Sample Preparation Approach Influences PAM50 Risk of Recurrence Score in Early Breast Cancer.
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SUBMITTER: Lien TG
PROVIDER: S-EPMC8657125 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe aim of this study was to investigate the prognostic value of the PAM50 intrinsic subtypes and risk of recurrence (ROR) score in patients with early breast cancer and long-term follow-up. A special focus was placed on hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) pN0 patients not treated with chemotherapy.MethodsPatients with early breast cancer (n = 653) enrolled in the observational Oslo1 study (1995-1998) were followed for distant recurrence and breast cancer death. Clinicopathological parameters were collected from hospital records. The primary tumors were analyzed using the Prosigna® PAM50 assay to determine the prognostic value of the intrinsic subtypes and ROR score in comparison with pathological characteristics. The primary endpoints were distant disease-free survival (DDFS) and breast cancer-specific survival (BCSS).ResultsOf 653 tumors, 52.2% were classified as luminal A, 26.5% as luminal B, 10.6% as HER2-enriched, and 10.7% as basal-like. Among the HR+/HER2- patients (n = 476), 37.8% were categorized as low risk by ROR score, 22.7% as intermediate risk, and 39.5% as high risk. Median follow-up durations for BCSS and DDFS were 16.6 and 7.1 years, respectively. Multivariate analysis showed that intrinsic subtypes (all patients) and ROR risk classification (HR+/HER2- patients) yielded strong prognostic information. Among the HR+/HER2- pN0 patients with no adjuvant treatment (n = 231), 53.7% of patients had a low ROR, and their prognosis at 15 years was excellent (15-year BCSS 96.3%). Patients with intermediate risk had reduced survival compared with those with low risk (p = 0.005). In contrast, no difference in survival between the low- and intermediate-risk groups was seen for HR+/HER2- pN0 patients who received tamoxifen only. Ki-67 protein, grade, and ROR score were analyzed in the unselected, untreated pT1pN0 HR+/HER2- population (n = 171). In multivariate analysis, ROR score outperformed both Ki-67 and grade. Furthermore, 55% of patients who according to the PREDICT tool ( http://www.predict.nhs.uk/ ) would be considered chemotherapy candidates were ROR low risk (33%) or luminal A ROR intermediate risk (22%).ConclusionsThe PAM50 intrinsic subtype classification and ROR score improve classification of patients with breast cancer into prognostic groups, allowing for a more precise identification of future recurrence risk and providing an improved basis for adjuvant treatment decisions. Node-negative patients with low ROR scores had an excellent outcome at 15 years even in the absence of adjuvant therapy.
| S-EPMC5686844 | biostudies-literature
Project description:Breast cancers detected after a negative breast screening examination and prior to the next screening are referred to as interval cancers. These cancers generally have poor clinical characteristics compared with screen-detected cancers, but associations between interval cancer and genomic cancer characteristics are not well understood. Mammographically screened women diagnosed with primary invasive breast cancer from 1993 to 2013 (n = 370) were identified by linking the Carolina Breast Cancer Study and the Carolina Mammography Registry. Among women with a registry-identified screening mammogram 0 to 24 months before diagnosis, cancers were classified as screen-detected (N = 165) or interval-detected (N = 205). Using logistic regression, we examined the association of mode of detection with cancer characteristics (clinical, IHC, and genomic), overall, and in analyses stratified on mammographic density and race. Interval cancer was associated with large tumors [>2 cm; OR, 2.3; 95% confidence interval (CI), 1.5-3.7], positive nodal status (OR, 1.8; 95% CI, 1.1-2.8), and triple-negative subtype (OR, 2.5; 95% CI, 1.1-5.5). Interval cancers were more likely to have non-Luminal A subtype (OR, 2.9; 95% CI, 1.5-5.7), whereas screen-detected cancers tended to be more indolent (96% had low risk of recurrence genomic scores; 71% were PAM50 Luminal A). When stratifying by mammographic density and race, associations between interval detection and poor prognostic features were similar by race and density status. Strong associations between interval cancers and poor-prognosis genomic features (non-Luminal A subtype and high risk of recurrence score) suggest that aggressive tumor biology is an important contributor to interval cancer rates. Cancer Prev Res; 11(6); 327-36. ©2018 AACR.
