DX Recurrence Score Research Articles

Nottingham prognostic x (NPx): a risk stratification tool in ER-positive HER2-negative breast cancer: a validation study.

In this study, we validate the use of Nottingham Prognostic x (NPx), consisting of tumour size, tumour grade, progesterone receptor (PR) and Ki67 in luminal BC. Two large cohorts of luminal early-stage BC (n = 2864) were included. PR and Ki67 expression were assessed using full-face resection samples using immunohistochemistry. NPx was calculated and correlated with clinical variables and outcome, together with Oncotype DX recurrence score (RS), that is frequently used as a risk stratifier in luminal BC. In the whole cohort, 38% of patients were classified as high risk using NPx which showed significant association with parameters characteristics of aggressive tumour behaviour and shorter survival (P < 0.0001). NPx classified the moderate Nottingham Prognostic Index (NPI) risk group (n = 1812) into two distinct prognostic subgroups. Of the 82% low-risk group, only 3.8% developed events. Contrasting this, 14% of the high-risk patients developed events during follow-up. A strong association was observed between NPx and Oncotype Dx RS (P < 0.0001), where 66% of patients with intermediate risk RS who had subsequent distant metastases also had a high-risk NPx. NPx is a reliable prognostic index in patients with luminal early-stage BC, and in selected patients may be used to guide adjuvant chemotherapy recommendations.

Abstract PS16-10: SPATIAL IMMUNE CELL DISTRIBUTION CAN REFINE PROGNOSIS IN EARLY-STAGE ER+/HER2-/LN- BREAST CANCER

Abstract Lymphocytic infiltrate is a known prognostic biomarker in estrogen receptor(ER)-negative breast cancers (BCs). Comparatively ER+ disease is putatively cold, however, there exists an infiltrate-rich subset of ER+ tumours with significant spatial heterogeneity and unknown clinical impact. Using serial sections taken from early-stage, ER+/HER2- breast tumours of Irish patients enrolled in the TAILORx trial (n=450), we aimed to investigate the prognostic potential of markers encompassing tumour architecture. Immunohistochemistry for Ki67 and CD45 (leukocyte common-antigen), and staining for haematoxylin and eosin was applied to all sections [1]. Classifiers for stromal fraction (SF), stromal-infiltrate (sTIL), Ki67-LI, and their spatial relationships within the tumour were generated using QuPath [2] and R Studio. Trained marker classifiers were validated against an expert pathologist (R2 of M-Score to: CD45%: 0.968, Ki67-LI: 0.814, sTIL: 0.864) to define observed lymphocytes as tumour or stromal-infiltrating, retain only tumour Ki67+ density, and to investigate SF. Cohort mean SF was 67.69% (range 16.35 – 98.29%), with marginally significant differences in recurrence prediction for cohort high v low SF by mean (c-index = 0.58, p&amp;lt; 0.032), and luminal A disease (p=0.037) only. sTILs did not differ significantly between high/low mean SF (Mann-Whitney p=0.6201), though sTIL was prognostic in the OncotypeDx intermediate Recurrence Score (RS) category overall (p=0.0076). This trend appeared strongest in intermediate RS patients receiving chemo-endocrine therapy (HT+CT) (p &amp;lt; 0.0001) vs endocrine therapy (HT) alone (p=0.86). Investigating the effects of prescribed therapy on sTIL-derived recurrence risk also revealed significant trends in those patients receiving HT+CT only (p &amp;lt; 0.00001) vs HT alone (p=0.26). Spatial analysis of sTILs suggest that tumours become more immune excluded as Oncotype Dx RS increases - particularly from intermediate to high RS (Wilcoxon Intermediate v High: p=0.0077), with significant differences in survival for high/low tumour-immune hotspots observed in Intermediate RS, HT+CT treated patients (p=0.0052). Further spatial analysis suggests that high normalised frequency of infiltrate [method adapted from 3] (within 7um of tumour cells) have negative prognostic impact for premenopausal patients (p=0.017), and inter-sectional analysis identifies niche tumour environments where high Ki67-LI colocalize with immune infiltrates[methods adapted from 4, 5], most notable in Intermediate RS tumours.. Overall these data suggest immune-spatial subsets can be used to refine risk stratification of ER+ breast cancer.

Abstract PO2-09-03: Twenty-one gene recurrence scores in individuals with breast cancer associated with PALB2 germline pathogenic variants

