Gene Expression Profiles Predict Complete Pathologic Response to Neoadjuvant Paclitaxel and Fluorouracil, Doxorubicin, and Cyclophosphamide Chemotherapy in Breast Cancer

Ayers, Mark; Symmans, W. Fraser; Stec, James; Damokosh, Andrew I.; Clark, Edwin; Hess, Kenneth R.; Lecocke, Michael; Métivier, J.-C.; Booser, Daniel J.; Ibrahim, Nuhad K.; Valero, Vicente; Royce, Melanie; Arun, Banu K.; Whitman, Gary J.; Ross, Jeffrey S.; Sneige, Nour; Hortobágyi, Gabriel N.; Pusztai, Lajos

doi:10.1200/jco.2004.05.166

Cited by 490 publications

(285 citation statements)

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“…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).…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

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

et al. 2006

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We analysed the molecular genetic profiles of breast cancer samples before and after neoadjuvant chemotherapy with combination doxorubicin and cyclophosphamide (AC). DNA was obtained from microdissected frozen breast core biopsies from 44 patients before chemotherapy. Additional samples were obtained before the second course of chemotherapy (D21) and after the completion of the treatment (surgical specimens) in 17 and 21 patients, respectively. Microarray-based comparative genome hybridisation was performed using a platform containing B5800 bacterial artificial chromosome clones (genome-wide resolution: 0.9 Mb). Analysis of the 44 pretreatment biopsies revealed that losses of 4p, 4q, 5q, 12q13.11 -12q13.12, 17p11.2 and 17q11.2; and gains of 1p, 2p, 7q, 9p, 11q, 19p and 19q were significantly associated with oestrogen receptor negativity. 16q21 -q22.1 losses were associated with lobular and 8q24 gains with ductal types. Losses of 5q33.3 -q4 and 18p11.31 and gains of 6p25.1 -p25.2 and Xp11.4 were associated with HER2 amplification. No correlations between DNA copy number changes and clinical response to AC were found. Microarray-based comparative genome hybridisation analysis of matched pretreatment and D21 biopsies failed to identify statistically significant differences, whereas a comparison between matched pretreatment and surgical samples revealed a statistically significant acquired copy number gain on 11p15.2 -11p15.5. The modest chemotherapy-driven genomic changes, despite profound loss of cell numbers, suggest that there is little therapeutic selection of resistant non-modal cell lineages.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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“…It is now well documented that NFAT proteins are also present in non-immune cells and regulate a variety of signaling pathways involved in cell growth and development (Baksh et al, 2002;Chuvpilo et al, 2002;Mancini and Toker, 2009;Muller and Rao, 2010). Importantly, members of the NFAT family, in particular NFAT5, have recently been involved in the migratory capacity of breast cancer cells (Jauliac et al, 2002;Ayers et al, 2004;Yoeli-Lerner et al, 2005;Mancini and Toker, 2009;Fougere et al, 2010;Muller and Rao, 2010).…”

Section: Introductionmentioning

confidence: 99%

Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

et al. 2012

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Ddx5 and ddx17 are two highly related RNA helicases involved in both transcription and splicing. These proteins coactivate transcription factors involved in cancer such as the estrogen receptor alpha, p53 and beta-catenin. Ddx5 and ddx17 are part of the splicing machinery and can modulate alternative splicing, the main mechanism increasing the proteome diversity. Alternative splicing also has a role in gene expression level regulation when it is coupled to the nonsensemediated mRNA decay (NMD) pathway. In this work, we report that ddx5 and ddx17 have a dual role in the control of the pro-migratory NFAT5 transcription factor. First, ddx5 and ddx17 act as transcriptional coactivators of NFAT5 and are required for activating NFAT5 target genes involved in tumor cell migration. Second, at the splicing level, ddx5 and ddx17 increase the inclusion of NFAT5 exon 5. As exon 5 contains a pre-mature translation termination codon, its inclusion leads to the regulation of NFAT5 mRNAs by the NMD pathway and to a decrease in NFAT5 protein level. Therefore, we demonstrated for the first time that a transcriptional coregulator can simultaneously regulate the transcriptional activity and alternative splicing of a transcription factor. This dual regulation, where ddx5 and ddx17 enhance the transcriptional activity of NFAT5 although reducing its protein expression level, suggests a critical role for ddx5 and ddx17 in tumor cell migration through the fine regulation of NFAT5 pathway.