| S-EPMC5984721 | biostudies-literature
Project description:Combining information from the tumor microenvironment (TME) with PAM50 Risk of Recurrence (ROR) score could improve breast cancer prognostication. Caveolin-1 (CAV1) is a marker of an active TME. CAV1 is a membrane protein involved in cell signaling, extracellular matrix organization, and tumor-stroma interactions. We sought to investigate CAV1 gene expression in relation to PAM50 subtypes, ROR score, and their joint prognostic impact. CAV1 expression was compared between PAM50 subtypes and ROR categories in two cohorts (SCAN-B, n = 5326 and METABRIC, n = 1980). CAV1 expression was assessed in relation to clinical outcomes using Cox regression and adjusted for clinicopathological predictors. Effect modifications between CAV1 expression and ROR categories on clinical outcome were investigated using multiplicative and additive two-way interaction analyses. Differential gene expression and gene set enrichment analyses were applied to compare high and low expressing CAV1 tumors. All samples expressed CAV1 with the highest expression in the Normal-like subtype. Gene modules consistent with epithelial-mesenchymal transition (EMT), hypoxia, and stromal activation were associated with high CAV1 expression. CAV1 expression was inversely associated with ROR category. Interactions between CAV1 expression and ROR categories were observed in both cohorts. High expressing CAV1 tumors conferred worse prognosis only within the group classified as ROR high. ROR gave markedly different prognostic information depending on the underlying CAV1 expression. CAV1, a potential mediator between the malignant cells and TME, could be a useful biomarker that enhances and further refines PAM50 ROR risk stratification in patients with ROR high tumors and a potential therapeutic target.
| S-EPMC10954762 | biostudies-literature
Project description:PURPOSE: To compare risk assignment by PAM50 Breast Cancer Intrinsic Classifier™ and Oncotype DX_Recurrence Score (RS) in the same population. METHODS: RNA was extracted from 151 estrogen receptor (ER)+ stage I-II breast cancers and gene expression profiled using PAM50 "intrinsic" subtyping test. RESULTS: One hundred eight cases had complete molecular information; 103 (95%) were classified as luminal A (n = 76) or luminal B (n = 27). Ninety-two percent (n = 98) had a low (n = 59) or intermediate (n = 39) RS. Among luminal A cancers, 70% had low (n = 53) and the remainder (n = 23) had an intermediate RS. Among luminal B cancers, nine were high (33%) and 13 were intermediate (48%) by the RS. Almost all cancers with a high RS were classified as luminal B (90%, n = 9). One high RS cancer was identified as basal-like and had low ER/ESR1 and low human epidermal growth factor receptor 2 (HER2) expression by quantitative polymerase chain reaction in both assays. The majority of low RS cases were luminal A (83%, n = 53). Importantly, half of the intermediate RS cancers were re-categorized as low risk luminal A subtype by PAM50. CONCLUSION: There is good agreement between the two assays for high (i.e., luminal B or RS > 31) and low (i.e., luminal B or RS < 18) prognostic risk assignment but PAM50 assigns more patients to the low risk category. About half of the intermediate RS group was reclassified as luminal A by PAM50.
| S-EPMC3336833 | biostudies-other
Project description:IntroductionThe 21-gene Recurrence Score(®) assay (Oncotype DX(®), Genomic Health, Inc.) is a validated predictor of recurrence risk/chemotherapy benefit in patients with estrogen receptor-positive (ER+) early-stage breast cancer treated with endocrine therapy. The Prosigna(®) assay (NanoString Technologies Inc.) is a validated prognosticator in postmenopausal patients with low-risk ER+ early-stage breast cancer treated with endocrine therapy. The assays were analytically/clinically developed and validated differently. This study focused on comparing recurrence risk estimates as determined by these assays and is the first blinded comparison of these assays on matched patient samples.MethodsSequential breast cancer specimens from postmenopausal, node-negative, ER+ patients treated at the Marin General Hospital were analyzed: first by the 21-gene assay then by the Prosigna assay in an independent lab blinded to the Recurrence Score results.ResultsThe final analysis included 52 patients. Correlation between the Recurrence Score and the Prosigna assay results was poor (r = 0.08). Agreement between risk classifications based on these assays was 54%; 4/7 of patients classified as high risk by the Prosigna assay had low Recurrence Score results. Two tumors with high Recurrence Score results had low ER expression (close to positivity threshold); both of which had a low/intermediate Prosigna assay result. The Prosigna assay classified 73.1% and 23.1% of samples as luminal A and luminal B, respectively. A range of Recurrence Score results was observed within the subtypes; 83% of luminal B samples had a low Recurrence Score result.ConclusionConsistent with prior comparisons between the 21-gene and other genomic assays, our study demonstrated substantial differences in the way patients are risk stratified, suggesting that the different assays are not interchangeable.FundingGenomic Health, Inc.
