Recurrence Score Risk Research Articles

Correlation of urinary comprehensive genomic profile with risk of recurrence of BCG-unresponsive non-muscle invasive bladder cancer treated with atezolizumab in SWOG S1605.

529 Background: Radical cystectomy is recommended for patients with BCG-unresponsive (BU) non-muscle invasive bladder cancer (NMIBC) due to high risk of progression. Improved methods for assessing these risks would greatly facilitate the potential for bladder preservation. Here, we tested the capacity of the urinary comprehensive genomic profile (uCGP) to predict event-free survival (EFS) in patients with BU-NMIBC treated with atezolizumab in the single arm phase 2 trial SWOG S1605. Methods: Urine was collected from patients with BU NMIBC (CIS, Ta, T1) treated with at least one dose of intravenous atezolizumab at baseline and before the 5th cycle of therapy (3 months). The uCGP was assessed using UroAmp (Convergent Genomics). Risk scores for recurrence at baseline and at 3 months were calculated by a prespecified machine learning algorithm incorporating alterations in 60 genes and low pass whole genome sequencing, and categorized as high versus low. Molecular response was classified based on change in uCGP between the two time points. Risk scores and molecular response were submitted to SWOG for clinical correlation with EFS using a Cox model, adjusting for CIS status. Time to event was calculated from date of study entry (baseline risk) or from the 2nd collection time (3-month risk) to first high grade (HG) recurrence or persistent CIS at 3 months. Death unrelated to bladder cancer and patients last known to be alive without HG recurrence were censored at date of last visit. Results: Samples were provided at baseline in 89 patients and before the 5th cycle in 77; 68 had both samples available for paired analysis. The risk score at baseline was classified as high in 69% of samples (73% for CIS ±Ta/T1 and 62% for Ta/T1). At 12 and 18 months the EFS probabilities were 26% and 23% for high-risk and 67% and 51% for low-risk patients, respectively, with a HR of 2.82 (95% CI: 1.58, 5.03; p<0.001). The risk score at the 3-month timepoint was classified as high in 81% of samples, and the EFS probabilities at 12 and 18 months after urine collection were 26% and 22% for high-risk and 80% and 72% for low-risk patients, respectively, with a HR of 3.39 (95% CI: 1.41, 8.13; p<0.006). Molecular response to treatment was classified as complete (CR) in 8%, partial (PR) in 14%, stable (SD) in 25% and progression (PD) in 46%, with 7% having no detectable genomic abnormalities at both time points. Clinical recurrence was observed by 18 months in 0/6 patients with CR, 7/9 (78%) with PR, 11/14 (79%) with SD and 25/33 (76%) with PD by genomic profile. Conclusions: This study suggests that uCGP at baseline and after 4 cycles of treatment can identify genomic patterns associated with an increased risk of HG persistence, recurrence or progression in BU NMIBC treated with immune checkpoint inhibition. Future studies will determine if this can be used to guide early treatment intensification.

The clinical value of a nomogram constructed from CEA, CA199, PT, FIB, tumor differentiation and TNM stage in colorectal cancer.

The accurate Tumor-Node-Metastasis (TNM) staging of colorectal cancer (CRC) is of great guiding significance for the judgment of tumor progression and prognosis, and the formulation of treatment strategies. The aim of this study was to construct a recurrence risk scoring (RRS) system and prognostic prediction model to improve the accuracy of staging, prognosis prediction, and clinical decision making in resectable CRC. CRC patients who underwent radical resection were retrospectively enrolled into study. Multivariable Cox regression model was applied to screen for independent prognostic factors. The RRS system is composed of independent prognostic factors which was awarded 1point each. A prognostic model composed of RRS and TNM staging system (RRS-TNM model) was applied to predict postoperative recurrence. TNM stage, tumor differentiation, preoperative elevated Carcinoembryonic Antigen, Carbohydrate Antigen 199, Prothrombin Time and Fibrinogen were the independent prognostic biomarkers. 173 of 540 patients had recurrence. The 5-year cumulative recurrence rate (5-y CRR) and disease-free survival (DFS) of postoperative p-TNM stage I, II, and III were 12.7% and 104.8 months, 26.5% and 89.3 months, and 55.5% and 57.3 months, respectively. The 5-y CRR and DFS of preoperative Low-risk (RRS 0-1score), Middle-risk (RRS 2-3scores), and High-risk (RRS 4-5scores) groups were 13.9% and 101.1 months, 40.9% and 75.5 months, and 70.2% and 41.1 months. The AUC (area under ROC curve) of RRS system was not inferior to that of TNM staging system (0.713 vs. 0.666; P= 0.093). The AUC (0.770) and C-index value (0.721) of RRS-TNM model were significantly better than both RRS and TNM staging system (P< 0.001). The RRS system accurately identifies CRC patients with high-risk recurrence preoperatively. Constructing a nomogram using the RRS system and TNM staging significantly improves the accuracy of staging and prognosis prediction, which is of great clinical significance for individualized clinical treatment and follow-up of CRC.

