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© 1999 American Society for Clinical Oncology 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 MutationsFrom the Departments of Therapeutic Radiology, Genetics, and Surgery, Yale University School of Medicine, New Haven, CT; Myriad Genetics, Inc, Salt Lake City, UT; and Department of Radiation Oncology, Thomas Jefferson University Hospital, Philadelphia, PA. Address reprint requests to Bruce G. Haffty, MD, Department of Therapeutic Radiology, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520-8040; email bruce.haffty{at}yale.edu
PURPOSE: Breast cancer patients treated conservatively with lumpectomy and radiation therapy (LRT) have an estimated lifetime risk of local relapse (ipsilateral breast tumor recurrence [IBTR]) of 10% to 15%. For breast cancer patients carrying BRCA1 or BRCA2 (BRCA1/2) mutations, the outcome of treatment with LRT with respect to IBTR has not been determined. In this study, we estimate the frequency of BRCA1/2 mutations in a study of breast cancer patients with IBTR treated with LRT. PATIENTS AND METHODS: Between 1973 and 1994, there were 52 breast cancer patients treated with LRT who developed an IBTR within the prior irradiated breast and who were willing to participate in the current study. From our database, we also identified 52 control breast cancer patients treated with LRT without IBTR. The control patients were individually matched to the index cases with respect to multiple clinical and pathologic parameters. Lymphocyte DNA specimens from all 52 locally recurrent patients and 15 of the matched control patients under age 40 were used as templates for polymerase chain reaction amplification and dye-primer sequencing of exons 2 to 24 of BRCA1, exons 2 to 27 of BRCA2, and flanking intron sequences. RESULTS: After LRT, eight (15%) of 52 breast cancer patients had IBTR with deleterious BRCA1/2 mutations. By age, there were six (40%) of 15 patients with IBTR under age 40 with BRCA1/2 mutations, one (9.0%) of 11 between ages 40 and 49, and one (3.8%) of 26 older than age 49. In comparison to the six (40%) of 15 of patients under age 40 with IBTR found to have BRCA1/2 mutations, only one (6.6%) of 15 matched control patients without IBTR and had a BRCA1/2 mutation (P = .03). The median time to IBTR for patients with BRCA1/2 mutations was 7.8 years compared with 4.7 years for patients without BRCA1/2 mutations (P = .03). By clinical and histologic criteria, these relapses represented second primary tumors developing in the conservatively treated breast. All patients with BRCA1/2 mutations and IBTR underwent successful surgical salvage mastectomy at the time of IBTR and remain alive without evidence of local or systemic progression of disease. CONCLUSION: In this study, we found an elevated frequency of deleterious BRCA1/2 mutations in breast cancer patients treated with LRT who developed late IBTR. The relatively long time to IBTR, as well as the histologic and clinical criteria, suggests that these recurrent cancers actually represent new primary breast cancers. Early onset breast cancer patients experiencing IBTR have a disproportionately high frequency of deleterious BRCA1/2 mutations. This information may be helpful in guiding management in BRCA1 or BRCA2 patients considering breast-conserving therapy.
