Adjuvant Chemotherapy Decisions Research Articles

Abstract PO4-20-03: HIPEx: Adjuvant palbociclib plus endocrine therapy in ER-positive HER2-negative early breast cancer with high recurrence score according to GenesWellTM BCT; a multi-center single arm phase II clinical trial (KCSG BR 19-13)

Abstract Background: In estrogen receptor (ER)-positive human epidermal growth factor receptor2 (HER2)-negative early breast cancer (EBC) patients, NCCN treatment guideline recommend 21-gene tests for decision of adjuvant chemotherapy if tumor size is over 0.5cm or node positive disease. In addition, GenesWellTM BCT is a prognostic assay that predict the risk of recurrence in patients with ER-positive HER2-negative and nodal stage 0-1 EBC. According to gene tests, EBC patients with high recurrence risk would have help from adjuvant chemotherapy to increase the rate of disease free survival but toxicities of chemotherapy are not negligible. Therefore, the effort for escaping adjuvant chemotherapy has been performed and currently CDK4/6 inhibitor would be considered as the substitute for cytotoxic chemotherapy in ER-positive HER2-negative EBC patients. Methods: HIPEx trial is a multi-center, phase II clinical trial to determine the efficacy of adjuvant palbociclib plus endocrine therapy in ER-positive HER2-negative EBC with high recurrence score according to GenesWellTM BCT (NCT04247633). Eligible patients are women who received curative surgery and diagnosed as ER-positive, HER2-negative and pathologic stage T1b-T2 and/or N0-1. Clinical recurrence risk is high according to the modified Adjuvant! Online guideline and GenesWellTM BCT score is 4 or more which being genomic high risk. Other criteria include ECOG performance status ≤1, adequate organ functions and availability of an archival surgical specimens. Patients receive palbociclib 125mg once daily for 21 days of 28-day cycle plus tamoxifen or aromatase inhibitor (anastrozole, letrozole or exemestane) once daily for every day. Palbociclib would be taken for two years and endocrine therapy for five years or more. If adjuvant radiotherapy is required, palbociclib should be taken two weeks after the end date of radiotherapy. If patients are premenopausal status, GnRH agonist is allowed. Primary endpoint is 3-year event free survival (EFS) rate of high clinical and genetic risk ER-positive EBC. Secondary endpoints include 3-year overall survival, quality of life, safety and tolerability of palbociclib with endocrine therapy as an adjuvant setting, exploratory analysis of predictive and prognostic biomarkers and the performance of GenesWellTM BCT for 3-year EFS rate. In total, 578 patients would be enrolled in this trial. Based on the previous results of GenesWell™ BCT in Korea, the 3-year EFS rate for the past control group (chemotherapy followed by endocrine therapy) is 87.0% and the treatment group in this clinical trial is assumed to be 90.5%.(hazard ratio for EFS = 0.717). Null hypothesis is the 3year-EFS rate in patients received adjuvant palbociclib and endocrine therapy is not less than that of the past control group. Alternative hypothesis is the 3year-EFS rate of this trial is less than that of the past control group (one-sided). Significance level is 0.025, power is 0.80. Considering 10% drop out rate, 4-years of accrual patient enrollment and 3-years of follow up period, 578 patients were required in this clinical trial. Citation Format: Ji-Yeon Kim, Sung Hoon Sim, Jieun Lee, In Hae Park, Kyong Hwa Park, Seock-Ah Im, Jee Hung Kim, Kyoung Eun Lee, Jeong Eon Lee, Jai Min Ryu, Young Kee Shin, Yeon Hee Park. HIPEx: Adjuvant palbociclib plus endocrine therapy in ER-positive HER2-negative early breast cancer with high recurrence score according to GenesWellTM BCT; a multi-center single arm phase II clinical trial (KCSG BR 19-13) [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 PO4-20-03.

Abstract PO4-07-05: Clinical evaluation of image-based risk profiling in breast cancer histopathology and comparison to an established gene expression assay

