eight or 55.1 per cent of sixty-nine patients survived seven years; for radical mastectomy, th i r ty or 48.8 per cent of sixty-two patients survived seven years.

With some knowledge of the natural history of m a m m a r y carcinoma, one would guess tha t the difference between the two series of cases is not significant. However, the only way to verify this is by the application of statistical methods. Furthermore, such data are more meaningful when applied in a sequence of yearly survival. The yearly decrement of survivors after simple mas tec tomy or less and after radical mastec- tomy, with the significance of the differences in terms of chi square, is presented in Table I.

The only one of these chi square values which might be of significance is tha t a t the end of the first year, for which P (or probabil i ty value) is <0.05. This means tha t the probabil i ty of the bet ter incidence of survival after one year being due to the different method of t reatment , tha t is, simple mastectomy, is less than one in twenty. I t is usual in biometrics, unless there are other nonstatistical considerations of impor- tance, to require tha t the probabil i ty of a difference not being due to chance be less than

one in twenty or P = <0.05. By a scanning of the other X 2 values for the second to the sev- enth years, it becomes apparent tha t all of the other differences are no more or less than could be expected by chance alone.

This exercise in analysis of one series of cases points up the tendency which m a n y clinicians and especially surgeons have of comparing sam- ples which are too small to have any possible significance, and of expressing the difference in terms of percentile value, often carried out to the second decimal place.

The obvious conclusions must be tha t the evaluation of clinical end results in terms of percentile values m a y be fallacy of the worst order, and tha t proper evaluation requires the cooperative effort of the clinician and of one who is trained in the statistical method, with both of the collaborators aware of the pitfalls which exist in the unsophisticated application of statistical methods in problems which are subject to biologic variants.

In an evaluation of m a m m a r y carcinoma, the following requirements should be manda tory : (1) Sample size should be adequate. In any analysis of pr imary t reatment , the number of patients should approach three hundred. For evaluation of therapy of recurrent or dissemi- nated breast cancer, smaller samples are proper if: (2) Biologic homogeneity is established. In disseminated disease, this m a y be accomplished with samples as small as a hundred patients. (3) The apparent differences in end results are subjected to statistical analysis, with the re- quirement tha t there is a reasonable certainty tha t differences in end results are not due to chance variations.

R A T E O F G R O W T H O F B R I ~ A S T C A N C E R

By application of mathemat ica l methods, new information has been accumulated in recent years on the rate of growth of human neo- plasms. I t has become possible to estimate, with some approach to accuracy, the relative duration of the preclinical and clinical phases of various forms of cancer. The expressions "preclinical" and "clinical" imply the phases of growth of a neoplasm before it is diagnosable by available methods, and the t ime at which a tumor becomes diagnosable. Radiologists have made notable contributions to these inquiries through their serial observations of the growth rates of various neoplasms. The first form of cancer in human subjects which was so studied

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was lung cancer, by such observers as Garland [5], Collins [6], and their co-workers. From such studies came the conclusions tha t squamous carcinoma of the lung had a mean prediagnostic duration of ten years or more, while pulmonary adenocarcinomas average over eighteen years in duration before becoming diagnosable. Spra t t reports tha t the t ime required for colonic car- cinoma to reach a diameter of 1.5 era. varies from four and a quarter to ten and two thirds years. In experimental neoplasms, M o t t r a m observed epitheliomas of murine skin which actually arose from a single cell; rapidly grow- ing versions of this lesion doubled in area in one week, w i t h a previsible phase of eighteen weeks and a visible period of six weeks [7].

Such calculations for m a m m a r y carcinoma were difficult, if not impossible, until the tech- nic of m a m m o g r a p h y became improved. In 1963 Gershon-Cohen, Berger, and Kilekstein [8] reported on serial observations of eighteen m a m m a r y lesions b y mammograms over periods of eighteen to fifty-four months. Estimations of the rate of growth obviously mus t begin with the t ime at which the neoplasm is large enough to produce a recognizable abnormal i ty on the x-ray film. I t has been proved repeatedly in recent years tha t m a m m o g r a p h y m a y be so accurate as to provide objective evidence of the presence of carcinoma of the breast before it is detectable by clinical examination. The mini- mal diameter which permits pa lpa tory recogni- tion of a three-dimensional lump in the breast is about 1 cm. I have excised areas of breast tissue in several pat ients to include a site in which the m a m m o g r a m has indicated the pres- ence of carcinoma, with a p r imary neoplasm which has been as small as 4 mm. in average diameter.