Abstract Background: The 21-gene recurrence score assay (Oncotype DX, Genomic Health Inc., CA) is prognostic, quantifies predicted benefit of adjuvant chemotherapy, and informs clinical decisions for patients with early-stage, hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer (BC). Differences in Oncotype recurrence scores (RS) in individuals with and without BRCA1 and BRCA2 (BRCA1/2) pathogenic variants (PV) have been demonstrated, but the results of this assay in patients with BC and germline PALB2 PV have not previously been described. This is of particular relevance as PALB2 BC has demonstrated biologic features similar to BRCA1/2 BC such as poly(adenosine diphosphate ribose) polymerase inhibitor (PARPi) sensitivity. Methods: Patients with early-stage, HR+, HER2-, invasive breast cancer and a germline PALB2 PV were ascertained from academic cancer center databases and the Prospective Registry of MultiPlex Testing (PROMPT), an online research registry for individuals who have had multigene panel testing for inherited cancer susceptibility. Study participants (pts) were categorized by age &amp;lt; 50 and ≥50. Oncotype DX RS were retrospectively reviewed and categorized as those that would and would not warrant consideration of chemotherapy (≥16 and &amp;lt; 16, respectively, for pts &amp;lt; 50; ≥26 and &amp;lt; 26, respectively, for pts ≥50). Yates corrected Chi-square tests were used to compare RS distributions between carriers and a previously published genetically unselected reference population. Results: Oncotype DX reports were reviewed for 20 pts with BC and germline PALB2 PV. Median RS was 19 (range 6-41) overall. Four patients were diagnosed under the age of 50 (range 33-48); median RS for these individuals was 19 (range 12-41). Sixteen patients were diagnosed at age 50 or greater (median 59, range 50-70); median RS for these individuals was also 19 (range 6-31). Compared to the genetically unselected reference population, Oncotype DX RS in pts with PALB2-associated BC demonstrated a numerical but not statistically significant shift in distribution towards categories in which chemotherapy would be considered. Among pts under the age of 50, 75% had Oncotype DX RS for which chemotherapy would be considered and 25% had Oncotype DX RS for which endocrine therapy alone would likely be recommended (p=0.726 compared to reference). Among pts aged 50 and older, 25% had Oncotype DX RS for which chemotherapy would be considered and 75% had Oncotype DX RS for which endocrine therapy alone would likely be recommended (p=0.579 compared to reference). Conclusions: Compared to data from the published genetically unselected commercial database, BC associated with PALB2 PV may have higher Oncotype DX RS reflective of intrinsically less favorable biology and greater therapeutic sensitivity. Larger datasets are forthcoming to confirm presence of significant differences in Oncotype DX RS distributions between BC with and without PALB2 PV. Table 1. Oncotype DX RS distribution by age among pts with gPALB2 PV and genetically unselected reference *Jakubowski et al., J Surg Oncol 2020. PMID 3249731 Citation Format: Payal Shah, Siddhartha Yadav, Jamie Brower, Jada Hamilton, Erica Simmons, Judy Garber, Kenneth Offit, Mark Robson, Fergus Couch, Susan Domchek. Twenty-one gene recurrence scores in individuals with breast cancer associated with PALB2 germline pathogenic variants [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-09-03.

Abstract PO4-07-06: Development of MRI-based Radiomics Nomogram for the Prediction of Recurrence in Patients with Luminal-type Breast Cancer: A Nested Case-Control Study

Abstract Purpose: The aim of this study was to develop a radiomics nomogram using breast MRI data and preoperative pathologic information to predict oncotype DX recurrence score (RS) in patients with estrogen receptor-positive early-stage breast cancer (EBC). Materials and methods: In this retrospective study, a total of 493 patients with EBC, diagnosed through core needle biopsy and who underwent preoperative breast MRI at a single institution between 2011 and 2017, were included. The patients were categorized based on RS, age at surgery, and nodal status, as suggested by the TAILORX trial, and out of the included patients, 249 were identified as likely to benefit from chemotherapy, while 244 were deemed safe to forgo chemotherapy. Radiomic features were extracted from three-dimensional segmentations of each tumor, and computer-extracted image phenotypes (CEIP) were generated from early post-contrast T1-weighted images, percent enhancement (PE) maps, and signal enhancement ratio (SER) maps. The patient cohort was divided into a training set (n=329) and a validation set (n=164). Feature selection and radiomics score construction were performed using elastic net, and a prediction model was developed using multivariate logistic regression analysis. The radiomics score, along with independent pathologic risk factors, was incorporated into a radiomics nomogram. Internal validation was conducted using an independent validation set (n=164). Results: The radiomics score, composed of 24 selected CEIPs, demonstrated a significant association with recurrence prediction (C-index, 0.769 for training set and 0.745 for validation set). The independent pathologic predictors included in the nomogram were histology, estrogen receptor status, progesterone receptor status, nuclear grade, histologic grade, HER1, CK56, P53, and Ki67 status, with a C-index of 0.858 for the training set and 0.774 for the validation set. Adding the radiomics score to the pathologic nomogram resulted in incremental values of 0.054 and 0.092, respectively. The radiomics nomogram showed favorable prediction of low-risk RS, with a C-index of 0.912 for the training set and 0.866 for the validation set. Conclusion: This study demonstrated that an MRI-based radiomics nomogram incorporating the radiomics score and preoperatively obtained pathologic data can effectively predict oncotype DX RS and the benefit of adjuvant chemotherapy in EBC patients. The model improves risk assessment availability and timeliness for patients with EBC. Citation Format: Minji Song, Hee Jung Shin. Development of MRI-based Radiomics Nomogram for the Prediction of Recurrence in Patients with Luminal-type Breast Cancer: A Nested Case-Control Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-07-06.

Molecular Characterization of HER2-Low Invasive Breast Carcinoma by Quantitative RT-PCR Using Oncotype DX Assay.