Establishment and Validation of the LI-RADS Morphologic Type II Hepatocellular Carcinoma Early Recurrence Risk Scoring System

BackgroundTumor morphology links to early recurrence of hepatocellular carcinoma. Controversy exists regarding the recurrence risk of Liver Imaging Reporting and Data System morphologic Type II hepatocellular carcinoma. This study aims to explore risk factors for early recurrence of Type II hepatocellular carcinoma. MethodsRetrospective analysis of hepatocellular carcinoma patients who underwent curative resection and preoperative contrast-enhanced MRI from June 2016 to June 2020. Our patients formed the development set, and hepatocellular carcinoma patients from the TCIA database served as validation. Univariable and multivariable Cox regression identified independent risk factors for early recurrence. A risk scoring system was established for risk stratification, and an early recurrence prediction model was developed and validated. Results95 Type II hepatocellular carcinoma patients were in the development set, and 29 cases were in the validation set. Early recurrence rates were 33.7% and 37.9%, respectively. Multivariate analysis revealed age, histological grade, AFP, and intratumoral hemorrhage as independent risk factors for early recurrence. The model's diagnostic performance for early recurrence was AUC = 0.817 in the development set. A scoring system classified patients into low-risk (scores ≤ 3) and high-risk (scores > 3) groups. The high-risk group had significantly lower recurrence-free survival (40.0% vs 73.2%, P = 0.001), consistent with the validation set (25.0% vs 73.3%, P = 0.028). ConclusionsThe risk scoring system demonstrated excellent discrimination and predictive ability, aiding clinicians in assessing early recurrence risk and identifying high-risk individuals effectively.

Predictive value of aMAP risk score for early recurrence of small hepatocellular carcinoma after microwave ablation

Objective: To explore the value of the aMAP risk score (age, male, albumin-bilirubin, and platelets) to predict early recurrence within one year after microwave ablation in patients with small hepatocellular carcinoma. Methods: This was a retrospective study that enrolled 142 patients diagnosed with hepatocellular carcinoma who were treated with microwave ablation in the Department of Hepatology Unit of Nanfang Hospital, Southern Medical University from July 2016 to July 2021. The cohort enrolled 121 male and 21 female patients, including 110 patients that were <60 years old. All the patients were followed-up after microwave ablation to evaluate residual tumor and recurrence of tumor by computed tomography or magnetic resonance imaging. The observation indices mainly included general data and imaging data of patients. Using the X-tile tools, patients were divided into two groups: a high aMAP score group and a low aMAP score group. Multivariate Cox regression analysis was conducted for comparison of independent risk factors. Results: Multivariate Cox regression showed that high aMAP score, maximum tumor diameter >20 mm, and high AFP were the independent risk factors of early recurrence (all P<0.05). Kaplan-Meier survival curves showed that the median recurrence-free survival was 25.5 months in the low aMAP score group and 6.1 months in the high aMAP score group (P=0.001). Conclusions: The aMAP score could predict the early recurrence within 1 year of small hepatocellular carcinoma after microwave ablation. Patients with high aMAP score should undergo rigorous postoperative follow-up evaluations..

308P Regression-based deep-learning predicts breast cancer recurrence risk score from pathology slides

308P Regression-based deep-learning predicts breast cancer recurrence risk score from pathology slides

Recurrence Risk Score Model for Evaluating the Impact of Postmastectomy Radiotherapy in Breast Cancer Patients with Pathologic Nodal Negative after Neoadjuvant Chemotherapy and Mastectomy

Recurrence risk score model was established to distinguish the recurrent risk of patients with pathologic nodal negative (ypN0) after neoadjuvant chemotherapy (NACT) and mastectomy and determine the impact of postmastectomy radiotherapy (PMRT). This multicenter retrospective study reviewed 766 patients who underwent mastectomy and NACT with ypN0 from 2000 to 2014. Recurrent risk score model was assigned proportionally to the relative contribution of independent prognostic factors in the multivariate Cox model of disease-free survival (DFS). Decision tree analysis was conducted to determine two optimal cutoff points for stratification. The median follow-up time was 74 months. The 5-year locoregional control (LRC), DFS, and overall survival (OS) rates for the entire group were 96.5%, 89.1% and 95.3%, respectively. 353 (46.1%) patients received PMRT and 413 (53.9%) patients did not. Patients with PMRT have more high-risk factors, including age <40 years, clinical stage III, grade III, or ER and PR negative. Chest wall and regional nodal region were irradiated in 307 (87.0%) and chest wall only in 46 (13.0%). The median radiation dose was 50 Gy (range: 36-60 Gy) in 25 fractions (range: 15-30 fractions). There were no significant differences between the PMRT and No-PMRT groups in the LRC, DFS and OS rates. Recurrent risk score model consisted of five factors and used a range of zero to eleven scoring points: age <40 years and clinical N1 stage for one point; clinical N2, NACT ≥4 cycles, lymphovascular invasion and ypT1-2 for two points; ypT3-4 for four points. 456 (59.5%) patients scoring zero to four points, 188 (24.5%) scoring five points and 122 (15.9%) scoring six to eleven points were assigned to the low-, intermediate-, and high-risk group. LRC, DFS and OS rates in three risk groups were significantly distinct from each other (5yr-LRC: 98.6% vs. 95.5% vs. 89.8%, p < .001; 5yr-DFS: 94.4% vs. 87.4% vs. 71.5%, p < .001; 5yr-OS: 97.6% vs. 93.2% vs. 90.0%, p < .001). PMRT had no impact on the LRC, DFS and OS rates in either low-, intermediate-, or high-risk group. The recurrence risk score model can effectively distinguish patients with different recurrent risk stratification. PMRT in patients with ypN0 after NAC and mastectomy cannot improve LRC, DFS or OS. Table 1. Survival outcomes and comparison between PMRT and No-PMRT arms in different groups.