The estimation of growth rate is based on a determination of the "doubling t ime" of a neo- plasm, tha t is, the t ime required for a tumor to double its diameter which means an eightfold volumetric increase, during its clinical or ob- servable phase. When these measurements are plotted on semilogarithmic charts against time, retrospective extensions will permit an estima- tion of the t ime at which the neoplasm was composed of a single cell or in the order of ten to twenty-five for most lesions in human sub- jects. From this beginning, i t became possible to calculate the number of doublings required until a given tumor became large enough to permit clinical recognition either by palpation

or on roentgenograms. Thus, the natural history of a given cancerous lesion becomes divisible into two phases: an invisible or preclinical period of growth and a visible or clinical phase.

Estimations of the preclinieal phase are, admittedly, approximations, and for two rea- sons: (1) the assumption is made by each in- vestigator using this method tha t mal ignant neoplasia in human subjects arises from a single precursor cell. This is inconsistent with current belief that, at least in carcinoma of the breast, there usually is an origin in multiple loci. (2) The method assumes tha t the mass which marks the site of cancer is composed entirely of neoplastic cells. As much as half of a " t umor" may be composed of hyperplastic stromal reac- tion, blood vessels, and other non-neoplastic elements. The factor of origin from a single cell versus multiple foci would seem to contribute only a minor inaccuracy; assuming a cancer cell is 10/~ in size, by the t ime a lesion is 1 mm. in diameter, there would be two and a half million cancer cells, the result of some twenty doublings in size. The contribution to tumor mass by non- neoplastic components introduces a more sig- nificant error. Most carcinomas of the breast are of the sclerosing variety, with desmoplastie reaction forming as much as 50 per cent of the volumetric total. Nevertheless, even if the cal- culations of total life-duration of such a neo- plasm are as much as 50 per cent in error, the method still provides a new approach to a bet ter estimation of the neoplastic life cycle than has formerly been available.

The da ta published by Gershon-Cohen, added to the serial observations of three addi- tional patients, indicated great variabil i ty in the doubling t ime of individual m a m m a r y carcinomas; the extremes are 23 and 209 days. There seems to be little correlation of histo- pathology with doubling times. As in the report of Gershon-Cohen there was a striking differ- ence in doubling t ime for women with and with- out axillary nodal metastasis as determined after radical mastectomy. In those whose dis- ease was limited to the breast, the average doubling t ime was 128 days; in pat ients in whom there was histologic evidence of metas- tasis to axillary nodes, doubling t ime averaged 85 days. I t should be noted tha t these estima- tions m a y not be accurate because of the small samples involved (ten and eight patients with stage I and stage II disease).

As shown in Figure 3 these differences in

Vol. 111, March 1966

440 M a c d o n a l d

× A' /

7 /

.* ~F "~ " ~ ,

I ° ~ ~ ' ' ~ .2ram I I I I 0cml [ I ~ " I I I

YEARS I 2 5 4 5 6 7 8 9 I0 II

I~. PHASE • • CLINICAL PHASE--~ PRECLI NICAL 8 YEARS 4 YEARS

F I o . 3. S c h e m a t i c r e p r e s e n t a t i o n o f l i f e c y c l e o f a c a r -

c i n o m a of the breast with a doubling time of 100 days. I ° to v represents preelinical phase, assuming a mean diameter of I cm. as the minimum for palpatory recogni- tion. A to A' represents curve of growth in clinical phase, of which I ° to v is the logarithm. (Reproduced from: Management of the Patient with Cancer. Edited by Thomas F. Nealon, Jr. Philadelphia, 1965. W. B. Saunders Co. )

doubling time, when used for calculation of the total life cycle of mammary cancer, produce astonishing answers. Assuming the size of a mammary cancer cell as 10/~, thir ty doublings are required to produce a tumor of 1 cm. in diameter. In the patient with the shortest ob- served period of doubling, or twenty-three days, a period of two years will elapse before the mass becomes 1 cm. in diameter. In a woman with breasts of average size, an experienced clinician will not often detect a breast cancer until it has reached a minimal size of 1 cm. in transverse measurement; in women with bulky breasts and a deeply located tumor, a neoplasm consider- ably larger than this may escape detection.

