Hereditary Breast Cancer

402 Pages·2007·6.072 MB·\402

by  Claudine Isaacs (Editor), Timothy R. Rebbeck (Editor)

H
ereditary
B
reast
C
anCer

H
ereditary
B
reast
C
anCer
Edited by
Claudine Isaacs
Georgetown University
Washington, DC, USA
Timothy R. Rebbeck
University of Pennsylvania School of Medicine
Philadelphia, Pennsylvania, USA
CRC Press
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Foreword
The timing of this book’s publication is ideal given the public health, medical, mole-
cular genetic implications, and the world-wide magnitude of breast cancer. This field is
impacted heavily by significant advances in screening and management opportunities,
which can belifesaving. These challenges are particularly evident when directed toward
high-riskgroupswherecertaintyofriskstatuscanoftenbeestablishedthroughmolecular
genetic testing, particularly BRCA1 and BRCA2 germline mutations.
The table of contents reads like a Who’s Who of the world’s most outstanding
cliniciansandscientistswhoare committed togreater elucidationofthemanymysteries
that continue to exist in breast cancer’s etiopathogenesis. Hereditary breast cancer’s
epidemiologyiscoveredbyatruepioneer,DougEaston;hissubjectmatterappropriately
merges into risk prediction by Lisa Walker, followed by the bioethics of genetic testing
byBethPeshkin.KenOffitandPeterThomdiscussthenitty-grittyofhowwecanobtain
optimum breast and ovarian cancer risk certainty once the deleterious mutation is
identified. At that point, we are able to delve deeply into the litany of other molecular
geneticbreastcancerriskdisorders,asevidencedbythediscussionofCowdensyndrome
by Zbuk and Eng, and Li-Fraumeni syndrome by Louise Strong.
It might appear that we have advanced significantly up the proverbial “learning
curve” for this disease. However, we must hold our breath, since we still have a vast
amounttolearn.ThisisevidencedinthechapterbyNathansonwhichelucidatessomeof
the rare causes of this disorder in families.
PATHOLOGY
Painstaking research (1–3) has shown distinctive differences in the histopathology of
breast cancers in BRCA1 mutation carriers which are more likely medullary or poorly
differentiated, have a low rate of carcinoma in situ, and lower estrogen receptor and
progesterone receptor positivity. In contrast, BRCA2 breast cancer shows a higher
frequency of lobular and tubulo-lobular breast cancer, and it is now judged to be more
similar tothe so-called “typical” or “common”type of breast cancer.Llamas andBrody
provideadditionalinsightintothebiologyofthesemutations,whileFoulkesandAkslen
further our knowledge about breast cancer’s pathology in the hereditary setting. The
pathology of the “second tumor of high risk,” namely, ovarian cancer, is addressed by
Penault-Llorca and Lakhani.
GENETIC COUNSELING
Genetic counseling strategies, particularly focusing on whom to test, are discussed in
depth by two extremely well-known representatives of the genetic counseling
community, Stopfer and Schneider. The important and related topic of BRCA testing is
discussed by Tavtigian. When interpreting breast-cancer-prone pedigrees, the genetic
counselor must constantly keep in mind that there will be BRCA1/BRCA2 mutation
iii
iv Foreword
positive individualswho will liveintotheir 70s,80s,oreven longer, andnevermanifest
carcinoma of the breast. Yet some of their first-degree relatives, i.e., sisters, brothers,
progeny,motherorfather,aswellassecond-degreerelatives,maybemutationcarriers,a
subset of whom will develop early-onset breast and/or ovarian cancer. Therefore, when
interpreting such pedigrees with reduced penetrance, one often asks, “What is really
happening that is responsible for these gaps in cancer occurrence in the family?” Often,
therelativelyinexperiencedclinicianmaynotappreciatethefactthatthegeneticissueis
not“skippingageneration”but,rather,heorshemaybedealingwiththephenomenonof
reduced penetrance. Fortunately, Pharoah discusses this evidence in the scientific depth
which it deserves.
But how do you deliver the so-called “good news” (absence of a BRCA mutation)
vs.the“badnews”(presenceofthemutation)whenprovidinggeneticcounseling?Thisis
a crucial issue, since many factors impact heavily upon its delivery. These include the
perception of insurance and/or employment discrimination; further confounders include
fear and anxiety about receiving this “dreaded news” of being a mutation carrier, which
will entail lifelong screening and decisions about prophylactic surgery. How will this
newsaffect marital relations,decisionsaboutpregnancy andcancer risktochildren,and
potential stereotyping by close family members? These complex concerns are discussed
by Graves and Schwartz.