21-gene expression assay and clinical outcomes of premenopausal patients with hormone receptor-positive breast cancer.

The prognostic role of the recurrence score (RS) based on the 21-gene expression assay in premenopausal women is not well delineated, and we investigated the association of outcomes and the RS in premenopausal patients who had 21-gene expression assay at Asan Medical Center, Seoul, Korea, between June 2005 and July 2018. Invasive breast cancer-free survival (IBCFS) by STEEP version 2.0 was compared according to the RS and clinical risk factors. A total of 554 patients were included in our study and 116 patients (20.9%) had age <40 years, 238 patients (43.0%) had luminal B subtype (Ki67 ≥ 20%), and 83 patients (15.0%) had RS >25. All patients received adjuvant tamoxifen ± chemotherapy. Overall, patients with RS >25 showed trend toward worse IBCFS from multivariable analysis (adjusted HR 1.89 [95% CI: 0.95-3.73], P = .069). When comparing outcomes according to age and luminal subtypes, patients with luminal B subtype and age <40 years (n = 60) showed significantly worse outcomes compared to the others (luminal A or luminal B + age ≥40 years, n = 494; adjusted HR 2.95 [95% CI: 1.49-5.82], log-rank P < .001). Among patients with luminal B subtype and age <40 years, there was no significant association observed between IBCFS and the RS (log-rank P = .51). In conclusion, while RS >25 showed association with poor outcomes in premenopausal women, it may have less prognostic significance among those with luminal B subtype and age <40 years.

The Prediction Analysis of Microarray 50 (PAM50) Gene Expression Classifier Utilized in Indeterminate-Risk Breast Cancer Patients in Hungary: A Consecutive 5-Year Experience.

Breast cancer has been categorized into molecular subtypes using immunohistochemical staining (IHC) and fluorescence in situ hybridization (FISH) since the early 2000s. However, recent research suggests that gene expression testing, specifically Prosigna® Prediction Analysis of Microarray 50 (PAM50), provides more accurate classification methods. In this retrospective study, we compared the results of IHC/FISH and PAM50 testing. We also examined the impact of various PAM50 parameters on overall survival (OS) and progression-free survival (PFS). We analyzed 42 unilateral breast cancer samples, with 18 classified as luminal A, 10 as luminal B, 8 as Human epidermal growth factor receptor 2 (HER2)-positive, and 6 as basal-like using PAM50. Interestingly, 17 out of the 42 samples (40.47%) showed discordant results between histopathological assessment and the PAM50 classifier. While routine IHC/FISH resulted in classification differences for a quarter to a third of samples within each subtype, all basal-like tumors were misclassified. Hormone receptor-positive tumors (hazard rate: 8.7803; p = 0.0085) and patients who had higher 10-year recurrence risk scores (hazard rate: 1.0539; p = 0.0201) had shorter OS and PFS. Our study supports the existing understanding of molecular subtypes in breast cancer and emphasizes the overlap between clinical characteristics and molecular subtyping. These findings underscore the value of gene expression profiling, such as PAM50, in improving treatment decisions for breast cancer patients.

Molecular features of androgen-receptor low, estrogen receptor-negative breast cancers in the Carolina breast cancer study

PurposeAndrogen receptor (AR) expression is absent in 40–90% of estrogen receptor (ER)-negative breast cancers. The prognostic value of AR in ER-negative patients and therapeutic targets for patients absent in AR remains poorly explored.MethodsWe used an RNA-based multigene classifier to identify AR-low and AR-high ER-negative participants in the Carolina Breast Cancer Study (CBCS; N = 669) and The Cancer Genome Atlas (TCGA; N = 237). We compared AR-defined subgroups by demographics, tumor characteristics, and established molecular signatures [PAM50 risk of recurrence (ROR), homologous recombination deficiency (HRD), and immune response].ResultsAR-low tumors were more prevalent among younger (RFD = + 10%, 95% CI = 4% to 16%) participants in CBCS and were associated with HER2 negativity (RFD = − 35%, 95% CI = − 44% to − 26%), higher grade (RFD = + 17%, 95% CI = 8% to 26%), and higher risk of recurrence scores (RFD = + 22%, 95% CI = 16.1% to 28%), with similar results in TCGA. The AR-low subgroup was strongly associated with HRD in CBCS (RFD = + 33.3%, 95% CI = 23.8% to 43.2%) and TCGA (RFD = + 41.5%, 95% CI = 34.0% to 48.6%). In CBCS, AR-low tumors had high adaptive immune marker expression.ConclusionMultigene, RNA-based low AR expression is associated with aggressive disease characteristics as well as DNA repair defects and immune phenotypes, suggesting plausible precision therapies for AR-low, ER-negative patients.

