bims-preonc 2024-12-15 papers

bims-preonc

Biomed News

on Precision oncology

Issue of 2024–12–15
twenty-one papers selected by
Ankita Daiya, OneCell Diagnostics Inc.

Genomic correlates of response and resistance to the irreversible FGFR1-4 inhibitor futibatinib based on biopsy and circulating tumor DNA profiling.
Adjuvant osimertinib therapy guided by ctDNA-assessed MRD in resected EGFR-mutated stage IA-IIA non-small-cell lung cancer: a randomized clinical trial study protocol.
AR alterations inform circulating tumor DNA detection in metastatic castration resistant prostate cancer patients.
Prognostic value of circulating tumor DNA at diagnosis and its early decrease after one cycle of neoadjuvant chemotherapy for patients with advanced epithelial ovarian cancer. An ancillary analysis of the CHIVA phase II GINECO trial.
BRCA1 & BRCA2 methylation as a prognostic and predictive biomarker in cancer: Implementation in liquid biopsy in the era of precision medicine.
Genomic landscape of circulating tumor DNA in HER2-low metastatic breast cancer.
Impact of molecular diagnostics and targeted cancer therapy on patient outcomes (MODIFY): a retrospective study of the implementation of precision oncology.
Association between genomic instability score and progression-free/overall survival in patients with newly diagnosed non-BRCA1/2 ovarian cancer.
Clinical Utility of a Circulating Tumor Cell-Based Cerebrospinal Fluid Assay in the Diagnosis and Molecular Analysis of Leptomeningeal Disease in Patients With Advanced Non-Small Cell Lung Cancer.
Complete remission after pembrolizumab monotherapy in a non-small cell lung cancer patient with PD-L1 negative, high tumor mutational burden, and positive tumor-infiltrating lymphocytes: A case report.
Potential predictive biomarkers in antitumor immunotherapy: navigating the future of antitumor treatment and immune checkpoint inhibitor efficacy.
Tumor sequencing before and after neoadjuvant chemoradiotherapy in locally advanced rectal cancer: Genetic tumor characterization and clinical outcome.
An Analytical Approach that Combines Knowledge from Germline and Somatic Mutations Enhances Tumor Genomic Reanalyses in Precision Oncology.
Next generation sequencing-based MSI scoring predict benefit in mismatch repair deficient tumors treated with nivolumab: follow-up on NCI-MATCH arm Z1D.
Circulating tumor cells in solid malignancies: From advanced isolation technologies to biological understanding and clinical relevance in early diagnosis and prognosis.
Mutations and MRD: clinical implications of clonal ontogeny.
Partial Response to Treatment with ALK Inhibitor in a Patient With SQSTM1-ALK Fusion Positive Lung Adenocarcinoma.
Liver Metastases are Associated with a Short Post-Progression Survival in a Real-World Group of Patients with Melanoma Treated with Checkpoint Inhibitors.
EGFR-V834L combined with L858R mutation reduced afatinib sensitivity and associated to early recurrence in lung cancer.
Safety and efficacy of adjuvant FOLFOX/FOLFIRI with versus without hepatic arterial infusion of floxuridine in patients following colorectal cancer liver metastasectomy (HARVEST trial): A randomized controlled trial.
Negative response to immunotherapy in dMMR or MSI-H gastric cancer with APC and PTEN mutations: a case report.

Ann Oncol. 2024 Dec 11. pii: S0923-7534(24)04976-7. [Epub ahead of print]

Genomic correlates of response and resistance to the irreversible FGFR1-4 inhibitor futibatinib based on biopsy and circulating tumor DNA profiling.

L Goyal, D DiToro, A Hollebecque, J A Bridgewater, M Shimura, A Kano, S Okamura, J L Silhavy, V Wacheck, A Halim, F Meric-Bernstam.

   BACKGROUND: Futibatinib is the only covalent inhibitor of FGFR1-4 to gain regulatory approval in oncology. Here, we present genomic analyses of tissue biopsies and circulating tumor DNA (ctDNA) from patients with one of nearly 20 tumor types treated with futibatinib in the phase I/II FOENIX study.
PATIENTS AND METHODS: Eligible patients included those with ctDNA samples collected per protocol at baseline and/or progression on futibatinib in the phase Ib portion of the study for FGF/FGFR-altered advanced solid tumors or the phase II portion of the study for FGFR2 fusion/rearrangement-positive cholangiocarcinoma. Assessments included analytical concordance between tumor and ctDNA analyses for detection of FGFR alterations, association of ctDNA-detected co-occurring genomic alterations with response to futibatinib, and determination of patterns of acquired resistance following progression on futibatinib.
RESULTS: Among 300 patients treated with futibatinib, 226 were eligible for this analysis, including 139 (62%) with cholangiocarcinoma. Among patients with known FGFR2 fusions/rearrangements, FGFR1 fusions, FGFR3 fusions, or FGFR2 amplifications per tissue analysis, detection rates in ctDNA for these aberrations were 84%, 0%, 11%, and 59%, respectively. Objective response rates on futibatinib were not significantly different between patients with TP53 altered versus unaltered solid tumors; progression-free survival was reduced in patients with CDKN2B altered versus unaltered cholangiocarcinoma (median, 4.8 versus 11.0 months; P=0.03). Acquired resistance to futibatinib was frequently polyclonal and driven by an array of mutations within the relevant FGFR kinase domain, predominantly V565L, V565F, and N550K variants.
CONCLUSIONS: In this largest and most systematic analysis of acquired resistance to an FGFR inhibitor from prospective clinical trials, emergence of secondary FGFR2 kinase domain mutations was observed in most patients receiving clinical benefit to futibatinib. ctDNA analysis shows clinically relevant potential as a noninvasive method for assessing genomic profiles, identifying patients who may benefit from FGFR inhibitor treatment, and exploring acquired resistance mechanisms.

