Absence Of pCR Research Articles

Validation of large language models for detecting pathologic complete response in breast cancer using population-based pathology reports

AimsThe primary goal of this study is to evaluate the capabilities of Large Language Models (LLMs) in understanding and processing complex medical documentation. We chose to focus on the identification of pathologic complete response (pCR) in narrative pathology reports. This approach aims to contribute to the advancement of comprehensive reporting, health research, and public health surveillance, thereby enhancing patient care and breast cancer management strategies.MethodsThe study utilized two analytical pipelines, developed with open-source LLMs within the healthcare system’s computing environment. First, we extracted embeddings from pathology reports using 15 different transformer-based models and then employed logistic regression on these embeddings to classify the presence or absence of pCR. Secondly, we fine-tuned the Generative Pre-trained Transformer-2 (GPT-2) model by attaching a simple feed-forward neural network (FFNN) layer to improve the detection performance of pCR from pathology reports.ResultsIn a cohort of 351 female breast cancer patients who underwent neoadjuvant chemotherapy (NAC) and subsequent surgery between 2010 and 2017 in Calgary, the optimized method displayed a sensitivity of 95.3% (95%CI: 84.0–100.0%), a positive predictive value of 90.9% (95%CI: 76.5–100.0%), and an F1 score of 93.0% (95%CI: 83.7–100.0%). The results, achieved through diverse LLM integration, surpassed traditional machine learning models, underscoring the potential of LLMs in clinical pathology information extraction.ConclusionsThe study successfully demonstrates the efficacy of LLMs in interpreting and processing digital pathology data, particularly for determining pCR in breast cancer patients post-NAC. The superior performance of LLM-based pipelines over traditional models highlights their significant potential in extracting and analyzing key clinical data from narrative reports. While promising, these findings highlight the need for future external validation to confirm the reliability and broader applicability of these methods.

Abstract PS04-03: Survival benefit of regional nodal irradiation in clinically node-positive breast cancer following neoadjuvant chemotherapy and breast-conserving surgery

Abstract Introduction: In recent years, there has been increasing use of neoadjuvant chemotherapy (NAC) and pathologic complete response (pCR) rates for certain breast cancer phenotypes (40-70%). Although encouraging, this has resulted in uncertainties in traditional axillary management. Meanwhile, clinically node-positive (cN+) patients who have a low burden of disease downstaged to node-negative (ypN0) after NAC and get breast-conserving surgery (BCS) may avoid an axillary lymph node dissection (cALND) but still have regional nodal irradiation (RNI) recommended regardless of axillary surgery. Those who remain node-positive (ypN+) undergo cALND and RNI with an increased risk of lymphedema. In this study, we evaluated the survival benefit of RNI in cN+ patients after NAC and BCS. Methods: We reviewed (cN+) stage I-III non-inflammatory female breast cancer patients who underwent NAC followed by BCS between 2010 and 2020 in the National Cancer Database (NCDB). Patients having a history of another malignancy who received hormone therapy or radiotherapy before surgery or whose pathologic nodal status (ypN) was unknown were excluded. Overall survival (OS) from surgery was compared between those who did and did not receive RNI. Patient and tumor characteristics were compared across subgroups using chi-square and Wilcoxon rank sum tests. Weighted Kaplan-Meier curves and log-rank tests were used to assess the effect of RNI on OS. As a sensitivity analysis, analyses were stratified based on yPN status. Finally, multivariable logistic regression was used to determine predictors of receiving RNI. Results: The 8,250 cN+ patients had a mean age of 54.6±11.1 years. In total, 69.1% of patients were White, 23.9% were Black, and 10.2% were Hispanic. The mean number of removed and positive nodes were 10.0 ±7.8 and 2.3±3.8. The most common histology and phenotype were invasive ductal carcinoma (IDC) in 94.3% and hormone-positive (HR+) in 41.0%. Breast and nodal pCR rates were 25.9% and 34.7%, with nodal pCR achieved in 20.7%, 46.0%, and 44.4% of HR+, HER2+, and triple-negative tumors. RNI was performed in 52.1% of the patients (45.3% of the yPN0 and 55.9% of the yPN+). The mean number of nodes removed was 10.4±7.8 in the RNI+ and 9.6±7.7 in the RNI- groups (P < 0.01). The mean number of positive nodes was 2.6±4.0 in the RNI+ and 1.9±3.6 in the RNI- groups (P < 0.01). On multivariable analysis, the predictors of RNI administration included the number of positive nodes (p < 0.01), cN stage (p < 0.01), cT3 (p < 0.01), and tumor phenotype (p < 0.01). Grade I tumors (p=0.04) and Medicare beneficiaries (p=0.01) were less likely to get RNI. The survival rates were 79.9% and 81.9% in the RNI+ and RNI– groups, with a median follow-up of 62.1±31.4 and 62.8±32.2 in the RNI+ and RNI- groups. In the entire cohort, ypN0 patients had improved OS when compared with ypN+ patients (p < 0.001), but in adjusted analyses, there was no difference in OS between those who did and did not receive RNI (p=0.6). There was also no difference in OS comparing those who did and did not receive RNI in the ypN0 (p=0.96) or ypN+ (p=0.76) groups. Conclusion: For breast cancer patients having a modest nodal burden of disease and BCS after NAC, traditional prognostic factors such as stage and nodal status, as well as phenotype, grade, and the presence or absence of pCR, impact overall survival. Although some such factors appear to bias practitioners into giving RNI for patients undergoing NAC and BCS, RNI after NAC and BCS does not improve OS, regardless of pCR status, even at a mean follow-up time of 5.5 years. Further studies evaluating the impact on local control and longer-term outcomes should be pursued to enable the creation of specific guidelines surrounding indications for RNI based on the initial burden of disease and the final response from NAC administration. Citation Format: Mahtab Vasigh, Richard Bleicher, Austin Williams, Allison Aggon, Mary Pronovost, Andrea Porpiglia, Matthew Pierotti, Christian Cruz Pico. Survival benefit of regional nodal irradiation in clinically node-positive breast cancer following neoadjuvant chemotherapy and breast-conserving surgery [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 PS04-03.

