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Originally published as JCO Early Release 10.1200/JCO.2006.06.3024 on November 28 2006 © 2007 American Society of Clinical Oncology. Breast Cancer Survival and Tumor Characteristics in Premenopausal Women Carrying the CHEK2*1100delC Germline Mutation
From the Departments of Epidemiology, Pathology, and Experimental Therapy, the Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam; and Departments of Surgery and Pathology, Leiden University Medical Center, the Netherlands Address reprint requests to Laura Van 't Veer, Department of Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; e-mail: l.vt.veer{at}nki.nl
Purpose Women carrying a CHEK2*1100delC germline mutation have an increased risk of developing breast cancer. This study aims to determine the proportion of CHEK2*1100delC carriers in a premenopausal breast cancer population, unselected for family history of breast cancer, and to investigate tumor characteristics and disease outcome with sufficient follow-up. Patients and Methods We identified a retrospective cohort of 1,479 patients, who received surgery for invasive breast cancer between 1970 and 1994. All patients were diagnosed before age 50. Paraffin-embedded tissue blocks were collected for DNA isolation (normal tissue), subsequent CHEK2*1100delC analysis, and tumor revision. Median follow-up was 10.1 years. Results We detected a CHEK2*1100delC germline mutation in 54 patients (3.7%). Tumor characteristics of CHEK2*1100delC carriers did not differ significantly from those of noncarriers. CHEK2*1100delC carriers had a two-fold increased risk (hazard ratio [HR], 2.1; 95% CI, 1.0 to 4.3; P = .049) of developing a second breast cancer and they had worse recurrence-free survival (HR, 1.7; 95% CI, 1.2 to 2.4; P = .006) and worse breast cancer–specific survival (HR, 1.4; 95% CI, 1.0 to 2.1; P = .072) compared with noncarriers. The poorer disease outcome of CHEK2*1100delC carriers could not be explained by the increased risk of second breast cancer. Conclusion Our study, which is representative for the premenopausal breast cancer population, reveals approximately 4% CHEK2*1100delC carriers have an increased risk of second breast cancer and a worse long-term recurrence-free survival rate. Their identification at time of diagnosis and prolonged intensive follow-up should be considered to optimize clinical management.
A substantial part of breast cancer arising in young women who do not carry a germline mutation in BRCA1 or BRCA2 may be explained by low- or moderate-penetrance genes.1 Hence, there is an ongoing search for mutations and polymorphisms that may be associated with breast cancer.2,3 One specific mutation in CHEK2, named CHEK2*1100delC, first detected4 but not specifically implicated5 in Li-Fraumeni families, accounts for part of breast cancer susceptibility in European and North American populations.6-9 The mutation does not seem to play a role in Ashkenazi Jewish families,10 in Australian multiple-case breast cancer families,11 nor in the Spanish population.12 A collaborative case-control analysis from five countries showed that CHEK2*1100delC carriers have an approximately two-fold increased risk of breast cancer.6 The CHEK2*1100delC germline mutation has been found to be present in 5% of breast cancer patients from non-BRCA1/2 breast cancer families.13,14 In addition, having a bilateral breast cancer or family history of bilateral breast cancer increased the probability of presence of a CHEK2*1100delC germline mutation.15,14 CHEK2 encodes a cell cycle checkpoint kinase that plays an important role in the DNA damage repair pathway, activated mainly by ataxia telangiectasia mutated (ATM) in response to double-strand DNA breaks, which results in phosphorylation of p53 and BRCA1.16,17 The 1100delC truncation eliminates the kinase domain and activity of Chk2, whereas the remaining wild-type allele is often lost in tumors, which results in the complete loss of Chk2 function.16 Thus, the CHEK2*1100delC mutation may not only predispose to breast cancer but also lead to a different outcome of disease, possibly reflected by differences in tumor characteristics or different response to treatment.17 Indications that the CHEK2*1100delC germline mutation may indeed predispose to a worse outcome of breast cancer were first suggested by a case-case study that showed an increased risk for contralateral breast cancer.18 In addition, one prospective cohort study with short follow-up showed a worse disease-free survival for CHEK2*1100delC carriers.19 We analyzed CHEK2*1100delC in an unselected breast cancer population of women diagnosed at age younger than 50 years to determine the contribution of this mutation to the long-term outcome of breast cancer.