Keywords:  Fibroblast growth factor receptor; cholangiocarcinoma; circulating tumor DNA; futibatinib

DOI:  https://doi.org/10.1016/j.annonc.2024.11.017
Am J Cancer Res. 2024 ;14(11): 5427-5433

Adjuvant osimertinib therapy guided by ctDNA-assessed MRD in resected EGFR-mutated stage IA-IIA non-small-cell lung cancer: a randomized clinical trial study protocol.

Kun Wang, Junrui Ma, Wei Luo, Qing Yin, Xugang Zhang, Yize Li, Hushan Zhang.

   AIMS: We investigate the value of postoperative minimal residual disease (MRD) detection using circulating tumor DNA (ctDNA) in guiding adjuvant therapy for patients with potentially high recurrence risk in non-small cell lung cancer (NSCLC) due to the presence of MRD.
PATIENTS AND METHODS: A randomized controlled trial will enroll stage IA-IIA NSCLC patients with Epidermal Growth Factor Receptor (EGFR) mutation and negative resection margins to evaluate the clinical value of MRD in guiding adjuvant osimertinib. That is, if the patient's peripheral blood does not show ctDNA (negative) after next generation sequencing (NGS) testing, postoperative observation and follow-up are sufficient. Conversely, if ctDNA is positive, the patient will be randomly assigned to two groups and receive adjuvant treatment with osimertinib or observation and follow-up. In total 1068 postoperative patients should be recruited, finally, 32 MRD positive patients were divided into a treatment group or an observation group.
PRIMARY ENDPOINT: progression-free survival (PFS). Secondary endpoints: 2- and 5-year PFS rates, regimen safety, and tolerability. Exploratory indicator in the MRD-positive group: ctDNA clearance rate at 12 and 24 months.
RESULTS AND CONCLUSIONS: This study provides crucial insights into therapy guidance for EGFR-mutated NSCLC patients with MRD, potentially enhancing patient outcomes.

Keywords:  EGFR; MRD; NSCLC; adjuvant therapy

DOI:  https://doi.org/10.62347/IFRH7248
Nat Commun. 2024 Dec 11. 15(1): 10648

AR alterations inform circulating tumor DNA detection in metastatic castration resistant prostate cancer patients.

Todd P Knutson, Bin Luo, Anna Kobilka, Jacqueline Lyman, Siyuan Guo, Sarah A Munro, Yingming Li, Rakesh Heer, Luke Gaughan, Michael J Morris, Himisha Beltran, Charles J Ryan, Emmanuel S Antonarakis, Andrew J Armstrong, Susan Halabi, Scott M Dehm.

Circulating tumor DNA (ctDNA) in plasma cell free DNA (cfDNA) of cancer patients is associated with poor prognosis, but is challenging to detect from low plasma volumes. In metastatic castration-resistant prostate cancer (mCRPC), ctDNA assays are needed to prognosticate outcomes of patients treated with androgen receptor (AR) inhibitors. We develop a custom targeted cfDNA sequencing assay, named AR-ctDETECT, to detect ctDNA in limiting plasma cfDNA available from mCRPC patients in the Alliance A031201 randomized phase 3 trial of enzalutamide with or without abiraterone. Of 776 patients, 59% are ctDNA-positive, with 26% having high ctDNA aneuploidy and 33% having low ctDNA aneuploidy but displaying AR gain or structural rearrangement, MYC/MYCN gain, or a pathogenic mutation. ctDNA-positive patients have significantly worse median overall survival than ctDNA-negative patients (29.0 months vs. 47.4 months, respectively). Here, we show that mCRPC patients identified as ctDNA-positive using the AR-ctDETECT assay have poor survival despite treatment with potent AR inhibitors in a phase 3 trial.

DOI: https://doi.org/10.1038/s41467-024-54847-1
Gynecol Oncol. 2024 Dec 12. pii: S0090-8258(24)01221-6. [Epub ahead of print]192 145-154

Prognostic value of circulating tumor DNA at diagnosis and its early decrease after one cycle of neoadjuvant chemotherapy for patients with advanced epithelial ovarian cancer. An ancillary analysis of the CHIVA phase II GINECO trial.

Henri Azaïs, Camille Brochard, Valérie Taly, Louise Benoit, Gwenaël Ferron, Isabelle Ray-Coquard, Benoit You, Sophie Abadie-Lacourtoisie, Coriolan Lebreton, Laurence Venat, Christophe Louvet, Laure Favier, Cyriac Blonz, Nadine Dohollou, Emmanuelle Malaurie, Coraline Dubot, Jean-Emmanuel Kurtz, Eric Pujade-Lauraine, Etienne Rouleau, Alexandra Leary, Anne-Sophie Bats, Hélène Blons, Pierre Laurent-Puig.

   OBJECTIVE: To evaluate the prognostic impact of circulating tumor DNA (ctDNA) detection at diagnosis (T0) and its early decrease after one cycle (T1) of neoadjuvant chemotherapy (NACT) in patients with advanced epithelial ovarian cancer (EOC) included in the CHIVA trial (NCT01583322).
METHODS: Blood samples were collected at T0 and before each administration of NACT. Circulating tumor DNA detection was performed by next-generation sequencing. Multivariate analysis was performed. A p-value of 0.05 was considered significant. Progression-free survival (PFS) and overall survival (OS) were compared between groups defined by ctDNA kinetic profile. Cox survival model was used to search variables associated with PFS and OS. Kaplan-Mayer curve was used to graphically express the differences in PFS and OS. A log-rank test compared the two curves.
RESULTS: 188 patients were included. Blood samples were available for 168 patients at T0 and for 160 patients at T0 and T1 to assess ctDNA ratio kinetics. At T0, 107 patients (63.7 %) had detectable ctDNA. At T1, 137 (85.6 %) patients had negative ctDNA or a decrease of more than 80 %. There was a significant benefit in either PFS (p = 0.0017) or OS (p = 0.0036) in favor of early decrease of ctDNA ratio. A favorable decrease was associated with a greater likelihood of being able to perform CRS (OR: 3.94 (CI95 % 1.45-10.70), p = 0.0074).
CONCLUSIONS: Early decrease of ctDNA ratio can provide prognostic information early in the management of patients, allowing a more accurate information to patients and an early preparation for CRS (prehabilitation).

