Scientific News

Key highlights from ESMO 2024 on liquid biopsy and lung tumors.

Reviewed by Silvia Calabuig and Susana Torres, Molecular Oncology Laboratory, General University Hospital Research Foundation, University General Hospital of Valencia, Valencia, Spain.

Research presented at ESMO 2024 has expanded our understanding of liquid biopsy, especially the application of circulating tumor DNA (ctDNA) in early-stage lung cancer. In this context, Wakelee et al. analyzed disease-free and overall survival based on ctDNA and PD-L1 status in stage II–IIIA NSCLC patients from the IMpower010 trial. They found that post-operative and post-chemotherapy ctDNA positivity was a negative prognostic factor for disease free survival after 5 yearss of follow up, highlighting the value of ctDNA as a predictive marker in early-stage lung cancer (Abstract 1211P). In a second poster presentation, Van den Heuvel et al. demonstrated that ctDNA could be detected in real-world clinical samples using tumour-informed methods, even when sample quality is suboptimal. They found that ctDNA has prognostic value when measured before and shortly after surgery, indicating its potential to guide decisions on (neo)adjuvant therapies by predicting patient outcomes more effectively (Abstract 1226P). Finally, a third poster highlighted the epidemiological value of ctDNA. In the ctDNA-Lung-Detect study, Khan et al. assessed ctDNA detection and its correlation with recurrence-free survival in early-stage resected NSCLC patients. They identified a group with non-shedding ctDNA tumors, revealing that these patients were less likely to be male or current smokers, had lower PD-L1 expression, and were more likely to possess identifiable driver mutations (Abstract 1236P).

Abstract details

• Wakelee H, et al. IMpower010: ctDNA status and 5y DFS follow up in patients (pts) with resected NSCLC who received adjuvant chemotherapy (chemo) followed by atezolizumab (atezo) or best supportive care (BSC). ESMO Congress 2024, Abstract 1211P
  Poster Display – Non-metastatic NSCLC, 14.09.2024, h. 12:00 – 13:00, Hall 6
• Van den Heuvel M, et al. Predictive value of circulating tumor DNA (ctDNA) before and shortly after curative treatment in early-stage non-small cell lung cancer (NSCLC), and exploration of (pre-)analytical factors. ESMO Congress 2024, Abstract 1226P.
• Khan S, et al. ctDNA-Lung-Detect: Profiling of non-shedding ctDNA early stage resected non-small cell lung cancers. ESMO Congress 2024, Abstract 1236P

Key highlights from ESMO 2024 on liquid biopsy and digestive tumors

Reviewed by Noelia Tarazona, Biomedical Research Institute INCLIVA, Hospital Clínico Universitario, Department Medical Oncology, University of Valencia, Valencia, Spain.

The abstracts presented at ESMO 2024 highlight significant advancements in the use of circulating tumor DNA (ctDNA) in colorectal cancer, showcasing its potential for improving the understanding of tumor dynamics and treatment response. Despite these promising developments, they have not yet led to changes in our current clinical practice. Studies such as the CAIRO5 trial (65O) demonstrated that DELFI-TF, a mutation-independent method, can predict tumor burden and clinical outcomes more accurately than traditional methods, while the PEGASUS trial (63O) revealed distinct molecular characteristics associated with MRD status through ctDNA analysis. In the CITRIC study (511MO) explored ctDNA-driven anti-EGFR rechallenge strategies, revealing promising results in patients with RAS wild-type metastatic CRC. Additionally, the NICHE-2 (LBA24) and pembrolizumab (510MO) trials reinforced the role of ctDNA as a key tool for monitoring immunotherapy efficacy, particularly in patients with dMMR colon cancer, where ctDNA dynamics predicted disease-free and overall survival. These findings emphasize ctDNA’s potential as a biomarker for treatment monitoring and outcome prediction, although further research is needed to integrate them into routine practice.

Abstracts

Abstract 65O A novel mutation-independent approach, DELFI-TF, was developed to estimate cfDNA tumor fraction in blood using genome-wide cfDNA fragmentation features. In a study of 153 metastatic CRC patients from the CAIRO5 trial, DELFI-TF scores showed strong correlation with mutant allele fractions (r=0.90, p<0.0001) and predicted ctDNA presence even when mutations were undetectable. DELFI-TF also predicted clinical outcomes, including progression-free and overall survival, outperforming imaging and CEA. The method was further validated in patients with late-stage lung cancer, highlighting its potential for treatment monitoring and outcome prediction.

