Early Detection Of Disease Progression Research Articles

Abstract PO2-15-02: Personalized circulating tumor DNA (ctDNA) monitoring can early identify disease progression and predict prognosis in patients with breast cancer undergoing neoadjuvant therapy

Abstract Background: Circulating tumor DNA (ctDNA) analysis offers a non-invasive method to assess tumor burden during treatment. Although some data have been reported on the use of ctDNA in neoadjuvant therapy (NAT) for breast cancer (BC), there is a lack of data on neoadjuvant efficacy and prognosis in China specifically using tumor-informed personalized ctDNA monitoring panel. Methods: We performed personalized ctDNA analyses at different time of NAT (before, during, and after) in 19 patients with Stage IIA-IIIB BC. WES was conducted on tumor tissues, and single nucleotide variants (SNVs) (20-40) were selected for each patient to ensure accurate and sensitive detection of individual ctDNA(Shanghai OrigiMed Co., Ltd.). Results: A total of 19 BC patients, 6 HER2-negative and 13 HER2-positive, were enrolled at the Breast Center, Fourth Hospital of Hebei Medical University (China) from June 2022 to May 2023. The median age of the patients was 53 (min-max: 28-64) years old. Through WES, it was discovered that 78.5% (3377/4303) of the mutated genes were unique to each patient. Additionally, 96.1% (637/663) of the selected tumor-informed SNVs were VUS variants. These findings suggest that tumor-informed ctDNA monitoring is more effective than panel-based ctDNA monitoring in BC. Among the patients, 84% (16/19) completed baseline blood collection, 63% (12/19) completed blood collection after NAT and 42% (8/12) patients completed blood collection after the surgery. The baseline positivity rate was 100%, and the baseline ctDNA variant allele frequency was significantly associated with T stage and N stage (both p < 0.01). This suggests that designing a panel based on puncture samples is feasible for ctDNA analysis. The detection of ctDNA before surgery after NAT correlated with the postoperative ctDNA status. Patients with persistently negative ctDNA during NAT were associated with pathologic complete response (pCR), although the difference was not statistically significant due to the small sample size (n=7). In 84% of patients, dynamic changes in ctDNA aligned with imaging findings, indicating a correlation between ctDNA and disease progression. A 56-year-old patient with HER2-negative stage IIIC BC had persistent ctDNA positivity during NAT. Imaging evaluation showed disease progression, with ctDNA allele frequency increasing 18 days before detection on imaging. After surgical tumor removal, the pathology assessment revealed a change in HER2 status from negative to positive. The patient received adjuvant chemotherapy combined with HER2-targeted therapy, resulting in a transition from positive to negative ctDNA status. The disease has remained stable for nearly 9 months. A 29-year-old patient with HER2-positive stage IIIA BC underwent NAT for 8 cycles. Due to drug intolerance, the treatment was interrupted multiple times during the first 4 cycles, and ctDNA remained positive. After modifying the treatment regimen in the 5th cycle, ctDNA became negative until the patient underwent surgery. The postoperative pathology evaluation revealed a pCR. Conclusions: Personalized ctDNA monitoring is more effective than panel-based ctDNA (a predefined set of cancer-associated genes) monitoring in BC. The status of ctDNA before and after surgery following NAT may be correlated, suggesting that patients with positive ctDNA before surgery may benefit from intensive therapy. More importantly, dynamic changes in ctDNA closely align with radiological findings, enabling early detection of disease progression and guiding treatment modifications. Citation Format: Yunjiang Liu, Chao Shi, Xiangmei Zhang, Xiaofei Ren, Shang Wu, Yaxian Wang, Yue Che, Zanmei Xu, Fei Pang. Personalized circulating tumor DNA (ctDNA) monitoring can early identify disease progression and predict prognosis in patients with breast cancer undergoing neoadjuvant therapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-15-02.

CASE REPORT : A RARE CASE OF CUTANEOUS DESMOID-TYPE FIBROMATOSIS

Desmoid fibromatosis (DF) is a rare, locally aggressive connective tissue malignancy primarily affecting musculoaponeurotic tissues, representing less than 3% of all neoplasms. This case report presents a 30-year-old male with cutaneous desmoid fibromatosis, a rare variant characterized by a painless, firm mass in the left shoulder region. Histopathological, immunohistochemical, and molecular analyses confirmed the diagnosis of desmoid cutaneous fibromatosis, with positive findings for nuclear beta-catenin. Management involved a multidisciplinary approach, with a conservative strategy due to the tumors size and location, emphasizing regular monitoring for recurrence. Differential diagnosis considerations included dermatomyofibroma and scar tissue. Treatment options for DF vary, with a shift towards observation as the primary strategy, particularly in cases where surgery may result in significant functional impairment. Medical treatment or surgery may be considered in symptomatic or progressive cases. Close surveillance and follow-up imaging are crucial for early detection of disease progression. cutaneous desmoid fibromatosis presents diagnostic challenges, highlighting the importance of early identification and biopsy to prevent misdiagnosis.

