May 13, 2011 — A new test might identify breast cancer patients who have a high probability of survival after taxane and anthracycline chemotherapy.
According to findings from a study published in the May 11 issue of the Journal of the American Medical Association, a test for response to and survival after sequential chemotherapy for ERBB2-negative breast cancer predicted chemoresistance, chemosensitivity, and endocrine sensitivity.
After excluding patients with predicted endocrine sensitivity, the authors found that the chemopredictive test algorithm had a positive predictive value of 56% for pathologic response (complete pathologic response or residual cancer burden).
They also observed that in 28% of patients predicted to be sensitive to treatment, 3-year distant relapse-free survival (DRFS) was 92%, with a significant absolute risk reduction of 18%.
Treatment sensitivity was predicted in 30% of patients in the estrogen receptor (ER)-positive phenotypic subgroup, and in 26% in the ER-negative subgroup. At 3 years, ER-positive patients achieved a DRFS of 97% and a significant absolute risk reduction of 11%.
Patients with ER-negative cancer predicted to be sensitive to treatment had significantly improved 3-year DRFS (83%), an absolute risk reduction of 26%, and a positive predictive value for pathologic response of 83%.
"Any test based on predicted sensitivity, resistance, or both to guide the selection of a standard adjuvant treatment regimen should predict a high probability of survival for patients predicted to be treatment sensitive . . . and a clinically meaningful survival difference between patients predicted to be treatment sensitive and insensitive. . . as well as improve on predictions using existing clinical pathological information," write the authors, who were led by Christos Hatzis, PhD, from Nuvera Biosciences Inc.
"The performance of our predictive test meets these criteria in an independent validation cohort," they add.
Need for Predictive Tests
There is a clinical need for predictive tests for patients with newly diagnosed ERBB2-negative breast cancer who might benefit from chemotherapy, the authors note. Identifying patients who have a high probability of survival after receiving the current standard chemotherapy regimen and endocrine therapy, if warranted, would reaffirm that treatment decision.
Conversely, the authors write, the ability to identify patients with a significant risk for relapse, despite the use of chemotherapy, could be used to recommend participation in an appropriate clinical trial of potentially more effective treatment.
Identified Treatment Sensitivity and Survival
Dr. Hatzis and colleagues hypothesized that a predictive test to determine patient response to and survival after sequential taxane and anthracycline chemotherapy for ERBB2-negative breast cancer would account for each of the following biological characteristics: tumor phenotype, sensitivity to adjuvant endocrine therapy (if ER-positive), chemoresistance, and chemosensitivity.
The prospective multicenter study was conducted from June 2000 to March 2010 to develop a predictor of response to and survival after chemotherapy for patients with invasive breast cancer.
In the discovery cohort, 227 biopsy samples were obtained, and all chemotherapy was administered as neoadjuvant treatment. In the validation group, 165 of 198 patients received all chemotherapy as neoadjuvant treatment.
The authors developed different predictive signatures for resistance and response to preoperative chemotherapy, which were derived from gene expression microarrays from newly diagnosed breast cancer patients (n = 310). Treatment sensitivity was predicted using the combination of signatures for sensitivity to endocrine therapy, chemoresistance, and chemosensitivity, with independent validation (198 patients) and comparison to other reported genomic predictors of chemotherapy response.
Overall, they noted that there was a significant association between predicted sensitivity to treatment and improved DRFS (P = .002). The diagnostic likelihood ratio for disease occurrence, compared with the absence of 3-year distant relapse or death, if patients were predicted to be treatment sensitive, was 0.33 (95% confidence interval, 0.07 to 0.72).
The authors point out that the 3-year DRFS in patients who were predicted to be sensitive to treatment at the time of their diagnosis was similar to the 3-year DRFS of 93% in the 21% of patients who achieved complete pathologic response after a regimen of neoadjuvant chemotherapy.
The 3-year DRFS for patients predicted to be insensitive to treatment was identical to the 3-year DRFS of 75% observed in those with residual disease.
There was no association between predicted treatment sensitivity/DRFS and the type of taxane therapy administered. Genomic predictions were independently and significantly associated with risk for distant relapse or death (sensitive vs insensitive; hazard ratio, 0.19; P = .002) after the data were adjusted for standard clinical and pathologic parameters.
When the genomic prediction was added to a multivariate Cox model, the predictive utility of the model significantly increased. In this model, higher clinical tumor stage and ER-negative status were associated with a statistically significantly greater risk for distant relapse or death.
The authors note that a predictive test with the performance observed in this study could potentially assist clinical decision-making and identify patients with stage II to III ER-positive and ERBB2-negative breast cancer who have excellent 3-year and 5-year DRFS (97%) after standard adjuvant treatment. But they conclude that it is "imperative to continue to evaluate the predictive accuracy of this test in additional validation studies."
The study was funded by grants from Susan G. Komen for the Cure, the National Cancer Institute, the Breast Cancer Research Foundation, the Safeway Foundation, and the Nellie B. Connally Breast Cancer Research Fund at the M.D. Anderson Cancer Center. Several of the coauthors report financial relationships with various pharmaceutical/biotech companies, as noted in the paper.
