Familial Cancer

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: 73–74, 2001. 2002 Kluwer Academic Publishers. Printed in the Netherlands.

Commentary on Eccles et al.: Familial breast cancer: an investigation into the outcome of treatment forearly stage disease

Julia Wong1 and Judy Garber2

1 Joint Center for Radiation Therapy; 2 Dana Farber Cancer Institute, Department of Adult Oncology, Boston, USA

Received 4 July 2001; accepted in revised form 13 August 2001

The authors have presented results of a carefully per-formed retrospective analysis of the treatment outcomeof early-stage breast cancer patients, with and withouta family history of breast cancer. The patients weregathered from several sources over a reasonably lengthyperiod, and include both women selected because ofyounger age at breast cancer diagnosis and a subgroupof family history-positive (FH+) patients collectedbecause they were known to harbor a germline BRCA1mutation. The primary objective of the study was toassess whether these groups had different outcomes withrespect to rates of local recurrence, contralateral breastcancer, relapse-free survival, and overall survival. Localtherapy included breast-conservation and mastectomy,and a range of systemic therapies were used. The mainfindings include similar local and distant recurrencerates in patients with familial vs. sporadic breast cancer,and a substantial excess of contralateral breast cancersamong patients with a positive family history. At amedian follow-up of 7 years, there were ipsilateralrecurrences in 22% of the FH+ and 24% of the FH–groups. Contralateral breast cancer occurred in 36% ofthe FH+ patients, in contrast to only 16% of the FH–patients. A non-significant trend towards worse relapse-free survival was seen in the FH+ patients, without adifference in overall survival.

This study has several strengths. One is the largenumber of patients for whom family history data wereavailable. Another is the presence of sufficient numbersof patients with known BRCA1 mutation status topermit detailed comparison to other subsets, althoughthe lack of BRCA2 mutation data makes some mis-classification likely. Concerns raised by the higherproportion of node status unknown patients in the FH+group are clearly acknowledged by the authors.

The data from Eccles et al. add to accumulatingobservations that are beginning to influence therapyrecommendations for newly-diagnosed women withstrong familial breast cancer history. Our experienceassessing the outcome of 201 young (age 36 or younger)patients with a positive family history (defined as

having a mother or sister with breast cancer before age50 or ovarian cancer at any age) is similar to that ofEccles et al., providing further reassurance that indi-viduals with potentially inherited forms of breast cancercan be safely managed with breast-conserving therapy[1]. Overall survival after BRCA1/2-associated ovariancancer is clearly superior to survival in non-mutationcarriers [2], but data on breast cancers are inconclusive[3, 4]. There is particular controversy surrounding thebest local therapy for patients with a BRCA1/2-associ-ated hereditary breast cancer predisposition.

Concerns about the role of radiotherapy in BRCA1/2-associated breast cancer come from both laboratory andclinical data. The complex formed by BRCA1/2 isinvolved in repair of DNA damage. As radiotherapy(RT) causes DNA damage, there has been concern thatRT may yield unexpected toxicities in carriers ofgermline BRCA1/2 mutations. Both BRCA1- andBRCA2-knock-out mice have been shown to be incom-petent to repair radiation-induced DNA damage, thoughthe mice hemizygous for either gene are able to repairthis damage as well as wild type mice [5–7]. In a recentpublication, Pierce et al. reported on 71 women withearly stage breast cancer and a known BRCA1/2mutation, matched to 213 women with sporadic breastcancer, all treated with breast-conserving surgery andRT [8]. No significant differences in acute or chronictoxicities were seen, nor were there significant differ-ences in 5-year actuarial local control, relapse-freesurvival or overall survival between the mutationcarriers and the sporadic cases. These data providereassurance that radiation therapy is a safe and effec-tive approach for this cohort. However, after correctingfor patients who underwent prophylactic mastectomy,Pierce et al. also observed contralateral breast cancer(CBC) in 22% of the mutation carriers at 5 years,compared with 2% among the sporadic cases (hazardratio, 8.58, p < 0.0001). They also observed secondprimary ovarian cancers among mutation carriers, notseen by Eccles et al. in this series. Other investigatorshave reported similar and conflicting findings [3, 9].