HER2 immunohistochemistry (IHC) reproducibility is suboptimal for HER-low cases (IHC 1+ or 2+). The Yale cohort included 214 stages I-II estrogen receptor positive breast cancers with IHC scores 0, 1+, and 2+ and routine Oncotype DX Recurrence Score (RS) results. The Exact Sciences (ES) cohort included 9 57 624 patients who had an Oncotype DX RS assay that assigns HER2-negative, equivocal, or positive status based on HER2 mRNA levels. HER2 mRNA levels varied across IHC categories but with increasing medians of 9.10 (n = 89), 9.20 (n = 71), and 9.45 (n = 54) in IHC 0, 1+, and 2+, respectively. 22.4% of HER2-low (1+/2+) cancer had RS > 25. Over 98% of HER-low cancers were HER2-negative by Oncotype DX assignment. Cancers with higher mRNA levels exist within IHC 0 and low categories, most of the HER2-low patients by IHC have low RS indicating no benefit from current adjuvant chemotherapies.

Differential distribution of actual and surrogate oncotype DX recurrence scores in breast cancer patients by age, menopausal status, race, and body mass index.

The Oncotype DX Recurrence Score (RS) is a widely used prognostic tool for estrogen receptor-positive breast cancer patients. Multiple surrogate models can predict RS with good accuracy. In this study we aimed to determine whether the RS and two surrogate indices were differentially distributed by age, menopausal status, race, and body mass index (BMI). 516 breast cancer cases treated at a single institution were analyzed. Epidemiologic data, RS, tumor size, grade, and biomarker data were abstracted. Breast Cancer Prognostic Score (BCPS) and modified Magee equation2 were used to calculate surrogate RS. Patients were stratified into different groups based on age, menopausal status, race, BMI, or a combination of strata. Mean and standard deviation were calculated for each group/subgroup. Age below median (< 63) was associated with higher RS, especially in obese and Black patients. RS was also higher in obese and Black patients in the premenopausal subgroup. Black patients had a higher RS compared to White women in the premenopausal and non-obese subgroups. BMI < 30 was associated with higher RS, especially in older, postmenopausal, and Black patients. Some of these observations were replicated by the two surrogate models. The surrogate recurrence scores were higher in the younger age group, in non-obese older/postmenopausal women, and in younger/premenopausal obese individuals. Higher RS was observed in younger and premenopausal breast cancer patients, especially among the Black and obese subgroups, and in non-obese patients, especially among Black and older/postmenopausal women, suggesting more aggressive disease in these subgroups. Some statistical differences could be replicated by both surrogate models, suggesting that they may have utility in breast cancer epidemiology studies that do not have access to Oncotype DX RS or patient outcome data.

Twenty-one gene recurrence scores in individuals with breast cancer associated with CHEK2 and ATM germline pathogenic variants.

10585 Background: The 21-gene recurrence score assay (Oncotype DX, Genomic Health Inc., CA) is prognostic, quantifies predicted benefit of adjuvant chemotherapy, and informs clinical decisions for patients with early-stage, hormone receptor-positive (HR+) breast cancer (BC). Differences in Oncotype recurrence scores (RS) in individuals with and without BRCA1 and BRCA2 pathogenic variants (PV) have been demonstrated, but the results of this assay in patients with BC and germline CHEK2 or ATM PV have not previously been described. This is of particular relevance as CHEK2 BC have been associated with a worse prognosis. Methods: Prospective Registry of MultiPlex Testing (PROMPT) is an online research registry for individuals who have had multigene panel testing for inherited cancer susceptibility. We retrospectively evaluated Oncotype DX recurrence scores from PROMPT participants (pts) with PV or likely PV in CHEK2 or ATM. Mood’s median tests were used to compare median RS, and Yates corrected Chi-square tests were used to compare RS distributions between carriers and a genetically unselected reference population. Results: Oncotype DX reports were reviewed for 75 pts with 77 BC (n = 50 pts with CHEK2 PV with 51 BC; n = 24 with ATM PV; n = 1 with CHEK2 and ATM PV with 2 BC). Among CHEK2 carriers, median RS was 17 (range 2-43) overall, 17 (2-36) for pts &lt; age 50, and 18.5 (8-43) for pts ≥age 50 (p-value 0.47), with distributions not significantly different than reference ( &lt; 50, p = 0.70; ≥50, p = 0.93). Ten pts had low penetrance CHEK2 alleles (p.S428F or p.I157T) with median RS 16 (9-28) compared to 18 (2-43) in those with other CHEK2 alleles (p = 0.35). Among ATM carriers, median RS was 17 (1-35) overall, 17 (1-35) for pts &lt; age 50, and 16 (11-32) for pts ≥age 50 (p = 0.51), with distributions also not significantly different ( &lt; 50, p = 0.78; ≥50, p = 0.79). Conclusions: Unlike data seen in BC associated with BRCA1 and BRCA2, Oncotype DX RS in individuals with CHEK2 and ATM-associated BC are similar to the published genetically unselected commercial database median RS of 16, with no clear difference based on penetrance of CHEK2 allele. Proportions of patients &lt; 50 and ≥50 with CHEK2 and ATM PV with RS within the range for chemoendocrine therapy consideration are also similar to the historical reference. The inferior prognosis that has been suggested in CHEK2 BC is not reflected in Oncotype DX RS. [Table: see text]

Differences of prediction performances by multigene assays in patients with breast cancer with distinct genetic backgrounds.

