Genetics, biomarkers, and control of breast cancer: A review

REVIEW ARTICLE Genetics, Biomarkers, and Control of Breast Cancer: A Review Henry T. Lynch, William A. Albano*, John J. Heieck, Gabriel M. Mulcahy, Jane F. Lynch, Michael A. Layton, and B. Shannon Danes

ABSTRACT: More has been written about the epidemiology of breast cancer than possibly any other form of cancer affecting mankind. However, in the face of this intense interest, only a paucity of attention has been given to the role of genetics in its etiology. This review represents an attempt by the investigators to provide a comprehensive coverage of hereditary breast cancer. Included are pertinent endogeneous and exogeneous risk factors, which in certain circumstances, may significantly influence the role of primary genetic factors. Hereditary breast cancer is heterogeneous. When discussing the subject, therefore, one must be precise relevant to the particular heterogeneous form of concern, based on differing tumor associations. It is probably not appropriate to discuss "hereditary breast cancer" without qualification of the specific hereditary breast cancer syndrome of concern; i.e., the SBLA syndrome, breast~ovarian cancer syndrome, and others. This reasoning also applies to attempts at linking biomarkers to hereditary breast cancer. Finally, in addition to ongoing discussions on the cardinal principles that associate with hereditary forms of breast cancer, its frequency, and new developments in biomarkers, we have provided surveillance~management programs that embrace those facets of the natural history of this disease.

INTRODUCTION T h e f a m i l i a l aggregation of breast c a n c e r was first r e c o r d e d in the R o m a n m e d i c a l literature a r o u n d 100 A.~. In spite of this l o n g h i s t o r i c a l e x p e r i e n c e , w e r e m a i n a b y s m a l l y i g n o r a n t a b o u t its e t i o l o g y and p a t h o g e n e s i s . M o r e s u r p r i s i n g is the relative i n a t t e n t i o n g i v e n to breast c a n c e r genetics at the basic scientific and c l i n i c a l levels. T h i s is u n f o r t u n a t e in that of t h e m y r i a d risk factors alleged to p r e d i s p o s e to breast cancer, the o n e w i t h the h i g h e s t degree of p r e d i c t a b i l i t y is a p o s i t i v e f a m i l y history. Our p u r p o s e is to p r o v i d e : (a) an a p p r a i s a l of c a r d i n a l features of h e r e d i t a r y breast cancer; (b) s c o p e a n d p e r s p e c t i v e for c o m p r e h e n s i o n of h e r e d i t a r y breast canFrom the Department of Preventive Medicine/Public Health (H.T.L., J.F.L., M.A.L.), Department of Surgery (W.A.A., J.J.H.), Hereditary Cancer Institute, Creighton University School of Medicine, Omaha, NE, the Department of Clinical Pathology (G.M.M.), University of Medicine and Dentistry of New Jersey, New Jersey College of Medicine, Newark, NJ, and the Department of Medicine (B.S.D.), Laboratory for Cell Biology, Cornell University Medical College, New York, NY.

Address requests for reprints to Dr. Henry T. Lynch, Professor and Chairman, Department of Preventive Medicine~Public Health, Creighton University School of Medicine, Omaha, NE 68178. Received August 18, 1983; accepted October 17, 1983. ~'Deceased July 7, 1983.

43 © 1984 by Elsevier Science Publishing Co., Inc. 52 Vanderbilt Ave., New York, NY 10017

Cancer Genetics and Cytogenetics 13, 43-92 (1984) 0165-4608/84/$03.00

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H . T . Lynch et al.

cer in context with the several other putative risk factors; (c) new findings on the frequency of the hereditary variant among the overall breast cancer burden; (d) onb going efforts at biomarker determination among the hereditary subset; and finally, (e) innovative measures toward the control of hereditary breast cancer.

Genetics and Breast Cancer: General Comments The primary concern of this review is to discriminate between sporadic and hereditary breast cancer as two different diseases with distinctive etiologies, pathogenesis, and natural history. Central to this issue will be an assessment of the status of variable risk factors (genetic and environmental) in hereditary breast cancer. Particular attention will be given to whether or not they might modulate the breast cancer-prone genotype and, thereby, have an influence on phenotype. Oliver [2] recognized the pertinence of this issue. He concluded that: • . . on a simple genetic basis . . . the high frequency of solitary cases may be due to the existence of two groups of causes for breast cancer, some being hereditary and others environmental• We should also consider the possible interrelationship between genes and an unknown environmental agent in which the gene may be present but unexpressed unless the proper environment coexists• Such temperamental genes are known in experimental animals and instances can be cited in man. There is a severe paucity of data dealing with these issues at the h u m a n level. This is unfortunate, since breast cancer-prone families could provide powerful models for retrospective-prospective studies directed toward the resolution of the m a n y perplexing concerns about g e n e t i c - e n v i r o n m e n t a l interactive p h e n o m e n a . [3, 4].

Frequency of Hereditary Breast Cancer in an Oncology Clinic In an effort to c o m p r e h e n d the frequency of hereditary forms of breast cancer in our oncology clinic, we evaluated family histories on 225 consecutively ascertained patients with breast cancer. Primary medical and pathologic documents were secured whenever possible so that cancer (all anatomic sites) could be verified. Pedigrees were constructed and reviewed with the patients. This enabled them to recall specific genealogic relationships with greater accuracy and detail; in some cases, this helped to clarify cancer occurrences w i t h i n their families. We operationally define "familial" breast cancer as the occurrence of two or more breast cancer-affected relatives w i t h i n the modified nuclear pedigree (inclusive of the proband). W i t h i n the familial aggregations lies the subset of putative hereditary breast cancer. It is difficult to operationally define hereditary breast cancer in the absence of specific physical signs and/or biomarkers that correlate significantly with genotype. Unfortunately, at the present time, genotype can only be inferred by the expression of phenotype (cancer). However, the occurrence of an alleged syndrome cancer w i t h i n a familial cancer clustering may be sporadic and of u n k n o w n etiology. It is important that this serious limitation be acknowledged w h e n assessing the concept of hereditary etiology of breast cancer. The pedigree must be extended and d o c u m e n t e d to confirm a putative hereditary cancer syndrome. The hereditary form includes those familial patients whose pedigree and clinical status demonstrate certain of the m e n t i o n e d cardinal features. Figure 1 shows a schematic breakdown of the 225 patients with respect to the percent of those showing familial or sporadic breast cancer. One h u n d r e d fifty-five

45

Breast Cancer-Review

BREAST CANCER PATIENTS (225) 100%

SPORADIC 82%

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2410 and 8790 PATIENT,FAMILIES IN 1982 with confidence coefficient 0 9 5

Figure I A schematic breakdown of 225 consecutively ascertained patients with breast cancer with respect to the percentage of those showing familial, hereditary, or sporadic breast cancer. patients were 50-years-old or older and 70 patients were under the age of 50. Genetic evaluation enabled assignment to three subsets: (a) familial aggregation, but lacking fulfillment of our hereditary criteria (13%); (b) hereditary breast cancer (5%); and (c) sporadic breast cancer (82%). In patients less than age 50, 11.4% fulfilled our criteria as consistent with hereditary breast cancer. Figure 2 shows those pedigrees that were considered to best fit the category of hereditary breast cancer. It is important to note that these are not extended pedigrees, but this work is in progress, although it may take a year or more for completion. These pedigrees exhibit multiple breast cancer occurrences with disease transmission through paternal (SJ347) or maternal (SJ389) lineages. In some instances, cancer occurred in both maternal and paternal lineages. Note markedly early age at onset (SJ389, SJ234) and/or bilaterality in various pedigrees (SJ347, SJ389, SJ255). Differing tumor combinations, particularly breast and gastrointestinal cancer (SJ301, SJ267) were also observed. The limited numbers of our sample and, therefore, the relatively small yield of informative pedigrees necessarily restricted the full phenotypic expression of tumor heterogeneity that we and others have encountered in larger series of breast cancer-prone families, In summary, in our study of 225 consecutively ascertained patients with breast cancer, it was found that 18% demonstrated familial aggregations. Our operational criteria of hereditary breast cancer was demonstrated in 5% of the total population. However, in probands less than age 50, 11.4% fit the hereditary criteria. We suspect that these observations are conservative, since family history may not have been completely ascertained in all patients. This would be a particular concern in older

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47

i n d i v i d u a l s and/or patients w h o s e relatives lived in remote areas where records may not have been available. In still other circumstances, at risk progeny of young or m i d d l e - a g e d affected p r o b a n d s may yet express the cancer phenotype. Finally, as already e m p h a s i z e d , these pedigrees have not yet been fully e x t e n d e d to allow for s y n d r o m e identification. The public health i m p a c t of familial breast cancer is e v i d e n c e d in that approximately 7 of every 1000 m e n and w o m e n from the general p o p u l a t i o n will have two or more first degree relatives with breast cancer. The A m e r i c a n Cancer Society pre dicted that 114,000 n e w cases of breast cancer were to occur in 1983. F r o m a s a m p l e of 225 breast cancer patients, 5% of patients showed findings consistent with a hereditary etiology, based on a modified nuclear pedigree. The standard deviation of this finding was estimated to be _+ 2.8%. Based on our data analysis, one can anticipate that the n u m b e r of patients with hereditary breast cancer s y n d r o m e s is s o m e w h e r e b e t w e e n 2410 and 8790 with a confidence coefficient of 0.95. It is important to note that each of these cases signifies a family w h e r e i n the risk of breast cancer is 50% for females in the direct lineage. This is extraordinary w h e n compared w i t h the general p o p u l a t i o n lifetime risk of 7%-9%. It is obvious that the public health i m p a c t of this p r o b l e m is enormous. We m u s t be highly precise in our description of hereditary breast cancer; therefore, it is a prerequisite that specific hereditary breast cancer s y n d r o m e identification be established through ascertainment of cancer of all anatomic sites in extended pedigrees. Animal Studies Extensive investigations in mice have clearly shown that cancer behaves as a t h r e s h o l d character that is influenced by a wide variety of genetic and extragenetic factors, and/or their interaction. Investigations of high and low breast cancer tumor strains in mice have h e r a l d e d major contributions to cancer genetic research, particularly as related to the identification of the mouse m a m m a r y t u m o r virus (MTV). In reviewing this subject, Heston [5] traced the original observation of MTV at the Jackson Laboratory in 1933 and that of Kortweg, in 1934, at the Netherlands Cancer Institute, utilizing strains from the Jackson Laboratory. W h e n these scientists crossed high and low m a m m a r y cancer-prone strains, and w h e n reciprocal crosses were made, they observed the F1 females to show a t e n d e n c y to develop m a m m a r y cancers w h e n their mothers were of the high tumor strain, but not w h e n their fathers were of the high tumor strain. Logically, it followed that some type of causative factor was t r a n s m i t t e d from the mother. Because the reciprocal F~ females were genetically identical, it seemed likely that it had to be an extra chromosomal factor. Subsequently, Bittner [6], e m p l o y i n g foster-nursing experiments, s h o w e d that this extra c h r o m o s o m e factor was transmitted through the milk, leading him to refer to it as the " m i l k agent." W h e n it was found to be filterable, it was identified as a m a m m a r y t u m o r virus. The mature virion is n o w referred to as the B particle. Heston et al. [5, 7], using h y b r i d i z a t i o n studies, showed that segregating genes controlled the r e p l i c a t i o n of the virus. In 1965, M u h l b o c k [8] d e v e l o p e d a very high tumor mouse strain referred to as "GR," w h e r e i n the B particle was s h o w n to be transmitted through the s p e r m and egg, as well as through the milk. Later investigations by Bentvelzen [9] suggested that the high m a m m a r y tumor susceptibility of GR was due to a single M e n d e l i a n factor. He also d e m o n s t r a t e d that male transmission of MTV was due to a single M e n d e l i a n factor. These observations led Bentvelzen to formulate his provirus theory for the transmission of the GR m a m m a r y tumor virus and p o s s i b l y other lines of MTV.

