Henry P Leis, Jr, MD
Risk factors in breast cancer Breast cancer is not a chance event that occurs randomly throughout the population. There are women who have an increased risk for developing it.l Furthermore, breast cancer appears to be due to a constellation of risk factors rather than to a single one. Genetic predisposition, carcinogen exposure (especially viruses), immunodeficiency, and adverse hormonal milieu are the most important of these.2 It is postulated that there are two main types of breast cancer associated with different age peaks and hormonal relationship^.^ The first type, occurring in the premenopausal
Henry P Leis, Jr, MD, FACS, FICS (honorary) is clinical professor and chief, breast service, department o f surgery, New York Medical College, New York City. He is a graduate o f Fordham University, New York City, and New York Medical College.
woman with an age peak of 45 to 49, seems to be related to the secretion of estradiol and estrone predominately by the ovaries. Estriol, the impeding or blocking agent against the potential carcinogenic effects of estradiol and estrone, is not secreted directly by the ovaries but is formed by the metabolism of estrone and estradiol. Parity seems to offer its protective influence against breast cancer in the postmenopausal group rather than in the premenopausal group. The protective influence of early parity appears to be related t o the high production of estriol during pregnancy. The estrio1 may be bound into the estrogen receptors in place of estrone and estradiol, exerting its influence chiefly in the postmenopausal patient where the estrogen milieu is unbalanced estrone, a strong ~arcinogen.~ The second type of breast cancer, occurring in the postmenopausal patient with an age peak at 65, seems to be related to adrenal function. Neither the ovaries nor the adrenals secrete significant quantities of either estradiol or estrone in the postmenopausal patient and of course the antagonistic hormone t o estrogen, progesterone, is no longer formed. Estrogen formation in the post-
AORN Journal, November 1975,Vol22, No 5
723
One in every 75 . . . Breast cancer is the most common type of cancer in women. One out of every 15 women, or about 7 percent will develop it during their normal life expectancy. The number of breast cancers has been increasing in the United States as evidenced by the rise from 69,600 new cases in 1971 to an estimated 90,000 in 1974. This increase is due largely to the fact that the female population has increased and women are living longer, reaching older age groups where breast cancer is more common. There has also been an increase in the incidence rates per 100,000 population in certain sections of the country, chiefly in women under 55 years of age. The question arises whether it is a true increase or a reflection of earlier diagnosis, better reporting, and the inclusion of the entity of lobular carcinoma in situ which was first described by Foote and Stewart in 1941. Breast cancer is the leading cause of cancer death in females, and it is the leading cause of death due to all causes in women
aged 40 to 44. Every 17 minutes in the United States, one woman dies from breast cancer. Dramatic changes have occurred in the mortality rates of some other organ cancers but despite the noteworthy improvement in survival rates, the mortality rates in breast cancer remained relatively unchanged for half a century. In the past decade, there has been a small but definite improvement in cure rates. With the increased incidence of breast cancer, even if the mortality rates remain fixed,there must be an improvement in overall mortality. This improvement seems to be due chiefly to earlier diagnosis rather than improved methods of therapy. The earlier the cancer is diagnosed, the better is the cure rate with appropriate therapy.
menopausal patient is due to the elaboration by the adrenals of a C-19 steroidal precursor, androstenedione, which is carried to the peripheral tissues by the bloodstream where it is ~ proconverted to e ~ t r o n e .Excessive duction of estrone by this mechanism has been definitely implicated in endometrial carcinoma. This continuous progesterone-unopposed production of estrone, which has a high carcinogenic potential, may well be of significance in the etiology of breast cancer. Numerous factors have been identified as being related to the development of breast cancer. These factors can be divided into major, prominent, possible, and questionable groups and evaluated accordingly. Major risk factors Sex. Over 99 percent of breast cancers occur in the female.6 Age. Seventy-five percent of breast
cancers are clinically detectable over the age of 40. However, since some cancers in a preclinical stage are detectable several years before this by the use of diagnostic aids,' women over 35 years of age are also considered to have an increased risk. Family history of breast cancer. The hereditary forms of breast cancer have an earlier age of onset and tend to be bilateral and multiple. Family history seems to have little influence on breast cancer risk in the postmenopausal patient especially if the cancer is unilateral. The increased risk for developing breast cancer reaches a ninefold level in women whose mother and sister have premenopausal, bilateral breast cancers.* Parity. Having borne offspring is very important especially as related to the age of the first birth with a decreased risk of three to fourfold if the
724
Biometv Branch, National Cancer Institute, Cancer Rates and Risks (Washington, DC: US Government Printing Office, Department of Health, Education, and Welfare No (NIH) 75-691, 7974); H Seidman, Statistlcai and Epidemiological Data on Cancer of the Breast (New York: American Cancer Society, 1972); E Silverberg, A I Molleb, "Cancer statistics 1974," Cancer 24 (1974) 2.
