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A generic cycling hypoxia-derived prognostic gene signature: application to breast cancer profiling.

Boidot R, Branders S, Helleputte T, Rubio LI, Dupont P, Feron O - Oncotarget (2014)

Bottom Line: The transcriptome associated with cycling hypoxia (CycHyp) could thus represent a prognostic biomarker of cancer progression.The CycHyp signature could also identify ER+HER2 node-negative breast cancer patients at high risk based on clinicopathologic criteria but who could have been spared from chemotherapy and inversely those patients classified at low risk based but who presented a negative outcome.The CycHyp signature is prognostic of breast cancer and offers a unique decision making tool to complement anatomopathologic evaluation.

View Article: PubMed Central - PubMed

Affiliation: Institut de Recherche Expérimentale et Clinique (IREC), Pole of Pharmacology and Therapeutics (FATH), Université catholique de Louvain, Brussels, Belgium. These authors contribued equally to this work.

ABSTRACT

Background: Temporal and local fluctuations in O2 in tumors require adaptive mechanisms to support cancer cell survival and proliferation. The transcriptome associated with cycling hypoxia (CycHyp) could thus represent a prognostic biomarker of cancer progression.

Method: We exposed 20 tumor cell lines to repeated periods of hypoxia/reoxygenation to determine a transcriptomic CycHyp signature and used clinical data sets from 2,150 breast cancer patients to estimate a prognostic Cox proportional hazard model to assess its prognostic performance.

Results: The CycHyp prognostic potential was validated in patients independently of the receptor status of the tumors. The discriminating capacity of the CycHyp signature was further increased in the ER+ HER2- patient populations including those with a node negative status under treatment (HR=3.16) or not (HR=5.54). The CycHyp prognostic signature outperformed a signature derived from continuous hypoxia and major prognostic metagenes (P<0.001). The CycHyp signature could also identify ER+HER2 node-negative breast cancer patients at high risk based on clinicopathologic criteria but who could have been spared from chemotherapy and inversely those patients classified at low risk based but who presented a negative outcome.

Conclusions: The CycHyp signature is prognostic of breast cancer and offers a unique decision making tool to complement anatomopathologic evaluation.

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Related in: MedlinePlus

Comparison of the prognostic potential of the CycHyp signature vs. Gene 70 (Mammaprint), Gene 76 and Oncotype Dx signatures(A) Kaplan-Meier survival curves of node-negative, untreated ER+/HER2- patients, as determined by using the indicated signature (DFS Mantel-Cox comparison); hazard ratio (HR), balanced classification rate (BCR) and C-index for the prediction in high risk vs. low risk groups are reported; HR are presented with their associated p-values. (B.) Forest plots of the hazard ratio (HR), Concordance index (CI), balance classification rate (BCR), sensitivity and specificity for the prediction in high risk vs. low risk groups; p-values refer to the comparisons of CycHyp vs. Gene 70 (Mammaprint), Gene 76 and Oncotype Dx. (C.) Graph represents the power of discrimination in high vs. low risk groups (expressed as the logarithm of the p-values of the logrank) of the ContHyp and CycHyp signatures (see red dots) versus 1,000 randomly generated signatures (yellow shapes depicting their distribution).
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Figure 3: Comparison of the prognostic potential of the CycHyp signature vs. Gene 70 (Mammaprint), Gene 76 and Oncotype Dx signatures(A) Kaplan-Meier survival curves of node-negative, untreated ER+/HER2- patients, as determined by using the indicated signature (DFS Mantel-Cox comparison); hazard ratio (HR), balanced classification rate (BCR) and C-index for the prediction in high risk vs. low risk groups are reported; HR are presented with their associated p-values. (B.) Forest plots of the hazard ratio (HR), Concordance index (CI), balance classification rate (BCR), sensitivity and specificity for the prediction in high risk vs. low risk groups; p-values refer to the comparisons of CycHyp vs. Gene 70 (Mammaprint), Gene 76 and Oncotype Dx. (C.) Graph represents the power of discrimination in high vs. low risk groups (expressed as the logarithm of the p-values of the logrank) of the ContHyp and CycHyp signatures (see red dots) versus 1,000 randomly generated signatures (yellow shapes depicting their distribution).

Mentions: To evaluate the performance of the CycHyp signature, we compared it with other well-established prognostic multigene assays for breast cancer, namely Gene70 or Mammaprint [14], Gene76 [17] and Oncotype Dx [15]. Using the same set of ER+ HER2- node negative patients as used in Figure 2D, we could determine the low vs. high risk patient stratification according to these signatures. The superior prognostic potential of the CycHyp signature could be captured from the Kaplan Meier curves obtained with the Gene 70, Gene76 and Oncotype DX signatures (compare Figure 3A with Figure 2D). Hazard ratios confirmed the net advantage of the CycHyp signature with a significantly higher value than the three other metagenes (Figure 3B). The concordance index, which is the probability of a high risk patient to relapse before a low risk patient, was also higher with the CycHyp signature (Figure 3B). Finally, the Balanced Classification Rate (BCR), which represents the average between sensitivity and specificity to discriminate between patients with progressing disease vs. disease-free at 5 years, was significantly higher for the CycHyp signature than the three other multigene assays (Figure 3B). The sensitivity of the CycHyp was above 80% and the specificity of the CycHyp signature was well above the level of the others (Figure 3B). Of note, the metrics corresponding to each data set taken separately is depicted in Suppl. Figure 2.