48

H . T . Lynch et al. Heston suggested that Bentvelzen's concept of a provirus paralleled Huebner and Todaro's concept of the oncogene [10]. The concepts differed, however, in that the virus that p r e s u m a b l y arises from the oncogene in its mature form is a C particle~ while the m a m m a r y tumor virus represents B particles and p r o d u c e s only mammary tumors. All mice that harbor MTV do not develop m a m m a r y tumors. This implies, therefore, that other factors, i n c l u d i n g hormones [i.e., estrogens), i m m u n o l o g i c factors, the c o m p o s i t i o n of the target organ per se, diet, and genetics, may be of etiologic i m p o r t a n c e in m a m m a r y t u m o r carcinogenesis [1-10].

Virologic Studies in Humans In 1971, Moore et al. [11] c o n c l u d e d that, "the similarities between a d e n o c a r c i n o m a of the breast in mice and w o m e n are too extensive to be coincidental; . . . h u m a n breast cancer m a y also be a viral disease." This postulate was based on observations of virus-like material that was m o r p h o l o g i c a l l y i n d i s t i n g u i s h a b l e from the Bittner agent in s p e c i m e n s of h u m a n m i l k in Parsi w o m e n from Bombay, India. Members of this ethnic group are k n o w n to have a significantly higher frequency of m a m m a r y cancer than their non-Parsi peers from Bombay and other parts of India. Schlom et al. [12] observed that particles from h u m a n milk contained reversetranscriptase activity. This particular enzyme is also described as R N A - d e p e n d e n t or RNA-directed DNA polymerase. It was found to catalyze the synthesis of DNA from the template p r o v i d e d by viral RNA [13, 14]. These observations have acquired new interest in light of the extension of the original concepts of the oncogene theory d e v e l o p e d by Huebner and Todaro [10]. This p h e n o m e n o n , as currently understood, depicts an oncogene as specific segments of DNA, w h i c h confer malignant neoplastic properties based on isolation from certain h u m a n cancer cell lines [15]. A difference between a h u m a n bladdercancer oncogene and its c o r r e s p o n d i n g normal allele recently has been observed [16, 17]. Pieces of h u m a n DNA harboring oncogenic potential have been isolated through a process k n o w n as transfection assay [18]. This involves pieces of DNA that are precipitated with calcium phosphate. This is then m i x e d with an indicator cell line, NIH/3T3, a nontransformed h u m a n fibroblast. The oncogenic DNA m a y be derived from any species, i n c l u d i n g humans. The genes are clones in specific p l a s m i d or bacteriophage vectors, thereby b e c o m i n g immortalized, and w h e n the gene cloning is incorporated w i t h transfection assay, an invaluable tool for isolation and analysis of h u m a n cancer genes is possible. Studies of two h u m a n b l a d d e r - c a r c i n o m a lines, n a m e l y EJ and T24, recently have been investigated, using restriction e n z y m e s in order to fragment the DNA. W i t h subsequent transfection assay and gene cloning, a sequence of 6600 nucleotide base-pairs was identified. Of interest was the remarkable h o m o l o g y that this sequence s h o w e d to an RNA t u m o r virus oncogene (v-Haras), w h i c h causes sarcoma in rats [19]. W h e n the oncogene was c o m p a r e d w i t h the corresponding DNA sequence isolated from normal b l a d d e r epithelium, and after breaking and r e c o m b i n a t i o n of the two DNA sequences, the site of the difference was identified and its DNA sequence was then determined. Herein, a single basepair transversion at position 35 in the functional p21 gene was observed. This trans version causes the 12th amino acid p r o d u c e d by p21 to be changed from glycine to valine. Several vital questions pertaining to these observations in general have been raised and, in particular, to the m e c h a n i s m involving p21: (a) the m a n n e r of alteration of a cell's growth-control apparatus leading to malignant change; (b) h o w universal the m e c h a n i s m might be; and (3) most crucial, how this might be harnessed so as to reverse changes s e c o n d a r y to malignant transformation in patients [20].

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A vexing question is, "What does this new technology have to offer us so far as providing greater elucidation of etiology and pathogenesis of hereditary breast cancer is concerned?" A partial answer might be derived through extending to breast cancer the recent findings of Sakaguchi et al. [21] on another exceedingly common tumor in man, namely, carcinoma of the colon. Specifically, these investigators postulated that the oncogene for colonic cancer resides on chromosome #12. We believe that the study of tissues from breast cancer-affected patients and those at highrisk for hereditary breast cancer could provide valuable insights into these pertinent questions. The inherent power of cancer predictability in a hereditary breast cancer model would enable investigators to identify those lineages within the pedigree that are not likely to harbor the breast cancer-prone genotype, those that will, in fact, manifest a deleterious genotype by virtue of having documented breast cancer, and those who are at 50% risk for this disease (progeny or siblings of hereditary breast cancer-affected individuals).

BREAST CANCER GENETICS IN MAN

Historical Perspective Historically, the first significant report on the genetics of human breast cancer was that of the famed French surgeon, Paul Broca, published in 1866 [22]. He traced the cause of death of 38 members of his wife's family through five generations between 1788 and 1856. Interestingly, 10 of the 24 women in this family died of breast cancer. He astutely documented all other malignant neoplasms, which included an excess of cancer of the gastrointestinal tract. He was concerned with the possibility of inheritance of a general cancer diathesis in the family. His sage observations, made prior to Mendel's discoveries, clearly indicated remarkable insight into the importance of genetic heterogeneity with respect to a variable tumor spectrum in hereditary breast cancer. Numerous subsequent reports have clearly documented the pertinence of these early observations by one of the true intellectual giants of medicine. It should now be axiomatic that investigators studying breast cancerprone families meticulously attempt to verify cancer of all anatomic sites [1]. Jacobsen [23], in 1946, found an increased frequency of breast cancer among female relatives of breast cancer probands compared with a control group. However, in accord with findings of Broca [22], he also observed an increase in cancer of all sites among relatives of breast cancer probands. So far as we can determine, this was the first substantiation of Broca's observations of tumor variability in breast cancer-prone families. Familial clustering of breast cancer had been verified repeatedly in formal studies during the first half of this century [23-30]. For most cases of breast cancer (probably over 85%), a multifactorial model, including variable genetic and environmental factors, had been considered to be appropriate for explaining its liability [30]. This view is consistent with evidence for individual variability giving rise to cancer susceptibility or resistance in processes associated with the metabolism of carcinogens and cocarcinogens [31-34]. Findings from epidemiologic studies of breast cancer also are in keeping with this rationale [32, 35].

Case-Control Studies Relatively little systematic attention was given to breast cancer genetics until the case/control studies of Macklin [29] in 1959. She studied the families of 295 breast cancer probands and compared them with two control groups: (A) one with cancer

50

H.T. Lynch et al. in some organ other than the breast; and (B) a second control group that had no history of cancer. The frequency of breast carcinoma was numerically increased in the female relatives of breast cancer probands compared with both control groups, and to the frequency expected in the general population. The control groups did not differ numerically from each other with respect to the frequency of breast carcinoma in their relatives, and both were comparable to that expected in the general population. This supported her contention that the role of genetic factors for breast cancer was site-specific. Subsequently, Macklin (36) demonstrated that parity played a significant etiologic role. Specifically, nulliparous individuals showed a higher frequency of breast carcinoma. In turn, the genetic factor appeared to be influenced by parity. Anderson [37, 38] subsequently showed that sisters and daughters of patients with bilateral breast cancer who were diagnosed premenopausally were at substantially increased risk when compared with relatives of breast cancer patients with unilateral disease who were diagnosed later in life. These observations signify the importance of what we refer to as cardinal clinical features of hereditary breast cancer. However, they only depict one important aspect of the problem. Others include such considerations as paternal transmission and tumor heterogeneity. These issues can be partially reconciled through the use of the modified nuclear pedigree enabling more critical examination of tumor significance in the pedigree. Specifically, in a disease of adult onset, such as breast cancer, the progeny (and in some cases, even the siblings) of the proband may be too young to have expressed the phenotype (cancer). Hence, more informative relatives are required. Therefore, we include both maternal and paternal grandparents, aunts, and uncles. We stress both maternal and paternal lineages, since the breast cancer gene(s) appears to be autosomally transmitted, thereby making it mandatory to pursue this course in pedigree ascertainment and analysis. When indicated, the pedigree should be extended for greater precision in hereditary breast cancer syndrome identification.

Extended Breast Cancer-Prone Kindreds Detailed medical-genetic studies of breast cancer-prone families with meticulous pathology correlation were initiated by Lynch et al. in the mid-1960s [39, 40]. These investigations have been continuous and now involve several hundred kindreds. They have aided in the comprehension of breast cancer genetics. This experience provides the basis for much of the material that follows.

Cardinal Characteristics of Hereditary Breast Cancer Hereditary breast cancer differs from its nonhereditary counterpart by virtue of the following clinical features: (A) significant early age of onset [41]; (B) excess of bilaterality [42]; (C) specific tumor associations [43-46]; (D) vertical transmission [1, 3]; and (E) improved survival over nonhereditary forms [47].

Early Age of Onset Early age of onset is a feature of virtually all varieties of hereditary cancer, including breast [41]. Haagensen [48] reported that only 1.8% of breast cancers were found under the age of 30 years. In our study of 52 hereditary breast cancer families, however, we observed 6.9% of patients to manifest breast cancer under the age of 30 years, and in 4.1% of them, it occurred under the age of 25 [41]. In a second study of 106 hereditary breast cancer patients, the average age of diagnosis was 49

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years [47]. Approximately one-third (35.2%) were under age 45 at the time of diagnosis. This contrasted with the average age of diagnosis in the American College of Surgeon's Breast Tumor Registry Study of 57 years, wherein only 15.9% of patients were diagnosed under age 45 [49]. Interestingly, some of the earliest ages of onset of breast cancer have been found in an uncommon variant of hereditary breast cancer [50]. We have observed an earlier age of onset among the daughters of breast canceraffected mothers who were members of families showing hereditary breast cancer [51]. Early age of onset in hereditary disorders, at one time, was thought to be the primary consequence of gene-determined events. This phenomenon was referred to as "anticipation." However, scientific evidence clearly shows the so-called biological implication of anticipation was in error [52]. A better explanation for earlier onset in hereditary diseases relates either to more sophisticated diagnostic techniques, greater patient awareness of signs and symptoms, or to changing environmental events that influence gene expression. The latter set of circumstances may explain the earlier onset of breast cancer in our high-risk families. In the study of 35 hereditary breast cancer kindreds who were ascertained by mother-daughter proband pairs with verified breast cancer, the mothers in this group, on the average, were born in 1894 and their daughters in 1920. The mean age at breast cancer diagnosis for these parent-offspring pairs was 57.1 years for the mothers and 44 years for the daughters, which constitutes a highly significant (p 0.01) 13-year intrapair difference [51]. In order to obviate problems related to incomplete follow-up and/or ascertainment, age-specific cancer rates among sisters of the mother-daughter probands were computed and compared. These data indicated that the cumulative breast cancer rates in the 20-79 age bracket were approximately equal for both generations (31%). However, they also clearly reflected a significantly (p ~ 0.05) higher rate of premenopausal breast cancer (onset before age 50) among sisters of the daughters than sisters of the mothers. On the assumption that random members of these two sister groups have comparable genetic susceptibilities to breast cancer, our data indicate that genotype/environmental interaction have resulted in earlier expression of carcinoma of the breast in the later generation of women from these families. Earlier onset of familial breast cancer in these kindreds may be a consequence of changes in the lifestyle of modern women. One consideration is the use of estrogens in the form of oral contraceptives (OC), beginning in the 1960s. Other possible factors include certain drugs (tranquilizers, amphetamines, antihistamines), increased cigarette smoking, alcohol usage, and significant changes in nutrition. Western civilizations are characterized by overnutrition via the increased consumption of meat protein and fats, resulting in taller and heavier women with earlier menarche.