Patient Selection and Study Design We conducted a retrospective cohort study of breast cancer patients diagnosed at age younger than 50 years. We included women who received surgery for invasive breast cancer (in the Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital [NKI-AVL; Amsterdam, the Netherlands], Leiden University Medical Center [LUMC; Leiden, the Netherlands], and two regional hospitals in Leiden) between 1970 and 1995. This specific period was chosen predominantly to provide sufficient follow-up for survival analysis.20 Patients in these hospitals who received surgery elsewhere were excluded because no paraffin-embedded tissue was available. We also excluded patients with a history of other malignancies, except nonmelanoma skin cancer. This study received approval of the Medical Ethical Committees of NKI-AVL and LUMC.
Data Collection CHEK2*1100delC mutation was evaluated by directed sequencing (primer sequences are available from the authors on request). If a mutation was detected, it was confirmed by sequencing the sample a second time. Of the 1,660 samples analyzed, 32 samples (2%) did not yield an interpretable result and were excluded. At analysis, CHEK2*1100delC results were available for 1,628 patients. However, 79 patients were excluded retrospectively during the study, in most cases because it became clear from the clinical and pathologic data that these patients had an earlier malignancy (n = 35, including two with a CHEK2*1100delC mutation [5.7%]) or noninvasive breast cancer (n = 39). The patients excluded were evenly distributed over the years of diagnosis (median, 1985; range, 1974 to 1994); however, they were diagnosed with breast cancer on average 2 years earlier than included patients (P < .05). All samples had already been analyzed for BRCA1 and BRCA2 Dutch founder mutations. Considering that BRCA carriers constitute a specific subgroup,21 these patients (n = 70) were also excluded from the analyses, including one patient with both a BRCA1 and CHEK2*1100delC mutation. Hence, 1,479 patients were included for analyses of breast cancer survival and tumor characteristics in CHEK2*1100delC carriers compared with noncarriers. For all patients, available tumor slides and tissue blocks were retrieved from the pathology archives. Of 1,479 patients included, no slides and tumor blocks could be retrieved for 2% of the patients. Of the 1,452 remaining patients, 16% to 20% of the samples could not adequately be typed for morphology and/or adequately graded (ie, the necessary slides were missing or quality of slides was not good enough for part of grading). Of 1,452 patients, 1,010 blocks (70%) were available and suitable to be included in the tissue array. Loss of cores in the slicing process, punches not containing tumor material, and unsuccessful coloring resulted in 89% to 91% of these 1,010 patients having scores for estrogen receptor, progesterone receptor, P53, and Her2/neu. Tumor information was less likely to be available for patients diagnosed in the earlier years of the study period. Tumor characteristics were all derived from a review of slides stained with hematoxylin and eosin and from tissue arrays including three punches per tumor. Tumor grading, according to the Bloom-Richardson method,22 tumor morphology typing, and scoring of the immunohistochemical stains of the tissue arrays was performed by one pathologist (J.L.P.). Immunohistochemical staining of the tissue arrays was performed at the Pathology Department of the NKI-AVL using monoclonal mouse antibodies for estrogen receptor (1D5 + 6F11, NeoMarkers; LabVision, Fremont, CA), progesterone receptor (PR-1; ImmunoLogic, Duiven, the Netherlands), P53 (DO-7; DAKO, Glostrup, Denmark), and Her2/neu (3B5,23 NeoMarkers; LabVision), the Power Vision detection kit (ImmunoLogic), and the Stainer Lab Vision 2D (LabVision). Each tissue array block of about 50 patient samples contained negative liver controls and in each run of staining, separate slides of negative and positive (levels of expression: low and high) breast tumors were included. A negative versus positive score was defined as no coloring versus any coloring of tumor cells for estrogen receptor and progesterone receptor, less than 10% versus more than 10% for P53, 0 or 1+ versus 2+ or 3+ for Her2/neu. In the analyses, the highest score of each immunohistochemical stain per patient was taken.
