bims-preonc 2024-11-17 papers

bims-preonc

Biomed News

on Precision oncology

Issue of 2024–11–17
28 papers selected by
Ankita Daiya, OneCell Diagnostics Inc.

Clinical Applications of Circulating Tumor DNA Profiling in GI Cancers.
Circulating tumor DNA methylation detection as biomarker and its application in tumor liquid biopsy: advances and challenges.
Current biological implications and clinical relevance of metastatic circulating tumor cells.
Genomic profiling and clinical utility of circulating tumor DNA in metastatic prostate cancer: SCRUM-Japan MONSTAR SCREEN project.
Unravelling mutational signatures with plasma circulating tumour DNA.
Investigating the Use of Circulating Tumor DNA for Sarcoma Management.
Personalized MRD Assessment in Peri-surgical ctDNA for Prognostic Prediction in Hepatocellular Carcinoma.
Redefining pancreatic cancer management with tumor-agnostic precision medicine.
Genomic alterations associated with early-stage disease and early recurrence in patients with colorectal cancer.
Prognostic impact of circulating tumor DNA detection in portal and peripheral blood in resected pancreatic ductal adenocarcinoma patients.
Incidental finding of leukaemia in circulating tumour DNA- the importance of a molecular tumour board.
Precision oncology platforms: practical strategies for genomic database utilization in cancer treatment.
A Phase III Randomized Trial of Integrated Genomics and Avatar Models for Personalized Treatment of Pancreatic Cancer: the AVATAR Trial.
Glioblastoma functional heterogeneity and enrichment of cancer stem cells with tumor recurrence.
A tumor-naive ctDNA assay detects minimal residual disease in resected stage II or III colorectal cancer and predicts recurrence: subset analysis from the GALAXY study in CIRCULATE-Japan.
Molecular profiling reveals novel therapeutic targets and clonal evolution in ovarian clear cell carcinoma.
Comparison of androgen receptor mutation detection between plasma extracellular vesicle DNA and cell-free DNA and its relationship to prostate cancer prognosis.
The role of STK11/LKB1 in cancer biology: implications for ovarian tumorigenesis and progression.
Genomic instability as a driver and suppressor of anti-tumor immunity.
How Have Massively Parallel Sequencing Technologies Furthered Our Understanding of Oncogenesis and Cancer Progression?
More subtle microsatellite instability better predicts fluorouracil insensitivity in colorectal cancer patients.
Prospective study on Oncotype DX® assay to assess recurrence risk in early ER-positive HER2-negative breast cancer patients with uncertain biological behavior by standard parameters and its impact on treatment recommendation: The POST trial.
Extracellular Histones Profiles of Pediatric H3K27-Altered Diffuse Midline Glioma.
Leveraging homologous recombination deficiency for sarcoma : Unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcoma.
Pancreatic Neuroendocrine Neoplasms: Classification and Novel Role of Endoscopic Ultrasound in Diagnosis and Treatment Personalization.
Evaluation of ploidy and the DNA index by flow cytometry in central nervous system tumors: a review.
Olaparib monotherapy in advanced triple-negative breast cancer patients with homologous recombination deficiency and without germline mutations in BRCA1/2: The NOBROLA phase 2 study.
Drug Survival and Clinical Course of Patients with Cancer Treated with Biologic Therapy for Psoriasis.

JCO Oncol Pract. 2024 Nov;20(11): 1481-1490

Clinical Applications of Circulating Tumor DNA Profiling in GI Cancers.

Francesca Battaglin, Heinz-Josef Lenz.

Over the next few years, the analysis of circulating tumor DNA (ctDNA) through liquid biopsy is expected to enter clinical practice and revolutionize the approach to biomarker testing and treatment selection in GI cancers. In fact, growing evidence support the use of ctDNA testing as a noninvasive, effective, and highly specific tool for molecular profiling in GI cancers. Analysis of blood ctDNA has been investigated in multiple settings including early tumor detection, minimal residual disease evaluation, tumor diagnosis and evaluation of prognostic/predictive biomarkers for targeted treatment selection, longitudinal monitoring of treatment response, and identification of resistance mechanisms. Here, we review the clinical applications, advantages, and limitations of ctDNA profiling for precision oncology in GI cancers.

DOI: https://doi.org/10.1200/OP.24.00167
MedComm (2020). 2024 Nov;5(11): e766

Circulating tumor DNA methylation detection as biomarker and its application in tumor liquid biopsy: advances and challenges.

Lingyu Li, Yingli Sun.

