F l•J•1t'
`
`I
`
`The
`New England
`Journal of Medicine
`
`Abstr.lets in the
`advertising
`sections
`
`Establishe d In 1812 ae The NEW ENGLAND JOURNAL OF MEDICINE AND SURGERY
`
`VOL UME 327
`
`JULY 30, 1992
`
`NUMBER S
`
`Original Articles
`Identification of the Uncultured Bacillus of
`Whipple's Disease . . .. . .. .. .. . . .. .. . .. . 293
`D .A. R£tMAr.t, T.M. SCHMJD'l', R .P. MACDERMOTT,
`AND s. F A LKOW
`A Bovine Albumin Peptide as a Possible Trig·
`ger of Insulin-Dependent Diabetes
`Mellitus . ......... . .............. .. .... 302
`J. KARJALAINEN AND OTHERS
`Treatment of Preterm Labor with the Beta·
`Adrenergic Agonist Ritodrine . . . . . . . . . . 308
`THE CANADIAN PRE'l'ERI-4 LABOR I NVESTIGATORS
`GROUP
`
`Treatment of Supraventricular Tachycardia
`Due to Atrioventricular Nodal Reentry
`by Radiofrequency Catheter Ablation
`of Slow-Pathway Conduction . . . . . • . . . • . 313
`W.M. jA<~KMAN AND OTHERS
`
`Review Articles
`Medical Progress: Breast Cancer (First of
`Three Parts)...... . ... . ................ 319
`J . R . H ARRIS, M . E. LIPPMAN, U. YER<mESI ,
`AND W. WJLL.ETI
`
`Seminars in Medicine of the Beth Israel
`Hospital, Boston: Metabolic Disturbances
`and Wasting in the Acquired Immunode·
`ficiency Syndrome • . .. . .. .. . . . .. . .. . . .. 329
`c. GRVNFELD AND K .R. FEINCOI.O
`
`Case Records of the
`Massachusetts General Hospital
`A 68-Year-Old Man with Acute Mitral
`Regurgitation . . . . . . . . . . . . . . . . . . . . • • . • . 338
`K.A. EAGLE AND J.T. FALLON
`
`Editorials
`Whipple's Disease- Rare Malady with Un(cid:173)
`common Potential . . . . . • • . . . . . • . . • • . . . . 346
`R.M. DONALDSON, jR.
`
`Is Insulin-Dependent Diabetes Mellitus Envi(cid:173)
`ronmentally Induced?. . . . . . . . . • • . . . • . . . 348
`N. MACLA REN AND M. ATKINSON
`
`P·Adrenergic Agonists for Preterm Labor . . . 349
`K.J. L eveNo AND r.c. CuNNINGHAM
`
`Sounding Board
`Pharmaceutical Promotions- A Free Lunch? 35 L
`D . R . W.wD
`
`Correspondence
`fj-Agonists and Death from Asthma. . . . . . • . . . . . . 354
`The Active Management of Labor • . . . . . . . . . • . . . 357
`Early versus Late Treatment with Zidovudine . . . . 359
`Clinical Problem-Solving: How Sure Is Sure
`Enough? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360
`Use of Ph.entolamine for Cocaine-Induced Myocar-
`dial Ischemia................. . ......... 361
`Selective Decontamination of the Digestive Tract . 361
`Fecal Incontinence . . . . . . . . . . . . . . . . . . . . . . . . • . 363
`Education or Promotion? . . . . • . . . . . . . . . . . . . . . . 363
`
`Book Reviews . . . . . . . . . . . . . . . . . . . . . . . . . . . 364
`
`Books Received. . . . . . . . . . • . . . . . . . . . . . . . . . 366
`
`Notices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367
`
`Corrections
`Selective Decontamination of the Digestive Tract
`Induction of Labor as Compared with Serial Ante-
`natal Monitoring in Post-term Pregnancy - A
`Randomized Controlled Trial . . . • . . . . . . . . . . 368
`
`363
`
`Owned, Published, and CCopyrighted, 1992, by the Massacbuntts Medical Society
`
`RESERVE COPY
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`BIOEPIS EX. 1040
`Page 1
`
`