Abstract Background: Among oestrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative early breast cancer, a significant proportion of patients are categorised as intermediate risk, based on classic clinico-pathological variables, thus providing limited information to guide adjuvant chemotherapy decisions. Prognostic risk profiling is an integrated part of modern breast cancer diagnostics to provide additional risk information for this patient group. Among the established prognostic assays based on gene expression, the Prosigna assay is widely used and provides an individual risk of recurrence (ROR) score and identifies intrinsic subtypes with associated survival outcomes. Pioneering artificial intelligence-based precision diagnostics, Stratipath Breast, is a deep learning-based image analysis tool that utilises digitised histopathological whole slide images to stratify intermediate risk patients in terms of risk of recurrence. Materials and methods: The study included 234 invasive breast tumours from patients with early ER-positive HER2-negative breast cancer, clinically assessed as intermediate risk tumours and eligible for chemotherapy. All tumours had therefore previously been analysed by the Prosigna assay in clinical routine at point of diagnosis between 2020 and 2022 at the Karolinska University Hospital and Södersjukhuset, Stockholm, Sweden. Clinicopathological data including Prosigna results (ROR score, risk group and intrinsic subtype) were extracted from medical records, along with the corresponding archived haematoxylin and eosin (HE)-stained formalin-fixed paraffin-embedded tissue slides. The HE slides were subsequently digitised and analysed by the Stratipath Breast tool. The agreement between the two tests for risk stratification was evaluated in this real-world breast cancer case series. Results: The Prosigna assay classified 76 (32.5%), 110 (47.0%) and 48 (20.5%) tumours as low, intermediate and high risk, respectively. The Stratipath Breast analysis identified 116 (49.6%) tumours as low risk and 118 (50.4%) as high risk. Among Prosigna intermediate risk tumours, 52 (47.3%) were stratified as low risk and 58 (52.7%) as high risk by Stratipath Breast. The overall agreement between the two tests for low risk and high risk groups was 71.0%, with a Cohen’s linear kappa of 0.42. Twelve of the 48 Prosigna high risk cases were classified as Stratipath low risk. ROR scores were higher in the Stratipath high risk group compared to the low risk group (p < 0.001), across all cases as well as in the Prosigna intermediate group. Among the 176 histological grade (NHG) 2 tumours, 97 (55.1%) and 79 (44.9%) were stratified as Stratipath low risk and high risk, respectively, whereas 66 (37.5%), 83 (47.2%) and 27 (15.3%) were stratified as Prosigna low, intermediate and high risk, respectively. The majority of NHG1 (10 of 12) and NHG3 (37 of 46) tumours were stratified as Stratipath low risk and high risk, respectively. For both risk profiling tests, NHG and Ki67 proliferation index differed between risk groups. Conclusions: In this study of clinically assessed intermediate risk ER-positive HER2-negative breast cancer, we observed a moderate agreement between Prosigna and Stratipath Breast for low risk and high risk groups. In addition, image-based risk profiling stratified more of the NHG2 tumours as high risk. Citation Format: Stephanie Robertson, Yinxi Wang, Wenwen Sun, Emelie Karlsson, Sandy Kang Lövgren, Mattias Rantalainen, Johan Hartman. Clinical evaluation of image-based risk profiling in breast cancer histopathology and comparison to an established gene expression assay [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 PO4-07-05.

Abstract PO3-17-11: The Utility of Oncotype DX in Grade 1 Hormone Receptor-Positive Early Breast Cancer: Insights from a Multicentric Real-World Data Study

Abstract Background: The Oncotype Dx (ODX) genomic risk score (RS) has become an essential tool in clinical practice for guiding adjuvant chemotherapy decisions in early-stage hormone receptor-positive (HR+), HER2-negative breast cancer (BC). Since some of the genes evaluated in the genomic RS tests are proliferation-related, the use of the test is less clear in tumors with low proliferation, such as histologic grade 1 tumors or those with a low Ki67-index. In contrast to common understanding, however, ODX RS is determined more strongly by estrogen-related features and only weakly by proliferation markers. Methods: This multicentric real-world data (RWD) study aimed to evaluate the usefulness of (ODX) in patients with grade 1 (G1) HR+, HER2-negative BC. The study population consisted of patients treated between 2009 and 2020 across nine Brazilian cancer centers. Key endpoints included the prevalence of high genomic RS in the histologic grade 1 cohort, recurrence rates based on genomic risk, and invasive disease-free survival (IDFS). Results: A total of 651 patients with HR+, HER2-negative BC who underwent Oncotype Dx testing were evaluated. Among 651 patients evaluated, 128 had HG1 tumors, constituting the focus of this analysis. The majority of patients were aged over 50 years (59.4%), had breast carcinoma of non-special type (75.8%), and Ki67 index lower than 20% (77%). Tumor stage distribution revealed 28.1% T1b, 50% T1c, and 14% T2 cases. Additionally, 74.2% were classified as N0, 9.4% as N1mic, and 16.4% as N1. According to the binary categorization based on Adjuvant! algorithm, 92.2% of patients (n=118) had a low clinical risk. ODx analysis showed that 21.9% had a low RS, 74.2% had an intermediate RS, and only 3.1% had a high RS. Among the few patients with a high genomic RS, only one patient did not receive adjuvant chemotherapy. With a median follow-up of 38.3 months, three patients experienced recurrence, all of whom had an intermediate RS. Among these cases, two patients were younger than 50 years, had low clinical risk, and a genomic RS of 18-24; both had locoregional recurrences. The third patient, aged over 50 years, had high clinical risk, a RS of 12, and had a distant recurrence. The recurrence rates according to Ki67 index were 1.1% for patients with Ki67 index < 20% and 7.1% for those with Ki67 index ≥ 20%. Notably, no recurrences were observed in the high genomic risk group. The estimated 5-year IDFS rate was 96.9% (95% CI 88.2% - 99.2%). Conclusion: In the context of G1 BC and low clinical risk, the utility and cost-effectiveness of ODX may be limited. These findings emphasize the importance of carefully assessing clinical risk when selecting patients for genomic RS tests, thereby optimizing resource utilization. Longer follow-up is planned for this RWD cohort. Citation Format: Renata Colombo Bonadio, Leandro Oliveira, Daniel Batista, Daniela Rosa, Artur Katz, Max Mano, Daniele Assad-Suzuki, Daniel Argolo, Solange Sanches, Rafael Kaliks, Débora Gagliato, Thais Megid, Daniel Musse, Tatiana Correa, Andrea Shimada, Romualdo Barroso-Sousa, Marcelle Cesca, Débora Gaudêncio, Larissa Moura, Julio Araujo, José Bines, Laura Testa. The Utility of Oncotype DX in Grade 1 Hormone Receptor-Positive Early Breast Cancer: Insights from a Multicentric Real-World Data 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 PO3-17-11.