63O The PEGASUS trial investigated post-surgical detection of ctDNA as a marker of MRD in colon cancer patients. MRD+ patients were at higher risk of relapse, while MRD- patients had a better prognosis. RNA sequencing of tumor samples from 152 patients revealed that MRD+ cases were enriched in stromal traits and cancer cell-intrinsic features, while MRD- cases were depleted in certain molecular subtypes. These findings demonstrate distinct transcriptional profiles linked to MRD status, highlighting biological diversity in tumors with similar clinical characteristics.

LBA24 In patients with dMMR colon cancer, the NICHE-2 trial demonstrated a 100% 3-year DFS following pre-surgical immunotherapy with ipilimumab and nivolumab. ctDNA analysis played a key role in monitoring treatment response, with ctDNA clearance observed in 94% of patients with a complete pathologic response (pCR) and 70% with a major pathologic response (MPR). By the MRD timepoint, all patients were ctDNA-negative. These ctDNA dynamics provide valuable insights into treatment efficacy and serve as a tool for monitoring in future organ-preservation studies.

510MO In this phase 2 trial, pembrolizumab demonstrated high organ preservation rates and strong oncologic outcomes in patients with localized MSI-H/dMMR cancers after three years of follow-up. Both DFS and OS were high at 80% and 94%, respectively. ctDNA clearance emerged as a key predictor of longer DFS and OS, highlighting its potential as a monitoring tool. Among non-operatively managed patients, 12 out of 13 retained their organs without disease progression. These findings underscore pembrolizumab’s efficacy and the importance of ctDNA in guiding long-term treatment outcomes.

511MO The CITRIC study, a phase II randomized trial, explored anti-EGFR rechallenge strategies in patients with RAS wild-type mCRC after progression on irinotecan and oxaliplatin. Using liquid biopsy for molecular screening, patients with RAS/BRAF/EGFR-ECD wild-type ctDNA were randomized to receive cetuximab and irinotecan (arm A) or investigator’s choice excluding anti-EGFR (arm B). Results showed that the cetuximab arm had a higher overall response rate (9.7% vs 0%) and disease control rate (71% vs 33.3%) compared to the control. These findings suggest that liquid biopsy-driven anti-EGFR rechallenge could be an effective treatment option in third-line settings for select patients.

Key highlights from ESMO 2024 on Liquid Biopsy and Breast Cancer

Reviewed by Sara López-Tarruella, Medical Oncology Service, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Universidad Complutense Madrid, GEICAM, CiberOnc.

In the breast cancer (BC) field, the ESMO committee invited exploration of evolving biomarkers in metastatic disease, posing the question: “Liquid, solid, or both?” This engaging educational session featured leading experts who discussed the potential and limitations of liquid biopsy compared to tissue biopsies. They also examined innovative biomarker approaches and artificial intelligence applications in this context.

Regarding the abstracts presented this year at ESMO 2024, numerous posters shed light on different aspects of liquid biopsy in BC—from methodology to clinical application. While no immediate clinical practice changes will derive from these data, the body of knowledge has been significantly reinforced.

In the early breast cancer (EBC) setting, Magbaunua et al. (Abstract 314P) previously reported that patients with residual cancer burden (RCB-II/III) after neoadjuvant therapy who tested negative for circulating tumor DNA (ctDNA) during and after treatment had a significantly lower risk of metastatic recurrence compared to ctDNA-positive patients. In this study, they analyze the I-SPY2 trial to explore the significance of undetectable ctDNA in patients with RCB-II/III by examining the prevalence of somatic variants included in ctDNA assays in matched serial non-responding tumors. The authors conclude that despite changes in the tumor mutational landscape, assay variants selected from pretreatment tumor DNA sequencing were highly conserved in serial tumor samples over time. Moreover, ctDNA dynamics in response to neoadjuvant therapy emerged as the only significant factor predictive of clinical outcomes in the multivariate analysis.

