Risk of Breast and Ovarian Cancer in Women With Strong Family Histories

The review of hereditary breastand ovarian cancer by Dr. Srivastava et al in this issue of Oncology represents an excellent attempt tosummarize the state of an increasingly complex field. The authors have an activeprogram in cancer risk assessment and genetics at the University of Vermont inBurlington, and their experience is apparent as they organize the burgeoningdata on risk assessment and management of carriers of BRCA1 and BRCA2 mutations.

Testing an AffectedFamily Member

The full set of issues facing women with hereditary breast orovarian cancers could not be addressed in detail in such an overview. A cancerdiagnosis is often the event that prompts the recognition that a hereditarypredisposition might be present in a family. Until all genes and theirrisk-conferring mutations are known, the preferred strategy for evaluating akindred for a possible hereditary predisposition remains the initial genetictesting of an affected family member. Ideally, this would be the affected familymember who is most likely to carry a mutation based on age at diagnosis (youngerrather than older), precise diagnosis (medullary breast cancer or papillaryserous ovarian cancer), and position in the pedigree. These characteristics areconsidered because of the possibility of phenocopies for a common disease likebreast cancer.

Even in a family with a documented mutation, sporadic breast andovarian cancers can occur. Available models consider this troubling issue byassigning higher prior probabilities of carrying a mutation to women diagnosedat younger ages, men with breast cancer, and women diagnosed with both breastand ovarian primary malignancies. A negative genetic analysis in a womandiagnosed with breast cancer at age 55 should not necessarily be the end of theevaluation of a kindred in whom early-onset breast and ovarian cancers clusterelsewhere.

Effect of BRCA1/2 Findingson Management

As noted by Srivastava et al, knowledge of a deleterious BRCA1or BRCA2 mutation is beginning to influence the management of newly diagnosedbreast cancers in mutation carriers. Demonstration of the increased risk ofsecond primary cancers in mutation carriers, and the effectiveness ofprophylactic mastectomy, have led women and their physicians to more carefullyconsider the risks and benefits of breast-conserving therapy compared tobilateral mastectomy for primary treatment. Factors that must also influencethese decisions include the age of the woman at diagnosis (since younger womenstand to gain more life expectancy) and overall prognosis (as women must survivetheir first tumor in order to benefit from preventing a second cancer.)[1] Themodel by Schrag et al also emphasizes the importance of an accurate geneticanalysis for women with cancer, in its estimation of additional survivalbenefits from prophylactic contralateral mastectomy of only 2 to 4 weeks forwomen without predisposing mutations.[1]

Similar clinical considerations influence decisions for womenwho recognize their hereditary risk after completion of initial cancertreatment. For many breast cancer survivors, the identification of an increasedrisk of ovarian cancer associated with a BRCA1 or BRCA2 mutation is an importantconsideration in the decision to undergo genetic testing. Given mountingconcerns about the insensitivity of available ovarian screening methods, and thegrowing evidence of the effectiveness and comparatively low complexity oflaparoscopic ovarian surgery, prophylactic oophorectomy is frequently the firstaction taken by women learning of their mutation carrier status. Women who havehad breast cancer are generally precluded from using hormone replacementtherapy, a factor that may influence their decisions about the timing ofoophorectomy.

Ovarian cancers that occur among mutation carriers have beenshown to carry better prognoses than similar sporadic tumors.[2] WhetherBRCA1/2-associated breast cancers respond differently to standard treatmentsthan sporadic tumors remains a controversial issue.[3] The recent demonstrationthat the microarray appearances of BRCA1/2-associated breast cancers differ notonly from sporadic cancers, but also from each other, may have importantimplications for future tailored therapies, as well as upcoming analyses of riskand outcome data for the two genes.[4]

Breast and ovarian cancer survivors often underestimate thepotential impact of learning that they carry a predisposing mutation that mayaccount for their malignancy.[5] Women who have had cancer are therefore likelyto benefit from genetic counseling as they consider not only whether to havetesting, but also when such information would be most useful to them and theirfamilies. Many insurers have begun to pay for genetic testing for women who meetspecific criteria, and to cover prophylactic surgical procedures as well.However, fewer insurers are willing to pay for testing in women with metastaticdisease, whose information may have a more direct application in the managementof risk in their relatives, rather than their own cancer care.

Conclusions

Srivastava et al have provided a comprehensive review of issuesin the recognition and management of hereditary breast and ovarian cancer risk.Similar efforts to provide data for other strong cancer predisposition geneswill be necessary as new genes continue to be identified for these and othermalignancies. The paradigms highlighted in this article are likely to be appliedrepeatedly as the clinical implications of these genes are elucidated.

References:

1. Schrag D, Kuntz KM, Garber JE, et al: Benefit of prophylacticmastectomy for women with BRCA1 or BRCA2 mutations. JAMA 283:3070-3072, 2000.

2. Boyd J, Sonoda Y, Federici MG, et al: Clinicopathologicfeatures of BRCA-linked and sporadic ovarian cancer. JAMA 283:2260-2265, 2000.

3. Phillips KA, Andrulis IL, Goodwin PJ: Breast carcinomasarising in carriers of mutations in BRCA1 or BRCA2: Are they prognosticallydifferent? J Clin Oncol 17:3367-3370, 1999.

4. Hedenfalk I, Duggan D, Chen Y, et al: Gene-expressionprofiles in hereditary breast cancer. N Engl J Med 344:601-602, 2001.

5. Dorval M, Patenaude AF, Schneider KA, et al: Anticipatedversus actual emotional reactions to disclosure of results of genetic tests forcancer susceptibility: Findings from p53 and BRCA1 testing programs. J ClinOncol 18:2135-2142, 2000.