Statistical Analysis
In 1,479 patients with invasive breast cancer, 54 CHEK2*1100delC carriers (3.7%) were identified (Table 1). CHEK2*1100delC carriers were younger than non-CHEK2*1100delC carriers, but did not differ significantly with respect to other characteristics of breast cancer or treatment (Table 1). In the noncarriers, 12 synchronous bilateral breast cancers were diagnosed (0.8%) compared with one (1.9%) in the CHEK2*1100delC carriers (P = .44). Breast cancer occurred in the family (any relative with breast cancer; data only available for NKI-AVL patients) in 30% of patients, irrespective of CHEK2*1100delC carriership.
Tumor characteristics of the first breast cancer of CHEK2*1100delC carriers did not differ significantly from those of noncarriers (Table 2). In addition, the proportion of tumors with angioinvasion (23%) and/or with lymphoid infiltration (22%) did not differ between the two groups.
Median follow-up (overall, 10.1 years) was similar for CHEK2*1100delC carriers and noncarriers (10.1 v 9.9 years; P = .31). In CHEK2*1100delC carriers, eight second breast cancers (15%; six contralateral, two ipsilateral) occurred, compared with 116 (8%; 100 contralateral, 11 ipsilateral, five unknown location) in noncarriers (P = .08). The risk of second breast cancer was two-fold increased in patients with a CHEK2*1100delC germline mutation compared with noncarriers (HR adjusted for age, 2.1; 95% CI, 1.0 to 4.3; P = .049; Fig 1). Occurrence of a second cancer not in the breast did not differ between the groups (5.6% and 5.3% in CHEK2*1100delC carriers and noncarriers, respectively).
CHEK2*1100delC carriers had a worse recurrence-free survival compared with noncarriers (HR adjusted for age, 1.7; 95% CI, 1.2 to 2.4; P = .006; Fig 1). The distribution of recurrences did not differ between the groups (13.6% local only, 3.4% locoregional or regional, 83% distant metastases [with or without locoregional or regional]). In addition, CHEK2*1100delC carriership did not seem to influence the site of first distant metastasis (defined by whether the first metastasis of a patient was to the bone/skeleton, organ(s), or skin; data not shown). The worse recurrence-free survival of CHEK2*1100delC carriers could not be explained by their increased risk of contralateral breast cancer (HR, 1.7; 95% CI, 1.2 to 2.4, from analysis censoring at contralateral breast cancer diagnosis). In addition, breast cancer–specific survival was worse in CHEK2*1100delC carriers compared with noncarriers (HR adjusted for age, 1.4; 95% CI, 1.0 to 2.1; P = .072; Fig 1). In the subset of patients for whom tumor characteristics were available, estrogen receptor, progesterone receptor, and P53 were found to be possible confounders in the CHEK2*1100delC breast cancer–specific survival analysis but not in the analysis with recurrence-free survival as outcome. If these prognostic markers were included in the breast cancer–specific survival analyses, the HR for CHEK2*1100delC remained of the same magnitude but became nonsignificant; for example, breast cancer–specific survival adjusted for age and estrogen receptor yielded an HR of 1.5 (95% CI, 0.9 to 2.6; P = .12). If we included all tumor characteristics and age, the breast cancer–specific survival HR for CHEK2*1100delC was 1.6 (95% CI, 0.8 to 3.0; P = .14).
