Oncotype DX Research Articles

Can Molecular Biomarkers Help Reduce the Overtreatment of DCIS?

Ductal carcinoma in situ (DCIS), especially in the era of mammographic screening, is a commonly diagnosed breast tumor. Despite the low breast cancer mortality risk, management with breast conserving surgery (BCS) and radiotherapy (RT) is the prevailing treatment approach in order to reduce the risk of local recurrence (LR), including invasive LR, which carries a subsequent risk of breast cancer mortality. However, reliable and accurate individual risk prediction remains elusive and RT continues to be standardly recommended for most women with DCIS. Three molecular biomarkers have been studied to better estimate LR risk after BCS-Oncotype DX DCIS score, DCISionRT Decision Score and its associated Residual Risk subtypes, and Oncotype 21-gene Recurrence Score. All these molecular biomarkers represent important efforts towards improving predicted risk of LR after BCS. To prove clinical utility, these biomarkers require careful predictive modeling with calibration and external validation, and evidence of benefit to patients; on this front, further research is needed. Most trials do not incorporate molecular biomarkers in evaluating de-escalation of therapy for DCIS; however, one-the Prospective Evaluation of Breast-Conserving Surgery Alone in Low-Risk DCIS (ELISA) trial-incorporates the Oncotype DX DCIS score in defining a low-risk population and is an important next step in this line of research.

Oncotype DX results increase concordance in adjuvant chemotherapy recommendations for early-stage breast cancer

Adjuvant chemotherapy recommendations for ER+/HER2− early-stage breast cancers (eBC) involve integrating prognostic and predictive information which rely on physician judgment; this can lead to discordant recommendations. In this study we aim to evaluate whether Oncotype DX improves confidence and agreement among oncologists in adjuvant chemotherapy recommendations. We randomly select 30 patients with ER+/HER2− eBC and recurrence score (RS) available from an institutional database. We ask 16 breast oncologists with varying years of clinical practice in Italy and the US to provide recommendation for the addition of chemotherapy to endocrine therapy and their degree of confidence in the recommendation twice; first, based on clinicopathologic features only (pre-RS), and then with RS result (post-RS). Pre-RS, the average rate of chemotherapy recommendation is 50.8% and is higher among junior (62% vs 44%; p < 0.001), but similar by country. Oncologists are uncertain in 39% of cases and recommendations are discordant in 27% of cases (interobserver agreement K 0.47). Post-RS, 30% of physicians change recommendation, uncertainty in recommendation decreases to 5.6%, and discordance decreases to 7% (interobserver agreement K 0.85). Interpretation of clinicopathologic features alone to recommend adjuvant chemotherapy results in 1 out of 4 discordant recommendations and relatively high physician uncertainty. Oncotype DX results decrease discordancy to 1 out of 15, and reduce physician uncertainty. Genomic assay results reduce subjectivity in adjuvant chemotherapy recommendations for ER +/HER2− eBC.

Treatment pattern of early-stage premenopausal breast cancer patients with low Oncotype DX score: Single center experience.

e12510 Background: The predictive value of Oncotype DX in early-stage node negative breast cancer had been previously well established. As per TAILORx, patients with a low Oncotype DX Recurrence Score RS (0–25) did not benefit from chemotherapy. Premenopausal patients are a crucial subgroup for which recommendations based on Oncotype DX are imprecise. Those with Oncotype DX RS 16-25 are thought to have a small benefit from chemotherapy. Our goal was to study the treatment pattern for this group of patients managed at our institution. Methods: We conducted a retrospective analysis to assess premenopausal patients with early-stage breast cancer who had Oncotype DX testing done. All eligible patients were compared based on whether chemotherapy was given or not. The primary endpoint evaluated was the rate of local recurrence. Univariate comparisons were assessed using t-tests or ANOVA for continuous variable &amp; chi-square for categorical variable. Results: A total of 506 patients younger than 50 years diagnosed between 01/2018 and 12/2020 who had an Oncotype DX available were identified. Of these, 344 were White, 137 were Black and 23 identified as another race. The average age of patients was 42.7 ± 5.5 years. Patients treated with chemotherapy were found to be on average younger than those who did not receive chemotherapy (42 years old vs 43.6 years old, P &lt; 0.0001). The average tumor size for patients who got chemotherapy was 3.26 cm compared to an average size of 2.78 cm for patients who avoided chemotherapy. 72.1% of patients with stage 2 disease had received chemotherapy compared to 38.1 % of patient with stage 1. There were 462 patients with RS &lt; 16, 28 patients with RS 16-25, and 16 patients with RS &gt; 25 as illustrated. Patients were followed from a range of 1.8 months to 30.7 months. There were 6 patients who had local recurrences identified, all of which had RS scores &lt; 16. Conclusions: In our study, 91.3% had RS &lt; 16 and generally should have avoided chemotherapy, however 35% of these patients continued to receive chemotherapy. Only 5.5% of our population had RS 16-25, a quarter of which (n = 7) received chemotherapy. Of those 7 patients, 3 had positive lymph node disease. None of these patients had disease recurrence to date. Patients with RS &gt;25 made up 3.2% of the population and would generally benefit from chemotherapy, however 12.5% of these patients did not end up receiving it. Using Oncotype DX in early-stage breast cancer helps avoid chemotherapy safely in majority of patients. [Table: see text]

Outcomes in premenopausal patients with HR+/HER2- breast cancer and lymph node micro-metastasis based on the 21-gene recurrence score.

