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An Integrated Approach to the Prediction of Chemotherapeutic Response in Patients with Breast Cancer

Publication ,  Journal Article
Salter, KH; Acharya, CR; Walters, KS; Redman, R; Anguiano, A; Garman, KS; Anders, CK; Mukherjee, S; Dressman, HK; Barry, WT; Marcom, KP ...
Published in: PLoS ONE
December 1, 2011

Background: A major challenge in oncology is the selection of the most effective chemotherapeutic agents for individual patients, while the administration of ineffective chemotherapy increases mortality and decreases quality of life in cancer patients. This emphasizes the need to evaluate every patient's probability of responding to each chemotherapeutic agent and limiting the agents used to those most likely to be effective. Methods and Results: Using gene expression data on the NCI-60 and corresponding drug sensitivity, mRNA and microRNA profiles were developed representing sensitivity to individual chemotherapeutic agents. The mRNA signatures were tested in an independent cohort of 133 breast cancer patients treated with the TFAC (paclitaxel, 5-fluorouracil, adriamycin, and cyclophosphamide) chemotherapy regimen. To further dissect the biology of resistance, we applied signatures of oncogenic pathway activation and performed hierarchical clustering. We then used mRNA signatures of chemotherapy sensitivity to identify alternative therapeutics for patients resistant to TFAC. Profiles from mRNA and microRNA expression data represent distinct biologic mechanisms of resistance to common cytotoxic agents. The individual mRNA signatures were validated in an independent dataset of breast tumors (P = 0.002, NPV = 82%). When the accuracy of the signatures was analyzed based on molecular variables, the predictive ability was found to be greater in basal-like than non basal-like patients (P = 0.03 and P = 0.06). Samples from patients with co-activated Myc and E2F represented the cohort with the lowest percentage (8%) of responders. Using mRNA signatures of sensitivity to other cytotoxic agents, we predict that TFAC non-responders are more likely to be sensitive to docetaxel (P = 0.04), representing a viable alternative therapy. Conclusions: Our results suggest that the optimal strategy for chemotherapy sensitivity prediction integrates molecular variables such as ER and HER2 status with corresponding microRNA and mRNA expression profiles. Importantly, we also present evidence to support the concept that analysis of molecular variables can present a rational strategy to identifying alternative therapeutic opportunities. © 2008 Salter et al.

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Published In

PLoS ONE

DOI

EISSN

1932-6203

Publication Date

December 1, 2011

Volume

6

Issue

9

Related Subject Headings

  • General Science & Technology
 

Citation

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Salter, K. H., Acharya, C. R., Walters, K. S., Redman, R., Anguiano, A., Garman, K. S., … Potti, A. (2011). An Integrated Approach to the Prediction of Chemotherapeutic Response in Patients with Breast Cancer. PLoS ONE, 6(9). https://doi.org/10.1371/journal.pone.0001908
Salter, K. H., C. R. Acharya, K. S. Walters, R. Redman, A. Anguiano, K. S. Garman, C. K. Anders, et al. “An Integrated Approach to the Prediction of Chemotherapeutic Response in Patients with Breast Cancer.” PLoS ONE 6, no. 9 (December 1, 2011). https://doi.org/10.1371/journal.pone.0001908.
Salter KH, Acharya CR, Walters KS, Redman R, Anguiano A, Garman KS, et al. An Integrated Approach to the Prediction of Chemotherapeutic Response in Patients with Breast Cancer. PLoS ONE. 2011 Dec 1;6(9).
Salter, K. H., et al. “An Integrated Approach to the Prediction of Chemotherapeutic Response in Patients with Breast Cancer.” PLoS ONE, vol. 6, no. 9, Dec. 2011. Scopus, doi:10.1371/journal.pone.0001908.
Salter KH, Acharya CR, Walters KS, Redman R, Anguiano A, Garman KS, Anders CK, Mukherjee S, Dressman HK, Barry WT, Marcom KP, Olson J, Nevins JR, Potti A. An Integrated Approach to the Prediction of Chemotherapeutic Response in Patients with Breast Cancer. PLoS ONE. 2011 Dec 1;6(9).

Published In

PLoS ONE

DOI

EISSN

1932-6203

Publication Date

December 1, 2011

Volume

6

Issue

9

Related Subject Headings

  • General Science & Technology