How do we clinically manage a typical hereditary breast-ovarian cancer (HBOC)
familywhereinDNAtestingprovestobenegative,anissuethatmayimpact asmanyas
30%to40%ofso-called“classical”HBOCfamilies?Inmycareerasacancergeneticist/
medicaloncologist,Ihaveinsistedthat,intheinterestofcaution,thesemutation-negative
but family-history-positive patients receive the same type of genetic counseling and
education about HBOC’s natural history as is given to BRCA mutation carriers should
theybeparticipantsinourrigorousscreeningandmanagementprogram(4).NoahKauff
deals convincingly with this key concept.
OVARIAN CANCER
WhatmayperhapsbethemoredeadlytumorinBRCAmutationcarriers,ovariancancer,
must be reckoned with. The clinical issue boils down to “How do we screen for this
disease?”(unfortunately,theanswerisverypoorly).Thenext“bombshell”forthepatient
to consider is the issue of “do or don’t” with respect to the preventive option of
prophylactic oophorectomy, once her family is completed. This important subject is
discussed by Lu and Skates. Similar options exist with respect to breast screening and
prophylactic surgery, as discussed by Smith and Isaacs.
GENOTYPIC/PHENOTYPIC HETEROGENEITY
Why is there such phenotypic heterogeneity in BRCA mutation carriers? Is it due to
risk modifiers, as discussed by Milne and Chenevix-Trench? Or is there something
comparableinBRCAmutationstothesituationthatexistsinAPCgermlinemutationsin
familial adenomatous polyposis (FAP) which give rise to genotype-phenotype
correlations?Forexample,awell-knownmodelisattenuatedFAP,whichischaracterized
by only occasional colonic adenomas with as many as 25 or 50 but rarely approaching
100.Thisphenomenonis attributed tomutationsbeforecodon 157,after codon1595,as
Foreword v
well as in the alternatively spliced region of exon 9. Other variations in the polyposis
expression occur, including patients with more than 1000 adenomas due to mutations
between codons 1250 and 1464; and even congenital hypertrophy of the retinal pigment
epithelium and desmoid tumors which have been found to correlate with mutations
betweencodons311and1444andafter144respectively(5).Clearly,theBRCAmutation
situation deserves comparable molecular genetic scrutiny.
THERAPY
In spite of the diagnostic measures available clinically that offer the potential for early
diagnosis, our increased ability to determine an individual’s risk status (significantly
abetted through the family history), the increasing body of knowledge regarding
hereditary cancer syndromy, and the power of molecular genetics, many high-risk
patientswillregrettablyfallthroughthecracksandmanifestcancer.Thiscanoccureven
in the case of a skilled and knowledgeable clinician treating a highly compliant patient.
This clearly leads us to consider treatment disciplines, namely surgery, chemotherapy,
and radiation therapy, which are covered in the discussions of local treatment issues by
Ben-David and Pierce. Systemic chemotherapy is explored in the chapter by Robson.
DISPARITIES
FunmeOlopadediscussesBRCA1andBRCA2mutationcarriersamongunderservedand
special populations. This issue is extremely important when considering how ethnic and
racial differences in cancer’s clinical and molecular genetic expression may impact
screening and management.
HISTORICAL PERSPECTIVE
Finally,fromahistoricalperspective,itispersonallyverymovingtometorealizethatso
muchhasbeenaccomplishedsincePaulBroca,theeminentFrenchsurgeon,publisheda
description of his wife’s family in 1866 (6). This family certainly qualified as the first
hereditarybreast-cancer-pronefamilytobedocumentedinthemedicalliterature.Then,a
century later, Lynch and colleagues (7–9) described for the first time the HBOC
syndrome.Thishereditarydisorderposedanexceedinglydifficult“selljob”tothebreast/
ovarian cancer research community. However, thanks to the discovery of BRCA1 and
BRCA2 mutations, its existence has been confirmed beyond doubt.
READERSHIP
Whoshouldreadthisbook?Frankly,itshouldbeontheshelfofallphysicianswhodeal,
howeverinfrequently,withhereditarybreastcanceranditsdifferingsyndromes.Itshould
beapreciousitemontheshelvesofallmedicallibraries.Geneticcounselorsneedtohave
thisbookconstantlyintheirpossession.Familymembersmayalsofindthebookusefulto
them, although they may need to discuss some of the more complicated aspects of the
science with their genetic counselor and/or cancer specialist. It is clear to me that this
vi Foreword
tome will prove to be of great value and should even merit translation into different
languages.
Henry T. Lynch
Creighton University
Omaha, Nebraska, U.S.A.
REFERENCES
1. Lynch H, Marcus JN, Watson P, Page D. Distinctive clinicopathologic features of BRCA1-
linkedhereditarybreastcancer. ProcAm SocClinOncol1994;13:56.