Keywords:  Biomarker; Circulating tumor DNA; Epithelial ovarian cancer; Gynecologic oncology; Liquid biopsy; Next generation sequencing

DOI:  https://doi.org/10.1016/j.ygyno.2024.12.004
Clin Epigenetics. 2024 Dec 06. 16(1): 178

BRCA1 & BRCA2 methylation as a prognostic and predictive biomarker in cancer: Implementation in liquid biopsy in the era of precision medicine.

Maria Panagopoulou, Theodoros Panou, Anastasios Gkountakos, Gesthimani Tarapatzi, Makrina Karaglani, Ioannis Tsamardinos, Ekaterini Chatzaki.

   BACKGROUND: BReast CAncer gene 1 (BRCA1) and BReast CAncer gene 2 (BRCA2) encode for tumor suppressor proteins which are critical regulators of the Homologous Recombination (HR) pathway, the most precise and important DNA damage response mechanism. Dysfunctional HR proteins cannot repair double-stranded DNA breaks in mammalian cells, a situation called HR deficiency. Since their identification, pathogenic variants and other alterations of BRCA1 and BRCA2 genes have been associated with an increased risk of developing mainly breast and ovarian cancer. Interestingly, HR deficiency is also detected in tumors not carrying BRCA1/2 mutations, a condition termed "BRCAness".
MAIN TEXT: One of the main mechanisms causing the BRCAness phenotype is the methylation of the BRCA1/2 promoters, and this epigenetic modification is associated with carcinogenesis and poor prognosis mainly among patients with breast and ovarian cancer. BRCA1 promoter methylation has been suggested as an emerging biomarker of great predictive significance, especially concerning Poly (ADP-ribose) Polymerase inhibitors (PARP inhibitor-PARPi) responsiveness, along with or beyond BRCA1/2 mutations. However, as its clinical exploitation is still insufficient, the impact of BRCA1/2 promoter methylation status needs to be further evaluated. The current review aims to gather the latest findings about the mechanisms that underline BRCA1/2 function as well as the molecular characteristics of tumors associated with BRCA1/2 defects, by focusing on DNA methylation. Furthermore, we critically analyze their translational meaning and the validity of BRCA methylation biomarkers in predicting treatment response.
CONCLUSIONS: We believe that BRCA1/2 methylation alone or combined with other biomarkers in a clinical setting is expected to change the scenery in prognosis and predicting treatment response in multiple cancer types and is worthy of further attention. The quantitative BRCA1 promoter methylation assessment might predict treatment response in PARPi and analysis of BRCA1/2 methylation in liquid biopsy might define patient subgroups at different time points that may benefit from PARPi. Finally, we suggest a pipeline that could be implemented in liquid biopsy to aid precision pharmacotherapy in BRCA-associated tumors.

Keywords:  BRCA1; BRCA2; Breast cancer; Cancer; DNA promoter methylation; Liquid biopsy; Ovarian; PARP inhibitors

DOI:  https://doi.org/10.1186/s13148-024-01787-8
Signal Transduct Target Ther. 2024 Dec 09. 9(1): 345

Genomic landscape of circulating tumor DNA in HER2-low metastatic breast cancer.

Zongbi Yi, Kaixiang Feng, Dan Lv, Yanfang Guan, Youcheng Shao, Fei Ma, Binghe Xu.

The large population of HER2-low breast cancer patients necessitates further research to provide enhanced clinical guidance. In this study, we retrospectively analyzed 1071 metastatic breast cancer (MBC) patients and the circulating tumor DNA (ctDNA) to investigate clinicopathological and genetic alterations of HER2-low MBC patients. The effect of HER2-low status on different treatment modalities was explored in two prospective clinical trials (NCT03412383, NCT01917279) and a retrospective study. Our findings suggest TP53, PIK3CA, and ESR1 are frequently mutated genes in HER2-low MBC. Compared to the HER2-0 group, mutations observed in the HER2-low group are more closely associated with metabolic pathway alterations. Additionally, among patients with ERBB2 mutations and treated with pyrotinib, the HER2-low group may experience superior prognosis when compared to the HER2-0 group. Notably, we did not find any statistically significant disparity in the response to chemotherapy, endocrine therapy, or CDK4/6 inhibitor therapy between HER2-0 and HER2-low breast cancer patients. Interestingly, within the subgroup of individuals with metabolic pathway-related gene mutations, we found that HER2-low group exhibited a more favorable response to these treatments compared to HER2-0 group. Additionally, dynamic analysis showed the HER2-low MBC patients whose molecular tumor burden index decreased or achieved early clearance of ctDNA after the initial two treatment cycles, exhibited prolonged survival. Moreover, we classified HER2-low MBC into three clusters, providing a reference for subsequent treatment with enhanced precision. Our study offers valuable insights into the biology of HER2-low MBC and may provide reference for personalized treatment strategies.

DOI: https://doi.org/10.1038/s41392-024-02047-0
Mol Oncol. 2024 Dec 11.

Impact of molecular diagnostics and targeted cancer therapy on patient outcomes (MODIFY): a retrospective study of the implementation of precision oncology.

Michaël Dang, Anna Schritz, Nikolai Goncharenko, Guy Berchem.