Early Detection of Disease Progression in Metastatic Cancers: Could CTCs Improve RECIST Criteria?

Early detection of disease progression is a crucial issue in the management of cancer patients, especially in metastatic settings. Currently, treatment selection mostly relies on criteria based on radiologic evaluations (RECIST). The aim of the present retrospective study is to evaluate the potential inclusion of circulating tumor cells (CTCs) in hybrid criteria. CTC counts from a total of 160 patients with different metastatic tumors were analyzed for this purpose. In our cohort, 73 patients were affected by breast cancer, 69 by colorectal cancer and 18 by prostate cancer. PFS and OS were evaluated according to the corresponding prediction of disease progression by CTCs and RECIST criteria. In breast cancer, CTC-I has an important impact on the progression-free survival (PFS) and overall survival (OS) values. When CTC-I predicted earlier than RECIST-I, the disease progression, the PFS and OS were shorter with respect to the opposite case. In particular, PFS was 11 (5-16) vs. 34 (23-45)-with p < 0.001-and OS was 80 (22-138) vs. 116 (43-189), p = 0.33. The results suggest a promising role of CTCs as complementary information which could significantly improve the clinical outcomes, and they encourage consideration of future trials to evaluate new hybrid criteria, particularly for patients with breast cancer.

CT features combined with RECIST 1.1 criteria improve progression assessments of sunitinib-treated gastrointestinal stromal tumors.

To explore the auxiliary value of combining CT features with existing response evaluation criteria in the prediction of progressive disease (PD) in gastrointestinal stromal tumors (GIST) patients treated with sunitinib. Eighty-one patients with GISTs who received sunitinib were included in this retrospective multicenter study and divided into training and external validation cohorts. Progression at six months was determined as a reference standard. The predictive performance of the RECIST 1.1 and Choi criteria was compared. CT features at baseline and the first follow-up were analyzed. Logistic regression analyses were used to determine the most significant predictors and develop modified criteria. A total of 216 lesions showed a good response and 107 showed a poor response in 81 patients. The RECIST 1.1 criteria performed better than the Choi criteria in predicting progression (AUC, 0.75 vs. 0.69, p= 0.04). The expanded/intensified high-enhancement area, blurred tumor-tissue interface, and progressive enlarged vessels feeding or draining the mass (EVFDM) differed significantly between lesions with good and poor responses in the training cohort (p= 0.001, 0.003, and 0.000, respectively). Multivariate analysis revealed that the expanded/intensified high-enhancement area (p= 0.001), progressive EVFDM (p= 0.000), and RECIST PD (p= 0.000) were independent predictive factors. Modified RECIST (mRECIST) criteria were developed and showed significantly higher AUCs in the training and external validation cohorts than the RECIST 1.1 criteria (training: 0.81 vs. 0.73, p= 0.002; validation: 0.82 vs. 0.77, p= 0.04). The mRECIST criteria, combining CT features with the RECIST 1.1 criteria, demonstrated superior performance in the prediction of early progression in GIST patients receiving sunitinib. The mRECIST criteria, which combine CT features with the RECIST 1.1 criteria, may facilitate the early detection of progressive disease in GIST patients treated with sunitinib, thereby potentially guiding the timely switch to late-line medications or combination with surgical excision. • The RECIST 1.1 criteria outperformed the Choi criteria in identifying progression of GISTs in patients treated with sunitinib. • GISTs displayed different morphologic features on CT depending on how they responded to sunitinib. • Combining CT morphologic features with the RECIST 1.1 criteria allowed for the prompt and accurate identification of progressing GIST lesions.

Aggressive Prostate Cancer in Patients Treated with Active Surveillance.

Active surveillance has emerged as a promising approach for managing low-risk and favorable intermediate-risk prostate cancer (PC), with the aim of minimizing overtreatment and maintaining the quality of life. However, concerns remain about identifying "aggressive prostate cancer" within the active surveillance cohort, which refers to cancers with a higher potential for progression. Previous studies are predictors of aggressive PC during active surveillance. To address this, a personalized risk-based follow-up approach that integrates clinical data, biomarkers, and genetic factors using risk calculators was proposed. This approach enables an efficient risk assessment and the early detection of disease progression, minimizes unnecessary interventions, and improves patient management and outcomes. As active surveillance indications expand, the importance of identifying aggressive PC through a personalized risk-based follow-up is expected to increase.

