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A systematic evaluation of multi-gene predictors for the pathological response of breast cancer patients to chemotherapy.

ABSTRACT: Previous studies have reported conflicting assessments of the ability of cell line-derived multi-gene predictors (MGPs) to forecast patient clinical outcomes in cancer patients, thereby warranting an investigation into their suitability for this task. Here, 42 breast cancer cell lines were evaluated by chemoresponse tests after treatment with either TFAC or FEC, two widely used standard combination chemotherapies for breast cancer. We used two different training cell line sets and two independent prediction methods, superPC and COXEN, to develop cell line-based MGPs, which were then validated in five patient cohorts treated with these chemotherapies. This evaluation yielded high prediction performances by these MGPs, regardless of the training set, chemotherapy, or prediction method. The MGPs were also able to predict patient clinical outcomes for the subgroup of estrogen receptor (ER)-negative patients, which has proven difficult in the past. These results demonstrated a potential of using an in vitro-based chemoresponse data as a model system in creating MGPs for stratifying patients' therapeutic responses. Clinical utility and applications of these MGPs will need to be carefully examined with relevant clinical outcome measurements and constraints in practical use.

SUBMITTER: Shen K

PROVIDER: S-EPMC3504014 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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A systematic evaluation of multi-gene predictors for the pathological response of breast cancer patients to chemotherapy.

Shen Kui K Song Nan N Kim Youngchul Y Tian Chunqiao C Rice Shara D SD Gabrin Michael J MJ Symmans W Fraser WF Pusztai Lajos L Lee Jae K JK

PloS one 20121121 11

Previous studies have reported conflicting assessments of the ability of cell line-derived multi-gene predictors (MGPs) to forecast patient clinical outcomes in cancer patients, thereby warranting an investigation into their suitability for this task. Here, 42 breast cancer cell lines were evaluated by chemoresponse tests after treatment with either TFAC or FEC, two widely used standard combination chemotherapies for breast cancer. We used two different training cell line sets and two independen ...[more]

PMID: 23185353

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Project description:Determining which patients with early-stage breast cancer should receive chemotherapy is an important clinical issue. Chemotherapy has several adverse side effects, impacting on quality of life, along with significant economic consequences. There are a number of multi-gene prognostic signatures for breast cancer recurrence but there is less evidence that these prognostic signatures are predictive of therapy benefit. Biomarkers that can predict patient response to chemotherapy can help avoid ineffective over-treatment. The aim of this work was to assess if the OncoMasTR prognostic signature can predict pathological complete response (pCR) to neoadjuvant chemotherapy, and to compare its predictive value with other prognostic signatures: EndoPredict, Oncotype DX and Tumor Infiltrating Leukocytes. Gene expression datasets from ER-positive, HER2-negative breast cancer patients that had pre-treatment biopsies, received neoadjuvant chemotherapy and an assessment of pCR were obtained from the Gene Expression Omnibus repository. A total of 813 patients with 66 pCR events were included in the analysis. OncoMasTR, EndoPredict, Oncotype DX and Tumor Infiltrating Leukocytes numeric risk scores were approximated by applying the gene coefficients to the corresponding mean probe expression values. OncoMasTR, EndoPredict and Oncotype DX prognostic scores were moderately well correlated according to the Pearson's correlation coefficient. Association with pCR was estimated using logistic regression. The odds ratio for a 1 standard deviation increase in risk score, adjusted for cohort, were similar in magnitude for all four signatures. Additionally, the four signatures were significant predictors of pCR. OncoMasTR added significant predictive value to EndoPredict, Oncotype DX and Tumor Infiltrating Leukocytes signatures as determined by bivariable and trivariable analysis. In this in silico analysis, OncoMasTR, EndoPredict, Oncotype DX, and Tumor Infiltrating Leukocytes were significantly predictive of pCR to neoadjuvant chemotherapy in ER-positive and HER2-negative breast cancer patients.