Also in the potentially curative scenario, Cabel et al. (Abstract 293P) addressed the suboptimal sensitivity of first-generation methods by assessing the clinical validity of an ultrasensitive ctDNA MRD assay at key landmarks across various EBC subtypes. The MSK-LINC study prospectively collected blood samples from EBC patients throughout their clinical care at MSKCC, using the Foresight CLARITY assay to detect MRD. The PhasED-Seq demonstrated high sensitivity and specificity for MRD detection in this EBC cohort. Notably, post-surgical ctDNA MRD positivity was associated with recurrence, while MRD negativity at baseline or MRD clearance by (neo)adjuvant therapy correlated with improved outcomes.

In the advanced BC (ABC) setting, we saw an intriguing report from Canada by Usman et al. (Abstract 87P). They evaluated the clinical value of ctDNA technology in treatment decision-making from a practical perspective, including triple-negative BC patients among other tumors. Their findings showed that in treatment-naïve, incurable, advanced-stage cancer, the identification of Tier 1 variants was comparable between tissue biopsy alone and combined tissue and liquid biopsy. Moreover, adding FoundationOne Liquid CDx to tissue testing proved complementary, with 75% concordance and identification of 10% liquid-exclusive Tier 1 variants.

Correlative ctDNA insights from pivotal clinical trials were also reported at ESMO 2024 for patients with advanced breast cancer (ABC). The TROPICS-02 study (Rugo et al., Abstract 412P) explored ctDNA’s value as an early surrogate marker for long-term outcomes in HR+/HER2- ABC patients. Results showed that baseline ctDNA mutant variant allele fraction (mVAF) and changes from baseline to Cycle 2 Day 1 were associated with survival outcomes and response in both treatment arms. The benefit of sacituzumab govitecan over treatment of physician’s choice (TPC) was observed regardless of baseline ctDNA levels or changes. Ueno et al. (Abstract 432P) reported data from the DESTINY-Breast04 trial, demonstrating that treatment with trastuzumab deruxtecan (T-DXd) showed clinically meaningful improvement in progression-free survival (PFS) and objective response rate (ORR) versus TPC across all biomarker subgroups analyzed. These subgroups included HER2 gene expression level, BRCA1/2 or homologous recombination repair (HRR) gene alteration status, DNA damage response (DDR)/cell proliferation signature status, and immune status. The ctDNA analysis used the Guardant OMNI panel to detect HER2-activating mutations, BRCA1/2 inactivating alterations, and HRR gene alterations. Bianchini et al. (Abstract 351P) reported the PFS analysis in clinically relevant subgroups from the phase 3 postMONARCH trial. This trial had previously shown a statistically significant PFS improvement with the addition of abemaciclib to fulvestrant in patients with HR+, HER2- ABC who had disease progression on a prior CDK4/6 inhibitor and endocrine therapy combination. Beyond clinically relevant subgroups—such as patients with liver metastasis, bone-only, or measurable disease—the key biomarker analysis (ctDNA analyzed by GuardantINFINITY assay) for ESR1 and PIK3CA/PTEN/AKT1 demonstrated consistent abemaciclib plus fulvestrant treatment effect in both biomarker-detected and non-detected populations. However, some subgroups had small sample sizes, precluding definitive conclusions.

Finally, among the liquid biopsy highlights in breast cancer, an intriguing retrospective pooled analysis led by Pastò et al. (Abstract 414P) explored the relationship between circulating tumor cells (CTCs) and brain metastases (BMs) in patients with ABC from 18 cohorts. All patients underwent CTC enumeration at baseline before starting a new treatment line. The results suggest that CTC count may be linked to BMs in a subtype-specific manner, and that the coexistence of BMs and >5 CTCs/7.5 mL significantly worsens survival.

ESMO 2024 highlighted liquid biopsy’s growing role in BC care, with ctDNA showing promise as biomarker for prognosis, treatment response, and disease monitoring. These advances point to its future integration into personalized cancer treatment.

Key highlights from ESMO 2024 on liquid biopsy: New perspectives in the diagnosis and treatment of gynecologic tumours.

Reviewed by Laura Muinelo and Carlota Roca, Liquid Biopsy analysis Unit, Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago de Compostela (IDIS), CIBERONC, Santiago de Compostela, Spain.