Abstract PO4-03-12: De-escalating treatment with neoadjuvant chemotherapy in early triple-negative breast cancer

Abstract Neoadjuvant chemotherapy (NAT) is a standard treatment in early triple-negative breast cancer, but the regimen and duration of this treatment are controversial. We analyze a cohort of early triple negative breast cancer treated with NAT with different schemas to determine its efficacy. 272 patients treated with NAT since 2001 to 2020 were selected. The median age of the group was 57 years (27-85), initial size 30 mm (9-122) and Ki67 expression was 60 (7-100). 107 patients (39.3%) had histologically confirmed initial axillary involvement and the regimens of chemotherapy used were carboplatin AUC 5 + weekly paclitaxel (80 mg/m2) x 4 cycles in 56 cases (21%) (SCHEME A), same scheme followed by 4 cycles of adriamycin 50 mg/m2 + cyclophosphamide 500 mg/m2 in 85 cases (31%) (SCHEME B), Adriamycin 50 mg/m2 + cyclophosphamide 500 mg/m2 × 4 cicles in 44 (16%) (SCHEME C) and Adriamycin 50 mg/m2 + cyclophosphamide 500 mg/m2 × 4 cicles followed by docetaxel 100 mg/m2 × 4 cicles in 87 (32%) (SCHEME D). We achieved a 51% of pathologic complete response (pCR),and a total of 24% of recurrences. The proportion of PCR and recurrence according to the different schemes is represented in the following table. The clinical factors associated with recurrence were the initial size (OR 8.6), the initial axillary involvement (OR 4.21) and the absence of pCR (OR 8.14), and for patients with pCR it was only the initial axillary involvement (OR 3.4). Patients that received schema A in NAT only presented a total of 5% of recurrence (3/56), only in patients with initial axillary involvement. The NAT schema with carboplatin AUC 5 + weekly paclitaxel (80 mg/m2) x 4 cycles is safe in patients without initial nodal involvement with high pathologic complete response (62%) and lower recurrence rate (9% in nonPCR and 3% in pCR). Therefore, it could be considered as a standard scheme of neoadjuvant chemotherapy for patients without axillary involvement. Table. SCHEMA A (20%) B (31%) C (16%) D (32%) Pcr 62% 63% 41% 37% Recurrence in pCR 3% 7% 16% 9% Recurrence in nonpCR 9% 16% 50% 63% Citation Format: Serafin Morales Murillo, Ariadna Gasol Cudós, Noemí Tuset Der-Abrain. De-escalating treatment with neoadjuvant chemotherapy in early triple-negative breast cancer [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 PO4-03-12.

Breast-conserving surgery is not associated with increased local recurrence in patients with early-stage node-negative triple-negative breast cancer treated with neoadjuvant chemotherapy

BackgroundNeoadjuvant chemotherapy (NACT) is routinely used for patients with triple-negative breast cancer (TNBC). Upfront breast-conserving therapy (BCT) consisting of breast-conserving surgery (BCS) and adjuvant radiotherapy (RT) has been shown to be associated with improved outcome in patients with early TNBC as compared to mastectomy. MethodsWe identified 2632 patients with early TNBC from the German Breast Group meta-database. Patients with cT1-2 cN0 and ypN0, available surgery and follow-up data were enrolled. Data of 1074 patients from 8 prospective NACT trials were available. Endpoints of interest were locoregional recurrence as first site of relapse (LRR), disease-free survival (DFS) and overall survival (OS). We performed univariate and multivariate Fine-Gray analysis and Cox regression models. ResultsAfter a median follow-up of 64 months, there were 94 (8.8%) locoregional events as first site of relapse. Absence of pathologic complete response (pCR) was associated with increased LRR upon uni- and multivariate analysis (hazard ratio [HR] = 2.28; p < 0.001 and HR = 2.22; p = 0.001). Type of surgery was not associated with LRR. Patients in the BCS-group had better DFS and OS (DFS: HR = 0.47; p < 0.001 and OS: HR = 0.40; p < 0.001). BCS was associated with improved DFS and OS upon multivariate analysis (DFS: HR = 0.51; p < 0.001; and OS HR = 0.43; p < 0.001), whereas absence of pCR was associated with worse DFS and OS (DFS: HR = 2.43; p < 0.001; and OS: HR = 3.15; p < 0.001). ConclusionsIn this retrospective analysis of patients with early stage node-negative TNBC treated with NACT, BCS was not associated with an increased risk of LRR but with superior DFS and OS.

Dose-dense neoadjuvant chemotherapy of operable and locally advanced inoperable triple negative breast cancer: First results of single-centre prospective trial

Introduction. Neoadjuvant chemotherapy (NACT) is the standard of care for II–III stages of TN BC. Complete pathomorphological response (pCR) is associated with a signifiant increase in event-free and overall survival. In addition, in the absence of pCR, post-neoadjuvant adjuvant therapy is prescribed, while if pCR is achieved, additional treatment is not carried out. Despite a large number of studies on NACT of TN BC, different NACT regimens in various clinical trials make it diffiult to interpret their results.Objective. To investigate the effiacy of 4ddAC followed by 12 weekly cycles of paclitaxel and carboplatin in TN BC (according to the RCB system and the frequency of pCR); determine the predictive factors for the effectiveness of this chemotherapy regimen, and the effect of dose intensity on the pCR rate.Methods. This prospective study included 154 patients with TN breast cancer who received dose-dence neoadjuvant chemotherapy from January 2017 to March 2022.Results. PCR rate was 53.25 % (n = 82), RCB 0–I was 66.88 % (n = 103), disease progression was observed in 3.25 % (n = 4). The frequency of germline mutations in the BRCA1/2 genes was 21.43 % (n = 33). The most common mutation was BRCA1 5382insC – 63.64 % (n = 21) of all BRCA1/2 mutations. Rare mutations detected by NGS accounted for 30.3 % (n = 10). The only factor associated with a signifiant increase in the pCR rate was age ≤50 years (p = 0.010), there was a trend towards an increase pCR rate in the subgroups T1–2 (p = 0.052) and BRCA1/2 mut (p = 0.080). There was no effect of the dose intensity on the achievement of pCR.Conclusions. This retrospective analysis is the largest study evaluating the effiacy of 4 ddAC followed by 12 PC in NACT TN BC. The regimen allows to achieve a high frequency of pCR, despite the large proportion of patients with locally advanced breast cancer. The high frequency of rare mutations in the BRCA1/2 genes and the potential therapeutic signifiance of this marker in residual disease treatment dictates the need for NGS in all patients with TN in breast cancer.