Having reached a size of 1 cm. in average diameter, relatively fewer doublings are re- quired for more impressive increase in size; only three more doublings are necessary for the in- crease from 1 to 2 cm. in average diameter. As indicated in Figure 3 the clinical or visible phase of a breast lesion is far shorter than its invisible or preclinical stage by a ratio of 1 : 2. A median value for the doubling interval seems to be in the area of a hundred days or roughly three months. The preelinical phase of such a lesion will occupy ninety months or nearly eight years, at which time its thirty doublings have brought it to the 1 em. size. The median survival of un- treated mammary cancer, after self-recognition or diagnosis, is twenty-seven to thirty months, which is the visible or clinical phase. This pro- duces a total duration of the neoplasm and of

the host of 120 months, or ten years after in- ception. Of this total life cycle, the preclinical phase occupies three fourths, the clinical por- tion one fourth.

These studies of calculated growth rates of cancer in human subjects and animals have provided new confirmation of the concept of biologic predeterminism [9]. With approxi- mately three fourths of the life cycle of a mammary carcinoma of median growth rate having gone by before clinical diag-nosis is pos- sible, it becomes obvious that the biologic balance between neoplasm and host has become established long before the clinician can exert any influence on the process. The so-called problem of "early diagnosis" becomes an ab- surdity in the face of this facet of the natural history of the disease. What difference can it make in the host-tumor relationship if the clin- ical diagnosis is made at the ninetieth month of the life of the neoplasm or at the ninety-sixth month? In those patients whose mammary lesions are more rapidly growing, with a shorter total life cycle, the same relative chronologic disproportion exists; however, during the shorter preelinical phase a more ominous growth pattern tends to produce more probability if not the certainty of regional and distant metas- tasis before clinical diagnosis becomes possible. By contrast, the slowly growing sluggards of mammary neoplasia are those in which the host has the upper biologic hand; the preclinical and clinical phases both are longer, diagnosis may be made late, treatment applied even later, with a favorable prognosis because of a predeter- mined biologic situation [10].

This relation of growth pattern to prognosis represents a process of biologically predeter- mined selection into curable and incurable cases. I t has been recognized since the earliest applica- tion of classical radical mastectomy that the most important determinant of prognosis is the presence or absence of axillary nodal metastasis. In general, the slower growing neoplasms which have not developed enough biologic potential to disseminate, even to regional nodes, are of smaller primary size than more actively grow- ing mammary lesions. Hence, there is an asso- ciation of smaller size of the primary lesion with more favorable prognosis which serves to main- tain the myth of "early diagnosis" and its supposed importance. To this general trend there are notable exceptions, as every clinician of experience knows. Some very bulky primary

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M a m m a r y C a r c i n o m a 441

tumors, such as lobular carcinoma and the so- called medullary neoplasms, are notable for their infrequent spread to regional nodes. Some very small breast lesions, occasionally so small as to be occult, set up distant metastases which dominate the clinical scene from its beginning.

These data indicate tha t when criteria of operabili ty are applied intelligently, the divi- sion of pat ients into operable and inoperable groups is actually a recognition of the influence of biologic predeterminism. The clinical setting in each pat ient is the result of a biologic balance, good or bad, which has become established during the major, preclinical interval in the life cycle of each carcinoma of the breast. This assumes tha t criteria of operabili ty are not limited to estimations of anatomic extent alone but include recognition of evidence of an un- favorable biologic pattern, such as a history of rapid growth, the presence of lymphedema, or e ry thema of the m a m m a r y skin.

When a surgeon becomes obsessed with a limitation of definitive operative management to the most favorable patients, he can produce a "superselect" group of operative candidates as by use of the triple biopsy procedure. The net result should be an impressive improvement in survival among the patients who are eligible for operation by such exacting standards, but there is no reason to believe tha t the total experience will show any improvement . There are indications tha t radical mas tec tomy has distinct palliative value for m a n y patients in the prevention of locally and regionally recur- rent carcinoma.

An unjustifiable degree of emphasis on "early diagnosis" not only has failed to improve end results in more than twenty years but also has done a twofold disservice to m a n y women. The clinical anxiety induced by the "ear ly" syn- drome has resulted in an increasing number of unnecessary surgical explorations of the breasts. Most of these are carried out for some phase of m a m m a r y dysplasia or so-called "cyst ic" dis- ease. Involut ionary changes in dysplasia do produce three-dimensional tumors in a minor fraction of women with this hormonally induced disorder, most commonly in the form of gross cysts or areas of sclerosing reaction. The scleros- ing process m a y simulate carcinoma and require excision for accurate differentiation. However, m a n y exploratory incisions are made because of the inability of the clinician to differentiate by palpation between the indurative changes of

dysplasia in the mens t ruant and a genuine space-occupying tumor or lump.