Deeply 3D-T1-TFE hypointense voxels are characteristic of phase-rim lesions in multiple sclerosis.

The development of new drugs for the treatment of progressive multiple sclerosis (MS) highlights the need for new prognostic biomarkers. Phase-rim lesions (PRLs) have been proposed as markers of progressive disease but are difficult to identify and quantify. Previous studies have identified T1-hypointensity in PRLs. The aim of this study was to compare the intensity profiles of PRLs and non-PRL white-matter lesions (nPR-WMLs) on three-dimensional T1-weighted turbo field echo (3DT1TFE) MRI. We then evaluated the performance of a derived metric as a surrogate for PRLs as potential markers for risk of disease progression. This study enrolled a cohort of relapsing-remitting (n = 10) and secondary progressive MS (n = 10) patients for whom 3T MRI was available. PRLs and nPR-WMLs were segmented, and voxel-wise normalized T1-intensity histograms were analyzed. The lesions were divided equally into training and test datasets, and the fifth-percentile (p5)-normalized T1-intensity of each lesion was compared between groups and used for classification prediction. Voxel-wise histogram analysis showed a unimodal histogram for nPR-WMLs and a bimodal histogram for PRLs with a large peak in the hypointense limit. Lesion-wise analysis included 1075 nPR-WMLs and 39 PRLs. The p5 intensity of PRLs was significantly lower than that of nPR-WMLs. The T1 intensity-based PRL classifier had a sensitivity of 0.526 and specificity of 0.959. Profound hypointensity on 3DT1TFE MRI is characteristic of PRLs and rare in other white-matter lesions. Given the widespread availability of T1-weighted imaging, this feature might serve as a surrogate biomarker for smoldering inflammation. Quantitative analysis of 3DT1TFE may detect deeply hypointense voxels in multiple sclerosis lesions, which are highly specific to PRLs. This could serve as a specific indicator of smoldering inflammation in MS, aiding in early detection of disease progression. • Phase-rim lesions (PRLs) in multiple sclerosis present a characteristic T1-hypointensity on 3DT1TFE MRI. • Intensity-normalized 3DT1TFE can be used to systematically identify and quantify these deeply hypointense foci. • Deep T1-hypointensity may act as an easily detectable, surrogate marker for PRLs.

Streptococcus gallolyticus infection: A neglected marker for colorectal cancer?

Background and study aimsColorectal cancer (CRC) is the second most common cancer in Malaysia and mostly detected at advanced stages due to lack of awareness of CRC symptoms and signs. CRC pathogenesis is multifactorial, and there is ambiguous evidence on association of Streptococcus gallolyticus infection with CRC that needs further attention.Thus, a case–control study was conducted to determine whether S. gallolyticus infection is a predictor for CRC occurrence among patients attending Sultan Ahmad Shah Medical Centre@IIUM (SASMEC@IIUM). Patients and methodsA total of 33 stool samples from patients diagnosed with CRC and 80 from patients without CRC attending surgical clinic of SASMEC@IIUM were collected and analyzed with iFOBT test and PCR assay to detect S. gallolyticus. ResultsIn this study, the proportion of S. gallolyticus infection was higher among patients with CRC (48.5%) compared with the control group (20%). Univariate analysis shows that occult blood in stool, S. gallolyticus infection and family history were significantly associated with the development of CRC (P < 0.05). Using the multivariate logistic regression model, positive stool PCR for S. gallolyticus had the lowest relative standard error and almost five times the odds of developing CRC after adjusting other factors (adjusted odds ratio = 4.7, 95% confidence interval = 1.7–12.6, relative standard error = 59.6%). ConclusionThis finding suggests that S. gallolyticus infection was the strongest predictor of CRC’s development in our study and potentially serves as a predictive marker for early detection of disease progression.

28P Rational thresholding of circulating tumor DNA copy number for early detection of disease progression in advanced metastatic breast cancer

28P Rational thresholding of circulating tumor DNA copy number for early detection of disease progression in advanced metastatic breast cancer

Factors associated with follow-up attendance of patients with oral squamous cell carcinoma: A retrospective cohort study.

This study examined the postoperative follow-up attendance of oral squamous cell carcinoma (OSCC) patients, evaluated some of the factors associated with it, and assessed its relationship with early detection of postoperative disease progression. An exploratory retrospective cohort study of 430 OSCC patients was conducted. We examined associations of follow-up attendance within the first year after surgery with selected demographic and clinical factors, and with early detection of disease progression. The mean number of follow-up visits within the first year after surgery was 3.9 out of the 12 recommended at our center; few patients were fully adherent. Age ≥70 years, unmarried status, high education level, and negative history of surgery for premalignant or malignant lesions from oral cavity or other sites were significantly associated with lower follow-up attendance. Greater follow-up attendance was significantly associated with early detection of disease progression during the first year after surgery (p=0.025). Adherence to follow-up visits was poor. Several sociodemographic and clinical factors were related to follow-up attendance, greater follow-up attendance was significantly associated with early detection of disease progression, and these should be further explored in future research.