The Added Prognostic Value of Oncotype Recurrence Score to AJCC Prognostic Staging System in Stage III ER+/HER2- Breast Cancer.

Prognostic prediction based on prognostic stage (PS) with the Oncotype DX recurrence score (RS) has not been validated in stage III ER+/HER2- breast cancer. This study aimed to evaluate the added prognostic significance of RS incorporated with the PS system and to compare the prognostic prediction improvement with anatomic TNM stage (AS) using nomogram construction. The SEER database was indexed to identify ER+/HER2- invasive ductal or lobular breast cancer in AS IIIA-IIIC with RS results diagnosed from 2004 to 2013. Patients with RS < 18, 18-30 and > 30 were categorized into low-, intermediate- and high-risk RS groups. Comparisons of the distribution of clinical-pathologic characteristics among RS risk groups were performed using Pearson's chi-square test. Breast cancer-specific survival (BCSS) was estimated using the Kaplan-Meier method and compared across RS or PS by log-rank test. Cox regression was used to evaluate the factors independently related to BCSS. A nomogram comprised of PS and RS was constructed with discrimination, calibration and clinical benefit evaluated. Altogether 629 patients who received RS were enrolled. There were 326 cases (51.8%) with low-risk RS, 237 (37.7%) with intermediate-risk RS and 66 (10.5%) with high-risk RS; 344 patients (54.7%) had PS IB, 84 (13.4%) had IIB, 150 (23.8%) had IIIA, 46 (7.3%) had IIIB, and only 5 had (0.8%) IIIC. Both PS and RS were independent prognostic factors for BCSS. There were significant or trends of differences in survival among RS within subtypes stratified by PS. There were significant differences in survival among PS only within intermediate-risk RS. A nomogram prediction 5-year BCSS was constructed with a c-index of 0.811. Lower histologic grade, positive PR and fewer positive lymph nodes were independently correlated with low-risk RS. PS incorporated with RS had improved prognostic significance for stage III ER+/HER 2- breast cancer.

Clinical Significance of Recurrence Risk Score for Conversion Surgery in Patients With Advanced Gastric Cancer.

To develop a recurrence risk score for determining the clinical indication for adjuvant chemotherapy in patients with initially unresectable advanced gastric cancer who underwent conversion surgery after chemotherapy. A total of 65 patients with stage IV gastric cancer who underwent conversion surgery after chemotherapy were retrospectively enrolled. We established a risk score based on clinicopathological factors related to recurrence after conversion surgery. Out of 65 patients, 40 (62%) had recurrence after conversion surgery. The 5-year overall survival rates in patients with and without recurrence were 14.4% and 87.1%, respectively (p<0.01). Multivariate logistic regression analysis identified the depth of tumor invasion (pT2-4) and histological tumor response (grade 0-1a) as an independent risk factor for disease recurrence (p=0.033 and p=0.048, respectively). A scoring system determined by these two factors was created; total score ranged from 0 to 2 points, and patients were categorized into three groups (scores of 0 vs. 1 vs. 2 points). This scoring system showed that 12 (18%), 15 (23%), and 38 (58%) patients had recurrence risk scores of 0, 1, and 2 points, respectively. There was a close relationship between a high score and the presence of tumor recurrence (p<0.01). Moreover, our model system had a high sensitivity for the prediction of recurrence, compared with the pathological stage. Recurrence risk score is a promising tool for assessing the need for adjuvant chemotherapy in patients with initially unresectable advanced gastric cancer after conversion surgery.

PAM50 intrinsic subtypes, risk of recurrence score and breast cancer survival in HIV-positive and HIV-negative patients—a South African cohort study

PurposeTreatment decision making for patients with breast cancer increasingly depends on analysis of markers or systems for estimating risk of breast cancer recurrence. Breast cancer intrinsic subtypes and risk of recurrence (ROR) scores have been found to be valuable in predicting survival and determining optimal treatment for individual patients. We studied the association of breast cancer survival with the PAM50 gene expression assay in HIV-positive and HIV-negative patients.MethodRNA was extracted from formalin-fixed paraffin-embedded specimens of histologically confirmed invasive carcinoma and was purified using the AllPrep® DNA/RNA FFPE kit, Qiagen (Hilden, Germany). The NanoString RUO PAM50 algorithm was used to determine the molecular subtype and the risk of recurrence score of each sample. The overall and disease-free survival were determined with comparison made among HIV-positive and -negative patients. We then generated Kaplan–Meier survival curves, calculated p-values and estimated hazard ratios and their 95% confidence intervals using Cox regression models.ResultsOf the 384 RNA samples analysed, 98.4% met the required RNA quality standard and the specified QC threshold for the test. Luminal B was the most common PAM50 intrinsic subtype and 82.1% of patients were at high risk for disease recurrence based on ROR score. HIV infection, PAM50-based HER2-enriched and basal-like intrinsic subtypes, and high ROR were associated with poor overall and disease-free survival. HIV-positive patients with luminal A & B subtypes had significantly worse survival outcomes than HIV-negative luminal patents.ConclusionAggressive tumour biology was common in our cohort. HIV infection, PAM50 HER2-enriched,basal-like intrinsic subtypes and high ROR score were associated with poor overall and disease-free survival. HIV infection impacted survival in patients with luminal subtypes only.