Project description:BackgroundNeoadjuvant chemotherapy is a key component of breast cancer treatment regimens and pathologic complete response to this therapy varies among patients. This is presumably due to differences in the molecular mechanisms that underlie each tumor's disease pathology. Developing genomic clinical assays that accurately categorize responders from non-responders can provide patients with the most effective therapy for their individual disease.MethodsWe applied our previously developed E2F4 genomic signature to predict neoadjuvant chemotherapy response in breast cancer. E2F4 individual regulatory activity scores were calculated for 1129 patient samples across 5 independent breast cancer neoadjuvant chemotherapy datasets. Accuracy of the E2F4 signature in predicting neoadjuvant chemotherapy response was compared to that of the Oncotype DX and MammaPrint predictive signatures.ResultsIn all datasets, E2F4 activity level was an accurate predictor of neoadjuvant chemotherapy response, with high E2F4 scores predictive of achieving pathologic complete response and low scores predictive of residual disease. These results remained significant even after stratifying patients by estrogen receptor (ER) status, tumor stage, and breast cancer molecular subtypes. Compared to the Oncotype DX and MammaPrint signatures, our E2F4 signature achieved similar performance in predicting neoadjuvant chemotherapy response, though all signatures performed better in ER+ tumors compared to ER- ones. The accuracy of our signature was reproducible across datasets and was maintained when refined from a 199-gene signature down to a clinic-friendly 33-gene panel.ConclusionOverall, we show that our E2F4 signature is accurate in predicting patient response to neoadjuvant chemotherapy. As this signature is more refined and comparable in performance to other clinically available gene expression assays in the prediction of neoadjuvant chemotherapy response, it should be considered when evaluating potential treatment options.

Project description:BACKGROUND:The main purpose was to investigate the correlation between magnetic resonance imaging (MRI)-based response patterns halfway through neoadjuvant chemotherapy and immunotherapy (NAC) and pathological tumor response in patients with breast cancer. Secondary purposes were to compare the predictive value of MRI-based response patterns measured halfway through NAC and after NAC and to measure interobserver variability. METHODS:All consecutive patients treated with NAC for primary invasive breast cancer from 2012 to 2015 and who underwent breast MRI before, halfway through (and after) NAC were included. All breast tumors were reassessed on MRI by two experienced breast radiologists and classified into six patterns: type 0 (complete radiologic response); type 1 (concentric shrinkage); type 2 (crumbling); type 3 (diffuse enhancement); type 4 (stable disease); type 5 (progressive disease). Percentages of tumors showing pathological complete response (pCR), > 50% tumor reduction and > 50% tumor diameter reduction per MRI-based response pattern were calculated. Correlation between MRI-based response patterns and pathological tumor reduction was studied with Pearson's correlation coefficient, and interobserver agreement was tested with Cohen's Kappa. RESULTS:Patients (n = 76; mean age 53, range 29-72 years) with 80 tumors (4 bilateral) were included. There was significant correlation between these MRI-based response patterns halfway through NAC and tumor reduction on pathology assessment (reader 1 r = 0.33; p = 0.003 and reader 2 r = 0.45; p < 0.001). Type-0, type-1 or type-2 patterns halfway through NAC showed highest tumor reduction rates on pathology assessment, with > 50% tumor reduction in 90%, 78% and 65% of cases, respectively. In 83% of tumors with type 0 halfway through NAC, pathology assessment showed pCR. There was no significant correlation between MRI-based response patterns after NAC and tumor reduction rates on pathology assessment (reader 1 r = - 0.17; p = 0.145 and reader 2 r = - 0.17; p = 0.146). In 41% of tumors with type 0 after NAC, pathology assessment showed pCR. CONCLUSION:MRI-based response patterns halfway through NAC can predict pathologic response more accurately than MRI-based response patterns after NAC. Complete radiological response halfway NAC is associated with 83% pCR, while complete radiological response after NAC seems to be correct in only 41% of cases.