571 Background: Postmenopausal patients with hormone receptor positive, HER2-negative (HR+/HER2-) early breast cancer (EBC) and 21-gene OncotypeDX (ODX) recurrence scores (RS) &lt;26 do not benefit from chemoendocrine therapy (‘CET’) compared to endocrine monotherapy (‘E’). The TAILORx and RxPONDER trials demonstrated this was consistent in node-negative and node-positive disease, respectively. In premenopausal patients, however, guidelines for those with low RS diverge between disease involving 0 (pN0) vs. 1-3 (pN1a-c) lymph nodes. Additionally, treatment decisions are less clear for patients with micro-metastasis (pN1mi), who comprised only about 10% of patients in RxPONDER. This study used the National Cancer Database (NCDB) to assess treatment patterns and survival outcomes in premenopausal patients with EBC and lymph node micro-metastasis. Methods: A cohort of patients aged &lt;50, diagnosed between 2004-2019 with HR+/HER2- EBC and who underwent ODX testing, was recruited from the NCDB. (A) Firstly, we described demographic and clinical characteristics of a sub-cohort with micro-metastasis using univariate statistics. (B) We confirmed the prognostic value of ODX in this sub-cohort with multivariate Cox regression analysis of overall survival (OS). (C) We explored patterns of practice amongst the total cohort with ODX &lt;26 with chi-squared testing for differences in CET use by nodal status. (D) To elucidate the predictive value of this assay, we performed Kaplan-Meier models comparing OS for those with RS &lt;26 receiving E vs. CET, controlling granularly for nodal status: (i) pN1a-c, (ii) pN1mi, and (iii) pN0. Results: Of n=72,068 patients aged &lt;50 with HR+/HER2- EBC and ODX data, 6.1% (n=4,402) had micro-metastasis. (A) The median age of this subgroup was 45 (IQR 41-47) years. Most tumors were grade II (n=2,472, 57.7%) with ductal histology (n=3,500, 80.3%). 73.4% of pN1mi cases had RS &lt;26, while 26.6% had RS ≥26. (B) Multivariate Cox regression – adjusting for comorbidity, race and chemotherapy use – confirmed significance in this pN1mi cohort of RS ≥26 prognosticating poorer OS compared to RS 0-15 (HR 4.42, 95% CI 2.35-8.31, p&lt;0.001). (C) 29.0% (n=1,033) of patients with pN1mi and ODX &lt;26 underwent CET, greater than 15.2% (n=6,568) with pN0 and less than 47.3% (n=2,884) with pN1a-c staging (p&lt;0.001). (D) A benefit in OS (p=0.017) was observed in cases with RS&lt;26 and pN1a-c using CET (5-year OS: 99%) vs. E (5-year OS: 97.5%), but not in pN1mi (p=0.49) or pN0 (p=0.57) disease. Conclusions: The management of premenopausal patients with HR+/HER2- EBC, isolated micro-metastasis, and ODX &lt;26 is unclear. Our large registry study found the addition of chemotherapy to endocrine therapy was associated with improved survival in cases with ODX&lt;26 involving 1-3 lymph nodes, but not in node-negative or micro-metastatic disease. Prospective trials are needed to confirm these findings.

Factors associated with oncotype and recurrence among a diverse breast cancer population seeking care at an urban safety-net hospital.