Evaluation of PAM50 intrinsic subtypes and risk of recurrence (ROR) scores in premenopausal women with early-stage HR+ breast cancer: A secondary analysis of the SOFT trial.

504 Background: The landmark Suppression of Ovarian Function Trial (SOFT) in premenopausal breast cancer patients revealed that the addition of ovarian function suppression (OFS) to adjuvant endocrine therapy with either tamoxifen (T+OFS) or exemestane (E+OFS) reduces the risk of recurrence compared with adjuvant tamoxifen alone. There are no biomarkers to aid decision-making about intensification of endocrine therapy with OFS. The purpose of this study is to assess the prognostic and predictive ability of PAM50 intrinsic subtypes and ROR scores in premenopausal women with HR+/HER2- breast cancer in the SOFT trial. Methods: Gene expression analyses were performed via the NanoString Breast Cancer 360 assay on RNA isolated from FFPE tumor samples from the SOFT trial that were HR+/HER2- (n=1245/3047). PAM50 subtype and ROR score were determined centrally by NanoString Technologies (Seattle, WA, USA), blinded to clinical characteristics, treatment and outcome. Median follow-up was 12 years. Primary endpoint in this study was distant recurrence-free interval (DRFI). Secondary endpoints were breast cancer-free interval (BCFI) and disease-free survival (DFS). Kaplan-Meier analysis and Cox proportional hazards regression models, stratified by prior chemotherapy and lymph node status, were used to evaluate the predictive performance of PAM50 intrinsic subtypes and ROR categories (low vs intermediate vs high), and secondarily ROR score as a continuous variable. We also investigated differences between very young (&lt;40yrs) vs young (&gt;40yrs) women. Results: Tumor samples from 1084/1245 (87%) patients successfully completed PAM50 testing and are included in this analysis. Patient characteristics in this cohort were similar to the entire SOFT trial population. Intrinsic subtype and ROR category distribution is described below. Subtype distribution significantly differed between very young vs young premenopausal women, with fewer luminal A and more luminal B and non-luminal tumors seen in the very young (p&lt;0.001). The ROR score distribution also differed significantly: in node-negative patients there were significantly more ROR-high scores amongst very young compared to young women (36% vs 14%, p&lt;0.001). Conclusion: Breast cancer diagnosed in very young women has aggressive disease biology. Prognostic and predictive analyses of both intrinsic subtypes and the ROR score are ongoing and will be presented at the meeting. Clinical trial information: NCT00066690 . [Table: see text]

Assessment of risk of overall and late distant recurrence by Breast Cancer Index in postmenopausal women with early-stage, HR+ breast cancer in the TEAM trial.

509 Background: Individual risk assessment of distant recurrence (DR) is particularly relevant for early-stage HR+ breast cancer patients, as they face a prolonged risk of recurrence even after adjuvant endocrine therapy. Previously, we have shown that the Breast Cancer Index (BCI) and BCIN+ risk groups are significantly prognostic for risk of overall (0-10y) and late (5-10y) distant recurrence in N0 and N1 breast cancer patients, respectively, enrolled in the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial. Here, the prognostic performance of BCI and BCIN+ as a continuous risk score for overall and late distant recurrence was evaluated in the TEAM trial. Methods: BCI testing was performed blinded to clinical outcome with BCI/BCIN+ risk scores calculated as previously described. Cox proportional hazard models adjusted for age, tumor size, grade and treatments were used to estimate hazard ratios (HRs) and the associated 95% confidence intervals (CIs) for BCI/ BCIN+ continuous risk scores. The 10y risk of overall and late DR were estimated as a function of risk scores from the Cox models using Breslow estimates. Results: Continuous risk curves for overall and late DR were obtained in patients who did not receive adjuvant chemotherapy and those who remained DR-free at 5 years regardless of chemotherapy, respectively, to reflect the two key time points for breast cancer treatment decision-making. InN0 patients not treated with chemotherapy (N = 1197), BCI was significantly prognostic for overall DR with a HR of 1.39 (95% CI 1.25-1.54; p &lt; 0.001), while BCIN+ was significantly prognostic in N1 patients who did not receive chemotherapy (N = 1319) with a HR of 4.29 (95% CI 2.93-6.28; p &lt; 0.001). Among patients who remained DR-free at 5 years, in the N0 subset (N = 1285), BCI was significantly prognostic for late DR with a HR of 1.23 (95% CI 1.07-1.42; p &lt; 0.001), while BCIN+ remained to be significantly prognostic in the N1 subset (N = 1762) with a HR of 2.78 (95% CI 1.75-4.43; p &lt; 0.001). Similar results were observed in the HER2- subset for both overall and late DR. Continuous risk curves for BCI and BCIN+ for overall and late DR showed an increasing risk of DR with higher BCI/BCIN+ scores. Conclusions: Results from this largest BCI study to date further support the use of BCI to provide individualized risk estimates for both overall and late DR in women with HR+ breast cancer to aid in personalized decision-making for adjuvant therapy. [Table: see text]

Clinical and analytical validation of a targeted gene expression biomarker predicting meningioma outcomes and radiotherapy responses.