`

`Vol. 327 No. 5
`
`MEDICAL PROGRESS- HARRIS ET AL.
`
`REVIEW ARTICLES
`
`(~-------M-E_D_I_C_AL __ P_R_O_G_RE __ s_s ______ _,]
`
`BREAST CANCER
`
`(First of Three Parts)
`
`j AY R. H ARRIS, M.D., MARC E. LIPPMAN, M.D.,
`UMBERTO VERONESI, M.D.,
`AND WALTER WtLI.E'l'T, 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~
`viewed in the journal, 1 the incidence of the disease has
`increased dramatically, heightening concern among
`physicians and women in general. [n 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·
`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.
`I n 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 t he strategies
`for diagnosis and therapy initiated in the 1970s and
`1980s, including their benefits and costs. Fin-ally,
`we describe the prospects for prevention and for
`more specific treatments based on evolving biologic
`knowledge.
`
`TREN DS IN I NCIDENCE AND MoRTA Lll'Y
`Breast cancer is a major affliction of women in afflu(cid:173)
`ent countries. On the basis of incidence rates for 1983
`through 1987 and mortality rates for 1987 in the Unit(cid:173)
`ed Statcs/ ·3 12 percent of all women will be give.n a
`diagnosis of breast cancer and 3.5 percent will die of
`the disease. The impact of breast ca ncer is magnified
`because women are at risk from their middle to later
`years. The incidence rates increase rapidly during the
`
`From lhe Departments of Radiation Oncology. Beth Israel Hospital and the
`Dnna-Farbet Cancer lnstii\Jie, and the Joint Center for Radiatlon Therapy, Har(cid:173)
`vard Medical School. Boston (J.R.H .); the. Vincent T. Lombardi Cancer Research
`Center and the Deparuuents of Medicine nnd Phannacology. Georgetown Uni·
`versity Medical Center, Washington, D.C. (M.E.L.): the lstiruto Nazionale per
`lo Studio e Ia Cufll dei TumOri, Milan, Italy \U.V. )~ and the Oe~nts of
`Epidemiology and Nutrition, H:uvard Scllool of Public Health and the Channing
`U.bor.ltory, Departments of Medicine, Harvard Medical School and Brigham
`and Women's Hospital. Boston (W.W .). Address reprint requests co Dr. Harris
`ill lhe Harvard Joint Center for Radiation Ther•PY• 50 Binney St . . Boston.
`MA 021 15.
`
`fourth decade and hecome 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 40 to 55 years of age. 3 I n less affluent parts of the
`world and in the Far East, the same pattern of in(cid:173)
`crease with age is seen,1 but the absolute rates are
`much lower at each age. In japan, {or example, the
`overall incidence of breast cancer has been only about
`one fifth that in the United States.''
`The rates of breast cancer have been steadily in(cid:173)
`creasing in the United States since formal tracking of
`cases lhrough registries began in the 1930s (Fig. 1).
`Between 1940 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 I mprovemen ts in the thor(cid:173)
`oughness of the registry, whose coverage became vir(cid:173)
`tually complete in the early 1970s/ 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 T he 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. I ncreases have occurred among all age groups
`since 1935, although the magnitude of the increase has
`been greatest among older women.8 Age-aqjustcd inci(cid:173)
`dence rates of breast cancer have increased in parallel
`among black and white women j n 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 I 950 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)
`aU mortality rate, despite increases in incidence, could
`be the 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,
`
`BIOEPIS EX. 1040
`Page 2
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`

`

`320
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`July 30, 1992
`
`ter; the incidence rate of tumors measuring 2 em or
`more has not changed appreciably.6 I n addition, the
`proportion of cases diagnosed while the tumor is in
`situ or localized increased substanlially,6 after having
`been stable during the l970s. 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, H owever, the incidence of larger tumors and
`those witl1 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 tl1e
`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. fn 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
`countries 5 and over time within countries10 and large
`increases in the rates of breast cancer among popu"
`lations migrating from nations with a low incidence
`to those with a high incidence16 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
`its relative risk- the incidence among persons pos·
`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
`
`O~~Tn~~nonMTMTn~nTnT~TMTnnT~
`1940 1945 1950 1955 1960 1965 1970 1975 1980 1985
`
`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. 1). 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 event11al(cid:173)
`ly be recognized clinically appears to be small; there is
`minimal underdetection of breast cancer in autopsy
`series, l:2 no excess incidence in a I 0-year period was
`seen in a randomized screening trial, 14 and little in(cid:173)
`crease was seen among ~omen 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 1960 and 1985 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. I n 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} 7 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 to an
`increase in tumors measuring less than 2 em in diame-
`
`BIOEPIS EX. 1040
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`