Role of neoadjuvant rectal score in prognosis and adjuvant chemotherapy decision-making in locally advanced rectal cancer following neoadjuvant short-course radiotherapy and consolidation chemotherapy

Objectives: To assess the prognostic impact of the neoadjuvant rectal (NAR) score following neoadjuvant short-course radiotherapy and consolidation chemotherapy in locally advanced rectal cancer (LARC), as well as its value in guiding decisions for adjuvant chemotherapy. Methods: Between August 2015 and August 2018, patients were eligible from the STELLAR phase III trial (NCT02533271) who received short-course radiotherapy plus consolidation chemotherapy and for whom the NAR score could be calculated. Based on the NAR score, patients were categorized into low (＜8), intermediate (8-16), and high (＞16) groups. The Kaplan-Meier method, log rank tests, and multivariate Cox proportional hazard regression models were used to evaluate the impact of the NAR score on disease-free survival (DFS). Results: Out of the 232 patients, 24.1%, 48.7%, and 27.2% had low (56 cases), intermediate (113 cases), and high NAR scores (63 cases), respectively. The median follow-up period was 37 months, with 3-year DFS rates of 87.3%, 68.3%, and 53.4% (P＜0.001) for the low, intermediate, and high NAR score groups. Multivariate analysis demonstrated that the NAR score (intermediate NAR score: HR, 3.10, 95% CI, 1.30-7.37, P=0.011; high NAR scores: HR=5.44, 95% CI, 2.26-13.09, P＜0.001), resection status (HR, 3.00, 95% CI, 1.64-5.52, P＜0.001), and adjuvant chemotherapy (HR, 3.25, 95% CI, 2.01-5.27, P＜0.001) were independent prognostic factors for DFS. In patients with R0 resection, the 3-year DFS rates were 97.8% and 78.0% for those with low and intermediate NAR scores who received adjuvant chemotherapy, significantly higher than the 43.2% and 50.6% for those who did not (P＜0.001, P=0.002). There was no significant difference in the 3-year DFS rate (54.2% vs 53.3%, P=0.214) among high NAR score patients, regardless of adjuvant chemotherapy. Conclusions: The NAR score is a robust prognostic indicator in LARC following neoadjuvant short-course radiotherapy and consolidation chemotherapy, with potential implications for subsequent decisions regarding adjuvant chemotherapy. These findings warrant further validation in studies with larger sample sizes.

Disparities in OncotypeDx Testing and Subsequent Chemotherapy Receipt by Geography and Socioeconomic Status.

OncotypeDx is a prognostic and predictive genomic assay used in early-stage hormone receptor-positive, HER2- (HR+/HER2-) breast cancer. It is used to inform adjuvant chemotherapy decisions, but not all eligible women receive testing. We aimed to assess variation in testing by demographics and geography, and to determine whether testing was associated with chemotherapy. For 1,615 women in the Carolina Breast Cancer Study with HR+/HER2-, Stage I-II tumors, we estimated prevalence differences (PD) and 95% confidence intervals (CI) for receipt of OncotypeDx genomic testing in association with and sociodemographic characteristics. We assessed associations between testing and chemotherapy receipt overall and by race. Finally, we calculated the proportion of eligible women receiving OncotypeDx by county-level rurality, census tract-level socioeconomic status, and Area Health Education Center regions. 38% (N = 609) of potentially eligible women were tested, with lower testing prevalences in Black (31%; PD, -11%; 95% CI, -16%-6%) and low-income women (24%; PD, -20%; 95% CI, -29% to -11%) relative to non-Black and higher income women. Urban participants were less likely to be tested than rural participants, though this association varied by region. Among women with low genomic risk tumors, tested participants were 29% less likely to receive chemotherapy than untested participants (95% CI, -40% to -17%). Racial differences in chemotherapy were restricted to untested women. Both individual and area-level socioeconomics predict likelihood of OncotypeDx testing. Variable adoption of OncotypeDx by socioeconomics and across geographic settings may contribute to excess chemotherapy among patients with HR+/HER2- cancers. See related In the Spotlight, p. 635.