Predicting treatment response for the safe non-operative management of patients with rectal cancer using an MRI-based deep-learning model.

e15648 Background: Neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision (TME) surgery has been the standard treatment for patients with locally advanced rectal cancer. Surgery, while effective in treating rectal cancer, can lead to significant long-term morbidity, such as bowel, urinary, and sexual dysfunction, and potential dependence on a colostomy for evacuation. A pathologic complete response (pCR) to neoadjuvant CRT suggests that TME surgery may not be necessary, as the tumor may have been effectively treated with CRT alone. However, the only definitive determination of pCR is based on a pathologic exam, which requires a surgical specimen. By comparing pre- and post-CRT images, clinical complete response (cCR) is a surrogate for pCR that does not require surgery. However, cCR is a poor proxy for pCR, with sensitivity and positive predictive values of 34.1% and 30.6% respectively1. Purpose: Our aim is to develop a multiparametric longitudinal MRI-based 3D deep-learning model to predict pCR in patients with locally advanced rectal cancer. Methods: We identified 360 patients with rectal cancer who had neoadjuvant CRT followed by surgical resection between January 2012 and December 2021 in an academic medical center. We have classified patients into two groups based on the presence or absence of pCR in their resected tumor specimen. We will train and validate a multiparametric longitudinal MRI-based 3D deep-learning model to predict pCR. Our model will use T1-weighted, T2-weighted with and without contrast, and/or diffusion-weighted MRIs before and after neoadjuvant CRT to predict pCR. Using multiparametric MRIs offers a comprehensive understanding of the tumor and surrounding tissue, and including longitudinal MRIs will provide valuable information on the impact of treatment. To assess the performance of the model, we will use receiver operating characteristic (ROC) analysis as well as positive and negative predictive values to evaluate its ability to predict pCR. Preliminary Results: Among 360 patients, 227 (63.1%) were male, 187 (51.9%) were Non-White, and the average age was 58.7 (SD of 13.3) years. The surgical pathology reports showed that 44 (12.2%) patients had achieved a pCR, while the visual assessment of post-CRT MRIs revealed that 49 (13.6%) had achieved a cCR. 1. Liu, C. et al. Predictive Value of Clinical Complete Response after Chemoradiation for Rectal Cancer. J. Am. Coll. Surg. 235, S51–S52 (2022).

Abstract PD15-06: PD15-06 Pathologic complete response and breast-conserving surgery are associated with improved prognosis in patients with early-stage triple-negative breast cancer treated with neoadjuvant chemotherapy

Abstract Background: Neoadjuvant chemotherapy (NACT) is standard of care for patients with triple-negative breast cancer (TNBC). Treatment response, especially pathologic complete response (pCR), is a strong predictive factor for treatment outcome. In the setting of up-front surgery, retrospective data have suggested improved outcome in patients with early TNBC that received breast-conserving surgery with adjuvant radiotherapy (BCT) as compared to mastectomy. Methods: We identified 2632 patients with early TNBC from the German Breast Group meta-database. Patients with cT1-2 cN0 and ypN0, available surgery and follow-up data were eligible for this project. A total of 1074 patients from 8 prospective NACT trials were analyzed. Endpoints of interest were locoregional recurrence as first site of relapse (LRR, other sites of recurrence were considered competing events), disease-free survival (DFS) and overall survival (OS); analyses were performed using univariate and multivariate Fine-Gray (for LRR) and Cox models including study, age, cT, surgery type and pCR. For the analyses including pCR as covariable, only patients at risk at the landmark time were evaluated. Results: Median age was 48 years, 69.6% of patients had cT2 tumors and 85.3% underwent BCS. Of the 1074 analyzed patients, 48.8% achieved pCR. After a median follow-up of 64 months, there were 94 (8.8%) locoregional events as first site of relapse. Upon univariate analysis, absence of pCR (hazard ratio [HR]=2.28; 95%CI 1.44-3.61; p&amp;lt; 0.001) and ypT-stage (ypT0/is vs. ypT1-3, HR=0.61; 95%CI 0.40-0.95; p=0.028) were significantly associated with LRR, while type of surgery, age and cT-stage were not. Upon multivariate analysis, absence of pCR was the only factor associated with increased risk of LRR (HR=2.22; 95%CI 1.38-3.58; p=0.001). Patients that underwent mastectomy (N=158) were significantly younger (age ≤ 50 years 72.8% vs. 59.9% for BCT [N=916]; p=0.002) DFS and OS was significantly better in patients who underwent BCT compared to mastectomy (DFS: HR=0.47; 95%CI 0.34-0.66; p&amp;lt; 0.001 and OS: HR=0.40; 95%CI 0.26-0.63; p&amp;lt; 0.001). In multivariate analysis, BCT was associated with a significantly better DFS and OS as compared to mastectomy (DFS: HR=0.51; 95%CI 0.36-0.72; p&amp;lt; 0.001; and OS HR=0.43; 95%CI 0.27-0.68; p&amp;lt; 0.001), whereas absence of pCR was associated with significantly worse DFS and OS (DFS: HR=2.43; 95%CI 1.78-3.31; p&amp;lt; 0.001; and OS: HR=3.15; 95%CI 1.94-5.10; p&amp;lt; 0.001). Conclusions: In this retrospective analysis from the GBG meta-database, treatment response, e.g. pCR, was the main determinant of locoregional recurrence in patients with early stage TNBC treated with NACT. BCT was associated with improved DFS and OS compared to mastectomy, which may at least in part reflect favorable patient selection. Citation Format: David Krug, Valentina Vladimirova, Michael Untch, Thorsten Kühn, Andreas Schneeweiss, Carsten Denkert, Beyhan Ataseven, Christine Solbach, Bernd Gerber, Hans Tesch, Michael Golatta, Sabine Seiler, Jörg Heil, Valentina Nekljudova, Sibylle Loibl. PD15-06 Pathologic complete response and breast-conserving surgery are associated with improved prognosis in patients with early-stage triple-negative breast cancer treated with neoadjuvant chemotherapy [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 PD15-06.