AORN Journal, November 1975, Vol22, No 5
first birth is before 18 years of age. There is a declining, but still decreased, risk up to the age of 25 for the first parity. There is an increased risk in unmarried women, infertile women, women with less than three children, and women with their first child after age 34. However, parity seems to offer its protective influence against the development of breast cancer in the postmenopausal group of patients rather than in the premenopausal group.9 Nursing, even when prolonged, does not appear to influence the incidence risk.1° Previous cancer in one breast. The risk of developing a primary cancer in the second breast after the first has been removed for cancer is about five times greater than the risk of initial breast cancer in the general population. Precancerous mastopathy type of fibrocystic disease. Patients with a precancerous mastopathy type of fibrocystic disease have a fivefold increased risk.12 The term, precancerous mastopathy, as coined by Black, includes patients with duct epithelial hyperplasia with atypia (with o r without papillomatosis) and apocrine metaplasia with atypia. Fibrocystic disease in general, however, has only about a two and one-half-fold risk increase.13 Prominent risk factors Prolonged total menstrual activity. There is an increased incidence of breast cancer in patients with menarche under 12 years of age, in those with 30 or more years of menstrual activity, and in those with menopause after age 55.14 Furthermore, artificial menopause (castration), especially before the age of 37, dramatically reduces the incidence of breast cancer.15 Early onset of menopause gives the same kind of pro-
tection for older women that early pregnancy does for younger women.ls Other organ cancers. There is an increased risk for developing breast cancer in women who have had a previous cancer of the ovary, colon, salivary gland, or endometrium" with the risk being most marked in endometrial cancer where a 30 percent increase in breast cancer has been reported over the expected number.'* Wet type cerumen (earwax). There seems to be a strong global association between the type of earwax (cerumen), wet or dry, which is controlled by a dominant gene in the apocrine glandular system of which the breast is a part. The incidence of breast cancer is increased in patients with the wet type of wax. This, like familial history, emphasizes the importance of genetic predisposition. High dietary fat intake. There is also considerable evidence suggesting an increased risk for developing breast cancer related to a high dietary fat intake correlating with the low incidence in Japan and Oriental countries where the dietary fat intake is 10w.19 Triad of obesity, diabetes, and hypertension. There is an increased risk of both breast and endometrial cancer in women who are obese, diabetic, and hypertensive, possibly related to an imbalance of adrenal estrogens.20 Hypothyroidism. There is also an increased incidence of breast and endometrial cancer in patients who are hypothyroid.21 Chronic psychologic stress. Chronic psychologic stress is frequently present in women with breast cancer. Stress may produce a risk increase by a n excess production of corticosteroids, which have an immunosuppressive effect, or by mobilization of fats produc-
AORN Journal, November 1975, Vol22, No 5
725
S
tress is frequently present in women with breast cancer.
ing results similar to a high dietary fat intake.22 Possible risk factors Heavy radiation exposure. Heavy radiation exposure has been shown to increase the incidence of breast cancer,23but the exposure from mammography, especially with the new low dose technique, would not seem to be significant even if mammography were done on a yearly basis over a 25-year period.24 Immunodeficiency. The host normally has an immunologic resistance or defense against the development of breast cancer. Any breakdown or decrease in this immunologic mechanism, such as produced by chemotherapeutic drugs, chemicals, or immunosuppressive drugs used in transplants, facilitates the development of cancer.25 Methods are becoming available to measure the degree of host resistance and thus identify people with an increased risk.2e The future of breast cancer control may well rest in immunology with the ability to identify immunodeficient patients, to immunize patients with vaccines against breast cancer, and to develop drugs that can increase host resistance (immunopotentiator~).~~ Viral carcinogen. Viral particles similar to those found in the milk of mice with breast cancer, which can be transmitted to the offspring through the milk causing mouse mammary
726
carcinoma, have been found in the milk of humans with breast cancer2* and in the milk of women with a familial history of breast cancer.29 This suggests the possibility of certain women being carriers of this virus raising the question of the propriety of women with a familial history of breast cancer nursing their offspring. It may be possible to develop a relatively easy way of identifying such carriers and developing a vaccine similar t o the one for mice to protect them against breast cancer.30 Adverse hormonal milieu. Certain patients with abnormal hormonal titers seem to have an increased risk for developing breast cancer. These include patients with low fractions of estriol,31 and those with subnormal levels of aetiocholanolone or androsterone or both.32 If simple methods t o measure levels of these hormone titers are developed, population screening may be possible in the future.33 Exogenous estrogen administration. There is no statistically valid evidence to show that exogenous estrogen administration, whether as birth control pills or as preparations containing estrogens for menopausal symptoms, increases the incidence of breast cancer.34However, if a cancer is present, it increases the rate of While there may not be any effect on breast cancer incidence in the population as a whole, there may be a
AORN Journal, November 1975,Vol22, No 5
subgroup of the population, namely nulliparous or late parous women, in which the administration of exogenous estrogens could increase the incidence risk.36 With any prolonged administration of exogenous estrogens, the preparation used should contain the estriol fraction that serves as an impeding or blocking agent against the potential carcinogenic effects of estrone and estradiol. Progesterone should also be given for its antagonistic effects on estrogens.37 Trauma. No definite relationship can be established between a single acute trauma (injury) and the inception of breast cancer in humans, but it is possible that trauma could aggravate preexisting c a r c i n ~ m a . ~ ~ Chemicals and drugs. Certain chemicals, such as polycyclic hydrocarbons, have been shown to induce breast cancer in laboratory animals.39Recent studies have reported that patients taking reserpine, a commonly used hypertensive drug, have had an increased incidence of breast cancer.40 Questionable risk factors The increased incidence of breast cancer reported in women living in the Western Hemisphere, in those living in a cold climate, in those in the upper socioeconomic group, in the white race as compared to the black and Oriental, and in Jewish women, may well be related to previously discussed factors
such as age of first parity, dietary fat intake, chronic psychologic stress, rather than being true epidemiological factors.41 Summary Increasing knowledge about the incidence and mortality rates of breast cancer has made a noteworthy impact on the public. The importance of the identification of women with an increased risk for developing breast cancer and of early diagnosis as related to cure rates is also becoming well recognized. Emphasis must now be placed on the discovery of the cause or causes of breast cancer and eradicating them. Until then, determining the best type of treatment for each individual patient with breast cancer is important. 0 Notes 1. H P Leis, Jr, A Raciti, The Search for the High Risk Patient. New Aspects of CancerPatients at High Risk, B A Stoll, ed. (London, England: Heineman Medical Books Ltd, 1975). 2. Leis and Raciti, Search for the High Risk Patient. 3. F DeWaard, E D Baanders-Van Halewijn, J Huizinga, “The bimodal age distribution of patients with mammary carcinoma; evidence for the existence of two types of human breast cancer,” Cancer 17 (1964) 141. 4. Leis and Raciti, Search for the High Risk Patient. 5. P Siiteri, “Endocrine aspects of breast cancer,” in Current Concepts in Breast Cancer, J R Castro, T S Meyler, D G Baken, eds. (Flushing, NY: Medical Examination Publishing Co, 1975).