The ESMO 2024 Congress showed important findings about the application of liquid biopsy to improve the management of gynecologic tumours. Among them, Re-VOLVE a phase II trial in women with ovarian cancer progressing post-PARP inhibitor in which the treatment after progression was defined based on the ctDNA analyses to real time assess the evolving genomic resistance mechanisms. Out of 20 patients receiving this personalized treatment 40% showed partial response and the 50% stable disease, reinforcing the value of the ctDNA characterization to identify resistance mechanisms and improve the treatment opportunities of patients with ovarian cancer. In line, the IMPRESS-Norway clinical trial showed the value of ctDNA assessment as a diagnostic tool for treatment recommendation to improve the access to targeted therapy advanced cancer patients, including a cohort of 53 patients with different gynecologic tumours such as endometrial, cervical and ovarian tumors. Of note in 13% of the patients analyzed in the study the actionable mutations found were different to the ones identified in the tumour tissue samples.

The BOVARY study evaluated whether liquid biopsy might be a surrogate of FFPE tissue for HRD determination in a cohort of 24 ovarian tumours. Only the plasma samples with the highest cfDNA concentrations (3 out of 17) yielded a valid HRD status using a low-pass whole genome sequencing approach. Although HRD status was concordant for all 3 samples this data reinforces the relevance of applying highly sensitive techniques for the ctDNA analysis.

Beyond ctDNA analyses Holger Heyn and collaborator addressed a spatio-temporal T cell clonal tracking in blood and match biopsies as a correlate of ICI efficacy in patients with refractory MSS/MSI EC treated with single dose Tremelimumab followed by Durvalumab or Durvalumab as monotherapy. Despite low efficacy of the dual treatment was observed in MSS patients, deep immune repertoire profiling detected profound expansion of circulating T cells in the blood associated with a better response to the ICI. As part of the MOCCA trial the peripheral immune cells were characterized in 23 patients with clear cell ovarian cancer before Durvalumab treatment. Patients with favourable response to durvalumab exhibited high levels of circulating T-cells, B-cells, NK-cells and specific cytokines (CCL11, CCL15, CCL2) while low levels of circulating neutrophils. These two studies reinforce the potential of peripheral immune cell tracking as tool to predict and monitor the efficacy of ICIs.

For improving early diagnosis Carvajal and collaborators presented WomEC, an innovative diagnostic test for endometrial cancer. Based on a highly sensitive protein panel, the test achieved an accuracy of 99%, with the potential to reduce current invasive procedures by 90%, thus revolutionizing early detection and improving the patient experience.

All the results presented in ESMO reinforce the importance of liquid biopsy testing for the early diagnosis and treatment guidance in advanced gynecologic tumors.

Abstracts details:

• I. Dyvik, L. Fagereng, T. Lien, et al. Comprehensive genomic profiling of circulating tumor DNA for treatment recommendation: a sub-project of IMPRESS-Norway. ESMO Congress 2024, Poster: 89P.
• P. Soberanis Pina, A. Oza, N Dhani et al. Re-VOLVE: phase II trial in women with Ovarian Cancer progressing post-PARP inhibitor with treatment. ESMO Congress 2024, Poster: 763P.
• H. Heyn, JL Melero, G. Deuner et al. Liquid biopsy tracking of immunotherapy-induced T cell dynamics in MSS colorectal and endometrial tumors. ESMO Congress 2024, Poster: 561P
• Javier Carvajal, Astrid Garcia, Lola Fernández, et al. A novel diagnostic test for the detection of endometrial cancer in uterine fluids. ESMO Congress 2024, Poster: 776P.
• F. Blanc-Durand, N. YL Ngoi, N. Kaliaperumal et al. Unlocking the Circulating Immune Landscape of Clear-Cell Ovarian Cancer: Insights from the MOCCA Trial. ESMO Congress 2024, Poster: 753P.
• Alexandre Harlé, Marie Husson, Cassandra Michel et al. Liquid biopsy for the determination of homologous recombination deficiency in patients with high-grade serous ovarian cancer: results of the BOVARY-pilot study. ESMO Congress 2024. 776P

Key highlights from ESMO 2024 on liquid biopsyJ: Overview of Two Studies on Ultrasensitive ctDNA Analysis

Reviewed by Rodrigo Toledo, Group Leader of the Biomarkers and Clonal Dynamics Laboratory in Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain.

