Cell Line Derived Multi-Gene Predictor of Pathologic Response to Neoadjuvant Chemotherapy in Breast Cancer: A Validation Study on US Oncology 02-103 Clinical Trial

Abstract

BackgroundThe purpose of this study is to assess the predictive accuracy of a multi-gene predictor of response to docetaxel, 5-fluorouracil, epirubicin and cyclophosphamide combination chemotherapy on gene expression data from patients who received these drugs as neoadjuvant treatment.MethodsTumor samples were obtained from patients with stage II-III breast cancer before starting neoadjuvant chemotherapy with four cycles of 5-fluorouracil/epirubicin/cyclophosphamide (FEC) followed by four cycles of docetaxel/capecitabine (TX) on US Oncology clinical trial 02-103. Most patients with HER-2-positive cancer also received trastuzumab (H). The chemotherapy predictor (TFEC-MGP) was developed from publicly available gene expression data of 42 breast cancer cell-lines with corresponding in vitro chemotherapy sensitivity results for the four chemotherapy drugs. No predictor was developed for treatment with trastuzumab. The predictive performance of TFEC-MGP in distinguishing cases with pathologic complete response from those with residual disease was evaluated for the FEC/TX and FEC/TX plus H group separately. The area under the receiver-operating characteristic curve (AU-ROC) was used as the metric of predictive performance. Genomic predictions were performed blinded to clinical outcome.ResultsThe AU-ROC was 0.70 (95% CI: 0.57-0.82) for the FEC/TX group (n=66) and 0.43 (95% CI: 0.20-0.66) for the FEC/TX plus H group (n=25). Among the patients treated with FEC/TX, the AU-ROC was 0.69 (95% CI: 0.52-0.86) for estrogen receptor (ER)-negative (n=28) and it was 0.59 (95% CI: 0.36-0.82) for ER-positive cancers (n=37). ER status was not reported for one patient.ConclusionsOur results indicate that the cell line derived 291-probeset genomic predictor of response to FEC/TX combination chemotherapy shows good performance in a blinded validation study, particularly in ER-negative patients.

Human B-cell cancer cell lines as a preclinical model for studies of drug effect in diffuse large B-cell lymphoma and multiple myeloma

“…Combining these datasets has led to the hypothesis that a human cancer cell line's grade of sensitivity to a given drug may be correlated to its profile of expression of a set of target genes. Some data support this concept [16][17][18], but it is not yet implemented into patient care owing to a range of controversies, mostly related to the NCI-60 tissue type, the drug screening end points, and the development of reproducible bioinformatic and statistical methods [19][20][21][22][23]. The application of NCI-60 data to hematopoietic tumors has further been questioned because the experiments included only six hematologic cell lines, with only two derived from MMand DLBCL-like patients [24].…”

“…This model has been fundamental for improving our understanding of cancer biology, for the Cancer Genome Project, and in drug design and development [6,8,14,17]. As reviewed in Table 1, it is important to characterize each HBCCL by its origin and properties.…”

The impact of Oncotype DX® recurrence score of paraffin-embedded core biopsy tissues in predicting response to neoadjuvant chemotherapy in women with breast cancer

“…The 21-gene assay calculated by Genomic Health for each of the 60 evaluable specimens, demonstrated a low (<18) in 27 (45%), intermediate (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) in 10 (17%) and high ( 31) Recurrence Score in 23 (38%) specimens (Table 2).…”

“…Interestingly, lower values of HER2 by RT-PCR were also associated with increased reduction in tumor size (p = 0.007). (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) 54.4 ± 32 6/10 = 60% High risk ( 31) 45.6 ± 37 11/23 = 48% * p = 0.21 and * * p = 0.43 for comparison among 3 RS groups. Due to a lack of association between both the continuous or categorical Recurrence Score and response, no attempt was made to identify an optimal score threshold for predicting response.…”

“…Literature on the topic varies according to the assay used. While some support the use of assays in this capacity [2,7,8,14,16,22,24], others question their validity in predicting response to NCT [20]. Few studies concentrate only on ER+ patients and the ability to predict NCT response in this subset [7,14].…”