Drs. Levine and Gemignanihave provided a comprehensivereview of the literatureregarding the management of patientswith hereditary breast/ovarian cancersyndrome. As noted, over 200,000new cases of breast cancer and 25,000new cases of ovarian cancer are estimatedfor 2003. Only a small portionof these cases will be hereditary;however, these are the cases that maybenefit from preventive measures. Thepotential for risk-reducing strategiesin these patients has become a criticalissue over the past several years. Thisreview highlights the salient featuresof identifying “at-risk” patients, aswell as the benefits and limitations ofsurgical prophylaxis.
Drs. Levine and Gemignanihave provided a comprehensivereview of the literatureregarding the management of patientswith hereditary breast/ovarian cancersyndrome. As noted, over 200,000new cases of breast cancer and 25,000new cases of ovarian cancer are estimatedfor 2003. Only a small portionof these cases will be hereditary;however, these are the cases that maybenefit from preventive measures. Thepotential for risk-reducing strategiesin these patients has become a criticalissue over the past several years. Thisreview highlights the salient featuresof identifying "at-risk" patients, aswell as the benefits and limitations ofsurgical prophylaxis.Prophylactic Mastectomy
Prophylactic mastectomy remainsan option for certain patients. The literaturereports a significant reductionin risk following prophylactic mastectomyamong high-risk women witha family history or BRCA-affecteddisease and among those with a personalhistory of unilateral breast cancer.The authors point out that due tosmall amounts of breast tissue thatremain following both subcutaneousand total mastectomy, the possibilityof subsequent malignancy cannot becompletely eradicated. The patientmust have a clear understanding ofthis concept, and the fact that longterm,regular, follow-up exams arenecessary after the prophylactic surgery.The follow-up method for thesepatients (physical exam, mammography,sonogram, magnetic resonanceimaging) remains controversial andrequires further evaluation.The authors allude to the conceptof sentinel node biopsy at the time ofprophylactic mastectomy. It should benoted that the incidence of occultbreast cancer among these women isreported to be approximately 5%.Performing a sentinel node biopsy atthe time of prophylactic surgery wouldspare the patient a second surgicalprocedure (ie, complete axillary nodedissection) should an occult malignancybe identified. Given that therisk-benefit ratio in this setting hasnot yet been clarified, the role of sentinelnode evaluation accompanyingprophylactic mastectomy remainsinvestigational.The decision to proceed with prophylacticmastectomy is a complexprocess that is intricately tied to thepatient's satisfaction with the procedure.The authors report that, likelydue to anxiety, there is a propensityfor women to overestimate their riskof breast cancer. It is also noted that5% to 30% of patients express regretwith their decision to undergo riskreducingsurgery. It is critical that patientsbe accurately counseled as totheir risk of carrying a germ-line mutation,understand the associated riskof developing a malignancy, and undergoBRCA testing when indicated.Being equipped with appropriate informationmay alleviate unnecessaryanxiety. Patients should be educatedas to the risks and benefits of nonsurgicaloptions such as increased surveillanceand/or chemoprophylaxiswith tamoxifen.Lastly, the authors point out thatemotional readiness is critical to asuccessful outcome. Women whoexpressed regret were generally thosewho perceived the decision-makingas being initiated by the physicianrather than the patient herself.Adequate counseling, education, andpsychosocial support by a multidisciplinaryteam in both the pre- and postoperativesetting can lead to a moresatisfying outcome for women facedwith this difficult situation.Prophylactic Oophorectomy
Prophylactic oophorectomy bearsa different set of concerns. In ovariancancer, the majority of patients arediagnosed at an advanced stage, whenthe chance for cure is slim. No effectivestrategy currently exists for earlierdiagnosis via increased/intensivesurveillance. Although prophylacticoophorectomy is associated with deprivationof natural estrogen in youngerpatients who are then faced withthe controversies of hormone replacementtherapy, most patients report areduction in anxiety and improvedquality of life. The procedure itself isgenerally performed on an outpatientbasis and with significantly lessphysical disfiguration than is associatedwith prophylactic mastectomy.The benefit of the procedure interms of reducing the risk of ovariancancer (85% to 96%) and breast cancer(53% to 70%) is well documented.The incidence of occult malignancyidentified at the time of prophylacticoophorectomy appears to be approximately4%. Recent data suggest thatperforming peritoneal lavage duringprophylactic oophorectomy may assistwith the detection of occult disease. The significance of positivecytology in the absence of histopathologicfindings remains unclear, butcertainly, the ease and minimal expenseof obtaining cytology supportits use. In addition, fallopian tube carcinomahas been associated withBRCA mutations. For this reason, thesuggested prophylactic procedurewould be a bilateral salpingo-oophorectomywith peritoneal cytology, unlessfuture investigations suggestotherwise.Hysterectomy
