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Journal of Clinical Oncology, Vol 26, No 6 (February 20), 2008: pp. 1015-1016 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.2140
In Reply:Center for Radiological Research, Department of Radiation Oncology, Columbia University Medical Center, New York, NY
Department of Radiation Oncology, Columbia University Medical Center, New York, NY
Departments of Mathematics and Physics, University of California Berkeley, Berkeley, CA We thank Drs Ponzone and Sismondi for their interesting comments. Regarding their first point, there is indeed some uncertainty as to the actual second-cancer risks in breast cancer survivors, Generally speaking, lower risk estimates in the literature have corresponded to shorter follow-up times—at least a 15-year follow-up is desirable. What appears beyond dispute, however, is that breast cancer risks are significantly elevated in the contralateral breast of long-term breast cancer survivors, compared with the overall population. We showed evidence1 that postlumpectomy radiotherapy of the affected (ipsilateral) breast significantly reduces the long-term, genetically based, second-cancer risk in that breast; hence, we suggested that low-dose prophylactic mammary irradiation (PMI) of the contralateral breast may represent a noninvasive technique for minimizing the elevated contralateral breast cancer risk in long-term breast cancer survivors. Ponzone and Sismondi do not question the suggestion that prophylactic mammary irradiation of the contralateral breast may reduce second-cancer risks in the contralateral breast (mechanistically, this is predicted to be through radiation inactivation of the pre-existing premalignant cells1). However, they raise three interesting points: (1) Ponzone and Sismondi point out that there may be some toxicity associated with PMI. This is true, of course, though we estimated1 these risks to be small at the proposed modest PMI doses (eg, 17 to 22 Gy, in 10 fractions). (2) Ponzone and Sismondi suggest that, even if PMI does reduce second-cancer risks in the contralateral breast, studies of contralateral prophylactic mastectomy (CPM) suggest that this may not result in a corresponding mortality reduction. The jury is still out on the relationship between CPM and mortality,2,3 though the largest study to date did conclude that it is indeed associated with decreased breast cancer mortality.4 Irrespective, a potentially sizable decrease in contralateral breast cancer risks, without the trauma of CPM, and independent of estrogen receptor status, would significantly improve the quality of life for long-term breast cancer survivors. (3) Finally, Ponzone and Sismondi raise the important question of the potential efficacy of contralateral-breast PMI for patients with breast cancer who are BRCA1/2 mutation carriers. This is indeed a significant issue, given the extraordinarily high rates of contralateral second cancers in these women.5-7 For example, Pierce et al7 recently showed a 39% risk of contralateral second cancer in BRCA1/2 carrier survivors at 15 years after treatment, which remains high even with tamoxifen or bilateral oophorectomy; this led the authors to conclude that "additional risk reduction interventions are needed in BRCA1/2 carriers interested in breast conservation, particularly for long-term control of the contralateral (uninvolved) breast."7 To estimate the benefit/risk balance for contralateral-breast PMI in breast cancer patients who are BRCA1/2 carriers, we need to know the sensitivity of BRCA1/2 cells for radiation-induced cell killing and mutagenesis and an estimate of the potentially increased number of premalignant cells in the contralateral breast of a BRCA1/2-carrier patient. Based on the available data,7-9 we would expect that, at the appropriate radiation dose, the benefit/risk balance for contralateral breast PMI would be still better for BRCA1/2-carrier patients with breast cancer, compared with women with sporadic breast cancer, largely because the potential second-cancer risks that could be eliminated by PMI are so large. Given this, we suggest that contralateral-breast PMI might indeed be the additional breast-conserving risk reduction intervention for BRCA1/2 carriers that Pierce et al7 called for. Contralateral breast cancer rates remain high for long-term breast cancer survivors, both BRCA1/2 carriers and others. It is in this context that we suggest that low-dose prophylactic mammary irradiation of the contralateral breast, which would be performed at the same time as standard postlumpectomy radiotherapy, is a breast-conserving estrogen-receptor–independent option that may have the potential to significantly decrease the disturbingly high second-cancer risks in the contralateral breast of long-term breast cancer survivors. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Brenner DJ, Shuryak I, Russo S, et al: Reducing second breast cancers: A potential role for prophylactic mammary irradiation. J Clin Oncol 25:4868-4872, 2007 2. Lostumbo L, Carbine N, Wallace J, et al: Prophylactic mastectomy for the prevention of breast cancer. Cochrane Database Syst Rev 4:CD002748, 2004[Medline] 3. Helzlsouer KJ: Contralateral prophylactic mastectomy: Quantifying benefits and weighing the harms. J Clin Oncol 23:4251-4253, 2005 4. Herrinton LJ, Barlow WE, Yu O, et al: Efficacy of prophylactic mastectomy in women with unilateral breast cancer: A cancer research network project. J Clin Oncol 23:4275-4286, 2005 5. Metcalfe K, Lynch HT, Ghadirian P, et al: Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 22:2328-2335, 2004 6. Robson M, Svahn T, McCormick B, et al: Appropriateness of breast-conserving treatment of breast carcinoma in women with germline mutations in BRCA1 or BRCA2: A clinic-based series. Cancer 103:44-51, 2005[CrossRef][Medline] 7. Pierce LJ, Levin AM, Rebbeck TR, et al: Ten-year multi-institutional results of breast-conserving surgery and radiotherapy in BRCA1/2-associated stage I/II breast cancer. J Clin Oncol 24:2437-2443, 2006 8. Buchholz TA, Wu X, Hussain A, et al: Evidence of haplotype insufficiency in human cells containing a germline mutation in BRCA1 or BRCA2. Int J Cancer 97:557-561, 2002[CrossRef][Medline] 9. Andreassen CN: Can risk of radiotherapy-induced normal tissue complications be predicted from genetic profiles? Acta Oncol 44:801-815, 2005[CrossRef][Medline] Related Correspondence
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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