Deep learning-guided adjuvant chemotherapy selection for elderly patients with breast cancer.

The efficacy of adjuvant chemotherapy in elderly breast cancer patients is currently controversial. This study aims to provide personalized adjuvant chemotherapy recommendations using deep learning (DL). Six models with various causal inference approaches were trained to make individualized chemotherapy recommendations. Patients who received actual treatment recommended by DL models were compared with those who did not. Inverse probability treatment weighting (IPTW) was used to reduce bias. Linear regression, IPTW-adjusted risk difference (RD), and SurvSHAP(t) were used to interpret the best model. A total of 5352 elderly breast cancer patients were included. The median (interquartile range) follow-up time was 52 (30-80) months. Among all models, the balanced individual treatment effect for survival data (BITES) performed best. Treatment according to following BITES recommendations was associated with survival benefit, with a multivariate hazard ratio (HR) of 0.78 (95% confidence interval (CI): 0.64-0.94), IPTW-adjusted HR of 0.74 (95% CI: 0.59-0.93), RD of 12.40% (95% CI: 8.01-16.90%), IPTW-adjusted RD of 11.50% (95% CI: 7.16-15.80%), difference in restricted mean survival time (dRMST) of 12.44 (95% CI: 8.28-16.60) months, IPTW-adjusted dRMST of 7.81 (95% CI: 2.93-11.93) months, and p value of the IPTW-adjusted Log-rank test of 0.033. By interpreting BITES, the debiased impact of patient characteristics on adjuvant chemotherapy was quantified, which mainly included breast cancer subtype, tumor size, number of positive lymph nodes, TNM stages, histological grades, and surgical type. Our results emphasize the potential of DL models in guiding adjuvant chemotherapy decisions for elderly breast cancer patients.

The 21-Gene Recurrence Score Assay Improved Multidisciplinary Treatment Compliance in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer Patients: An Analysis of 2,323 Patients.

The 21-gene recurrence score (RS) can guide adjuvant chemotherapy decisions in the multidisciplinary treatment (MDT) of patients with early breast cancer. This study aimed to evaluate the influence of the 21-gene RS assay on patient' compliance with MDT and its association with disease outcomes. Patients diagnosed with pN0-1, hormone receptor-positive, human epidermal growth factor receptor-2-negative breast cancer between January 2013 and June 2019 were enrolled. A logistic regression model was used to identify parameters associated with treatment adherence. Prognostic indicators were evaluated using the Cox proportional hazard models. After the assay, patients were less likely to violate the treatment plan (14.9% vs. 23.1%, p < 0.001), and higher compliance rates were observed for chemotherapy (p = 0.042), radiotherapy (p = 0.012), and endocrine therapy (p < 0.001). Multivariable analysis demonstrated that the 21-gene RS assay (odds ratio [OR], 1.43; 95% confidence interval [CI], 1.09-1.88; p = 0.009) was independently associated with MDT compliance. Moreover, compliance with MDT was independently associated with better disease-free survival (hazard ratio, 0.43; 95% CI, 0.29-0.64; p < 0.001), regardless of the 21-gene RS assay (interaction p = 0.842). The 21-gene RS assay improved the MDT compliance rate in patients with early breast cancer. Adherence to MDT is associated with a better prognosis.

Adjuvant chemotherapy decision-making in stage II colon adenocarcinoma associated with patients’ age and high-risk factors

Adjuvant chemotherapy decision-making in stage II colon adenocarcinoma associated with patients’ age and high-risk factors

Circulating Tumour DNA Guided Adjuvant Chemotherapy Decision Making in Stage II Colon Cancer-A Clinical Vignette Study.