e12537 Background: The landmark trials, TAILORx and RxPONDER have established Oncotype DX (ODX) as a prognostic and predictive tool in the management of estrogen receptor positive (ER+), early-stage breast cancer. However, recent studies have revealed existing racial disparities in the ODX test. These findings call into question whether ODX is generalizable to diverse populations. We evaluated the prognostic value of ODX RS at an urban, academic safety net hospital. Methods: We conducted a single-institution retrospective study of patients diagnosed with invasive breast cancer and had an ODX test performed between January 1, 2010 to December 31, 2021. Demographic, tumor and treatment characteristics were obtained. Chi-square and ANOVA were used to examine associated factors among recurrences and non-recurrences. Results: We identified 315 patients diagnosed with ER+ breast cancer with an ODX test obtained. Racial breakdown was 47% White, 35% Black and 18% Other. 69% of the patients had public or no insurance. 20% of the patients had a low RS (0-10), 62% had intermediate (11-25) and 18% were high (26-100). 264 patients had no evidence of recurrence, 15 patients had a local or distant recurrence and 36 were unknown. Recurrence was significantly associated with younger age (p = 0.04), higher histologic grade (P &lt; 0.001, &lt; 0.001), intermediate oncotype score (p = 0.002) and no receipt of chemotherapy (p = 0.014). Focused analysis of the recurrence cohort demonstrates a significant proportion with an Intermediate ODX RS classification (93.3%, P = 0.001). 53% had distant recurrence, 20% had received adjuvant chemotherapy and 93.3% were adherent to hormonal therapy. Conclusions: In a diverse patient population, recurrences were significantly more likely among younger patients with high grade tumors, intermediate RS and those who did not receive chemotherapy. Further investigation and understanding whether Oncotype DX is generalizable to diverse breast cancer patient populations is needed.

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]

NRG-BR007: A phase III trial evaluating de-escalation of breast radiation (DEBRA) following breast-conserving surgery (BCS) of stage 1, HR+, HER2-, RS ≤18 breast cancer.

TPS623 Background: Approximately 50% of newly diagnosed invasive breast cancers are stage 1, with the majority being ER/PR-positive, HER2-negative. Genomic assays such as the Oncotype DX have identified patients (pts) with reduced risk of distant metastasis and without benefit from chemotherapy added to endocrine therapy, freeing them from excess toxicity. Genomic assays are also recognized as prognostic for in-breast recurrence (IBR) after BCS and could similarly allow de-escalation of adjuvant radiotherapy (RT). Reducing overtreatment is of interest to pts, providers, and payers. Methods: We hypothesize that BCS alone is non-inferior to BCS plus RT for in-breast recurrence and breast preservation in women intending endocrine therapy (ET) for stage 1 invasive breast cancer (ER &amp;/or PR positive, HER2-negative with an Oncotype DX Recurrence Score [RS] of ≤18). Stratification is by age (&lt;60; ≥60), tumor size (≤1 cm; &gt;1-2cm), and RS (&lt;11, 11-18). Pts are randomized post-BCS to Arm 1 with breast RT using standard methods (hypo- or conventional-fractionated whole breast RT with/without boost, or APBI) with ≥5 yrs of ET (tamoxifen or AI) or Arm 2 with ≥5 yrs of ET (tamoxifen or AI) alone. The specific regimen of ET in both arms is at the treating physician’s discretion. Eligible pts are stage 1: pT1 (≤2 cm), pN0, age ≥50 to &lt;70 yrs, s/p BCS with negative margins (no ink on tumor), s/p axillary nodal staging (SNB or ALND), ER &amp;/or PR positive (ASCO/CAP), HER2-negative (ASCO/CAP), and Oncotype DX RS of ≤18 (diagnostic core biopsy or resected specimen). Primary endpoint is in-breast recurrence (invasive breast cancer or DCIS). Secondary endpoints are breast conservation rate, invasive in-breast recurrence, relapse-free interval, distant disease-free survival, overall survival, patient-reported breast pain, patient-reported worry about recurrence, and adherence to ET. We assume a clinically acceptable difference in IBR of 4% at 10 yrs to judge omission of RT as non-inferior (10-yr event-free survival for RT group is 95.6% vs 91.6% for the omission of RT group). BR007 is powered to detect non-inferiority with 80% power and a one-sided α=0.025, assuming that there would be a ramp-up in accrual in the first two years (leveling off in Yrs 3-5); 1,670 pts (835 per arm) are required for randomization. Conservative loss to follow-up is 1% per yr. Some of the T1a pts screened may have Oncotype DX scores &gt;18, making them ineligible for the study. In the accrual process, 1,714 pts will be required to register to ensure that our final randomized cohort is 1,670 pts. Current accrual (02-08-2023) is 370 screened and 323 randomized (~87% of predicted accrual). Clinical trial information: NCT04852887 .

Identifying anatomopathological factors associated with a Oncotype DX 21-gene recurrence score higher than 25 in menopaused women.