AORN Journal, November 1975, Vol22, No 5
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6. H P Leis, Jr, Diagnosis and Treatment of Breast Lesions (Flushing, NY: Medical Examination Publishing Co, 1970). 7. Leis, Diagnosis and Treatment of Breast Lesions; H P Leis, Jr, “Multidisciplinary approach to the early diagnosis of breast cancer,” lnternational Surgery 56 (1971) 135; Leis and Raciti, Search for the High Risk Patient. 8. D E Anderson, ”A genetic study of human breast cancer,” Journal of the National Cancer lnstitute 48 (1972) 1029; D E Anderson, “The role of genetics in human cancer,” Cancer 24 (1974) 130. 9. J E Dunn, Jr, “Epidemiology and possible identification of high-risk group that could develop cancer of the breast,” Cancer 23 (1969) 775; B MacMahon, et al, “Age at first birth and breast cancer risk,” Bulletin of the World Health Organization 43 (1970) 209; H Seidman, Statistical and Epidemiological Data on Cancer of the Breast (New York: American Cancer Society, 1972). 10. B MacMahon, et al, “Lactation and cancer of the breast: A summary of an international study,” Bulletin of the World Health Organization 42 (1970) 185. 11. H P Leis, Jr, “Selective, elective prophylactic, contralateral simple mastectomy,” Cancer 28 (1971) 956; H P Leis, Jr, “Primary cancer in the second breast,” in Multiple Primary Malignant Tumors, I Severi, ed. (Monteluce, Italy: Perugia University Medical School Press, 1974); H P Leis, Jr, et al, “The second breast,” New York State Journal of Medicine 65 (1965) 2460; G F Robbins, J W Berg, “Bilateral primary breast cancers,” Cancer 17 (1964) 1501; J A Urban, ”Bilateral breast cancer,” Cancer 24 (1969) 826. 12. M M Black, et al, “Association of atypical characteristics of benign breast lesions with sub sequent rise of breast cancer,” Cancer 29 (1972) 338; C M Karpas, et al, “Relationship of fibrocystic disease to carcinoma of the breast,” Annals of Surgery 162 (1965) 1; H P Leis, Jr, “Pramalignant breast lesions,” in Symposium on Neoplastic and Reconstructive Problems of the Female Breast, R Snyderman, ed. (St Louis: C V Mosby Co, 1973) 11. 13. H H Davis, M Simons, J B Davis, “Cystic disease and carcinoma of the breast: Relationship to carcinoma,” Cancer 17 (1964) 957. 14. Seidman, Statistical and Epidemiological Data on Cancer of the Breast; S Shapiro, et al, ”The search for risk factors in breast cancer,” American Journal of Public Health 58 (1968) 820; D Trichopoulos, B MacMahon, P Cole, “Menopause and breast cancer risk,” Journal of the National Cancer lnstitute 48 (1972) 605. 15. Dunn, “Epidemiology and possible identification“; T Hirayama, E L Wynder, “A study of the
728
epidemiology of cancer of the breast: The influence of hysterectomy,” Cancer 15 (1962) 28. 16. Dunn, “Epidemiology and possible identification”; Hirayama and Wynder, “A study of the epidemiology.” 17. B S Schoenberg, R A Greenberg, A Eisenberg, “Occurrence of certain multiple primary cancers in females,” Journal of the National Cancer lnstitute 43 (1969) 15. 18. B MacMahon, J H Austin, “Association of carcinomas of the breast and corpus uteri,” Cancer 23 (1969) 275. 19. K K Caroll, E B Gammel, E R Plunkett, “Dietary fat and mammary cancer,” Canadian Medical Association 98 (1968) 590; A N Papaioannou, “Etiologic factors in cancer of the breast,” Surgery, Gynecology & Obstetrics 138 (1974) 257; E L Wynder, “Identification of women at high risk for breast cancer.” Cancer 24 (1969) 1235. Baanders-Van Halewijn, 20. DeWaard, Huizinga, “The bimodal age distribution”; A S Ketcham, ”Predictable categories of increased risk to breast cancer,” AORN Journal 19 (1974) 852. 21. K Blackwinkel, A S Jackson, “Some features of breast cancer and thyroid deficiency,” Cancer 17 (1964) 1174; G A Edelstyn, A R Lyons, R B Welbourn, “Thyroid function in patients with mammary cancer,” Lancet 1 (1958) 670; Papaioannou, “Etiologic factors in cancer of the breast.” 22. E B Feldman, A C Carter, ”Circulatory lipids and lipoproteins in women with metastatic breast carcinoma,” Journal of Clinical Endocrinology and Metabolism 33 (1971) 8; Papaioannou, “Etiologic factors in cancer of the breast.” 23. I MacKenzie, “Breast cancer following multiple fleuroscopies,” British Journal of Cancer 19 (1965) 1; F A Mettler, Jr, L H Hempelmann, A M Dutton, “Breast neoplasms in women treated with x-rays for acute postpartum rnastitis,” Journal of the National Cancer lnstitute 43 (1969) 803; D Schottenfeld, A M Lilienfeld, H Diamond, ”Some observations on the epidemiology of breast cancer among males,” American Journal of Public Health 53 (1963) 890; C K Wanebo, et al, “Breast cancer after exposure to the atomic bombings of Hiroshima and Nagasaki,” New England Journal of Medicine 279 (1968) 667. 24. P Strax, “Practical mass screening for earlier breast cancer detection,” Postgraduate Course 045 #15, American College of Obstetricians & Gynecologists Meeting, Las Vegas. 25. Papaioannou, “Etiologic factors in cancer of the breast”; B Serrou, et al, “lmmunodepression” in Multiple Primary Malignant Tumors, I Severi, ed. (Monteluce, Italy: Perugia University Medical School Press, 1974).