Bilateral and Multiple Primary Cancer Bilateral breast cancer and excess of multiple primary cancer (various sites) is an integral feature of hereditary breast cancer. Study of 198 patients from 75 breast cancer-prone pedigrees showed the cumulative risk to the contralateral breast in patients whose first breast cancer was diagnosed premenopausally to be 46.4% over 20 years of survival [42].

Vertical Transmission The breast cancer genotype is transmitted in a vertical manner from one generation to the next in accord with an autosomal dominant pattern. The expression of the cancer phenotype is dependent, in part, on the penetrance of the gene and, possi-

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bly, exposure to specific carcinogenic promoters. The deleterious gene may be transmitted through either maternal or paternal lineages (Fig. 3) [1, 53], although males are rarely affected.

Prolonged Survival Survival characteristics were tabulated retrospectively for 106 patients with hereditary breast cancer (20 unrelated families) [47]. The 5-year disease-free survival rate was found to be 67% in our hereditary breast cancer population. This was significantly better (p < 0.05) than the 45.2% 5-year survival in the ACS Tumor Registry Study [49]. We do not believe that earlier cancer diagnosis was a factor, in that the clinical stages in both the hereditary and ACS audit series were similar, nor can we attribute better survival in the hereditary population as resulting from the fact that patients, on the average, were younger than the corresponding ACS Tumor Registry population. This assumption is based on review of a variably sized series of patients with early onset breast cancer, which showed markedly poorer prognoses when compared with patients diagnosed later in life [49]. Our findings are supported by those of Langlands [54], who also observed improved survival in a series of patients with familial breast cancer.

Genetic Heterogeneity The occurrence of similar phenotypes may result from differing genotypes. In hereditary breast cancer-prone families, frequently we find carcinoma of the breast in variable association with cancer of other anatomic sites. Carcinoma of the breast and ovary [45] (Fig. 4), for example, may be expressed as a t u m o r pattern in one family, while an exceedingly more complex tumor spectrum may occur in another. Such an example of the latter is breast cancer in consort with sarcoma, brain tumors, laryngeal and lung cancers, leukemia, and adrenal cortical carcinoma (acronym, SBLA syndrome) [50] (Fig. 5). Currently identified hereditary breast cancer syndromes are included schematically in Figure 6, although their individual incidence has not yet been defined.

Male Breast Cancer Genetics Breast cancer occurs in excess in patients withKlinefelter's syndrome [1], as well as in several disorders characterized as cancer-associated genodermatoses [55] (further discussion will follow). Schwartz et al. [56] described the second incidence of familial male breast carcinoma wherein a father and son were affected with this disease. It was of interest that both of these patients showed a similar histologic type, papillary adenocarcinoma, a lesion that rarely is found in male breast cancer. The investigators concluded that this could have been a fortuitous occurrence, or it could be due to as yet unrecognized etiologic factors. Finally, a remarkable family with male breast cancer recently has been called to our attention for consultation by Dr. Richard A. King, of the University of Minnesota. In this family were two brothers with verified adenocarcinoma of the breast. One of the affected brothers

Figure 3

Schematic illustration of variation of maternal and paternal transmission of breast

cancer. (With permission of Lynch HT, eta]. (1978): Management of familial breast cancer. II. Case reports, genetic counseling, and team concept. Arch Surg 113:1961-1067.

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POLYGENIC

Figure 6

Schematic illustrating hereditary breast cancer syndromes.

(With permission of Lynch HT, et al. (19811: Surveillance and management of hereditary breast cancer. Breast 7:2 9.)

had both a son and daughter that were affected with breast cancer. Observations of male-to-male t r a n s m i s s i o n of breast cancer, such as these, are extremely cogent and consonant w i t h our conviction that hereditary breast cancer is inherited as an autosomal dominant. CUTANEOUS SIGNS (MARKERS) AND BREAST CANCER (CANCERASSOCIATED GENODERMATOSES) There are more than 50 cancer-associated genodermatoses w h e r e i n cutaneous signs, c o u p l e d w i t h features of family history and genetic principles, b e s p e a k cancer risk for specific targeted organs [55]. A classic example involving breast cancer occurs in C o w d e n ' s disease [1].

Cowden's Disease Brownstein [57] has extensively r e v i e w e d Cowden's disease and its association with breast cancer. This autosomal d o m i n a n t l y inherited disorder is characterized by m u l t i p l e t r i c h o l e m m o m a s . These lesions characteristically a p p e a r on the face (Fig. 7), but also m a y be found on the dorsal and ventral aspects of the h a n d s and feet, as well as on the forearms; oral fibromas and p a p i l l o m a s also are c o m m o n in

Breast C a n c e r - R e v i e w

57

patients w i t h C o w d e n ' s syndrome. These lesions may have a cobblestone appearance, particularly on the inner aspects of the lips. W o m e n with C o w d e n ' s disease also d e v e l o p virginal h y p e r t r o p h y of their breasts. In most autosomal d o m i n a n t diseases, m a r k e d variability of p h e n o t y p e occurs. Hence, some patients w i t h C o w d e n ' s disease may show only m i n i m a l cutaneous signs, w h i l e in others it m a y be severe, as s h o w n in Figure 7. In a review of 37 cases (16 male, 21 female) w i t h C o w d e n ' s disease, i n c l u d i n g both p u b l i s h e d and u n p u b l i s h e d examples of this disease, Brownstein d i d not encounter breast cancer occurrence in any of the men, although one had gynecomastia. However, breast cancer already had d e v e l o p e d in 10 of 21 w o m e n with Cowden's disease. In those w o m e n with Cowden's disease and breast cancer, bilateral breast cancer was observed in 4 and unilateral breast cancer in 6. A m o n g those 11 w o m e n w i t h C o w d e n ' s s y n d r o m e in w h o m breast cancer had not yet developed, 3 had mothers with breast cancer and 1 had a maternal g r a n d m o t h e r with breast cancer. Most of these w o m e n had additional breast disease, i n c l u d i n g fibroadenomas, fibrocystic disease, virginal hypertrophy, and malformations of the n i p p l e and areola. Brownstein suggested that the 47% incidence of breast cancer in w o m e n with C o w d e n ' s disease was a m i n i m a l estimate, in that some of the patients reported were relatively young; one of the patients with extensive fibrocystic disease of the breast had u n d e r g o n e p r o p h y l a c t i c simple mastectomies. Other lesions in C o w d e n ' s disease i n c l u d e t h y r o i d goiter, thyroid adenoma, hyp o t h y r o i d i s m , and c a r c i n o m a of the thyroid. Polyps have been observed throughout the gastrointestinal tract, i n c l u d i n g the esophagus. One patient had carcinoma of the cecum.

Figure 7 Facial tricholemmomas from 35-year-old woman with oral fibromas, hypothyroidism, xanthomas, vitiligo, and severe fibrocystic disease of the breasts. Prophylactic bilateral simple mastectomies were performed. (With permission of Brownstein MH (1981): Genetics and Breast Cancer, HT Lynch (ed). Van Nostrand Reinhold, New York.)

58

H . T . Lynch et al.

Brownstein urged that greater attention be given to the d o c u m e n t a t i o n of breast cancer in C o w d e n ' s disease, since indications among dermatologists suggest that the c o n d i t i o n is not exceedingly rare. Finally, one of us (H.T.L.) p r o v i d e d consultation on a 35-year-old white female nurse who had had pathologic d o c u m e n t a t i o n of m u l t i p l e t r i c h o l e m m o m a s . A review of her family history failed to reveal any other example of these cutaneous lesions. Furthermore, there was no evidence of breast cancer in the family. Medical history on her maternal and paternal lineage was limited. On the strength of the unequivocal evidence of the m u l t i p l e t r i c h o l e m m o m a s (a dermatopathologist believed these were p a t h o g n o m i c for Cowden's disease in this patient), her history of severe fibrocystic disease of the breast and m a m m o g r a p h i c evidence of dysplasia, c o u p l e d w i t h the patient's fear of breast cancer, a r e c o m m e n d a t i o n for p r o p h y l a c t i c bilateral m a s t e c t o m y was given. Soberingly, carcinoma of the breast and positive axillary nodes were found in the surgical specimen.

Leser-Trelat Sign The Leser-Trelat sign is characterized by the s u d d e n a p p e a r a n c e and r a p i d increase in size and n u m b e r of seborrheic keratoses in association with cancer. Lynch et al. [58] r e v i e w e d the subject and found 20 cases of this u n u s u a l p h e n o m e n o n reported in the literature. More than 50% were associated w i t h a d e n o c a r c i n o m a s and none were found to be familial. They reported the first familial e x a m p l e involving a 41year-old black female and her 74-year-old black mother, each of w h o m manifested a d e n o c a r c i n o m a of the breast and classical c l i n i c a l - p a t h o l o g i c evidence of the Leser-Trelat sign (Fig. 8). No other members of the family s h o w e d cutaneous lesions or cancer. The etiologic and pathologic significance of this unique observation remains elusive.

Peutz-Jegher's Syndrome and Breast Cancer Riley and Swift [59] s t u d i e d a p r o b a n d and her paternal grandmother, each of w h o m manifested bilateral breast carcinoma and the Peutz-Jegher's syndrome. An ovarian sex-cord tumor with annular tubules was an incidental finding on oophorectomy, w h i c h was part of the treatment of the p r o b a n d ' s p r e m e n o p a u s a l breast cancer. The investigators state that, as a result of prior reports of breast cancer in this disorder, the Peutz-Jegher's s y n d r o m e gene m a y be associated with increased risk for breast cancer. However, based on these limited data, we w o u l d not consider this c o n d i t i o n as a marker for breast cancer.

BIOMARKERS AND HEREDITARY BREAST CANCER GPT and Gene Linkage King et al. [60] suggested the existence of genetic linkage of breast cancer susceptibility with the glutamate pyruvate transaminase (GPT) locus in certain cancer-prone families. Herein, the breast cancer susceptibility allele m a y be c h r o m o s o m a l l y linked to GPT. This p o l y m o r p h i c genetic marker has been p r o v i s i o n a l l y assigned to c h r o m o s o m e #16. These studies were performed on breast cancer-prone families from our extensive resource. More recently, Go et al. [61] s t u d i e d segregation analysis on 18 of our large families. In 16, the results were consistent with the hypothesis of a genetic etiology for their breast cancer. In the r e m a i n i n g two families, breast cancer a p p e a r e d to be more e n v i r o n m e n t a l in origin. It was c o n c l u d e d that

Breast C a n c e r - R e v i e w

59

Figure 8 The left back and front, respectively, of the 41-year-old daughter (A,B) and the 74year-old mother (C,D) with Leser-Trelat sign. The numbers indicate the biopsy sites of the seborrheic keratoses. (With permission of Lynch HT, et al. (1982): Leser-Trelat sign in mother and daughter with breast cancer. ] Med Genetic 19:218-221.)

autosomal d o m i n a n t susceptibility alleles best explained breast cancer susceptibility in families with p r e m e n o p a u s a l breast cancer and ovarian cancer, and in four of the kindreds with primary postmenopausal cancer. Two families showing the SBLA syndrome demonstrated findings compatible with an autosomal d o m i n a n t mode of genetic transmission. In a c o m p a n i o n paper,

60

H . T . Lynch et al.