e15156 Background: Oncotype DX recurrence score is a predictive assay clinically used to estimate the risk of distant recurrence for patients with hormone receptor positive (HR+) early breast cancer (EBC) and to predict the benefit of adjuvant chemotherapy, based on molecular factors of the tumor itself. This retrospective study examines the factors that are linked to a Recurrent score (RS) higher than 25, indicating adjuvant chemotherapy for menopaused women with hormone receptor positive early breast cancer. Methods: 157 patients diagnosed with HR+, HER 2 negative early breast cancer who underwent Oncotype DX testing during their treatment between November 2018 and December 2022 were included in the study. Of these 157 patients, 114 were older than 50 years old and with complete data. Univariate and multivariate logistic regression analysis were used to select pathological factors associated with a RS higher than 25. The receiver operating characteristic (ROC) curve was used to assess the optimal threshold of Estrogen receptor (ER), Progesterone receptor (RP) and Ki67. Results: Median age was 65 years (IQR: 59-71). 57 patients (47.5%) had a T1 tumor and 48% of patients had negative lymph nodes. Most of the patients had a Scarff-Bloom-Richardson (SBR) grade 1 (12%) or grade 2 tumor (70%), and 18% of the patients had grade 3 breast cancer. The cell proliferation marker Ki67 was higher than 30 % for 28 patients (23%). The RS was higher than 25 for 17 patients out of 120 patients. Multivariate logistic regression analysis showed that Ki67 higher than 30% was significant associated with RS &gt; 25 (p = 0.01). To predict a RS &gt; 25, the optimal threshold were respectively 80% for the PR, 90% for the ER and 30% for the Ki67. The area under the ROC curve (AUC) were respectively 0.70, 0.60 and 0.88. With the threshold of 30% for Ki67, the sensitivity was 0.76 and specificity 0.89. Conclusions: The use of the Oncotype DX test is validated and useful to better decide the absence of chemotherapy indication in adjuvant situation in some patients with HR+ cancers. However, access to it remains difficult and expensive in some countries with limited resources. Ki67 and SBR grade could be used as an indication for adjuvant chemotherapy but cannot replace Oncotype DX.

Predictive models of recurrence from transcriptomic signatures of the tumor microenvironment and cell cycle in stage III colon cancer from PETACC-8 and IDEA France trials.

3523 Background: The objective of this work was to establish predictive models of the risk of recurrence in stage III colon cancer (CC) based on transcriptomic signatures of the tumor microenvironment (TME) and cell cycle from the PETACC-8 (training set) and IDEA- France (validation set) trials. Methods: 3'RNAseq was performed in 1733 patients from the PETACC-8 trial (85%) and 1263 patients from the IDEA-France trial (63%). 4 transcriptomic signatures were analyzed: a signature reflecting T-cells infiltration named "Immunoscore-Like", a signature reflecting M2 macrophage infiltration named "M2-like", the expression of CXCL13 (reflecting B cells infiltration) and a score based on the Oncotype DX® Colon Cancer RS using the same formula from the stromal score and the cell cycle score, named “Oncotype DX Like”. In the 1st multivariate model, we analyzed the 4 signatures separately with a dichotomization into "high" and "low" with the best cut point value for the prediction of time to recurrence (TTR) in PETACC-8 trial. In the 2nd multivariate model, we defined a score named “IPS” (Immune Proliferative Stromal), corresponding to the number of deleterious signatures (“high” or “low” depending on the signatures), ranging from 0 to 4. Results: The 1st multivariate model, built from PETACC-8 trial, showed that these 4 signatures were significantly associated with TTR with a protective effect of Immunoscore Like and CXCL13 "high" (HR: 0.66, p = 0.003 and 0.60, p &lt; 0.001 respectively) and a deleterious effect of M2 Like and Oncotype Like “high” (HR: 1.28, p = 0.05 and HR: 1.37, p = 0.01, respectively), independently of known prognostic factors, with a C-index of 0.73. This model was applied to the IDEA-France cohort by calculating a predictive score for each patient, with TTR significantly different depending on the quartile of this score with a 3-year TTR ranging from 55% for the lowest quartile to 90% for the highest quartile (p &lt; 0.001). In the 2nd model, in the 2 cohorts, IPS score was independently associated with TTR with a HR increasing with the IPS score, independently of T and N stage and intra-tumoral CMS heterogeneity (Table). Conclusions: Using transcriptomic data of patients with stage III CC from 2 large-scale adjuvant trials, two predictive models based on signatures of the TME and the cell cycle, provide important information in addition to known prognostic factors for patient stratification on risk of recurrence. Beyond T and N stage, for the decision of adjuvant chemotherapy in stage III CC, the combination of these different variables could be exploited in the future for personalized care (de-escalation, intensification). [Table: see text]

Informative tools to optimize neoadjuvant therapy in ER positive, HER2 negative breast cancers.