Practical Application of Circulating Tumor-Related DNA of Human Papillomavirus in Liquid Biopsy to Evaluate the Molecular Response in Patients with Oropharyngeal Cancer.

Recent findings have shown that human papillomavirus (HPV) DNA is present in the blood as a tumor-specific biomarker (circulating tumor-related HPV; ctHPV) in patients with HPV-related oropharyngeal cancer (HPV-related OPC). The molecular response (MR) in patients with HPV-related OPC can be defined as the change in the number of ctHPV copies in relation to its initial quantity. The optimal model for assessing the MR using a liquid biopsy (LB) should be based on the E6/E7 sequences of the viral genome. MR assessment can help to evaluate the intensity of ongoing treatments in relation to the tumor response. The evaluation of the residual disease at the end of therapy may also be performed by MR assessment. If a partial MR (pMR) is found, caution is indicated and a subsequent LB should be considered, due to the likelihood of disease progression. Complete radiological and clinical responses together with a complete MR (cMR) convincingly indicate a low risk of treatment failure. Moreover, molecular recurrence (Mrec) during a follow-up, confirmed in two consecutive assays, even despite the lack of any other clinical or radiological symptoms of progression, indicates patients at high risk of disease recurrence. In conclusion, MR by ctHPV assessment may hasten the early detection of disease progression, at any stage of the management of the patient with HPV-related OPC.

Prostate Cancer: Management of Biochemical Recurrence after Surgery.

Radical prostatectomy (RP) is one of the primary treatment options for localised prostate cancer (PCa). Despite its curative intent, 1/3 of patients will experience biochemical recurrence (BCR) during follow-up. Experts have devoted efforts to associate the influence of each individual factor with the risk of BCR to select the optimal treatment for each patient. Optimal management must aim to find a balance between delaying the onset of metastatic disease and overtreating an indolent disease with treatments that can affect quality of life of the patients. Thus far, effective treatment options for men with BCR remain controversial in terms of ideal treatment timing (adjuvant vs. salvage), radiotherapy (RT) fields and doses, selection and duration of systemic therapy and potential synergies between treatments and their therapeutic sequencing. Next-generation imaging techniques, such as Prostate-Specific Membrane Antigen Positron Emission Tomography, are used for early detection of disease progression and exact site of recurrence or progression, thereby enhancing decision making for future disease management. In this review, we evaluate available evidence of controversial topics regarding BCR after RP and explore future directions, such as prognostic and/or predictive factors of response, genetic panels, second-generation hormone treatments, ultra-hypofractionated RT and ongoing clinical trials in this clinical scenario.

Circulating Tumor DNA correlates with Lactate Dehydrogenase, CYFRA 21-1, and CRP levels in patients with advanced NSCLC.

Purpose: To investigate potential association between selected tumor markers and laboratory parameters (lactate dehydrogenase [LDH], neutrophils, hemoglobin, neutrophils, lymphocytes, C-reactive protein, albumin, carcinoembryonic antigen, and cytokeratin 19 fragment 21-1 [CYFRA 21-1]) and circulating tumor DNA (ctDNA) with survival in patients with advanced non-small cell lung cancer (NSCLC). Patients and Methods: The study encompassed 82 patients from a single center. All patients had (localy-) advanced adenocarcinomas. ctDNA was determined before starting therapy and at 6 weeks follow-up. Laboratory parameters were measured before each cycle of therapy and oncomarkers before starting the therapy as standard clinical practice. Mann-Whitney U test, Cox proportional hazards model, Fisher's exact test, and Kaplan-Meier survival estimation with Gehan-Wilcoxon test were used for statistical analysis of the corresponding variables. Results: We have confirmed predictive or prognostic significance for some of the selected laboratory markers and oncomarkers. Above all, we demonstrate a significant relationship between the levels of LDH and the oncomarker CYFRA 21-1 and the presence or absence of ctDNA at the time of diagnosis. We also demonstrate significantly lower CRP levels in patients within whom the ctDNA disappeared during treatment. A similar but statistically insignificant trend was observed for LDH. Conclusions: CYFRA 21-1, LDH and probably CRP correlate with ctDNA levels in NSCLC. Repeated measurement of these markers could thus help in early detection of disease progression in the same way as does ctDNA monitoring.

