Vol. 327 No. 5
`
`MEDICAL PROGRESS - HARRIS ET AL.
`
`319
`
`REVIEW ARTICLES
`
`(-~~~-M-E_n_•_c_A_L_P_R_OG~-R-ES_s~~~--J
`
`BREAST CANCER
`
`(First of Three Parts)
`
`jAY R. HARRIS, M.D., MARC E. LIPPMAN, M.D.,
`UMBERTO VERONESI, M.D.,
`AND WALTER WILLETT, M.D., DR.P.H.
`
`BREAST cancer is a major public health problem
`
`of great interest and importance to physicians in
`a variety of specialties. Since this topic was last re(cid:173)
`viewed in the Journal, 1 the incidence of the disease has
`increased dramatically, heightening concern among
`physicians and women in general. In addition, long(cid:173)
`term results are now available from clinical trials initi(cid:173)
`ated in the 1970s and 1980s to evaluate the usefulness
`of early detection with mammography and physical
`examination, breast-conserving treatment with limit(cid:173)
`ed breast surgery and irradiation, and adjuvant sys(cid:173)
`temic therapy with hormonal therapy and chemo(cid:173)
`therapy. Furthermore, in the light of newly gained
`knowledge, new strategies for addressing this problem
`have been proposed.
`In this review, we describe the recent trends in in(cid:173)
`cidence and mortality and the epidemiologic features
`that may be responsible for the rise in incidence.
`We summarize the evidence evaluating the strategies
`for diagnosis and therapy initiated in the 1970s and
`1980s, including their benefits and costs. Finally,
`we describe the prospects for prevention and for
`more specific treatments based on evolving biologic
`knowledge.
`
`TRENDS IN INCIDENCE AND MORTALITY
`Breast cancer is a major affiiction of women in affiu(cid:173)
`ent countries. On the basis of incidence rates for 1983
`through 1987 and mortality rates for 1987 in the Unit(cid:173)
`3 12 percent of all women will be given a
`ed States,2
`'
`diagnosis of breast cancer and 3.5 percent will die of
`the disease. The impact of breast cancer is magnified
`because women are at risk from their middle to later
`years. The incidence rates increase rapidly during the
`
`From the Departmeocs of Radiation Oncology, Beth Israel Hospital and lhc
`Dana-Farber Cancer lnsticute, and lhc Joint Center for Radiation Therapy. Har(cid:173)
`vanl Medical School, Boston (J.R.H.); the Vincent T. Lombanli Cancer Research
`Center and the Departments of Medicine and Pharmacology, Georgetown Uni(cid:173)
`versity Medical Center, Washington, D.C. (M.E.L.); the lstilUto Nazionale per
`lo Studio e la CUra dei Tunioci, Milan, Italy (U.V.); and the Oepanments of
`Epidemiology and Nutrition, Harvanl School of Public Health and the Channing
`Laboratory, Deparunents of Medicine, Harvanl Medical School and Brig)uun
`and Women's Hospital, Boston (W.W.). Address reprint icquests to Dr. Harris
`at the Harvard Joint Center for Radiation Therapy, SO Binney St., Boston,
`MA02115.
`
`fourth decade and become substantial before the age
`of 50, thus creating a long-lasting source of concern
`for women and a need for vigilance. After menopause,
`the incidence rates continue to increase with age, but
`less dramatically than before. Breast cancer is the
`leading cause of death among American women who
`are 4-0 to 55 years of age. 3 In less affluent parts of the
`world and in the Far East, the same pattern of in(cid:173)
`crease with age is seen,4 but the absolute rates are
`much lower at each age. In Japan, for example, the
`overall incidence of breast cancer has been only about
`one fifth that in the United States.5
`The rates of breast cancer have been steadily in(cid:173)
`creasing in the United States since formal tracking of
`cases through registries began in the 1930s (Fig. 1).
