Population-based screening for breast and ovariancancer risk due to BRCA1 and BRCA2Efrat Gabai-Kaparaa,b,1, Amnon Lahadb,c,1, Bella Kaufmand, Eitan Friedmane,f, Shlomo Segevg, Paul Renbauma,Rachel Beeria, Moran Gala, Julia Grinshpun-Cohena, Karen Djemalh, Jessica B. Mandelli, Ming K. Leei, Uziel Bellerj,Raphael Cataned, Mary-Claire Kingi,2, and Ephrat Levy-Lahada,b,2

aMedical Genetics Institute, Shaare Zedek Medical Center, Jerusalem 91031, Israel; bFaculty of Medicine, Hebrew University Medical School, Jerusalem 91120,Israel; cDepartment of Family Medicine, Clalit Health Services, Jerusalem 91120, Israel; dInstitute of Oncology, Sheba Medical Center, Tel Hashomer 52621,Israel; eSusanne Levy Gertner Oncogenetics Unit, Sheba Medical Center, Tel Hashomer 52621, Israel; fSackler School of Medicine, Tel Aviv University,Tel-Aviv 69978, Israel; gInstitute of Medical Screening, Sheba Medical Center, Tel Hashomer 52621, Israel; hTerem Family Medical Center, Jerusalem 92345,Israel; iDepartments of Medicine and Genome Sciences, University of Washington, Seattle, WA 98195; and jDepartment of Obstetrics and Gynecology, ShaareZedek Medical Center, Jerusalem 91031, Israel

Contributed by Mary-Claire King, August 19, 2014 (sent for review July 17, 2014; reviewed by Anne M. Bowcock and Karl Skorecki)

In the Ashkenazi Jewish (AJ) population of Israel, 11% of breastcancer and 40% of ovarian cancer are due to three inheritedfounder mutations in the cancer predisposition genes BRCA1 andBRCA2. For carriers of these mutations, risk-reducing salpingo-oophorectomy significantly reduces morbidity and mortality. Pop-ulation screening for these mutations among AJ women may bejustifiable if accurate estimates of cancer risk for mutation carrierscan be obtained. We therefore undertook to determine risks ofbreast and ovarian cancer for BRCA1 and BRCA2 mutation carriersascertained irrespective of personal or family history of cancer.Families harboring mutations in BRCA1 or BRCA2were ascertainedby identifying mutation carriers among healthy AJ males recruitedfrom health screening centers and outpatient clinics. Female rela-tives of the carriers were then enrolled and genotyped. Amongthe female relatives with BRCA1 or BRCA2 mutations, cumulativerisk of developing either breast or ovarian cancer by age 60 and80, respectively, were 0.60 (± 0.07) and 0.83 (± 0.07) for BRCA1carriers and 0.33 (± 0.09) and 0.76 (± 0.13) for BRCA2 carriers. Riskswere higher in recent vs. earlier birth cohorts (P = 0.006). Highcancer risks in BRCA1 or BRCA2 mutation carriers identified throughhealthy males provide an evidence base for initiating a generalscreening program in the AJ population. General screening wouldidentify many carriers who are not evaluated by genetic testingbased on family history criteria. Such a program could serve asa model to investigate implementation and outcomes of populationscreening for genetic predisposition to cancer in other populations.

genomics

Inherited mutations in BRCA1 and BRCA2 predispose to highrisks of breast and ovarian cancer. Among female mutation

carriers, presymptomatic surgical measures significantly reducemorbidity and mortality (1, 2). In particular, risk-reducing sal-pingo-oophorectomy (i.e., the removal of ovaries and fallopiantubes from a woman without ovarian cancer) reduces risk both ofbreast cancer and of ovarian cancer, as well as overall mortality(1). However, for many mutation carriers identified followingtheir first cancer diagnosis, genetic testing was not previouslyindicated because family history did not suggest inherited cancerpredisposition (3–5, 6). From a prevention perspective, it is amissed opportunity to identify a woman as a BRCA1 or BRCA2mutation carrier only after she develops cancer.Among Ashkenazi (European) Jews (AJ), three mutations,

BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT,account for the great majority of inherited cancer risk due toBRCA1 and BRCA2 (7). In the AJ population, 2.5% of personscarry one of these three mutations (8), and the mutations ac-count for 11% of breast cancer (3) and 40% of ovarian cancer (9,10). These observations suggest that genetic testing in the AJpopulation for these mutations fulfills WHO criteria for pop-ulation screening (11, 12): The disease is an important public

health burden to the target population; prevalence and attribut-able risk of disease due to the mutations are known; and effectiveinterventions exist. However, one necessary piece of informationremains unknown: What is the disease risk to mutation carriersascertained from the general population, rather than carriersidentified based on family history (13)?Previous studies assessing cancer risks due to mutations in

BRCA1 and BRCA2 ascertained carriers through high-incidencefamilies (14), through a single index case with breast or ovariancancer (3, 15) or through both affected and unaffected carriers(16). In a 1997 study of AJ volunteers, most index cases had noprevious cancer diagnosis, but the percentage of index cases witha family history of breast cancer was approximately double thatof unselected AJs (17). In principle, these strategies could haveyielded risk estimates different from those of carriers ascertainedfrom the local host population, if cancer risk in BRCA1 or BRCA2carriers were influenced by familial factors other than the BRCA1or BRCA2 mutation, such as modifier genes or shared environ-ment (18). In addition, in almost all of these studies, risk esti-mates were based on imputing carrier status, rather than ondirect genetic testing of BRCA1 and BRCA2. This year, the

Significance

Inherited mutations in the tumor suppressor genes BRCA1 andBRCA2 predispose to very high risks of breast and ovariancancer. For carriers of these mutations, risk-reducing surgerysignificantly reduces morbidity and mortality. General pop-ulation screening for BRCA1 and BRCA2 mutations in youngadult women could be feasible if accurate estimates of cancerrisk for mutation carriers could be obtained. We determinedthat risks of breast and ovarian cancer for BRCA1 and BRCA2mutation carriers ascertained from the general population areas high as for mutation carriers ascertained through personalor family history of cancer. General screening of BRCA1 andBRCA2 would identify many carriers who are currently notevaluated and could serve as a model for population screeningfor genetic predisposition to cancer.

Author contributions: E.G.-K., A.L., M.-C.K., and E.L.-L. designed research; E.G.-K., A.L.,B.K., E.F., S.S., P.R., R.B., M.G., J.G.-C., K.D., J.B.M., U.B., R.C., M.-C.K., and E.L.-L. performedresearch; E.G.-K., A.L., P.R., M.K.L., M.-C.K., and E.L.-L. analyzed data; A.L., M.-C.K., andE.L.-L. wrote the paper; and B.K., E.F., S.S., K.D., and U.B. referred participants.

Reviewers: A.M.B., Imperial College London; and K.S., Technion – Israel Institute ofTechnology.

The authors declare no conflict of interest.1E.G.-K. and A.L. contributed equally to this work.2To whom correspondence may be addressed. Email: mcking@u.washington.edu orlahad@szmc.org.il.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1415979111/-/DCSupplemental.

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Recommendation Statement on BRCA Testing from the USPreventive Services Task Force recommended against populationscreening for BRCA1 and BRCA2 mutations, because cancer riskto mutation carriers in the general population was not yet known(19). To address this gap, in this study we assessed breast andovarian cancer risks in confirmed carriers of BRCA1 and BRCA2mutations ascertained from the general population. The studywas undertaken in the AJ population, because screening for onlythree founder mutations is sufficient to capture nearly all inheritedcancer risk in this population due to BRCA1 and BRCA2 (7).

ResultsIndex Subjects as Surrogates for the General AJ Population.Of 8,222male index subjects enrolled, DNA samples from 8,195 subjects(99.7%) were successfully genotyped for the three AJ mutationsin BRCA1 and BRCA2 (Fig. 1). Of the 8,195 subjects, 175 carrieda mutant allele: 91 in BRCA1, 81 in BRCA2, and 3 in bothBRCA1 and BRCA2. Carrier frequencies were 1.14% (94/8195)for BRCA1, 1.03% (84/8195) for BRCA2, and 2.17% (178/8195)for the three alleles combined. Approximately equal numbers of

male mutation carriers were members of families with high in-cidence or low incidence of breast or ovarian cancer (SI Appendix,Table S3), a profile also observed in other studies of AJ familiesharboring BRCA1 and BRCA2 mutations (3, 5, 6).An important consideration in generalizing from this study