THE CONSERVATIVE management of breast cancer with lumpectomy followed by radiation therapy (LRT) to the intact breast has been firmly established as an acceptable standard of care for the majority of women with early stage breast cancer.1,2 Long-term follow-up data have consistently demonstrated a 0.5%- to 2%-per-year actuarial risk of ipsilateral breast tumor recurrence (IBTR).3-7 Although the majority of breast tumor recurrences can be effectively salvaged with mastectomy, IBTR is an event that has a significant impact on the patient's overall quality of life, psychosocial well-being, and medical costs.4-7 Although there have been conflicting reports regarding a number of clinical and pathologic features that are associated with IBTR, there has been a consistent correlation between young patient age and higher IBTR rates.7-13 However, family history of early onset breast/ovarian cancer has not consistently been associated with an increased risk of IBTR after LRT.14-19 The recent cloning and identification of BRCA1 and BRCA2 (BRCA1/2) germline mutations has resulted in numerous publications regarding the epidemiologic and clinical significance of these mutations.20-30 Although the metastatic potential for breast cancer patients with mutations in BRCA1/2 seems to be similar to their counterparts with sporadic breast cancer, the biologic behavior, with respect to the risk of second tumors, has been shown to be substantially different. The long-term risk of developing a contralateral tumor in a BRCA1/2 patient diagnosed with breast cancer approaches 60% to 70%.30-36 This has led many patients and clinicians to strongly consider bilateral mastectomy at the time of breast cancer diagnosis in patients with a known BRCA1/2 deleterious mutation. Given that BRCA1/2 patients, who undergo conservative surgery and radiation, maintain an intact breast with all residual cells in both breasts harboring the same deleterious mutations, we hypothesized that these patients may be at significant long-term risk for developing second primary tumors in the ipsilateral as well as the contralateral breast. Despite the potential significant clinical impact of this issue, there is a paucity of data evaluating treatment outcome in early stage breast cancer patients with BRCA1/2 mutations, with respect to LRT.37-40 The paucity of data is related not only to the fact that the BRCA1/2 genes were only recently discovered and characterized but also to the necessity of long-term follow-up to be able to assess the risk of local relapse or second primary tumors developing in conservatively treated patients. Our institution initiated conservative treatment in the 1970s and has maintained a detailed database of 1,546 patients with follow-up exceeding 12 years. This afforded us a unique opportunity to address the issue of long-term IBTRs in women undergoing breast-conserving therapy who may be carriers of germline BRCA1/2 mutations.
Patient Population Base The records of patients with early stage breast cancer treated with LRT in the facilities of the Department of Therapeutic Radiology at Yale-New Haven Hospital (New Haven, CT) between 1973 and 1994 were retrospectively reviewed. All patient data, including age, stage, hormone receptor status, lymph node status, histologic parameters, adjuvant therapy, and outcomes including local, regional, and distant metastasis, were entered into a computerized database. Patients experiencing an IBTR were identified as potential participants for this study. Of 1,546 patients treated in this time interval, 112 patients had experienced an IBTR as a first site of failure. Because of the nature of the study and the requirement for informed consent, patients with IBTR who had died were not eligible for analysis. A total of 52 patients with IBTR consented to participate and served as the primary population base for the current study. Because the patients participating in the study had to be alive and willing to participate, there is an obvious selection bias introduced into this study with regard to survival and distant metastasis between the entire patient population with local relapse (112 patients) and the 52 patients consenting to enrollment onto the study. The majority (52 of 63 contacted) of living patients consented to enrollment onto the study. The characteristics of the 52 patients with IBTR as a first site of failure are given in Table 1. Also, for comparison, the characteristics of the remainder of nonparticipating patients are listed in Table 1. With the exception of the fact that the majority of untested IBTR patients had expired, it is evident that there are no significant differences between the clinical and pathologic characteristics of the tested and untested cohorts.