Correspondence to: Judy Garber, Dana Farber Cancer Institute, Department of Adult Oncology, 44 Binney Street SM 210, MA 02115,Boston, USA; Tel: 617 632 2282; Fax: 617 632 2649; E-mail: judy_garber@dfci.harvard.edu

The consistent observations of elevated rates ofcontralateral primary breast cancer among mutationcarriers has led to concerns about breast conservingtherapy as the optimal strategy for that group of women.In a decision analysis examining effects of prophylacticsurgical interventions among mutation carriers after abreast cancer diagnosis, Schrag et al. estimated sub-stantial life expectancy gains for patients youngest atdiagnosis, patients with high-penetrance mutations, andthose with a good prognosis [10]. On average, aBRCA1/2 mutation carrier age 30 years at diagnosiswould gain 0.6–2.1 years from prophylactic contralat-eral mastectomy.

However, the same model estimated a near absenceof benefit from contralateral prophylactic mastectomyfor women who do not carry a BRCA1/2 mutation (lessthan 4 weeks for a 30-year-old woman without aBRCA1/2 mutation).

Such findings prompt the main question raised by theEccles et al. study: Is family breast cancer history a suf-ficient surrogate for genetic test results to justify its usein consideration of appropriate local treatment recom-mendations for newly diagnosed breast cancers? Familybreast cancer history, even when strictly defined, is notable to perfectly distinguish women with BRCA1/2mutations [11]. Conversely, germline BRCA1/2 muta-tions account for no more than 30% of kindreds likelyto carry a genetic breast cancer predisposition based oncomplex features [12]. Features of the family historyassociated with higher probability of identifying agermline BRCA1/2 mutation can be considered inquantitative models [13]. The family history in themanuscript under discussion is more broadly andvariably defined, and not likely to overlap consistentlywith the results of direct genetic analysis.

The implications of the above findings are several.The available data on treatment outcome in breastcancer patients with a BRCA1/2 mutation suggest thatbreast-conserving surgery with RT is a safe and effec-tive approach. However, patients carrying a BRCA1/2mutation carry a higher risk of contralateral breast andovarian cancer, and may want to consider preventiveapproaches. For these reasons, we support the notionthat genetic testing for a BRCA1/2 mutation may bevaluable at diagnosis in certain subgroups of patients,especially young patients with node-negative disease.

At our institution, most patients currently do notundergo genetic testing prior to definitive local therapy.However, we do use age at diagnosis, ethnicity andfamily history to identify patients in whom the priorprobability of carrying a BRCA1/2 mutation isincreased. We currently do not consider the presenceof a BRCA1/2 mutation to be a contraindication to RT,but rather an indication for a more extensive discus-sion of contralateral breast cancer risk and the poten-tial role of bilateral mastectomy, provided the risk ofsystemic recurrence from the index cancer is low. Weare in the process of developing a feasibility protocolto assess genetic testing around the time of diagnosis.

A recent ASCO abstract reported preliminary results ofearly limited genetic testing offered at diagnosis to 165patients with at least a 10% probability of carrying aBRCA1/2 mutation [14]. Seventy-one percent (117/165)of the eligible subjects agreed to testing, with accep-tance of testing correlated with younger patient age(p = 0.02) and surgical recommendations regardinggenetic testing and its impact on local therapy (p = 0.05).

In summary, the study by Eccles et al. of a diversegroup of patients adds to the data that patients with aknown or likely inherited susceptibility to breast cancer(either by virtue of a BRCA1 mutation or positivefamily history) have increased risk of additional primarybreast cancers. Further study will help determine theoptimal management of patients with inherited andfamilial breast cancer.

References

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12. Ford D, Easton DF, Stratton M et al. Genetic heterogeneity andpenetrance analysis of the BRCA1 and BRCA2 genes in breastcancer families. The Breast Cancer Linkage Consortium. Am JHum Genet 1998; 62: 676–89.

13. Berry DA, Parmigiani G, Sanchez J et al. Probability of carryinga mutation of breast-ovarian cancer gene BRCA1 based on familyhistory [see comments]. J Natl Cancer Inst 1997; 89: 227–38.

14. Isaacs C KE, Brogan B, Peshkin BN et al. Acceptance and impactof BRCA1/2 testing in newly diagnosed high risk breast cancerpatients. Proceedings American Society Clinical Oncology A149.J Clinical Oncology 2001: 38a.

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