2009 Background: Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and current indications for postoperative radiotherapy are controversial. Here we report multicenter clinical and analytical validation of a gene expression biomarker using 1856 retrospective and prospective meningiomas from 12 institutions across 3 continents. Our results reveal the gene expression biomarker provides additional information for meningioma outcomes compared to other classification systems, including prediction of radiotherapy responses. Methods: Gene expression profiling and regularized Cox regression was performed on a discovery cohort of 173 meningiomas to generate a 34-gene expression biomarker and continuous risk score for local recurrence. The model and thresholds for low, intermediate, and high-risk scores were locked and applied to 3 validation cohorts: a multicenter retrospective clinical validation cohort (N = 6 centers, N = 866 meningiomas, median follow-up 5.2 years), a prospective investigator-blinded clinical validation cohort from RTOG 0539 (N = 103 meningiomas, median follow-up 8.4 years), and an analytical validation set for test/re-test and FFPE/frozen analyses, as well as comparison across different platforms for gene expression quantification (N = 8 centers, N = 1219 meningiomas). Gene expression biomarker performance was compared to 9 contemporary molecular classification systems. Favorable versus unfavorable meningiomas were defined as gene expression low risk with any resection, or gene expression intermediate risk with gross-total resection (favorable), versus gene expression intermediate risk with subtotal resection, or gene expression high risk with any resection (unfavorable). Results: The biomarker outperformed WHO grade (5-year local freedom from recurrence [LFFR] delta-AUC 0.11, 95% CI 0.07-0.17, p &lt; 0.001) and all other classification systems for LFFR and OS on multivariate analysis, achieving a negative predictive value for recurrence at 5-years of 91.9%. The biomarker was predictive for LFFR after postoperative radiotherapy, with a hazard ratio of 0.33 for unfavorable primary WHO grade 2 meningiomas (95% CI 0.14-0.76, P = 0.009), and 0.54 for unfavorable propensity-matched meningiomas across all WHO grades (95% CI 0.37-0.78, p = 0.0001). The biomarker reclassified 39.8% of prospectively collected meningiomas from RTOG 0539, including downstaging 30.5% of patients who received postoperative radiotherapy, and was independently prognostic for overall survival on multivariate analysis. Conclusions: A targeted gene expression biomarker improves discrimination of meningioma outcomes compared to recent classification systems and predicts postoperative radiotherapy responses.

Racial/ethnic differences in 21-gene recurrence score and survival among estrogen receptor-positive breast cancer patients.

511 Background: Despite studies on racial/ethnic disparities in breast cancer patients, there is limited literature evaluating association of racial/ethnic differences with 21-gene recurrence score (RS) and survival differences stratified by RS risk categories. We performed an observational cohort study to evaluate such disparities in context of RS. Methods: The National Cancer Database (NCDB) was queried for patients with ER-positive, pT1-3N0-1aM0 breast cancer who received surgery followed by adjuvant endocrine therapy with available RS from 2006 to 2018. Racial/ethnic groups were stratified by non-Hispanic White (NHW), Hispanic White (HW), Black, and Asian/Pacific Islander (API). Our primary endpoint was overall survival (OS). Logistic multivariable analysis (MVA) was built upon baseline patient and tumor characteristics to evaluate variables associated with RS &gt; 25. Cox MVA was used to evaluate OS. Interaction term analysis was used to identify heterogeneous association of racial/ethnic groups and RS; if significant, subgroup analyses compared magnitude of racial/ethnic differences stratified by RS. To address immortal time bias, Cox MVA analyses were repeated after excluding patients with post-diagnosis survival &lt; 6 months. P values were two-sided. Bonferroni correction was used for multiple comparisons (NHW vs HW women, NHW vs Black women, and NHW vs API women) with p values less than 0.017 being statistically significant. Results: A total of 140,133 women (median [interquartile range (IQR)] age, 60 [52-67] years) were included for analysis. 115,651 (82.5%), 8,213 (5.9%), 10,814 (7.7%), and 5,455 (3.9%) were NHW, Hispanic, Black, and API women respectively. Median (IQR) follow up was 66.2 mo. (48.0-89.8). Logistic MVA showed compared to NHW women, Black women were associated with higher RS (26 or higher vs &lt; 26: adjusted odds ratio [aOR] 1.19, 95% confidence interval [CI] 1.12-1.26, p &lt; 0.001), while HW (aOR 0.93, 95% CI 0.86-1.00, p = 0.04) and API (aOR 1.03, 95% CI 0.95-1.13, p = 0.45) were not. Cox MVA showed compared to NHW, Black women were associated with worse OS (adjusted hazards ratio [aHR] 1.10, 95% CI 1.02-1.19, p = 0.012) while HW (aHR 0.85, 95% CI 0.77-0.94, p = 0.001) and API (aHR 0.66, 95% CI 0.56-0.77, p &lt; 0.001) were not. There was significant interaction between race/ethnicity and RS (interaction p = 0.006). Subgroup analysis found similarities in those with RS &lt; 26, while only API women were associated with improved OS among those with RS ≥ 26. After excluding those with post-diagnosis survival &lt; 6 mo., our findings remained comparable. Conclusions: To our knowledge, this is the largest nationwide oncology database study to suggest that Black women are associated with higher RS, while HW and API are not. It also suggests that Black women are associated with worse OS among those with RS &lt; 26, while API are associated with improved OS regardless of RS compared to NHW women.