| S-EPMC4679783 | biostudies-literature
Project description:Purpose: Hormone receptor-positive (HR+) breast cancer is clinically and biologically heterogeneous, and subgroups with different prognostic and treatment sensitivities need to be identified.Experimental Design: Research-based PAM50 subtyping and expression of additional genes was performed on 63 patients with HR+/HER2- disease randomly assigned to neoadjuvant multiagent chemotherapy versus endocrine therapy in a phase II trial. The biology associated with treatment response was used to derive a PAM50-based chemoendocrine score (CES). CES's predictive ability was evaluated in 4 independent neoadjuvant data sets (n = 675) and 4 adjuvant data sets (n = 1,505). The association of CES, intrinsic biology, and PAM50 risk of relapse (ROR) was explored across 6,007 tumors.Results: Most genes associated with endocrine sensitivity were also found associated with chemotherapy resistance. In the chemotherapy test/validation data sets, CES was independently associated with pathologic complete response (pCR), even after adjusting for intrinsic subtype. pCR rates of the CES endocrine-sensitive (CES-E), uncertain (CES-U), and chemotherapy-sensitive (CES-C) groups in both data sets combined were 25%, 11%, and 2%, respectively. In the endocrine test/validation data sets, CES was independently associated with response. Compared with ROR, >90% of ROR-low and ROR-high tumors were identified as CES-E and CES-C, respectively; however, each CES group represented >25% of ROR-intermediate disease. In terms of survival outcome, CES-C was associated with poor relapse-free survival in patients with ROR-intermediate disease treated with either adjuvant endocrine therapy only or no adjuvant systemic therapy, but not in patients treated with (neo)adjuvant chemotherapy.Conclusions: CES is a genomic signature capable of estimating chemoendocrine sensitivity in HR+ breast cancer beyond intrinsic subtype and risk of relapse. Clin Cancer Res; 23(12); 3035-44. ©2016 AACR.
| S-EPMC5449267 | biostudies-literature
Project description:BackgroundThere is currently no instrument to stratify patients presenting with ischemic stroke according to early risk of recurrent stroke. We sought to develop a comprehensive prognostic score to predict 90-day risk of recurrent stroke.MethodsWe analyzed data on 1,458 consecutive ischemic stroke patients using a Cox regression model with time to recurrent stroke as the response and clinical and imaging features typically available to physician at admission as covariates. The 90-day risk of recurrent stroke was calculated by summing up the number of independent predictors weighted by their corresponding beta-coefficients. The resultant score was called recurrence risk estimator at 90 days or RRE-90 score (available at: http://www.nmr.mgh.harvard.edu/RRE-90/).ResultsSixty recurrent strokes (54 had baseline imaging) occurred during the follow-up period. The risk adjusted for time to follow-up was 6.0%. Predictors of recurrence included admission etiologic stroke subtype, prior history of TIA/stroke, and topography, age, and distribution of brain infarcts. The RRE-90 score demonstrated adequate calibration and good discrimination (area under the ROC curve [AUC] = 0.70-0.80), which was maintained when applied to a separate cohort of 433 patients (AUC = 0.70-0.76). The model's performance was also maintained for predicting early (14-day) risk of recurrence (AUC = 0.80).ConclusionsThe RRE-90 is a Web-based, easy-to-use prognostic score that integrates clinical and imaging information available in the acute setting to quantify early risk of recurrent stroke. The RRE-90 demonstrates good predictive performance, suggesting that, if validated externally, it has promise for use in creating individualized patient management algorithms and improving clinical practice in acute stroke care.