`Between 194-0 and 1982, the age-standardized inci(cid:173)
`dence rose by an average of 1.2 percent per year in
`Connecticut, which has the oldest cancer registry in
`continuous operation. 6 Improvements in the thor(cid:173)
`oughness of the registry, whose coverage became vir(cid:173)
`tually complete in the early 1970s,7 are unlikely to
`account for more than 25 percent of the increase that
`occurred before 1982. Between 1982 and 1986, the
`incidence in the United States rose more sharply, at
`4 percent per year.6 The time trends seen in Connecti(cid:173)
`cut appear to reflect the experience in other parts of
`the United States, for which only recent data are avail(cid:173)
`able. Increases have occurred among all age groups
`since 1935, although the magnitude of the increase has
`been greatest among older women.8 Age-adjusted inci(cid:173)
`dence rates of breast cancer have increased in parallel
`among black and white women in the United States
`since 1975; rates among postmenopausal black women
`remain about 15 percent lower than those among post(cid:173)
`menopausal white women, but the rates among pre(cid:173)
`menopausal black women are now slightly higher than
`those among white women. 2 As in the United States,
`long-term increases in the incidence of breast cancer
`are being observed worldwide, in both industrialized
`10
`and developing countries.9
`•
`The age-adjusted mortality rates for breast cancer,
`in contrast to the incidence rates, have been remark(cid:173)
`ably stable in the United States (Fig. 1). However, the
`time trends appear to vary depending on the age at
`diagnosis; since 1950 mortality rates have increased
`by about 15 percent among women over the age of 55
`and declined by about the same amount among those
`younger than 45. 11 The declining mortality among
`younger women appears to be best characterized as
`applying to women born after about 1935 in Connecti(cid:173)
`cut and after about 1950 nationwide. 12 Since 1975 the
`mortality rates among black women have increased
`substantially and are now slightly higher than those
`for white women. 13 The relative constancy of the over(cid:173)
`all mortality rate, despite increases in incidence, could
`be 4le result of more complete reporting of incident
`cases, increases in a more benign form of disease, ear(cid:173)
`lier detection, or advances in treatment. These factors,
`
`The New England Journal of Medicine
`Downloaded from nejm.org at REPRINTS DESK INC on August 17, 2015. For personal use only. No other uses without permission.
` Copyright © 1992 Massachusetts Medical Society. All rights reserved.
`
`1 of 10
`
`Celltrion, Inc., Exhibit 1040
`
`

`

`320
`
`THE i'VEW ENGLA'.'ID JOURNAL OF MEDICINE
`
`July 30, 1992
`
`80
`
`-gs 100
`«lo
`Q)O
`0
`-
`c: 0
`a>o
`"O~
`'(j Qi
`.5 a. 60
`.... Q)
`
`Q) -0 Ill
`c: .!::;..
`Ill;:;. 40
`<i'=
`-
`Ill
`"'t:
`<U 0
`~~
`IXl
`
`20
`
`Incidence
`
`Mortality
`
`01-.-r~~~~~~..-.....,...,...,,..,...,.. ....... .,...,...,,..,...,..,........,...,...,......,..,........,..,-i
`1~1~1~1~1~1~1m1~1~1~
`
`Figure 1. Age-Standardized Incidence of Breast Cancer and Mor(cid:173)
`tality Rates in Connecticut from 1940 to 1988.
`The data are from the Surveillance. Epidemiology, and End(cid:173)
`Results Program (Miller B: personal communication).
`
`all of which appear to be contributing to the diver(cid:173)
`gence of incidence and mortality, are discussed subse(cid:173)
`quently.