All patients enrolling onto the study had an extensive interview for a complete family history, with a pedigree profile through at least three generations. All interviews were conducted by one of the authors (E.H.) and were then reviewed and scored by a certified genetics counselor (E.M.) who was blinded to all clinical information and BRCA1 or BRCA2 mutational status. The genetics counselor reviewed, in detail, the family pedigree of each patient, and, based on this overview of the pedigree, the family history was scored as no significant family history, moderate family history, or strong family history of breast cancer. After obtaining informed consent, patients underwent a standard phlebotomy procedure, from which blood was collected for lymphocyte DNA purification, as previously described.41,42 Patients were then assigned a unique study identification number, which was subsequently used to maintain confidentiality. Although the unique identification number could be linked to the clinical record for this study, all subsequent identification was made by the study number. The purpose of the study was to assess whether the frequency of BRCA1/2 mutations in our locally recurrent breast cancer population was higher than expected. We determined that comparison to databases of patients in high-risk clinics would not be appropriate because our patients were not selected for family history of breast or ovarian carcinoma but, instead, were simply selected on the basis of having suffered an IBTR after LRT in our general breast cancer population base. Furthermore, patients from databases of BRCA1/2 populations may not have been treated in a similar fashion nor have the length of follow-up that our population had. Therefore, the most appropriate control group would be our own patients who were treated with LRT but did not experience an IBTR. Initially, each of the 52 patients who experienced an IBTR were matched to 52 control patients who did not experience an IBTR. Patients were primarily matched by age (± 5 years), year of treatment (± 5 years), and stage. It would have been more ideal to attempt to match age within 1 or 2 years. However, because patients had to be alive, contacted, and willing to participate, it was not feasible to match more precisely. After matching primarily for age, stage, and year of treatment, other factors such as histologic subtype, laterality, margin status, and primary tumor size were considered in attempt to obtain as close a match as possible. Although no attempt was made to match for family history or Ashkenazi descent, these parameters turned out to be evenly balanced. DNA sequencing was performed on all 52 index cases and 15 control patients who were matched to each of the 15 index cases under age 40. Although it would have been reasonable to DNA sequence all of the control patients, including those older than age 40, the low frequency of BRCA1/2 mutations identified in the IBTR population older than age 40 made it unnecessary to sequence the controls of the same age group. As will be shown below, only two of 38 patients with IBTR older than age 40 at initial diagnosis had deleterious mutations in BRCA1 or BRCA2. Other reasons for not sequencing control patients older than age 40 were the infinitely small likelihood of finding a different rate of mutations in this group and limited available funds. Complete sequencing of the BRCA1 and BRCA2 genes was performed on the isolated constitutional DNA from all 52 IBTR index patients and 15 patients from the control group who were under age 40 at diagnosis. DNA was sequenced using polymerase chain reaction amplification of exons 2 to 24 of BRCA1 and exons 2 to 27 of BRCA2 with 82 pairs of polymerase chain reaction primers. All mutations that resulted in truncated BRCA1 or BRCA2 protein, the IVS8+2T > A BRCA1 mutation, resulting in truncated BRCA1 protein through aberrant splicing, and the BRCA2 Y42C missense mutation, were considered deleterious and appropriately scored.41
Statistics
The median follow-up from the date of original diagnosis for the 52 IBTR patients was 14.5 years compared with 14.9 years for the entire population of breast cancer patients in our database (P = NS). The median age in the index population was 49.5 years compared with 51.0 years in the 112 IBTR patients (P = NS). The median time to IBTR for the 52 patients in the index population was 4.7 years (Table 1) and did not differ from the median time to IBTR (4.3 years) for the 112 breast cancer patients with IBTR. Table 1 lists the characteristics of the index cases, as well as the characteristics of the remaining 60 untested IBTR patients. As listed in Table 2, the index and control patients under age 40 who were completely sequenced for BRCA1/2 were well matched by all major clinical and pathologic criteria. The index and control patients under age 40 were almost identical with regards to both family history of breast/ovarian cancer and Ashkenazi ancestry. As previously noted, although we attempted to match age as closely as possible and although patients under age 40 were of similar menopausal status, there was a slight but statistically significant age difference, with the index cases having a mean age 2.67 years younger than the controls (Table 2).