To our knowledge, this study is the first to show a worse 10-year recurrence-free survival in CHEK2*1100delC carriers. We also observed a trend toward worse breast cancer–specific survival in CHEK2*1100delC carriers. Furthermore, we confirm for the first time in an unselected breast cancer cohort (unselected for family history and not subject to survival bias) that is representative for the premenopausal breast cancer population, that CHEK2*1100delC carriers have a two-fold increased risk of developing a second breast cancer (mostly contralateral), but that this could not explain their less favorable survival. Earlier results had been reported from a case-case study and a cohort study with short follow-up.18,19 Our findings are supported by a study (carriers matched with noncarriers [1:3] by stratification for age and year of diagnosis within a prospective breast cancer series) with much shorter follow-up (median, 3.8 years) that showed worse distant metastasis-free (HR, 2.8; 95% CI, 1.2 to 6.6) and disease-free survival (HR, 3.9; 95% CI, 1.9 to 7.8), but not overall survival.19 We considered multiple confounders in our analysis, resulting in an adjustment for age. CHEK2*1100delC carriers seemed to have a slightly higher stage, but adjusting for stage in Cox regression analysis did not change our results. In addition, CHEK2*1100delC carriers seemed to have had mastectomy more often than noncarriers. However, one would expect that this would have led to better survival and thus to a smaller difference in survival between CHEK2*1100delC carriers and noncarriers. The two-fold risk increase for second breast cancer in CHEK2*1100delC carriers, based on our cohort with a mean follow-up of 10 years, is probably a more accurate reflection of the risk in the current (premenopausal) breast cancer population than earlier estimates with much wider CIs: an odds ratio of 6.5 (95% CI, 1.5 to 28.8) reported in a case-case study18 and an HR of 5.7 (95% CI, 1.7 to 19.7) with short follow-up.19 It may be that the increased risk of contralateral breast cancer in CHEK2*1100delC carriers is modified by radiotherapy for the first breast cancer.18 In the general breast cancer population, radiotherapy only slightly increases the risk of cancer in the contralateral breast, which receives a dose of several gray units of leakage and scattered radiation.24,25 However, increased risk has been reported for women who were younger than 45 years of age when they were treated (relative risk, 1.59).24 To our knowledge, no such data exist for second ipsilateral primary breast cancers, but the risk of ipsilateral recurrences is reduced after radiotherapy in the general breast cancer population.25 Radiation-induced DNA damage initiates a complex series of overlapping responses responsible for the maintenance of genome integrity. Candidate genes (eg, BRCA1, BRCA2, CHEK2, ATM, MDM2, and P53) involved in DNA damage repair signaling are implicated as excellent candidates for a role in radiation-induced breast cancer.26 The risk of contralateral breast cancer after breast-conserving therapy (including radiotherapy) is increased in BRCA1/2 carriers, whereas these patients seem to have only a small nonsignificant increased risk for breast recurrences (recurrences in BRCA1/2 carriers are suggested to be mostly second primary cancers and not true recurrences) compared with noncarriers.27 Unfortunately, our sample size did not allow for such analyses in CHEK2*1100delC carriers. This study demonstrates that the CHEK2*1100delC germline mutation is present in a significant proportion (3.7%) of Dutch breast cancer patients diagnosed before the age of 50 years. This proportion is in line with earlier reports on the prevalence of the CHEK2*1100delC germline mutation. Generally, estimates were somewhat higher in non-BRCA1/2 families, or other families with multiple breast cancer occurrences of all ages (range, 3.1% to 6.1%),6,7,13,14 and lower in unselected breast cancer patients of all ages (range, 1% to 2.5%).6,7,8,14 In our study, the presence of a family history of breast cancer was not associated with CHEK2*1100delC carriership. Our definition of family history was not as strict as in other studies. One report showed increasing prevalence of CHEK2*1100delC with increasing number of individuals diagnosed with breast cancer before age 60,13 and others detected a higher proportion of CHEK2*1100delC carriers (3.1%) compared with controls (1.4%) if one or more family members were affected with breast or ovarian cancer.14 However, these studies included small numbers and women of all ages. CHEK2*1100delC carriers did not appear to have tumor characteristics associated with worse prognosis and even seemed to have tumors