The impact of expression profiling on prognostic and predictive testing in breast cancer

Abstract

Expression profiling has been extensively applied to the study of breast cancer and undoubtedly is changing the way breast cancer is perceived. Over the past few years, several groups have described prognostic “signatures” (gene lists) that are purported to be more accurate prognostic factors than well established clinical and pathological features. In addition, cDNA and oligonucleotide microarrays have also been used to devise predictive “signatures” in the setting of neoadjuvant chemotherapy setting. However, it seems that the enthusiasm with this new technology has led most of us to turn a blind eye to some serious methodological problems which are evident in landmark papers on breast cancer expression profiling. These issues include small and biased cohorts of patients, inappropriate statistical analysis and lack of thorough validation of the technology. In this review, we critically revisit the most relevant cDNA microarray studies on breast cancer prognosis and prediction published to date. Although the results are promising, further optimisation and standardisation of the technique and properly designed clinical trials are required before microarrays can reliably be used as tools for clinical decision making.

Microarray-based comparative genomic hybridisation of breast cancer patients receiving neoadjuvant chemotherapy

“…Gene 'signatures' or predictors have been devised for several chemotherapy regimens, including paclitaxel followed by fluorouracil, AC, AC/doxorubicindocetaxel and taxane only chemotherapy (Chang et al, 2003(Chang et al, , 2005bAyers et al, 2004;Hannemann et al, 2005;Cleator et al, 2006). Although these results are promising, the exceedingly small sample size and limitations with the current technology and analysis methods have so far precluded definitive conclusions (Brenton et al, 2005;Reis-Filho et al, 2006b).…”

“…In the last 20 years, a multitude of prognostic and predictive markers have been tested, however only oestrogen receptor, progesterone receptor and HER2 are currently used to tailor the therapy of breast cancer patients (Goldhirsch et al, 2005). The use of expression arrays to derive molecular profiles that are predictive of clinical outcome has received great attention in the last 5 years (van't Veer et al, 2005;Reis-Filho et al, 2006b), especially in the neoadjuvant setting (Davidson and Morrow, 2005). Predictive signatures for different neoadjuvant chemotherapy regimens have been reported by some investigators but with less success by others (Chang et al, 2003;Ayers et al, 2004;Cleator and Ashworth, 2004;Chang et al, 2005a;Hannemann et al, 2005;Iwao-Koizumi et al, 2005;Modlich et al, 2005;Rouzier et al, 2005;Dressman et al, 2006;Reis-Filho et al, 2006b).…”

“…The use of expression arrays to derive molecular profiles that are predictive of clinical outcome has received great attention in the last 5 years (van't Veer et al, 2005;Reis-Filho et al, 2006b), especially in the neoadjuvant setting (Davidson and Morrow, 2005). Predictive signatures for different neoadjuvant chemotherapy regimens have been reported by some investigators but with less success by others (Chang et al, 2003;Ayers et al, 2004;Cleator and Ashworth, 2004;Chang et al, 2005a;Hannemann et al, 2005;Iwao-Koizumi et al, 2005;Modlich et al, 2005;Rouzier et al, 2005;Dressman et al, 2006;Reis-Filho et al, 2006b). Although some of these results are promising, issues related to the instability of mRNA, experimental design and data analysis have led many to call into question the validity of current approaches (Ransohoff, 2004;Brenton et al, 2005;Ioannidis, 2005;Reis-Filho et al, 2006b).…”

Quantitative immunohistochemical expression of c Kit in breast carcinomas is predictive of patients' outcome

“…In the latter group of patients lacking specific targets for hormone and trastuzumab therapy, there is a need to identify new targets for tailored treatments. Genome microarray analysis (Perou et al, 2000;Sorlie et al, 2003) and expression profiling (Reis-Filho et al, 2006) have recently been used to characterise five groups of breast cancers that can also be identified by immunohistochemical screening. In particular, for the triple-negative (ER-PgR-HERnegative) tumours, this deeper molecular insight into tumour characterisation should allow new targets for tailored therapies to be identified.…”

The determination of changes in the expression of genes for selected specific transcriptional factors in in vitro ductal breast cancer cells under the influence of paclitaxel

“…Identification of molecular alterations in the DNA copy number and expression profiles are useful to identify new chromosomal regions involved. The same applies to genes relative to the advancement of neoplastic processes as therapeutic targets [48,49]. As it could be seen from this study and studies conducted by other researchers, the association between the genes are very complex, which is why getting to know how this machinery functions is one of the greatest challenges for biologists and medical scientists.…”