King et al. [62] provided a further assessment of linkage analysis of the subject kindreds s h o w i n g autosomal d o m i n a n t inheritance patterns. In seven of the kindreds s h o w in g primarily p r e m e n o p a u s a l breast cancer and in five of the families showing a c o m b i n a t i o n of breast and ovarian carcinoma, a d o m i n a n t susceptibility allele was postulated to be linked to the genetic marker GPT, with a lod score of 1.95 at zero recombination. In three of the families with primarily p o s t m e n o p a u s a l breast cancer, none of 21 genetic markers p r o v i d e d any e v i d e n c e for linkage to either a d o m i n a n t or recessive susceptibility allele. Of further interest is the finding of a positive lod score for linkage to a recessive susceptibility allele for acid phosphatase, w h e r e a lod score of 0.78 at 40% recombination was observed. However, this was informative in only a single kindred. Confirmation in other families w o u l d more firmly establish the existence of a gene increasing susceptibility to breast cancer and/or associated tumors. What are the etiologic and public health implications of these putative linkage findings? This is best expressed by King et al. [62]: Elucidation of a genetic model (or models) for inheritance of susceptibility to breast cancer would have several important implications for breast cancer etiology and prevention. First, it would be possible to detect genetically susceptibile young women in families at high risk of breast cancer long before clinical symptoms of the disease appear. Genetic and preventive medical counselling for such individuals would thus become a real possibility. Furthermore, it would be possible to determine if more than one genetically-influenced form of breast cancer exists, and the pattern of its (or their) transmission in families. It would also be possible to investigate why some genetically susceptible women do not develop breast cancer. The influence of cultural and environmental factors on breast cancer risk in the general population is well established. Do these same factors modify the increased risk of genetically susceptible women, or do other factors, perhaps of less importance in the general population, protect some genetically susceptible women from development of breast cancer? Epidemiologic methods can be applied to this genetic concept of incomplete penetrance. Finally, what are the biochemical and physiological mechanisms by which a gene increases breast cancer susceptibility? The linkage of a marker locus and breast cancer susceptibility in some families may offer an excellent opportunity to elucidate breast cancer etiology. Using linkage analysis, it is ultimately possible to identify genetically susceptible young women who have not yet developed breast cancer, and other young women in the same family who are at low risk. By comparing appropriate immunological, biochemical, and endocrinological parameters of these high and low risk young women, it may be possible to determine how breast cancer susceptibility genes are expressed. Such understanding could lead ultimately to the prevention of familial breast cancer.

Secretory Activity of Apocrine Glands The ceruminous, mammary, and certain axillary sweat glands are histologically of the apocrine type, and their secretions are b i o c h e m i c a l l y similar. Ear wax, or cerumen, is an apocrine gland p r o d u c t that may occur in either of two states, " w e t " or " d r y . " This characteristic of the wax appears to be u n d er genetic control. Capitalizing u p o n these facts, Petrakis et al. [63, 64] studied the secretory activity of the breast, and concurrently evaluated the wet or dry characteristics of the patient's ear wax. The study i n v o l v e d 601 nonlactating w o m e n w h o se racial background included Chinese, Caucasian, Mexican-American, Black, Japanese, and Filipino. The highest frequency of secretors was among the Caucasian w o m e n and the lowest n u m b e r of secretors was among the Oriental women. The frequency of secretors declined in both groups w i t h advancing age, the decline being most marked in

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61

the Chinese w o m e n , w h o also s h o w e d a small yield of breast fluid at any age. These investigators [63] c o n c l u d e d that (the pattern) appears to parallel the decline in estrogen secretion by the ovaries associated with menopause and the decrease in breast glandular mass associated with advancing age . . . secretory activity in over half of the post-menopausal Caucasian women may be indicative of persistent epithelium function . . . The finding of persistent secretory activity throughout life, the striking differences in secretor frequency between Caucasian and Oriental women may be relevant to epidemiologic studies of the etiology of breast c a n c e r . . . The low breast cancer risk in Oriental women may be related to an overall decreased secretory activity of the nonlactating breast, especially among those women with dry cerumen.It is hypothesized that a decreased secretory activity would minimize the exposure of the breast epithelium to exogeneous and endogeneous carcinogens. •

.

.

Recently, Petrakis [65] studied the relationship between the presence of dysplastic e p i t h e l i a l cells in n i p p l e aspirates of breast fluid and wet or dry c e r u m e n phenotype among 1150 white and Asian A m e r i c a n women. He observed a statistically significant greater p r o p o r t i o n of p r e m e n o p a u s a l white w o m e n of the wet c e r u m e n p h e n o t y p e (compared to dry type) to have cytologic d y s p l a s i a (relative risk, 6.5). The effect was not observed in p o s t m e n o p a u s a l women. These observations were in s u p p o r t of the h y p o t h e s i s that an apocrine genetic factor affecting breast gland secretion m a y influence exposure of breast e p i t h e l i u m to potential carcinogenic substances. It w o u l d be of interest to d e t e r m i n e if secretory activity of the breast and ear wax characteristics m a y s h o w patterns that might correlate w i t h genetic risk status in breast cancer-prone kindreds. In turn, it w o u l d be intriguing to determine if endocrine profiles found in w o m e n at high genetic breast cancer risk by F i s h m a n et al. [66-68] might correlate with secretory activity of the breast and the characteristics of the ear wax.

H L A

In spite of theoretical expectations, the search for an HLA association w i t h breast cancer, to date, generally has been u n r e w a r d i n g [1]. A recent study by Bouillenne and Deneufbourg [69] has s h o w n a putative association b e t w e e n HLA antigen A28 in m e n o p a u s a l n u l l i p a r o u s w o m e n with breast cancer. The frequency of this antigen was 26% versus 7% in controls (p corrected -- 0.038) w i t h relative risk = 6.63 (p ~ 0.001). A m o n g seven u n r e l a t e d breast cancer-prone kindreds, Lynch et al. [70] observed the most prevalent HLA h a p l o t y p e s and antigens for cancer patients to be h a p l o t y p e s HLA 29-12, HLA 1-8, HLA 2-40, HLA 24-7, and HLA antigens A2, B12, A29, B7, A24, B40, A1, B8, and A l l . Elevations of m a n y infrequently occurring HLA h a p l o t y p e s were observed; n a m e l y A l l , A15, A24, A29, B35, and B40, and h a p l o t y p e s HLA 29-12, HLA 2-40, HLA 2-15, and HLA 7-24. HLA h a p l o t y p e 29-12 was of particular interest, in that it occurred w i t h a p p r o x i m a t e l y the same frequency as HLA h a p l o t y p e 1-8. More important, however, was the fact that HLA h a p l o t y p e 29-12 occurred in five of the seven breast cancer-prone kindreds. The relative risk for those carrying the HLA 29-12 h a p l o t y p e c o m p a r e d with those without it was 1.5. A l t h o u g h this estimate i n d i c a t e d a trend, it was not statistically significant. Finally, none of the HLA antigens or haplotypes, i n c l u d i n g HLA 92-12, a p p e a r e d to segregate exclusively with cancer prone lines w i t h i n these kindreds. In s u m m a r y , no single HLA antigen or h a p l o t y p e was found c o m m o n to our seven breast cancer-prone kindreds. It is a p p a r e n t that HLA associations with he-

62

H.T. Lynch et al. reditary cancer, should they in fact exist, will only be determined through studies of large numbers of extended kindreds with three or more informative generations sampled and/or retrohaplotyped.

Glycoprotein (gp52) Ohno et al. [71] observed an immunohistochemically detectable antigen that is immunologically related to the protein moiety of the 52,000 dalton glycoprotein (gp52) of the MTV to be present in human breast cancer. In a study of 131 patients they observed a significantly higher percentage of patients showing, a positive family history for breast cancer to express the antigen gp52 in their tumors. While based on limited numbers, and in many cases incomplete family histories, these investigators nevertheless suggest that their observations warranted further investigations.

Dermatoglyphics Seltzer [72] studied dermatoglyphics in 119 white females. Thirty-four had histologically verified breast cancer, 53 were at high risk (defined as having either a first order female relative with breast cancer, a history of nulliparity, or severe bilateral fibrocystic mastopathy). Thirty-two were controls (female patients in the Baltimore Longitudinal Study on Aging at the Gerontology Research Center of the National Institutes on Aging) who, on the basis of physical examination and family history review, showed an absence of cancer or any of the features that characterized the high-risk group. Of interest was the fact that 32.4% of the breast cancer patients had six or more whorls, compared with 3.1% of the controls. Furthermore, 95% of the individuals with six or more whorls either manifested cancer or were at high risk. Thus, a ten-fold difference between breast cancer patients and controls was observed, and the high-risk patients fell between the cancer and control populations with respect to the number of whorls. The investigators could not determine the effect of a positive family history on the dermatoglyphic patterns of the breast cancer high-risk patients, but they are planning future studies to address this important issue. An association between breast cancer and an increased incidence of whorls has been noted previously [73]. In addition, Atasu and Teletar [74] and Lynch et al. [75] found increased whorls in patients with a variety of differing cancers. The simple noninvasive procedure of dermatoglyphics merits further investigation in hereditary breast cancer.

Juvenile Papillomatosis Rosen et al. [76] evaluated 84 patients from the Juvenile Papillomatosis Registry. Twenty-six percent of the patients reported that breast cancer had occurred in one or more female relatives. This may not represent a significant association. Nevertheless, the investigators suggested that juvenile papillomatosis of the breast may be a marker for breast cancer for the patients' families and also that patients affected by juvenile papillomatosis should have long-term follow up in that they themselves may be at increased risk for breast cancer.

Epithelial Dysplasia in Breast Fluid Cells Petrakis et al. [77] observed a strong association between epithelial dysplasia and breast cancer in the study of breast fluid epithelial cells obtained by nipple aspiration. They observed a higher proportion of women with positive family histories

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63

(first degree breast cancer-affected relative) to show dysplastic cells in breast fluid w h e n c o m p a r e d w i t h w o m e n who d i d not have such a family history. In addition, w h e n family history status was correlated with other breast cancer risk-factors, a higher p r o p o r t i o n of w o m e n with d y s p l a s i a was observed among those who had a first degree relative with breast cancer and for w h o m other risk factors were present. This suggested a d d i t i v e or synergistic effects of these factors on breast epithelium. These investigators c o n c l u d e d that breast e p i t h e l i u m in w o m e n with positive family histories of breast cancer m a y be more liable to abnormal differentiation from e n v i r o n m e n t a l risk factors.

Radiation Sensitivity Li et al. [78] s t u d i e d two sisters w h o manifested breast cancer 4 and 11 years following diagnosis of H o d g k i n ' s disease. These patients had received an estimated several h u n d r e d rads of scatter radiation to the affected breast tissues during the treatment of their H o d g k i n ' s disease. It was of interest that a third sister, in a d d i t i o n to five other w o m e n in the paternal line, manifested breast cancer. The authors c o n c l u d e d that the second p r i m a r y cancers of the breast in the two sisters w i t h Hodgkin's disease were the result of interactions between genetic factors and the carcinogenic effects from the radiation exposure.

Genetics and Mammographic Patterns Wolfe et al. [79] have suggested that m a m m o g r a p h i c patterns m a y p r o v i d e risk indices for breast cancer. This assertion was based on the study of m a m m o g r a m s from 110 mothers and their daughters, 122 sister pairs, and a like n u m b e r of unrelated controls m a t c h e d for age, r e p r o d u c t i v e history, and personal family history of breast cancer. They observed a familial influence in the m a m m o g r a m s based on pattern similarities that a p p e a r e d to be significantly stronger in the cases w h e n c o m p a r e d with the unrelated controls. This was affected by premature age changes in daughters and younger sisters as e v i d e n c e d by a decrease in DY and an increase in P2 patterns. T h e y suggested that m a m m o g r a p h y on first degree relatives w i t h high risk P2-DY patterns should be given priority consideration.

Laterality and Breast Cancer King et al. [80] s t u d i e d breast cancer laterality in 15 high-risk extended breast cancer-prone families. Laterality was not observed in these kindreds. This observation was in striking contrast to previous studies from London and Denmark, w h i c h reported significant concordance for t u m o r laterality in related breast cancer patients. It was c o n c l u d e d that the lack of laterality may reflect an increasing i n c i d e n c e of sporadic breast cancer among the genetically susceptible families or, alternatively, there m a y be an i n d e p e n d e n t d e t e r m i n a t i o n of cancer susceptibility and tumor laterality.