  High-throughput genomic analyses are being implemented in clinical practice. MODIFY is a retrospective study of the first introduction of genomic profiling and molecular tumor boards in the country of Luxembourg. The primary objective was to assess whether patients derived a clinical benefit by measuring the percentage of patients who presented a progression-free survival (PFS) on matched therapy (PFS2) 1.3-fold longer than PFS on previous therapy (PFS1). A total of 94 patients were included. In total, 45 patients (53.57% of patients with successful next-generation sequencing [NGS] analysis) were found to have an actionable mutation. Of these, 11 patients received the treatment recommended by the molecular tumor board, another 12 received best-supportive care, and 20 were treated with conventional therapy. PFS2 and PFS1 data were available for eight patients. The PFS2/PFS1 ratio was ≥ -1.3 in 62.5% (n = 5/8; CI [30.38, 86.51]) of patients; three patients showed a partial response, and median overall survival (OS) was 7.3 months. Although the examined population was small, this study further supports evidence indicating that patients with advanced cancer benefit from molecular profiling and targeted therapy.

Keywords:  PFS ratio; genomic profiling; matched therapy; precision oncology

DOI:  https://doi.org/10.1002/1878-0261.13785
Gynecol Oncol. 2024 Dec 07. pii: S0090-8258(24)01217-4. [Epub ahead of print]192 120-127

Association between genomic instability score and progression-free/overall survival in patients with newly diagnosed non-BRCA1/2 ovarian cancer.

Stephen Graves, Mackenzie W Sullivan, Anusha Adkoli, Qin Zhou, Alexia Iasonos, Pier Selenica, Carol Aghajanian, Ying L Liu, William Tew, Yukio Sonoda, Lora H Ellenson, Dennis Chi, Roisin E O'Cearbhaill, Britta Weigelt, Rachel N Grisham.

   OBJECTIVE: We sought to describe the association between genomic instability score (GIS) and progression-free survival (PFS) and overall survival (OS) in patients with newly diagnosed, non-BRCA1/2 ovarian cancer.
METHODS: Homologous recombinant deficiency (HRD) status was based on a cutoff of ≥42 GIS; patients <42 were categorized with homologous recombination proficiency (HRP). We collected type and duration of maintenance therapy, among other variables, and built a multivariate model with landmark analysis at 6 months from baseline and applied it for time-dependent variables.
RESULTS: Increasing GIS as a continuous variable was associated with improved PFS and OS in our cohort. Overall, median PFS was significantly longer in patients with HRD ovarian cancer (35.4 months, 25.4-NE) than in those with HRP disease (14.9 months, 13.1-16.2; p < 0.001). Median OS was 36.2 months (32.4-NE) for HRP and not reached for HRD (p = 0.002). Notably, in patients with HRP ovarian cancer, we observed a shorter median PFS in those who received a poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi) than in those who did not (12.7 months for HRP with PARPi vs 15.2 months for HRP without PARPi).
CONCLUSIONS: Our results demonstrate that in newly diagnosed advanced non-BRCA1/2 ovarian cancer, GIS as a continuous variable is associated with longer PFS and OS. In patients with HRP ovarian cancer, PARPi treatment may be associated with shorter PFS, which warrants further evaluation.

Keywords:  BRCA-negative homologous recombination deficiency outcomes; Homologous recombination deficiency testing; Maintenance therapy; Ovarian cancer; Overall survival; PARP inhibitor

DOI:  https://doi.org/10.1016/j.ygyno.2024.11.011
JCO Precis Oncol. 2024 Dec;8 e2400373

Clinical Utility of a Circulating Tumor Cell-Based Cerebrospinal Fluid Assay in the Diagnosis and Molecular Analysis of Leptomeningeal Disease in Patients With Advanced Non-Small Cell Lung Cancer.

Jyoti Malhotra, Ramya Muddasani, Jeremy Fricke, Isa Mambetsariev, Amanda Reyes, Razmig Babikian, Shaira Therese Dingal, Pauline Kim, Erminia Massarelli, Lisa Feldman, Mike Chen, Michelle Afkhami, Ravi Salgia.

PURPOSE: Leptomeningeal disease (LMD) is associated with significant morbidity and mortality for metastatic non-small cell lung cancer (NSCLC). We describe our clinical experience in evaluating the use of cerebrospinal fluid (CSF)-derived circulating tumor cells (CTCs) for the diagnosis of LMD and the detection of genomic alterations in CSF cell-free DNA (cfDNA).
METHODS: Patients with NSCLC who had CSF collection as part of routine clinical care for suspected LMD were included in the study. CSF was evaluated for CTCs and cfDNA using a commercial assay (CNSide; Biocept, San Diego, CA), and molecular profiling was performed. Molecular testing results from sequencing of tumor tissue and plasma circulating tumor DNA were collected. cMET and human epidermal growth factor receptor 2 (HER2) expression analysis was performed using fluorescence in situ hybridization (FISH).
RESULTS: Twenty-two patients were included (77% female; median age 60 years). Sixty-four percent had sensitizing EGFR mutations, and 32% had an atypical EGFR mutation. Thirteen of the 22 patients (59%) were diagnosed with LMD using the CSF CTC assay. Five of these 13 patients (38%) had negative CSF cytology for LMD, and two patients (15%) had normal magnetic resonance imaging brain imaging. Seven of the 13 patients (54%) had sufficient CTCs to perform molecular profiling. The concordance with tissue next-generation sequencing was 100%, and the driver mutation was identified in all seven patients with the CSF cfDNA assay. cMET expression and HER2 expression via FISH were noted in 11 patients (50%) and four patients (18%) respectively.
CONCLUSION: We detected higher sensitivity to diagnose LMD using CSF CTC-based assay; 38% of LMD cases identified using this assay were missed by standard CSF cytology. CSF molecular testing using CSF cfDNA demonstrated high concordance with tissue-based molecular testing.