526 Background: The 21-gene (Oncotype Dx), PAM50 (Prosigna) and Chinese-based 28-gene (RecurIndex) are validated genomic assays that provide prognostic information for distant recurrence risk in patients with hormone receptor (HR)-positive, HER2-negative early breast cancer (EBC). In this study, we aim to compare the differences in prediction performance by different multigene assays and gene expression profiles between the Eastern and the Western. Methods: Under the Affymetrix U133 platforms, the differences in gene expressions and risk scores from the Eastern population comprised of GSE20685 (n = 327) and part of GSE45255 (n = 95), and the Western population GSE25066 (n = 508) and the European in GSE45255(n = 44) were analyzed respectively. Patients were stratified by 21-gene Recurrence Scores (RS) of low (0-10), intermediate (11-25) and high (26-100) and categorized by ROR-S score of PAM50 of low (0-40), intermediate (41-60) and high (61-100). For 28-gene, a recurrence index for distant recurrence (RI-DR) cutoff of 33 was used to classify patients into high- and low-risk groups. Wilcoxon rank test was used to test for continuous variables and the chi-square test was used for categorical variables. Results: The Western population has significantly higher RS (85.9 vs. 65.5, p &lt; 0.001) and ROR-S (57.4 vs.53.7, p = 0.034) scores than the Eastern population. The distribution of 28-gene risk groups was significantly different between races with a higher proportion of high-risk in the Western (10.5% vs. 6.6%, p = 0.035). The low-risk patients in the Eastern stratified by 28-gene assay had significantly higher distant metastasis-free survival (DMFS) rates than high-risk (80% vs. 52%, p &lt; 0.001), which compared with Oncotype Dx RS (96% vs. 76%, p &lt; 0.001) and PAM50 ROR-S (93% vs. 72%, p &lt; 0.001). At the same time, the analysis of gene expressions revealed significantly high expressions of YWHAB, SF3B5, CKAP5, and DDX39A in the Eastern than that in the Western. However, most genes from 21-gene and ROR-S were more highly expressed in the Western than that in the Eastern. Conclusions: 21-gene and PAM50 provide the good performance and show similar patterns in the prognosis of EBC; However, the DMFS rate of the high-risk in the Eastern population determined by 28-gene was much lower than 21-gene and PAM50, which means there are bigger chemo-benefit in the high-risk from 28-gene. In conclusion, 28-gene has better performance in the prognosis of the Eastern population and is a more suitable tool for Eastern breast cancer patients.

Estrogen receptor positive breast cancer in an Afro-Caribbean cohort.

e12550 Background: Estrogen receptor-positive breast cancer (EBC) accounts for 78% of breast cancer (BC) cases in the United States, and with better prognosis compared to other BC subtypes. There is limited information on the incidence, presentation, and outcomes of BC in black women from the Caribbean. We describe the clinicopathologic features and treatment outcomes of EBC in this underrepresented immigrant patient population. Methods: This is a retrospective study conducted at Kings County Hospital, a public hospital in a Brooklyn, New York neighborhood with the second highest population of Afro-Caribbeans in the United States. Demographics and clinicopathological data of patients diagnosed with BC from 2015-2018 were collected from the hospital’s tumor registry. Descriptive statistics and Chi-square testing were used to analyze the data. Results: Of the 299 women with a BC diagnosis, 185 (62%) had EBC, with median age of 61, and median BMI of 29.9. Stratification by menopausal status revealed 75% of these patients were post-menopausal. 37% of pre-menopausal and 28% of post-menopausal women presented with lymph node involvement (LNI). At diagnosis, 61% of patients had localized disease, 30% regional LNI, and 9% distant metastases. Sub-analysis revealed 25%, 22%, 28%, 16% and 9% with stages 0, I, II, III and IV respectively. 39% of patients presented with Nottingham Grade 3, 50% with Grade 2, and 11% with Grade 1 disease. 25% of patients without LNI had Oncotype Dx testing. 22% of these had Recurrence Score (RS) less than 11, 50% RS 11-25, and 28% RS 26 or higher. Of the 27 patients who received neoadjuvant treatment, 22% had complete pathologic response, 37% had partial response, and 33% had disease progression. 81% of patients self-identified as Afro-Caribbean, 27% reported first- or second-degree relatives with a BC diagnosis and 22% first-degree relatives with non-breast malignancy. At time of data analysis, at median of 6 years, 75% of all patients were relapse and progression-free. Lasting response was correlated with cancer stage (p &lt; 0.01) but independent of tumor grade and Oncotype Dx RS (p = 0.18 and p = 0.29, respectively). Conclusions: In our study, Afro-Caribbean women with EBC presented with high-grade tumors and high incidence of regional LNI. Pre-menopausal women had a higher incidence of nodal involvement. Notable was a strong family history of cancer implying inherited or familial cancer syndromes. Progression-free survival was lower than expected and correlates with disease stage, but not with low Oncotype Dx RS. Further research is warranted to investigate better prognostic tools for this population.

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.