Estrogens and Breast Cancer To date, there is no confirmatory evidence linking estrogen use to the i n d u c t i o n or p r o m o t i o n of h e r e d i t a r y breast cancer. Definitive studies dealing w i t h this p r o b l e m will be difficult to interpret, in that the breast cancer risk to i n d i v i d u a l s harboring the deleterious gene a p p r o a c h e s 100%. If estrogens are s h o w n to p l a y a role, it m a y m o d i f y the p h e n o t y p e (breast cancer) expression, such as by causing an earlier age of onset and/or accentuating the risk for bilaterality.

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H . T . Lynch et el.

Short et el. [81] suggest that exposure of the breast duct e p i t h e l i u m to u n o p p o s e d estradiol, with the p r o d u c t i o n of prolonged anovular menstrual cycles at the menarche or prior to m e n o p a u s e , may be an important risk factor in breast cancer, thereby warranting a p p r o p r i a t e concern about exogeneous estrogens.

Oral Contraceptives (OC) Knowledge about OC agents and their possible carcinogenic effect is l i m i t e d in that e x p o s e d p o p u l a t i o n s were not available on a large scale until the mid-1960's [82]. Two recent studies [83, 84] from Britain cautiously suggest that conclusive evidence linking OC to breast cancer was lacking. Of potential concern is the breast cancer risk to young w o m e n who p o s t p o n e their first pregnancy through the use of OC. Pike et el. [85] in a case/control s t u d y involving 163 w o m e n with age of onset of breast cancer at 32 years or less, observed a statistically significant correlation bet w e e n the n u m b e r of m o n t h s of usage of OC agents prior to the first full-term pregn a n c y and the risk of d e v e l o p i n g breast cancer. Those using OC more than 97 mo prior to the birth of their first child had more than 3 times the risk of d e v e l o p i n g breast cancer prior to age 32 w h e n c o m p a r e d with m a t c h e d controls. A crucial omission in these studies was the failure to stratify for family history. Brinton et el. [86] suggested that OC usage t e n d e d to increase the breast cancer risk among those w o m e n who had a positive family history of this disease. Black et el. [87] found the family history to be a significant covariable in the relationship between OC usage and breast cancer. Specifically, they observed an increased breast cancer risk in w o m e n using OC whose grandmothers or aunts had breast cancer. Moreover, it was found that OC usage favored invasive transition in family historypositive women, but it impeded this step in w o m e n lacking such a positive family history of breast cancer [88]. Interestingly, Paffenbarger et el. [89] postulated that OC m a y accelerate the malignant process in transformed cells. Finally, Matthews et el. [90] studied 93 patients who manifested breast cancer and w h o had used OC prior to diagnosis and c o m p a r e d them with 93 control patients w i t h breast cancer who were m a t c h e d for age and parity. More patients in the study group had a family history of breast cancer. The investigators did not define w h a t constituted a "positive family history." A d d i t i o n a l studies involving e x t e n d e d k i n d r e d s with a high degree of verification of breast cancer c o u p l e d with careful staging of this disease are needed. Until the state of the art relevant to OC usage and hereditary breast cancer is fully clarified, we advise high-risk m e m b e r s of hereditary breast cancer families to avoid the use of estrogens.

Endocrine Function The question of e n d o c r i n e i n v o l v e m e n t in the etiology of breast cancer has been investigated i n t e n s i v e l y in m a n y laboratories (35, 91-105). These studies have focused p r i m a r i l y on identifying possible differences in e n d o c r i n e profiles b e t w e e n w o m e n w i t h breast cancer and normal controls. The results obtained have been conflicting, and failed to reveal any consistent differences that c o u l d be related to the presence of disease. A valid argument can be m a d e that the initiation of events that result in subsequent clinical manifestation of the disease occurs in the hormonal m i l i e u of the early p r e m e n o p a u s a l and postpubertal p e r i o d and that, therefore, this is the relevant age at w h i c h possible e n d o c r i n e differences need to be examined (96, 105-109). For prospective studies of this type, the general p o p u l a tion presents major technical p r o b l e m s in view of the large numbers of subjects required and the long time span before the results can be correlated with the disease.

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An alternative to studying larger populations, where breast cancer etiology may be considerably heterogeneous, would be the study of premenopausal unaffected women who are at a predictable hereditary risk for breast cancer. They could then be compared with carefully matched controls who do not have a positive family history of breast cancer. Such an approach was employed by Fishman et al. [66, 67]. It involved an in-depth study in which hormone levels throughout the menstrual cycle in 30 young women at high risk for familial breast cancer were compared with 30 matched controls. No significant differences between these populations were observed in the plasma levels of prolactin, LH, FSH, estrone, estradiol, or estriol at any stage of the menstrual cycle, although a consistent trend toward lower values in all of these except estriol was noted in the high-risk population [66]. Analysis of urinary metabolites, on the other hand, revealed highly significant differences in estrone and estradiol glucuronides, with high-risk individuals excreting lower amounts of these metabolites than controls [67]. These investigations have been extended to include differences in urinary estrone sulfate and in plasma androsterone sulfate content. Plasma androsterone sulfate was significantly lower in the high-risk subjects. A compensatory increase in the urinary estrogen sulfates was observed. Day-by-day analysis of these differences showed that they were most pronounced in the periovulatory period of the cycle. It was concluded that the genetic risk for breast cancer is associated with an abnormality in estrogen conjugation at a specific time of the ovulatory cycle [68]. Increasing attention has been focused on estrogen-16~-hydroxylase and its products, 16~-hydroxyestrone and estriol, because of evidence that 16~-hydroxylation is increased in women with breast cancer [110]. In addition, there are preliminary data indicating that this reaction is increased prior to the onset of breast cancer and that the increase is not a result of the disease. Dr. H. Leon Bradlow (Rockefeller University) has observed that this reaction is elevated in mice that develop malignant mammary tumors (C3H/OuJ) and is quite low in mice that do not develop mammary tumors (C57/Br/J). These findings were present when the mice were 6wk-of-age, well before the onset of tumor development (personal communication). 16~-hydroxyestrone, the initial product of 16~-hydroxylation, possesses a combination of unusual biological properties. It is highly estrogenic in spite of only minimal binding affinity for the classical estrogen receptor [111]. In addition, it circulates free in blood because it does not bind to the sex hormone binding globulin and most importantly it possesses the unique property of forming covalent bonds with primary amino groups of proteins [112]. This latter property provides a mechanism for their long-term presence in target cells either by linking to the receptor itself or the chromatin regulatory proteins. It is possible that the decrease in the excretion of E1 and E2 glucuronides that have been described [66, 68], is compensated for by an increase in urinary 16-OH-estrone present as either the glucurhide or the sulfate. Suggestive data for increased sulfation of the parent hormone in the high-risk patients may account, in part, for increased 16c~-hydroxylation since it has been reported that estrone sulfate is a preferential precursor for 16c~-hydroxylation over the free compound [113]. The issue of the role of exogenous estrogens in breast cancer has been a vexing one, as evidenced by conflicting findings from one study to the next. We discuss it in the present setting because it is possible that patients at genetic risk for breast cancer may be predisposed either to direct effects of exogenous estrogen or they may have inherited benign breast disease which, given the presence of additional risk factors (including estrogen), could cause them to undergo a complex set of interactions; i.e., exogenous estrogen plus other risk factors such as oophorectomy plus specific forms of benign breast disease; namely epithelial hyperplasia or papillomatosis, which may then act synergistically toward the production of breast cancer. For example, recent data by Thomas et al. [114] showed a very complex rela-

66

H . T . Lynch et al. tionship between m u l t i p l e factors and association with exogenous estrogen. The risk of breast cancer was found in their study of 1439 white w o m e n w h o were initially treated for b i o p s y - p r o v e d benign breast disease from 1942 to 1975, and who were followed through 1976 for d e v e l o p m e n t of breast cancer. The so-called traditional risk factors, such as age at m e n a r c h e and birth of first child, nulliparity, and, to a lesser extent, age at artificial menopause, were related to the risk of breast cancer. Of interest was the fact that exogenous estrogen, w h e n taken prior to the initial benign breast disease, d i d not alter breast cancer risk. However, subsequent use (here p r i m a r i l y involving conjugated estrogens) e l i m i n a t e d the protective effect of artificial m e n o p a u s e and " . . . a p p e a r e d to act synergistically with epithelial hyperplasia or p a p i l l o m a t o s i s in the initial lesion and calcification of that lesion to increase the risk of breast cancer." A n o t h e r interesting finding was that of a marked increase in risk of breast cancer in succeeding breast cancer cohorts, a p h e n o m e n o n that could not be e x p l a i n e d by s i m p l e changes in any of the other risk factors u n d e r consideration. Unfortunately, the role of genetics was not investigated in this interesting study. Painstaking efforts at prospective studies of patients from breast cancer-prone families w h o are users of OC and, ideally, biopsies where benign breast disease is suspected will be needed. In context with this approach, a systematic study of all k n o w n risk factors, with m e t i c u l o u s recording of estrogen usage (with quantity and type, as well as duration) will be essential in order to d e t e r m i n e w h e t h e r or not a particular risk is present, and if so, a quantitative d e t e r m i n a t i o n of the full i m p a c t of the subject risk and/or its interaction with other risks will be required. Confounding the issue will be problems of genetic heterogeneity; i.e., the risk m a y vary in patients and families prone to carcinoma of the breast and ovary versus those w i t h site-specific h e r e d i t a r y breast cancer versus those with the SBLA syndrome, or other hereditary variants of breast cancer.

New Approaches to Investigation of Hormonal Effects Epidemiologic evidence suggests that the e n d o c r i n e m i l i e u in the early r e p r o d u c tive years of a w o m a n ' s life determines the risk for the d e v e l o p m e n t of breast cancer m a n y years later [115]. If one accepts this assertion, then e n d o c r i n e studies conducted following the diagnosis of breast cancer could be m i s l e a d i n g relevant to the etiologic role of h o r m o n a l factors in the onset of breast cancer. Logically, it follows that prospective studies of e n d o c r i n e profiles obtained well in advance of the onset of breast cancer w o u l d be more meaningful. A n e x a m p l e of such a s t u d y is one that has been ongoing on the Isle of Guernsey. Results from this s t u d y suggest the existence of e n d o c r i n e differences related p r i m a r i l y to the androgenic h o r m o n e s w h i c h appear to correlate with increased risk for breast cancer [116, 117].

Pathology The question of w h e t h e r familial breast tumors m a y show morphologic specificity is not yet resolved. On the one hand, there are reasons to believe that a specificity of m o r p h o l o g i c findings in familial breast cancer is u n l i k e l y to emerge. Consider the following: 1. There have been studies showing familial and nonfamilial cases of breast cancer to have similar distributions of histopathologic types [118, 119]. 2. Growing in the same host and, therefore, w i t h i n the same genetic matrix, bilateral breast cancers often show different morphologic patterns (although the patterns in the two breasts are the same in 4 0 % - 4 5 % of cases) [120].