BRCA1 and BRCA2 Deleterious Mutation Analysis
The frequency of mutations in the IBTR population under age 40 ( six of 15 patients, 40%) was higher than anticipated. It is notable that the 40% frequency of BRCA1/2 mutations in the IBTR patient population under age 40 (not selected for family history of breast cancer) is significantly higher than our age-matched control group without IBTR. Although the control group under age 40 had a slightly higher age by 2.67 years, the 15% mutation rate in the control population is more in line with the expected frequency in an unselected group of breast cancer patients under age 40. The 40% mutation rate of IBTR index patients under age 40 is unusually high; the rate is even higher than the frequency of BRCA1/2 mutations noted in patients under the age of 40 with strong family histories screened in high-risk clinics.22,24,25,29 Mean time to IBTR in the breast cancer patients with BRCA1 or BRCA2 deleterious mutations was 8.7 years (Table 4). It is notable that the time to ITBR in carriers of BRCA1/2 mutations was considerably longer than the mean time to IBTR for the overall population of patients with IBTR (4.3 years). This suggests that the IBTR experienced in these patients represent de novo primary breast cancers as opposed to clonogenic recurrences, which usually occur within the first few years after LRT.7 In an effort to confirm our clinical impression that these events in patients with BRCA1/2 mutations represent second primary cancers, a detailed comparison of the primary tumor and IBTR is given in Table 3. Notably, both the location and histology of the relapse were distinct from the original primary tumor in the majority of cases. Furthermore, five of the eight patients with BRCA1/2 mutations had bilateral breast cancer, confirming other reports of a high lifetime risk of contralateral breast cancer in BRCA1/2 breast cancer patients. These data clearly support the hypothesis that early stage breast cancer patients undergoing breast conserving surgery who are BRCA1/2 carriers have a high risk of both ipsilateral and contralateral events. Although this finding would be anticipated given that all residual cells in both breasts harbor the same mutation, such data have not been previously reported. In contrast to the patients with deleterious mutations, as listed in Table 4, IBTR patients with wild type BRCA1/2, as well as IBTR patients in the untested cohort, were less likely to have tumors that were classified as new primary tumors by location and/or histology. It should be noted that all patients who had BRCA1 or BRCA2 mutations in this study underwent successful surgical salvage treatment with mastectomy at the time of IBTR and remain alive without evidence of further local or systemic progression, with a median follow-up time of 7.7 years after breast relapse (Tables 3 and 5).
BRCA1 and BRCA2 Missense Mutations of Unknown Significance
Pedigree Analysis
In this study, we demonstrated that breast cancer patients with IBTR after LTR have an elevated frequency of BRCA1/2 deleterious mutations. This finding has important implications because LRT remains the preferable standard of care for the majority of patients with early stage breast cancer. Although the choice of surgical treatment options for most patients is a personal issue, given the equivalent survival rates with mastectomy, the majority of women diagnosed with breast cancer who are deemed acceptable candidates will opt for breast conserving treatment. Management options with respect to both local and systemic therapy are, for patients and clinicians, complex decisions with significant medical, socio-economic, and psychologic consequences. For patients with strong family histories of breast cancer and, more recently, patients with BRCA1/2 deleterious mutations, these issues are further complicated by the potential differences in biologic behavior of the disease with respect to the risk of contralateral breast cancer, metastasis, and local-regional recurrence. As additional data regarding the natural history and biologic behavior of breast cancers with BRCA1/2 mutations unfolds, patients will be better able to cope with their disease and the decision-making process. To date, there is a paucity of available data regarding the issue of local relapse after LRT in patients with a BRCA1 or BRCA2 mutation. Some clinicians would recommend prophylactic bilateral mastectomy in women with deleterious BRCA1 or BRCA2 mutations who have not even been diagnosed with breast cancer. Therefore, it follows that unilateral and perhaps bilateral mastectomy may be recommended in breast cancer patients with BRCA1 or BRCA2 mutations at the time of breast cancer diagnosis, even if they are acceptable candidates for LRT.31-35 The reason for the lack of meaningful available data on this important clinical topic is two-fold. First, the gene has only recently been identified and sequenced; therefore, only a minority of breast cancer patients has documentation of BRCA1/2 status. Secondly, with respect to IBTR, long-term follow-up is necessary, particularly given our findings that the average time from initial diagnosis to IBTR is approximately 8 years in BRCA1/2 carriers. The current study provides data that suggest women who carry germline BRCA1 or BRCA2 mutations may be at higher risk for IBTR than their counterparts who do not harbor these germline mutations. Several other studies