JAMA. 2011;305:1873-1881. Abstract
According to findings from a study published in the May 11 issue of the Journal of the American Medical Association, a test for response to and survival after sequential chemotherapy for ERBB2-negative breast cancer predicted chemoresistance, chemosensitivity, and endocrine sensitivity.
After excluding patients with predicted endocrine sensitivity, the authors found that the chemopredictive test algorithm had a positive predictive value of 56% for pathologic response (complete pathologic response or residual cancer burden).
They also observed that in 28% of patients predicted to be sensitive to treatment, 3-year distant relapse-free survival (DRFS) was 92%, with a significant absolute risk reduction of 18%.
Treatment sensitivity was predicted in 30% of patients in the estrogen receptor (ER)-positive phenotypic subgroup, and in 26% in the ER-negative subgroup. At 3 years, ER-positive patients achieved a DRFS of 97% and a significant absolute risk reduction of 11%.
Patients with ER-negative cancer predicted to be sensitive to treatment had significantly improved 3-year DRFS (83%), an absolute risk reduction of 26%, and a positive predictive value for pathologic response of 83%.
"Any test based on predicted sensitivity, resistance, or both to guide the selection of a standard adjuvant treatment regimen should predict a high probability of survival for patients predicted to be treatment sensitive . . . and a clinically meaningful survival difference between patients predicted to be treatment sensitive and insensitive. . . as well as improve on predictions using existing clinical pathological information," write the authors, who were led by Christos Hatzis, PhD, from Nuvera Biosciences Inc.
"The performance of our predictive test meets these criteria in an independent validation cohort," they add.
Need for Predictive Tests
There is a clinical need for predictive tests for patients with newly diagnosed ERBB2-negative breast cancer who might benefit from chemotherapy, the authors note. Identifying patients who have a high probability of survival after receiving the current standard chemotherapy regimen and endocrine therapy, if warranted, would reaffirm that treatment decision.
Conversely, the authors write, the ability to identify patients with a significant risk for relapse, despite the use of chemotherapy, could be used to recommend participation in an appropriate clinical trial of potentially more effective treatment.
Identified Treatment Sensitivity and Survival
Dr. Hatzis and colleagues hypothesized that a predictive test to determine patient response to and survival after sequential taxane and anthracycline chemotherapy for ERBB2-negative breast cancer would account for each of the following biological characteristics: tumor phenotype, sensitivity to adjuvant endocrine therapy (if ER-positive), chemoresistance, and chemosensitivity.
The prospective multicenter study was conducted from June 2000 to March 2010 to develop a predictor of response to and survival after chemotherapy for patients with invasive breast cancer.
In the discovery cohort, 227 biopsy samples were obtained, and all chemotherapy was administered as neoadjuvant treatment. In the validation group, 165 of 198 patients received all chemotherapy as neoadjuvant treatment.
The authors developed different predictive signatures for resistance and response to preoperative chemotherapy, which were derived from gene expression microarrays from newly diagnosed breast cancer patients (n = 310). Treatment sensitivity was predicted using the combination of signatures for sensitivity to endocrine therapy, chemoresistance, and chemosensitivity, with independent validation (198 patients) and comparison to other reported genomic predictors of chemotherapy response.
Overall, they noted that there was a significant association between predicted sensitivity to treatment and improved DRFS (P = .002). The diagnostic likelihood ratio for disease occurrence, compared with the absence of 3-year distant relapse or death, if patients were predicted to be treatment sensitive, was 0.33 (95% confidence interval, 0.07 to 0.72).
The authors point out that the 3-year DRFS in patients who were predicted to be sensitive to treatment at the time of their diagnosis was similar to the 3-year DRFS of 93% in the 21% of patients who achieved complete pathologic response after a regimen of neoadjuvant chemotherapy.
The 3-year DRFS for patients predicted to be insensitive to treatment was identical to the 3-year DRFS of 75% observed in those with residual disease.
There was no association between predicted treatment sensitivity/DRFS and the type of taxane therapy administered. Genomic predictions were independently and significantly associated with risk for distant relapse or death (sensitive vs insensitive; hazard ratio, 0.19; P = .002) after the data were adjusted for standard clinical and pathologic parameters.
When the genomic prediction was added to a multivariate Cox model, the predictive utility of the model significantly increased. In this model, higher clinical tumor stage and ER-negative status were associated with a statistically significantly greater risk for distant relapse or death.
The authors note that a predictive test with the performance observed in this study could potentially assist clinical decision-making and identify patients with stage II to III ER-positive and ERBB2-negative breast cancer who have excellent 3-year and 5-year DRFS (97%) after standard adjuvant treatment. But they conclude that it is "imperative to continue to evaluate the predictive accuracy of this test in additional validation studies."
The study was funded by grants from Susan G. Komen for the Cure, the National Cancer Institute, the Breast Cancer Research Foundation, the Safeway Foundation, and the Nellie B. Connally Breast Cancer Research Fund at the M.D. Anderson Cancer Center. Several of the coauthors report financial relationships with various pharmaceutical/biotech companies, as noted in the paper.
JAMA. 2011;305:1873-1881. Abstract
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