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© 2000 American Society for Clinical Oncology
BRCA1/2 Germline Mutations: A Marker for Radioresistance or Radiosensitivity?Kenneth Norris Jr Comprehensive Cancer Center University of Southern California Keck School of Medicine Los Angeles, CA To the Editor:Turner et al1 have reported provocative data on the frequency of BRCA1/BRCA2 germline mutations (15%) among 52 breast cancer patients originally treated using segmental mastectomy and radiation who had developed ipsilateral breast tumor recurrences. As they pointed out, the histologic, topographic, and chronologic characteristics of the recurrences described suggest that they were more likely to be new primary tumors developing within the residual breast tissue. The data reported are interpreted as preliminary evidence of a possible inherent radioresistance among these patients. However, as suggested by Dr Hellman2 in the accompanying editorial, attempts to translate to the clinic the in vitro data on BRCA1-deficient cells would lead to opposite conclusions. BRCA1-deficient mouse embryonic stem cells display an inability to repair oxidative DNA damage and, thus, inherent increased radiosensitivity.3,4 Deficits of transcription-coupled repair in transcriptionally active DNA of premenopausal breast cells subject to cycling hormones could explain the age incidence of these new cancers after radiation exposure.4,5 Therefore, the hypothesis of these new tumors representing radiation-induced secondary malignancies should also be entertained. In addition to the hypothesis of increased sensitivity of BRCA1/2 mutant carriers to the carcinogenic effect of high-dose radiation, the possibility of a risk associated with much lower radiation dose (in diagnostic x-ray range) cannot be excluded.6 For instance, a higher proportion of excess radiation-induced cancers has been reported in relatives of BRCA1 carriers than in unrelated individuals.7 As already proposed,2 prospective collection of data from large cohorts of BRCA1/2 mutant carriers would assure the correct methodologic setting to confirm Turner et al’s data while controlling for other risk factors, including lifetime radiation exposure. Accurate information regarding the lifetime exposure to diagnostic x-rays among index cases and controls could identify an independent risk factor for the development of these breast cancers. Particular focus should be given to the frequency and technical characteristics of mammograms: the risk-to-benefit ratio of mammographic surveillance might be unfavorable in these individuals. We believe this question deserves immediate attention because it is in exactly this population that health care providers are currently recommending mammographic surveillance every 6 months. Most importantly, it would be tragic to deny mutation carriers with early breast cancer the options of breast preservation if therapeutic doses of radiation seem not to be implicated in the risk for second malignancies. Finally, possible associations between lack of BRCA1/2 function and repair of radiation damage in the clinic may help elucidate physiologic signal transduction pathways that mediate sensitivity to low-dose radiation occasionally observed in sporadic patients. REFERENCES
1.
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 Oncol 17:3017-3024, 1999
2.
Hellman S: The key and the lamppost. J Clin Oncol 17:3007-3008, 1999 (editorial)
3.
Gowen LC, Avrutskaya AV, Latour AM, et al: BRCA1 required for transcription-coupled repair of oxidative DNA damage. Science 281:1009-1012, 1998
4.
Hanawalt PC: Transcription-coupled repair and human disease. Science 266:1957-1958, 1994 5. Land CE: Studies of cancer and radiation dose among atomic bomb survivors: The example of breast cancer. JAMA 274:402-407, 1995[Abstract] 6. Modan B, Chetrit A, Alfandary E, et al: Increased risk of breast cancer after low-dose irradiation. Lancet 1:629-631, 1989 (published erratum appears in Lancet 1:916, 1989)[Medline] 7. Chakborty R, Little MP, Sancaranarayanan K: Cancer predisposition, radiosensitivity and the risk of radiation-induced cancers. IV: Prediction of risk in relatives of cancer-predisposed individuals. Radiat Res 149:493-507, 1998[Medline]
ResponseYale University School of Medicine New Haven, CT In Reply:The letter from Drs Formenti and Preston-Martin pose some interesting questions regarding radiosensitivity/radioresistance in patients with BRCA1/2 germline mutations. I would interpret our preliminary studies recently published in the Journal of Clinical Oncology as suggesting that patients with germline BRCA1/2 mutations who undergo breast-conserving therapy may, due to their underlying predisposition to develop breast cancer, have an elevated risk of developing second primary tumors in the residual breast tissue.1 As pointed out in our detailed analysis of each of the BRCA1/2 patients with a local relapse, the timing, as well as the comparisons in location and histology, strongly suggests that these events do not represent "radioresistant" relapses but are more likely to be "de nouveau" second primary events. It seems that the risk of developing early "true recurrences" in this population is low and that breast cancers in BRCA1/2 carriers are at least as radiosensitive or, perhaps as some laboratory data suggest, more radiosensitive than sporadic breast cancers. Our previously published data cannot directly address the issue of radiation-induced malignancies raised in the letter by Formenti and Preston-Martin. Currently, we are collecting data on a larger cohort of conservatively treated patients with early-onset breast cancer who have a median follow-up of nearly 15 years. All of these patients are being tested for the BRCA1/2 mutation to assess the 10- to 15-year actuarial risk of ipsilateral and contralateral breast cancer events as a function of BRCA1/2 status. Although this study is not yet complete, my preliminary analysis seems to demonstrate that in BRCA1/2 carriers who underwent lumpectomy and radiation, the risk of ipsilateral and contralateral events runs a similar course, at least through 10 to 15 years. Furthermore, the long-term risk of contralateral events in these patients does not seem to differ substantially from the reported long-term risks of contralateral events in BRCA1/2 carriers who had undergone unilateral mastectomy (presumably without irradiation). Acknowledging the obvious caveats in interpreting the relatively limited available literature, these data suggest that therapeutic doses of irradiation have neither an adverse nor protective effect on the risk of second breast cancer events in patients with BRCA1/2 mutations, and there is no compelling evidence that indicates BRCA1/2 carriers differ from sporadic patients with respect to second malignancies "induced" by radiation. I agree with Formenti and Preston-Martin that this is an area worthy of investigation, but given the available literature, I see no immediate cause for concern regarding the appropriate clinical use of diagnostic and/or therapeutic doses of radiation in BRCA1/2 carriers. Currently, I approach the management of a patient with a germline BRCA1/2 mutation similar to that of a patient with sporadic breast cancer, but counsel these patients regarding the long-term risks of developing second breast malignancies. It remains to be determined whether hormonal manipulation with tamoxifen, oophorectomy, or other estrogen receptor modulators can modify these risks. It is hoped that future clinical and laboratory studies will help to better define the impact of BRCA1/2 status on the appropriate screening and local and systemic management of breast cancer. REFERENCES 1. 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 Oncol 17:3017-3024, 1999 This article has been cited by other articles:
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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