DOI: https://doi.org/10.1200/PO-24-00373
Medicine (Baltimore). 2024 Dec 06. 103(49): e40369

Complete remission after pembrolizumab monotherapy in a non-small cell lung cancer patient with PD-L1 negative, high tumor mutational burden, and positive tumor-infiltrating lymphocytes: A case report.

Suoni Li, Jiequn Ma, Jie Bai, Zheng Zhao.

RATIONALE: Immune checkpoint inhibitors have been used to treat cancer patients. Non-small cell lung cancer (NSCLC) patients with a high expression level of programmed cell death ligand-1 (PD-L1) could benefit from immune checkpoint inhibitor monotherapy. However, treating NSCLC patients with PD-L1 negative is still a clinical challenge. The utilization of new-type tumor markers as predictive indicators of therapeutic efficacy, with the aim of guiding clinical medication strategies, has emerged as a paramount focus of clinical investigation and interest.
PATIENT CONCERNS AND DIAGNOSES: We reported a 72-year-old male with cough diagnosed as poorly differentiated metastatic lung adenocarcinoma (cT3N2M1, stage IV). He tested negative for driver gene mutations, and PD-L1 negative (＜1%), but a high tumor mutational burden (30.9 and 39.1 mutations/Mb in the lung tissue and blood, respectively), and positive tumor-infiltrating lymphocytes.
INTERVENTIONS: The patient received pembrolizumab monotherapy.
OUTCOMES: After 8 treatment cycles over 5 months, repeat examinations showed significantly reduced lung mass and circulating tumor DNA abundance. The patient reached clinical complete remission and had long-term survival with no significant adverse events.
LESSONS: A comprehensive evaluation of multiple tumor biomarkers should be considered in NSCLC patients. Pembrolizumab monotherapy could benefit NSCLC patients with negative driver genes, PD-L1 negative, a high tumor mutational burden, and positive tumor-infiltrating lymphocytes.

DOI: https://doi.org/10.1097/MD.0000000000040369
Front Oncol. 2024 ;14 1483454

Potential predictive biomarkers in antitumor immunotherapy: navigating the future of antitumor treatment and immune checkpoint inhibitor efficacy.

Xiangyu Yin, Yunjie Song, Wanglong Deng, Neil Blake, Xinghong Luo, Jia Meng.

  Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment modality, offering promising outcomes for various malignancies. However, the efficacy of ICIs varies among patients, highlighting the essential need of accurate predictive biomarkers. This review synthesizes the current understanding of biomarkers for ICI therapy, and discusses the clinical utility and limitations of these biomarkers in predicting treatment outcomes. It discusses three US Food and Drug Administration (FDA)-approved biomarkers, programmed cell death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), and microsatellite instability (MSI), and explores other potential biomarkers, including tumor immune microenvironment (TIME)-related signatures, human leukocyte antigen (HLA) diversity, non-invasive biomarkers such as circulating tumor DNA (ctDNA), and combination biomarker strategies. The review also addresses multivariable predictive models integrating multiple features of patients, tumors, and TIME, which could be a promising approach to enhance predictive accuracy. The existing challenges are also pointed out, such as the tumor heterogeneity, the inconstant nature of TIME, nonuniformed thresholds and standardization approaches. The review concludes by emphasizing the importance of biomarker research in realizing the potential of personalized immunotherapy, with the goal of improving patient selection, treatment strategies, and overall outcomes in cancer treatment.

Keywords:  MSI; PD-L1; TMB; emerging biomarkers; immune checkpoint inhibitors; immunotherapy

DOI:  https://doi.org/10.3389/fonc.2024.1483454
Clin Transl Radiat Oncol. 2025 Jan;50 100894

Tumor sequencing before and after neoadjuvant chemoradiotherapy in locally advanced rectal cancer: Genetic tumor characterization and clinical outcome.

Kerstin Clasen, Nadja Ballin, Leon Schütz, Irina Bonzheim, Olga Kelemen, Michael Orth, Cihan Gani, Olaf Rieß, Stephan Ossowski, Maximilian Niyazi, Christopher Schroeder.

   Background and purpose: Neoadjuvant chemoradiotherapy (NCRT) is a standard treatment option for locally advanced rectal cancer. However, there is still conflicting data about the genetic landscape and potential dynamics during and after NCRT. This study evaluated oncogenic driver mutations before NCRT and investigated corresponding resection samples after treatment.
Materials and methods: In 17 patients the pre-therapeutic biopsy and in ten cases the related resection specimen were investigated by next-generation sequencing using a dedicated cancer panel (708 genes). Oncogenic driver mutations and tumor mutational burden (TMB) were compared pre- and post NCRT to evaluate stability of the genomic landscape. TMB and frequently detected driver mutations were correlated with outcome parameters.
Results: In our corresponding tumor samples before and after NCRT 95.2 % of the oncogenic driver mutations could be found in both specimens whereas one ATM and one RYR1 mutation were not detectable after NCRT. TMB decreased in all patients after neoadjuvant treatment. KRAS ± TP53 mutations and TMB ≥ 5 were associated with impaired outcome.
Conclusion: Most oncogenic driver mutations investigated persisted after neoadjuvant treatment. At the same time, we did not observe ascending TMB after treatment but decline. Thus, NCRT does not seem to induce a relevant number of new driver mutations or mutational burden. Genetic profiling implies the potential to support tumor-informed approaches and outcome estimation in future.

Keywords:  ATM; KRAS; Next-generation sequencing; Radiotherapy; TP53; Tumor mutational burden

DOI:  https://doi.org/10.1016/j.ctro.2024.100894
J Comput Biol. 2024 Dec 11.

An Analytical Approach that Combines Knowledge from Germline and Somatic Mutations Enhances Tumor Genomic Reanalyses in Precision Oncology.

Elias DeVoe, Honey V Reddi, Bradley W Taylor, Samantha Stachowiak, Jennifer L Geurts, Ben George, Reza Shaker, Raul Urrutia, Michael T Zimmermann.

