Microsatellite Instability Is Correlated with Lymph Node-positive Breast Cancer1

We analyzed 8! cases of primary breast carcinoma and 7 cases of fibroadenoma for microsatellite instability at eight loci. Twenty-seven cases (33.3 % ) manifested aberrant microsatellite alleles: 7 (8.6%) at one locus and 20 (24.7%) at two or more loci [tumors with replication error-positive (RER+) phenotype]. No evidence of microsatellite instability was observed in fibroadenomas. We investigated correlations between RER+ phenotype and clinicopathological characteristics of the carcinomas. The RER+ phenotype was statistically associated with large tumor diameter; of i9 RER+ tumors with measured size, 16 were >2 cm, compared to 28 of 58 tumors with no evidence of microsatellite instability or with shifts in allele sizes limited to one locus (P 0.005, 2 test). Consistently, there was also a strong statistical association between RER+ phenotype and lymph node metastasis; 14 of 19 RER+ tumors with known lymph node status were N+, compared to 15 of 59 tumors with no evidence of microsatellite instability or with allele shifts limited to one locus (P 0.0002, 2 test). Correlations with age of patients, proliferative activity, histotype (ductal versus lobular), and grade of differentiation were not statistiReceived 7/16/96; revised 10/14/96; accepted I 1/5/96. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. I This study was supported by an Associazione Italiana per Ia Ricerca sul Cancro grant (to R. M-C.), by Grant 94.0116l.PF39 from Consiglio Nazionale delle Ricerche-Applicazioni Cliniche delle Ricerca Oncologica. and by Ministero Universit#{232} Ricerca Scientifica e Technologica grants. 2 To whom requests for reprints should be addressed. Phone: 39-(871)-355323 or 355-333; Fax: 39-(871 )-355-322: E-mail: [email protected]. cally significant, although the RER+ phenotype was more frequent in lobular and high-grade ductal carcinomas, in carcinomas with high proliferative activity, and in carcinomas from patients 50 years. Data concerning cancer(s) in first and/or second degree relatives were available for 66 cases, including 33 positive and 33 negative for family history of cancer. No correlations were detected between RER+ phenotype and family history of cancer. In conclusion, our results indicate that in breast cancer, microsatellite instability is associated with clinicopathological parameters that are considered predictors of recurrent disease and aggressive behavior. INTRODUCTION In breast cancer, the status and relevance of mierosatellite instability, as detected by the presence of random tumor-associated shifts in the length of mierosatellite repeats, is currently being debated. Peltom#{228}ki et al. ( 1 ) and Lothe et a!. (2) did not report microsatellite RERs3 in mammary carcinomas. Other investigators found random shifts in the size of microsatellite alleles in 5-21% of the eases (3-6). On the other hand, Patel et a!. (7) observed microsatellite alterations, including both instability and losses of constitutional mierosatellite alleles. in all of the 1 1 cases studied. Recent studies suggest intriguing correlations between microsatellite instability and elinieopathologieal parameters of breast carcinomas (5, 6, 8-10). In a previous report. we analyzed eight microsatellite loci in 28 sporadic primary breast carcinomas (5). The presence of aberrant mierosatellite alleles, detected in six eases (21%), significantly correlated with the lobular histotype and with lymph node involvement. A trend was also observed associating microsatellite instability and large tumor diameter. Remarkably. these results were at variance with those reported for other types of tumor with mierosatellite instability and with observations deriving from an independent study conducted on breast carcinomas. In fact, the presence of a RER+ phenotype. characterized by allele shifts at multiple loci. has been associated with indolent behavior and better prognostic indicators in gastrointestinal tumors (2, 1 1-13). A similar relationship was suggested in breast cancer by the clinical behavior of the few cases with microsatellite instability studied by Jrinsson ci (ii. (6). The present report investigates the status of eight microsatellite loei in 81 breast carcinomas, most of which had been characterized for a series of elinicopathological parameters, including age, histotype, grade, size, axillary lymph node status, proliferative activity, as determined using the ILL technique, 3 The abbreviations used are: RER. replication error: RER+. RER positive; TLI, thymidine labeling index; HNPCC. hereditary nonpolyposis colorectal carcinoma. Research. on April 15, 2017. © 1997 American Association for Cancer clincancerres.aacrjournals.org Downloaded from