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3. A single breast t u m o r often shows a m i x e d morphologic pattern [121]. 4. Intrafamilial breast cancers m a y be of different histopathologic types [122, 123]. On the other hand, there are reasons to t h i n k that familial breast tumors m a y yet be f o u n d to show some degree of m o r p h o l o g i c specificity u n d e r certain circumstances. First, there have been a n u m b e r of familial clusters in w h i c h two or more family m e m b e r s d e v e l o p e d breast carcinomas of similar morphology. In a previous survey of the literature, five twin pairs were recorded w h o had breast cancers of the same morphology, as were six n o n - t w i n familial occurrences in w h i c h two or more family m e m b e r s had breast cancers of the same histopathologic type [123]. Since that survey was made, Holzgreve et al. [124] reported the d e v e l o p m e n t of lobular carcinoma in situ in each m e m b e r of a monozygotic t w i n pair, and Rosen et al. [122] have r e p o r t e d two sets of n o n - t w i n sisters, each of w h o m d e v e l o p e d infiltrating duct carcinoma, and also one pair of twin sisters, each of w h o m d e v e l o p e d infiltrating duct c a r c i n o m a plus lobular carcinoma in situ. Furthermore, there have been reports suggesting that breast cancers occurring on a familial basis are associated with certain histopathologic types of the disease in n o n r a n d o m fashion. Thus, in our own investigation, we found that of 75 familial breast cancers subjected to pathologic review, 12 (16%) were of m e d u l l a r y or circ u m s c r i b e d type, c o m p a r e d w i t h only 2 of 54 (3.7%) s p o r a d i c a l l y occurring breast cancers [123]. The sporadic cases, however, were not m a t c h e d with the familial cases for age and other e p i d e m i o l o g i c variables. In another investigation, Rosen et al. [122] r e v i e w e d a series of 1024 w o m e n treated for breast cancer at Memorial Hospital in New York City. Thirty-one percent of the patients had a family history of breast cancer but, overall, considering all classes of relatives, a positive family history for breast cancer was not related in a significant w a y to any histopathologic type of this tumor. Nevertheless, patients in this study w h o had m e d u l l a r y carcinoma gave a history of maternal breast cancer w i t h increased frequency, and there also was an u n e x p e c t e d l y high frequency of breast cancer in at least one sister of those patients w h o had lobular carcinoma. The investigators c o n s i d e r e d that the increased frequency of breast cancer in mothers of patients with m e d u l l a r y carcin o m a m a y have been due to the low m e a n age that they found to be characteristic for this t u m o r type, because an increased frequency of maternal breast cancer was associated w i t h p r e m e n o p a u s a l and p e r i m e n o p a u s a l occurrences of all histologic varieties of tumors occurring in the series. The breast cancer case/control s t u d y of LiVolsi et al. [125] m a y be cited to support the c o n c l u s i o n that there is a lack of morphologic specificity in familial breast cancer, since no statistically significant association between t u m o r m o r p h o l o g y and family history of breast cancer was established in this investigation. In fact, however, LiVolsi et al. [125] d i d discern a trend towards an association b e t w e e n lobular c a r c i n o m a and a history of breast cancer in the family. In still another recent investigation, Lagios et al. [126] found that 6 of 15 patients (40%) w i t h tubular c a r c i n o m a of the breast had a family history of breast cancer in a mother, maternal aunt, or sister, w h i l e only 16% of the total n u m b e r of their patients with breast cancer that was other than tubular in type h a d a similar history. Thus, w h i l e it is clear that familial breast cancers, c o n s i d e r e d as a whole, do not show a consistent specificity of histopathologic type, it is still possible that, w i t h i n i n d i v i d u a l families that are affected by concentrations of breast cancer, there m a y be genetic or nongenetic factors working in such a m a n n e r as to effect the expression of a characteristic morphology. A d d i t i o n a l studies are n e e d e d in order to further explore this possibility. It is p e r t i n e n t to m e n t i o n here that, just as information concerning occurrences of breast cancer in families m a y harbor the potential of contributing to an under-

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H.T. Lynch et al. standing of genetic factors of importance in this disease, it is also possible that knowledge of geographic and ethnic variations in breast cancer morphology may have the potential of making a similar contribution. We have summarized many past investigations that had either supported or failed to support the existence of differences in breast cancer histopathology in different geographic locations and among different ethnic groups [123]. The information available was highly variable. Of particular interest, however, several studies had found differences between the morphologic characteristics of breast tumors occurring in Japan and those occurring in the United States. Five separate investigations had confirmed the relative frequency of medullary carcinoma in Japan to be higher than in the United States [127-131], and four of these investigations also had reported an increased frequency of lymphoid infiltration in breast tumors occurring in Japan [128-131]. In addition, three separate studies had found a relatively lower frequency of medullary carcinoma in whites compared with blacks in the United States [132-134]. Since we compiled the material in our previous survey, reports concerning breast cancer morphology in various geographic areas and among various ethnic groups have continued to accumulate [135-145], but the significance of these studies in terms of their possible contribution to our knowledge of genetic factors in breast cancer is still uncertain.

In Vitro Hyperdiploidy To detect in vitro cancer prone gene expressions, three areas have been utilized: (a) the experimental model--extensive family pedigrees having lineages with and without known gene carriers (those clinically affected) of such a cancer mutated gene in consecutive generations, as well as a random sample of those affected with the same breast cancer without a family history; (b) the test system--dermal monolayer fibroblast cultures established from split-thickness skin biopsies (Fig. 9); and (c) assay systems for the incidence of alterations in chromosome complement (percentage of different alterations in chromosome complement in metaphase preparations). Figure 10 shows an example of in vitro hyperdiploidy in a cell at metaphase. Skin biopsies were obtained from 16 breast cancer patients (7 from hereditary breast cancer families and 9 from families without a clear history of hereditary breast cancer), and one patient with cancer other than breast, 12 family members (6 from families with breast cancer, 6 from families without this cancer, and one

Figure 9 Methodology used for the establishment of monolayer (mixed fibroblastic and epithelioid) cultures from human skin biopsies. (With permission of Lynch HT, et al. (1981): Gastrointestinal Cancer, JR Straehlein and MM Romsdahl (eds). Raven Press, New York.) . ~ /

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spouse), as well as 20 clinically normals w i t h o u t a history of solid tumors (Table 1). Families of breast cancer patients are seen in Figures 11-15. Dermal m o n o l a y e r cultures were established from these split-thickness biopsies by standard culture methods (Fig. 9) [146]. Cultures were grown in plastic petri dishes in Eagle's minim u m essential m e d i u m (EMEM) with 15% (volume) fetal bovine serum in an atm o s p h e r e of 5% CO2 in air, pH 7.0-7.4. Cultures routinely were checked for bacterial c o n t a m i n a t i o n and m y c o p l a s m a and found to be u n co n t am i n at ed . Cells were grown in culture for 15-25 wk (5-10 subcultures by trypsinization after the primary explant culture) before assays were performed. Prior to the assays, a co d ed n u m b e r was assigned to each culture so that its identity w o u l d not be k n o w n until completion of the assays. To d e t e r m i n e the i n c i d e n c e of alterations in c h r o m o s o m e c o m p l e m e n t , each cell sample was plated at an initial cell concentration of 1 × 1 0 4 cells into m u l t i p l e 28 cm 2 plastic petri dishes containing m e d i u m w i t h 15% fetal bovine serum. After 48hr growth, the m e d i u m was c o m p l e t e l y changed. A p p r o x i m a t e l y 24 hr later, w h e n a burst of mitoses was observed, c h r o m o s o m e preparations were m a d e and evaluated for the i n c i d e n c e of alterations in c h r o m o s o m e c o m p l e m e n t (hyperdiploidy i n c l u d i n g tetraploidy). Only if more than 100 mitoses were co u n t ed per slide was the preparation c o n s i d e r e d to reflect the mitotic activity of that culture.

Hypothesis In vitro research on cancer prone genes has been based on the hypothesis that a cell (such as that derived from a skin biopsy) considered normal by all criteria, w h e n grown in culture w o u l d demonstrate a mutant cancer prone genotype through specific changes in cellular functions. Incidence of such an in vitro cellular abnormality in c o n s e c u t i v e generations; that is, vertical transmission from clinically affected to its offspring, w o u l d be c o n s i d e r e d e v i d e n c e of an in vitro expression of a cancer prone gene. One of these cellular abnormalities, presumably due to in vitro expressions of germinal mutations, is an alteration in c h r o m o s o m e c o m p l e m e n t , hyperdiploidy w i t h a normal occurrence of tetraploidy.

Table 1

Occurrence of in vitro h y p e r d i p l o i d y a in dermal m o n o l a y e r cultures derived from i n d i v i d u a l s w i t h breast cancer and from family m em b er s 1st degree relative of breast cancer-affectedb

Putative genetic risk status

Hereditary Breast Cancer Nonhereditary Breast Cancer Possible Hereditary Breast Cancer Controls c

Total individuals studied

14 8 8

Clinically affected (breast)

Clinically affected (other)

Unaffected

Spouse of affected

OCCURRENCE OF HYPERDIPLOIDY~j + + + 6 1 0 0 3 3 1 3 0 0 1 3 3 2 1 0 0 2

20 (all negative for hyperdiploidy)

'A metaphase scored hyperdiploid if chromosome number was greater than 46, exclusive of 92 (tetraploid). bDetermined by family pedigrees. ~Normals without a family history of solid tumors. ~76-118 chromosomes/metaphase; +, present;-, absent; exclusive of tetraploidy.

+ 1 0 0

0 0 0

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B CSU C Lk Mel Ov Pr sk St Ut

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Figure 11 Occurrence of in vitro hyperdiploidy from members of families considered to be nonhereditary breast cancer families.

Diploidy with a low (0%-7%) incidence of tetraploidy has been a constant feature in monolayer cultures derived from dermal biopsies from individuals without a family cancer history; the incidence of increased tetraploidy being approximately 1.4% in this group [147], whereas hyperdiploidy (chromosome number more than 46 per metaphase, excluding tetraploidy) rarely was observed in such cultures, irrespective of genotype. Two alterations in chromosome complement [increased tetraploidy and hyperdiploidy with a normal occurrence of tetraploidy) in dermal monolayer fibroblast

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H . T . Lynch et al.

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Figure 12 Occurrence of in vitro hyperdiploidy from members of families considered to be nonhereditary breast cancer families. (See legend for Fig. 11.)

cultures have been c o n s i d e r e d in vitro expressions of certain cancer prone genes. In the autosomal d o m i n a n t colon cancer s y n d r o m e s [148], this h y p e r d i p l o i d y has been solely t e t r a p l o i d y (92 c h r o m o s o m e s per metaphase), w h i c h a p p e a r e d to reflect a critical alteration in the cell cycle [149]. H y p e r d i p l o i d y w i t h a n o r m a l occurrence of t e t r a p l o i d y has been observed in certain heritable solid tumors (pancreatic cancer clusters [150] and the familial atypical m u l t i p l e mole m e l a n o m a (FAMMM) [151]). The in vitro data presented in Table 1 substantiated the occurrence of this alteration in heritable breast cancer. Thus, in vitro h y p e r d i p l o i d y w i t h a n o r m a l occurrence of t e t r a p l o i d y was not specific for any one of the cancer genotypes for heritable solid tumors studied, but a p p e a r e d to be an in vitro expression of a group of cancer genes associated with certain heritable solid tumors. In vitro h y p e r d i p l o i d y has the distinct clinical potential for genotype identification over linkage studies in that it does not require m u l t i p l e biologic s a m p l e s of a large k i n d r e d for its interpretation. Since h y p e r d i p l o i d y has now been observed in several distinct h e r e d i t a r y cancer s y n d r o m e s (Table 2), we c o n c l u d e that this biomarker is p o t e n t i a l l y useful for the identification of an increasingly large n u m b e r of cancer genes. Therefore, it s h o u l d not be c o n s i d e r e d specific for any single cancer prone genotype. Hence, the marker must always be a p p r a i s e d in consort w i t h the family history. GENETIC-EPIDEMIOLOGIC--STATISTICAL STRATEGIES Using classical e p i d e m i o l o g i c strategies, it is difficult to isolate the effects of single variables in any multifactorial system since, i n d i v i d u a l l y , these effects u s u a l l y are small. However, it is generally accepted [152] that m a n y c o m m o n diseases m a y be m i m i c k e d by single genes (or c h r o m o s o m e aberrations); e.g., colon cancer in Gardner's syndrome, heart disease in familial h y p e r l i p i d e m i a , and breast cancer in Cowd e n ' s disease and Klinefelter's syndrome). Presumably, the genes d e t e r m i n i n g these s y n d r o m e s have a major effect at a specific point in the pathogenesis of disease.