`Whether the increase in the incidence of breast can(cid:173)
`cer has been the result of more widespread use of
`screening mammography has been examined in sever(cid:173)
`al analyses. The initiation of a screening program will
`temporarily increase the incidence by advancing the
`time of diagnosis, as was noted nationally in 1974
`through 1976 (Fig. I). If screening is not repeated, a
`deficit of incident cases will ensue; if screening is per(cid:173)
`formed regularly, a new steady-state incidence will be
`achieved at a rate close to that which will occur with(cid:173)
`out screening. The number of breast cancers diag(cid:173)
`nosed in screening programs that would not eventual(cid:173)
`ly be recognized clinically appears to be small; there is
`minimal underdetection of breast cancer in autopsy
`series, 12 no excess incidence in a 10-year period was
`1 and little in(cid:173)
`seen in a randomized screening trial, 1
`·
`crease was seen among women undergoing mammog(cid:173)
`raphy for routine screening in a national program for
`the detection of breast cancer. 15 In an Oregon prepaid
`health plan, only 9 percent of cases diagnosed in 1985
`were initially detected by screening mammography,
`and it was estimated that screening could account for
`no more than 5 percent of incident cases.16 However,
`most of the increase between I 960 and l 985 was ac(cid:173)
`counted for by tumors with estrogen receptors, sug(cid:173)
`gesting a hormonal influence and the possibility that
`the increase may be due to a more benign form of
`breast cancer. In the United States as a whole, the
`annual rate of screening mammography among wom(cid:173)
`en over the age of 50 years did not appear to exceed 15
`percent in 1984. 17 Because screening causes at most a
`transient rise in incidence and because its use was not
`widespread at least through the early 1980s, it can
`explain little of the long-term increase in the incidence
`of breast cancer.
`The upsurge in the incidence of breast cancer that
`began in the early 1980s is almost entirely due io an
`increase in tumors measuring less than 2 cm in diame-
`
`ter; the incidence rate of tumors measuring 2 cm or
`more has not changed appreciably.6 In addition, the
`proportion of cases diagnosed while the tumor is in
`situ or localized increased substantially,6 after having
`been stable during the I 970s. 11 These findings as well
`as an improved two-year survival rate are compatible
`with the concomitant substantial increase in the use of
`screening mammography.6 To the extent that the re(cid:173)
`cent acceleration in the incidence of breast cancer rep(cid:173)
`resents the transient rise expected in the early stages
`of a screening program, it will eventually result in the
`prevention of deaths due to breast cancer during this
`decade. However, the incidence of larger tumors and
`those with regional or distant metastases at diagnosis
`has not decreased,6 which would be expected if a
`screening program was implemented and the true in(cid:173)
`cidence was constant. This indicates that the under(cid:173)
`lying long-term increase in the incidence of breast
`cancer has continued through the 1980s and suggests
`that no major decline in mortality rates should be ex(cid:173)
`pected in the near future. Stable mortality rates in the
`face of an apparent true increase in incidence suggest
`that the earlier detection of cases in more recent years,
`and possible improvements in treatment, have im(cid:173)
`proved survival sufficiently to offset the rising inci(cid:173)
`dence.
`Although the very recent surge may be due largely
`to the increased use of mammographic screening, the
`much larger increase over the past half century ap(cid:173)
`pears to be real. Breast cancer is clearly continuing to
`increase, especially among postmenopausal women,
`and will require even greater attention on the part of
`researchers and clinicians. In particular, specific fac(cid:173)
`tors that explain the long-term increase should be
`sought.
`
`RISK FACTORS
`Large variations in the rates of breast cancer among
`countries5 and over time within countries 10 and large
`increases in the rates of breast cancer among popu(cid:173)
`lations migrating from nations with a low incidence
`to those with a high incidence18 indicate the existence
`of major nongenetic determinants of breast cancer
`and the potential for prevention. The elucidation
`of specific risk factors for breast cancer is important
`to understand the observed variation among and with(cid:173)
`in countries, to identify women who could benefit
`from intensified surveillance or prophylactic treat(cid:173)
`ment, to select subjects for participation in interven(cid:173)
`tion studies, and to modify factors that will ultimately
`reduce risk.
`The strength of a risk factor is typically indicated by
`the incidence among persons pos(cid:173)
`its relative risk -
`sessing a characteristic in question divided by the inci(cid:173)
`dence among otherwise similar persons without the
`characteristic. The relation of a risk factor to the dis(cid:173)
`ease, however, can be complex for a number of rea(cid:173)
`sons. Many risk factors are measured as continuous
`variables (for example, the age at which breast cancer
`was diagnosed in a relative and the ages of women at
`
`The New England Journal of Medicine
`Downloaded from nejm.org at REPRINTS DESK INC on August 17, 2015. For personal use only. No other uses without permission.