Correlation between Magee score and recurrence score in Indian patients with breast cancer.

e12555 Background: Recurrence score (RS) from Oncotype Dx (ODx) test predict chemotherapy benefit in estrogen receptor (ER) positive, and HER2-negative patients with breast cancer. ODx is an expensive test in an Indian practice setting - cost of adjuvant chemotherapy is one-sixth of the cost of the test. Magee equations use histopathological variables, and semiquantitative results from ER, PR and Ki-67, to calculate Magee score (MS) and provide a cost-effective surrogate mechanism for predicting RS. We aimed to assess the correlation between MS and RS in an Indian setting. Methods: Pathology reports were obtained from oncologists in India. Immunohistochemistry for ER and PR were reported using the Allred system. Therefore, two methods were identified to estimate H-scores - using a calculated method (A), and using an expert-approximated (B) method. MS were calculated by a single investigator blinded to the RS. MS and RS were then assessed for correlation via the Pearson correlation method. MS were arbitrarily stratified into ≤ 15, 15 - 30, and ≥ 30, and their overall agreement (OA) or concordance with RS risk categories, ≤ 15, 15 - 30, and ≥ 30, were assessed. The OA was assessed by determining the proportion of patients in similar risk categories across low, intermediate and high-risk RS and MS. Results: Among 34 patients included in the study, 38% (13) had an RS ≤ 15, 38% (13) had an RS between 15 and 30, and 23% (8) had an RS ≥ 30. Correlation coefficient between MS and RS was 0.78 for both methods of estimation (p&lt;0.0001). The OA between MS-A and RS, and MS-B and RS were 59% (20/34) and 47% (16/34) respectively. The concordance between low-risk MS-A and RS is 78% (n=9) and between low-risk MS-B and RS is 50% (n=20). The concordance between high-risk MS-A and RS is 100% (n=2) and high-risk MS-B and RS is 100% (n=2). Conclusions: Although there is good correlation between RS and MS, the concordance between the two in similar risk categories is not optimal. Of the two methods to estimate H-score from Allred score, the calculated method seems to be more optimal. Our pilot study shows good correlation between MS and RS. We recommend that pathologists incorporate H-score as part of the reporting of ER and PR. A larger prospective study will be useful to test our hypothesis for the use of MS as a predictive tool for adjuvant chemotherapy in breast cancer.

Analytical validation of the 7-gene biosignature for prediction of recurrence risk and radiation therapy benefit for breast ductal carcinoma in situ.

Ductal carcinoma in situ (DCIS), is a noninvasive breast cancer, representing 20-25% of breast cancer diagnoses in the USA. Current treatment options for DCIS include mastectomy or breast-conserving surgery (BCS) with or without radiation therapy (RT), but optimal risk-adjusted treatment selection remains a challenge. Findings from past and recent clinical trials have failed to identify a 'low risk' group of patients who do not benefit significantly from RT after BCS. To address this unmet need, a DCIS biosignature, DCISionRT (PreludeDx, Laguna Hills, CA), was developed and validated in multiple cohorts. DCISionRT is a molecular assay with an algorithm reporting a recurrence risk score for patients diagnosed with DCIS intended to guide DCIS treatment. In this study, we present results from analytical validity, performance assessment, and clinical performance validation and clinical utility for the DCISionRT test comprised of multianalyte assays with algorithmic analysis. The analytical validation of each molecular assay was performed based on the Clinical and Laboratory Standards Institute (CLSI) guidelines Quality Assurance for Design Control and Implementation of Immunohistochemistry Assays and the College of American Pathologists/American Society of Clinical Oncology (CAP/ASCO) recommendations for analytic validation of immunohistochemical assays. The analytic validation showed that the molecular assays that are part of DCISionRT test have high sensitivity, specificity, and accuracy/reproducibility (≥95%). The analytic precision of the molecular assays under controlled non-standard conditions had a total standard deviation of 6.6 (100-point scale), where the analytic variables (Lot, Machine, Run) each contributed <1% of the total variance. Additionally, the precision in the DCISionRT test result (DS) had a 95%CI ≤0.4 DS units under controlled non-standard conditions (Day, Lot, and Machine) for molecular assays over a wide range of clinicopathologic factor values. Clinical validation showed that the test identified 37% of patients in a low-risk group with a 10-year invasive IBR rate of ~3% and an absolute risk reduction (ARR) from RT of 1% (number needed to treat, NNT=100), while remaining patients with higher DS scores (elevated-risk) had an ARR for RT of 9% (NNT=11) and 96% clinical sensitivity for RT benefit. The analytical performance of the PreludeDx DCISionRT molecular assays was high in representative formalin-fixed, paraffin-embedded breast tumor specimens. The DCISionRT test has been analytically validated and has been clinically validated in multiple peer-reviewed published studies.