Project description:PurposeTo evaluate diffusion weighted MRI (DW-MR) as a response metric for assessment of neoadjuvant chemotherapy (NAC) in patients with primary breast cancer using prospective multi-center trials which provided MR scans along with clinical outcome information.Materials and methodsA total of 39 patients with locally advanced breast cancer accrued from three different prospective clinical trials underwent DW-MR examination prior to and at 3-7 days (Hull University), 8-11 days (University of Michigan) and 35 days (NeoCOMICE) post-treatment initiation. Thirteen patients, 12 of which participated in treatment response study, from UM underwent short interval (<1hr) MRI examinations, referred to as "test-retest" for examination of repeatability. To further evaluate stability in ADC measurements, a thermally controlled diffusion phantom was used to assess repeatability of diffusion measurements. MRI sequences included contrast-enhanced T1-weighted, when appropriate, and DW images acquired at b-values of 0 and 800 s/mm2. Histogram analysis and a voxel-based analytical technique, the Parametric Response Map (PRM), were used to derive diffusion response metrics for assessment of treatment response prediction.ResultsMean tumor apparent diffusion coefficient (ADC) values generated from patient test-retest examinations were found to be very reproducible (|ΔADC|<0.1x10-3mm2/s). This data was used to calculate the 95% CI from the linear fit of tumor voxel ADC pairs of co-registered examinations (±0.45x10-3mm2/s) for PRM analysis of treatment response. Receiver operating characteristic analysis identified the PRM metric to be predictive of outcome at the 8-11 (AUC = 0.964, p = 0.01) and 35 day (AUC = 0.770, p = 0.05) time points (p<.05) while whole-tumor ADC changes where significant at the later 35 day time interval (AUC = 0.825, p = 0.02).ConclusionThis study demonstrates the feasibility of performing a prospective analysis of DW-MRI as a predictive biomarker of NAC in breast cancer patients. In addition, we provide experimental evidence supporting the use of sensitive analytical tools, such as PRM, for evaluating ADC measurements.

Project description:BackgroundThe current use of targeted therapy plus neoadjuvant chemotherapy for inflammatory breast cancer (IBC) is based on data extrapolated from studies in non-IBC. We conducted a systematic review to determine whether neoadjuvant chemotherapy plus targeted therapy results in a higher pathologic complete response (pCR) rate than neoadjuvant chemotherapy alone in patients with IBC.Method and findingsThis systematic review was registered in the PROSPERO register with registration number CRD42018089465. We searched MEDLINE & PubMed, EMBASE, and EBSCO from December 1998 through July 2020. All English-language clinical studies, both randomized and non-randomized, that evaluated neoadjuvant systemic treatment with or without targeted therapy before definitive surgery and reported the pCR results of IBC patients. First reviewer extracted data and assessed the risk of bias using the Risk of Bias In Non-randomized Studies of Interventions tool. Second reviewer confirmed the accuracy. Studies were divided into 3 groups according to systemic treatment: chemotherapy with targeted therapy, chemotherapy alone, and high-dose chemotherapy with hematopoietic stem cell support (HSCS). Of 995 screened studies, 23 with 1,269 IBC patients met the inclusion criteria. For each of the 3 groups of studies, we computed a weighted average of the pCR rates across all studies with confidence interval (CI). The weighted averages (95% CIs) were as follows: chemotherapy with targeted therapy, 31.6% (26.4%-37.3%), chemotherapy alone, 13.0% (10.3%-16.2%), and high-dose chemotherapy with HSCS, 23.0% (18.7%-27.7%). The high pCR by targeted therapy group came from anti-HER2 therapy, 54.4% (44.3%-64.0%). Key limitations of this study included no randomized clinical studies that included only IBC patients.ConclusionNeoadjuvant chemotherapy plus targeted therapy is more effective than neoadjuvant chemotherapy alone for IBC patients. These findings support current IBC standard practice in particular the use of anti-HER2 targeted therapy.