Circulating tumour DNA (ctDNA) is a promising biomarker that may better identify stage II colon cancer (CC) patients who will benefit from adjuvant chemotherapy (AC) compared to standard clinicopathological parameters. The DYNAMIC study demonstrated that ctDNA-informed treatment decreased AC utilisation without compromising recurrence free survival, but medical oncologists' willingness to utilise ctDNA results to inform AC decision is unknown. Medical oncologists from Australia, Canada and New Zealand were presented with clinical vignettes for stage II CC comprised of two variables with three levels each (age: ≤50, 52-69, ≥70 years; and clinicopathological risk of recurrence: low, intermediate, high) and were queried about ctDNA testing and treatment recommendations based on results. Sixty-four colorectal oncologists completed at least one vignette (all vignettes, n = 59). The majority of oncologist were Australian (70%; Canada: n = 13; New Zealand: n = 6) and had over 10 years of clinical experience (n = 41; 64%). The proportion of oncologists requesting ctDNA testing exceeded 80% for all vignettes, except for age ≥ 70 and low-risk disease (63%). Following a positive ctDNA result, the proportion of oncologists recommending AC (p < 0.01) and recommending oxaliplatin-based doublet (p < 0.01) increased in all vignettes. Following a negative result, the proportion recommending AC decreased in all intermediate and high-risk vignettes (p < 0.01).

Novel nomogram to predict the overall survival of postoperative patients with gastric signet

BackgroundThe TNM staging system cannot accurately predict the prognosis of postoperative gastric signet ring cell carcinoma (GSRC) given its unique biological behavior, epidemiological features, and various prognostic factors. Therefore, a reliable postoperative prognostic evaluation system for GSRC is required. This study aimed to establish a nomogram to predict the overall survival (OS) rate of postoperative patients with GSRC and validate it in the real world.MethodsClinical data of postoperative patients with GSRC from 2002 to 2014 were collected from the Surveillance, Epidemiology, and End Results database and randomly assigned to training and internal validation sets at a 7:3 ratio. The external validation set used data from 124 postoperative patients with GSRC who were admitted to the Affiliated Tumor Hospital of Harbin Medical University between 2002 and 2014. The independent risk factors affecting OS were screened using univariate and multivariate analyses to construct a nomogram. The performance of the model was evaluated using the C-index, receiver operating characteristic curve (ROC), calibration curve, decision analysis (DCA) curve, and adjuvant chemotherapy decision analysis.ResultsUnivariate/multivariate analysis indicated that age, stage, T, M, regional nodes optimized (RNE), and lymph node metastasis rate (LNMR) were independent risk factors affecting prognosis. The C-indices of the training, internal validation, and external validation sets are 0.741, 0.741, and 0.786, respectively. The ROC curves for the first, third, and fifth years in three sets had higher areas under the curves, (training set, 0.782, 0.864, 0.883; internal validation set, 0.781, 0.863, 0.877; external validation set, 0.819, 0.863, 0.835). The calibration curve showed high consistency between the nomogram-predicted 1-, 3-, and 5-year OS and the actual OS in the three queues. The DCA curve indicated that applying the nomogram enhanced the net clinical benefits. The nomogram effectively distinguished patients in each subgroup into high- and low-risk groups. Adjuvant chemotherapy can significantly improve OS in high-risk group (P = 0.034), while the presence or absence of adjuvant chemotherapy in low-risk group has no significant impact on OS (P = 0.192).ConclusionsThe nomogram can effectively predict the OS of patients with GSRC and may help doctors make personalized prognostic judgments and clinical treatment decisions.

The budget impact of utilizing the Oncotype DX Breast Recurrence Score test from a US healthcare payer perspective

Background and objectivesThe Oncotype DX Breast Recurrence Score test is used to estimate distant recurrence risk of hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2–) early-stage breast cancer and inform decisions on the use of adjuvant chemotherapy. A model-based budget impact analysis compared the Oncotype DX test in combination with clinical–pathological risk against using clinical–pathological risk alone for HR+/HER2– node-negative (N0) and node-positive (N1; 1–3 axillary lymph nodes) early-stage breast cancer patients.Materials and methodsTest and medical costs associated with treatment of breast cancer were assessed through a US healthcare payer perspective. Distributions of patients by Recurrence Score result and distant recurrence probabilities with chemo-endocrine and endocrine therapy were derived from the TAILORx (N0) and RxPONDER (N1) trials. Changes in budget impact were evaluated over a 5-year horizon for a 1,000,000-member hypothetical health plan.ResultsWith the Oncotype DX test, there was an incremental budget impact of $261,067 (per member per month (PMPM): $0.004), in the N0 population, and $56,143 (PMPM: $0.001) in the N1 population over the 5-year period. The largest budget impact reduction in the N0 population was attributed to reduced breast cancer recurrence costs (incremental: −$633,457, PMPM: −$0.011), while chemotherapy sparing reduced costs in the N1 population (incremental: −$94,884, PMPM: −$0.002).ConclusionThe clinical benefit of using the Oncotype DX test to inform adjuvant chemotherapy decisions has been shown in multiple randomized controlled trials. This analysis demonstrated that while using the Oncotype DX test to inform adjuvant chemotherapy decisions may slightly increase US healthcare costs over an initial 5-year time horizon (driven by a cost increase in the first year with cost savings reflected in remaining 4 years), there is significant scope for cost savings when assessing beyond this period due to avoided downstream costs of distant recurrence and long-term chemotherapy adverse events. PMPM costs also remain low across all populations examined, demonstrating a close-to-neutral budget impact.