`

`Vol. 327 No. 5
`
`MEO!Ct\L PROGRESS - HARRIS ET AL.
`
`321
`
`Table 1. Established and Probable Risk Factors tor Breast Cancer.
`
`Family hiscory or
`bn:~~St cancer
`
`Age at menarche
`
`Age at binh of
`Jst chnd
`
`Age at menopaus:
`
`Benign breast
`disease
`
`Radiation
`
`Obesity
`
`Height
`
`Oral contraceptive
`use
`Postmenopausal estro(cid:173)
`gcn·replacemenl
`chernpy
`
`Alcohol use
`
`No I~Hiegree
`relative.~
`affected
`
`16 YT
`
`Before 20 yr
`
`45- 54 yr
`
`No biopiy or
`3Spirarion
`
`No special
`e~posure
`I Oih percentile
`
`I Oih percentile
`
`Never used
`
`Never used
`
`Nondrinker
`
`RIS>t C'AlEOOOY
`
`Mother affected before
`the age of 60
`Mother uffeeled ~iter
`the age of 60
`Two l St·degree rei a-
`lives affected
`II Yt
`12 yr
`13 yr
`14 yr
`15 yr
`20-24 yt
`25-29 yr
`;;o30 yr
`Nulliparous
`After 55 yr
`Before 45 yr
`Oophorectomy before
`35 yr
`Any benign diso:ase
`Proliferation only
`Atypical hyperplasia
`A1omic bomb (100 rad)
`Repealed ftuoroscopy
`90th percentile:
`Age. 30-49 yr
`Age. ;oso yr
`90th percentile:
`Age. 30- 49 'Jf
`Age , ;.so yr
`Current uset
`P~~St uset
`Current use all as:es
`Age. <55 yr
`Age, 50- 59 yr
`Age. :;.6() yr
`Past use
`1 drink/day
`2 drinks/day
`3 drinks/day
`
`"'IYPICAL
`Rf.LATIV£
`RISK
`
`Snmv
`
`2.0
`
`1.4
`
`Nurses' Heahh Study•
`
`NursClS' Health Study•
`
`4- 6
`
`Gail et al / 9
`
`Kampert et al.10
`
`White"
`
`Trichopoulos et at. 22
`
`1.3
`1.3
`1.3
`1.3
`1.1
`1.3
`1.6
`1.9
`1.9
`1.5
`0.7
`0.4
`
`J.5
`2.0
`4.0
`3.0
`1.5- 2.0
`
`Willenetal. l:'
`Dupont and Page24
`Dupont and Pnge24
`Boice and Monson25
`McGregor et al. 26
`Tn:rli 11
`
`0.8
`1.2
`
`1.3
`1.4
`1.5
`1.0
`1.4
`1.2
`1.5
`2,1
`1.0
`1.4
`1,7
`2.0
`
`Trclli11
`
`Romieu et at. U>
`
`Colditz ct al. 29
`
`Longnecker et al.30
`
`40.3t The excess relative risk declines with the age of
`the relative at the time of diagnosis. 33•;1~ 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 rdatives with breast cancer (Nurses'
`Health Srudy: 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 Y0 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 14Y However, this variable may
`account for a substantial part of the international dif~
`ferences, because the contrasts are more substantial;
`in China the average age at menarche is I 7 years,36 as
`compared with 12.8 years in the United States.37
`N ulliparity and a late age at first birth both increase
`the lifetime incidence of breast cancer. 2t•38 The risk of
`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;
`
`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,
`comp arisons 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 inrerest; 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 determi11ed 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 lor
`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 I. As can
`be appreciated, the established risk factors for breast
`cancer- a family history of breast cancer, early men(cid:173)
`arche, late age at first childbirth, late age at meno(cid:173)
`pause, history of benign breast disease, and exposure
`are generally associated with
`to ionizing radiation -
`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
`•32
`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 Of!c first-degree relative with breast
`cancer34 and may be as high as 4 to 6 for those with
`rwo affected first-degree relatives.t9 The risks are
`heightened if the cancer was bilatcral.~ 1•32 For a wom(cid:173)
`an with a sister who had bilateral breast cancer before
`the age of 50, the lifetime cumulb.tive 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
`
`l
`
`· U~publish<:ll pro<poctive data wore obeaJn<d from Grolwn COtdlu: lpenonat oommunicalion) ,
`IRetalive risk~ moy be higher lor women grven • dlar.no•i• or hreasa csnttr before !be Age or 40,
`
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`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.311
`An earlier age at the birth of a second child further
`reduces the risk of breast cancer.:'!! After an a djust(cid:173)
`ment lo r the ages of the women at the births of their
`child ren, the number of births has at most a small
`40 Although
`influence on the risk of breast cancer.39
`•
`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 tha t for a nulliparo'Us woman that lasts for one to
`two decades, lbllowed by a risk that is lower than that
`for a nulliparous woman later in life.
`A late age at menopa use increases the risk of breast
`cancer; the incidence is doubled among women with
`natural menopause afiter the age of 55 as compared
`with those in whom it occurs before the age of 45.2~•41
`In the extreme, women with bilateral oophorectom y
`bdore 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.~'
`A history of benign breast disease has long been
`known tO increase the risk ol' breast cancer slightly.
`H owever, the term ''benign breast disease'' covers a
`heterogeneous group of histopathologic entities and
`42 As compared with
`needs to be defined specifically.21
`·
`women without a history of breast biopsy or aspira(cid:173)