504 Serum S100B and LDH biomarkers as potential predictive markers of metastatic melanoma

Melanoma is a malignant skin tumor in which progression of the disease occurs most frequently in the first 3 years after removal of the primary tumor, and metastasis can occur at any time and any place. However, early detection of disease progression improves prognosis and patient survival, and tumor markers may help us in this. Serum markers and radiological imaging methods are used in daily practice, but serum markers may be more readily available and more suitable for close monitoring of the disease.

Frontmind: A Phase III, Multicenter, Randomized, Double-Blind Study of Tafasitamab + Lenalidomide + R-CHOP Versus R-CHOP Alone for Newly Diagnosed High-Intermediate and High-Risk Diffuse Large B-Cell Lymphoma

Background R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) is the standard of care for newly diagnosed and untreated diffuse large B-cell lymphoma (DLBCL); however, approximately 30-40% of patients relapse or become refractory. Furthermore, the 5-year overall survival (OS) is lower in high-risk DLBCL patients than in low-risk patients. Co-administration of lenalidomide (LEN) with R-CHOP improved both progression-free survival (PFS) and OS in the ECOG-ACRIN E1412 trial but not in the Phase III ROBUST study, in which a lower dose of LEN was used, despite a positive trend in 2-year PFS rate in a subgroup analysis of patients with high-risk disease. POLARIX (NCT03274492) evaluated a modified regimen substituting polatuzumab vedotin for vincristine (pola-R-CHP), showing a modest improvement in PFS without OS benefit between treatment arms, indicating an unmet clinical need remains. Tafasitamab, an Fc-enhanced, humanized, anti-CD19 monoclonal antibody, in combination with LEN was granted accelerated approval in the US (2020) and conditional/accelerated approval by the EMA (2021) and other regulatory authorities for the treatment of adult patients with relapsed/refractory DLBCL not otherwise specified, including DLBCL arising from low-grade lymphoma, and who are ineligible for ASCT. It is a preferred regimen in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for this setting. CD19 and CD20 are broadly expressed on the surface of DLBCL cells, and a treatment strategy targeting both of these B cell surface molecules may limit target evasion in patients exhibiting low CD20 expression and reduce resistance to R-CHOP. Additionally, LEN is an immunomodulatory drug with antineoplastic activity and enhances antibody-dependent cellular cytotoxicity with tafasitamab and rituximab. The addition of tafasitamab + LEN to R-CHOP may provide further therapeutic benefit in patients with newly diagnosed and untreated DLBCL. The Phase Ib First-MIND (NCT04134936), randomized, safety study of R-CHOP + tafasitamab ± LEN in patients with newly diagnosed and untreated DLBCL showed that tafasitamab + LEN does not affect the dosing and scheduling of R-CHOP, with toxicities similar to those expected with R-CHOP alone (ASH 2021; #3556). frontMIND (NCT04824092) will investigate the efficacy and safety of R-CHOP + tafasitamab + LEN versus R-CHOP alone in previously untreated patients with high-intermediate and high-risk DLBCL. Methods frontMIND is a Phase III, multicenter, randomized, double-blind, placebo-controlled study. As of June 2, 2022, more than 350 study sites have been activated in over 25 countries globally (Figure 1). The study is currently enrolling, with a planned sample size of 880 patients; as of June 6, 2022, more than 50% of the planned sample size have been enrolled in the study. Eligible patients include adults aged 18‒80 years with previously untreated, local biopsy-proven CD20+ DLBCL and high-grade B cell lymphoma (double-hit/triple-hit lymphoma if deemed ineligible for a more aggressive treatment) with IPI score 3-5 (age-adjusted IPI 2-3 if ≤60 years), Eastern Cooperative Oncology Group performance status 0-2, and a time from diagnostic biopsy to start of treatment within 28 days (Figure 2). Patients will be randomized 1:1 to receive six 21-day cycles of either R-CHOP + tafasitamab (12 mg/kg IV, Days 1, 8, and 15) + LEN (25 mg orally, Days 1-10) in the experimental arm or R-CHOP + tafasitamab placebo (0.9% saline solution IV, Days 1, 8, and 15) + LEN placebo (orally, Days 1-10) in the control arm. Patients will be followed for safety and efficacy up to 60 months after the treatment ends. The primary endpoint is investigator-assessed PFS. Secondary endpoints include investigator-assessed event-free survival, OS, safety, and tafasitamab serum concentration (trough and Cmax levels). The sensitivity and specificity of minimal residual disease (MRD) for early detection of disease progression is an exploratory endpoint; further MRD parameters may also be investigated. The study is funded by MorphoSys AG and conducted with the scientific support of members of the Fondazione Italiana Linfomi and the German Lymphoma Alliance. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Minimal Residual Disease Monitoring By Targeted Mass Spectrometry Allows Early Relapse Detection in Multiple Myeloma