e12595 Background: Neoadjuvant therapy (NAT) in HR+/HER2- tumors is often disputable. While the role of Oncotype DX has been well established in adjuvant settings, its clinical utility and potential implementation for prediction of NAT benefit requires further study. This ongoing study aims to report the feasibility of Oncotype DX testing on core biopsy specimens prior to NAT in patients with operable HR+/HER2- breast cancer. The effect of the recurrence score (RS) on systemic treatment recommendations and its correlation to dynamic markers of proliferation and NAT response will be evaluated. Methods: Participants with clinical T2-T4 and/or node positive HR+/HER2- breast cancer had Oncotype DX testing done prior to NAT. Clinico-pathological information, treatment regimens, clinical, radiologic, and pathological responses were recorded. Results: Of the 48 patients with HR+/HER2- breast cancer referred to BC Cancer Vancouver for consideration of NAT between September 2021 and January 2023, 26 were eligible and enrolled in the study. The success rate of the Oncotype DX on core biopsy samples was 96%. The mean turnaround time from patient consent to RS report was 19 calendar days. Approximately 32% of tumors had a RS equal or higher than 26 while 4% had a score less than 10. Nearly 25% of neoadjuvant treatment recommendations were changed based on the RS. Overall, 33% of patients received neoadjuvant chemotherapy, 54% received neoadjuvant endocrine treatment, and 12.5% proceeded with upfront surgery. Conclusions: The success rate of Oncotype DX testing on core biopsy samples was excellent. There were multiple factors that influenced trial enrollment, highlighting the low uptake and equipoise of NAT use in HR+/HER2- tumors. The Oncotype DX testing resulted in a change in systemic treatment plan in 25% of patients. Analyses are ongoing to correlate the recurrence score to NAT response, dynamic Ki-67 changes and breast MRI changes. Clinical trial information: NCT03790813 .

A quality improvement initiative on the utility of the Oncotype DX breast cancer assay in a community hospital.

e13072 Background: Since the advent of Oncotype DX (ODX) breast recurrence score (RS) assay, the use of adjuvant chemotherapy (CT) in the treatment of breast cancer has significantly reduced. This test not only estimates the benefit of CT, but also determines the risk of distant recurrence in patients with early-stage breast cancer with hormone-receptor (ER/PR) positive, human epidermal growth factor receptor (HER) 2-negative, and axillary lymph node negative or positive (1-3 positive nodes) disease. All patients are categorized based on their scores ranging from 0-100 as follows: low (RS≤10), intermediate (RS11-25) and high risk (RS≥26). Further studies proved that adjuvant CT is beneficial in pre-menopausal women with RS 0-25, however offered no benefit to post-menopausal women in the same category. The aim of our study was to assess the implementation of these guidelines in a community hospital in an underserved area. Methods: At Mercy Catholic Medical Center, we performed a retrospective analysis on 303 female patients with newly diagnosed breast cancer, identified between January 2017 – October 2022. We included patients with ER/PR+, HER2-, lymph node negative or positive, who had undergone surgery and were to receive endocrine therapy with or without adjuvant CT. Patients who were lost to follow-up or did not undergo the genetic testing were excluded from the study. We then analyzed the treatment strategies based on RS categories. All patients who did not receive CT was either because it was not indicated (old age, post-menopausal) or patients refused. Results: 81 patients underwent ODX testing among whom, 60.5%, 35.8%, and 3.7% patients were Black, White and Hispanic/Asian, respectively. 1.2%, 9.8%, 18.51%, 34.56%, 35.08% were aged ≤40, 41-50, 51-60, 61-70 and ≥71 years, respectively. Based on the RS, we identified 29.62% in low risk, 56.79% in intermediate risk, and 13.5% in high-risk categories. 100% patients in the high-risk category were prescribed CT and only 7.4% patients with RS 0-25 received CT. 12 patients were found to be lymph node positive, among whom, 3 had RS≥26 and 2 were pre-menopausal, all of whom were prescribed CT. Out of these, 7 were post-menopausal with RS 0-25 and only 1 received CT. Conclusions: Our hospital data suggests that implementation of ODX and adherence to its guidelines has significantly helped avoid CT and its related side effects in the low and intermediate risk categories. Implementation of this cost-effective test has consistently increased in the last two decades and is now an imperative tool in clinical decision-making specially in community hospitals serving underprivileged populations. [Table: see text]

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.

Correlation between Oncotype DX, Predict, and Nottingham Prognostic Index on HR+, HER2- early breast cancer treatment: The current value of molecular testing.