  Background: Expanded analysis of tumor genomics data enables current and future patients to gain more benefits, such as improving diagnosis, prognosis, and therapeutics. Methods: Here, we report tumor genomic data from 1146 cases accompanied by simultaneous expert analysis from patients visiting our oncological clinic. We developed an analytical approach that leverages combined germline and cancer genetics knowledge to evaluate opportunities, challenges, and yield of potentially medically relevant data. Results: We identified 499 cases (44%) with variants of interest, defined as either potentially actionable or pathogenic in a germline setting, and that were reported in the original analysis as variants of uncertain significance (VUS). Of the 7405 total unique tumor variants reported, 462 (6.2%) were reported as VUS at the time of diagnosis, yet information from germline analyses identified them as (likely) pathogenic. Notably, we find that a sizable number of these variants (36%-79%) had been reported in heritable disorders and deposited in public databases before the year of tumor testing. Conclusions: This finding indicates the need to develop data systems to bridge current gaps in variant annotation and interpretation and to develop more complete digital representations of actionable pathways. We outline our process for achieving such methodologic integration. Sharing genomics data across medical specialties can enable more robust, equitable, and thorough use of patient's genomics data. This comprehensive analytical approach and the new knowledge derived from its results highlight its multi-specialty value in precision oncology settings.

Keywords:  genomic data interpretation; genomics; precision medicine; precision oncology; reanalysis

DOI:  https://doi.org/10.1089/cmb.2023.0461
Clin Cancer Res. 2024 Dec 13.

Next generation sequencing-based MSI scoring predict benefit in mismatch repair deficient tumors treated with nivolumab: follow-up on NCI-MATCH arm Z1D.

Jonathan D Schoenfeld, Nilofer S Azad, Jacob Gross, Li Chen, Michael J Overman, Katrina Kao, Latifa F Jackson, Donna Brunnquell, Xiangning Bu, Christina Coppola, Ping Guan, Jennifer Lee, David Sims, Rebecca Fuchs, Jason L Weirather, Kathleen L Pfaff, Lauren Gunasti, Srin Ranasinghe, Stanley R Hamilton, Victoria Wang, Peter J O'Dwyer, Catherine J Wu, Scott J Rodig, David R Patton, Lyndsay Harris.

PURPOSE: Mismatch repair deficient (dMMR) tumors have demonstrated favorable responses to immune checkpoint inhibition targeting PD-1. However, more in-depth identification of predictors of response could further refine patient selection for immunotherapy treatment.
EXPERIMENTAL DESIGN: We undertook integrated evaluation performed on samples collected from 28 of 42 patients enrolled on the NCI-MATCH arm Z1D trial that evaluated PD-1 inhibition treatment with nivolumab in patients with non-colorectal dMMR tumors. Genomic analyses were performed using next-generation sequencing (NGS), whole exome sequencing, and RNA sequencing and supplemented by multiplex immunofluorescence performed on tissue samples.
RESULTS: In this dMMR population, more extensive alterations of microsatellites as assessed by measures of NGS was associated with clinical benefit and tumor mutational burden. RNA sequencing further revealed associations between clinical benefit and immune infiltration index. Gene sets enriched in patients with clinical benefit included interferon signaling, antigen processing and PI3K-AKT-mTOR signaling, while hedgehog signaling was found to be enriched in subjects lacking clinical benefit.
CONCLUSIONS: These genomic data highlight the importance of immune infiltration and antigen presentation in dMMR tumors that respond to immune checkpoint blockade. In addition, they suggest that, even within a dMMR population, NGS based measures of MSI could serve as biomarkers of immunotherapy response.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-0427
Biochim Biophys Acta Rev Cancer. 2024 Dec 09. pii: S0304-419X(24)00167-7. [Epub ahead of print] 189236

Circulating tumor cells in solid malignancies: From advanced isolation technologies to biological understanding and clinical relevance in early diagnosis and prognosis.

Divya Janjua, Apoorva Chaudhary, Udit Joshi, Tanya Tripathi, Alok Chandra Bharti.

  Circulating tumor cells (CTCs) are shed from primary tumors and travel through the body via circulation, eventually settling to form micrometastases under favorable conditions. Numerous studies have identified CTCs as a negative prognostic indicator for survival across various cancer types. CTCs mirror the current heterogeneity and genetic and biological state of tumors, making their study invaluable for understanding tumor progression, cell senescence, and cancer dormancy. However, their isolation and characterization still poses a major challenge that limits their clinical translation. A wide array of methods, each with different levels of specificity, utility, cost, and sensitivity, have been developed to isolate and characterize CTCs. Moreover, innovative techniques are emerging to address the limitations of existing methods. In this review, we provide insights into CTC biology addressing spectra of markers employed for molecular analysis and functional characterization. It also emphasizes current label-dependent and label-independent isolation procedures, addressing their strengths and limitations. SIGNIFICANCE: A comprehensive overview of CTC biology, their molecular and functional characterization, along with their current clinical utility will help in understanding the present-day extent to which the clinical potential of CTCs is getting tapped in personalized medicine.

Keywords:  Circulating tumor cells (CTCs); diagnosis; distant metastasis; liquid biopsy; prognosis

DOI:  https://doi.org/10.1016/j.bbcan.2024.189236
Hematology Am Soc Hematol Educ Program. 2024 12 06. 2024(1): 150-157

Mutations and MRD: clinical implications of clonal ontogeny.

Jerald Radich.

Measurable residual disease (MRD) is a strong but imprecise predictor of relapse in acute myeloid leukemia. Many patients fall into the outlier categories of MRD positivity without relapse or MRD negativity with relapse. Why? We will discuss these states in the context of "clonal ontogeny" examining how mutations, clonal structure, and Darwinian rules impact response, resistance, and relapse.

