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Evaluation of a chemoresponse assay as a predictive marker in the treatment of recurrent ovarian cancer: further analysis of a prospective study.

Tian C, Sargent DJ, Krivak TC, Powell MA, Gabrin MJ, Brower SL, Coleman RL - Br. J. Cancer (2014)

Bottom Line: Women with persistent or recurrent epithelial ovarian cancer (n=262) were empirically treated with one of 15 therapies, blinded to assay results.On the basis of 3000 simulations, the mean HR for mismatch was 0.81 (95% range=0.66-0.99), with 3.4% of HRs less than 0.67, indicating that HR for match is lower than for mismatch.These analyses provide supportive evidence that this chemoresponse assay is a predictive marker, demonstrating its ability to discern specific therapies that are likely to be more effective among multiple alternatives.

View Article: PubMed Central - PubMed

Affiliation: Precision Therapeutics, Inc., 2516 Jane Street, Pittsburgh, PA 15203, USA.

ABSTRACT

Background: Recently, a prospective study reported improved clinical outcomes for recurrent ovarian cancer patients treated with chemotherapies indicated to be sensitive by a chemoresponse assay, compared with those patients treated with non-sensitive therapies, thereby demonstrating the assay's prognostic properties. Due to cross-drug response over different treatments and possible association of in vitro chemosensitivity of a tumour with its inherent biology, further analysis is required to ascertain whether the assay performs as a predictive marker as well.

Methods: Women with persistent or recurrent epithelial ovarian cancer (n=262) were empirically treated with one of 15 therapies, blinded to assay results. Each patient's tumour was assayed for responsiveness to the 15 therapies. The assay's ability to predict progression-free survival (PFS) was assessed by comparing the association when the assayed therapy matches the administered therapy (match) with the association when the assayed therapy is randomly selected, not necessarily matching the administered therapy (mismatch).

Results: Patients treated with assay-sensitive therapies had improved PFS vs patients treated with non-sensitive therapies, with the assay result for match significantly associated with PFS (hazard ratio (HR)=0.67, 95% confidence interval (CI)=0.50-0.91, P=0.009). On the basis of 3000 simulations, the mean HR for mismatch was 0.81 (95% range=0.66-0.99), with 3.4% of HRs less than 0.67, indicating that HR for match is lower than for mismatch. While 47% of tumours were non-sensitive to all assayed therapies and 9% were sensitive to all, 44% displayed heterogeneity in assay results. Improved outcome was associated with the administration of an assay-sensitive therapy, regardless of homogeneous or heterogeneous assay responses across all of the assayed therapies.

Conclusions: These analyses provide supportive evidence that this chemoresponse assay is a predictive marker, demonstrating its ability to discern specific therapies that are likely to be more effective among multiple alternatives.

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Related in: MedlinePlus

Association of clinical treatment assay result (match) with PFS. Patients treated with assay-sensitive treatments experienced a median PFS of 8.8 months, whereas those treated with assay-non-sensitive treatments experienced a median PFS of 5.9 months. Reproduced by kind permission of Elsevier from Rutherford et al (2013).
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fig1: Association of clinical treatment assay result (match) with PFS. Patients treated with assay-sensitive treatments experienced a median PFS of 8.8 months, whereas those treated with assay-non-sensitive treatments experienced a median PFS of 5.9 months. Reproduced by kind permission of Elsevier from Rutherford et al (2013).

Mentions: As previously reported, the assay result for match was significantly associated with PFS (HR=0.67, 95% CI=0.50–0.91, P=0.009), with patients treated with an assay-sensitive therapy showing an improvement in PFS as compared with assay-non-sensitive (I+R) patients (Figure 1). This association was consistent after controlling for clinical covariates (HR=0.66, 95% CI=0.47–0.94, P=0.020; Rutherford et al, 2013). The average prognostic value of assay results for multiple different therapies was examined using the assay results for mismatch, in which the assay result for one treatment was randomly selected from the (up to) 15 designated therapies with equal probability for each patient, and the association with PFS was estimated. Based on 3000 repeated re-samplings, the mean HR for mismatch was 0.81 (95% range=0.66–0.99) (Figure 2A). Based on the distribution of HRs for mismatch, only 3.4% of HRs were <0.67 (Figure 2A). When multivariate analysis was performed, the HRs were 0.66 and 0.88, based on match and mismatch, respectively, with only 0.7% of HRs from mismatch <0.66 (Figure 2B). The results for OS were similar. In univariate analysis, the HRs for death were 0.61 and 0.76, based on match and mismatch, respectively, with 5.3% of HRs from mismatch <0.61; in multivariate analysis, the HRs were 0.59 and 0.79, based on match and mismatch, respectively, with 3.6% of HRs from mismatch <0.59. The HRs obtained from both match and mismatch analyses demonstrate the prognostic value of the assay (i.e., HR for both match and mismatch are significantly less than 1.0). More importantly, these results also indicate that the HR for match is materially lower than that for mismatch which supports the predictive nature of the assay.