Development and testing of a polygenic risk score for breast cancer aggressiveness

Aggressive breast cancers portend a poor prognosis, but current polygenic risk scores (PRSs) for breast cancer do not reliably predict aggressive cancers. Aggressiveness can be effectively recapitulated using tumor gene expression profiling. Thus, we sought to develop a PRS for the risk of recurrence score weighted on proliferation (ROR-P), an established prognostic signature. Using 2363 breast cancers with tumor gene expression data and single nucleotide polymorphism (SNP) genotypes, we examined the associations between ROR-P and known breast cancer susceptibility SNPs using linear regression models. We constructed PRSs based on varying p-value thresholds and selected the optimal PRS based on model r2 in 5-fold cross-validation. We then used Cox proportional hazards regression to test the ROR-P PRS’s association with breast cancer-specific survival in two independent cohorts totaling 10,196 breast cancers and 785 events. In meta-analysis of these cohorts, higher ROR-P PRS was associated with worse survival, HR per SD = 1.13 (95% CI 1.06–1.21, p = 4.0 × 10–4). The ROR-P PRS had a similar magnitude of effect on survival as a comparator PRS for estrogen receptor (ER)-negative versus positive cancer risk (PRSER-/ER+). Furthermore, its effect was minimally attenuated when adjusted for PRSER-/ER+, suggesting that the ROR-P PRS provides additional prognostic information beyond ER status. In summary, we used integrated analysis of germline SNP and tumor gene expression data to construct a PRS associated with aggressive tumor biology and worse survival. These findings could potentially enhance risk stratification for breast cancer screening and prevention.

Abstract 1412: Co-existence of TP53 mutation confers endocrine resistance in PIK3CA-mutated ER+HER2- breast cancer

Abstract Background: PIK3CA mutation is commonly found in estrogen receptor (ER)+ human epidermal growth factor receptor-2 (HER2)- breast cancer (BC) and can be therapeutically targeted by alpelisib, an alpha-specific PIK3CA inhibitor. While previous studies presented conflicting results on the prognostic influence of PIK3CA mutation among ER+HER2- breast cancer, few have been able to address causes of the prognostic discrepancy on a clinical level. In this study, we investigated clinical and genomic features according to a coexistence of TP53 mutation in PIK3CA mutated ER+HER2- breast cancer. Methods: Tumor tissue based next generation sequencing (NGS) was analyzed for 224 HR+ HER2- BC patients from April 2017 to August 2021 in Gangnam Severance Hospital, Seoul, South Korea. Matching clinical records with patient information were reviewed retrospectively. Clinicopathologic features including age, tumor size, histologic grade (HG), TNM stage, estrogen receptor (ER) expression, progesterone (PgR) expression, Ki-67, and Oncotype Dx Recurrence Score (RS) were analyzed. Further analysis was carried out using The Cancer Genome Atlas (TCGA) to explore the relationship of mutation status with intrinsic subtype and risk of recurrence (ROR) score. Results: We identified PIK3CA mutation (PIK3CA m) in 105 (46.9%) of 224 patients, and of these, TP53 co-mutation was found in 25 (23.8%). None of clinicopathologic features were different according to PIK3CA mutation. When PIK3CA m cohort was analyzed according to TP53 mutation (TP53 m) status, tumors with TP53 m presented unfavorable features such as higher HG (p&amp;lt;0.001), lower PgR expression (TP53 wt: Median 7 versus TP53 m: Median 5, p=0.027), and higher N stage (p=0.008). It also displayed a significantly higher proliferative profiles with Ki-67 (TP53 wt: Median 15 versus TP53 m: Median 20, p&amp;lt;0.001) and Oncotype Dx RS (TP53 wt: Median 15 versus TP53 m: Median 26.5, p=0.002). In the 539 ER+HER2- breast cancer from the TCGA database, PIK3CA and TP53 co-mutation was found in 33 (6.1%). Distribution of intrinsic subtypes revealed a higher rate of Luminal B in PIK3CA and TP53 co-mutant tumors (51.5%) than in PIK3CA m and TP53 wt tumors (14.3%, p&amp;lt;0.001). The ROR score was found to be higher in the PIK3CA-TP53 co-mutation compared to PIK3CA m alone (p&amp;lt;0.001). Conclusion: Unlike PIK3CA mutation, PIK3CA and TP53 co-mutation clearly divided multiple clinicopathologic features of HR+ HER2- BC including with. Poorer prognosis of co-mutation was also corroborated by TCGA analysis of intrinsic subtype and ROR score. These findings indirectly suggest that co-mutation of TP53 gene may be associated with less sensitivity to PIK3CA targeted therapy in PIK3CA m ER+HER2- breast cancers. Further research is warranted to improve an efficacy of PIK3CA targeted therapy for PIK3CA m ER+ breast cancer with endocrine-resistant factors. Citation Format: Yoonwon Kook, Kyungsoo Kim, Ji Soo Jang, Seung Ho Baek, Soong June BAe, Joon Jeong, Sung Gwe Ahn. Co-existence of TP53 mutation confers endocrine resistance in PIK3CA-mutated ER+HER2- breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1412.