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TLE3 is not a predictive biomarker for taxane sensitivity in the NCIC CTG MA.21 clinical trial

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ABSTRACT

Background:: TLE3, a nuclear transcriptional repressor downstream of WNT signalling pathways, has been hypothesised as predictive of benefit from adjuvant taxane.

Methods:: MA.21 tissue microarrays were constructed from 1097 out of 2104 (52%) patients. TLE3 staining by immunohistochemistry used validated methodology. Continuous TLE3+ (percentage of cells staining positive) was assessed with both visual and automated scoring. The primary objective was to test the predictive effect of TLE3 on relapse-free survival using the MA.21 EC/T and CEF arms and the previously defined cut-point of 30% of cells staining positive in ⩾1 core/tumour.

Results:: MA.21 patients had 83.2% TLE3 positive (TLE3+) tumours by visual score and 80.6% TLE3+ by automated image analysis while the previously observed rate of TLE3+ cases was 58.6%. TLE3 expression was significantly associated with ER expression (91.2% of ER-positive tumours were TLE3+ P<0.0001). At median 8-year follow-up, there was no evidence of a predictive effect of TLE3 expression with respect to taxane benefit using the established 30% or exploratory quartile cut-points.

Conclusions:: Proportionately more MA.21 patient tumours than expected were TLE3+. The pre-specified TLE3+ cut-point of 30% was not predictive of taxane benefit. TLE3 expression does not represent a viable biomarker for taxane benefit in breast cancer.

No MeSH data available.


Image analysis of TLE3 staining and outcome by treatment arm. (A) Recurrence-free survival by Image analysis of TLE3: Status stratified by allocation to EC/T or CEF: TLE− CEF=patients with <30% TLE3 tumour-positive cells allocated to CEF arm. TLE3+ CEF=patients with ⩾30% TLE3 tumour-positive cells allocated to CEF arm. TLE− EC/T=patients with <30% TLE3 tumour-positive cells allocated to EC/T arm. TLE3+ EC/T=patients with ⩾30% TLE3 tumour-positive cells allocated to EC/T arm. (B) Recurrence-free survival for TLE3-positive cases by image analysis of TLE3: Status stratified by allocation to EC/T or CEF: CEF=patients allocated to CEF arm. EC/T=patients allocated to EC/T arm. (C) Recurrence-free survival for TLE3 negative cases by image analysis TLE3: Status stratified by allocation to EC/T or CEF: CEF=patients allocated to CEF arm. EC/T=patients allocated to EC/T arm.
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fig2: Image analysis of TLE3 staining and outcome by treatment arm. (A) Recurrence-free survival by Image analysis of TLE3: Status stratified by allocation to EC/T or CEF: TLE− CEF=patients with <30% TLE3 tumour-positive cells allocated to CEF arm. TLE3+ CEF=patients with ⩾30% TLE3 tumour-positive cells allocated to CEF arm. TLE− EC/T=patients with <30% TLE3 tumour-positive cells allocated to EC/T arm. TLE3+ EC/T=patients with ⩾30% TLE3 tumour-positive cells allocated to EC/T arm. (B) Recurrence-free survival for TLE3-positive cases by image analysis of TLE3: Status stratified by allocation to EC/T or CEF: CEF=patients allocated to CEF arm. EC/T=patients allocated to EC/T arm. (C) Recurrence-free survival for TLE3 negative cases by image analysis TLE3: Status stratified by allocation to EC/T or CEF: CEF=patients allocated to CEF arm. EC/T=patients allocated to EC/T arm.

Mentions: Similar results were obtained with automated image analysis. There were no significant differences in RFS based on TLE3 status and allocation to EC/T or CEF (Figure 2A; P=0.18). For TLE3+ tumours (Figure 2B), the HR for patients allocated EC/T compared with those allocated CEF was 0.84 (95% CI 0.56 to 1.26; P=0.40); however, that for TLE3− tumours was 0.50 (95% CI 0.22 to 1.16; P=0.10, Figure 2C). Quartile cut-points again indicated no significant univariate effect of treatment allocation for TLE3+ patients on RFS (Supplementary Figure 4A, with first quartile cut-point, P=0.56; Supplementary Figure 4B, with median cut-point, P=0.83).