DOI: https://doi.org/10.1182/hematology.2024000541
Eur J Case Rep Intern Med. 2024 ;11(12): 004887

Partial Response to Treatment with ALK Inhibitor in a Patient With SQSTM1-ALK Fusion Positive Lung Adenocarcinoma.

Brenda Paola Rodriguez Arroyo, Alvaro Mondragón-Cardona, Rafael Adrián Pacheco-Orozco, Andrea Tamayo, Juan Camilo Moreno, Juan Camilo Baena-Valencia.

   Introduction: Lung cancer is the second most common cancer worldwide and the leading cause of cancer deaths; non-small cell lung cancer (NSCLC) constitutes about 85% of lung cancer cases, with ALK fusions representing 3-6% of them. The SQSTM1-ALK fusion is a rare finding in NSCLC, accounting for only 1.1% of ALK rearrangements. We present a case of lung adenocarcinoma with documentation of SQSTM1-ALK fusion that showed a partial response to alectinib.
Case description: This case details the clinical course of a 71-year-old, non-smoking woman with no significant medical history who presented with confusion, aphasia and multiple cerebral lesions detected on imaging. Further investigations revealed a stage IV lung adenocarcinoma with metastases to the brain and adrenal gland. Molecular profiling identified a rare SQSTM1-ALK fusion mutation alongside other genetic abnormalities, including low programmed death-ligand 1 expression and ROS1 kinase protein presence. Treatment with alectinib, initiated based on the identified ALK fusion, resulted in significant tumour regression in the lungs and complete resolution of the adrenal mass, as evidenced by follow-up imaging and clinical assessments.
Conclusion: This case highlights the efficacy of alectinib in treating rare ALK fusion variants in and underscores the importance of comprehensive molecular profiling in guiding targeted therapy decisions.
LEARNING POINTS: Recognition of rare ALK fusions This case highlights the importance of identifying rare ALK fusions, such as SQSTM1-ALK, in non-small cell lung cancer (NSCLC), which can guide personalised treatment strategies.Utility of advanced molecular diagnostics The use of next-generation sequencing alongside immunohistochemistry is crucial for accurately detecting ALK and ROS1 rearrangements, avoiding false positives and enabling the identification of druggable mutations.Impact of personalised medicine This case reinforces the value of personalised medicine in NSCLC, where molecular profiling can uncover unique genetic alterations, allowing for more tailored and potentially more effective treatments.

Keywords:  ALK fusion; alectinib; next-generation sequencing; non-small cell lung carcinoma

DOI:  https://doi.org/10.12890/2024_004887
Oncol Ther. 2024 Dec 11.

Liver Metastases are Associated with a Short Post-Progression Survival in a Real-World Group of Patients with Melanoma Treated with Checkpoint Inhibitors.

Miriam Mengoni, Thomas Tüting, Evelyn Gaffal, Andreas D Braun.

   INTRODUCTION: The introduction of immunotherapy (IT) has transformed clinical care of patients with metastatic melanoma. However, many patients still die as a result of progressive disease. Here we analyzed how IT improved survival in a real-world setting. Additionally, we investigated whether IT alters the dynamics and pattern of metastatic progression in different organs resulting from tissue-specific immune microenvironments.
METHODS: We retrospectively compared a group of 61 patients with metastatic melanoma (24 female, 37 male) treated with IT between 2015 and 2018 with a historical control group of 56 patients with metastatic melanoma (21 female, 35 male) treated with chemotherapy between 2005 and 2008 regarding treatment response rates and overall survival as well as the timing and distribution of metastatic progression.
RESULTS: Patients with metastatic melanoma treated with IT showed increased response rates and longer overall survival when compared with patients treated with chemotherapy. In addition, treatment with IT altered the dynamics but not the pattern of metastatic progression when compared with treatment with chemotherapy. Interestingly, patients receiving IT lived significantly longer after metastatic progression to lymph nodes, lungs and brain, but not after metastatic progression to the liver.
CONCLUSION: Our results confirm the efficacy of IT in a real-world setting. The altered dynamics of metastases supports studies suggesting a unique role of immune privilege in the liver tissue microenvironment that increases resistance to immunotherapy.

Keywords:  Immune privilege; Immunotherapy; Liver; Melanoma; Metastasis

DOI:  https://doi.org/10.1007/s40487-024-00320-4
Transl Lung Cancer Res. 2024 Nov 30. 13(11): 3067-3082

EGFR-V834L combined with L858R mutation reduced afatinib sensitivity and associated to early recurrence in lung cancer.

Nanao Terada, Hayato Koba, Shigeki Nanjo, Hideharu Kimura, Akihiro Nishiyama, Taro Yoneda, Takayuki Takeda, Hiroki Shirasaki, Koichi Nishi, Takashi Sone, Tadaaki Yamada, Koichi Takayama, Kazuhiko Shibata, Hiroki Matsuoka, Toshiyuki Kita, Kazuhiro Nagata, Yuichi Tambo, Noriyuki Ohkura, Johsuke Hara, Kazuo Kasahara, Shinji Kohsaka, Hiroyuki Mano, Seiji Yano.