1601 Background: The Oncotype DX Breast Recurrence Score (ODX) assay is a 21-gene assay validated in hormone receptor-positive, HER2 negative invasive breast cancer (BC) to predict chemotherapy benefit and risk of distant recurrence at 10 years regardless of node status and is also a strong predictor of mortality. ODX can minimize the misuse of chemotherapy, financial burden, and improve clinical outcomes. ODX is not widely used in Ecuador due to socioeconomic and healthcare access disparities; instead, many physicians stratify patients' risk according to clinicopathological and immunohistochemical features. We aim to compare the differences between ODX and two of the most common stratification clinical tools: Predict Score (PS) and Nottingham prognostic index (NPI). Methods: Retrospective analysis of women with early BC who underwent ODX testing in Ecuador from May 2020 to January 2023. Inclusion criteria: early BC (T1-T3 / N0-N1a); estrogen receptor (ER) positive; HER2 negative by immunohistochemistry; and available data of tumor size, grade, lymph node status, and Ki67 proliferation index. Exclusion criteria: patients with recurrent BC, incomplete pathology, or immunohistochemistry data. PS and NPI were calculated using online tools. The correlation between PS, NPI, and ODX scores was analyzed using Spearman's correlation coefficient in SPSS. Results: 77 patients underwent ODX testing, of which 58 patients (mean age 55 years old) met the inclusion criteria. Invasive breast carcinoma not otherwise specified was the most common type (48 patients (82%). Risk scores generated by PS correlated strongly with NPI for all patients (r=0.47; p ≤ 0.001). A strong correlation was also found between ODX and NPI (0.79, p&lt;0.027). Risk scores were then stratified by patient risk category. For low-risk patients, 68% of correspondence between ODX and PS was found, and 98% between ODX and NPI. Intermediate-risk patients showed a correspondence between ODX and PS of 5% and 9% for ODX and NPI. High-risk patients showed a correspondence of 50% between ODX and PS and 17% between ODX and NPI. Conclusions: ODX risk recurrence for low-risk patients is highly correlated with PS and NPI. For Intermediate and high-risk patients determined by PS and NPI, ODX testing provided valuable and prognostic information and should be considered to guide adjuvant treatment. [Table: see text]

Does RSClin provide additional information over classic clinico-pathologic scores (PREDICT 2.1, Influence, CTS-5)? A TEAM Pathology substudy.

533 Background: Gene-expression profiling tests (e.g. Oncotype, Mammaprint, Prosignia, Breast Cancer Index and EndoPredict) are widely used in the care of patients with early-stage hormone positive breast cancer (node negative or 1-3 lymph nodes). However, these tests are resource intensive, and few studies have compared their value with either free and widely available clinico-pathologic risk calculators (e.g. PREDICT 2.1, INFLUENCE 2.0, and CTS-5) or tools that combine genomic testing with clinico-pathologic data (e.g. RSClin). The TEAM pathology substudy population was used to compare these different predicted model scores with outcomes. Methods: The TEAM pathology study consists of 3284 postmenopausal hormone positive breast cancer patients treated with either exemestane or tamoxifen followed by exemestane. Accrual was from 2001 to 2006. Genes comprising the multi-parametric Oncotype Dx were used to train signatures to create true assay results. Patient data was then used to calculate recurrence scores through various tools. This included clinico-pathologic models and their respective endpoints PREDICT 2.1 (overall survival at 5 years), INFLUENCE 2.0 (distant metastasis at 5 years), CTS-5 (distant recurrence risk at year 5-10), the purely genomic Oncotype Dx trained results (distant recurrence risk at 9 years), as well as the new clinico-pathologic RSClin (distant recurrence risk at 10 years). We compared the level of association between these predictive model scores using Spearman correlation coefficients. The prognostic ability of each model was contrasted for each outcome using Harrell’s C-statistic. Results: Results were available for CTS-5 (3022 patients), INFLUENCE 2.0 (3485 patients), ODx-trained (3825 patients), and RSClin (3029 patients). Correlation coefficients showed low correlation between Influence ( r= 0.25) and CTS-5 ( r= 0.17) with Oncotype-Dx trained results, and high correlation between RSClin ( r = 0.84) and Oncotype-Dx trained results. The concordance index was similar (0.65 to 0.68) for all models with distant metastasis-free survival as the outcome. Analysis is ongoing and further results will be available at the time of presentation. Conclusions: Other clinico-pathologic tools such as Influence 2.0 and CTS-5 have good prognostic ability when compared to Oncotype Dx-trained results and RSClin. [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.

Treatments and clinical outcomes in stage II colon cancer (CC) patients (pts) with 12-gene Oncotype DX Colon Recurrence Score assay-guided therapy: Real-world data.