population to the Israeli AJ population as a whole was whetherthese 8,195 male index subjects were representative of the gen-eral AJ population with respect to family history of breast andovarian cancer. The concern was that males with family historiesof breast or ovarian cancer might be more likely to consent toparticipation, leading to more severely affected families in thestudy cohort than in the population as a whole. Three lines ofevidence addressed this question. First, carrier rates for thefounder mutations among index males were similar to carrierrates reported by other studies of the Israeli AJ population (8).Second, among the male index subjects born between 1940 and1975, 9.6% reported a diagnosis of breast cancer in theirmothers. In comparison, for the Israeli AJ female populationborn between 1920 and 1950 (i.e., the generation of the mothersof the index subjects), the Israeli Cancer Registry reported

Fig. 1. Study design: the testing protocol and the number of participants at each step. Purple indicates stages common to all males index subjects; blueindicates stages for noncarriers only; red indicates stages for carriers only; gray bars indicate end of participation (1). A subset of noncarriers was matched tocarriers for age, area of residence, and recruitment locale (2). Of the 175 male index subjects with mutations, 3 were related to another carrier, so 172 familieswere represented.

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a cumulative incidence of breast cancer to the year 2009 of 9.4%(SI Appendix, SI Methods). Third, parental origin of mutationcould be determined for 78 index males carrying mutations. In-heritance was maternal for 41 index males (53%) and paternalfor 37 index males (47%), close to the 50:50 ratio expected ifindex male carriers participated without regard to family history.Combined, these observations suggest that the 8,195 male indexsubjects were representative of the general Israeli AJ populationwith respect to BRCA1 and BRCA2 genotypes and with respectto family history of breast cancer.

Analysis BRCA1 and BRCA2Mutations in Female Relatives. The principalgoal of the study was to determine the risks of breast and ovariancancer among women with BRCA1 or BRCA2 mutations ascer-tained through an unaffected male index subject. The 175 maleindex subjects with mutations were asked to provide new DNAsamples to confirm mutation status, to undergo genetic counseling,and to refer their female relatives to the study (Fig. 1). These 175male index subjects represented 172 different families. From thesefamilies, 629 informative relatives (431 women and 198 men) wereultimately enrolled, among whom 211 female mutation carrierswere identified.Risks of breast cancer, ovarian cancer, and either breast or

ovarian cancer to these female mutation carriers are shown inTable 1 and Fig. 2. Cumulative incidences of either breast orovarian cancer, by ages 60 and 80 respectively, were 0.60 (± 0.07)and 0.83 (± 0.07) for carriers of BRCA1 mutations and 0.33(± 0.09) and 0.76 (± 0.13) for carriers of BRCA2 mutations (Fig.2A). Cumulative incidences specifically of breast cancer, by ages60 and 80, respectively, were 0.41 (± 0.06) and 0.60 (± 0.10) forcarriers of BRCA1 mutations and 0.26 (± 0.08) and 0.40 (± 0.11)or carriers of BRCA2 mutations (Fig. 2B). Cumulative incidencesspecifically of ovarian cancer, by ages 60 and 80, respectively,were 0.27 (± 0.07) and 0.53 (± 0.11) for carriers of BRCA1mutations and 0.07 (± 0.05) and 0.62 (± 0.18) for carriers ofBRCA2 mutations (Fig. 2C).These cumulative incidence estimates were based on fully gen-

otyped sibships. To address potential biases resulting from exclu-sion of incompletely genotyped sibships, cumulative incidences

were also estimated for all sibships, after imputing probabilities ofcarrier status for women who were not genotyped. Imputation wascarried out independently based on risks estimated from two pre-vious studies (3, 20) as well as from this one. Analyses based onfully genotyped sibships and analyses based on all sibships yieldedvery similar risk estimates for breast cancer and ovarian cancer inBRCA1 carriers and for breast cancer in BRCA2 carriers (Table 1and SI Appendix, Table S5). Estimates of ovarian cancer risk by age80 in BRCA2 carriers were higher based on fully genotyped sibships(0.62 ± 0.18; Table 1) than estimates based on all sibships (0.37–0.45 ± 0.08–0.12; SI Appendix, Table S5).