Moving HER2-low breast cancer predictive and prognostic data from clinical trials into the real world.

Background: Previous data, mostly from clinical trials, reported that HER2-low status is associated with low pathological complete response (pCR), and favourable prognosis. Since these findings suggest the existence of an additional breast cancer subtype, we questioned if the predictive/prognostic value of HER2-low was also relevant in the real world. Methods: Data from non-metastatic breast cancer patients treated with neoadjuvant chemotherapy and surgery (2009–2020) were retrieved from our institutional prospectively-maintained registry. Univariable and multivariable logistic models were implemented to study the association between pCR and baseline HER2 status. Univariable analysis of disease-free survival (DFS) was performed through Kaplan-Meier survival curves and log-rank tests. Results: Starting from a total of 790 consecutive cases, we identified 444 newly-diagnosed breast cancer patients featuring HER2 immunohistochemistry (IHC) 0 (HER2-0, n = 109), and 1 + or IHC 2+/in situ hybridization negative (HER2-low, n = 335) receiving anthracycline and taxane-based regimens in 88.9% of cases. Most of the patients were diagnosed with stage II (67.3%) and there was no difference of disease presentation according to HER2-status. pCR was attained by 71 (16.0%) patients and was significantly associated with increased DFS (p = 0.031). Compared to HER2-0, HER2-low cases were more likely hormone receptor-positive (81.2% vs. 43.1%, p < 0.001), well-differentiated (47.5% vs. 26.6%, p = 0.001), less proliferative (21.5% vs. 8.3%, p = 0.001) and less responsive to treatment (pCR 11.6% vs. 29.4%, p < 0.0001). There was no difference in DFS according to HER2 status, though hormone-receptor (HR) negative/HER2-low cases tended to have a worse prognosis compared to HR-negative/HER2-0. By pCR achievement, 3-years DFS was 87.5.% (75.1–100%) vs. 71.6% (65.9–77.8%) (p = 0.161) in HER2-low and 89.1% (75.8–100%) vs. 72.1% (59.7–87.0%) (p = 0.092) in HER2-0. Conclusion: Our real-world data show that HER2-low breast cancer patients represent roughly a half of the cases treated with neoadjuvant therapy, and have poor treatment response. In absence of pCR, HER2-low breast cancer patients have a dismal prognosis, especially when primary tumor hormone receptor status is negative. Studies are therefore needed to define the biology of these tumors for new therapeutic targets and to incorporate HER2-targeting agents in early-stage treatment.

Predictive Biomarkers of Response to Neoadjuvant Chemotherapy in Breast Cancer: Current and Future Perspectives for Precision Medicine.

Simple SummaryDespite the increased use of neoadjuvant chemotherapy in the early setting of breast cancer, there is a clinical need for predictive markers of response in daily practice. In the era of precision medicine and personalized treatment, new predictive markers that enable the better selection of patients for specific therapies are required. In this review, we describe the current knowledge about the molecular biomarkers used for clinical decision making for patients with breast cancer. We also report how microenvironment-driven intratumoral heterogeneity may influence the validation of biomarkers useful for precision medicine. We provide an overview of promising biomarkers, including pathological markers, genetic signatures, radiological techniques and liquid biopsies, with a great potential to be implemented in routine clinical practice. Finally, we discuss the use of relevant pre-clinical models of breast cancer to integrate microenvironmental specificities in order to identify and validate reliable biomarkers of (non-)response to neoadjuvant chemotherapy.Pathological complete response (pCR) after neoadjuvant chemotherapy in patients with early breast cancer is correlated with better survival. Meanwhile, an expanding arsenal of post-neoadjuvant treatment strategies have proven beneficial in the absence of pCR, leading to an increased use of neoadjuvant systemic therapy in patients with early breast cancer and the search for predictive biomarkers of response. The better prediction of response to neoadjuvant chemotherapy could enable the escalation or de-escalation of neoadjuvant treatment strategies, with the ultimate goal of improving the clinical management of early breast cancer. Clinico-pathological prognostic factors are currently used to estimate the potential benefit of neoadjuvant systemic treatment but are not accurate enough to allow for personalized response prediction. Other factors have recently been proposed but are not yet implementable in daily clinical practice or remain of limited utility due to the intertumoral heterogeneity of breast cancer. In this review, we describe the current knowledge about predictive factors for response to neoadjuvant chemotherapy in breast cancer patients and highlight the future perspectives that could lead to the better prediction of response, focusing on the current biomarkers used for clinical decision making and the different gene signatures that have recently been proposed for patient stratification and the prediction of response to therapies. We also discuss the intratumoral phenotypic heterogeneity in breast cancers as well as the emerging techniques and relevant pre-clinical models that could integrate this biological factor currently limiting the reliable prediction of response to neoadjuvant systemic therapy.