with a slightly better prognosis (lower grade, more often estrogen receptor positive), albeit nonsignificantly. This finding is consistent with two other studies reporting tumor characteristics, although a higher proportion of estrogen receptor and progesterone receptor positivity19 and tumors with higher grade8 have been reported in CHEK2*1100delC carriers compared with noncarriers. The latter was mostly due to a higher proportion of grade 2 tumors (not grade 3), which was also the most prevalent tumor grade in the CHEK2*1100delC carriers in our study. It should be noted that the number of CHEK2*1100delC tumors in all three studies is rather small. It may be that the apparent higher chance of recurrence in breast cancer patients with a CHEK2*1100delC germline mutation originates from tumor characteristics not included in the common breast cancer markers panel presented in these articles. A methodologic strength of our study is that one pathologist reviewed all tumors. Unfortunately for many patients tumor information was missing (18% to 43%; Table 2); however, it is unlikely that the relatively high proportion of missing data introduced a bias in our study. First, the proportion of unknown tumor markers was not significantly different between patients with and without a CHEK2*1100delC germline mutation (Table 2). Second, the pathologist reviewed all samples without knowledge of carrier status. Reduced power due to a relatively small number of patients with known tumor characteristics probably is the reason for the nonsignificant effect (albeit of similar magnitude) of CHEK2*1100delC on breast cancer–specific survival when including tumor characteristics as covariates. However, additional research including other tumor characteristics is necessary to draw a definitive conclusion about whether tumor characteristics play a role in the worse survival seen in CHEK2*1100delC carriers. The worse recurrence-free survival may also be due to differences in response to therapy,17 as has been suggested for BRCA1 carriers.28 However, in our data, response to adjuvant treatment (recurrence-free survival after chemotherapy and/or hormonal therapy) was not different for CHEK2*1100delC carriers compared with noncarriers (data not shown). Our findings indicate that a single germline mutation in the DNA damage repair pathway has the ability to change the disease outcome of breast cancer. Based on a consecutive series of breast cancer patients, unselected for family history, we showed that CHEK2*1100delC carriers have an increased risk of second breast cancer and worse long-term recurrence-free survival. More research is needed to explore tumor characteristics of CHEK2*1100delC carriers and to investigate gene-treatment interactions. The sizable proportion of CHEK2*1100delC carriers warrants research into the pros and cons of mutation screening of young breast cancer patients,29 because diagnostic testing is feasible. CHEK2*1100delC carrier patients could potentially benefit from individualized clinical management, including prolonged and intensive follow-up, compared with breast cancer patients in general.
The authors indicated no potential conflicts of interest.
Conception and design: Marjanka K. Schmidt, Rob A.E.M. Tollenaar, Flora E. van Leeuwen, Laura J. Van 't Veer Administrative support: Marjanka K. Schmidt Provision of study materials or patients: Rob A.E.M. Tollenaar, Vincent T.H.B.M. Smit, Johannes L. Peterse Collection and assembly of data: Marjanka K. Schmidt, Sanne R. de Kemp, Cees J. Cornelisse, Vincent T.H.B.M. Smit, Johannes L. Peterse, Flora E. van Leeuwen, Laura J. Van 't Veer Data analysis and interpretation: Marjanka K. Schmidt, Rob A.E.M. Tollenaar, Annegien Broeks, Flora E. van Leeuwen, Laura J. Van 't Veer Manuscript writing: Marjanka K. Schmidt, Rob A.E.M. Tollenaar, Flora E. van Leeuwen, Laura J. Van 't Veer Final approval of manuscript: Marjanka K. Schmidt, Rob A.E.M. Tollenaar, Sanne R. de Kemp, Annegien Broeks, Cees J. Cornelisse, Vincent T.H.B.M. Smit, Johannes L. Peterse, Flora E. van Leeuwen, Laura J. Van 't Veer
We thank Nachet Islam and Carla Schippers (NKI-AVL), Nel Kuipers and Rob Keizer (LUMC) for tissue block collection and tissue slicing; Bart Maertzdorf (NKI-AVL) for DNA isolation and database management; Renate de Groot and the Pathology Department (NKI-AVL) for making tissue arrays and staining slides; Frans Hogervorst (NKI-AVL) for advice; Arnout van der Plas, Ben Nota, and Siegina Klaver for DNA preparation (NKI-AVL); Roelof Pruntel (NKI-AVL) for sequencing; Maartje Hooning (NKI-AVL) for follow-up data collection; and Anouk Pijpe, Rob van der Spruit, and Renate Udo for data collection, data entry, tissue block collection, and administration.