Effect of Birth Cohort on Risk Among Mutation Carriers. Previousstudies reported higher breast cancer risks among BRCA1 andBRCA2 mutation carriers from more recent, compared withearlier, birth cohorts (3, 15, 21). Similarly, in the present study,combined breast and ovarian cancer incidence was higher forcarriers in more recent birth cohorts (Fig. 3). Among womenborn in or before 1958 (the median year of birth for mutationcarriers), cumulative incidence of breast or ovarian cancer was0.22 by age 50 and 0.78 by age 80. For women born after 1958,cumulative incidence of breast or ovarian cancer was 0.84 by age50. Age-specific cancer risks, controlled for gene, were 3.8-foldhigher for carriers in the younger vs. the older birth cohort (P =0.006; Fig. 3). Per year of later birth, hazard ratios, controlled forgene, were 1.041 (P = 0.04) for ovarian cancer and 1.033 (P =0.01) for breast cancer.

DiscussionTo evaluate whether evidence supports population screening forBRCA1 and BRCA2 mutations, we assessed breast and ovariancancer risks among female mutation carriers ascertained throughhealthy males. The males who comprised the screening serieswere representative of the general Israeli AJ population withrespect to mutation prevalence and family history of cancer.Risks of breast and ovarian cancer to females with BRCA1mutations ascertained via these healthy males were comparableto risk estimates in previous studies with ascertainment throughaffected index cases (SI Appendix, Table S6) (3, 20, 22). Incontrast, a notable difference between this and other studies isthat BRCA2 mutation carriers in this study have a higher risk ofovarian cancer and a lower risk of breast cancer than do BRCA2mutation carriers in other studies (SI Appendix, Tables S6 andS7) (2, 16). Differences in site of first cancer may reflect a lowerprevalence in the Israeli population of nongenetic risk factors forbreast cancer, such as late age at first pregnancy, and thereforereduced competing risk. In comparison with studies of BRCA2 innon-AJ populations, a second contributing factor may be thelocation of BRCA2 6174delT in the BRCA2 “ovarian cancercluster region,” where mutations may be associated with higherovarian cancer risks (23). To some extent, risks of breast andovarian cancer likely compensate for one another, yieldingcombined risks for developing either breast or ovarian cancerthat are similar across studies. Breast cancer risks among mu-tation carriers in Israel are rapidly increasing (Fig. 3), with thetime trend particularly marked for BRCA2 carriers. This increaseis likely due both to improvements in screening for breast cancerand to trends toward escalating nongenetic risk factors for breastcancer, such as younger age at menarche and older age at firstchildbirth. These strong birth cohort effects suggest that for bothBRCA1 and BRCA2, most published risk estimates, which reflectmultiple generations of carriers, underestimate risk to carriersamong present-day young women.Integration of genomic advances into public health requires well-

characterized genetic tests for clearly actionable mutations (24).In the AJ population, evidence supporting testing for the un-ambiguously damaging founder mutations in BRCA1 and BRCA2is provided by the results of this study, by previous studies of the

Table 1. Cumulative incidence of breast or ovarian canceramong women with mutations in BRCA1 or BRCA2, ascertainedvia unaffected males

To age, y BRCA1 (SE) BRCA2 (SE)

Risk of breast cancer30 0.02 (0.02) 040 0.17 (0.04) 0.04 (0.03)50 0.35 (0.06) 0.09 (0.05)60 0.41 (0.06) 0.26 (0.08)70 0.52 (0.08) 0.32 (0.09)80 0.60 (0.10) 0.40 (0.11)

Risk of ovarian cancer40 0 050 0.05 (0.03) 0.03 (0.03)60 0.27 (0.07) 0.07 (0.05)70 0.47 (0.10) 0.13 (0.07)80 0.53 (0.11) 0.62 (0.18)

Risk of either breast orovarian cancer

30 0.03 (0.02) 040 0.23 (0.05) 0.04 (0.03)50 0.41 (0.06) 0.16 (0.06)60 0.60 (0.07) 0.33 (0.09)70 0.77 (0.07) 0.47 (0.11)80 0.83 (0.07) 0.76 (0.13)