`tion, women who hav·e lesions with any prolilerative
`epithelial changes have twice the risk of breast cancer
`and those with atypical hyperplasia about four times
`the risk.24,'12 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 lo r 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 h as a stronger association with
`mortality from breast cancer, due in part to delayed
`diagnosis among more obese women"" and to a worse
`prognosis that is independent of the stage of cancer!~
`Other features have been associated with breast
`cancer, but 'they are not as firmly established as those
`noted above. T allness is associated with an increased
`risk of breast cancer jnternationally<H; and in numer(cid:173)
`ous case- control and cohort studies.45•47' 49 The use of
`oral contraceptives appears to increase the risk of
`breast cancer by about 50 percent, but the excess risk
`drops rapidJy after the drug is stopped,28•50 suggest(cid:173)
`ing a late-stage tumor-promoting effect. H owever, is(cid:173)
`sues related to their use early in reproductive life re(cid:173)
`main unsettled; in sever al recent case-control studies
`among women younger than 45 years/' 1•5~ 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 tl1e risk of breast
`cancer by about 40 percent among women who are
`actively taking them/ 9 with little increase among
`those who are no longer taking them .53 This increased
`risk among current users a ppears to be con centra ted
`among older women, who also tend to take them for
`longer periods. Combining progesterone with estrogen
`replacement, which reduces the risk of endometrial
`cancer, docs 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•5~
`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 potentia l risk factors have been studied, but
`the findings have been inconclusive. The fat compos i(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 countrjes. 10 However,
`only weak56•57 or none.xistent23·56·~9 associations have
`been seen in case-control and cohort studies. I n 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 oils.fiO;
`however, there is little evidence that these fats a re
`rela ted 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)
`pa usal women in some studies,63
`4 but not in other
`•(j
`large investiga tions.65
`66 Participation in varsity a tWe t(cid:173)
`•
`ics was associated with reduced risk in one study ,li7 but
`not in another.';~~
`To convey the effect of various risk {actors in combi(cid:173)
`nation, Gail and collcaguesl!' have compiled detailed
`tables of estimates of the cu mulative incidence of
`breast cancer among women a t specific ages and ac(cid:173)
`cording to the number of first-degree relatives wtth
`breast cancer, age at menarche, age at first live birth,
`and number of biopsies for benign breast disease. For
`example, the cumulative 30-yca r incidence or breast
`cance1· for a 50-year-old woman would be approxi·
`ma tely 20 percent if she had her menarche at the age
`of II years, had two first-degree rdatives with breast
`cancer, and delivered iher first child after the age of 30.
`If she had no first-d egree relatives with breast cancer,
`her risk would be a pproxima tely 9 percent.
`The accumulated data on risk factors for breast can~
`cer suggest several biologic mechanisms. GcJlctic f.'1C(cid:173)
`tors clearly contribute, and a search is now in progres$
`for DNA mutations associated with this increased risk .
`Estrogenic stimulation increases the r isk69 ; the elevat(cid:173)
`ed risk among users of estrogen supplements29 sup(cid:173)
`ports this m echanism most directly, and the effects of
`age at menarche and menopa use, obesity among post-
`
`BIOEPIS EX. 1040
`Page 5
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`

`

`Vol. 32 7 No.5
`
`MEDICAL PROGRESS - HARRIS ET AL,
`
`32:1
`
`menopausal women , and the therapeutic effect of ta(cid:173)
`moxifen therapy 70 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-com rol
`studies/ 1•72 the limited size of prospective studies,IH1
`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 tbe incidence of mammary
`rumors in animals,60• 7~ may also be relevant to hu(cid:173)
`mans. This relation is reflected in the positive associ(cid:173)
`ation between height a11d the risk of breast cancer,~5
`and may underlie many of the differences in the rates
`77
`among countries.-}6•
`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)
`;lrche has declined from an average of about 17 years
`two centuries ago to an average or 12.8 years, but it
`has been stable in the United States since the 1940s.37
`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 Wides pread 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
`chan 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 ( unpu b(cid:173)
`ushed 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 identifica tion 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 fi rst-degree rdative
`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. T hese 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