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© 1999 American Society for Clinical Oncology
The Key and the LamppostThe University of Chicago, Center for Advanced Medicine, Chicago, IL IN THIS ISSUE of the Journal of Clinical Oncology, Turner et al1 report on the likelihood of BRCA1/BRCA2 mutations in patients with locally recurrent breast cancer after lumpectomy and radiation as compared with matched patients who do not have recurrences. They demonstrate that such mutations are more common in patients with recurrences and occur primarily in young patients. These recurrences are seen in other quadrants of the breast and occur late, suggesting that, rather than recurrences of the treated tumor, they represent new primary tumors elsewhere in the treated breast. How are we to use this information, how does it relate to other studies in the literature, and—the question that seems to me to be most pertinent—do patients with BRCA1/BRCA2 mutations have a higher likelihood of local recurrences? If so, are these recurrences different from those in patients who do not have these mutations? This question is not addressed in this article, but it is in the literature to which the authors refer.2,3 The following are the related questions referred to in the literature: Do young patients have a greater likelihood of local recurrences than older patients? As a subgroup, do young patients with a family history of breast cancer have a different frequency or type of breast cancer recurrence? My review of this literature shows that young women have a higher local recurrence frequency than older women, but that these are early, rather than late, recurrences. However, in a recent article, Peto et al4 determined that in an outbred United Kingdom population, only 5.9% of breast cancers in women under 36 were in patients with deleterious mutations in BRCA1/2 genes, which suggests that age alone is a poor surrogate for the presence of these mutations. Chabner et al5 and Chen et al6 reported no difference in local recurrence frequency in young patients with family histories as compared with young patients without family histories of breast cancer. Even family history and young age do not predict for BRCA mutations because such young women with strong family histories are only about 50% likely to have deleterious mutations in these genes.4 Fortunately, the question of whether the frequency and pattern of recurrence vary in BRCA1/2 heterozygotes was directly addressed at the 1999 Annual Meeting of the American Society of Clinical Oncology (ASCO), where Pierce et al7 reported a multi-institutional study of recurrence frequency in patients treated with lumpectomy and radiation as a function of whether or not they were BRCA1/BRCA2 heterozygotes. They found no difference, but unlike the Turner article1 reported in this issue, their median follow-up was only 5 years rather than the 11 years reported by Turner et al. Although this is reassuring, the limited follow-up period prevents a full evaluation of late recurrences, especially those putative new primary tumors found in Pierce et al's report. Turner et al refer to a smaller, similar study reported in abstract form at the 1998 ASCO Annual Meeting2 that also showed no increase in recurrences but suffered as well from limited follow-up and to an especially interesting study by Verhoog et al3 that showed no difference in local recurrence when breast conservation was compared with mastectomy. How then do we explain the higher probability of BRCA mutations in recurrent as compared with nonrecurrent breast cancer patients and that these recurrences are elsewhere in the breast, presumably new primary tumors? Turner et al1 imply that since the likelihood of BRCA1/2 deleterious mutations is higher in young patients with recurrence than in matched patients without recurrence, the mutations are associated with a greater likelihood of recurrence. While this may be the case, the logic is not compelling. I offer three alternative conjectures: First, this is a chance occurrence and has no importance. Second, BRCA heterozygotes have better local control consistent with the increase in radiation sensitivity of BRCA1-deficient cell lines.8 If this is the case and if one is only studying those whose tumors recur, then this group of patients would less likely to have "true recurrences," and since only recurrent patients are studied, they will be much more likely to have new primary tumors elsewhere in the breast. Third, since we know that BRCA mutated cells have increased radiation sensitivity, perhaps they are also more carcinogenic. Such a possibility suggests that the Pierce group should continue to observe their patients closely to ensure there isn't a plethora of late recurrences. Turner et al1 suggest that the results in their article are important in advising patients, but I am unclear how they help. Young patients with breast cancer, especially those with BRCA mutations, have a high incidence of contralateral breast cancer; in this series, five of the eight patients who experienced a recurrence had a contralateral cancer as well. Advising these patients is not so much a question of whether or not they should have a lumpectomy and radiation but rather whether observation is a satisfactory policy for either breast, because even if the ipsilateral recurrence is not found to be a problem, contralateral new primary cancer surely is. This increased likelihood of breast cancer in either breast is what must be considered in choosing breast preservation versus bilateral mastectomy. Only if the patient is willing to observe the contralateral breast are ipsilateral events an issue. The enthusiasm with which one recommends conservative management in BRCA heterozygotes willing to observe the other breast depends on how much breast preservation increases the risk of recurrence as compared with mastectomy. This cannot be ascertained from Turner et al's study, but the Pierce abstract7 is quite encouraging, with the important proviso that we must await the full article describing this study and considerably longer follow-up. My tentative opinion is that there seems to be no increase in early recurrences in patients with BRCA mutations, but we await further observation before evaluation of the likelihood of late recurrence. The implications of the current study are more likely due to how the study was done. Considering only patients with recurrences and asking whether they had mutated BRCA is the obverse of the direct question asked by Pierce et al.7 It reminds me of the parable of the key and the lamppost, which describes a man searching for a lost key underneath a lamppost. When questioned as to exactly where the key was lost, he indicated that it was lost elsewhere but that he was searching under the lamppost because the light was better there. The key to the question addressed by Turner et al is not to be found with this experimental design. Despite the better light afforded by looking only at patients experiencing recurrence, the proper method is to look at recurrence frequency in a population of patients who have deleterious BRCA mutations and compare that with those who do not. So far, those studies do not reveal an increase in recurrences. 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 Oncol17:3017-3024, 1999 2. Robson M, Levine D, Brown K, et al: Results of breast conservation therapy (BCT) for invasive breast cancer in women with BRCA mutations. Proc Am Soc Clin Oncol17:548a,, 1998 (abstr 2103) 3. Verhoog LC, Brekelmans CTM, Seynaeive C, et al: Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1. Lancet351:316-321, 1998[Medline]
4.
Peto J, Collins N, Barfoot R, et al: Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst91:943-949, 1999 5. Chabner E, Nixon A, Gelman R, et al: Family history and treatment outcome in young women after breast-conserving surgery and radiation therapy for early-stage breast cancer. J Clin Oncol16:2045-2051, 1998[Abstract] 6. Chen LM, Mundt AJ, Powers C, et al: Significance of family history in breast cancer treated with breast conservation therapy. Breast J2:238-245, 1996 7. Pierce L, Strawderman M, Narod S, et al: No deleterious effects of radiotherapy in women who are heterozygote for a BRCA-1 or BRCA-2 mutation following breast-conserving therapy. Proc Am Soc Clin Oncol18:86a,, 1999 (abstr 326)
8.
Gowen LC, Avrutskaya AV, Latour AM, et al: BRCA1 required for transcription-coupled repair of oxisative DNA damage. Science281:1009-1012, 1998
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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