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BRCA1/BRCA2 in Breast-Conserving Therapy

Thomas Jefferson University Hospital, Philadelphia, PA
Yale University School of Medicine, New Haven, CT

To the Editor: The Editorial by Hellman in the October 1999 issue¹ critiques our article regarding the frequency of BRCA1/2 mutations in a cohort of conservatively treated locally recurrent breast cancer patients. The thrust of the criticism seems to be in the case-control design of the study. Although case-control studies do have potential problems with respect to selection biases, it is a scientifically valid and time-tested methodology. Case-control designs have formed the basis of clinical studies in all aspects of medicine. In simple terms, one is evaluating whether individuals with a specified outcome (in our study, conservatively treated patients with ipsilateral breast tumor relapse [IBTR]), in contrast to matched individuals without that outcome (in our study, conservatively treated patients without IBTR), differ in regard to the parameter to be evaluated (in our study, BRCA1/2 mutations). While we acknowledge relatively small numbers in our study, the fundamental design of the study is sound, matching was done as closely as possible, and the study was done in a prospective fashion with a specific hypothesis. Our initial hypothesis was that there would be no difference in the frequency of germline BRCA1/2 mutations between the cases and controls, but we found, with a probability of P < .03, that the null hypothesis was void. Although we concur with Hellman that a more desirable study would clearly have been to test all individuals in the database to assess the actuarial risk of IBTR as a function of BRCA1/2 status, the logistics and funding for such an undertaking (given an estimated cost of $2,000/test) were not feasible at that time. One must acknowledge the tremendous amount of effort, funding, and extensive participation of patients as well as investigators that is required to conduct these studies. As we stated in our Discussion, however, we have since initiated a study, performing complete sequencing of the BRCA1/2 gene in a larger cohort of patients under age 40, that will yield the actuarial risk of IBTR as a function of BRCA1/2 status. Until results from this and other studies are available, our report in the Journal of Clinical Oncology presents the first available data to suggest a higher frequency than expected of germline BRCA1/2 mutations in a cohort of conservatively treated patients with locally recurrent breast cancer. The potential corollary to this finding is that patients with BRCA1/2 mutations may be at higher risk for late IBTR.

A critical observation from our report is that the median time to IBTR in patients with BRCA1/2 mutations exceeded 7 years. Our long median follow-up time of over 14 years was necessary to observe these late local relapses, and the clinical-pathologic assessment of the primary tumors and relapses strongly suggests that these events represent second primary tumors and not true recurrences. It is therefore not surprising that studies with follow-up periods of less than 8 years will fail to make these observations. Since all residual breast tissue harbors the same mutations, the development of late second primary tumors in the residual tissue in these patients does in fact make biologic sense. Although treatment decisions should not be made based solely on the data presented in our article, we believe the information presented provides valuable insights into the natural history of IBTR in patients with BRCA1/2 mutations. We clearly state in our Discussion that the clinical implications of our study are complicated and must take into account the limitations of the current study. We acknowledge that larger confirmatory studies are warranted, and as noted above, such studies are currently being conducted by ourselves as well as others.

REFERENCES

1. Hellman S: The key and the lamppost. J Clin Oncol17:3007-3008, 1999[Free Full Text]

2. Turner BC, Harrold E, Matloff E, et al: BRCA1/BRCA2 germline mutations in locally recurrent breast cancer patients after lumpectomy and radiation therapy: Implications for breast-conserving management in patients with BRCA1/BRCA2 mutations. J Clin Oncol17:3017-3024, 1999[Abstract/Free Full Text]

Response

University of Chicago, Chicago, IL

In Reply: The authors misinterpret my concerns. I have no quarrel with case-control studies in general, but rather that the question as to whether there is a greater likelihood of recurrence in patients with BRCA1/2 mutations is not addressed by this experiment. This experiment asks the obverse question: In a series of recurrent patients, do these mutations occur more frequently? Although an increase in BRCA1/2 mutations was found, this observation is consistent with a number of alternative explanations (see Editorial) that are indistinguishable in design.

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