364-OR: Apolipoprotein A-I and Clinical Remission in Adults with Type 1 Diabetes-InLipoDiab1 Study

Introduction: Apolipoprotein A-I (Apo A-I) , the main protein in high-density lipoproteins, improves beta-cell function and insulin sensitivity in experimental models and in people with type 2 diabetes. In those with type 1 diabetes (DM1) , clinical remission (CR) is a key factor for improved prognosis. However, predictors of CR in DM1 are not well described. Whether Apo A-I predicts CR in patients with DM1 remains unknown. Aim To assess the relationship between baseline Apo A-I at the time of diagnosis of DM1 with the presence of CR after 12 months of the disease. Methods: The participants of Insulin Therapy and Lipoproteins' Profile in Type 1 Diabetes Study (InLipoDiab1; NCT02306005) were prospectively observed from the onset of the disease (the blood collection was performed before exogenous insulin administration) through 12 months. The final observation included 53 adults (62% men, age at onset 27±6 years) . DM1 was confirmed with guideline-based criteria on the presence of specific autoantibodies. The endpoint was the presence of pCR at the end of observation, which was defined as IDAA1C ≤ 9, according to the definition by Mortensen et al.: A1C (%) + [4 × insulin dose (U/kg/day) ]. Apo A-I was measured in serum with an ELISA kit. The group was divided into two according to the presence and absence of pCR. Results: At 12 months, pCR was present in 43 participants (81%) . Baseline serum Apo A-I was significantly lower in participants without pCR versus those with the presence of pCR [0.79 (0.39-1.58) vs. 4.51 (0.95-5.93) mg/dl, p=0.002, respectively]. In multiple logistic regression, higher baseline Apo A-I was associated with the presence of pCR after 12 months, adjusted for sex, age, weight and the presence of diabetic ketoacidosis at onset (OR 1.74 (CI 95% 1.02-2.96) , p=0.03) . Conclusion: The higher Apo A-I serum concentration at onset of DM1 the higher chance is for pCR in adults with DM1, after 12 months of observation. Higher serum Apo A-I levels seem to be a good prognostic factor for pCR of DM1. Disclosure A.Uruska: Other Relationship; Lilly, Novo Nordisk. A.Rohatgi: Speaker's Bureau; CSL Behring. A.Cieluch: None. A.Grzelka-wozniak: Other Relationship; Novo Nordisk, Roche Diabetes Care. J.Flotynska: None. A.Pypec: None. D.Zozulinska-ziolkiewicz: Advisory Panel; Dexcom, Inc., Medtronic, Speaker's Bureau; Abbott Diabetes, Ascensia Diabetes Care, AstraZeneca, BIOTON S.A., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck &amp; Co., Inc., Novo Nordisk, Sanofi. Funding Kosciuszko Foundation and Poznan University of Medical Sciences

Integrative analysis of urine cell-free DNA for the detection of residual disease in localized bladder cancer patients.

559 Background: We previously developed a liquid biopsy assay to measure urine tumor DNA (utDNA) levels based on detection of single nucleotide variants (SNVs) in urine cell-free DNA (cfDNA). Nonsilent SNV detection in urine from muscle-invasive bladder cancer (MIBC) patients prior to radical cystectomy (RC) was associated with pathologic residual disease and worse progression-free survival (Chauhan et al., PLOS Medicine, 2021). Given the multiple types of genomic alterations present in bladder cancer (BC), here we developed a multi-omics approach for estimating utDNA levels without restricting our approach to SNVs. We performed ultra-low pass whole genome sequencing (ULP-WGS) based copy number analysis and urine Cancer Personalized Profiling by deep Sequencing (uCAPP-Seq) of urine cell-free DNA to predict pathologic complete response (pCR) in localized BC patients. Methods: We acquired urine preoperatively from 65 BC patients (69% muscle-invasive) on the day of standard-of-care RC, and after neoadjuvant chemotherapy in 48% of patients. We performed ULP-WGS of urine cfDNA from all 65 BC patients and 11 healthy adults. utDNA levels based on genome-wide copy number alterations (CNAs) in urine cfDNA was estimated using ichorCNA. In order to derive a SNV-based utDNA level as well, uCAPP-Seq was applied to urine cfDNA samples derived from 42 patients using a 145 kb panel of 49 consensus driver genes commonly mutated in MIBC. Results: In our cohort of 65 BC patients, 55% of patients achieved pCR ( n = 36) while 45% had residual disease detected in their surgical sample (no pCR; n = 29). Comparing ULP-WGS-derived utDNA levels between the groups, patients with no pCR had significantly higher CNA-derived tumor fractions in urine compared to patients with pCR (median 8.9% vs 1.8%, p = 0.01) and healthy adults ( n = 11) (median 8.9% vs 0%, p = 0.006). Further analysis with uCAPP-Seq in 42 patients revealed that nonsilent SNV-based utDNA detection correlated significantly with the absence of pCR ( p &lt; 0.001) with a sensitivity of 81% and specificity of 81%. Moreover, utDNA-positive patients exhibited significantly worse progression-free survival compared to utDNA-negative patients (HR = 7.4; 95% CI: 1.4–38.9; p = 0.02). Conclusions: Bladder cancer patients who did not attain a pCR at the time of RC had greater genome-wide copy number alterations and nonsilent single nucleotide variants in their urine cfDNA compared to patients with pCR. These results suggest that integrative multi-omics of urine derived from MIBC patients has potential real-world clinical impact for bladder-sparing approaches in select patients.

Gestion de la crise COVID-19 dans une organisation multicentrique de dialyse au cours des trois premières vagues : retour d’expérience de NephroCare France

At the start of the COVID crisis, NephroCare operated 40 dialysis units in 7 regions, with 2,740 hemodialysis patients. The national COVID-19 crisis team implemented early the necessary measures to ensure the safety of dialysis patients and caregivers in the context of the pandemic. These measures were mostly traditional, but some were specific to our organization. They were modified during the 3 successive waves. The first wave mainly impacted NephroCare Ile-de-France which recorded 75% of the contaminations with an impact on the dialysis parameters of non-COVID patients which was not found during the second wave due to reduced stress (34% of contaminations) and a better management of COVID+ patients. The effectiveness of the measures put in place is suggested by the absence of PCR+ in asymptomatic patients and the perfect adequacy of the anti-SARS-CoV2 antibodies with the diagnosis of COVID in one severely impacted Ile-de-France unit, opposite to literature reporting significant rates of positive PCR or serology in asymptomatic patients. In addition, the contamination rate was calculated below the national rate reported by the Biomedicine Agency. The third wave was marked by the implementation of the anti-SARS-CoV2 vaccination with a proportion of vaccinated patients not different from national data and a decrease in COVID cases at the end of the third wave while the national incidence remained stable on the period. In conclusion, this experience of facing an unprecedented serious situation showed the responsiveness of the organization, significant innovations and the efficacy of the implemented measures.