AORN Journal, November 1975, Vol22, No 5
26. M M Black, “Human breast cancer: A model for cancer immunology,” Israel Journal of Medical Sciences 9 (1973) 284; M M Black, H P Leis, Jr, “Cellular responses to autologous breast cancer tissue-sequential observations” Cancer 32 (1973) 384; M M Black, et al, ”Cellular hypersensitivity to breast cancer: Assessment by a leukocyte migration procedure,” Cancer 33 (1974) 952. 27. Leis and Raciti, Search for the High Risk Patient. 28. L Dmochowski, G Seman, H S Gallagher, “Viruses as possible etiologic factors in human breast cancer,” Cancer 24 (1969) 1241; D H Moore, J Charney, B Kramarky, ”Search for a human breast cancer virus,” Nature 229 (1971) 611. 29. J Schlom, S Spiegelman, D H Moore, “Reverse transcriptase and high molecular weight RNA in particles from mouse and human milk,” Journal of the National Cancer Institute 48 (1972) 1197. 30. M M Black, et al, ”Effect of murine milk samples and human breast tissues on human leukocyte migration indices,” Cancer Research 34 (1974) 1054; J Charney, D H Moore, ”Neutralization of murine mammary tumor virus by sera of women with breast cancer,’’ Nature 229 (1971) 627; Leis and Raciti, Search for the High Risk Patient; F Squartini, “Muttiple cancers in the mammary gland system,” in Multiple Primary Malignant Tumors I Severi, ed. (Monteluce, Italy: Perugla University Medical School Press, 1974). 31. P Cole, B MacMahon, “Hypothesis: Oestrogen fractions during early reproductive life in the etiology of breast cancer,’’ Lancet 1 (1969) 604; H M Lemon, “Abnormal estrogen metabolism and tissue estrogen receptor proteins in breast cancer,” Cancer 25 (1970) 423; H M Lemon, et al, “Reduced estriol excretion in patients with breast cancer prior to endocrine therapy,” Journal of the American Medicat Association 196 (1966) 1128; B MacMahon, P Cole, J B Brown, “Oestrogen profiles of Asian and North American women,” Lancet 2 (1971) 900. 32. R D Bulbrook, J L Hayward, D S Allen, “Further observations on steroid excretion and subsequent breast cancer in Guernsey,” in Hormonal Aspects in the Epidemiology of Human Breast Cancer, J H DeBussy, ed. (Amsterdam, 1969) 163; R D Bulbrook, J L Hayward, C C Spicer, “Relation between urinary androgen and corticoid excretion and subsequent breast cancer,” Lancet 21 (1971) 395. 33. Leis and Raciti, Search for the High Risk Patient. 34. H P Leis, Jr, “The pill and the breast,” New York State Journal of Medicine 70 (1970) 2911; Leis and Raciti, Search for the High Risk Patient.
35. C Huggins, N C Yang, “Induction and extinction of mammary carcinoma,” Science 137 (1962) 257. 36. M M Black, H P Leis, Jr, “Mammary carcinogenesis,” New York State Journal of Medicine 72 (1972) 1601. 37. Leis, “The pill and the breast”; Leis and Raciti, The Search for the High Risk Patient. 38. Leis, Diagnosis and Treatment of Breast Lesions; Leis and Raciti, Search for the High Risk Patient; L Pelner, “Host-tumor antagonism XVll Trauma and Cancer,” Journal of the American Geriatrics Society 9 (1961) 58-76. 39. G M Bonser, J A Dossett, J W Jull, Human and Experimental Breast Cancer (London: Pitman Medical Publishing Co, 1961). 40. B Armstrong, N Stevens, R Doll, “A retrospective study of the association between the use of Rauwolfia derivatives and breast cancer,’’ Lancet (September 1974). 41. Leis and Raciti, Search for the High Risk Patient.
People, pets, missed by hospital patients Separation from specific persons and material things causes the greatest loneliness in hospitals, according to a Medical College of Virginia (MCV) researcher. Gloria Francis, director of nursing research in the MCV School of Nursing at Virginia Commonwealth University, said that younger people become lonelier because they have a deep investment in specific persons and material things, which have been removed from their life schedule during a hospital stay. Having interviewed about 300 patients, Francis says that other people are missed most by hospitalized patients, followed by pets, stereo, radio, records, and television. Perhaps some of the loneliness could be alleviated, she said, if hospitals allowed brief visits by children and controlled pets. However, she explained there are benefits to being lonely. “Hospitalized patients go through a reflective period. They have a lot of time to think about the people who aren’t with them. They assess relationships over the years and often decide to make them better, and many of them do.”