published online ahead of print at www.jco.org on November 27, 2006. Supported by the Dutch Cancer Society and the Dutch National Genomics Initiative. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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The CHEK2 Breast Cancer Case-Control Consortium: CHEK2*1100delC and susceptibility to breast cancer: A collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies. Am J Hum Genet 74:1175-1182, 2004[CrossRef][Medline] 7. Friedrichsen DM, Malone KE, Doody DR, et al: Frequency of CHEK2 mutations in a population based, case-control study of breast cancer in young women. Breast Cancer Res 6:R629-R635, 2004[CrossRef][Medline] 8. Kilpivaara O, Bartkova J, Eerola H, et al: Correlation of CHEK2 protein expression and c.1100delC mutation status with tumor characteristics among unselected breast cancer patients. Int J Cancer 113:575-580, 2005[CrossRef][Medline] 9. Rashid M, Jakubowska A, Justenhoven C, et al: German populations with infrequent CHEK2*1100delC and minor associations with early-onset and familial breast cancer. Eur J Cancer 41:2896-2903, 2005[CrossRef][Medline] 10. Offit K, Pierce H, Kirchhoff T, et al: Frequency of CHEK2*1100delC in New York breast cancer cases and controls. BMC Med Genet 4:1, 2003[Medline] 11. Jekimovs CR, Chen X, Arnold J, et al: Low frequency of CHEK2 1100delC allele in Australian multiple-case breast cancer families: Functional analysis in heterozygous individuals. Br J Cancer 92:784-790, 2005[CrossRef][Medline] 12. Osorio A, Rodriguez-Lopez R, Diez O, et al: The breast cancer low-penetrance allele 1100delC in the CHEK2 gene is not present in Spanish familial breast cancer population. Int J Cancer 108:54-56, 2004[CrossRef][Medline] 13. Meijers-Heijboer H, van den Ouweland A, Klijn J, et al: Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 31:55-59, 2002[CrossRef][Medline] 14. Vahteristo P, Bartkova J, Eerola H, et al: A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet 71:432-438, 2002[CrossRef][Medline] 15. Johnson N, Fletcher O, Naceur-Lombardelli C, et al: Interaction between CHEK2*1100delC and other low-penetrance breast-cancer susceptibility genes: A familial study. Lancet 366:1554-1557, 2005[CrossRef][Medline] 16. Bartek J, Lukas J: Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell 3:421-429, 2003[CrossRef][Medline] 17. Craig AL, Hupp TR: The regulation of CHK2 in human cancer. Oncogene 23:8411-8418, 2004[CrossRef][Medline] 18. Broeks A, de Witte L, Nooijen A, et al: Excess risk for contralateral breast cancer in CHEK2*1100delC germline mutation carriers. Breast Cancer Res Treat 83:91-93, 2004[CrossRef][Medline] 19. de Bock GH, Schutte M, Krol-Warmerdam EM, et al: Tumour characteristics and prognosis of breast cancer patients carrying the germline CHEK2*1100delC variant. J Med Genet 41:731-735, 2004 20. Schmidt MK, van Leeuwen FE, Klaren HM, et al: Genetic research with stored human tissue: A coding procedure with optimal use of information and protection of privacy [in Dutch]. Ned Tijdschr Geneeskd 148:564-568, 2004[Medline] 21. Lakhani SR, Jacquemier J, Sloane JP, et al: Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J Natl Cancer Inst 90:1138-1145, 1998 22. Elston CW, Ellis IO: Pathological prognostic factors in breast cancer: I. The value of histological grade in breast cancer—Experience from a large study with long-term follow-up. Histopathology 19:403-410, 1991[Medline] 23. van de Vijver MJ, Peterse JL, Mooi WJ, et al: Neu-protein overexpression in breast cancer: Association with comedo-type ductal carcinoma in situ and limited prognostic value in stage II breast cancer. N Engl J Med 319:1239-1245, 1988[Abstract] 24. Boice JD Jr, Harvey EB, Blettner M, et al: Cancer in the contralateral breast after radiotherapy for breast cancer. N Engl J Med 326:781-785, 1992[Abstract] 25. Early Breast Cancer Trialists' Collaborative Group (EBCTCG): Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 366:2087-2106, 2005[Medline] 26. Bennett LM: Breast cancer: Genetic predisposition and exposure to radiation. Mol Carcinog 26:143-149, 1999[CrossRef][Medline] 27. Pierce L, Levin A, Rebbeck T, et al: Multi-institutional 10-year results of breast-conserving surgery and radiotherapy in BRCA1/2-associated stage I/II breast cancer. J Clin Oncol 24:2437-2443, 2006 28. Kennedy R, Quinn J, Mullan P, et al: The role of BRCA1 in the cellular response to chemotherapy. J Natl Cancer Inst 96:1659-1668, 2004 29. Daly M: Tailoring breast cancer treatment to genetic status: The challenges ahead. J Clin Oncol 22:1776-1777, 2004 Submitted March 1, 2006; accepted August 16, 2006.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