` Copyright © 1992 Massachusetts Medical Society. All rights reserved.
`
`2 of 10
`
`Celltrion, Inc., Exhibit 1040
`
`

`

`Vol. 327
`
`'.'o. 5
`
`MEDICAL PROGRESS - HARRIS ET i\L.
`
`321
`
`Table 1. Established and Probable Risk Factors tor Breast Cancer.
`
`RISK FACTOR
`
`Family history of
`breast cancer
`
`Age a1 menarche
`
`Age al birth of
`Isl child
`
`Age a1 menopause
`
`Benign breast
`disease
`
`Radiation
`
`Obesity
`
`Height
`
`Oral comraccp1ive
`use
`Pos1menopausal eslro·
`gen-replacement
`therapy
`
`Alcohol use
`
`menarche, the birth of the first
`child, and menopause), and their
`relative risks can be quite arbitrary,
`depending on the segments along
`the continuum that are compared.
`To evaluate the potential causes
`of breast cancer and the reasons
`for the international differences,
`comparisons of extremes are of(cid:173)
`ten of interest, such as an age of
`11 years at menarche as compared
`with an age of 16 years. From a
`clinical perspective, however, the
`group with the highest risk on the
`basis of any particular factor is usu(cid:173)
`ally of primary interest; the relative
`risk for this group as compared with
`that for the rest of the population
`will typically be much smaller than
`when it is compared with the group
`with the lowest risk. Furthermore,
`the risk for an individual woman
`cannot be determined by multiply(cid:173)
`ing the relative risk by the average
`risk for the population because the
`general population includes per(cid:173)
`sons with and without the risk fac(cid:173)
`tor. In addition, the occurrence of
`an elevated risk in association with
`a given factor does not necessarily
`imply causation; however, this in(cid:173)
`formation may still be useful for
`prediction.
`A number of variables that pre(cid:173)
`dict the occurrence of breast cancer
`and their typical relative risks are
`described briefly in Table 1. As can
`be appreciated, the established risk factors for breast
`a family history of breast cancer, early men(cid:173)
`cancer -
`arche, late age at first childbirth, late age at meno(cid:173)
`pause, history of benign breast disease, and exposure
`to ionizing radiation -
`are generally associated with
`only weak or moderate elevations in risk. The excep(cid:173)
`tions occur in uncommon subgroups of these vari(cid:173)
`ables; for example, a family history of breast cancer at
`a young age or a family history of bilateral disease.31
`12
`·:
`A family history of breast cancer, particularly when
`the diagnosis was made in the mother or a sister at a
`young age, can be an important risk factor for breast
`cancer. 33 As compared with the risk among women
`having no first-degree relatives with breast cancer,
`overall the relative risk is on the order of 1.5 to 2 for
`women who have one first-degree relative with breast
`cancer34 and may be as high as 4 to 6 for those with
`two affected first-degree relatives. 19 The risks are
`heightened if the cancer was bilateral. 31
`32 For a wom(cid:173)
`•
`an with a sister who had bilateral breast cancer before
`the age of 50, the lifetime cumulative risk of breast
`cancer appears to be greater than 50 percent, and it is
`even higher if the sister was affected before the age of
`
`COMPARISON
`CAH!GORV
`
`RISK C•TEOOkY
`
`No lsl·degree
`relatives
`affected
`
`16 yr
`
`Before 20 yr
`
`45-54 yr
`
`No biopsy or
`aspin1ion
`
`No special
`exposure
`10th percentile
`
`10th percen1ile
`
`Never used
`
`Never used
`
`Nondrinker
`
`Mother affected before
`the age of 60
`Mother affected after
`the age of 60
`Two I st-degree rel a-
`Ii ves affected
`II yr
`12 yr
`13 yr
`14 yr
`15 yr
`20-24 yr
`25 - 29 yr
`,,,30 yr
`Nulliparous
`After 55 yr
`Before 45 yr
`Oophorec1omy before
`35 yr
`Any benign disease
`Proliferation only
`Atypical hyperplasia
`Atomic bomb (100 rad)
`Repeated fluoroscopy
`90th percentile:
`Age, 30- 49 yr
`Age, "'50 yr
`90th percentile:
`Age, 30- 49 yr
`Age, "'50 yr
`Current uset
`Past uset
`Curren! use all ages
`Age, <55 yr
`Age, 50- 59 yr
`Age, ;;.60 yr
`Past use
`I drink/day
`2 drinks/day
`3 drinks/day
`
`TYPICAi.
