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. 2014 Oct 14;111(8):1532-41.
doi: 10.1038/bjc.2014.444. Epub 2014 Aug 7.

Predicting response and survival in chemotherapy-treated triple-negative breast cancer

A Prat  1 , A Lluch  2 , J Albanell  3 , W T Barry  4 , C Fan  5 , J I Chacón  6 , J S Parker  7 , L Calvo  8 , A Plazaola  9 , A Arcusa  10 , M A Seguí-Palmer  11 , O Burgues  2 , N Ribelles  12 , A Rodriguez-Lescure  13 , A Guerrero  14 , M Ruiz-Borrego  15 , B Munarriz  16 , J A López  17 , B Adamo  18 , M C U Cheang  5 , Y Li  5 , Z Hu  5 , M L Gulley  5 , M J Vidal  18 , B N Pitcher  19 , M C Liu  20 , M L Citron  21 , M J Ellis  22 , E Mardis  22 , T Vickery  22 , C A Hudis  23 , E P Winer  24 , L A Carey  5 , R Caballero  25 , E Carrasco  25 , M Martín  26 , C M Perou  27 , E Alba  12
Affiliations

Predicting response and survival in chemotherapy-treated triple-negative breast cancer

A Prat et al. Br J Cancer. .

Abstract

Background: In this study, we evaluated the ability of gene expression profiles to predict chemotherapy response and survival in triple-negative breast cancer (TNBC).

Methods: Gene expression and clinical-pathological data were evaluated in five independent cohorts, including three randomised clinical trials for a total of 1055 patients with TNBC, basal-like disease (BLBC) or both. Previously defined intrinsic molecular subtype and a proliferation signature were determined and tested. Each signature was tested using multivariable logistic regression models (for pCR (pathological complete response)) and Cox models (for survival). Within TNBC, interactions between each signature and the basal-like subtype (vs other subtypes) for predicting either pCR or survival were investigated.

Results: Within TNBC, all intrinsic subtypes were identified but BLBC predominated (55-81%). Significant associations between genomic signatures and response and survival after chemotherapy were only identified within BLBC and not within TNBC as a whole. In particular, high expression of a previously identified proliferation signature, or low expression of the luminal A signature, was found independently associated with pCR and improved survival following chemotherapy across different cohorts. Significant interaction tests were only obtained between each signature and the BLBC subtype for prediction of chemotherapy response or survival.

Conclusions: The proliferation signature predicts response and improved survival after chemotherapy, but only within BLBC. This highlights the clinical implications of TNBC heterogeneity, and suggests that future clinical trials focused on this phenotypic subtype should consider stratifying patients as having BLBC or not.