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H . T . Lynch et el.

Table 2

In vitro c h r o m o s o m e c o m p l e m e n t s in dermal m o n o l a y e r cultures for heritable cancer s y n d r o m e ° Alterations in chromosome number per metaphase

Increased in vitro tetraploidy~ Colonic cancer with discrete polyps Cancer family syndrome Gardner syndrome Malignant rhabdoid tumor Oldfield syndrome

Hyperdiploidy~ exclusive of tetraploidy FAMMM Hereditary breast Hereditary melanoma Hereditary ovarian cancer Hereditary pancreatic cancer (pancreatic family clusters)

Site-specific colon cancer Teratocarcinoma

Normal chromosome number per metaphase Diploidy Familial osteomas Familial polyposis coli Juvenile polyposis Neurofibromatosis Peutz-Jegher syndrome Turcot syndrome Xeroderma pigmentosum

aEstablished on clinical phenotypes and family pedigree data. hChromosome number per metaphase, 92. ~Chromosome number greater than 46 exclusive of 92 (tetraploid).

A l t h o u g h these h e r e d i t a r y c o n d i t i o n s m a y account for only a small portion of affected patients, they present ideal e x p e r i m e n t a l m o d e l s for isolating the effects of i n d i v i d u a l genetically controlled pathways. Their study in large k i n d r e d s w i t h affected m e m b e r s m a y p r o v i d e the most useful results for u n d e r s t a n d i n g basic genetic m e c h a n i s m s associated w i t h the pathogenesis of c o m m o n disease [152, 153]. The initial step in this process is the identification of families w i t h a high freq u e n c y of the disease, as has been done in cancer of the breast [1], as well as other anatomic sites, such as ovarian c a r c i n o m a [45, 154, 155]. A major gene h y p o t h e s i s is s u p p o r t e d in these families by the m e n t i o n e d cardinal signs; i.e., early onset of the breast c a n c e r - p h e n o t y p e and b y an excess of bilateral breast cancer and other m u l t i p l e p r i m a r y tumors, such as breast and ovarian carcinomas. For example, as a l r e a d y m e n t i o n e d , A n d e r s o n [36] c o n c l u d e d that genetic factors appear to be more i m p o r t a n t for p r e m e n o p a u s a l bilateral patients than for p o s t m e n o p a u s a l unilateral patients. Lynch [3,156] has e m p h a s i z e d the need to d o c u m e n t cancer of all anatomic sites in familial aggregations. His observations of specific t u m o r associations w i t h i n large k i n d r e d s are consistent w i t h genetic heterogeneity in hereditary breast cancer [43, 46, 50]. Elston et el. [157, 158] have d e v e l o p e d statistical m e t h o d s for fitting different m o d e l s to e x p l a i n the pattern of clustering of a disease p h e n o t y p e in large kindreds. Geared t o w a r d the detection of M e n d e l i a n ratios, these m e t h o d s are referred to as segregation analyses.

Age at First Pregnancy and Hereditary Breast Cancer Onset There is a p a u c i t y of e p i d e m i o l o g i c studies directed t o w a r d the assessment of risk factors in hereditary breast cancer. Early age at first full-term pregnancy generally has been regarded as being protective against breast cancer in the general p o p u l a tion [35]. We were curious, therefore, about h o w age at first pregnancy might influence the natural history of breast cancer in patients with the h e r e d i t a r y form of this

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disease. A study of 162 females from the Creighton Hereditary Breast Cancer Family Resource at 50% risk of developing breast cancer was performed to elucidate this matter [159]. In contrast to previous findings in populations at large [35], our results indicate no significant increased frequency of breast cancer with a later age at first pregnancy (t = 1.1, NS). In addition, we looked at 72 of these females who eventually developed the disease, and in whom data relevant to their age at first fullterm pregnancy was available. Regression analysis of diagnosis versus age at first full-term pregnancy revealed a best fit line that was examined for statistical significance with the Students' t-test. For purposes of comparison, we performed the same analysis on 197 consecutively ascertained breast cancer patients from the Creighton-St. Joseph Oncology Clinic. In this group, early age at first pregnancy was associated with a significantly earlier age of breast cancer onset (p < 0.05, t = 2.66). In the hereditary cohort, no significant association between age at first fullterm birth and age at onset of breast cancer was observed. Comprehension of the etiologic significance of this vexing issue remains obscure [160]. However, recall that Fishman et al. [68] have shown that patients at 50% risk for breast cancer from our hereditary breast cancer resource showed decreased E1 a n d E 2 glucuronide conjugates in their urine when compared with meticulously matched controls from a nonhereditary population. In addition, although increased estrone sulfate conjugates noted in the urine just escaped statistical significance, this finding suggests a possible shift from glucuronide to sulfate conjugation in high-risk females, since sulfate conjugates are more biologically active than glucuronide conjugates [68]. One might speculate that this shift predisposes to cancer generation in the hereditary population irrespective of pregnancy status, whereas, in the consecutive series fluctuating levels of estrogens at pregnancy provide the stimulus for tumor growth. We believe that our observations should be interpreted cautiously, pending its assessment in a larger number of well documented hereditary breast cancerprone kindreds. However, the data suggest that environmental interaction has only a limited effect on the manifestation of cancer in genetically predisposed individuals. It is of interest that at the infrahuman level, using the rat as a model, chemically induced tumors provided an interesting parallel to the above findings in humans. Specifically, prior pregnancy rendered rat mammary tissue less susceptible to chemical carcinogenesis [161]. However, when the pregnancy followed exposure to the carcinogen, the interval between exposure and the presentation of tumors was shortened [162, 163]. This seems to parallel our findings in the consecutively ascertained series. It would be of further interest to investigate this relationship in strains that demonstrate an endogeneous predisposition to developing breast cancer. Cumulative Lifetime Breast Cancer Risk in Breast Cancer Kindreds

A study of 638 females at 50% "genetic" risk from our hereditary resource was performed to calculate the cumulative lifetime breast cancer risk [164], according to the statistical method of Colton [165]. Probands and all of their affected first degree relatives from ascending previous generations were discarded from the analysis to exclude experimental sampling bias. The cumulative lifetime risk of developing breast cancer (± 5.7%, SEI was detemined to be 56%, which is highly significant when compared with the 4.08% risk that was calculated from the general population by these methodologies. This observation adds further support to the hypothesis that hereditary breast cancer is transmitted as a sex-associated autosomal dominant factor.

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HEREDITARY BREAST CANCER: CLINICAL INTEGRATION

Hereditary breast cancer (HBC) demonstrates a distinct natural history (cardinal features) from its sporadic counterpart. These observations form the basis for the clinical management of this entity. The frequency of HBC and its associated public health consequence mandates strong clinical consideration. Integration of the cardinal features into a screening family history allows the knowledgeable clinician to identify high risk kindreds. Modified Nuclear pedigree

A screening family history combining first and informative second degree relatives (Fig. 16) provides a concise and easily obtained format for integration of the cardinal features [1]. Their presence in the modified nuclear pedigree should alert the clinician to the possibility of hereditary cancer. Syndrome confirmation may require extended pedigree development and is beyond the reach of the average physician. However, pattern recognition within the screening family history allows for the institution of specific management protocols (Fig. 17). Figure 16

Strategy for assessing hereditary breast cancer. and management of hereditary

(With permission of Lynch HT, et al. (1981): Surveillance breast cancer. Breast 7:2-9.)

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Figure 17 Managementimplications of hereditary breast cancer. (With permission of Lynch HT, et al. (1981): SurveilJance and management of hereditary breast cancer. Breast 7:2-9.)

Counseling A dialogue between an informed patient and physician is the cornerstone of a management program. Counseling should be both family- and individual-oriented. Discussions center on management and surveillance protocols, risk to future generations, unaffected male transmission, and improved survival. Honesty and understanding are used to counter negative or fatalistic attitudes, not uncommon in families where cancer has been the rule rather than the exception. In established kindreds, counseling is instituted during the teenage years, and includes males and spouses where appropriate [1].

Surveillance The age-adjusted death rate for breast cancer has not improved appreciably over the past 20 years [49, 166, 167] despite advances in screening techniques, including mammography, ultrasound, and thermography [168, 169]. Mass screening programs have allowed for earlier detection [170-173], but usually are not recommended for women under the age of 50 [174]. However, new American Cancer Society guidelines recommend baseline mammography at age 35, and then beginning at age 40 this should be performed every 2 years. This approach has been recommended as a result of reduced radiation exposure in the newer available technology, coupled with an increased cancer yield in this age group. High risk (50%) relatives from

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hereditary breast cancer families represent a defined population at the highest risk for premenopausal development of breast cancer. It follows that unaffected members of such kindreds must be included in an intensive surveillance program. Self breast-examination (SBE), when performed on a routine basis, has led to the discovery of smaller lesions [171, 173,175]. High risk relatives are carefully instructed in SBE by a member of our cancer genetics team, and its importance is reinforced on each subsequent visit. In addition, biannual breast examination by a physician aware of the hereditary risk is strongly advocated. A baseline mammography on the hereditary (50% risk) patients is obtained by age 20 and repeated on a biennial basis. All suspicious physical or radiographic lesions must be evaluated either by aspiration or biopsy. There is no option for observation in this high risk group. The physician screening this group of patients should be familiar with techniques of localization for nonpalpable lesions [176, 177]. The role of random fine-needle aspiration [178] and cytologic examination of nipple aspirates [179,180] currently are being investigated as possible screening tools. Physician/Patient Compliance In the current absence of a defined biomarker of the deleterious genotype, our primary approach is surveillance. Unfortunately, this approach requires compliance by both physician and family members over a period of several decades. Poor compliance, cancer phobia, increasing mammographic dysplasia [79, 181], atypical fibrocystic disease [182], or breasts that are difficult to evaluate clinically, merit consideration of prophylactic surgery. The identification of a biomarker detectable prior to manifestation of the cancer phenotype will place emphasis on prophylactic surgery.

Management of Cancer Affected Family Members Appropriate surgery and decision for adjuvant chemotherapy or radiotherapy should be performed in context with the patient's age and stage of disease. Unless the patient presents with advanced or metastatic disease, the physician should evaluate the contralateral breast for synchronous lesions. At minimum, a detailed contralateral breast exam and mammography should be peformed. In addition, contralateral breast biopsy [183] or fine-needle aspiration [178] with negative physical or mammographic exams is advocated.

Management of the Contralateral Breast Bilateral breast cancer frequently is observed within hereditary breast cancer syndromes increasing to 50% at 20 years [42]. In clinical situations where the primary lesion has been controlled, prophylactic contralateral mastectomy is recommended. The timing of contralateral mastectomy is based on the clinical stage of the primary lesion and, when possible, is correlated with reconstruction of the ipsilateral breast. Patients with stage I disease are considered candidates either immediately [183186] or in 3-6 mo. Patients with a more advanced stage of disease, or those undergoing adjuvant therapy, are deferred until the primary lesion is considered controlled. Reconstruction and prophylactic mastectomy are best performed by a reconstructive surgeon [186]. An aggressive approach to the contralateral breast is indicated once the cancer phenotype is manifested, thus confirming the presence of the genotype within hereditary syndromes. Patients not considered candidates for prophylactic surgery due to medical or personal reasons should be placed in an intensive surveillance program.