Evaluation of a chemoresponse assay as a predictive marker in the treatment of recurrent ovarian cancer: further analysis of a prospective study.

Tian C, Sargent DJ, Krivak TC, Powell MA, Gabrin MJ, Brower SL, Coleman RL - Br. J. Cancer (2014)

Association of clinical treatment assay result (match) with PFS. Patients treated with assay-sensitive treatments experienced a median PFS of 8.8 months, whereas those treated with assay-non-sensitive treatments experienced a median PFS of 5.9 months. Reproduced by kind permission of Elsevier from Rutherford et al (2013).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150278&req=5

fig1: Association of clinical treatment assay result (match) with PFS. Patients treated with assay-sensitive treatments experienced a median PFS of 8.8 months, whereas those treated with assay-non-sensitive treatments experienced a median PFS of 5.9 months. Reproduced by kind permission of Elsevier from Rutherford et al (2013).
Mentions: As previously reported, the assay result for match was significantly associated with PFS (HR=0.67, 95% CI=0.50–0.91, P=0.009), with patients treated with an assay-sensitive therapy showing an improvement in PFS as compared with assay-non-sensitive (I+R) patients (Figure 1). This association was consistent after controlling for clinical covariates (HR=0.66, 95% CI=0.47–0.94, P=0.020; Rutherford et al, 2013). The average prognostic value of assay results for multiple different therapies was examined using the assay results for mismatch, in which the assay result for one treatment was randomly selected from the (up to) 15 designated therapies with equal probability for each patient, and the association with PFS was estimated. Based on 3000 repeated re-samplings, the mean HR for mismatch was 0.81 (95% range=0.66–0.99) (Figure 2A). Based on the distribution of HRs for mismatch, only 3.4% of HRs were <0.67 (Figure 2A). When multivariate analysis was performed, the HRs were 0.66 and 0.88, based on match and mismatch, respectively, with only 0.7% of HRs from mismatch <0.66 (Figure 2B). The results for OS were similar. In univariate analysis, the HRs for death were 0.61 and 0.76, based on match and mismatch, respectively, with 5.3% of HRs from mismatch <0.61; in multivariate analysis, the HRs were 0.59 and 0.79, based on match and mismatch, respectively, with 3.6% of HRs from mismatch <0.59. The HRs obtained from both match and mismatch analyses demonstrate the prognostic value of the assay (i.e., HR for both match and mismatch are significantly less than 1.0). More importantly, these results also indicate that the HR for match is materially lower than that for mismatch which supports the predictive nature of the assay.

Bottom Line: Women with persistent or recurrent epithelial ovarian cancer (n=262) were empirically treated with one of 15 therapies, blinded to assay results.On the basis of 3000 simulations, the mean HR for mismatch was 0.81 (95% range=0.66-0.99), with 3.4% of HRs less than 0.67, indicating that HR for match is lower than for mismatch.These analyses provide supportive evidence that this chemoresponse assay is a predictive marker, demonstrating its ability to discern specific therapies that are likely to be more effective among multiple alternatives.

View Article: PubMed Central - PubMed

Affiliation: Precision Therapeutics, Inc., 2516 Jane Street, Pittsburgh, PA 15203, USA.

ABSTRACT

Background: Recently, a prospective study reported improved clinical outcomes for recurrent ovarian cancer patients treated with chemotherapies indicated to be sensitive by a chemoresponse assay, compared with those patients treated with non-sensitive therapies, thereby demonstrating the assay's prognostic properties. Due to cross-drug response over different treatments and possible association of in vitro chemosensitivity of a tumour with its inherent biology, further analysis is required to ascertain whether the assay performs as a predictive marker as well.

Methods: Women with persistent or recurrent epithelial ovarian cancer (n=262) were empirically treated with one of 15 therapies, blinded to assay results. Each patient's tumour was assayed for responsiveness to the 15 therapies. The assay's ability to predict progression-free survival (PFS) was assessed by comparing the association when the assayed therapy matches the administered therapy (match) with the association when the assayed therapy is randomly selected, not necessarily matching the administered therapy (mismatch).

Results: Patients treated with assay-sensitive therapies had improved PFS vs patients treated with non-sensitive therapies, with the assay result for match significantly associated with PFS (hazard ratio (HR)=0.67, 95% confidence interval (CI)=0.50-0.91, P=0.009). On the basis of 3000 simulations, the mean HR for mismatch was 0.81 (95% range=0.66-0.99), with 3.4% of HRs less than 0.67, indicating that HR for match is lower than for mismatch. While 47% of tumours were non-sensitive to all assayed therapies and 9% were sensitive to all, 44% displayed heterogeneity in assay results. Improved outcome was associated with the administration of an assay-sensitive therapy, regardless of homogeneous or heterogeneous assay responses across all of the assayed therapies.

Conclusions: These analyses provide supportive evidence that this chemoresponse assay is a predictive marker, demonstrating its ability to discern specific therapies that are likely to be more effective among multiple alternatives.

Show MeSH
Related in: MedlinePlus