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AJ alleles (2, 3, 22), and by the existence of effective interventionfor carriers (1, 2). A great advantage of population screening isidentification of all carriers, not only those from families witha significant cancer history. In this study, 51% (85 of 167) familiesharboring BRCA1 or BRCA2 mutations had little or no history ofrelevant cancer (SI Appendix, Table S3). These families were smalland included few females with mutations who had reached theages of highest cancer risk. Young women in these families wouldnot have been tested in the absence of a general screening pro-gram. Population screening also enables carriers to be identifiedregardless of their relatives’ willingness to divulge informationon cancer diagnosis or genetic test results. It also enables carriersto be identified independent of physician referral, a potentiallyimportant consideration. A recent survey in the United Statesrevealed that only 19% of primary care physicians accuratelyassessed family history for BRCA1/BRCA2 testing (25). In BRCA1/BRCA2 families in France, most eligible relatives are not referredfor testing (26). In the present study in Israel, only 35% (29 of 82)of high-cancer-incidence families had been referred previously forgenetic counseling, despite its availability within the Israeli uni-versal single-payer health care system.Implementation of a population-screening program for cancer

genetics presents new challenges. Traditional cancer geneticcounseling including both pretest and posttest counseling is im-practical on a large scale. In this study, this two-stage process wasretained only for a small subset of index males. This study designprovided mutation carriers with another opportunity to reconsidertheir decision to be tested, reflecting early concerns about possiblenegative effects of knowledge of carrier status. These concerns havelessened as testing for cancer predisposition has gained acceptanceand its medical benefits have become apparent. There is alreadysome evidence that receiving limited pretest information does notaffect satisfaction with BRCA1 and BRCA2 testing (27), suggestingthat extensive posttest counseling can be limited to carriers. Geneticscreening will need to be integrated into adult primary care,entailing special outreach to family practitioners and to community-based physicians, as well as to the public. The AJ community hasconsiderable experience with genetic carrier screening for autoso-mal recessive pediatric disorders. Such screening is widely acceptedand has led to significant prevention of diseases such as Tay-Sachs(28). However, genetic screening for an autosomal dominant,common adult-onset disease has not yet been attempted, and raisesunique issues: Carriers are themselves at risk, and their offspringare at 50% risk of inheriting any mutation identified, regardlessof partner choice. Further research would be necessary to optimizecost-effective implementation, which may vary between cultures andmedical systems (29).This study was performed in an AJ population, but its

results are widely applicable. Among persons of any ethnicityundergoing clinical exome or genome sequencing for con-ditions other than cancer, damaging mutations in BRCA1 andBRCA2 identified incidentally are already considered to besufficiently actionable to require reporting (30). Furthermore, itis now possible to identify, in one test and at reasonable cost, allactionable mutations in BRCA1 and BRCA2, as well as in all otherknown breast and ovarian cancer genes (31, 32). Such analysesreveal all variation: both unambiguously damaging mutationsand variants of unknown significance. The AJ population isunusual in that the mutational burden of BRCA1 and BRCA2is essentially limited to three unambiguously damaging alleles.We suggest that population screening efforts focus on clearlydamaging mutations, such as those evaluated in this project.BRCA1 and BRCA2 were identified in the mid-1990s, and

A

B

C

Fig. 2. Cumulative incidence of breast and ovarian cancer among womenwith mutations in BRCA1 and BRCA2. Cumulative incidence rates were es-timated for confirmed female mutation carriers from fully genotyped sib-ships. Blue indicates BRCA1 carriers; green indicates BRCA2 carriers. (A)Cumulative risk of developing either breast or ovarian cancer. Risk differedsignificantly for carriers of mutations in BRCA1 vs. BRCA2 (P = 0.004). (B)Cumulative risk of breast cancer. Risk differed significantly for carriers of

mutations in BRCA1 vs. BRCA2 (P = 0.02). (C) Cumulative risk of developingovarian cancer. Difference in risk for carriers of mutations in BRCA1 vs.BRCA2 was not significant (P = 0.16).

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patent issues that in the United States previously limited completegenomic analysis of BRCA1 and BRCA2 have been largelyresolved (33). We suggest that the time has come to apply ourknowledge of these genes to consideration of a general screeningprogram, with the aim of reducing the burden of breast andovarian cancer.