Compliance to genomic test recommendations to guide adjuvant chemotherapy decision-making in the case of hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, in real-life settings.

Genomic tests are a useful tool for adjuvant chemotherapy decision-making in the case of hormone receptor-positive (HR+), and human epidermal growth factor receptor 2-negative (HER2-) breast cancer with intermediate prognostic factors. Real-life data on the use of tests can help identify the target population for testing. French multicentric study (8 centers) including patients, all candidates for adjuvant chemotherapy for HR-positive, HER2-negative early breast cancer. We describe the percentage of tests performed outside recommendations, according to the year of testing. We calculated a ratio defined as the number of tests required to avoid chemotherapy for one patient, and according to patient and cancer characteristics. We then performed a cost-saving analysis using medical cost data over a period of 1 year from diagnosis, calculated from a previous study. Finally, we calculated the threshold of the ratio (number of tests required to avoid chemotherapy for one patient) below which the use of genomic tests was cost-saving. A total of 2331 patients underwent a Prosigna test. The ratio (performed test/avoided chemotherapy) was 2.8 [95% CI: 2.7-2.9] in the whole population. In the group following recommendations for test indication, the ratio was 2.3 [95% CI: 2.2-2.4]. In the case of non-abidance by recommendations, the ratio was 3 [95% CI: 2.8-3.2]. Chemotherapy was avoided in 841 patients (36%) following the results of the Prosigna test. The direct medical costs saved over 1 year of care were 3,878,798€ and 1,718,472€ in the group of patients following test recommendations. We calculated that the ratio (performed test/avoided chemotherapy) needed to be under 6.9 for testing to prove cost-saving. The use of genomic testing proved cost-saving in this large multicentric real-life analysis, even in certain cases when the test was performed outside recommendations.

Survival results according to Oncotype Dx recurrence score in patients with hormone receptor positive HER-2 negative early-stage breast cancer: first multicenter Oncotype Dx recurrence score survival data of Turkey.

The Oncotype Dx recurrence score (ODx-RS) guides the adjuvant chemotherapy decision-making process for patients with early-stage hormone receptor-positive, HER-2 receptor-negative breast cancer. This study aimed to evaluate survival and its correlation with ODx-RS in pT1-2, N0-N1mic patients treated with adjuvant therapy based on tumor board decisions. Estrogen-positive HER-2 negative early-stage breast cancer patients (pT1-2 N0, N1mic) with known ODx-RS, operated on between 2010 and 2014, were included in this study. The primary aim was to evaluate 5-year disease-free survival (DFS) rates according to ODX-RS. A total of 203 eligible patients were included in the study, with a median age of 48 (range 26-75) and median follow-up of 84 (range 23-138) months. ROC curve analysis for all patients revealed a recurrence cut-off age of 45 years, prompting evaluation by grouping patients as ≤45 years vs. >45 years. No significant difference in five-year DFS rates was observed between the endocrine-only (ET) and chemo-endocrine (CE) groups. However, among the ET group, DFS was higher in patients over 45 years compared to those aged ≤45 years. When stratifying by ODx-RS as 0-17 and ≥18, DFS was significantly higher in the former group within the ET group. However, such differences were not seen in the CE group. In the ET group, an ODx-RS ≥18 and menopausal status were identified as independent factors affecting survival, with only an ODx-RS ≥18 impacting DFS in patients aged ≤45 years. The ROC curve analysis for this subgroup found the ODx-RS cut-off to be 18. This first multicenter Oncotype Dx survival analysis in Turkey demonstrates the importance of Oncotype Dx recurrence score and age in determining treatment strategies for early-stage breast cancer patients. As a different aproach to the literature, our findings suggest that the addition of chemotherapy to endocrine therapy in young patients (≤45 years) with Oncotype Dx recurrence scores of ≥18 improves DFS.