addressing this issue provide some conflicting results. In a study by Chabner et al,15 which evaluates family history data suggestive of inherited breast cancer susceptibility, no association between familial breast cancer and IBTR was noted. Our own data,17 as well as studies by Peterson et al14 and Chen et al,16 concur that family history is not associated with a higher risk of local relapse. However, two additional studies, limited to patients with ductal carcinoma in situ, by McCormick et al18 and Hiramatsu et al,19 did note a correlation between family history and local relapse. It is notable that all of these studies did not evaluate actual germline mutations as risk factors for local relapse but used family history as a surrogate. A recent report by Robson et al,37 which evaluated actual BRCA1/2 status, noted a 12% risk of local relapse at 5 years in 25 BRCA1/2 patients who underwent breast conserving surgery. Although this risk of local relapse seems slightly high at 5 years, it was not significantly higher than the study's population with sporadic breast cancer who underwent breast conserving therapy. It should be noted, however, that their follow-up was only 6 years. Because we have demonstrated in the current study that the median time to local relapse for BRCA1/2 carriers was nearly 8 years, it is not surprising that series with shorter follow-up times will fail to show higher IBTR rates in BRCA1/2 carriers undergoing LRT. Another report that supports our findings is a recent study by Seynaeve et al,38 which reported a high rate of IBTR in a case control study of patients with strong family histories or patients from BRCA1/2 families who underwent LRT. Although it is not clear how many of their patients actually underwent BRCA1/2 sequencing, they note that the late local failure rate in their familial breast cancer patients was significantly higher than sporadic cases and project a 10-year local failure rate of 27% and a 13-year local failure rate of 48%. Of interest, a prior study from the same group with presumably shorter follow-up, reported by Verhoog et al,39 did not demonstrate an elevated risk of local relapse in conservatively treated familial breast cancer patients, which emphasized the importance of a longer follow-up term in addressing this clinical issue. Another study by Gaffney et al,40 on patients treated by both mastectomy and conservative surgery, had too few conservatively treated patients with long-term follow-up to make definitive conclusions regarding outcome but noted no adverse effects with respect to tolerance to radiation in BRCA1/2 patients. The interpretation of these data is complicated, and the clinical implications must take into consideration many issues, including the limitations of the current study. Most importantly, our sample of patients was biased by the fact that all participants had to be alive to give informed consent and have blood drawn at the time of the study. Therefore, a significant number of patients who experienced local breast tumor relapse and subsequently died secondary to metastatic disease or other causes were, by definition, excluded from this study. Whether these patients with earlier, more aggressive local relapses who subsequently metastasized had germline BRCA1 or BRCA2 deleterious mutations is unknown. Two of our IBTR patients who had early local relapses and subsequently developed metastasis did not have mutations in BRCA1 or BRCA2. Notably, all patients in the current study who had BRCA1 or BRCA2 deleterious mutations underwent salvage treatment with mastectomy and remain free of further local and systemic disease. A significant finding in the current series is the long time to IBTR in the patients with BRCA1 or BRCA2 germline mutations. Most of these local breast tumor relapses are likely to represent new primary tumors developing in the residual breast tissue. The comparison of histology and tumor location between the initial tumor and the IBTR is consistent with our hypothesis that these late IBTR events represent de novo cancers. The long time to IBTR in BRCA1/2 carriers in the current series further supports this hypothesis. In contrast, patients with wild type BRCA1/2 status and our untested cohort were likely to develop IBTR events that were a combination of true relapses and new primary tumors. The fact that five of the eight patients who had deleterious mutations with an IBTR also had contralateral breast cancer supports the concept that both breasts are at significant risk for subsequent events. It must be emphasized that the long median follow-up of more than 14 years in our patient population was essential to observe these late events in both the ipsilateral and contralateral breast. Future studies evaluating mutations in BRCA1/2 as risk factors for IBTR are cautioned that an adequate long-term follow-up period is necessary to detect these late IBTRs. Although further studies are clearly needed, it seems that the frequency of deleterious BRCA1/2 mutations of 40% in patients under age 40 sustaining an IBTR after LRT is higher than would be expected. Previous studies have shown that approximately 10% of women with breast cancer under the age of 35 not selected for family history or ethnic group will have deleterious BRCA1 mutations. Furthermore, other studies have shown that only 21% of Ashkenazi women with breast cancer had BRCA1 deleterious mutations.24-29 Thus, the 