AORN Journal, November 1975, Vol22, No 5
729
Risk factors in breast cancer Breast cancer is not a chance event that occurs randomly throughout the population. There are women who have an increased risk for developing it.l Furthermore, breast cancer appears to be due to a constellation of risk factors rather than to a single one. Genetic predisposition, carcinogen exposure (especially viruses), immunodeficiency, and adverse hormonal milieu are the most important of these.2 It is postulated that there are two main types of breast cancer associated with different age peaks and hormonal relationship^.^ The first type, occurring in the premenopausal
Henry P Leis, Jr, MD, FACS, FICS (honorary) is clinical professor and chief, breast service, department o f surgery, New York Medical College, New York City. He is a graduate o f Fordham University, New York City, and New York Medical College.
woman with an age peak of 45 to 49, seems to be related to the secretion of estradiol and estrone predominately by the ovaries. Estriol, the impeding or blocking agent against the potential carcinogenic effects of estradiol and estrone, is not secreted directly by the ovaries but is formed by the metabolism of estrone and estradiol. Parity seems to offer its protective influence against breast cancer in the postmenopausal group rather than in the premenopausal group. The protective influence of early parity appears to be related t o the high production of estriol during pregnancy. The estrio1 may be bound into the estrogen receptors in place of estrone and estradiol, exerting its influence chiefly in the postmenopausal patient where the estrogen milieu is unbalanced estrone, a strong ~arcinogen.~ The second type of breast cancer, occurring in the postmenopausal patient with an age peak at 65, seems to be related to adrenal function. Neither the ovaries nor the adrenals secrete significant quantities of either estradiol or estrone in the postmenopausal patient and of course the antagonistic hormone t o estrogen, progesterone, is no longer formed. Estrogen formation in the post-
AORN Journal, November 1975,Vol22, No 5
723
One in every 75 . . . Breast cancer is the most common type of cancer in women. One out of every 15 women, or about 7 percent will develop it during their normal life expectancy. The number of breast cancers has been increasing in the United States as evidenced by the rise from 69,600 new cases in 1971 to an estimated 90,000 in 1974. This increase is due largely to the fact that the female population has increased and women are living longer, reaching older age groups where breast cancer is more common. There has also been an increase in the incidence rates per 100,000 population in certain sections of the country, chiefly in women under 55 years of age. The question arises whether it is a true increase or a reflection of earlier diagnosis, better reporting, and the inclusion of the entity of lobular carcinoma in situ which was first described by Foote and Stewart in 1941. Breast cancer is the leading cause of cancer death in females, and it is the leading cause of death due to all causes in women
aged 40 to 44. Every 17 minutes in the United States, one woman dies from breast cancer. Dramatic changes have occurred in the mortality rates of some other organ cancers but despite the noteworthy improvement in survival rates, the mortality rates in breast cancer remained relatively unchanged for half a century. In the past decade, there has been a small but definite improvement in cure rates. With the increased incidence of breast cancer, even if the mortality rates remain fixed,there must be an improvement in overall mortality. This improvement seems to be due chiefly to earlier diagnosis rather than improved methods of therapy. The earlier the cancer is diagnosed, the better is the cure rate with appropriate therapy.
menopausal patient is due to the elaboration by the adrenals of a C-19 steroidal precursor, androstenedione, which is carried to the peripheral tissues by the bloodstream where it is ~ proconverted to e ~ t r o n e .Excessive duction of estrone by this mechanism has been definitely implicated in endometrial carcinoma. This continuous progesterone-unopposed production of estrone, which has a high carcinogenic potential, may well be of significance in the etiology of breast cancer. Numerous factors have been identified as being related to the development of breast cancer. These factors can be divided into major, prominent, possible, and questionable groups and evaluated accordingly. Major risk factors Sex. Over 99 percent of breast cancers occur in the female.6 Age. Seventy-five percent of breast
cancers are clinically detectable over the age of 40. However, since some cancers in a preclinical stage are detectable several years before this by the use of diagnostic aids,' women over 35 years of age are also considered to have an increased risk. Family history of breast cancer. The hereditary forms of breast cancer have an earlier age of onset and tend to be bilateral and multiple. Family history seems to have little influence on breast cancer risk in the postmenopausal patient especially if the cancer is unilateral. The increased risk for developing breast cancer reaches a ninefold level in women whose mother and sister have premenopausal, bilateral breast cancers.* Parity. Having borne offspring is very important especially as related to the age of the first birth with a decreased risk of three to fourfold if the
724
Biometv Branch, National Cancer Institute, Cancer Rates and Risks (Washington, DC: US Government Printing Office, Department of Health, Education, and Welfare No (NIH) 75-691, 7974); H Seidman, Statistlcai and Epidemiological Data on Cancer of the Breast (New York: American Cancer Society, 1972); E Silverberg, A I Molleb, "Cancer statistics 1974," Cancer 24 (1974) 2.