Urine tumor DNA detection of minimal residual disease in muscle-invasive bladder cancer treated with curative-intent radical cystectomy: A cohort study.

BackgroundThe standard of care treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy, which is typically preceded by neoadjuvant chemotherapy. However, the inability to assess minimal residual disease (MRD) noninvasively limits our ability to offer bladder-sparing treatment. Here, we sought to develop a liquid biopsy solution via urine tumor DNA (utDNA) analysis.Methods and findingsWe applied urine Cancer Personalized Profiling by Deep Sequencing (uCAPP-Seq), a targeted next-generation sequencing (NGS) method for detecting utDNA, to urine cell-free DNA (cfDNA) samples acquired between April 2019 and November 2020 on the day of curative-intent radical cystectomy from 42 patients with localized bladder cancer. The average age of patients was 69 years (range: 50 to 86), of whom 76% (32/42) were male, 64% (27/42) were smokers, and 76% (32/42) had a confirmed diagnosis of MIBC. Among MIBC patients, 59% (19/32) received neoadjuvant chemotherapy. utDNA variant calling was performed noninvasively without prior sequencing of tumor tissue. The overall utDNA level for each patient was represented by the non-silent mutation with the highest variant allele fraction after removing germline variants. Urine was similarly analyzed from 15 healthy adults. utDNA analysis revealed a median utDNA level of 0% in healthy adults and 2.4% in bladder cancer patients. When patients were classified as those who had residual disease detected in their surgical sample (n = 16) compared to those who achieved a pathologic complete response (pCR; n = 26), median utDNA levels were 4.3% vs. 0%, respectively (p = 0.002). Using an optimal utDNA threshold to define MRD detection, positive utDNA MRD detection was highly correlated with the absence of pCR (p < 0.001) with a sensitivity of 81% and specificity of 81%. Leave-one-out cross-validation applied to the prediction of pathologic response based on utDNA MRD detection in our cohort yielded a highly significant accuracy of 81% (p = 0.007). Moreover, utDNA MRD–positive patients exhibited significantly worse progression-free survival (PFS; HR = 7.4; 95% CI: 1.4–38.9; p = 0.02) compared to utDNA MRD–negative patients. Concordance between urine- and tumor-derived mutations, determined in 5 MIBC patients, was 85%. Tumor mutational burden (TMB) in utDNA MRD–positive patients was inferred from the number of non-silent mutations detected in urine cfDNA by applying a linear relationship derived from The Cancer Genome Atlas (TCGA) whole exome sequencing of 409 MIBC tumors. We suggest that about 58% of these patients with high inferred TMB might have been candidates for treatment with early immune checkpoint blockade. Study limitations included an analysis restricted only to single-nucleotide variants (SNVs), survival differences diminished by surgery, and a low number of DNA damage response (DRR) mutations detected after neoadjuvant chemotherapy at the MRD time point.ConclusionsutDNA MRD detection prior to curative-intent radical cystectomy for bladder cancer correlated significantly with pathologic response, which may help select patients for bladder-sparing treatment. utDNA MRD detection also correlated significantly with PFS. Furthermore, utDNA can be used to noninvasively infer TMB, which could facilitate personalized immunotherapy for bladder cancer in the future.

Tracking minimal residual disease with urine tumor DNA in muscle-invasive bladder cancer after neoadjuvant chemotherapy.

e16514 Background: Standard-of-care for muscle-invasive bladder cancer (MIBC) consists of neoadjuvant chemotherapy (NAC) followed by radical cystectomy. The inability to noninvasively assess minimal residual disease (MRD) after NAC limits our ability to offer bladder-sparing treatment. We perform urine tumor DNA (utDNA) analysis to identify pathologic complete response (pCR) at the time of cystectomy in patients receiving NAC. Methods: We applied CAPP-Seq to urine cell-free DNA samples acquired on the day of radical cystectomy from 19 MIBC patients treated with NAC. utDNA variant-calling was performed without prior tumor mutational knowledge using a panel of 49 consensus driver genes mutated in MIBC. The utDNA level for each patient was represented by the duplex-supported non-silent driver mutation with the highest variant allele fraction (vAF) after removing germline variants. We also serially tracked utDNA variants in two patients before, during, and after NAC. Results: Comparing patients with residual disease detected in their cystectomy specimen ( n = 10) to those who achieved a pCR ( n = 9), median utDNA levels were 2.4% vs. 0%, respectively ( P = 0.006). Using an optimal utDNA threshold to define MRD detection, positive utDNA MRD was highly correlated with the absence of pCR ( P = 0.003). Analysis of two patients’ serial urine samples revealed utDNA dynamics that were consistent with treatment responses in real-time. In one patient who ultimately achieved a pCR, four non-silent driver mutations were detectable pre-NAC, including ERCC2 N238S (7.8% vAF) associated with increased chemosensitivity. One week after starting NAC, ERCC2 N238S increased by 1.6-fold in urine, as did PIK3CA E726K which increased by 8.4-fold. Four weeks post-NAC, however, all mutations previously detected in this patient’s urine became undetectable, consistent with the patient’s pCR and long-term disease-free survival. Conversely, another patient harbored two non-silent driver mutations in PLEKHS1 (1.9% vAF) and KMT2D (4.9% vAF) pre-NAC. One week after starting NAC, both mutations decreased dramatically by 8.0- and 4.3-fold, respectively. By three weeks post-NAC, however, these mutations progressively increased by 5.2-fold on average, which correlated with a lack of pCR as well as post-treatment disease progression. Two newly detected non-silent driver mutations in ARID1A and ERBB2 also emerged on NAC and persisted following completion of chemotherapy , likely reflecting the development of treatment resistance. Conclusions: utDNA MRD after NAC but before radical cystectomy for MIBC correlated significantly with pathologic response, which could help personalize patient selection for bladder-sparing treatments in the future. Serial monitoring of utDNA variants during NAC can reveal dynamic mutational changes that reflect real-time treatment responses as well as ultimate disease-free survival.

Long-term outcomes of patients with HER2+ breast cancer with small-size residual disease (≤ypT1) in the absence of pathological response after trastuzumab-based neoadjuvant chemotherapy and without adjuvant T-DM1: A monocentric retrospective study.