The role of hysterectomy in highriskpatients remains controversial.There is little evidence to support anincreased risk of endometrioid adenocarcinomasof the uterus in the presenceof BRCA mutations. Uterinepapillary serous carcinomas have recentlybeen associated with BRCAmutations.[4,5] At present, the dataare controversial and, therefore, thisrelationship cannot be stated with certainty. The most definitive datalinking endometrial adenocarcinomaswith high-risk women appear to bethose from women with breast cancerwho are being treated with tamoxifen.Although the data suggest thatthe majority of tamoxifen-inducedendometrial cancers are low grade,recent studies have indicated thattamoxifen users are at significantlyincreased risk of mixed mesodermaltumors or other uterine sarcomas comparedto matched controls (15.4% vs2.9%).A review of all National SurgicalAdjuvant Breast and Bowel Projecttrials reported the incidence of sarcomato be 0.17/1,000 women-years inpatients randomized to tamoxifen,compared to 0 in patients randomizedto placebo. Of the 12 sarcomasthat were identified, 9 weremixed mesodermal tumors. Thesedata, along with multiple case reports,have prompted the Food and DrugAdministration to amend the warninglabel on tamoxifen packaging toinclude the risk of uterine sarcomas.Despite this finding, the significantbenefit that tamoxifen affords breastcancer patients clearly outweighs therisks of uterine malignancies. However,it would be the patients whorequire tamoxifen therapy and planto undergo risk-reducing surgery whowould benefit most from the additionof hysterectomy to the prophylacticprocedure.Similar to prophylactic mastectomy,risk-reducing salpingo-oophorectomyis not guaranteed to preventpapillary serous carcinoma of the peritoneum.This disease has been associatedwith BRCA germ-line mutationsand, unfortunately, follows a clinicalcourse that is indistinguishable fromovarian cancer.[9,10]Conclusions
In conclusion, Levine and Gemignanihave presented a thorough summaryof the data available forcounseling women who are at highriskor carry a known BRCA germlinemutation. Once these patientshave been identified, they should beoffered extensive multidisciplinarycounseling through a recognizedscreening program. By doing so, patientswill be better equipped to makeeducated and rational decisions in theirown behalf.
The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
Jemal A, Murray T, Samuels A, et al:Cancer statistics, 2003. CA Cancer J Clin 53:5-6, 2003.
Dupont EL, Kuhn MA, McCann C, et al:The role of sentinel lymph node biopsy in womenundergoing prophylactic mastectomy. Am JSurg 180:274-277, 2000.
Colga TJ, Boerner SL, Murphy J, et al:Peritoneal lavage cytology: An assessment ofits value during prophylactic oophorectomy.Gynecol Oncol 85:397-403, 2002.
Goldman NA, Goldberg GL, RunowiczCD, et al: BRCA mutations in women withconcurrent breast carcinoma and uterine papillaryserous carcinoma (abstract 882). Proc AmSoc Clin Oncol 21:221a, 2002.
Hornreich G, Beller U, Lavie O, et al: Isuterine serous papillary carcinoma a BRCArelateddisease? Case report and review ofthe literature. Gynecol Oncol 75:300-304,1999.
Goshen R, Chu W, Elit L, et al: Is uterinepapillary serous adenocarcinoma a manifestationof the hereditary breast-ovarian cancersyndrome? Gynecol Oncol 79:477-481,2000.
Bergman L, Beelen ML, Gallee MP, etal: Risk and prognosis of endometrial cancerafter tamoxifen for breast cancer. ComprehensiveCancer Centres’ ALERT group. Assessmentof liver and endometrial cancer riskfollowing tamoxifen. Lancet 356:881-887,2000.
Wickerham DL, Fisher B, Wolmark N,et al: Association of tamoxifen and uterinesarcoma. J Clin Oncol 20:2758-2760,2002.
Fields AL, Goldberg GL, Runowicz CD:The association of BRCA1 and BRCA2 germlinemutations in patient with papillary serouscarcinoma of the peritoneum. Soc Gynecol Oncol33:73a, 2002.
Menczer J, Chetrit A, Barda G, et al:Frequency of BRCA mutations in primary peritonealcarcinoma in Israeli Jewish women. GynecolOncol 88:58-61, 2003.