Implication of MRI Risk Stratification System on the Survival Benefits of Adjuvant Chemotherapy After Neoadjuvant Chemoradiotherapy in Patients With Locally Advanced Rectal Cancer

To investigate the implication of a Magnetic resonance imaging (MRI) risk stratification system on the selection of patients with locally advanced rectal cancer (LARC) who can benefit from adjuvant chemotherapy (ACT) after neoadjuvant chemoradiotherapy (NCRT). This retrospective study included 328 patients with LARC who underwent NCRT and surgery. The median follow-up duration was 79 months (Interquartile range, 66-94 months). Cox logistic regression analysis was used to identify MRI risk factors and develop a risk stratification system to stratify patients into groups with high and low risks. Kaplan-Meier curves of distant metastasis-free survival (DMFS) and overall survival (OS) were used to show the benefits of ACT and stratify results based on the MRI risk stratification system and postoperative pathological staging. An MRI risk stratification system was built based on four MRI risk factors, including MRI-identified T3b-T4 stage, N1-N2 stage, extramural venous invasion, and tumor deposits. 74 (22.6%) patients with 3-4 MRI risk factors were classified into the MRI high-risk group. ACT could significantly improve 5-year DMFS (19.2% versus 52.1%; p<0.001) and OS (34.6% versus 75.0%; p<0.001) for patients in the MRI high-risk group, while ACT had no survival benefit for patients in the MRI low-risk group. The benefits of ACT were not observed in patients with any pathological staging subgroups (ypT0-2N0, ypT3-4N0, and ypN+). Patients in the MRI high-risk group could benefit from ACT, regardless of postoperative pathological staging. Baseline MRI should be considered more in ACT decision-making.

Cost-effectiveness analysis of a circulating tumor DNA-based molecular residual disease assay to guide adjuvant chemotherapy decisions in patients with resectable early stage colorectal cancer.

e18929 Background: An ongoing prospective study in patients with stage II or III colorectal cancer (CRC) has demonstrated ctDNA testing to be prognostic of recurrence risk and predictive of adjuvant chemotherapy (ACT) benefit. From the perspective of a US payer, we aimed to investigate the cost effectiveness of incorporating ctDNA analysis using the commercially available molecular residual disease (MRD) assay (Signatera™) into standard practice to aid in adjuvant chemotherapy decision-making, where traditional high-risk clinicopathological (CP) features have not shown a significant benefit of ACT in Stage II CRC. Methods: We developed a decision model to project lifetime clinical and economic consequences of different adjuvant treatment-guiding strategies. The model was parameterized using a follow-up of up to 2-years from a recently published data from GALAXY study and the cost data from the US literature. GALAXY is an observational arm of the ongoing CIRCULATE-Japan study (UMIN000039205) that analysed pre-surgical and post-surgical ctDNA in patients with stage II-IV resectable CRC. Costs are presented in 2023 US dollars. Future costs and benefits were discounted at 3%. Results: Compared to the CP predictors alone-based strategy, ctDNA analysis using the MRD assay in combination with CP predictors-based strategy led to an increase of 0.8 life years and 0.7 quality adjusted-Life Years (QALY) and cost savings of $9,771 per patient. Conclusions: The addition of MRD detection by ctDNA to traditional CP predictors aids in adjuvant chemotherapy decision-making in patients with stage II or III resectable CRC and is likely to be cost effective in the US healthcare system. ctDNA testing should therefore be considered for adoption in this disease setting.

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]

A senescence-related signature for predicting the prognosis of breast cancer: A bioinformatics analysis.

Breast cancer is a heterogeneous disease with diverse prognosis and treatment outcomes. Current gene signatures for prognostic prediction are limited to specific subtypes of breast cancer. Cellular senescence is a state of irreversible cell cycle arrest that affects various physiological and pathological processes. This study aimed to develop and validate a senescence-related signature for predicting the prognosis of breast cancer patients. We retrieved 744 senescence-associated genes from the SeneQuest database and analyzed their expression profiles in 2 large datasets of breast cancer patients: The Cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC). We used univariate Cox regression analysis, least absolute shrinkage and selection operator (LASSO) regression, and multivariate Cox regression analysis to derive a 29-gene senescence-related risk signature. The risk signature was significantly associated with disease-specific survival (DSS), clinical characteristics, molecular subtypes, and immune checkpoint genes expressions in both datasets. The risk signature also stratified high-risk and low-risk patients within the same clinical stage and molecular subtype. The risk signature was an independent prognostic factor for breast cancer patients. The senescence-related signature may be a useful biomarker for predicting prognosis and immunotherapy response of breast cancer patients. The risk signature may also guide adjuvant chemotherapy decisions, especially in hormone receptor positive (HR+) and human epidermal growth factor receptor type 2 (HER2)- subtypes.