AORN Journal, November 1975, Vol22, No 5
first birth is before 18 years of age. There is a declining, but still decreased, risk up to the age of 25 for the first parity. There is an increased risk in unmarried women, infertile women, women with less than three children, and women with their first child after age 34. However, parity seems to offer its protective influence against the development of breast cancer in the postmenopausal group of patients rather than in the premenopausal group.9 Nursing, even when prolonged, does not appear to influence the incidence risk.1° Previous cancer in one breast. The risk of developing a primary cancer in the second breast after the first has been removed for cancer is about five times greater than the risk of initial breast cancer in the general population. Precancerous mastopathy type of fibrocystic disease. Patients with a precancerous mastopathy type of fibrocystic disease have a fivefold increased risk.12 The term, precancerous mastopathy, as coined by Black, includes patients with duct epithelial hyperplasia with atypia (with o r without papillomatosis) and apocrine metaplasia with atypia. Fibrocystic disease in general, however, has only about a two and one-half-fold risk increase.13 Prominent risk factors Prolonged total menstrual activity. There is an increased incidence of breast cancer in patients with menarche under 12 years of age, in those with 30 or more years of menstrual activity, and in those with menopause after age 55.14 Furthermore, artificial menopause (castration), especially before the age of 37, dramatically reduces the incidence of breast cancer.15 Early onset of menopause gives the same kind of pro-
tection for older women that early pregnancy does for younger women.ls Other organ cancers. There is an increased risk for developing breast cancer in women who have had a previous cancer of the ovary, colon, salivary gland, or endometrium" with the risk being most marked in endometrial cancer where a 30 percent increase in breast cancer has been reported over the expected number.'* Wet type cerumen (earwax). There seems to be a strong global association between the type of earwax (cerumen), wet or dry, which is controlled by a dominant gene in the apocrine glandular system of which the breast is a part. The incidence of breast cancer is increased in patients with the wet type of wax. This, like familial history, emphasizes the importance of genetic predisposition. High dietary fat intake. There is also considerable evidence suggesting an increased risk for developing breast cancer related to a high dietary fat intake correlating with the low incidence in Japan and Oriental countries where the dietary fat intake is 10w.19 Triad of obesity, diabetes, and hypertension. There is an increased risk of both breast and endometrial cancer in women who are obese, diabetic, and hypertensive, possibly related to an imbalance of adrenal estrogens.20 Hypothyroidism. There is also an increased incidence of breast and endometrial cancer in patients who are hypothyroid.21 Chronic psychologic stress. Chronic psychologic stress is frequently present in women with breast cancer. Stress may produce a risk increase by a n excess production of corticosteroids, which have an immunosuppressive effect, or by mobilization of fats produc-
AORN Journal, November 1975, Vol22, No 5
725
S
tress is frequently present in women with breast cancer.
ing results similar to a high dietary fat intake.22 Possible risk factors Heavy radiation exposure. Heavy radiation exposure has been shown to increase the incidence of breast cancer,23but the exposure from mammography, especially with the new low dose technique, would not seem to be significant even if mammography were done on a yearly basis over a 25-year period.24 Immunodeficiency. The host normally has an immunologic resistance or defense against the development of breast cancer. Any breakdown or decrease in this immunologic mechanism, such as produced by chemotherapeutic drugs, chemicals, or immunosuppressive drugs used in transplants, facilitates the development of cancer.25 Methods are becoming available to measure the degree of host resistance and thus identify people with an increased risk.2e The future of breast cancer control may well rest in immunology with the ability to identify immunodeficient patients, to immunize patients with vaccines against breast cancer, and to develop drugs that can increase host resistance (immunopotentiator~).~~ Viral carcinogen. Viral particles similar to those found in the milk of mice with breast cancer, which can be transmitted to the offspring through the milk causing mouse mammary
726
carcinoma, have been found in the milk of humans with breast cancer2* and in the milk of women with a familial history of breast cancer.29 This suggests the possibility of certain women being carriers of this virus raising the question of the propriety of women with a familial history of breast cancer nursing their offspring. It may be possible to develop a relatively easy way of identifying such carriers and developing a vaccine similar t o the one for mice to protect them against breast cancer.30 Adverse hormonal milieu. Certain patients with abnormal hormonal titers seem to have an increased risk for developing breast cancer. These include patients with low fractions of estriol,31 and those with subnormal levels of aetiocholanolone or androsterone or both.32 If simple methods t o measure levels of these hormone titers are developed, population screening may be possible in the future.33 Exogenous estrogen administration. There is no statistically valid evidence to show that exogenous estrogen administration, whether as birth control pills or as preparations containing estrogens for menopausal symptoms, increases the incidence of breast cancer.34However, if a cancer is present, it increases the rate of While there may not be any effect on breast cancer incidence in the population as a whole, there may be a
AORN Journal, November 1975,Vol22, No 5
subgroup of the population, namely nulliparous or late parous women, in which the administration of exogenous estrogens could increase the incidence risk.36 With any prolonged administration of exogenous estrogens, the preparation used should contain the estriol fraction that serves as an impeding or blocking agent against the potential carcinogenic effects of estrone and estradiol. Progesterone should also be given for its antagonistic effects on estrogens.37 Trauma. No definite relationship can be established between a single acute trauma (injury) and the inception of breast cancer in humans, but it is possible that trauma could aggravate preexisting c a r c i n ~ m a . ~ ~ Chemicals and drugs. Certain chemicals, such as polycyclic hydrocarbons, have been shown to induce breast cancer in laboratory animals.39Recent studies have reported that patients taking reserpine, a commonly used hypertensive drug, have had an increased incidence of breast cancer.40 Questionable risk factors The increased incidence of breast cancer reported in women living in the Western Hemisphere, in those living in a cold climate, in those in the upper socioeconomic group, in the white race as compared to the black and Oriental, and in Jewish women, may well be related to previously discussed factors
such as age of first parity, dietary fat intake, chronic psychologic stress, rather than being true epidemiological factors.41 Summary Increasing knowledge about the incidence and mortality rates of breast cancer has made a noteworthy impact on the public. The importance of the identification of women with an increased risk for developing breast cancer and of early diagnosis as related to cure rates is also becoming well recognized. Emphasis must now be placed on the discovery of the cause or causes of breast cancer and eradicating them. Until then, determining the best type of treatment for each individual patient with breast cancer is important. 0 Notes 1. H P Leis, Jr, A Raciti, The Search for the High Risk Patient. New Aspects of CancerPatients at High Risk, B A Stoll, ed. (London, England: Heineman Medical Books Ltd, 1975). 2. Leis and Raciti, Search for the High Risk Patient. 3. F DeWaard, E D Baanders-Van Halewijn, J Huizinga, “The bimodal age distribution of patients with mammary carcinoma; evidence for the existence of two types of human breast cancer,” Cancer 17 (1964) 141. 4. Leis and Raciti, Search for the High Risk Patient. 5. P Siiteri, “Endocrine aspects of breast cancer,” in Current Concepts in Breast Cancer, J R Castro, T S Meyler, D G Baken, eds. (Flushing, NY: Medical Examination Publishing Co, 1975).