3620 Background: The role of adjuvant chemotherapy (CT) in stage II CC is debated. The validated 12-gene Oncotype DX Colon Recurrence Score test provides a Recurrence Score (RS) result (range, 0-100) which estimates recurrence risk (RR) in stage II/III pts. We studied treatment and clinical outcomes in CC pts in whom treatment decisions incorporated the RS result. Methods: This prospectively designed cohort study included all stage II, MMR-P, CC pts who underwent the 12-gene Oncotype DX testing through Clalit between 1/2011 and 12/2016 and had available data with minimum 3-yr follow-up. Kaplan-Meier (KM) estimates and log-rank tests were used to compare RR and CC specific mortality (CCSM) between RS categories. Multivariable analysis (MVA) identified variables associated with RR/CCSM. Results: The analysis included 938 pts. Median age, 68 (IQR, 60-76) yrs; 96% had T3 tumors, and 89% had ≥12 nodes examined. Median RS was 26 (IQR, 19-33). The 3 RS categories (0-29, 30-40, and 41-100) included 65%, 24%, and 11% of pts, respectively. The overall CT use rate was 24%, with a significant difference between the 3 categories (14%, 36%, and 60%, respectively, P&lt; .0001). Pts with very low RS (0-15) comprised 14% of the cohort (CT use rate, 11%). Younger pts, and those with invasion/perforation/obstruction were more likely to receive CT. Clinical outcomes with a median follow up of 6.9 (IQR, 5.5-8.6) yrs are presented (Table). Among untreated pts, KM estimates for RR and CCSM differed significantly between the 3 RS categories ( P&lt; .0001). Outcome of untreated RS 0-15 pts was excellent. In an MVA model, male sex, presence of invasion/perforation/obstruction and higher RS category (RS 41-100 vs 0-29 and vs 30-40, but not RS 30-40 vs 0-29) were associated with increased RR. For CCSM, the results were similar, but this time age ≥70 yrs replaced sex as a significant prognostic variable. Clinical outcomes within each RS group did not differ significantly between treated and untreated pts, but were numerically better with CT in the RS 41-100 group. Conclusions: This real-world analysis showed that the RS results provide independent prognostic information in stage II CC. Further studies are needed to investigate the potential role of the RS result as a predictor of CT benefit, but the data suggest that this benefit may be limited to pts with high RS results. [Table: see text]

Impact of HER2 low expression in the Oncotype DX RS in patients with operable hormone receptor positive early stage breast cancer.

575 Background: Two thirds of breast carcinomas are human epidermal growth factor receptor 2 (HER2) low. To date, it is still unclear whether hormone receptor (HR) positive HER2 low tumors represent a distinct biological subtype. HER2 low status is not considered an independent predictive factor for benefit from adjuvant chemotherapy in HR positive early breast cancer. We aim to investigate the impact of HER2 low expression on the established predictive biomarker Oncotype DX RS in a cohort of patients with HR positive HER2 negative early breast cancer. Methods: Retrospective study of patients with stage I-III HR positive HER2 negative breast cancer treated with upfront surgery between 2019-2022 at the Weill Cornell Breast Center and for whom Oncotype DX RS test was available. Patients were grouped to HER2-0 (immunohistochemistry (IHC) score of 0) or HER2 low (IHC score of 1+ or, 2+ with non-amplified in situ hybridization) expression. Clinicopathological characteristics and Oncotype DX RS were compared across the different categories of HER2 expression. Results: Of 509 patients included, 37% and 63% were grouped as HER2-0 and HER2 low, respectively. Median age at diagnosis was 61 years [IQR 50-69]. Sixty-eight percent of patients were postmenopausal. Stage I, II and III corresponded to 76%, 23% and 1% of patients, respectively. Seven percent of patients had nodal involvement. Ductal carcinoma was the most common histological type (75%) followed by lobular carcinoma (17%). Most tumors had low-intermediate histological grade (81%) with a median Ki-67 of 10% [IQR 5-15]. No significant difference was observed in clinicopathological characteristics between the HER2-0 and HER2 low groups. The overall median Oncotype DX RS was 16 [IQR 11-21]. The median Oncotype DX RS based on a HER2 expression of 0, 1+ and 2+ was 15, 17 and 17, respectively. There was no statistically significant difference between the Oncotype DX RS score and HER2 expression, when comparing HER2-0 to HER2 low (p = 0.578), HER2-0 to HER2-1+ (p = 0.775) and HER2-0 to HER2-2+ (p = 0.157). In the pre-menopausal and lobular carcinoma subgroups, the median Oncotype DX RS was 15 [IQR 9-21] and 17 [IQR 12-22], respectively; and there was no statistically significant difference between the Oncotype DX RS score and HER2 expression (p &gt; 0.05). Post-surgery, 87%, 66% and 13% of patients received endocrine therapy, chemotherapy and radiation therapy, respectively. Median follow up time was 16 months [IQR 8-34]. Disease recurrence was documented in 9 (2%) patients. Conclusions: In this study, we found no differences in the Oncotype DX RS and the prognostic pathological features between the HER2-0 and HER2 low groups which is in line with previous retrospective studies. Survival analysis was limited by the median follow up. Further studies on the understanding of the biology of HER2-low and its clinical implications in early breast cancer are needed.

Breast cancer staging for patients with “low risk” disease: Are they all the same?