Abstract P1-07-09: Clinical and pathologic characteristics in early breast cancer Her2-low and high risk Oncotype DX RS

Abstract Background: Recent data suggest that HER2-low breast cancer (BC) may represent a distinct entity. Approximately 55-60% of BC are considered as Her2-low, of which 80% are Luminal-like tumors. Recent studies support potential clinic-pathological and molecular features differences between Estrogen Receptor (ER) positive HER2-low and ER positive Her2-0 disease. Among patients (pts) with high genomic risk (Oncotype DX RS) HER2-low expression was associated with a significant improvement in overall survival compared to Her2-0. The objective of our study is to compare disease characteristics and outcomes between HER2-low and Her2-0 in estrogen receptor (ER) positive, early (e) BC. (Murtai R et al. The Breast. 60(2021)62-69. Methods: A single center retrospective study of all pts. with ER positive, Her2 negative eBC, for whom Oncotype DX test was performed between 1/Nov/2012 and 14/Febr/2019. The pts were separated into HER2-low (immunohistochemistry (IHC) +1 or + 2 and in situ hybridization not amplified) or HER2-0. Clinic-pathological features included were: demographics, tumour size, nodal status, histologic grade, Her2 expression, ER and progesterone receptor (PR), Ki-67, presence of lymph-vascular (LV1) tumor cell invasion and Oncotype recurrence score (RS) result. Results: A total of 344 pts were screened, of whom 297 pts were included (Exclusion for: Her2 “negative” expression (45 pts); HER2 positive disease by IHC (1 pts); metastatic disease (1 pts)). The distribution of HER2-0 and HER2-low subgroups was 121 pts (41%) and 176 pts (59%). The pathological characteristics according to Her2 expression status are summarized in Table 1. Median age was 57 year (38-79), similar between both groups: Her2-0 58 yr (41-78) and 56 yr (38-79) in Her2 low. The postmenopausal status was 76 pts (62,8%) Her2-0 Vs 113 pts (64,2%) in Her2 low. 1 pts was male. Proliferation Index: Ki67% &amp;lt; 20 was: 65 pts (53,7%) Her2-0 Vs 86 pts (48,5%) in Her2 low; 65 pts (13,5%) had Lympho-vascular invasion in Her2 low; 115 pts (95%) were ER positive in Her2-0 Vs 157 pts (89,2%) in Her2 low; PR positive &amp;gt; 20 was 106 pts (87,6%) in Her2-0 Vs 137 (78,7%) in Her2 Low. The median follow-up was 72 month (SD+- 22,52). 5 pts had a recurrence: 4 pts were Her2 low (1 local and 3 distant metastasis) and 1 Her2-0 with distant metastasis. Most of the pts received adjuvant hormone therapy. There were no statistically significant differences between both groups owing to neither the clinic-pathologic features nor the recurrence score. It was not reached the mínimum number of events for a survival analysis. Conclusions: Our results show that HER2-low eBC pts have similar characteristics and survival rates compared to HER2-0 BC pts without significant differences. Table 1. Baseline pathological characteristics. Citation Format: Elena Galve, Fernando Pikabea-Diaz, Borja Lopez-de-San-Vicente-Hernandez, Covadonga Figaredo-Berjano, Jairo Legaspi-Folgueira, Maria Angeles Sala-Gonzalez, Juan Fernando Arango-Arteaga, Sara Fernandez-Ferrer, Pablo Leonardo Loaiza-Jaramillo, Pablo Casado-Cuesta, Marina Temino-Frances, Anne Bilbao-Penas, Purificacion Martinez-del-Prado. Clinical and pathologic characteristics in early breast cancer Her2-low and high risk Oncotype DX RS [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-07-09.

Evaluation oncotype DX® 21-gene recurrence score andclinicopathological parameters: a single institutional experience.

Oncotype DX recurrence score (RS) is a clinically validated assay, which predicts the likelihood of disease recurrence in oestrogen receptor-positive/HER2-negative (ER+/HER2-) breast cancer (BC). In this study we aimed to compare the performance of Oncotype DX against the conventional clinicopathological parameters using a large BC cohort diagnosed in a single institution. A cohort (n= 430) of ER+/HER2- BC patients who were diagnosed at the Nottingham University Hospitals NHS Trust and had Oncotype DX testing was included. Correlation with the clinicopathological and other biomarkers, including the proliferation index, was analysed. The median Oncotype DX RS was 17.5 (range=0-69). There was a significant association between high RS and grade 3 tumours. No grade 1BC or grade 2 tumours with mitosis score 1 showed high RS. Low RS was significantly associated with special tumour types where none of the patients with classical lobular or tubular carcinomas had a high RS. There was an inverse association between RS and levels of ER and progesterone receptor (PR) expression and a positive linear correlation with Ki67 labelling index. Notably, six patients who developed recurrence had an intermediate RS; however, four of these six cases (67%) were identified as high-risk disease when the conventional clinical and molecular parameters were considered. Oncotype DX RS is correlated strongly with the conventional clinicopathological parameters in BC. Some tumour features such as tumour grade, type, PR status and Ki67 index can be used as surrogate markers in certain scenarios.

The effect of non-oncology drugs on clinical and genomic risk in early luminal breast cancer

An effect of non-oncology medications on cancer outcome has been proposed. In this study, we aimed to systematically examine the impact of commonly prescribed non-oncology drugs on clinical risk and on the genomic risk [based on the Oncotype DX recurrence score (RS)] in early breast cancer (BC). We collected data on clinical risk (stage and grade), genomic risk (Oncotype DX RS), and on non-oncology medications administered to 1423 patients with estrogen receptor-positive human epidermal growth factor receptor 2-negative BC during the month of their surgery. The influence of various medications on clinical and genomic risks was evaluated by statistical analysis. Out of the multiple drugs we examined, levothyroxine was significantly associated with a high Oncotype DX RS (mean 24.78; P < 0.0001) and metformin with a low Oncotype DX RS (mean 14.87; P < 0.01) compared with patients not receiving other non-oncology drugs (mean 18.7). By contrast, there were no differences in the clinical risk between patients receiving metformin, levothyroxine, or no other non-oncology drugs. Notably, there was no association between the consumption of levothyroxine and metformin and proliferation marker (Ki67) levels, but both drugs were significantly associated with progesterone-related features, suggesting that they influence genomic risk through estrogen-dependent signaling. The results of this study indicate a significant impact of metformin and levothyroxine on clinical decisions in luminal BC, with potential impact on the clinical course of these patients.