`RELATIVE
`RISK
`
`2.0
`
`1.4
`
`STUDY
`
`Nurses' Heallh Study•
`
`Nurses' Heahh Study•
`
`4- 6
`
`Gail el al .19
`
`Kampen c1 al. 20
`
`Whitc21
`
`Trichopoulos el aL 22
`
`1.3
`1.3
`1.3
`1.3
`I.I
`1.3
`1.6
`1.9
`1.9
`1.5
`0.7
`0.4
`
`1.5
`2 .0
`4.0
`3.0
`1.5- 2.0
`
`Willen et al.2 l
`Dupont and Page"
`Oupon1 and Page~
`Boice and Monson"
`McGregor el al. 26
`Trc11i21
`
`0.8
`1.2
`
`13
`1.4
`l.5
`1.0
`1.4
`1.2
`1.5
`2. 1
`l.0
`1.4
`1.7
`2.0
`
`Tretli27
`
`Romicu el al. 18
`
`Colditz e1 al. 29
`
`Longnecker el al. w
`
`40.3 1 The excess relative risk declines with the age of
`the relative at the time of diagnosis. 33•35 For a woman
`whose mother had unilateral breast cancer after the
`age of 60, the excess relative risk is only about 40
`percent greater than that associated with having
`no first-degree relatives with breast cancer (Nurses'
`Health Study: unpublished data). An intensive search
`for DNA markers of familial risk is ongoing and will
`be described later.
`Early menarche is a well-established but weak risk
`factor. 20 The relative risk is approximately 1.2 for
`women in whom menarche occurred before the age of
`12 as compared with women in whom it occurred at
`the age of at least 14. 17 However, this variable may
`account for a substantial part of the international dif(cid:173)
`ferences, because the contrasts are more substantial;
`in China the average age al menarche is 17 years,36 as
`compared with 12.8 years in the United States.37
`Nulliparity and a late age at fi rst birth both increase
`16 The risk of
`the lifetime incidence of breast cancer. 2 1
`·'.
`breast cancer among women who have their first child
`after the age of 30 is about twice as high as that among
`those who have their first child before the age of 20;
`
`.. Unpublished prospecrive data were ublaintd from Graham Coldil.t (personal communication).
`t Rclative risks may be highe-r for women given a diagnosis of breas-1 ,-ancer before the age of 40.
`
`The New England Journal of Medicine
`Downloaded from nejm.org at REPRINTS DESK INC on August 17, 2015. For personal use only. No other uses without permission.
` Copyright © 1992 Massachusetts Medical Society. All rights reserved.
`
`3 of 10
`
`Celltrion, Inc., Exhibit 1040
`
`

`

`322
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`July 30, 1992
`
`women who have their first child after the age of 35
`have a slightly higher risk than nulliparous women.38
`An earlier age at the birth of a second child further
`reduces the risk of breast cancer.39 After an adjust(cid:173)
`ment for the ages of the women at the births of their
`children, the number of births has at most a small
`influence on the risk of breast cancer.39•40 Although
`pregnancy before the age of 30 reduces the lifetime
`risk of breast cancer, recent evidence suggests a more
`complex pattern of a transiently increased risk relative
`to that for a nulliparous woman that lasts for one to
`two decades, followed by a risk that is lower than that
`for a nulliparous woman later in life.
