Correspondence
Prognosis of Breast Cancer in Carriers of BRCA1 and BRCA2 Mutations
N Engl J Med 2007; 357:1555-1556October 11, 2007
- Article
To the Editor:
Rennert et al. (July 12 issue)1 report that a BRCA1 or BRCA2 mutation was not a significant predictor of mortality from breast cancer in an Israeli population-based cohort. However, 43% of potential cases were not included because tumor samples or medical records could not be retrieved, and excluded cases were more likely than included cases to be fatal. If BRCA1 carriers have more aggressive tumors,2 leading to earlier death, this could result in a spuriously improved prognosis (Neyman bias). In addition, the investigators did not study tumor grade (associated with mutation status),3 nor did they identify prognostic effects of tumor and nodal stage, raising concerns about internal validity. Furthermore, greater chemotherapy use among carriers (37%) than among noncarriers (24%) suggests that decisions about chemotherapy may have been influenced by factors such as family history, leading to a spurious treatment benefit in carriers. Finally, insufficient detail was provided regarding chemotherapy use (BRCA1-associated breast cancer may have increased sensitivity to agents causing double-strand DNA breaks4 and reduced sensitivity to mitotic spindle poisons) for a full understanding of the effect of chemotherapy in carriers of these mutations.5
5 ReferencesPamela J. Goodwin, M.D.
Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada
pgoodwin@mtsinai.on. ca Kelly-Anne Phillips, M.B., B.S., M.D.
Peter MacCallum Cancer Centre, East Melbourne 8006, AustraliaDee W. West, Ph.D.
Northern California Cancer Center, Fremont, CA 945381
Rennert G ,Bisland-Naggan S ,Barnett-Griness O , et al. Clinical outcomes of breast cancer in carriers of BRCA1 and BRCA2 mutations. N Engl J Med 2007;357:115-123
Full Text | Web of Science | Medline2
Phillips KA ,Andrulis IL ,Goodwin PJ . Breast carcinomas arising in carriers of mutations in BRCA1 or BRCA2: are they prognostically different? J Clin Oncol 1999;17:3653-3663
Web of Science | Medline3
Quenneville LA ,Phillips KA ,Ozcelik H , et al. HER-2/neu status and tumor morphology of invasive breast carcinomas in Ashkenazi women with known BRCA1 mutation status in the Ontario Familial Breast Cancer Registry. Cancer 2002;95:2068-2075
CrossRef | Web of Science | Medline4
Cortez D ,Wang Y ,Qin J ,Elledge SJ . Requirement of ATM-dependent phosphorylation of Brca1 in the DNA damage response to double-strand breaks. Science 1999;286:1162-1166
CrossRef | Web of Science | Medline5
Bryski T, Gronwald J, Huzarski T, et al. Response to neo-adjuvant chemotherapy in women with BRCA1-positive breast cancers. Breast Cancer Res Treat (in press).
To the Editor:
Can a BRCA mutation change clinical treatment decisions with regard to breast cancer? If it can, genetic testing should be included in the pretreatment diagnostic workup of patients with breast cancer and a family history. But it does not, according to Rennert et al. How reliable is this conclusion? Rennert et al. report the results of a small retrospective study during a time when treatment has changed. There were unexpected results: tumor size had no prognostic significance, and survival was better for BRCA1 (triple-negative) carriers than for BRCA2 (estrogen-receptor–positive) carriers.
Currently, pretreatment genetic testing for high-risk patients permits individualized treatment decisions.1 New data from unbiased studies are required to predict differences in clinical outcome among BRCA carriers.
1 ReferencesDimitrios H. Roukos, M.D.
Ioannina University, 45110 Ioannina, Greece
droukos@cc.uoi. gr 1
Roukos DH ,Briasoulis E . Individualized preventive and therapeutic management of hereditary breast ovarian cancer. Nat Clin Pract Oncol 2007;4:578-590
CrossRef | Web of Science | Medline
Author/Editor Response
Both Goodwin et al. and Roukos were surprised by the lack of a prognostic effect of tumor size on survival in BRCA1-positive patients with breast cancer. Among noncarriers, the adjusted hazard ratio associated with a tumor size greater than 2 cm (vs. ≤2 cm) was 2.8 (95% confidence interval [CI], 2.2 to 3.5; P<0.001), and among BRCA1 mutation carriers, the corresponding hazard ratio was 1.1 (95% CI, 0.5 to 2.8; P not significant). We think that this is an important finding with clinical implications (especially for screening), and we anticipate that it will be replicated by others. A lack of correspondence between tumor size and lymph-node status has been reported both for BRCA1 carriers1 and for patients with triple-negative breast cancers.2
There is no reason to believe that the decision to undergo chemotherapy in our study (or any other study) was influenced by family history; typically, the use of chemotherapy is determined on the basis of tumor stage and grade, and BRCA1-associated tumors are almost always of high grade. We agree that BRCA1-associated breast cancers may be insensitive to spindle poisons, and we thank Goodwin and her colleagues for bringing attention to our recent report on the possible ineffectiveness of taxanes for BRCA1 carriers in the neoadjuvant setting.3
We agree with Roukos that the principal findings of our study are limited by the fact that we studied a cohort of women in whom breast cancer was diagnosed in 1987 or 1988 and that relevant changes in treatment may have been introduced since then. The chemotherapy most commonly used in Israel in 1987 and 1988 was cyclophosphamide, methotrexate, and fluorouracil; today, many of these patients would receive doxorubicin (Adriamycin) and cyclophosphamide plus paclitaxel. If there were a differential response to the newer treatments, based on mutation status, then our findings would not be generalizable to patients in whom breast cancer was diagnosed in 2007. Better to start with a new cohort of patients who received the diagnosis in 2007 and to follow them for the next 20 years. But who is to say that standard treatment will not change once again — and again we will be forced to start from scratch?
3 ReferencesGad Rennert, M.D., Ph.D.
Carmel Medical Center, Haifa 34362, Israel
rennert@tx.technion. ac. il Steven Narod, M.D.
Women's College Research Institute, Toronto, ON M5G 1N8, Canada1
Foulkes WD ,Metcalfe KA ,Hanna W , et al. Disruption of the expected positive correlation between breast tumor size and lymph node status in BRCA1-related breast carcinoma. Cancer 2003;98:1569-1577
CrossRef | Web of Science | Medline2
Dent R ,Trudeau M ,Pritchard KI , et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 2007;13:4429-4434
CrossRef | Web of Science | Medline3
Byrski T, Gronwald J, Huzarski T, et al. Response to neo-aduvant chemotherapy in women with BRCA1-positive breast cancers. Breast Cancer Res Treat (in press).
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