TLE3 is not a predictive biomarker for taxane sensitivity in the NCIC CTG MA.21 clinical trial
Image analysis of TLE3 staining and outcome by treatment arm. (A) Recurrence-free survival by Image analysis of TLE3: Status stratified by allocation to EC/T or CEF: TLE− CEF=patients with <30% TLE3 tumour-positive cells allocated to CEF arm. TLE3+ CEF=patients with ⩾30% TLE3 tumour-positive cells allocated to CEF arm. TLE− EC/T=patients with <30% TLE3 tumour-positive cells allocated to EC/T arm. TLE3+ EC/T=patients with ⩾30% TLE3 tumour-positive cells allocated to EC/T arm. (B) Recurrence-free survival for TLE3-positive cases by image analysis of TLE3: Status stratified by allocation to EC/T or CEF: CEF=patients allocated to CEF arm. EC/T=patients allocated to EC/T arm. (C) Recurrence-free survival for TLE3 negative cases by image analysis TLE3: Status stratified by allocation to EC/T or CEF: CEF=patients allocated to CEF arm. EC/T=patients allocated to EC/T arm.
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fig2: Image analysis of TLE3 staining and outcome by treatment arm. (A) Recurrence-free survival by Image analysis of TLE3: Status stratified by allocation to EC/T or CEF: TLE− CEF=patients with <30% TLE3 tumour-positive cells allocated to CEF arm. TLE3+ CEF=patients with ⩾30% TLE3 tumour-positive cells allocated to CEF arm. TLE− EC/T=patients with <30% TLE3 tumour-positive cells allocated to EC/T arm. TLE3+ EC/T=patients with ⩾30% TLE3 tumour-positive cells allocated to EC/T arm. (B) Recurrence-free survival for TLE3-positive cases by image analysis of TLE3: Status stratified by allocation to EC/T or CEF: CEF=patients allocated to CEF arm. EC/T=patients allocated to EC/T arm. (C) Recurrence-free survival for TLE3 negative cases by image analysis TLE3: Status stratified by allocation to EC/T or CEF: CEF=patients allocated to CEF arm. EC/T=patients allocated to EC/T arm.
Mentions: Similar results were obtained with automated image analysis. There were no significant differences in RFS based on TLE3 status and allocation to EC/T or CEF (Figure 2A; P=0.18). For TLE3+ tumours (Figure 2B), the HR for patients allocated EC/T compared with those allocated CEF was 0.84 (95% CI 0.56 to 1.26; P=0.40); however, that for TLE3− tumours was 0.50 (95% CI 0.22 to 1.16; P=0.10, Figure 2C). Quartile cut-points again indicated no significant univariate effect of treatment allocation for TLE3+ patients on RFS (Supplementary Figure 4A, with first quartile cut-point, P=0.56; Supplementary Figure 4B, with median cut-point, P=0.83).

View Article: PubMed Central - PubMed

ABSTRACT

Background:: TLE3, a nuclear transcriptional repressor downstream of WNT signalling pathways, has been hypothesised as predictive of benefit from adjuvant taxane.

Methods:: MA.21 tissue microarrays were constructed from 1097 out of 2104 (52%) patients. TLE3 staining by immunohistochemistry used validated methodology. Continuous TLE3+ (percentage of cells staining positive) was assessed with both visual and automated scoring. The primary objective was to test the predictive effect of TLE3 on relapse-free survival using the MA.21 EC/T and CEF arms and the previously defined cut-point of 30% of cells staining positive in &#10878;1 core/tumour.

Results:: MA.21 patients had 83.2% TLE3 positive (TLE3+) tumours by visual score and 80.6% TLE3+ by automated image analysis while the previously observed rate of TLE3+ cases was 58.6%. TLE3 expression was significantly associated with ER expression (91.2% of ER-positive tumours were TLE3+ P&lt;0.0001). At median 8-year follow-up, there was no evidence of a predictive effect of TLE3 expression with respect to taxane benefit using the established 30% or exploratory quartile cut-points.

Conclusions:: Proportionately more MA.21 patient tumours than expected were TLE3+. The pre-specified TLE3+ cut-point of 30% was not predictive of taxane benefit. TLE3 expression does not represent a viable biomarker for taxane benefit in breast cancer.

No MeSH data available.