6584 Background: Studies have shown that a low (&lt;11) Oncotype DX recurrence score (RS) is associated with better survival outcomes. RS is currently included in the AJCC prognostic staging criteria. Not all patients with a low RS are downstaged. It has been suggested that a low RS should further downstage patients regardless of other disease factors. We explored survival outcomes for patients with a low RS to assess if additional patients should be downstaged. Methods: Using the National Cancer Database, female patients ages 18-75 with invasive unilateral pT1-3, pN0-1, M0 hormone receptor positive (ER+ and/or PR+), HER2- breast cancer and a RS &lt;11, diagnosed 2010-2018 were identified. Patients who received neoadjuvant treatment were excluded. Patients were grouped based on the AJCC 8th edition prognostic stage (IA, IB, IIA, IIB, IIIA). Variables were summarized, and unadjusted overall survival (OS) was estimated using the Kaplan-Meier method. Cox proportional hazards models were used to estimate the association of stage with OS after adjustment for available covariates. Results: Of the 54,961 patients with a RS &lt;11, median follow-up was 57.7 months (95% CI 57.3-58.1), and median age was 61yo (IQR 52-67). Most tumors were grade 1 (37.6%) or 2 (56.9%) with ductal histology (75.3%). The median tumor size was 1.5 cm (IQR 1-2), and most were pN0 (83.3%). Although most patients with a RS &lt;11 were stage IA (94.2%), some had a higher stage assignment (5.1% stage IB, 0.6% IIA, 0.1% IIB, &lt;0.01% IIIA). Most patients (93.4%) received endocrine therapy (ET), and few (3%) received chemotherapy. Patients treated with chemotherapy more often had younger age, lobular histology, higher grade, larger tumor size, and/or pN+ disease (all p&lt;0.001). Unadjusted OS was reduced with higher stage (log-rank p&lt;0.001), and this remained true when limited to only those who received ET without chemotherapy (log-rank p&lt;0.001). After adjustment for relevant covariates including treatment, higher stage remained associated with worse OS [stage IA: ref; IB: HR 1.66 (95% CI 1.34-2.05); IIA: HR 2.29 (95% CI 1.44-3.65); IIB: HR 2.48 (95% CI 1.03-5.95); overall p&lt;0.001]. Conclusions: For patients with a low RS, survival outcomes vary with current AJCC prognostic disease stage, suggesting that not all patients with a RS &lt;11 should be downstaged based on RS alone. Anatomic and other non-genomic factors remain relevant when assessing prognosis. [Table: see text]

ECOG-ACRIN E2197: Comparison of HER2 gene expression by RT-PCR across all HER2 immunohistochemistry groups with recurrence analysis.

515 Background: Accurate assessment of HER2-low [immunohistochemical (IHC) score of 1+ or 2+ and in-situ hybridization negative] breast cancer is clinically relevant following DESTINY-Breast04. In hormone receptor positive breast cancers, Oncotype DX assay Recurrence Score results are widely used to guide adjuvant chemotherapy selection, and standardized quantitative HER2 mRNA reference-normalized expression levels by RT-PCR are included in patient reports. Previously, a high degree of concordance between central IHC and quantitative HER2 by RT-PCR was demonstrated in E2197. Here, we compare quantitative HER2 gene expression using Oncotype DX assay within all IHC subgroups and risk of recurrence in E2197. Methods: Data analyzed were from a case-control sample from E2197 (no adjuvant anti-HER2 therapy) of 755 patients. Central IHC for HER2 used duplicate 1.0 mm microarrays (HercepTest, Dako) and scored per 2007 ASCO/CAP guidelines. Based on quantitative reference-normalized RT-PCR measures of HER2 expression, cases were assigned: positive ≥11.5 units, equivocal ≥10.7 to &lt;11.5 units, and negative &lt;10.7 units (1 unit increase represents ~2-fold increase in RNA). Spearman’s rank correlation was used to measure strength of association between the 2 methods. Cox proportional hazards regression was used to evaluate the association between quantitative HER2 expression and recurrence (defined as invasive breast cancer in local, regional, or distant sites). Analyses were weighted to account for study design. Results: 48% were IHC 0, 11% were IHC 1+, 23% were IHC 2+, and 18% were IHC 3+. 85% were HER2 negative, 3% equivocal, and 11% positive by RT-PCR. While there was moderately strong correlation between HER2 IHC and HER2 gene expression by RT-PCR [Spearman’s rho: 0.63 (95% CI: 0.59, 0.67); p&lt;0.001], there were wide and overlapping ranges of HER2 gene expression across all IHC categories with almost identical medians and inter-quartile ranges for HER2 IHC 1+ and 2+ (n=248; see table). An exploratory analysis showed 86% of IHC 0, 97% of IHC 1+, and 99% of IHC 2+ had HER2 &gt;8 units. After controlling for baseline clinicopathologic features (age, hormone receptor status, grade, size, and nodal status), continuous quantitative HER2 expression was associated with time to recurrence in HER2 IHC 0 to 2+ [HR 1.17 per 1-unit increase in HER2 (95% CI 1.01, 1.35; p=0.036)]. Conclusions: There was a wide range of quantitative HER2 gene expression using Oncotype DX assay across all IHC categories; continuous HER2 expression is independently associated with recurrence. Quantitative HER2 expression may be useful for identification of HER2-low breast cancer. Further studies are needed. [Table: see text]