A second and contrary byproduct of the "earliness" complex is a tendency to regard large pr imary carcinomas of the breast as in- operable on the factor of size alone. In one series of cases of numerical significance, those pr imary lesions more than 5 era. in average diameter and otherwise eligible for radical mas tec tomy were found to be without axillary nodal metastasis in one of every five instances. Assuming tha t six of every ten patients with such stage I lesions survive ten or more years without recurrence, the surgical neglect of such women is a severe impairment to maximal con- trol of the disease.

S U M M A R Y

The massive educational, diagnostic, and therapeutic a t tack on m a m m a r y carcinoma of the past two decades has failed to alter rates of incidence and morta l i ty of this most frequent malignant neoplasm in female patients.

Reports on the therapy of m a m m a r y cancer in the surgical l i terature often lack significance through selected samples of small size and the lack of statistical validation.

The most impor tant single factor in the prognosis of carcinoma of the breast is the biologic balance between the host and the neo- plasm. Recent methods of estimation of the total life cycle of m a m m a r y carcinoma indicate that three fourths of its duration occupy the preclinical, prediagnosable phase. In a breast lesion of median growth rate, the preclinical interval has a duration of some eight years while the clinical phase occupies about two years in the untreated patient.

These data endorse the concept of biologic predeterminism and lend little if any support to the case for "ear ly" diagnosis. Nevertheless, an intelligent application of the criteria of opera- bility is of essential importance. For eligible patients, classical radical mas tec tomy continues to demonstrate its usefulness both in cure of the curable and more effective palliation of the in- curable.

Acknowledgment: I acknowledge with grati- tude the consultative assistance in biometrics of Stanley C. Harris, PH.D., Northwestern Univer- sity. Da ta which contributed to this discussion include several sources: St. Vincent 's Hospital, Los Angeles; Subcommittee on Breast and

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442 Macdonald

Genital Cancer, Committee on Research, Amer- ican Medical Association; Joint Committee on Ablative Procedures in Disseminated Mam- mary Carcinoma (American College of Surgeons and American College of Physicians).

R E F E R E N C E S

1. GRISWOLD, M. H., WILDER, C. S., CUTLER, S. J., and POLLACK, E. S. Cancer in Connecticut, 1935- 1951, p. 144. Connecticut State Depar tment of Health, 1955.

o. AXTELL, L. M., BRESLOW, L., and EISENBBRO, H. Trends in survival ra tes of cancer patients: Con- necticut and California. Nat. Cancer D~st. Mono., 6: 49, 1961.

3. BERKSO~, J. and GAGE, R. P. Calculation of sur- vival rates for cancer. Proc. Staff Meet. Mayo Clin., 25: 270, 1950.

4. CRILE, G., JR. Rationale of simple mastectomy

without radiation for clinical stage 1 cancer of the breast. Surg. Gynec. & Obst., 120: 975, 1965.

5. GARLAND, L. H., COWLSON, W., and WOLLIN, E. The rate of growth and apparent durat ion of un- t reated pr imary bronchial carcinoma. Cancer, 16: 694, 1963.

6. COLLINS, V. P., LOEFPLER, R. K., and TIvEY, H. Observations on growth rates of human tumors. Am. J. Roentgenol., 76: 988, 1956.

7. MOTTRAM, J. C. On origin of tar tumors in mice, whether from single cells or many cells. J. Path. & Bact., 28: 128, 1955.

8. GERSHON-COHBN, J., BERGER, S. M., and KILCK- STEIN, H. S. Roentgenography of breast cancer moderating concept of biologic predeterminism. Cancer, 16: 961, 1963.

9. MACDONALD, I. Biologic predeterminism iu human cancer. Surg. Gynec. & Obst., 92: 443, 1951.

10. MACDONALD, I. Indications of the fundamental biology of mammary carcinoma. Proc. Third Nat. Cancer Confer., p. 87. Philadelphia, 1957. J. B. Lippineott Co.

American Journal of Surgery