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6. H P Leis, Jr, Diagnosis and Treatment of Breast Lesions (Flushing, NY: Medical Examination Publishing Co, 1970). 7. Leis, Diagnosis and Treatment of Breast Lesions; H P Leis, Jr, “Multidisciplinary approach to the early diagnosis of breast cancer,” lnternational Surgery 56 (1971) 135; Leis and Raciti, Search for the High Risk Patient. 8. D E Anderson, ”A genetic study of human breast cancer,” Journal of the National Cancer lnstitute 48 (1972) 1029; D E Anderson, “The role of genetics in human cancer,” Cancer 24 (1974) 130. 9. J E Dunn, Jr, “Epidemiology and possible identification of high-risk group that could develop cancer of the breast,” Cancer 23 (1969) 775; B MacMahon, et al, “Age at first birth and breast cancer risk,” Bulletin of the World Health Organization 43 (1970) 209; H Seidman, Statistical and Epidemiological Data on Cancer of the Breast (New York: American Cancer Society, 1972). 10. B MacMahon, et al, “Lactation and cancer of the breast: A summary of an international study,” Bulletin of the World Health Organization 42 (1970) 185. 11. H P Leis, Jr, “Selective, elective prophylactic, contralateral simple mastectomy,” Cancer 28 (1971) 956; H P Leis, Jr, “Primary cancer in the second breast,” in Multiple Primary Malignant Tumors, I Severi, ed. (Monteluce, Italy: Perugia University Medical School Press, 1974); H P Leis, Jr, et al, “The second breast,” New York State Journal of Medicine 65 (1965) 2460; G F Robbins, J W Berg, “Bilateral primary breast cancers,” Cancer 17 (1964) 1501; J A Urban, ”Bilateral breast cancer,” Cancer 24 (1969) 826. 12. M M Black, et al, “Association of atypical characteristics of benign breast lesions with sub sequent rise of breast cancer,” Cancer 29 (1972) 338; C M Karpas, et al, “Relationship of fibrocystic disease to carcinoma of the breast,” Annals of Surgery 162 (1965) 1; H P Leis, Jr, “Pramalignant breast lesions,” in Symposium on Neoplastic and Reconstructive Problems of the Female Breast, R Snyderman, ed. (St Louis: C V Mosby Co, 1973) 11. 13. H H Davis, M Simons, J B Davis, “Cystic disease and carcinoma of the breast: Relationship to carcinoma,” Cancer 17 (1964) 957. 14. Seidman, Statistical and Epidemiological Data on Cancer of the Breast; S Shapiro, et al, ”The search for risk factors in breast cancer,” American Journal of Public Health 58 (1968) 820; D Trichopoulos, B MacMahon, P Cole, “Menopause and breast cancer risk,” Journal of the National Cancer lnstitute 48 (1972) 605. 15. Dunn, “Epidemiology and possible identification“; T Hirayama, E L Wynder, “A study of the
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epidemiology of cancer of the breast: The influence of hysterectomy,” Cancer 15 (1962) 28. 16. Dunn, “Epidemiology and possible identification”; Hirayama and Wynder, “A study of the epidemiology.” 17. B S Schoenberg, R A Greenberg, A Eisenberg, “Occurrence of certain multiple primary cancers in females,” Journal of the National Cancer lnstitute 43 (1969) 15. 18. B MacMahon, J H Austin, “Association of carcinomas of the breast and corpus uteri,” Cancer 23 (1969) 275. 19. K K Caroll, E B Gammel, E R Plunkett, “Dietary fat and mammary cancer,” Canadian Medical Association 98 (1968) 590; A N Papaioannou, “Etiologic factors in cancer of the breast,” Surgery, Gynecology & Obstetrics 138 (1974) 257; E L Wynder, “Identification of women at high risk for breast cancer.” Cancer 24 (1969) 1235. Baanders-Van Halewijn, 20. DeWaard, Huizinga, “The bimodal age distribution”; A S Ketcham, ”Predictable categories of increased risk to breast cancer,” AORN Journal 19 (1974) 852. 21. K Blackwinkel, A S Jackson, “Some features of breast cancer and thyroid deficiency,” Cancer 17 (1964) 1174; G A Edelstyn, A R Lyons, R B Welbourn, “Thyroid function in patients with mammary cancer,” Lancet 1 (1958) 670; Papaioannou, “Etiologic factors in cancer of the breast.” 22. E B Feldman, A C Carter, ”Circulatory lipids and lipoproteins in women with metastatic breast carcinoma,” Journal of Clinical Endocrinology and Metabolism 33 (1971) 8; Papaioannou, “Etiologic factors in cancer of the breast.” 23. I MacKenzie, “Breast cancer following multiple fleuroscopies,” British Journal of Cancer 19 (1965) 1; F A Mettler, Jr, L H Hempelmann, A M Dutton, “Breast neoplasms in women treated with x-rays for acute postpartum rnastitis,” Journal of the National Cancer lnstitute 43 (1969) 803; D Schottenfeld, A M Lilienfeld, H Diamond, ”Some observations on the epidemiology of breast cancer among males,” American Journal of Public Health 53 (1963) 890; C K Wanebo, et al, “Breast cancer after exposure to the atomic bombings of Hiroshima and Nagasaki,” New England Journal of Medicine 279 (1968) 667. 24. P Strax, “Practical mass screening for earlier breast cancer detection,” Postgraduate Course 045 #15, American College of Obstetricians & Gynecologists Meeting, Las Vegas. 25. Papaioannou, “Etiologic factors in cancer of the breast”; B Serrou, et al, “lmmunodepression” in Multiple Primary Malignant Tumors, I Severi, ed. (Monteluce, Italy: Perugia University Medical School Press, 1974).