CtDNA guided adjuvant chemotherapy versus standard of care adjuvant chemotherapy after curative surgery in patients with high risk stage II or stage III colorectal cancer: a multi-centre, prospective, randomised control trial (TRACC Part C)

BackgroundCirculating tumour DNA (ctDNA) to detect minimal residual disease (MRD) is emerging as a biomarker to predict recurrence in patients with curatively treated early stage colorectal cancer (CRC). ctDNA risk stratifies patients to guide adjuvant treatment decisions. We are conducting the UK’s first multi-centre, prospective, randomised study to determine whether a de-escalation strategy using ctDNA to guide adjuvant chemotherapy (ACT) decisions is non-inferior to standard of care (SOC) chemotherapy, as measured by 3-year disease free survival (DFS) in patients with resected CRC with no evidence of MRD (ctDNA negative post-operatively). In doing so we may be able to spare patients unnecessary chemotherapy and associated toxicity and achieve significant cost savings for the National Health Service (NHS).MethodsWe are recruiting patients with fully resected high risk stage II and stage III CRC who are being considered for ACT into the study which uses results from a plasma-only ctDNA assay to guide treatment decisions. Eligible patients are randomised 1:1 to receive ctDNA-guided chemotherapy versus SOC chemotherapy. The primary endpoint is the difference in DFS at 3 years between the trial arms. Secondary endpoints include the proportion of patients in the ctDNA-guided arm who are ctDNA negative post-operatively and receive de-escalated ACT compared to the standard arm, the difference in overall survival (OS), neurotoxicity and quality of life between the arms, and the cost-effectiveness of ctDNA-guided therapy compared to SOC treatment. We hypothesise that using a ctDNA-guided approach to ACT decisions is non-inferior to SOC. Target accrual is 1621 patients over 4 years, which will provide a power of 80% with an alpha of 0.1 to demonstrate non-inferiority with a margin of 1.25 in survival of the ctDNA-guided approach compared to SOC. We anticipate approximately 50 UK centres will participate. The study opened with the Guardant Reveal plasma-only ctDNA assay in August 2022.DiscussionThe trial will determine whether ctDNA guided ACT is non-inferior to SOC ACT in patients with fully resected high risk stage II and stage III resected CRC, with the potential to significantly reduce unnecessary ACT and the toxicity associated with it.Trial registrationNCT04050345.

Abstract ED11-1: Hormone receptor positive breast cancer

Abstract Estrogen receptor (ER) positive breast cancer is a heterogeneous group of diseases. While the major goal of neoadjuvant treatment in patients with locally advanced disease is to downstage the cancer to facilitate resectability and breast-conserving surgery, there is increasing evidence that response in the neoadjuvant setting has prognostic implications in predicting long term relapse outcomes. However, questions remain as to strategies that optimize neoadjuvant treatment selection of endocrine therapy versus chemotherapy, and whether adjuvant therapy could be tailored based on treatment response in the neoadjuvant setting. In this lecture, we will discuss evolving data regarding pathologic and molecular characteristics of ER positive breast cancer that assist with treatment selection in the neoadjuvant setting and the potential role of pathologic and biomarker response to neoadjuvant endocrine therapy in tailoring adjuvant chemotherapy decisions. Citation Format: Cynthia Ma. Hormone receptor positive breast cancer [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 ED11-1.

Adjuvant Therapy in Breast Cancer Patients With Microscopic Residual Disease

IntroductionSurgical resection is the gold standard for early-stage breast cancer. Positive surgical margins are associated with poor outcome. Endocrine therapy (ET) is recommended as primary systemic treatment for hormone receptor positive (HR+) breast cancer after surgery. We hypothesized that chemoenocrine therapy (CET) would not be associated with improved survival relative to ET for patients with positive margins. Materials and methodsThe National Cancer Database was queried for pathologic stage I HR + HER2-breast cancer patients treated with partial mastectomy and adjuvant whole-breast irradiation between 2004 and 2017. The adjuvant treatment approaches to positive surgical margins were investigated and compared. Overall survival was compared between systemic treatment groups using multivariable cox proportional hazards regression. ResultsAmong 228,453 patients, a positive surgical margin (microscopic residual disease, R1) was identified in 3561 (1.6%) patients. Compared with complete resections, positive margin was associated with inferior overall survival (hazard ratio [HR] = 1.276, P = 0.003). Among the R1 patients, 78.7% received ET only, 11.7% received CET, 1.2% received chemotherapy only, and 8.5% received no systemic therapy. After controlling for patient, facility, and tumor characteristics, ET provided greatest survival benefit (relative to no therapy, HR = 0.378, P < 0.001) followed by CET (HR = 0.446, P = 0.020). Compared with ET alone, CET is not associated with additional overall survival benefit (HR = 1.179, P = 0.595). ConclusionsCET appeared not to be associated with an improved overall survival in early stage HR + HER2-breast cancer with microscopic residual disease relative to ET. Positive surgical margins therefore are probably not a relevant clinical factor for adjuvant chemotherapy decision-making.