`A late age at menopause increases the risk of breast
`cancer; the incidence is doubled among women with
`natural menopause after the age of 55 as compared
`•41
`with those in whom it occurs before the age of 45.22
`In the extreme, women with bilateral oophorectomy
`before the age of 35 had one third the risk of women
`with natural menopause in studies conducted before
`hormone-replacement therapy became standard prac(cid:173)
`tice. 41
`A history of benign breast disease has long been
`known to increase the risk of breast cancer slightly.
`However, the term "benign breast disease" covers a
`heterogeneous group of histopathologic entities and
`needs to be defined specifically.24
`42 As compared with
`•
`women without a history of breast biopsy or aspira(cid:173)
`tion, women who have lesions with any proliferative
`epithelial changes have twice the risk of breast cancer
`and those with atypical hyperplasia about four times
`the risk.24•42 Lesions without proliferative changes are
`associated with little or no excess risk. Four to 10 per(cid:173)
`cent of benign biopsy specimens show atypical hyper(cid:173)
`plasia.24·42
`Exposure to ionizing radiation, particularly be(cid:173)
`tween puberty and the age of 30, can substantially
`increase the risk of breast cancer.25·26 However, expo(cid:173)
`sure to clinically important levels is rare.
`Obesity is not an important risk factor for breast
`cancer, and among premenopausal women it is actual(cid:173)
`ly associated with a reduced incidence.27·43 Among
`postmenopausal women, it has a weak but clinically
`unimportant positive association with the incidence of
`breast cancer, but it has a stronger association with
`mortality from breast cancer, due in part to delayed
`diagnosis among more obese women44 and to a worse
`prognosis that is independent of the stage of cancer. 45
`Other features have been associated with breast
`cancer, but they are not as firmly established as those
`noted above. Tallness is associated with an increased
`risk of breast cancer internationally46 and in numer(cid:173)
`ous case-control and cohort studies.45·4749 The use of
`oral contraceptives appears to increase the risk of
`breast cancer by about 50 percent, but the excess risk
`drops rapidly after the drug is stopped,28•50 suggest(cid:173)
`ing a late-stage tumor-promoting effect. However, is(cid:173)
`sues related to their use early in reproductive life re(cid:173)
`main unsettled; in several recent case-control studies
`among women younger than 45 years,51·52 the use of
`oral contraceptives for more than a few years was as-
`
`sociated with increases in risk irrespective of when
`they were used. The use of postmenopausal estrogen
`supplements appears to increase the risk of breast
`cancer by about 40 percent among women who are
`actively taking them,29 with little increase among
`those who are no longer taking them.53 This increased
`risk among current users appears to be c;;oncentrated
`among older women, who also tend to take them for
`longer periods. Combining progesterone with estrogen
`replacement, which reduces the risk of endometrial
`cancer, does not appear to decrease the incidence of
`breast cancer, and may add to it.54 Alcohol consump(cid:173)
`tion, even at the level of about one drink per day, has
`been associated with a moderate increase in risk in
`most, but not all, case- control and cohort studies. 30•55
`As for the more traditionally recognized risk factors
`described previously, the magnitude of associations
`between these less well-established variables and the
`risk of breast cancer is not strong.
`Other potential risk factors have been studied, but
`the findings have been inconclusive. The fat composi(cid:173)
`tion of the diet has been thought to influence the risk
`of breast cancer, in great part because of the large
`differences in rates between countries.10 However,
`•57 or nonexistent23·58
`•59 associations have
`only weak56
`been seen in case-control and cohort studies. In ani(cid:173)
`mals, mammary tumors appear to be most strongly
`promoted by linoleic acid (the primary dietary poly(cid:173)
`unsaturated fat) and inhibited by n-3 marine oils60;
`however, there is little evidence that these fats are
`related to breast cancer in humans. An inverse rela(cid:173)
`tion between breast cancer and the total intake of vita(cid:173)
`min A has been observed in some studies,61·62 but the
`validity of this finding is far from resolved. Lactation
`has been found to reduce the risk among premeno(cid:173)
`pausal women in some studies,63·64 but not in other
`large investigations.65•66 Participation in varsity athlet(cid:173)
`ics was associated with reduced risk in one study,67 but
`not in another.68
`To convey the effect of various risk factors in combi(cid:173)
`nation, Gail and colleagues19 have compiled detailed
`tables of estimates of the cumulative incidence of
`breast cancer among women at specific ages and ac(cid:173)
`cording to the number of first-degree relatives with
`breast cancer, age at menarche, age at first live birth,
`and number of biopsies for benign breast disease. For
`example, the cumulative 30-year incidence of breast
`cancer for a 50-year-old woman would be approxi(cid:173)
`mately 20 percent if she had her menarche at the age
`of 11 years, had two first-degree relatives with breast
`cancer, and delivered her first child after the age of 30.