Background Multiple myeloma (MM) is a clonal plasma cell disorder found in the bone marrow that produces a monoclonal immunoglobulin (M-protein). With blood based electrophoretic assays such as serum protein electrophoresis (SPEP) the M-protein is monitored, but with limited sensitivity. Minimal residual disease (MRD) negativity during remission correlates with prolonged progression free survival. Lack of sensitivity prevents MRD detection by conventional blood based assays. Bone marrow based assays such as next-generation sequencing (NGS) are highly sensitive in measuring MRD. However, bone marrow biopsies introduce a risk of non-representative sampling and are invasive, which limits repeated testing. Frequent MM monitoring during remission could provide actionable information on disease activity and treatment response. Earlier detection of disease progression could lead to early intervention and, potentially, patient survival benefits. Aim The aim of this study was to perform M-protein monitoring on blood samples of MM patients with sensitive targeted mass spectrometry (MS-MRD), to show the capabilities of this MRD-approach. Methods Forty-one MM patients were selected from the IFM 2009 study (ClinicalTrials.gov number: NCT01191060) with 13-31 serum samples per patient collected longitudinally over 29-60 months follow-up. RNA sequences, NGS-MRD, and SPEP data were available to us. All patients were treated with lenalidomide, bortezomib, and dexamethasone, but only treatment arm B received autologous stem-cell transplantation (ASCT). For each patient, 2 unique tryptic peptides from the M-protein were selected, 1 peptide was selected for patients with only light chain M-protein. For early increases in disease activity, absolute M-protein quantification (g/dL) was performed based on tryptic peptides and stable isotope-labeled peptide as an internal standard. Results Out of a total of 929 measured samples, M-protein was detected in 879 samples by MS-MRD and only in 195 samples by SPEP. Furthermore, MS-MRD showed a 78% concordance with NGS-MRD with 14 samples being MS-MRD positive but NGS-MRD negative. Sensitivity can vary per patient and was estimated between 0.03-0.57 mg/dL in this cohort. Based on the M-protein profiles obtained with MS-MRD, during the maintenance treatment, increase of disease activity was observed in a subset of patients from arm A whereas all patients from arm B, who received ASCT, showed a persistent M-protein decrease. An increase of MM disease activity was observed earlier with MS-MRD in 13 out of 14 patients known to progress during the serum collection period, with a median of 455 days gained compared to the original trial data (p<0.0001). Figure 1 shows MS-MRD data showing disease activity 16 months prior to the known progression. Conclusion A non-invasive and sensitive MS-MRD assay for frequent MM monitoring was implemented on clinical trial samples. MS-MRD showed that patients who received ASCT had a more durable response with decreasing M-protein levels. Moreover, in 93% of the cases an increase of disease activity was detected earlier than with conventional blood tests by more than a year. Future perspective The dynamic information on disease activity that is provided by the MS-MRD can provide patients with feedback on their disease status after each checkup, and can provide clinicians options for evidence based treatment escalation or de-escalation. While the overall patient benefit of such personalized treatment still needs to be assessed in clinical trials, we expect that this can improve patient quality of life and allow for more efficient use of pharmacotherapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prognostic value of circulating tumour DNA during post-radiotherapy surveillance in locally advanced esophageal squamous cell carcinoma.

The potential of circulating tumour DNA (ctDNA) as a reliable biomarker for relapse/metastasis early detection and prognosis in esophageal squamous cell carcinoma (ESCC) after radiotherapy/chemoradiotherapy (RT/CRT) initiation requires comprehensive investigation. Treatment-naive locally advanced ESCC patients with available baseline plasma samples were prospectively enrolled from November 2018 to January 2020. RT/CRT was delivered with a simultaneous integrated boost of radiation dose. Serial plasma samples were collected at baseline (T0 ), week 4 of RT/CRT (T1 ), 1-3 (T2 ) and 3-6 months post-RT/CRT (T3 ). ctDNA was analysed using next-generation sequencing of 474 cancer-relevant genes. A total of 128 plasma samples from 40 eligible patients were analysed (median age: 64 [range: 40-78], 88% males, 95% stage III/IV), and the median follow-up time was 20.6 months (range: 12.2-33.3). During the post-RT/CRT surveillance including 36 patients, radiological progression was observed in 16 patients, and 69% (11/16) had detectable post-RT/CRT ctDNA prior to radiological progression, with a median lead time of 4.4 months compared with radiological imaging. ctDNA positivity at T1 (hazard ratio, HR: 3.60, 95% confidence interval, CI: 1.30-10.01) or T2 (HR: 5.45, 95% CI: 1.72-17.26) indicated inferior progression-free survival (PFS). ctDNA clearance between T0 -T1 (HR: 0.31, 95% CI: 0.08-1.13) or T0 -T2 (HR: 0.11; 95% CI: 0.02-0.61) was associated with relatively favourable PFS. Similar results were obtained when focusing on patients without esophagectomy after RT/CRT. Notably, detectable ctDNA at T1 was a potential indicator of high local recurrence risks (HR: 4.43, 95% CI: 1.31-15.04). ctDNA was identified as a robust biomarker for early detection of disease progression and post-RT/CRT prognosis stratification in ESCC. Detectable ctDNA at week 4 of RT/CRT might indicate higher local recurrence risks, implying the potential clinical utility of ctDNA tests in guiding post-RT/CRT treatments for locoregional control in ESCC.