MethodsParticipants. The study was approved by the institutional review boards of allparticipating institutions and by Israel’s National Human Subjects Commit-tee. All participants provided written informed consent. Male index subjectsand their relatives of those index subjects with BRCA1 or BRCA2 mutationswere recruited between June 2004 and December 2010, as outlined in Fig. 1and SI Appendix, SI Methods. Males visiting health-related settings through-out Israel were offered participation if they were age 30 or older, identifiedall four grandparents as AJ, and had no personal history of cancer (SI Ap-pendix, Table S1). Family history of cancer was not a criterion for or againstparticipation. Males who chose to participate provided a blood or buccalsample from which DNA was extracted and genotyped for BRCA1 185delAG,BRCA1 5382insC and BRCA2 6174delT (SI Appendix, Table S2). All malescarrying at least one of these mutations were recontacted and invited forgenetic counseling. Institutional review board requirements did not allow

results to be disclosed to participants until the participant received geneticcounseling and the test was repeated. Therefore, to maintain blindness ofthe participants to the test results, an equal number of males with none ofthese BRCA1 or BRCA2 mutations, matched to mutation carriers for age,town of residence, and recruitment locale, were similarly recontacted andinvited for genetic counseling. All recontacted subjects were told that theyhad a 50% chance of being a carrier. At the follow-up visit, full counselingwas provided by a genetic counselor who was unaware of the results of thefirst test. Counseled participants interested in receiving test results gaveconsent for a second (repeat) test. Each counseled participant provided adetailed family history and a blood sample, which was tested for all three AJmutations. All results were identical for the original and repeat tests. Resultswere reported to participants in a posttest counseling session. Participantsidentified as carriers were asked to refer all adult female relatives for ge-netic counseling and testing. Matched subjects without mutations were notasked to participate further. For each family carrying a BRCA1 or BRCA2mutation, family history of cancer was obtained through personal reportand verified whenever possible through the Israel Cancer Registry (ICR) andhospital records. Family history was assessed both from information pro-vided by the male index subject at study entry and subsequently from in-formation provided by all counseled relatives. Living relatives were counseledand tested for the three AJ mutations. For deceased relatives, genotypeswere obtained by testing archived pathology specimens and by testingsurviving relatives.

Statistical Methods. Characteristics of index subjects with vs. without muta-tions were compared by t test for continuous variables, χ2 tests for cate-gorical variables, and McNemar tests for categorical variables in pairedsubjects. All P values were two-tailed and confidence intervals calculated atthe 95% level. Cumulative incidences of breast cancer and of ovarian, fal-lopian tube, or primary peritonieal cancer among female mutation carrierswere determined using Kaplan–Meier analysis and Cox proportional hazardmodels. Ages of affected women were censored at age of first diagnosis.Ages of unaffected women were censored at age at death, age at mostrecent follow-up, or age at risk-reduction surgery, whichever came first.Women were excluded from analysis if born before 1910 or if cause of deathwas unknown. Results are shown for fully genotyped sibships, i.e., those inwhich genotypes were confirmed for all sisters, affected and unaffected.Fully genotyped sibships are likely to be smaller and younger than othersibships, but are less prone to survival bias, if deceased relatives could not begenotyped, or to refusal bias, if presence or absence of cancer diagnosisinfluenced consent to be tested. An alternate analysis including all femalecarriers, with genotypes identified either directly by genetic testing or im-puted statistically, is given in the SI Appendix, SI Results. A sensitivity analysisto assess the possible effect on risk estimates of consent bias based on familyhistory of breast cancer is also given in SI Appendix, SI Results and Table S4.

ACKNOWLEDGMENTS. We thank Dr. Lital Keynan-Boker and Dr. MichaBarchana for providing data from the Israel Cancer Registry; Dr. NavaEpstein, Dorina Katzenellenbogen, Pesya Ashki, and Haya Hackett for helpwith study coordination and recruitment; and Hafez Jabara, Anat Yadin,Ariella Tomer, Irit Kisslov, and Hila Gadelki for laboratory and databaseassistance. We thank the participants and their families for their willingnessand cooperation. This work was supported by the Breast Cancer ResearchFoundation, the Israel National Institute for Health Policy Research, the IsraelCancer Association, and National Institutes of Health Grant R01CA157744.

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