Shear-wave elastography-based nomograms predicting 21-gene recurrence score for adjuvant chemotherapy decisions in patients with breast cancer

PurposeTo develop and validate nomograms based on shear-wave elastography (SWE) combined with clinicopathologic features for predicting Oncotype DX recurrence score (RS) for use with adjuvant systemic therapy guidelines. MethodsIn a retrospective study, patients with breast cancer who underwent definitive surgery of the breast between August 2011 and December 2019 were eligible for this study. Those with surgery between August 2011 and March 2019 were assigned to a development set and the rest were assigned to an independent validation set. Clinicopathologic features and SWE elasticity indices were assessed with logistic regression to develop nomograms for predicting RS ≥ 16 and ≥ 26. Analysis of the area under the receiver operating characteristic curve (AUROC) was used to assess the performance of the nomograms. ResultsOf a total 381 women (mean age, 51 ± 9 years), 286 (mean age, 51 ± 9 years) were in the development set and 95 (mean age, 51 ± 9 years) in the validation set. All SWE elasticity indices were independently associated with each RS cutoff (odds ratio, 1.006–1.039 for RS ≥ 16; odds ratio, 1.008–1.076 for RS ≥ 26). Nomograms based on SWE combined with clinicopathologic features were developed and validated for RS ≥ 16 (mean elasticity [AUROC, 0.74; 95% CI: 0.68, 0.80] and maximum elasticity [AUROC, 0.74; 95% CI: 0.69, 0.80]) and for RS ≥ 26 (mean elasticity [AUROC, 0.81; 95% CI: 0.73, 0.89], maximum elasticity [AUROC, 0.82; 95% CI: 0.74, 0.89], and elasticity ratio [AUROC, 0.86; 95% CI: 0.80, 0.93]). ConclusionNomograms based on SWE can predict Oncotype DX RS for use in adjuvant systemic therapy decisions.

Prognostic Comparison between Oncotype DX® and a 23-Gene Classifier, RecurIndex®, on the Taiwan Breast Cancer Population.

The applicability of the Oncotype DX® (Genomic Health, Inc., Redwood City, CA, USA) recurrence score (RS) in Asian populations is unclear. A 23-gene classifier, RecurIndex® (Amwise Diagnostics, Pte. Ltd., Singapore), has been developed based on the gene expression profiles of early-stage breast cancer patients of ethnic Han Chinese population in Taiwan. This study aimed to compare the performance of the Oncotype DX® RS with the RecurIndex® recurrence index (RI) for predicting relapse-free survival. Therefore, we calculated both the RI and RS for 110 early stage breast cancer patients, with the cut-off value for high-risk recurrence set at 26 and 29 for the RS and the RI, respectively. With relapse-free interval (RFI) as the primary endpoint, the concordance between RS and RI was 78.2% (Kappa value = 0.297). For a median follow-up interval of 27 months, there was a statistically significant difference in RFI between the high- and low-risk groups defined by the RI (p = 0.04) but not between risk groups defined by the RS (p = 0.66). In conclusion, whereas there was high concordance between the RecurIndex® RI and the Oncotype DX RS, the current data showed that the RI had a better discrimination for recurrence risk than the RS. Subsequent studies with larger sample sizes will be needed to confirm the superiority of the RI over the RS in the Asian population.

The Role of Post-Mastectomy Radiation Therapy in Patients with pT3N0 Breast Cancer and Low Genomic Recurrence Score

<h3>Purpose/Objective(s)</h3> The role of post-mastectomy radiotherapy (PMRT) in patients with pT3 pN0 breast cancer remains controversial. We previously showed a correlation between PMRT and improved overall survival (OS) in pT3N0 patients who do not receive chemotherapy. However, it is unknown whether this correlation extends to patients with low genomic recurrence score (RS). In this analysis, we used the National Cancer Database (NCDB) to investigate the benefit of PMRT in pT3N0 patients with low RS. <h3>Materials/Methods</h3> We performed an analysis of NCDB patients with pT3N0 breast cancer who had low Oncotype DX RS (ORS) (< 25) and did not receive systemic chemotherapy. Patients were matched for baseline patient, tumor, and treatment characteristics using inverse probability of treatment weighting to minimize the impact of potential confounding variables. We stratified patients based on receipt of PMRT and compared OS using Kaplan-Meier estimates. Univariate and doubly-robust multivariable analyses were used to correlate PMRT and various baseline characteristics with OS. <h3>Results</h3> We identified 444 patients with pT3N0 breast cancer who had undergone mastectomy and had low-risk genomic assay scores who did not receive systemic chemotherapy. After IPTW matching, there were no significant differences in baseline patient characteristics. In the PMRT group, 44% received treatment to the chest-wall only, and 66% patients received chest wall and regional nodal irradiation. PMRT was associated with improved overall survival on both the univariate (HR=0.201; 95% CI=0.05-0.78; p=0.021) and doubly-robust multivariable analyses (HR=0.128; 95% CI=0.02-0.66; p=0.014). Receipt of endocrine therapy was also found to significantly improve overall survival (p=0.02). We attempted to repeat the analysis in patients with RS >25 who received chemotherapy, but we only identified a total of 78 such patients and could not perform a robust analysis. <h3>Conclusion</h3> This cohort analysis shows a strong correlation between PMRT and improved OS in pT3N0 patients with low ORS who do not receive chemotherapy. It is possible that with the de-escalation of chemotherapy and axillary surgery in this patient population in the modern era, the benefit of locoregional treatment with radiotherapy is magnified. Our analysis suggests that prospective data are needed before de-escalation of radiotherapy for these patients based on ORS.