| S-EPMC2809031 | biostudies-literature
Project description:To identify a group of patients who might benefit from the addition of weekly paclitaxel to conventional anthracycline-containing chemotherapy as adjuvant therapy of node-positive operable breast cancer. The predictive value of PAM50 subtypes and the 11-gene proliferation score contained within the PAM50 assay were evaluated in 820 patients from the GEICAM/9906 randomized phase III trial comparing adjuvant FEC to FEC followed by weekly paclitaxel (FEC-P). Multivariable Cox regression analyses of the secondary endpoint of overall survival (OS) were performed to determine the significance of the interaction between treatment and the (1) PAM50 subtypes, (2) PAM50 proliferation score, and (3) clinical and pathological variables. Similar OS analyses were performed in 222 patients treated with weekly paclitaxel versus paclitaxel every 3 weeks in the CALGB/9342 and 9840 metastatic clinical trials. In GEICAM/9906, with a median follow up of 8.7 years, OS of the FEC-P arm was significantly superior compared to the FEC arm (unadjusted HR = 0.693, p = 0.013). A benefit from paclitaxel was only observed in the group of patients with a low PAM50 proliferation score (unadjusted HR = 0.23, p < 0.001; and interaction test, p = 0.006). No significant interactions between treatment and the PAM50 subtypes or the various clinical-pathological variables, including Ki-67 and histologic grade, were identified. Finally, similar OS results were obtained in the CALGB data set, although the interaction test did not reach statistical significance (p = 0.109). The PAM50 proliferation score identifies a subset of patients with a low proliferation status that may derive a larger benefit from weekly paclitaxel.
| S-EPMC3608881 | biostudies-literature
Project description:BackgroundStudies of obesity and survival among patients with breast cancer produce conflicting results, possibly because of heterogeneity by molecular subtype.MethodsThis study examined whether the association of body mass index (BMI) at diagnosis with breast cancer recurrence and survival varied across subtypes defined by PAM50 (Prediction Analysis of Microarray 50) gene expression. Included were 1559 Kaiser Permanente Northern California members ages 18 to 79 years who had PAM50 assays and were diagnosed with American Joint Committee on Cancer stage I through III breast cancer from 1996 to 2013. Patients reported weight and height. Cox regression models were adjusted for age, menopause, race/ethnicity, stage, and chemotherapy.ResultsOver a median of 9 years (maximum, 19 years), 378 women developed recurrent disease, and 312 died from breast cancer. Overall, BMI was not associated with breast cancer recurrence or survival when controlling for subtype (eg, the hazard ratio per 5 kg/m2 of BMI was 1.05 [95% confidence interval, 0.95-1.15] for breast cancer-specific death). However, associations varied by subtype. Among women with luminal A cancers, those who had class II/III obesity, but not class I obesity or overweight, had worse outcomes. When women who had a BMI ≥35 kg/m2 were compared with those who had a BMI from 18.5 to <25 kg/m2 , the hazard ratio was 2.24 (95% confidence interval,1.22-4.11) for breast cancer-specific death and 1.24 (95% confidence interval, 1.00-1.54) for recurrence. There was no association within luminal B, basal-like or human epidermal growth factor over-expressing subtypes.ConclusionsAmong patients who had accurately classified breast cancer subtypes based on gene expression, a BMI ≥35 kg/m2 was adversely associated with outcomes only among those who had luminal A cancers. Research is needed into whether tailoring recommendations for weight management to tumor characteristics will improve outcomes. Cancer 2017;123:2535-42. © 2017 American Cancer Society.
| S-EPMC5474169 | biostudies-literature
Project description:Luminal subtypes and the 21-gene recurrence score (RS) are important factors in the decision-making process for adjuvant chemotherapy in patients with hormonal receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. However, their effect on adjuvant chemotherapy decisions in the real world has not been thoroughly investigated, particularly for patients of the luminal A-like subtype with a high RS or the luminal B-like subtype with a low RS. The present study, a total of 772 HR+/HER2- patients who underwent 21-gene testing, were included in a retrospective analysis. The impact of clinicopathological factors and the 21-gene RS on chemotherapy recommendation was analyzed in the whole population and for patients of different luminal subgroups. The results revealed that chemotherapy was highly recommended for patients of younger age, with larger tumor size, node involvement, higher grade, luminal B-like subtype and higher RS. A high RS was identified to be the most important impact factor for chemotherapy recommendation among all patients [odds ratio (OR), 62.54; 95% CI, 25.58-152.92], the luminal A-like group (OR, 435.05; 95% CI, 29.90-6331.06) and the luminal B-like group (OR, 57.20; 95% CI, 22.42-145.96). For patients of the luminal A-like subtype with a high RS or patients of the luminal B-like subtype with low RS, the 21-gene RS was demonstrated to be the most important independent factor for chemotherapy recommendation, with an adjusted OR of 134.52 (95% CI, 10.39-1741.89). In conclusion, luminal subtypes and the 21-gene RS were found to be associated with chemotherapy recommendation for HR+/HER2- patients. For patients with a discordant luminal subtype and 21-gene RS risk, the 21-gene RS score was found to be the most important factor that influences chemotherapy decision, which warrants further clinical evaluation.
| S-EPMC6757308 | biostudies-literature