`If she had no first-degree relatives with breast cancer,
`her risk would be approximately 9 percent.
`The accumulated data on risk factors for breast can(cid:173)
`cer suggest several biologic mechanisms. Genetic fac(cid:173)
`tors clearly contribute, and a search is now in progress
`for DNA mutations associated with this increased risk.
`Estrogenic stimulation increases the risk69; the elevat(cid:173)
`ed risk among users of estrogen supplements29 sup(cid:173)
`ports this mechanism most directly, and the effects of
`age at menarche and menopause, obesity among post-
`
`The New England Journal of Medicine
`Downloaded from nejm.org at REPRINTS DESK INC on August 17, 2015. For personal use only. No other uses without permission.
` Copyright © 1992 Massachusetts Medical Society. All rights reserved.
`
`4 of 10
`
`Celltrion, Inc., Exhibit 1040
`
`

`

`Vol. 327 No. 5
`
`MEDICAL PROGRESS - HARRIS ET AL.
`
`323
`
`menopausal women, and the therapeutic effect of ta(cid:173)
`moxifen therapy70 are also likely to be mediated by this
`mechanism. Studies of endogenous estrogen levels in
`relation to the risk of breast cancer are currently in(cid:173)
`conclusive because of the possibility that the levels
`may be influenced by the disease in case-control
`74
`studies, 71 •72 the limited size of prospective studies, 73
`•
`and the poor reproducibility of many serum hormone
`assays. Another mechanism is suggested by the find(cid:173)
`ing that pregnancy early in life reduces the lifetime
`risk of breast cancer; the protective effect may result
`from pregnancy-induced differentiation of breast stem
`cells. 75 Finally, restriction of food intake early in life,
`which profoundly reduces the incidence of mammary
`76 may also be relevant to hu(cid:173)
`tumors in animals,60
`•
`mans. This relation is reflected in the positive associ(cid:173)
`ation between height and the risk of breast cancer,45
`and may underlie many of the differences in the rates
`77
`among countries. 46
`•
`Can the established risk factors for breast cancer
`account for the substantial increase in the incidence of
`breast cancer over the past 40 years? The age at men(cid:173)
`arche has declined from an average of about 17 years
`two centuries ago to an average of 12.8 years, but it
`has been stable in the United States since the l 940s.3'
`Adult height has increased substantially over the past
`150 years in the United States, but it also tended to
`stabilize sometime about 1940 among the middle and
`upper classes. 78•79 Thus, to the extent that the im(cid:173)
`provements in childhood nutrition reflected by the age
`at menarche and ultimate height adversely influence
`the risk of breast cancer, cohorts of women born be(cid:173)
`fore about 1940 will continue to have successively
`higher age-specific rates, but those born after this time
`should have little further increase.
`Changes in the age at which women bear children
`explain little of the long-term increases in breast
`cancer, although recent delays in the time of first
`pregnancies could increase future rates by about
`9 percent. 11
`21 Widespread use of estrogen-replace(cid:173)
`•
`ment therapy has almost certainly contributed to
`the higher incidence among postmenopausal women.