Correlation of the Ki67 Working Group prognostic risk categories with the Oncotype DX Recurrence Score in early breast cancer.

The relationship between Ki67 assessed by immunohistochemistry (IHC) and the Oncotype DX Recurrence Score (RS) is unclear. The objective of this study was to determine the correlation between the 21-gene RS and IHC-measured Ki67 with the prognostic classification groups recommended by the International Ki67 Working Group (IKWG). The authors performed a retrospective chart review of women who had hormone receptor (HR)-positive, human epidermal growth factor receptor 2-negative early breast cancer with zero to three positive lymph nodes and both Ki67 and the 21-gene RS performed at their institution from 2013 to 2021. Patients were categorized into low (≤5%), intermediate (6%-29%), and high Ki67 groups (≥30%) according to IKWG recommendations. Overall agreement and risk-stratified agreement between Ki67 and RS were assessed with the proportion of agreement and the κ statistic. The study included 525 patients with HR-positive breast cancer. Among the 49% of patients with intermediate Ki67 values of 6%-29%, the distribution of low (0-10), intermediate (11-25), and high RS (26-100) was 19%, 66%, and 15%, respectively. There was slight agreement (κ=0.01-0.20) between Ki67 and RS (κ=0.027) in the overall population, although this was not significant (p=.1985). There was fair agreement (κ=0.21-0.40) between high Ki67 and RS values (κ=0.280; p < .0001). A higher progesterone receptor percentage was associated with lower RS values (p > .0001) but not lower Ki67 values. A positive nodal status and a larger tumor size were associated with higher Ki67 values (p=.0059 and p < .0001) but not with RS. In this group of patients selected to have a 21-gene RS, there was no significant correlation between Ki67 and RS in the overall population, and there was fair agreement between high Ki67 and high RS values. In patients with early-stage, hormone receptor-positive breast cancer, decisions on adjuvant chemotherapy are based on certain biological features of the cancer and genomic assays such as the Oncotype DX Recurrence Score (RS). The goal of this study was to determine the correlation between Ki67, a marker of proliferation, and the Oncotype DX RS, a 21-gene assay demonstrated to be predictive of an adjuvant chemotherapy benefit in patients with early-stage breast cancer. In 525 patients, the authors did not find a significant correlation between Ki67 and RS.

The relationship of oncotype Dx Recurrence Score (RS) with Ki 67 in early stage breast cancer patients in a community based cancer center in rural central Nebraska.

e12566 Background: Oncotype Dx recurrence score (RS), is a prognostic and predictive test utilized for decision making in adjuvant therapy of 0-3 node/hormone receptor positive(HR+)/ HER-2-negative early breast cancer. Ki-67 is a marker of proliferating cells and is associated with prognosis and response. Immunohistological (IHC) assessment of Ki 67 expression is less expensive and with the approval of CDK inhibitors in the high risk adjuvant setting, it is increasingly being utilized in clinical decision making. A moderate to strong correlation between Ki67 and Oncotype Dx RS has been reported in the literature. We sought to examine the relationship of Ki 67 to Oncotype Dx RS in a community-based cancer center in rural central Nebraska. Methods: Forty-three consecutive postmenopausal breast cancer patients(pts) diagnosed and treated at our community based cancer center between 2020-2021 with T1–2 N0-1 M0, HR+, HER-2-negative disease were evaluated for histological type, tumor size, Nottingham grade, HR levels, Ki 67 expression (low &lt; 10%, intermediate 10 ≥ Ki67 &lt; 25 high ≥ 25), and Oncotype Dx RS(low &lt;16,intermediate 16⩽RS&lt;26), high ⩾26). Ki 67 and Oncotype Dx RS were treated as continuous variables to calculate a Pearson correlation coefficient. Results: Mean age at diagnosis was 59.4 years (range 48-89). Mean tumor diameter was 15.6 mm. 78.9% were intermediate histologic grade and 9.7% patients had lymph node involvement. Median expression of ER and PR were 90% (5-100) and 70% (0-100), respectively. The mean Ki 67 value was 17.5 (range 5-60 %), and mean Oncotype RS was 14.4 (range 4-34). There was a positive linear correlation between Ki 67 expression and Oncotype Dx RS (Pearson Correlation Coefficient=0.49, P-value &lt;0.001). The vast majority of high Ki 67 pts (80%) had high/intermediate Oncotype RS. All pts with low Ki 67 (100%) had low/intermediate RS. Conclusions: Our community based rural cancer center data support a linear, statistically significant, positive correlation between Ki 67 and Oncotype Dx RS in early stage 0-3 node/HR+ positive breast cancer pts. Increasing use of Ki 67 testing in different clinical settings will generate more data to better define this correlation.[Table: see text]

Comparison of predicted benefit using RS clin versus observed benefit in a U.S. registry of stage I ER-positive HER2-negative high oncotype DX RS breast cancer.