The Prognostic Value of Circulating Tumor DNA during Post-Radiotherapy Surveillance in Esophageal Squamous Cell Carcinoma

<h3>Purpose/Objective(s)</h3> Esophageal squamous cell carcinoma (ESCC) is a common form of esophageal carcinoma in East Asian countries, while there is an unmet need for reliable biomarkers aiding in early detection of relapse/metastasis and prognosis stratification. Here, we investigated whether circulating tumor DNA (ctDNA) tests could detect relapse/metastasis prior to radiological imaging, and explored the prognostic value of ctDNA monitoring after radiotherapy/chemoradiotherapy (RT/CRT) in ESCC. <h3>Materials/Methods</h3> Treatment-naive locally advanced ESCC patients with available baseline plasma samples were prospectively enrolled from November 2018 to January 2020. RT/CRT was delivered with a simultaneous integrated boost of radiation dose (37.8–50.4Gy to subclinical areas at risk and 44.94–59.92 Gy to the gross tumor and involved lymph nodes). Serial plasma samples were collected at baseline (T₀) and four landmark time-points: week 4 of RT/CRT (T₁), 1–3 months post RT/CRT (T₂), 3–6 months post RT/CRT (T₃), and at least 12 months post RT/CRT (T₄). ctDNA was analyzed using next-generation sequencing of 474 cancer-relevant genes. Kaplan-Meier curves were generated for progression-free survival (PFS), overall survival (OS), locoregional recurrence-free survival (LRFS), as well as distant metastasis-free survival (DMFS), and Cox proportional hazards models were fitted to estimate hazard ratios (HR) with 95% confidence intervals (CI). <h3>Results</h3> A total of 139 plasma samples from 40 eligible patients were analyzed (median age: 64 [range: 40–78], 88% males, 95% stage III/IV, 70% baseline ctDNA shedding), and the median follow-up time was 20.6 months (range: 12.2–33.3). Radiological progression was observed in 17 patients, of whom 13 (77%) had detectable post-RT/CRT ctDNA with a mean lead time of 5.5 months compared to radiological imaging. ctDNA positivity at T₁ or T₂ was associated with inferior PFS (T₁, HR: 3.60, 95% CI: 1.30–10.01; T₂, HR: 5.45, 95% CI: 1.72–17.26) and OS (T₁, HR: 2.70, 95% CI: 0.99–7.36; T₂, HR: 4.02, 95% CI: 1.27–12.75). Patients achieving ctDNA clearance between T₀ and T₁/T₂ had superior PFS compared to those with failure to clear ctDNA (T₁, HR: 0.31, 95% CI: 0.08–1.13; T₂, HR: 0.11; 95% CI: 0.02–0.61). Furthermore, ctDNA positivity at T₁ was identified as a potential indicator of worse LRFS (HR: 4.43, 95% CI: 1.31–15.04), while it was less profoundly associated with DMFS. <h3>Conclusion</h3> ctDNA was identified as a robust biomarker for early detection of disease progression and post-RT/CRT prognosis stratification in ESCC. Detectable ctDNA at week 4 of RT/CRT might indicate higher local recurrence risks, implying the potential clinical utility in guiding post-RT/CRT treatments for locoregional control.

Consensus on early detection of disease progression in patients with multiple sclerosis.

BackgroundEarly identification of the transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive MS (SPMS) can be challenging for clinicians, as diagnostic criteria for SPMS are primarily based on physical disability and a holistic interpretation.ObjectiveTo establish a consensus on patient monitoring to identify promptly disease progression and the most useful clinical and paraclinical variables for early identification of disease progression in MS.MethodsA RAND/UCLA Appropriateness Method was used to establish the level of agreement among a panel of 15 medical experts in MS. Eighty-three items were circulated to the experts for confidential rating of the grade of agreement and recommendation. Consensus was defined when ≥66% agreement or disagreement was achieved.ResultsConsensus was reached in 72 out of 83 items (86.7%). The items addressed frequency of follow-up visits, definition of progression, identification of clinical, cognitive, and radiological assessments as variables of suspected or confirmed SPMS diagnosis, the need for more accurate assessment tools, and the use of promising molecular and imaging biomarkers to predict disease progression and/or diagnose SPMS.ConclusionConsensus achieved on these topics could guide neurologists to identify earlier disease progression and to plan targeted clinical and therapeutic interventions during the earliest stages of SPMS.