A generic cycling hypoxia-derived prognostic gene signature: application to breast cancer profiling.

Boidot R, Branders S, Helleputte T, Rubio LI, Dupont P, Feron O - Oncotarget (2014)

Comparison of the prognostic potential of the CycHyp signature vs. Gene 70 (Mammaprint), Gene 76 and Oncotype Dx signatures(A) Kaplan-Meier survival curves of node-negative, untreated ER+/HER2- patients, as determined by using the indicated signature (DFS Mantel-Cox comparison); hazard ratio (HR), balanced classification rate (BCR) and C-index for the prediction in high risk vs. low risk groups are reported; HR are presented with their associated p-values. (B.) Forest plots of the hazard ratio (HR), Concordance index (CI), balance classification rate (BCR), sensitivity and specificity for the prediction in high risk vs. low risk groups; p-values refer to the comparisons of CycHyp vs. Gene 70 (Mammaprint), Gene 76 and Oncotype Dx. (C.) Graph represents the power of discrimination in high vs. low risk groups (expressed as the logarithm of the p-values of the logrank) of the ContHyp and CycHyp signatures (see red dots) versus 1,000 randomly generated signatures (yellow shapes depicting their distribution).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4196175&req=5

Figure 3: Comparison of the prognostic potential of the CycHyp signature vs. Gene 70 (Mammaprint), Gene 76 and Oncotype Dx signatures(A) Kaplan-Meier survival curves of node-negative, untreated ER+/HER2- patients, as determined by using the indicated signature (DFS Mantel-Cox comparison); hazard ratio (HR), balanced classification rate (BCR) and C-index for the prediction in high risk vs. low risk groups are reported; HR are presented with their associated p-values. (B.) Forest plots of the hazard ratio (HR), Concordance index (CI), balance classification rate (BCR), sensitivity and specificity for the prediction in high risk vs. low risk groups; p-values refer to the comparisons of CycHyp vs. Gene 70 (Mammaprint), Gene 76 and Oncotype Dx. (C.) Graph represents the power of discrimination in high vs. low risk groups (expressed as the logarithm of the p-values of the logrank) of the ContHyp and CycHyp signatures (see red dots) versus 1,000 randomly generated signatures (yellow shapes depicting their distribution).
Mentions: To evaluate the performance of the CycHyp signature, we compared it with other well-established prognostic multigene assays for breast cancer, namely Gene70 or Mammaprint [14], Gene76 [17] and Oncotype Dx [15]. Using the same set of ER+ HER2- node negative patients as used in Figure 2D, we could determine the low vs. high risk patient stratification according to these signatures. The superior prognostic potential of the CycHyp signature could be captured from the Kaplan Meier curves obtained with the Gene 70, Gene76 and Oncotype DX signatures (compare Figure 3A with Figure 2D). Hazard ratios confirmed the net advantage of the CycHyp signature with a significantly higher value than the three other metagenes (Figure 3B). The concordance index, which is the probability of a high risk patient to relapse before a low risk patient, was also higher with the CycHyp signature (Figure 3B). Finally, the Balanced Classification Rate (BCR), which represents the average between sensitivity and specificity to discriminate between patients with progressing disease vs. disease-free at 5 years, was significantly higher for the CycHyp signature than the three other multigene assays (Figure 3B). The sensitivity of the CycHyp was above 80% and the specificity of the CycHyp signature was well above the level of the others (Figure 3B). Of note, the metrics corresponding to each data set taken separately is depicted in Suppl. Figure 2.

Bottom Line: The transcriptome associated with cycling hypoxia (CycHyp) could thus represent a prognostic biomarker of cancer progression.The CycHyp signature could also identify ER+HER2 node-negative breast cancer patients at high risk based on clinicopathologic criteria but who could have been spared from chemotherapy and inversely those patients classified at low risk based but who presented a negative outcome.The CycHyp signature is prognostic of breast cancer and offers a unique decision making tool to complement anatomopathologic evaluation.

View Article: PubMed Central - PubMed

Affiliation: Institut de Recherche Expérimentale et Clinique (IREC), Pole of Pharmacology and Therapeutics (FATH), Université catholique de Louvain, Brussels, Belgium. These authors contribued equally to this work.

ABSTRACT

Background: Temporal and local fluctuations in O2 in tumors require adaptive mechanisms to support cancer cell survival and proliferation. The transcriptome associated with cycling hypoxia (CycHyp) could thus represent a prognostic biomarker of cancer progression.

Method: We exposed 20 tumor cell lines to repeated periods of hypoxia/reoxygenation to determine a transcriptomic CycHyp signature and used clinical data sets from 2,150 breast cancer patients to estimate a prognostic Cox proportional hazard model to assess its prognostic performance.

Results: The CycHyp prognostic potential was validated in patients independently of the receptor status of the tumors. The discriminating capacity of the CycHyp signature was further increased in the ER+ HER2- patient populations including those with a node negative status under treatment (HR=3.16) or not (HR=5.54). The CycHyp prognostic signature outperformed a signature derived from continuous hypoxia and major prognostic metagenes (P<0.001). The CycHyp signature could also identify ER+HER2 node-negative breast cancer patients at high risk based on clinicopathologic criteria but who could have been spared from chemotherapy and inversely those patients classified at low risk based but who presented a negative outcome.

Conclusions: The CycHyp signature is prognostic of breast cancer and offers a unique decision making tool to complement anatomopathologic evaluation.

Show MeSH
Related in: MedlinePlus