589 Background: The Katherine trial has shown that adjuvant T-DM1 improved invasive disease free survival (iDFS) of patients with HER2+ breast cancer who did not achieve a pathological complete response (pCR) with trastuzumab-based neoadjuvant chemotherapy (NAC). However, some subgroups may benefit less from this treatment escalation. Methods: All HER2+ breast cancer patients treated with trastuzumab-based NAC between 2006 and 2016 were retrieved from our institution’s database. Neo- or adjuvant T-DM1 was an exclusion criterion. We then selected the patients who did not achieve a pCR and analyzed the outcome (iDFS and overall survival (OS)) according to ypT, ypN and several factors analyzed in the Katherine trial. Results: Out of the 182 patients, 117 patients reached the inclusion criteria. Patient’s characteristics were similar to the trastuzumab arm of the Katherine trial. With a median follow-up of 75.4 months (29.3–149.7), 28 events (24%) occurred, among which 22 distant relapses. In univariate analysis, ≤ypT1 vs &gt; ypT1, ypN0 vs ypN+, no capsular rupture, signs of histological response (Sataloff not D in T or N) were associated with a better iDFS. In multivariate analysis, only ypT status remained significant. Of note, patients with ≤ypT1 (ypTis, ypT0, ypTmic, ypT1) (n = 81; 69%) had an excellent outcome: 3 years (y) and 5y iDFS rates of 90% (83.6-96.8) and 88.6% (81.9-95.9) respectively. The remaining patients (n = 36; 31%) had a significantly lower 3y and 5y iDFS: 69.2% (55.6-86.2) and 59.5% (45-78.6) respectively (p = 0.0017). OS in a multivariate analysis was also improved in pts with the smaller residual and/or node negative disease (3y OS rates of 100% (100-100) vs 92.1% (85.7-99); 5y OS rates of 96% (90.7-100) vs 81.1% (71.6-91.9); p = 0.02). Conclusions: In the absence of pCR after trastuzumab-based NAC, patients with pathological response scored as ≤ypT1 (ypTis,ypT0, ypTmic, ypT1) have an excellent outcome. These patients may derive less benefit from adjuvant T-DM1.

Prognostic impact of high stromal tumor-infiltrating lymphocytes (sTIL) in the absence of pathologic complete response (pCR) to neoadjuvant therapy (NAT) in early stage triple negative breast cancer (TNBC).

583 Background: Pathologic complete response is an excellent surrogate for disease-free survival (DFS) and overall survival (OS) in TNBC. High sTIL is associated with improved pCR rates in TNBC. Recent data suggest that high sTIL is also associated with improved outcomes in patients who received no chemotherapy for early stage TNBC (Park, Annals of Oncology, 2019). Thus, we hypothesized that high sTIL may have prognostic impact in patients who do not achieve pCR to NAT. Methods: Pretreatment core biopsies from 182 patients with early-stage TNBC enrolled on the ARTEMIS trial (NCT02276443) were evaluated for sTIL by H&amp;E. Patients were stratified according to sTIL (low &lt; 30%, and high &gt; 30%) and pCR (patients with pCR vs. no pCR). The primary outcome measure was DFS, defined from the date of diagnosis to the first local recurrence, distant metastases or death. Cox proportional hazards regression model was used. During follow-up 33 events for DFS were observed. Results: Among subjects who achieve pCR, DFS was excellent regardless of sTIL status and significantly better than those without pCR (p &lt; 0.05). However, patients with high sTIL and no pCR demonstrated significantly worse DFS compared to all subjects having pCR (HR 0.18, 95% CI 0.04-0.76, p = 0.02). Additionally, we did not find a significant difference between high and low sTIL patients who did not achieve pCR. Conclusions: In early TNBC receiving NAT, for patients failing to achieve pCR, high sTIL was not associated with improved DFS; outcomes were comparable to those with low sTIL without pCR. Thus, high sTIL at baseline does not appear to confer an intrinsic prognostic benefit in the absence of pCR.

Enhancing the Critical Role of Core Needle Biopsy in Breast Cancer

The aim of this literature review is to derive detailed information on the significance of core needle biopsy in the diagnosis and effective treatment of breast cancer, according to current evidence, in an era of targeted therapy dependent on breast cancer stage and subtype. Preoperative diagnosis by core biopsy is rendered obligatory due to its crucial role not only in precise surgical management but also in segregating patients that often present with complete pathologic response (pCR) after neoadjuvant chemotherapy (NAC). Even in the absence of pCR, proper therapeutic management of these patients show significantly better prognosis in progression free survival (PFS) and overall survival (OS).

Abstract P6-10-06: Amsterdam 70-gene profile (MammaPrint) low risk, even in the HER2 positive subset, identifies a population of women with lower early risk for recurrence despite low response rates to chemotherapy and to HER2 targeted therapy