544 Background: The 21-gene recurrence score assesses the risk of distant breast cancer recurrence and predicts the benefit of adjuvant chemotherapy in ER positive early-stage breast cancer. However, clinicopathologic risk factors continue to impact absolute benefit of adjuvant chemotherapy. Absolute benefit of adjuvant chemotherapy in low clinicopathologic risk Stage I ER positive breast cancer with high Oncotype RS is an important clinical component of shared decision making. The RSClin clinical tool, which integrates the 21-gene recurrence score (RS) and clinicopathologic features, was found to be more prognostic than RS result alone. We assessed RS Clin predicted benefit and compared to absolute benefit in low clinicopathologic risk Stage I ER positive breast cancer with high Oncotype RS as observed in the NCDB. Methods: Using the National Cancer Data Base (NCDB), we identified female patients age 18-75, ER positive and Her 2 negative, 21 gene signature high risk &gt; 25 with negatives surgical margins, &lt;2cm, lymph node negative breast cancers, who had received endocrine therapy with either Tam or AI diagnosed during 2010 - 2017. Clinicopathologic factors and RS were entered into the RSClin calculator, and a predicted benefit of chemotherapy was calculated for each patient. Using NCDB data, Cox proportional hazards regression models were used to project absolute survival benefit at 10 years from diagnosis for those who did vs those who did not receive chemotherapy. NCDB-derived absolute benefit of chemotherapy was compared to estimated absolute benefit as predicted by the RSClin tool. Results: 18,226 patients were identified. Stages T1a = 670(4%), T1b = 4,289(23%), and T1c = 13,267(73%). Median age 59 years (21-75). Race white 84% (15,365), black 10% (1840), and other 1021(6%). AI use 80% (14,711) was greater than Tam use 20% (3515). Chemotherapy was administered in 75% (13,827) of patients. Most patients had high or intermediate grade disease, G3 45% (8225), G2 46% (8328), and G1 9% (1672). Median duration of follow up was 57 months (2-160). Probability of death T1b at 10yrs with chemotherapy was 8.5%, and without chemotherapy was 15.1% with an absolute benefit of 6.6%. Predicted benefit in T1b using RS Clin at 10yrs was 10.8%. Probability of death for T1c at 10yrs with chemotherapy was 15.1%, and without chemotherapy was 23.5% with an absolute benefit of 8.4%. Predicted benefit in T1c using RS Clin at 10yrs was 14%. Conclusions: Patients with stage IB and IC hormone receptor positive HER2 negative breast cancers with high RS had a lower absolute benefit than predicted by RS Clin. The RSClin tool overestimated benefit of therapy in both IB and IC stages requiring caution when using this tool in patients with the lowest clinicopathologic risks.

Selected Articles from This Issue

There is consensus that benzene exposure is causally related to acute myeloid leukemia (AML), but accurate description of the AML-benzene exposure response curve (ERC) is still needed for risk assessment. Scholten and colleagues hypothesized that using data from both human and animal studies could increase precision of the estimated ERC for benzene induced AML. The authors found that risk estimates based on the complete dataset (23 experimental and observation studies) were more precise, but also that harmonization steps required to fit the Bayesian meta-regression model involve a range of assumptions that need to be critically evaluated, as they seem crucial for successful implementation.Screening reduces lung cancer mortality, but the low specificity of current eligibility criteria has blocked implementation. Risk biomarkers (e.g. AHRR methylation of leukocyte DNA) might mitigate this. Jacobsen and colleagues utilized the Copenhagen City Heart Study which included >9,200 individuals with detailed smoking information and >20 years of lung cancer follow-up. AHRR methylation was added to 7 established eligibility criteria. NLST criteria plus AHRR methylation <55% led to a 22% lower predicted screening burden and a specificity for 5-year lung cancer of 84.0%. AHRR hypomethylation provides predictive lung cancer risk information on top of detailed smoking history and might be useful in lung cancer screening.Policy models used to examine the effectiveness of colorectal cancer screening and surveillance assume colonoscopy is very sensitive for detection of adenomas. This simulation study by Rutter and colleagues examined these assumptions and found evidence that colonoscopy sensitivity circa 1990 was lower than generally assumed for adenomas smaller than 10mm, and potentially much lower for adenomas smaller than 6mm. These findings highlight the importance of evaluating model assumptions. Colonoscopy is a highly effective screening and diagnostic test, though it may have been less effective for colorectal cancer prevention than previously estimated.Oncotype DX recurrence score (ODX- RS) is a prognostic biomarker for early-stage, node-negative, estrogen receptor-positive (ER+) breast cancer. Using data from the clinical oncology National Cancer Database, this study of 227,259 eligible breast cancer cases by Moore and colleagues found that white patients were more likely to receive an ODX RS test compared with Black, Hispanic, and Asian American patients. Furthermore, black patients had higher proportions of high-risk scores compared with non-black patients. ODX RS was similarly predictive for total mortality across all races/ethnicities. These findings emphasize the importance of developing strategies to increase ODX RS uptake among racial/ethnic minorities and call for more investigations on potential racial/ethnic differences in breast cancer biology.