`Some have claimed that increased fat consumption is a
`probable explanation for the rise in incidence, 10 but
`this assertion is based on data for fat production rather
`than intake; fat intake has actually been declining in
`the United States for the past 40 years.80 Increased
`alcohol consumption by younger women may have
`contributed appreciably if the observed association
`with incidence is causal; alcohol consumption at the
`age of 18 was three times higher among Nurses'
`Health Study participants born between 1960 and
`1964 than among those born 40 years earlier ( unpub(cid:173)
`lished data). Although an increase in the incidence of
`breast cancer would have been expected on the basis
`of changes in known and suspected risk factors,
`whether these factors can quantitatively account for
`the observed increase remains unclear.
`The known risk factors for breast cancer do not col(cid:173)
`lectively allow the identification of a small high-risk
`group that accounts for a large proportion of women
`
`with the disease. For example, in the Nurses' Health
`Study, women in whom menarche occurred before the
`age of 11, who had their first child after the age of 35,
`who had a history of benign breast disease, or who
`had a history of breast cancer in a first-degree relative
`composed 41 percent of the population and together
`had only a 54 percent greater incidence of breast can(cid:173)
`cer than did the remaining women (unpublished
`data) . Furthermore, the excess incidence in the study
`population accounted for by these variables was only
`18 percent. A small group of women, those with a
`mother or sister who has had bilateral breast cancer at
`a young age or multiple first-degree relatives with
`breast cancer at a young age, may have cumulative
`lifetime risks of 30 percent or more. These women
`warrant particularly careful follow-up by physicians
`experienced in breast disease, but they account for a
`small fraction of all breast cancers. Unfortunately,
`even women without identifiable risk factors have an
`appreciable lifetime risk of breast cancer (approxi(cid:173)
`mately 6 percent through the age of 80), 19 and they
`will benefit from regular screening for breast cancer.
`From the standpoint of identifying risk factors to
`prevent breast cancer, our knowledge is even more
`disappointing. It is either impossible or culturally un(cid:173)
`acceptable to modify some of the clearly established
`risk factors. Although great strides have been made in
`the identification of lifestyle variables that are risk
`factors for cardiovascular disease and some forms of
`cancer, this paradigm may not necessarily apply to
`breast cancer. The search for modifiable risk factors
`has not been exhausted and must continue. However,
`to the extent that the high incidence of breast cancer
`in affluent countries is the result of rapid growth and
`early maturation of children resulting from historical(cid:173)
`ly unprecedented nutritional abundance and the con(cid:173)
`trol of infectious disease, the lifestyle changes needed
`to reduce the risk of breast cancer substantially may
`not be feasible. If this is the case, prevention may
`depend on artificial manipulation of hormones and
`growth regulators that underlie the known risk predic(cid:173)
`tors, such as a woman's age at the birth of her first
`child and at menopause.
`
`SCREENING
`One potentially important strategy in reducing the
`mortality from breast cancer is earlier detection. Earli(cid:173)
`er diagnosis is hypothesized to result in treatment be(cid:173)
`fore the tumor metastasizes and thus to avert death
`due to the disease. The main methods for earlier detec(cid:173)
`tion of breast cancer have been mammography and
`physical examination performed by a trained health
`professional. Other potential methods of screening,
`such as self-examination of the breasts, have not yet
`been demonstrated to be of value,81 and some meth(cid:173)
`ods, such as thermography and CT scanning, have
`been shown not to be of value. The ability of mam(cid:173)
`mography to detect cancers well before they are ap(cid:173)
`parent on physical examination has been indisputably
`established. The usefulness of mammography in re(cid:173)
`cent years has been enhanced by technical advances
`
`The New England Journal of Medicine
`Downloaded from nejm.org at REPRINTS DESK INC on August 17, 2015. For personal use only. No other uses without permission.
` Copyright © 1992 Massachusetts Medical Society. All rights reserved.
`
`5 of 10
`
`Celltrion, Inc., Exhibit 1040
`
`

`

`THE :'\E\.\' E ~G LA i'\D JOCRNAI. OF ~1EDICl:\E
`
`.July :io. 1992
`
`that provide increased visualization of the breast pa(cid:173)
`renchyma (and reduce exp