Two studies presented at the ESMO meeting emphasized the value of using an ultrasensitive circulating tumor DNA (ctDNA) assay (Next Personal assay) to monitor cancer patients, particularly those with lung cancer and patients undergoing immunotherapy for various types of cancer. These studies demonstrated the potential of ctDNA analysis to detect minimal residual disease (MRD), predict outcomes, and monitor treatment response.

Study 1: Monitoring Non-Small Cell Lung Cancer (NSCLC)

Abstract #: LBA9 : Clinical insights from ultra-sensitive tumor-informed ctDNA tracking across the TRACERx cohort. Research Team: Led by Professor Charles Swanton from Cancer Research UK, University College London, and the Francis Crick Institute. This study analyzed over 400 patients with non-small cell lung cancer as part of the TRACERx project, using an ultrasensitive ctDNA assay. It represents one of the largest and most comprehensive MRD studies in lung cancer, focusing on tracking ctDNA to assess the risk of recurrence and monitor treatment effectiveness.

Key Findings:

• High Sensitivity for Residual Disease Detection: The assay demonstrated strong detection rates for residual disease within the first 120 days after surgery, also known as the “landmark period.”
• Detection in the Ultrasensitive Range: A significant portion (42%) of detected cases occurred at ultrasensitive levels (less than 80 parts per million), highlighting the assay’s capability to detect very low levels of ctDNA.
• Preoperative Predictive Value: ctDNA detected before surgery correlated with clinical outcomes, especially in patients with lung adenocarcinoma, the most common subtype of NSCLC.
• Dynamic Monitoring During Adjuvant Therapy: MRD tracking during adjuvant treatment enabled stratification of patients by their risk of recurrence, potentially guiding personalized treatment strategies.
• Early Recurrence Detection: The assay identified early signs of cancer recurrence months before conventional imaging techniques could detect them, allowing for early intervention.

Study 2: Monitoring Late-Stage Cancer Patients Undergoing Immunotherapy

Abstract #: 223P: Tumor whole genome sequencing-based ultrasensitive ctDNA analysis as an early biomarker for clinical outcome in immune checkpoint inhibitor (ICI) phase 1 clinical trials and a tool for beyond progressive disease by Irecist. Research Team: Led by Dr. Rodrigo Toledo and Dr. Elena Garralda from the Vall d’Hebron Institute of Oncology (VHIO). This study examined a large cohort of over 200 late-stage cancer patients receiving immunotherapy, using an ultrasensitive ctDNA assay. It significantly expanded on earlier findings presented in the year by including a more comprehensive dataset and a validation set, thereby reinforcing the reliability of the results.

Key Findings:

• Correlation Between ctDNA Levels and Survival: Patients who showed a significant reduction in ctDNA levels during immunotherapy had a markedly longer overall survival compared to those with minimal or no decrease in ctDNA, suggesting that ctDNA monitoring could serve as a valuable early indicator of treatment efficacy.
• Incorporation of a Validation Set: The inclusion of a validation cohort strengthened the findings and provided more robust evidence for the clinical utility of ctDNA monitoring in late-stage cancer patients.
• Distinction Between True Progression and Pseudoprogression: ctDNA trajectories in patients who continued immunotherapy beyond unconfirmed progression (iuPD) were useful in differentiating between true disease progression (limited benefit beyond iuPD) and pseudoprogression (prolonged benefit beyond iuPD). This insight could aid in decision-making regarding the continuation of immunotherapy despite apparent disease progression on imaging.

Clinical Implications

The findings from these two studies underscore the clinical importance of ultrasensitive ctDNA assays for:

• Early Detection of Recurrence: Identifying recurrence before imaging can allow for timely intervention and potentially improve outcomes.
• Stratification of Patients: Assessing recurrence risk and monitoring treatment response can help tailor treatment strategies to individual patients.
• Monitoring Immunotherapy Response: Distinguishing true progression from pseudoprogression may enable more accurate treatment decisions for patients undergoing immune checkpoint inhibitor therapy.

Overall, the data supports the use of ctDNA analysis as a promising tool for enhancing cancer care by providing early and personalized insights into disease progression and treatment response.