In lymph node‐negative invasive breast carcinomas, specific chromosomal aberrations are strongly associated with high mitotic activity and predict outcome more accurately than grade, tumour diameter, and oestrogen receptor

Abstract

The objectives of this study were to analyse whether specific chromosomal gains and losses in lymph node-negative breast cancer correlate with other features and to evaluate their prognostic value. Seventy-six lymph node-negative breast carcinomas (median follow-up 46 months; range 9-105 months) were used. Histological grade, tumour type, maximal tumour diameter, oestrogen/progesterone receptor (ER/PR), mitotic activity index (MAI), and mean nuclear area (MNA) were assessed. Whole genome DNA analysis was performed by comparative genomic hybridization (CGH). Chromosomal aberrations were compared with classical and other prognostic features. Kaplan-Meier curves and multivariate survival analysis (Cox model) were used to assess the prognostic value of the CGH and other data. Fifteen (21.4%) out of 70 patients (six cases were lost to follow-up) developed locoregional (n=3) or distant metastases (n=12). The following criteria were prognostic for (any) recurrence (in decreasing significance): 3q gain, simultaneous gain at 1q and 8q, MAI < versus > or =10, MNA < versus > or =63 microm. Loss of 1p occurred significantly more often in the large group of ductal breast carcinomas with a MAI > or =10 (n=38) than in cancers with a MAI<10. Moreover, 8/15 (53%) patients with recurrences had a gain at 3q, as opposed to three (5.5%) of the 55 recurrence-free patients. This association was even stronger in ductal carcinomas (hazard ratio=10.9, p<0.0001). Cox regression revealed that the 3q gain was the strongest prognostic factor; other features did not have additional prognostic value. In conclusion, loss of 1p is associated with a high MAI. A gain of 3q is a stronger predictor of recurrence than grade, MAI, and other features in invasive breast cancers.

Gene expression meta-analysis identifies chromosomal regions and candidate genes involved in breast cancer metastasis

“…At 1q an early LOH study found association to 1q21 [14] and CGH has been used to demonstrate prognostic disadvantage of simultaneously gain of 1q and 8q [15]. Our analysis point at the distal end of the chromosome 1q arm and refines the region to 1q41-42.…”

8p deletion is strongly linked to poor prognosis in breast cancer

“…The ability to detect a clinical utility of 8p deletion measurement in small cohorts is obviously caused by the high rate of positive cases (almost 50%) and a particularly strong prognostic impact of this feature. It is noteworthy, however, that several other small cohorts failed to find associations with tumor phenotype 14,16,[34][35][36]59 or patient death. [34][35][36] Limitations of our study include that retrospectively collected data are used for estimating the prognostic value of 8p deletion.…”

“…Our findings are also in the range of studies using alternative methods for deletion analysis. These studies reported 8p loss in 19-60% of breast cancers using loss of heterozygosity (LOH) analysis, 15,16,26,27,32 18-42% 42 of cancers analyzed by conventional comparative genomic hybridization (CGH), 11,25,29,31,34,38,43 and 32-71% of cancers examined by array-based CGH. 12,44 It is noteworthy, that all methods analyzing extracted DNA from disintegrated tissues are influenced by ploidy changes and contamination with normal cells, which inevitably impacts the assay sensitivity and varies markedly between individual tumors.…”

“…[17][18][19][20][21][22][23][24] Some breast cancer studies found associations between 8p deletions and advanced tumor stage, [25][26][27] highgrade, 28 metastatic growth, 25,27,29 familial breast cancer risk, 30 and poor prognosis, 25,27,29,31 but these associations could not be confirmed by others. 14,[32][33][34][35][36][37][38][39] To better understand the clinical relevance of 8p deletions in breast cancer, including association to tumor grade, pathological tumor stage, patient survival, hormone receptor status, and amplifications of HER2, MYC and CCND1, we analyzed more than 2,100 breast cancers with clinical follow-up data. FISH was applied for 8p deletion analysis because it is the only method enabling for direct counting of gene copy numbers in histological sections.…”

Molecular profiling of invasive breast cancer by multiplex ligation-dependent probe amplification-based copy number analysis of tumor suppressor and oncogenes

“…19 Therapeutic or prognostic significance of other frequently amplified genes such as cyclin D1 (CCND1) 20 or frequent loss of genes such as E-cadherin (CDH1) is less clear, and comparative genomic hybridization (CGH) studies have pointed to many more genes and chromosomal loci with potentially important copy number changes. [21][22][23] Nevertheless, no single gene copy number seems to completely explain prognosis or response to therapy of individual breast cancer patients. A simultaneous analysis of copy number changes of a variety of genes involved in prognosis and therapy response may thus be very useful for molecular profiling of individual breast cancer patients.…”