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“…10 In addition, sequential taxane and anthracycline-containing regimes are used most commonly in the neoadjuvant setting. Thus, Ayers et al 11 tried to identify a 74-gene signature associated with pCR to sequential paclitaxel plus 5-fluorouracil (5-FU)/doxorubicin/cyclophosphamide (FAC), and Hess et al 12 reported using a 31-gene classifier as a predictor of pCR to the same regimen with similar diagnostic accuracy.…”

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“…In the studies by Ayers et al 11 and Hess et al, 12 tumor samples were obtained with fine-needle aspiration (FNA) before patients received neoadjuvant chemotherapy. Because, currently, patients usually undergo core-needle tumor biopsy (eg, Mammotome; HH Ethicon Endosurgery, Johnson and Johnson Company, Langhorne, Penn) before they receive neoadjuvant chemotherapy, and a sufficient sample volume for the gene expression assay is easily obtainable, we believe that core-needle samples constitute a better source for the assay than FNA samples.…”

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confidence: 99%

Prediction of pathologic complete response to sequential paclitaxel and 5-fluorouracil/epirubicin/cyclophosphamide therapy using a 70-gene classifier for breast cancers

Naoi

Kishi

Tanei

et al. 2011

Cancer

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BACKGROUND. Sequential administration of paclitaxel plus combined fluorouracil, epirubicin, and cyclophosphamide (P-FEC) is 1 of the most common neoadjuvant chemotherapies for patients with primary breast cancer and produces pathologic complete response (pCR) rates of 20% to 30%. However, a predictor of pCR to this chemotherapy has yet to be developed. The authors developed such a predictor by using a proprietary DNA microarray for gene expression analysis of breast tumor tissues. METHODS. Tumor samples were obtained from 84 patients with breast cancer by core-needle biopsy before the patients received P-FEC, and the gene expression profile was analyzed in those samples to construct a classifier for predicting pCR to P-FEC. In addition, the authors analyzed the gene expression profile of tumor tissues that were obtained at surgery from 105 patients with lymph node-negative and estrogen receptor-positive breast cancer who received adjuvant hormone therapy alone to determine the prognostic significance of the classifier. RESULTS. The 70-gene classifier for predicting pCR to P-FEC was constructed by using the training set (n ¼ 50) and subsequently was validated successfully in the validation set (n ¼ 34), revealing high sensitivity (88%; 95% confidence interval [CI], 47%-100%) and high negative predictive value (93%; 95% CI, 68%-100%). Specificity and positive predictive value were 54% (95% CI, 33%-73%) and 37% (95% CI, 16%-62%), respectively. Among the various parameters (estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and Ki-67 status, etc), the 70-gene classifier had the strongest association with pCR (P ¼ .015). In an additional study, genetically assumed complete responders were associated significantly (P ¼ .047) with a poor prognosis. CONCLUSIONS. The 70-gene classifier that was constructed for predicting pCR to P-FEC for breast tumors was successful, with high sensitivity and high negative predictive value. The classifier also appeared to be useful for predicting the prognosis of patients with lymph node-negative and estrogen receptor-positive breast cancer who receive adjuvant hormone therapy alone. Cancer 2011;117:3682-

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Gene Expression Profiles Predict Complete Pathologic Response to Neoadjuvant Paclitaxel and Fluorouracil, Doxorubicin, and Cyclophosphamide Chemotherapy in Breast Cancer

Abstract: Our results suggest that transcriptional profiling has the potential to identify a gene expression pattern in breast cancer that may lead to clinically useful predictors of pCR to T/FAC neoadjuvant therapy.

Cited by 490 publications

References 17 publications

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

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

Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

Prediction of pathologic complete response to sequential paclitaxel and 5-fluorouracil/epirubicin/cyclophosphamide therapy using a 70-gene classifier for breast cancers

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