Project description:PurposeWe aimed to determine the rate of pathological complete response (pCR), clinicopathological factors associated with pCR, and clinical outcomes following neoadjuvant chemotherapy in locally advanced breast cancer.MethodsMedical records of patients who had undergone neoadjuvant chemotherapy for breast cancer between January 2007 and September 2011 were retrospectively reviewed, and the pCR rates were calculated according to three sets of criteria: the National Surgical Adjuvant Breast and Bowel Project (NSABP), the MD Anderson Cancer Center (MDACC), and the German Breast Group (GBG). Tumors were classified as luminal A like, luminal B like, human epidermal growth factor receptor 2 (HER2), or triple-negative. pCR and clinical outcome, including overall survival (OS) and disease-free survival (DFS) rates were analyzed at the median follow-up of 54.2 months.ResultsOf a total of 179 patients who had received neoadjuvant chemotherapy, 167 patients (93.3%) had locally advanced breast cancer and 12 patients (6.7%) had early-stage breast cancer. The majority of patients (152 patients, 89.4%) received anthracycline-based neoadjuvant chemotherapy. The objective clinical response rate was 61.5%, comprising clinical partial response in 5.5% and clinical complete response in 3.9% of patients. Twenty-one (11.7%), 20 (11.2%), and 17 patients (9.5%) achieved pCR according to NSABP, MDACC, and GBG definitions, respectively. pCR rates, as defined by NSABP, according to breast cancer subtype were 4.4%, 9.7%, 24.2%, and 19.2% in luminal A like, luminal B like, HER2, and triple-negative subtypes, respectively. Patients who achieved pCR had significantly better DFS (5-year DFS rates, 80% vs. 53%, p=0.030) and OS (5-year OS rates, 86% vs. 54%, p=0.042) than those who did not.ConclusionThe pCR rate following neoadjuvant chemotherapy for breast cancer in Thai women attending our institution was 11.7%; pCR was more frequently observed in HER2 and triple-negative breast tumor subtypes. Patients who achieved pCR had significantly improved survival.

Project description:ImportanceAmong patients with breast cancer, inconsistent findings have been published on racial disparities in achieving pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT).ObjectiveTo investigate whether racial disparities exist in achieving pCR and what factors contribute to them.Design, setting, and participantsWithin the ongoing Chicago Multiethnic Epidemiologic Breast Cancer Cohort (ChiMEC), which consists of a prospectively ascertained cohort of patients with breast cancer, 690 patients with stage I to III breast cancer receiving NACT were identified for this single-institution study at the University of Chicago Medicine. Patients diagnosed between 2002 and 2020 (median follow-up: 5.4 years) were included; next-generation sequencing data on tumor-normal tissue pairs were available from 186 ChiMEC patients, including both primary and residual tumor samples. Statistical analysis was performed from September 2021 to September 2022.ExposuresDemographic, biological, and treatment factors that could contribute to disparities in achieving pCR.Main outcomes and measurespCR was defined as the absence of invasive cancer in the breast and axillary nodes, irrespective of ductal carcinoma in situ.ResultsThe study included 690 patients with breast cancer, with a mean (SD) age of 50.1 (12.8) years. Among the 355 White patients, 130 (36.6%) achieved pCR compared to 77 of the 269 Black patients (28.6%; P = .04). Not achieving pCR was associated with significantly worse overall survival (adjusted hazard ratio, 6.10; 95% CI, 2.80-13.32). Black patients had significantly lower odds of achieving pCR compared with White patients in the hormone receptor-negative/ERBB2+ subtype (adjusted odds ratio, 0.30; 95% CI, 0.11-0.81). Compared with White patients with ERBB2+ disease, Black patients were more likely to have MAPK pathway alterations (30.0% [6 of 20] vs 4.6% [1 of 22]; P = .04), a potential mechanism of anti-ERBB2 therapy resistance. Tumor mutational burden and somatic alterations in several genes (eg, FGF4, FGF3, CCND1, MCL1, FAT1, ERCC3, PTEN) were significantly different between the primary and residual tumors.Conclusions and relevanceIn this cohort study of patients with breast cancer, racial disparities in response to NACT were associated with disparities in survival and varied across different breast cancer subtypes. This study highlights the potential benefits of better understanding the biology of primary and residual tumors.

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A systematic evaluation of multi-gene predictors for the pathological response of breast cancer patients to chemotherapy.

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A systematic evaluation of multi-gene predictors for the pathological response of breast cancer patients to chemotherapy.

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