40% (six of 15 patients) mutational frequency in our IBTR patients under age 40 is significantly higher than the 5% (one of 15 patients) noted in our own control patients under age 40 who were not selected for family history and is higher than the mutational frequency observed in extremely high-risk populations of women with breast cancer. It should be noted that the current study does not address the issue of whether breast cancer patients with BRCA1 or BRCA2 mutations are at higher risk for postmastectomy chest wall relapses after mastectomy. As previously noted, the long interval from initial diagnosis to IBTR in the current series suggests the IBTR events may be new primary tumors developing in the residual breast tissue6,7 Because the volume of residual breast tissue containing the dominant mutation is substantially reduced after mastectomy compared with conservative surgery, we would not predict a high rate of second primary tumors on the chest wall of postmastectomy patients. Clearly, data regarding this issue is needed, and clinical databases with young postmastectomy patients need to be analyzed for germline mutations and the subsequent risk of chest wall relapse. It also should be noted that chemoprophylaxis with tamoxifen or other antiestrogenic agents was rarely used in our study population. None of the patients with IBTR in the current series under age 40 were on tamoxifen. Because our data indicates that these patients are at increased risk for second primary tumors in the conservatively treated breast, chemoprophylaxis with tamoxifen or other estrogen receptor modulators is an important issue. Whether chemoprophylaxis will reduce the IBTR rate in breast cancer patients with BRCA1 or BRCA2 mutations electing breast conserving surgery is a critically important area worthy of further investigation. The issue of mastectomy in carriers of BRCA1/BRCA2 mutations at the time of breast cancer diagnosis and potential life expectancy gains will need to be further investigated. Two recent reports using different model systems with available retrospective data suggested that a 30-year-old woman with a BRCA1 or BRCA2 deleterious mutation gains from 2.8 to 5.3 years of life expectancy from prophylactic mastectomy. These results, however, do not necessarily apply to the woman faced with the diagnosis of breast cancer who is a probable BRCA1 or BRCA2 carrier. Although our data suggest a high rate of late local relapse in BRCA1/2 carriers undergoing LRT, all of these patients were successfully salvaged with mastectomy. Furthermore, the late IBTR rate may be reduced with antiestrogen chemoprophylaxis. Therefore, even when faced with the potential for a higher risk of IBTR, a patient may opt for breast conserving surgery as long as those risks are understood and the implications of the decision are based on available data such as is presented here. In summary, the current study provides evidence that breast cancer patients who experience IBTR have a significantly higher frequency of BRCA1 and BRCA2 deleterious mutations than would be expected in an age-matched control population of similarly treated breast cancer patients. In patients older than age 40 who experienced IBTR, few had BRCA1/BRCA2 mutations. Therefore, for these patients, who clearly represent the majority of breast cancer patients, BRCA1/2 mutational status may not be a clinically significant issue. However, in breast cancer patients under age 40 who experienced an IBTR, we found 40% had germline BRCA1/BRCA2 gene mutations. The increased frequency of BRCA1/2 deleterious mutations in patients with breast cancer who sustained IBTR suggests a relatively high rate of local relapse in patients with early onset breast cancer. However, the long interval between initial diagnosis and breast tumor relapse as well as a comparison of the pathology and location of the relapses suggest that these events are likely to represent second primary tumors. Although larger confirmatory studies are clearly warranted, our study suggests that the BRCA1/2 status of breast cancer patients under age 40 considering breast conservation strategies may be an important variable in assessing the long-term risk of IBTR. Currently, we are in the process of testing a larger unselected cohort of younger patients undergoing breast conserving therapy with long-term follow-up to assess the actuarial risk of IBTR as a function of BRCA1/2 status. These data help guide clinicians and patients in the difficult decision-making process regarding surgical treatment options and chemoprophylaxis at the time of breast cancer diagnosis in the management of familial breast cancer.
Supported by funds provided by the Betty R Sheffer Foundation, The Ethel F. Donaghue Woman's Health Investigator Program, and the Department of Therapeutic Radiology, Yale University School of Medicine.
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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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ABSTRACT
INTRODUCTION
2 analysis, overall survival, and distant disease-free survival (DDFS). Overall survival and DDFS were calculated by the life table method, with differences between the curves tested by the log-rank statistics test. The differences in the frequency of BRCA1 or BRCA2 mutations between the index and control samples were tested using McNemar's Y statistic for a single-sided hypothesis test. 