   Background: The third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is widely used as a first-line treatment for EGFR-mutated non-small cell lung cancer (NSCLC). However, there is no established treatment for osimertinib resistance, so second-generation afatinib is an alternative treatment option. The purpose of this study was to elucidate gene alterations associated with afatinib efficacy and resistance by analyzing cell-free DNA (cfDNA) obtained from patients with EGFR-mutated NSCLC.
Methods: This study was conducted as a prospective clinical trial in patients with EGFR-mutated NSCLC at multiple institutions. We analyzed plasma cfDNA from the patients treated with afatinib as the first-line therapy.
Results: Paired specimens were obtained before and at the time of resistance to afatinib treatment, and specimens only at afatinib resistance were obtained from 22 and 18 patients, respectively. In plasma cfDNA from the 22 cases, driver EGFR mutations were detected in 13 cases (59.1%), and the compound V834L mutation was detected in two cases in cis with EGFR-L858R mutation. The median progression-free survival (mPFS) was remarkably shorter in patients with V834L than in all 22 cases (4.2 vs. 9.2 months). Moreover, we detected V834L and T790M combined with EGFR-L858R in the cfDNA from one patient resistant to afatinib. Preclinical experiments using EGFR-L858R, with or without V834L, in Ba/F3 cells revealed that V834L with L858R conferred resistance to low concentrations of EGFR-TKIs, including afatinib and osimertinib. In three cases of EGFR-L858R+V834L, other co-mutations, including TP53, CTNNB1, and RB1, were detected either before or after afatinib resistance.
Conclusions: These results suggested that V834L cooperates with other coexisting mutations to influence the therapeutic efficacy of EGFR-TKIs.

Keywords:  Co-mutation; cell-free DNA (cfDNA); epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI); liquid biopsy; resistance

DOI:  https://doi.org/10.21037/tlcr-24-471
Eur J Cancer. 2024 Nov 30. pii: S0959-8049(24)01761-1. [Epub ahead of print]214 115154

Safety and efficacy of adjuvant FOLFOX/FOLFIRI with versus without hepatic arterial infusion of floxuridine in patients following colorectal cancer liver metastasectomy (HARVEST trial): A randomized controlled trial.

De-Shen Wang, William Pat Fong, Lei Wen, Yan-Yu Cai, Chao Ren, Xiao-Jun Wu, Tian-Qi Zhang, Fei Cao, Meng-Xuan Zuo, Bin-Kui Li, Yun Zheng, Li-Ren Li, Gong Chen, Pei-Rong Ding, Zhen-Hai Lu, Rong-Xin Zhang, Yun-Fei Yuan, Zhi-Zhong Pan, Yu-Hong Li.

   BACKGROUND: Hepatic artery infusion (HAI) chemotherapy, particularly with floxuridine (FUDR), has previously shown effectiveness in improving recurrence-free survival (RFS) in colorectal cancer (CRC) patients with colorectal liver metastases (CRLM). Nonetheless, its adjuvant use alongside modern systemic chemotherapy remains unevaluated.
PATIENTS AND METHODS: The HARVEST trial is an open-label, randomized, controlled study conducted from May 2018 to August 2021. CRC patients with resectable primary tumors and CRLM were recruited and randomized to receive standard systemic chemotherapy only (non-HAI group) or in combination with HAI-FUDR (HAI group). However, due to a FUDR manufacturing shortage, the study was terminated early after enrolling 92 patients. The primary endpoint was the 3-year RFS rate, with secondary endpoints including overall survival (OS), liver-specific RFS, and adverse events.
RESULTS: Of the 92 randomized patients, 77 were included in the modified intention-to-treat analysis. Three-year RFS rates were comparable between the HAI (N = 38) and non-HAI (N = 39) groups (31.4 % vs. 34.4 %; P = 0.28). However, improved 1-year RFS and a longer expected five-year OS were observed in the HAI group. While exploratory subgroup analysis suggested potential RFS benefits for patients with multiple liver metastases, RAS/BRAF mutations, and positive postoperative ctDNA methylation, multivariable analysis did not identify these as independent factors. Safety analysis showed comparable chemotherapy-related adverse events, except for a higher occurrence of ALT elevation in the HAI group.
CONCLUSIONS: While our study showed no significant difference in three-year RFS, adjuvant chemotherapy intensification with HAI-FUDR is feasible and may offer early benefits in RFS and long-term OS. Nonetheless, a larger sample size is needed for validation and identifying which patient subgroup might benefit from this regimen.
TRIAL REGISTRATION: ClinicalTrials.gov: NCT03500874.

Keywords:  Adjuvant chemotherapy; Colorectal cancer liver metastases; Hepatic arterial infusion; Overall survival; Recurrence-free survival

DOI:  https://doi.org/10.1016/j.ejca.2024.115154
Front Oncol. 2024 ;14 1484802

Negative response to immunotherapy in dMMR or MSI-H gastric cancer with APC and PTEN mutations: a case report.

Jiang Liu, Xiumei Zhang, Qun Ren, Chuanjun Song, Jianhe Yu, Yin Cai, Dadong Chen.

   Background: Microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) represents a distinct molecular phenotype observed in malignant tumors. These tumors typically exhibit high levels of programmed cell death 1 ligand 1 (PD-L1) expression and high tumor mutational burden (TMB), resulting in an enhanced response to immune checkpoint inhibitors (ICI) therapy. The emergence of ICI has transformed the therapeutic strategy of gastric cancer (GC). Immune checkpoint blockade significantly improves the survival of gastric cancer patients, especially those with MSI-H or dMMR. However, it's worth noting that not all patients with MSI-H respond favorably to this treatment. It has been reported that factors such as tumor heterogeneity, alterations in the tumor microenvironment, and aberrant activation of tumor-related signaling pathways have been linked with resistance to ICI therapy.
Case presentation: Here, we describe a case of dMMR and MSI-H GC with adenomatous polyposis coli (APC) and phosphatase and tensin homolog deleted on chromosome ten (PTEN) mutations that failed to respond to anti-PD-1 combined with anti-HER2 (human epidermal growth factor receptor-2) therapy and chemotherapy. We attempted to elucidate the underlying causes and mechanisms behind this lack of response, and to provide new insights into treatment options for these patients.
Conclusions: Mutations of key genes within tumor-related signaling pathways and the infiltration of CD8+T cells in the tumor microenvironment may influence the efficacy of immunotherapy for MSI-H solid tumors.

Keywords:  case report; gastric cancer; immunotherapy; microsatellite instability high; mismatch repair-deficient

DOI:  https://doi.org/10.3389/fonc.2024.1484802