Serum immunoinflammatory-related protein complexes as personalized biomarkers for monitoring disease progression and response to treatment in lung cancer patients

BackgroundAlthough routine surveillance to detect lung cancer recurrence with clinical imaging is recommended, early detection of disease progression has a major role in avoiding over-treatment. MethodsHere, serum immunoinflammatory-related protein complexes (IIRPCs) of a series of 1331 serum samples collected from 119 patients during the follow-up period were isolated using native-PAGE and then their levels were quantified. The associations of representative IIRPCs levels at their beginning, maximum, and minimum and the ratios of the maximum or minimum to the beginning IIRPCs levels with clinical characteristics were statistically analyzed. ResultsThe statistical results indicate that patients with these ratios below the first quantiles of the minimum ratios had shorter progressive-free survival (PFS) and the follow-up time points for 108 of 113 patients with over 1.5-fold change in IIRPCs level relative to the beginning level as the beginning time point of humoral immune response has a median lead time of 61.9 weeks (IQR, 30.9–105.3) relative to progressive disease(PD) detected using clinical imaging. ConclusionsThese findings suggest that changes in IIRPCs levels may be early-warning signals of disease progression and response to treatment for lung cancer patients.

FrontMIND: A phase III, randomized, double-blind study of tafasitamab + lenalidomide + R-CHOP versus R-CHOP alone for newly diagnosed high-intermediate and high-risk diffuse large B-cell lymphoma.

TPS7590 Background: Up to 40% of patients relapse or are refractory (R/R) to R-CHOP, the current standard of care for diffuse large B-cell lymphoma (DLBCL), indicating an unmet need, particularly in patients with high-intermediate and high-risk disease (IPI 3–5). POLARIX (NCT03274492) evaluated a modified regimen substituting polatuzumab vedotin for vincristine (pola-R-CHP), demonstrating modest improvement in PFS with no OS benefit between treatment arms. The addition of lenalidomide (LEN) to R-CHOP improved both PFS and OS in the ECOG-ACRIN E1412 trial but not in the Phase III ROBUST study, in which a lower dose of LEN was used, despite a positive trend toward 2-year PFS in a subgroup analysis. The chemo-free immunotherapy tafasitamab + LEN has received accelerated approval in the United States (2020), and conditional marketing authorization in Europe and Canada (2021) in adult patients with R/R DLBCL ineligible for ASCT based on L-MIND (NCT02399085). The primary analysis of First-MIND (NCT04134936), a Phase Ib randomized safety study of R-CHOP + tafasitamab ± LEN in patients with previously untreated and newly diagnosed DLBCL, demonstrated that adding tafasitamab + LEN does not impair dosing and scheduling of R-CHOP, with toxicities similar to those expected with R-CHOP alone (ASH 2021; #3556). frontMIND (NCT04824092) will investigate the efficacy and safety of R-CHOP + tafasitamab + LEN vs R-CHOP alone in previously untreated patients with high-intermediate and high-risk DLBCL. Methods: frontMIND is a Phase III, multicenter, randomized, double-blind, placebo-controlled study. Approximately 880 patients are planned to be randomized at ̃350 centers in North and South America, Europe, and Asia-Pacific. Eligible patients aged 18‒80 years with previously untreated local biopsy-proven, CD20+ DLBCL with IPI score 3–5 (age-adjusted IPI 2–3 if ≤60 years), and ECOG PS 0–2 will be enrolled. Patients with transformed lymphoma (except double or triple hit lymphoma) are excluded. Patients will be randomized 1:1 to receive six 21-day (D) cycles of either R-CHOP + tafasitamab (12 mg/kg intravenously, D 1, 8, and 15) + LEN (25 mg orally, D1–10) or R-CHOP + tafasitamab and LEN placebos. Patients will be followed for up to 5 years after the end of treatment. The primary endpoint is investigator-assessed PFS. Secondary endpoints include investigator-assessed event-free survival, OS, safety, and tafasitamab serum concentration (trough and Cmax levels). Sensitivity and specificity of minimal residual disease for early detection of disease progression is an exploratory endpoint; further MRD parameters may also be investigated. The study is funded by MorphoSys AG and conducted with the scientific support of members of the Fondazione Italiana Linfomi and the German Lymphoma Alliance. Clinical trial information: NCT04824092.