Abstract Importance: It is essential to refine the populations most likely to benefit from targeted chemotherapy combinations. Background: MINDACT showed that molecularly low risk patients, as assessed by the Amsterdam 70-gene profile MammaPrint® (Agendia) (MP), did not benefit from chemotherapy. In the I-SPY2 trial, MP low risk Hormone Receptor (HR) positive/HER2 negative patients are not eligible; however, HR negative or HER2 positive patients were considered high risk and included for treatment with chemotherapy plus novel agents. The neoadjuvant setting provides an opportunity to evaluate whether molecularly low risk HER2 positive patients are good candidates for neoadjuvant chemo/anti-HER2 therapy, where pathologic complete response (pCR) and 3-year outcomes are measured. Objective: To evaluate and further characterize the fraction of and outcomes for patients molecular low-risk disease in the I-SPY2 trial. Methods: The I-SPY2 platform trial is an ongoing multicenter phase 2 multi-arm study utilizing adaptive design and evaluating efficacy and tolerability of investigational agents in combination with standard-of-care chemotherapy for patients with high-risk anatomic stage II/III breast cancer. Patients with HR+HER2- MP low-risk tumors are not eligible. All enrolled patients undergo pretreatment biopsy for genomic evaluation of early recurrence risk with MP for risk stratification and with the 80-gene BluePrint® (Agendia) test for intrinsic subtype classification. Primary endpoint of the study is pCR in breast and lymph nodes (ypT0/is, ypN0). Secondary outcomes included event-free survival (EFS) and distant-recurrence free survival (DRFS). Following standard neoadjuvant treatment with or without a concomitant investigational agent, patients are followed for long-term outcomes. EFS and DRFS at 3 and 5 years in the pCR vs non-pCR groups within histologic and molecular subtypes are determined using the Kaplan Meier method. Results: Of the 1038 enrolled patients by November 2016, 24 patients (3.2%) had molecular low-risk disease as determined by MP. Of these, 21 (87.5%) had HR+HER2+, 1 (4.2%) had HR-HER2+, and 2 (8.4%) had HR-HER2-. BluePrint expression subtyping classified 17 as luminal-type, 6 HER2 enriched-type and 1 basal type. One patient withdrew consent for follow-up. Of the 23 remaining, none achieved pCR and only one (HR+/HER2+) had an EFS event (with median follow-up of 4.3 years). Overall, EFS and DRFS data were available for 950 of the 1038 patients (as of February 2019), with median follow-up of 3.8 years. Of the 173 HR+HER2+ in this cohort, 20 (11.6%) had molecular low-risk tumors. The EFS and DRFS for the 173 HER2+HR+ pCR group is 97% and 98% (non-pCR group 89% and 94%), respectively at 3 years. Removing the molecular low-risk HER2+ patients from the denominator reveals the worse outcome for patients with non pCR: EFS 86% and DRFS 92% at 3 years. The difference is more apparent at 5 years, changing from 74% to 66% for EFS and from 81% to 75% for DRFS. Intrinsic subtypes vary and do not predict early risk. Conclusions: I-SPY2 focuses on women with high clinical risk with only 3.2% of enrolled patients having low molecular risk tumors. However, 12% of HER+ breast cancer enrolled patients had molecular low risk tumors of which 95% were also HR+. In this group, early recurrence is very low despite absence of pCR and irrespective of intrinsic subtype. Refining the population using molecular high-risk classification of patients reveals a greater difference between the pCR and non-pCR groups within the HR+HER2+ subtype in the EFS and DRFS analysis. Clinical trial designs could address the opportunity to find more targeted and less toxic treatments for the HER2+ low molecular risk patient population. Citation Format: Paula R Pohlmann, Christina Yau, Angela DeMichele, Claudine Isaacs, Judy C Boughey, Nola Hylton, Michelle E Melisko, Jane Perlmutter, Hope S Rugo, W. Fraser Symmans, I-SPY 2 TRIAL Consortium, Donald A Berry, Laura Esserman. Amsterdam 70-gene profile (MammaPrint) low risk, even in the HER2 positive subset, identifies a population of women with lower early risk for recurrence despite low response rates to chemotherapy and to HER2 targeted therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-10-06.

Diabetes Mellitus and Metformin Are Not Associated With Breast Cancer Pathologic Complete Response

BackgroundMetformin use has been linked to pathologic complete response (pCR) following neoadjuvant chemotherapy for several malignancies. We aimed to investigate the association of diabetes mellitus (DM) and metformin use with pCR in breast cancer. Materials and methodsAll breast cancer patients who received neoadjuvant chemotherapy during June 2013-October 2016 at two academic medical centers were identified. A retrospective cohort study evaluated patients who did and did not achieve pCR. Multivariable logistic regression identified independent predictors of pCR, specifically looking at metformin use and DM. ResultsThe study group included 351 breast cancer patients, with 90 (25.6%) achieving pCR after neoadjuvant chemotherapy. The rate of DM did not differ between those with and without pCR, nor did the rate of metformin use. Multivariable logistic regression identified HER2-positive tumors and smaller preoperative tumor size as predictors of pCR. The estrogen receptor (ER) positivity was associated with an absence of pCR. Importantly, neither DM nor metformin use was predictive of pCR. ConclusionsThis study by the two institutions supports previous data of tumor-related factors known to be associated with pCR; however, the current analysis found neither DM nor metformin to be independently associated with pCR. Thus, additional prospective study is warranted prior to validating metformin as an antitumor agent.

Evaluation of CHROMagar ESBL and Double Disk Synergy Test (DDST) for Screening of Extended Spectrum Beta-lactamase Producing Uropathogens in South-South Nigeria

Background/Purpose: The aim of this study was to evaluate the effectiveness of CHROMagar ESBL in comparison with Double Disc Synergy Test (DDST) for the detection of ESBL producing uropathogens.&#x0D; Methods: Six hundred and sixty urine samples were collected from pregnant women attending antenatal at General hospital Ikot Ekpene, Eket and Oron. Two hundred and fifty eight isolates were obtained while two hundred and thirty one isolates were ESBL producers. Microbact 24E(Oxoid, UK) was used in the identification of bacterial isolates, antibiotic susceptibility test was done using Kirby-Bauer disk diffusion method following CLSI guidelines using commercially available disc (Oxoid Ltd). Double disk synergy test was carried out on the isolates and inoculation was done using CHROMagar ESBL (France).&#x0D; Results: The prevalence of ESBL 35% was recorded. The sensitivity and specificity of DDST was 88% and 89%, respectively. CHROMagar showed an increase in sensitivity and specificity at 48 h with 98% and 99.0%, respectively. 80% of the ESBL producing isolates were multi drugs resistant. The predominant bacterial pathogens were Enterobacter cloacae (23%), Proteus mirabilis (14%) and Acinetobacter baumanii (13.4%).The ESBL producing isolates showed maximum resistance against Ceftazidime (90%), Cefotaxime (91%), Azetronam (95%), Amikacin (68.2%) followed by ofloxacin (70%) while maximum sensitivity was seen for imipenem (90%) and Augumentin (80%). The study demonstrated that CHROMagar was superior and more sensitive than DDST.&#x0D; Conclusion: CHROMagar ESBL seems to be the most reliable method among phenotypic methods for detection of ESBL in the absence of PCR.