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26. M M Black, “Human breast cancer: A model for cancer immunology,” Israel Journal of Medical Sciences 9 (1973) 284; M M Black, H P Leis, Jr, “Cellular responses to autologous breast cancer tissue-sequential observations” Cancer 32 (1973) 384; M M Black, et al, ”Cellular hypersensitivity to breast cancer: Assessment by a leukocyte migration procedure,” Cancer 33 (1974) 952. 27. Leis and Raciti, Search for the High Risk Patient. 28. L Dmochowski, G Seman, H S Gallagher, “Viruses as possible etiologic factors in human breast cancer,” Cancer 24 (1969) 1241; D H Moore, J Charney, B Kramarky, ”Search for a human breast cancer virus,” Nature 229 (1971) 611. 29. J Schlom, S Spiegelman, D H Moore, “Reverse transcriptase and high molecular weight RNA in particles from mouse and human milk,” Journal of the National Cancer Institute 48 (1972) 1197. 30. M M Black, et al, ”Effect of murine milk samples and human breast tissues on human leukocyte migration indices,” Cancer Research 34 (1974) 1054; J Charney, D H Moore, ”Neutralization of murine mammary tumor virus by sera of women with breast cancer,’’ Nature 229 (1971) 627; Leis and Raciti, Search for the High Risk Patient; F Squartini, “Muttiple cancers in the mammary gland system,” in Multiple Primary Malignant Tumors I Severi, ed. (Monteluce, Italy: Perugla University Medical School Press, 1974). 31. P Cole, B MacMahon, “Hypothesis: Oestrogen fractions during early reproductive life in the etiology of breast cancer,’’ Lancet 1 (1969) 604; H M Lemon, “Abnormal estrogen metabolism and tissue estrogen receptor proteins in breast cancer,” Cancer 25 (1970) 423; H M Lemon, et al, “Reduced estriol excretion in patients with breast cancer prior to endocrine therapy,” Journal of the American Medicat Association 196 (1966) 1128; B MacMahon, P Cole, J B Brown, “Oestrogen profiles of Asian and North American women,” Lancet 2 (1971) 900. 32. R D Bulbrook, J L Hayward, D S Allen, “Further observations on steroid excretion and subsequent breast cancer in Guernsey,” in Hormonal Aspects in the Epidemiology of Human Breast Cancer, J H DeBussy, ed. (Amsterdam, 1969) 163; R D Bulbrook, J L Hayward, C C Spicer, “Relation between urinary androgen and corticoid excretion and subsequent breast cancer,” Lancet 21 (1971) 395. 33. Leis and Raciti, Search for the High Risk Patient. 34. H P Leis, Jr, “The pill and the breast,” New York State Journal of Medicine 70 (1970) 2911; Leis and Raciti, Search for the High Risk Patient.
35. C Huggins, N C Yang, “Induction and extinction of mammary carcinoma,” Science 137 (1962) 257. 36. M M Black, H P Leis, Jr, “Mammary carcinogenesis,” New York State Journal of Medicine 72 (1972) 1601. 37. Leis, “The pill and the breast”; Leis and Raciti, The Search for the High Risk Patient. 38. Leis, Diagnosis and Treatment of Breast Lesions; Leis and Raciti, Search for the High Risk Patient; L Pelner, “Host-tumor antagonism XVll Trauma and Cancer,” Journal of the American Geriatrics Society 9 (1961) 58-76. 39. G M Bonser, J A Dossett, J W Jull, Human and Experimental Breast Cancer (London: Pitman Medical Publishing Co, 1961). 40. B Armstrong, N Stevens, R Doll, “A retrospective study of the association between the use of Rauwolfia derivatives and breast cancer,’’ Lancet (September 1974). 41. Leis and Raciti, Search for the High Risk Patient.
People, pets, missed by hospital patients Separation from specific persons and material things causes the greatest loneliness in hospitals, according to a Medical College of Virginia (MCV) researcher. Gloria Francis, director of nursing research in the MCV School of Nursing at Virginia Commonwealth University, said that younger people become lonelier because they have a deep investment in specific persons and material things, which have been removed from their life schedule during a hospital stay. Having interviewed about 300 patients, Francis says that other people are missed most by hospitalized patients, followed by pets, stereo, radio, records, and television. Perhaps some of the loneliness could be alleviated, she said, if hospitals allowed brief visits by children and controlled pets. However, she explained there are benefits to being lonely. “Hospitalized patients go through a reflective period. They have a lot of time to think about the people who aren’t with them. They assess relationships over the years and often decide to make them better, and many of them do.”
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