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Prophylactic Mastectomy: Rationale In an effort to decrease the mortality and morbidity of patients developing breast cancer, novel and differing approaches have been developed. Education of the general population to earlier detection of breast malignancy has been only partially successful. Certainly, most patients discover their own malignant masses (90%95%), and then seek medical attention [49, 171,175]. However, Pennisi [187] argues that despite this apparent educational success, the National Surgical Adjuvant Breast Project showed that the average size of a new breast malignancy is still 3 cm /stage II). Since a small nidus of malignant cells must double 30 times before reaching a palpable size of 1 cm, and since doubling times may vary anywhere from 23 to 209 days (with an accepted average of 100 days), a malignant tumor could be present for at least 2 years before clinical manifestation [166]. The risk for distant metastasis during this time period may be significant since electron microscopy has demonstrated that the basement membrane of ductal malignancies may rupture early, allowing metastasis to develop prior to clinical presentation of the primary tumor [166]. Additionally, studies have demonstrated a 5% incidence of axillary metastasis with "noninvasive" lesions, and 15% with minimally invasive lesions [188]. Consequently, the need to identify high-risk patients for consideration of other treatment modalities before the appearance of an overt malignancy certainly is warranted. The rationale for prophylactic mastectomies in high-risk patients is based on the developmental concept for breast malignancy. Simply, this hypothesis assumes that normal breast tissue must undergo a premalignant state prior to further degeneration into malignancy. Experimental data using animal models appears to support this concept and it seems reasonable to apply it to the clinical situation [188]. Prophylactic mastectomy should minimize breast tissue and, hence, the risk for malignant degeneration. Prophylactic subcutaneous mastectomy (PSM) has received criticism for failure to remove all existing breast tissue [189]. In the "standard" subcutaneous mastectomy, a cuff of breast tissue is left beneath the nipple to insure an adequate blood supply. Additionally, critics felt breast residuals may be left in skin and in the pectoralis fascia based on Hickens' work in 1940 [190]. In an attempt to ameliorate this problem, PSMs performed on high-risk patients from our Cancer Genetics Center include removal of the nipple core and the elevation of thin skin flaps from the underlying breast mounds. Patient Selection PSM is utilized in two clinical situations within the hereditary breast cancer syndromes: (a) contralateral mastectomy in cancer affected family members; and (b) bilateral PSMs in highly selected, unaffected, but high-risk (50%) family members [184]. It must be stressed, however, that surveillance remains our primary option in high-risk family members in lieu of a defined biomarker of genotype. Prior to the actual surgery, the patient is counseled regarding the goals of the procedure and possible complications. The patient must understand that the primary surgical goal is to minimize the risk for breast cancer development by removing as much of the breast tissue as possible. Aesthetic results should never compromise the extent of the mastectomy, and the procedure should not be considered cosmetic surgery. The patient should be informed of the potentiality of an occult carcinoma. In the event a second primary is detected, treatment options should be outlined prior to prophylactic surgery. The post-op appearance of the breast after PSM is described, including the early results, compared with the expected late re-

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H.T. Lynch et al. suits. The patient is instructed regarding the site and appearance of the scars of the nipple/areola complex, if it is to be removed and replaced as a skin graft. Decreased sensation of the skin area for 1-2 years post-op, and hypopigmentation in the nipple graft should be expected. Obviously, no breast feeding can occur after PSM.

Prophylactic Mastectomy for Hereditary Breast Cancer In high risk patients, the nipple/areola complex is outlined by an elliptical incision. A second incision is made to separate the areola from the nipple, which remains attached to the breast m o u n d (Fig. 18A). The areola is removed as a split-thickness skin graft and placed in a saline-moist sponge (Fig. 18B). Prior to regrafting in the noncancer-affected patient, the 3athologist performs frozen sections of the areola base to avoid tumor implantation [191]. Thin skin flaps are developed and the breast m o u n d with its axillary tail is surgically removed (Fig. 18C). The specimen is tagged with a suture at the nipple site and at the axillary tail to allow proper orientation for microscopic exam. The pathologist, who is aware of the patient's genetic risk, evaluates the breast immediately with frozen sections [192]. At our institution, each breast is sectioned

Figure 18 Sequential approach to surgical management of hereditary nonaffected high risk breast (see text for details).

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into thin slices, no more than 1 cm in thickness, immediately following mastectomy. The breast is then meticulously examined by an experienced pathologist. The role of specimen mammography currently is being evaluated in the interpretation of such specimens [169, 176]. A complete and thorough pathologic evaluation is mandated, because of the hereditary risk and the need to alter clinical approach if unsuspected cancer is discovered. If no cancer is discovered at frozen section, reconstruction is performed. The reconstructive surgeon places a silicone breast prosthesis in a pocket developed beneath the pectoralis major muscle (Fig. 18D). The muscle is closed and the skin envelope is approximated (Fig. 18F). The areola graft is sutured to its new position in a deepithelialized area of the breast envelope (Fig. 18E). In situations where invasive cancer is found on frozen section at the time of PSM (not an uncommon occurrence), the surgical procedure immediately is converted to a modified radical mastectomy by the cancer surgeon. If the permanent studies on the frozen section negative breasts show invasive or in situ cancer, the treatment alternatives are outlined to the patient. A low axillary dissection is performed for in situ lesions, and invasive cancer is treated in standard fashion, usually converting the procedure to a modified radical mastectomy.

Clinical Queries Based on our observed distinctive natural history for hereditary breast cancer, two immediate clinical questions must be considered: (a) Is there a genetic effect on results from adjuvant therapy? Hereditary breast cancer is more common in premenopausal women, but is associated with an improved survivorship. Based on this knowledge, it becomes increasingly important to stratify for family history all patients entered into adjuvant treatment protocols for breast cancer. Such a consideration is mandated because of possible unknown pharmacogenetic differences between sporadic and hereditary subgroups. We are concerned that observed improvement in premenopausal adjuvant trials may reflect a genetic influence upon survival; and (b) What about the long-term effect of local excision and primary radiation in the treatment of breast cancer in the hereditary subset? We have demonstrated that the risk to the contralateral breast is 50% at 20 years within the hereditary group. It has been our recommendation that such patients expressing the cancer phenotype should undergo removal of all breast tissue when feasible. The long-term risk with conservative surgery to the contralateral breast, and remaining ipsilateral breast tissue, must be strongly considered in primary treatment decision making, in patients with genetic breast cancer syndromes. In summary, the clinical approach to hereditary breast cancer requires an informed patient and physician. This entity poses a major public health problem, and is the significant determinant of high risk premenopausal women destined to develop breast cancer. Knowledge of its natural history allows for development of specific management and surveillance protocols. DISCUSSION This review has covered wide-ranging interest in determining which patients in the general population are at greatest risk for developing breast cancer. It is apparent that patients at highest risk are those who are members of families that portray the cardinal features of the hereditary form of this disease. Herein, the progeny or sisters of a breast cancer-affected individual will show an approximate 50% risk for the development of this disease. However, the clinician must be fully cognizant of genetic heterogeneity based on tumor associations so that, in certain circumstances,

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cancer of other anatomic sites must be m e t i c u l o u s l y appraised. For example, carcinoma of the ovary in the case of hereditary breast/ovarian carcinoma syndromes, may form the basis for d e t e r m i n a t i o n of risk factors. In other circumstances, males may be vulnerable to certain cancers as in the SBLA syndrome, w h e r e i n a w i d e spectrum of tumors must be a p p r a i s e d for the estimation of cancer risk to any ind i v i d u a l w i t h i n the pedigree. Since, with few exceptions, Cowden's disease (for example), p r e m o n i t o r y physical signs are u n i f o r m l y lacking as a basis for risk factor estimation in breast cancer, the search for biomarkers that correlate w i t h genotype must continue to be given the highest possible priority in the study of this disease(s). We have discussed several biomarkers, i n c l u d i n g wet or dry cerumen, cytologic evidence of d y s p l a s i a in breast secretion, linkage studies of GPT, and most recently, the finding of in vitro h y p e r d i p l o i d y in cultured skin fibroblasts. With respect to the latter, we have shown in vitro h y p e r d i p l o i d y to occur with increased frequency in breast canceraffected i n d i v i d u a l s , as well as in their p r i m a r y high risk progeny and/or siblings. This particular b i o m a r k e r takes on a d d e d meaning w h e n one considers that in vitro h y p e r d i p l o i d y s h o u l d n o t occur in so-called normal i n d i v i d u a l s w i t h i n a population. In vitro tetraploidy, on the other hand, has been found among a p p r o x i m a t e l y 0 % - 7 % of the so-called normal p o p u l a t i o n [147]. Yet, even w i t h i n this subset of the p o p u l a t i o n showing increased in vitro tetraploidy, certain patients have been s h o w n to have positive family histories and, therefore, m a y be bearers of the cancer prone genotype. In vitro h y p e r d i p l o i d y has also been found in patients prone to ovarian carcin o m a and in FAMMM. Our new observation in hereditary breast cancer merits verification in a continuing cohort of patients w i t h well defined hereditary breast cancer syndromes. Given the heterogeneity of hereditary breast cancer, it is possible that in vitro h y p e r d i p l o i dy m a y be exhibited in certain hereditary forms, while it m a y be absent in others. Therefore, clinical trials testing the sensitivity and specificity of this biomarker must be performed on m e t i c u l o u s l y d o c u m e n t e d k i n d r e d s with the several hereditary cancer syndromes. Ideally, a risk factor-profile will be compiled, w h e r e i n a battery of biomarkers m a y be c o n c o m i t a n t l y investigated so that the best possible means for identifying patients at high risk for the disease might be established. This w o u l d then have major relevance to surveillance/management measures by signifying patients who have the highest risk of d e v e l o p i n g this disease versus those whose risk may a p p r o a c h that of the general population. These biomarkers also s h o u l d be a p p r a i s e d in context w i t h protooncogene technology [21]. The study of patients from breast cancer prone kindreds, with particular e m p h a s i s on those who show evidence of one or more of the subject biomarkers, i n c l u d i n g in vitro h y p e r d i p l o i d y , should provide a powerful m o d e l in the search for a breast cancer-transforming gene(s). This is conceivably c o m p a r a b l e to the h u m a n colonic a d e n o c a r c i n o m a transforming gene recently identified as a cellular homologue of the Kirsten sarcoma (v-ras), w h i c h was used to assign the human cellular Kirsten ras2 gene to c h r o m o s o m e #12 by the Southern h y b r i d i z a t i o n m e t h o d [21]. In summary, h e r e d i t a r y breast cancer has been d e m o n s t r a t e d to be distinct from its sporadic counterpart. Environmental influences, although certainly i m p o r t a n t in overall breast cancer etiology, have been shown to have little, if any, effect on the expression of the hereditary variant. Supported in part by a grant from the Fraternal Order of Eagles and the Council for Tobacco Research, USA, Inc., Grant no. 1297AR2.

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DEDICATION W i l l i a m A l e x a n d e r A l b a n o , M.D. A u g u s t 6, 1 9 4 5 - J u l y 7, 1983

This Review Article in Cancer Genetics and Cytogenetics is dedicated to the memory of our beloved colleague, William Albano, M.D., who suffered an untimely death at age 37. A dedicated family man, Bill was in the midst of a career that combined his extraordinary skills in surgical oncology with his brilliant insights into research in cancer genetics. His greatest focus of research interest in this field was in hereditary breast cancer. Bill was an extremely dedicated and compassionate surgical oncologist. He would become terribly saddened with discovery of positive lymph nodes and/or other evidences of cancer metastasis in his patients. He was particularly troubled by the plight of women that comprise the hereditary subset of breast cancer; namely, w o m e n with young children and at the very peak of their lives. Dr. Albano fervently hoped that knowledge gleaned from his research in cancer genetics could aid in the recognition of those patients highly vulnerable to this disease. He firmly believed they would benefit from the highly targeted surveillance/management programs he was so steadfastly developing. Bill was willing to travel thousands of miles to visit cancer-prone families. W h e n he wasn't performing clinical examinations during our "field visits," he devoted his time to the education of high-risk family members. Before leaving the clinic, he insisted that these women demonstrate their full comprehension of the surveillance plan, including self breast examination and knowledge of their cancer risk status. Bill was a profound listener. He was always empathetic to the needs of his patients. He thoroughly understood the deep emotional conflicts experienced by patients at risk for hereditary breast cancer. Those who have worked with members of hereditary cancer-prone families will fully appreciate the impact of this problem. All of us share the loss of our colleague.