2. MarcusJN,WatsonP,PageDL,etal.Hereditarybreastcancer:pathobiology,prognosis,and
BRCA1andBRCA2genelinkage. Cancer1996;77:697–709.
3. Marcus JN, Page DL, Watson P, Narod SA, Lenoir GM, Lynch HT. BRCA1 and BRCA2
hereditarybreastcarcinoma phenotypes.Cancer1997;80(suppl):543–556.
4. Lynch HT, Marcus JN, Lynch JF, Snyder CL, Rubinstein WS. Breast cancer genetics:
heterogeneity,moleculargenetics,syndromediagnosis,andgeneticcounseling.In:BlandKI,
Copeland EMI, editors. The Breast: Comprehensive Management of Benign and Malignant
Disorders.3ed.St.Louis,MO:Saunders; 2004p.376–411.
5. NieuwenhuisMH,VasenHFA.CorrelationsbetweenmutationsiteinAPCandphenotypeof
familial adenomatous polyposis (FAP): A review of the literature. Crit Rev Oncol Hematol
2007;61:153–161.
6. BrocaPP.Traite´ destumeurs.Paris:Asselin;1866.
7. LynchHT,KrushAJ.Carcinomaofthebreastandovaryinthreefamilies.SurgGynecolObstet
1971;133(4):644–648.
8. LynchHT,KrushAJ.Geneticpredictabilityinbreastcancerrisk:surgicalimplications.Arch
Surg1971;103:84–88.
9. LynchHT,KrushAJ,LemonHM,KaplanAR,ConditPT,BottomleyRH.Tumorvariationin
familieswithbreastcancer. JAMA 1972;222:1631–1635.
Preface
The existence of hereditary breast cancer has been recognized for centuries. Hereditary
breastcancerwasfirstdescribedindetailin1866bytheFrenchsurgeonPaulBroca(1),
who characterized the pattern of breast and other cancers in members of his wife’s
family.Thisearlydescriptionofahereditarysyndromeinvolvingbreastcancerwasrefined
in the subsequent 100 years to firmly establish that hereditary breast cancer occurs in a
smallbutsignificantpercentageofthepopulation,thatsomediscretesyndromesinvolving
breastcancerexist,andthatthesesyndromesareexplainedbymutationsinsinglegenes.
Within the past three decades, the underlying genetic causes of hereditary breast cancer
have been identified and characterized. These genes include TP53 (in Li-Fraumeni
Syndrome), PTEN (in Cowden Syndrome), BRCA1 and BRCA2 (in hereditary breast/
ovariancancersyndrome),LKB1(inPeutz-JeghersSyndrome),andothers.
Research regarding hereditary breast cancer is now sufficiently developed to
provide a strong understanding of the basic biology and epidemiology underlying
hereditarybreastcancer,andtoallowtranslationofthisknowledgeintoclinicalpractice.
Building on the tremendous recent growth in our knowledge and application of genetic
information in understanding and managing hereditary breast cancer, we have designed
this volume to provide an overview of our accumulated knowledge of hereditary breast
cancer, and as a guide to the current state of clinical practice. While a number of
specialized referral centers exist, there has also been a growing interest in the use of
genetic risk assessment, testing, and counseling for breast cancer in the wider medical
community, including primary care physicians, gynecologists, oncologic surgeons,
radiation oncologists, and medical oncologists. Thus, there is a critical need to better
understand the epidemiology of hereditary breast cancer, apply cancer risk assessment
models, and implement cancer prevention and screening options for individuals with
hereditary breast cancer. A major goal of this text is to disseminate information in a
comprehensive way to both specialist researchers and clinicians as well as the wider
community of individuals with interests in hereditary breast cancer.
Toaccomplishthisgoal,wepresentavolumeorganizedinfivesections.Inthefirst
section, we provide an overview of genetic epidemiology, risk assessment models, and
ethical considerations for genetic testing in hereditary breast cancer. In the second
section, we present a comprehensive overview of hereditary breast cancer syndromes
with known etiologies, including those associated with BRCA1 or BRCA2 mutations,
Cowden Syndrome, Li-Fraumeni Syndrome, other rare syndromes involving breast
cancer, and those that may be associated with low-penetrance genetic variants. In the
third section, we present more detailed information about BRCA1 and BRCA2, which
comprise the most common explanations for hereditary breast cancer. This section
includes discussion of the biology of BRCA1- and BRCA2-associated breast cancer,
genetic testing and counseling issues, molecular diagnosis, modifiers of risk, issues for
underserved populations, and psychological impact of genetic testing. In the final two
sections,wepresentacomprehensivediscussionofthecancerscreening,prevention,and
treatment options for BRCA1- and BRCA2-associated breast and ovarian cancers.
vii