Correspondence

Breast-Cancer Genomics

N Engl J Med 2003; 349:910-911August 28, 2003

Article

To the Editor:

In Figure 1 of their article, Wooster and Weber (June 5 issue)1 ignore an important paradox by dismissing mutations in the ATM (ataxia–telangiectasia mutated) gene as not contributing to breast cancer. Current theories propose that ATM senses DNA damage and then signals BRCA1. For example, ATM phosphorylates BRCA1, signaling it to arrest the cell cycle after DNA damage due to ionizing radiation. Pathogenic BRCA1 mutations markedly increase the risk of breast cancer. The dependence of BRCA1 on ATM thus makes it logical that mutations in the ATM gene would also increase the risk of breast cancer. Similarly, mutations in the CHEK2 gene increase the risk of breast cancer, and CHEK2 may have functional links with ATM.2,3 The authors accept the idea of a “BRCA3” gene with little hesitation, although such a gene has not yet been identified. ATM could actually represent BRCA3, according to claims that heterozygotes for ATM mutations may account for up to 20 percent of cases of breast cancer. Stipulations to these claims are required because of data that do not support the presence of excess truncating ATM mutations in early-onset breast cancer.4 However, a clearer discussion of at least the proposed relations among ATM, CHEK2, and BRCA1 would facilitate clinical application and help resolve this confusing paradox.

Bernard Friedenson, Ph.D.
University of Illinois–Chicago College of Medicine, Chicago, IL 60612

4 References

1. 1

   Wooster R, Weber BL. Breast and ovarian cancer. N Engl J Med 2003;348:2339-2347
   Full Text | Web of Science | Medline

2. 2

   Falck J, Mailand N, Syljuasen R, Bartek J, Lukas J. The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature 2001;410:842-847
   CrossRef | Web of Science | Medline

3. 3

   Witt E, Ashworth A. D-day for BRCA2. Science 2002;297:534-534
   CrossRef | Web of Science | Medline

4. 4

   FitzGerald MG, Bean JM, Hegde SR. Heterozygous ATM mutations do not contribute to early onset of breast cancer. Nat Genet 1997;15:307-310
   CrossRef | Web of Science | Medline

To the Editor:

I take exception to Wooster and Weber's statement that “among mutation carriers, this procedure [prophylactic mastectomy or prophylactic oophorectomy] has been shown to reduce the risk of breast and ovarian cancer by more than 60 percent and 95 percent, respectively.” Although it has been well documented that prophylactic mastectomy does not result in the removal of all breast tissue,1 ovarian cancer cannot develop in women who undergo prophylactic oophorectomy, with the very rare exception of cases in which some ovarian tissue is inadvertently left in situ because of unrecognized adherence of a portion of the ovary to the pelvic sidewall. What does happen in a small percentage of women who undergo prophylactic oophorectomy is the subsequent development of papillary serous carcinoma of the peritoneum, which is a diffuse involvement of the lining of the peritoneal surfaces with a carcinoma identical to papillary serous carcinoma of the ovary and in which there is no demonstrable primary ovarian carcinoma.2 This distinction is important because women who undergo prophylactic oophorectomy still need postoperative surveillance for the possible development of papillary serous carcinoma of the peritoneum.

M. Steven Piver, M.D.
Sisters of Charity Hospital, Buffalo, NY 14225
mpiver@chsbuffalo.org

2 References

1. 1

   Meijers-Heijboer H, van Geel B, van Putten WLJ, et al. Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2001;345:159-164
   Full Text | Web of Science | Medline

2. 2

   Piver MS, Jishi MF, Tsukada Y, Nava G. Primary peritoneal carcinoma after prophylactic oophorectomy in women with a family history of ovarian cancer: a report of the Gilda Radner Familial Ovarian Cancer Registry. Cancer 1993;71:2751-2755
   CrossRef | Web of Science | Medline

Author/Editor Response

In response to Dr. Piver, we agree that papillary serous carcinoma of the peritoneum is a more accurate term than ovarian cancer to describe the disseminated intraperitoneal cancer that can occur after prophylactic oophorectomy. However, this clinical entity is indistinguishable in presentation and prognosis from the stage III papillary serous ovarian carcinoma that can occur in women with intact ovaries. The source of papillary serous carcinoma of the peritoneum remains unknown, but regardless of its origin, it most commonly appears as disseminated intraperitoneal disease, and almost never as a resectable tumor mass. In our own series of 259 carriers of BRCA1 and BRCA2 mutations who underwent prophylactic oophorectomy, 2 patients (0.7 percent) received a diagnosis of papillary serous carcinoma of the peritoneum after a mean follow-up of 10.7 years.1 Thus, given the low incidence of this carcinoma after prophylactic oophorectomy in the highest-risk population studied to date, and given the absence of data showing that the outcome of this carcinoma can be altered by surveillance, it is difficult to make a case for screening women at high risk for papillary serous carcinoma of the peritoneum after prophylactic oophorectomy.

In response to Dr. Friedenson, we agree that ATM mutations have a plausible role in heritable susceptibility to breast cancer. A number of findings — the function of ATM in response to DNA damage, susceptibility to breast cancer in association with genetic mutations in this pathway, the segregation of ATM mutations in a few families with breast cancer, the excess rate of breast cancer in female family members of ATM homozygotes, and findings in a recently developed murine model — all support this hypothesis.2,3 However, as we stated, these data remain controversial because of conflicting reports3 and because of the absence of specific ATM sequence variants that are consistently associated with a significantly increased risk of breast cancer. Thus, at present, we believe that ATM is best represented within the approximately 50 percent of genes associated with breast-cancer susceptibility that remain unidentified or uncharacterized.

Barbara L. Weber, M.D.
Abramson Family Cancer Research Institute, Philadelphia, PA 19104

Richard Wooster, Ph.D.
Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom

3 References

1. 1

   Rebbeck TR, Lynch HT, Neuhausen SL, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 2002;346:1616-1622
   Full Text | Web of Science | Medline

2. 2

   Balmain A, Gray J, Ponder B. The genetics and genomics of cancer. Nat Genet 2003;33:Suppl:238-244
   CrossRef | Web of Science | Medline

3. 3

   Khanna KK. Cancer risk and the ATM gene: a continuing debate. J Natl Cancer Inst 2000;92:795-802
   CrossRef | Web of Science | Medline

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