  Circulating tumor DNA (ctDNA) methylation, an innovative liquid biopsy biomarker, has emerged as a promising tool in early cancer diagnosis, monitoring, and prognosis prediction. As a noninvasive approach, liquid biopsy overcomes the limitations of traditional tissue biopsy. Among various biomarkers, ctDNA methylation has garnered significant attention due to its high specificity and early detection capability across diverse cancer types. Despite its immense potential, the clinical application of ctDNA methylation faces substantial challenges pertaining to sensitivity, specificity, and standardization. In this review, we begin by introducing the basic biology and common detection techniques of ctDNA methylation. We then explore recent advancements and the challenges faced in the clinical application of ctDNA methylation in liquid biopsies. This includes progress in early screening and diagnosis, identification of clinical molecular subtypes, monitoring of recurrence and minimal residual disease (MRD), prediction of treatment response and prognosis, assessment of tumor burden, and determination of tissue origin. Finally, we discuss the future perspectives and challenges of ctDNA methylation detection in clinical applications. This comprehensive overview underscores the vital role of ctDNA methylation in enhancing cancer diagnostic accuracy, personalizing treatments, and effectively monitoring disease progression, providing valuable insights for future research and clinical practice.

Keywords:  biomarker; circulating tumor DNA; liquid biopsy; methylation; tumor

DOI:  https://doi.org/10.1002/mco2.766
Clin Exp Med. 2024 Nov 15. 25(1): 7

Current biological implications and clinical relevance of metastatic circulating tumor cells.

Reza Shahhosseini, SeyedAbbas Pakmehr, Anis Elhami, Maha Noori Shakir, Abdullah Ali Alzahrani, Mais Mazin Al-Hamdani, Munther Abosoda, Ali Alsalamy, Majid Mohammadi-Dehcheshmeh, Tahereh Ezazi Maleki, Hossein Saffarfar, Payam Ali-Khiavi.

  Metastatic disease and cancer recurrence are the primary causes of cancer-related deaths. Circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) are the driving forces behind the spread of cancer cells. The emergence and development of liquid biopsy using rare CTCs as a minimally invasive strategy for early-stage tumor detection and improved tumor management is a promising advancement in recent years. However, before blood sample analysis and clinical translation, precise isolation of CTCs from patients' blood based on their biophysical properties, followed by molecular identification of CTCs using single-cell multi-omics technologies is necessary to understand tumor heterogeneity and provide effective diagnosis and monitoring of cancer progression. Additionally, understanding the origin, morphological variation, and interaction between CTCs and the primary and metastatic tumor niche, as well as and regulatory immune cells, will offer new insights into the development of CTC-based advanced tumor targeting in the future clinical trials.

Keywords:  Cancer metastasis; Circulating tumor cells; Disseminated tumor cells; Liquid biopsy; Targeted therapy

DOI:  https://doi.org/10.1007/s10238-024-01518-6
BJC Rep. 2024 Apr 03. 2(1): 28

Genomic profiling and clinical utility of circulating tumor DNA in metastatic prostate cancer: SCRUM-Japan MONSTAR SCREEN project.

Masaki Shiota, Nobuaki Matsubara, Taigo Kato, Masatoshi Eto, Takahiro Osawa, Takashige Abe, Nobuo Shinohara, Koshiro Nishimoto, Yota Yasumizu, Nobuyuki Tanaka, Mototsugu Oya, Takao Fujisawa, Satoshi Horasawa, Yoshiaki Nakamura, Takayuki Yoshino, Norio Nonomura.

BACKGROUND: Circulating tumor DNA (ctDNA) testing has emerged as a novel tool for cancer precision medicine. This study investigated the genomic profiling and clinical utility of ctDNA in metastatic prostate cancer.
METHODS: This is a nation-wide prospective observational study. Patients treated with systemic treatment for metastatic castration-sensitive prostate cancer (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC) were included. ctDNA was analyzed using FoundationOne Liquid®CDx at enrollment. In a subset of patients, ctDNA after disease progression and tissue prior to the initiation of treatment were examined using FoundationOne Liquid®CDx and FoundationOne®CDx, respectively.
RESULTS: The frequency of AR alterations and homologous recombination repair (HRR) defect was higher in mCRPC compared with mCSPC. Tumor mutational burden was correlated between tissue and ctDNA at pre-treatment, as well as ctDNA between at pre-treatment and at post-treatment. Patients with HRR defect were associated with shorter time to castration resistance in androgen deprivation therapy/combined androgen blockade, but not in androgen receptor pathway inhibitor, compared with patients without HRR defect in mCSPC. Time to treatment failure in patients with AR amplification or AR mutation was shorter compared with patients without AR alterations in mCRPC.
CONCLUSIONS: This study revealed valuable findings for the clinical care of metastatic prostate cancer. Especially, predictive factors such as HRR defect in mCSPC should be validated in the future.