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Figures

Figure 1
Figure 1
Adjusted odds ratios (ORs) for pathologic complete response (pCR) of various clinical–pathological variables and gene signatures (for unit increase) in (A) TNBC patients in GEICAM/2006-03, (B) TNBC and BLBC in GEICAM/2006-03, (C) TNBC patients in MDACC and (D) TNBC and BLBC in MDACC. The PAM50-based signatures represent either a correlation coefficient to a gene expression centroid (for basal like, HER2 enriched, luminal A, luminal B and normal) or a score (for RORS, proliferation score and RORP), and they are evaluated as continuous variables. The claudin-high signature represents an Euclidean distance to the claudin-low centroid, and it is evaluated as a continuous variable. Each signature has been standardised to have a mean of 0 and a s.d. of 1. The size of the square is inversely proportional to the s.e.; horizontal bars represent the 95% CIs of ORs. Statistically significant variables are shown in blue. Each gene signature has been evaluated individually after adjustment for standard clinical–pathological variables. The variables used for adjustment were treatment arm, age at diagnosis, nodal status and tumour size (GEICAM/2006-03); and tumour size, age at diagnosis and histological grade (MDACC).
Figure 2
Figure 2
Adjusted survival HRs of various clinical–pathological variables and gene signatures (for unit increase) in (A) TNBC and (B) TNBC and BLBC treated with adjuvant chemotherapy in GEICAM/9906, (C) BLBC not treated with adjuvant chemotherapy in METABRIC and (D) BLBC treated with adjuvant chemotherapy in METABRIC. The PAM50-based signatures represent either a correlation coefficient to a gene expression centroid (for basal like, HER2 enriched, luminal A, luminal B and normal) or a score (for RORS, proliferation score and RORP), and they are evaluated as continuous variables. The claudin-high signature represents an Euclidean distance to the claudin-low centroid, and it is evaluated as a continuous variable. Each signature has been standardised to have a mean of 0 and a s.d. of 1. The size of the square is inversely proportional to the s.e.; horizontal bars represent the 95% CIs of HRs. Statistically significant variables are shown in blue. Each gene signature has been evaluated individually after adjustment for standard clinical–pathological variables. The variables used for adjustment were treatment arm, age at diagnosis, nodal status and tumour size (GEICAM/9906); and tumour size, age at diagnosis and nodal status (METABRIC).
Figure 3
Figure 3
Kaplan–Meier survival analysis in GEICAM/9906 and METABRIC data sets based on the PAM50 proliferation score. Patients with (A) TNBC and (B) TNBC and BLBC treated with adjuvant chemotherapy in GEICAM/9906, (C) BLBC not treated with adjuvant systemic chemotherapy (no AST) in METABRIC and (D) BLBC treated with adjuvant chemotherapy (CT) in METABRIC.
Figure 4
Figure 4
Associations of clinical–pathological variables and gene signatures with RFS in 314 patients with BLBC of the CALGB/9741 cohort. (A) Adjusted survival HRs of various clinical–pathological variables and gene signatures (for unit increase). The PAM50-based signatures represent either a correlation coefficient to a gene expression centroid (for basal like, HER2 enriched, luminal A, luminal B and normal) or a score (for RORS, proliferation score and RORP), and they are evaluated as continuous variables. The claudin-high signature represents an Euclidean distance to the claudin-low centroid, and it is evaluated as a continuous variable. Each signature has been standardised to have a mean of 0 and a s.d. of 1. The size of the square is inversely proportional to the s.e.; horizontal bars represent the 95% CIs of HRs. Statistically significant variables are shown in blue. The variables used for adjustment were treatment arm, age at diagnosis, nodal status and tumour size. (B) Kaplan–Meier survival analysis in the subset of patients with BLBC in the CALGB/9741 data set based on the PAM50 proliferation score (using tertiles).
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References

    1. Adamo B, Anders C. Stratifying triple-negative breast cancer: which definition(s) to use. Breast Cancer Res. 2011;13:105. - PMC - PubMed
    1. Alba E, Chacon J, Lluch A, Anton A, Estevez L, Cirauqui B, Carrasco E, Calvo L, Segui M, Ribelles N, Alvarez R, Sanchez-Muñoz A, Sanchez R, Garcia-Asenjo J, Rodriguez-Martin C, Escudero M, Albanell J. A randomized phase II trial of platinum salts in basal-like breast cancer patients in the neoadjuvant setting. Results from the GEICAM/2006-03, multicenter study. Breast Cancer Res Treat. 2012;136:487–493. - PubMed
    1. Bastien RR, Rodriguez-Lescure A, Ebbert MT, Prat A, Munarriz B, Rowe L, Miller P, Ruiz-Borrego M, Anderson D, Lyons B, Alvarez I, Dowell T, Wall D, Segui M, Barley L, Boucher K, Alba E, Pappas L, Davis C, Aranda I, Fauron C, Stijleman I, Palacios J, Anton A, Carrasco E, Caballero R, Ellis M, Nielsen T, Perou C, Astill M, Bernard P, Martin M. PAM50 breast cancer subtyping by RT-qPCR and concordance with standard clinical molecular markers. BMC Med Genomics. 2012;5:44. - PMC - PubMed
    1. Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, Ollila DW, Sartor CI, Graham ML, Perou CM. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res. 2007;13:2329–2334. - PubMed
    1. Cheang M, Martin M, Nielsen T, Prat A, Rodriguez-Lescure A, Ruiz A, Chia S, Shepherd L, Voduc D, Bernard P, Ellis M, Perou C, Di Leo A, Carey L.2012Quantitative hormone receptors, triple-negative breast cancer (TNBC), and molecular subtypes: a collaborative effort of the BIG-NCI NABCG Proceedings of the American Society of Clinical Oncology1–5 June 2012; Chicago, IL, USA, a1008.

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