DOI: https://doi.org/10.1038/s44276-024-00049-7
Nat Commun. 2024 Nov 14. 15(1): 9876

Unravelling mutational signatures with plasma circulating tumour DNA.

Sebastian Hollizeck, Ning Wang, Stephen Q Wong, Cassandra Litchfield, Jerick Guinto, Sarah Ftouni, Richard Rebello, Sehrish Kanwal, Ruining Dong, Sean Grimmond, Shahneen Sandhu, Linda Mileshkin, Richard W Tothill, Dineika Chandrananda, Sarah-Jane Dawson.

The use of circulating tumour DNA (ctDNA) to profile mutational signatures represents a non-invasive opportunity for understanding cancer mutational processes. Here we present MisMatchFinder, a liquid biopsy approach for mutational signature detection using low-coverage whole-genome sequencing of ctDNA. Through analysis of 375 plasma samples across 9 cancers, we demonstrate that MisMatchFinder accurately infers single-base and doublet-base substitutions, as well as insertions and deletions to enhance the detection of ctDNA and clinically relevant mutational signatures.

DOI: https://doi.org/10.1038/s41467-024-54193-2
J Clin Med. 2024 Oct 31. pii: 6539. [Epub ahead of print]13(21):

Investigating the Use of Circulating Tumor DNA for Sarcoma Management.

Paige Darville-O'Quinn, Nalan Gokgoz, Kim M Tsoi, Irene L Andrulis, Jay S Wunder.

  Background/Objectives: Sarcomas are a heterogeneous group of cancers, many with high rates of recurrence and metastasis, leading to significant morbidity and mortality. Due to a lack of early diagnostic biomarkers, by the time recurrent disease can be clinically detected, it is often extensive and difficult to treat. Here, we sought to investigate methods of detecting ctDNA in sarcoma patient plasma to potentially monitor disease recurrence, progression, and response to treatment. Methods: Whole-exome sequencing of matched tumor and blood samples revealed patient-specific mutations, which were used to develop personalized assays to detect ctDNA in patient plasma. Since ctDNA is present in extremely low quantities, detection requires highly sensitive methodologies. Droplet digital PCR is highly sensitive; however, it is limited in that it can only be used to target one tumor variant at a time. Therefore, a protocol combining multiplex PCR and targeted amplicon sequencing was developed. Results: ddPCR was successfully able to detect tumor-specific mutations in plasma, confirming the presence of ctDNA in sarcoma patients. Multiplex PCR followed by amplicon sequencing was able to detect multiple tumor variants simultaneously, although it was not as sensitive as ddPCR. Additionally, ctDNA was detected in patient plasma collected at two different time points. Conclusions: This work demonstrates that although there is a lack of recurrent biomarkers, personalized assays detecting ctDNA have the potential to be used to monitor disease progression in sarcoma.

Keywords:  biomarkers; cell-free DNA; circulating tumor DNA; ctDNA; ddPCR; liquid biopsy; multiplex PCR; sarcoma; soft tissue sarcoma

DOI:  https://doi.org/10.3390/jcm13216539
Clin Cancer Res. 2024 Nov 11.

Personalized MRD Assessment in Peri-surgical ctDNA for Prognostic Prediction in Hepatocellular Carcinoma.

Jie Hu, Haoran Tang, Can-Can Jia, Xiang-Yu Zhang, Ying Xu, Jin-Peng Tan, Jia Fan, Shidong Jia, Jian Zhou.

OBJECTIVE: Detecting residual disease is a critical clinical requirement in the peri-surgical management of patients with resectable hepatocellular carcinoma (HCC). Previous studies focused on specific genomic regions exhibiting limited sensitivity and failed to meet the minimal residual disease (MRD) testing threshold. We introduce a next-generation sequencing (NGS) based assay, informed by baseline samples, facilitating MRD detection in hepatectomized HCC patients and offering prognostic predictions.
EXPERIMENTAL DESIGN: This study involved 88 HCC patients who underwent surgical resections January 2016 to May 2016 in Zhongshan Hospital Fudan University. Tumor and normal tissue samples were collected during surgery, while plasma samples were obtained both before surgery and up to seven days post-surgery. Using an NGS-based personalized circulating tumor DNA assay, we analyzed MRD in both pre-surgical and post-surgical blood samples and the correlation with prognosis.
RESULTS: With a median follow-up period of 80.7 months, our findings demonstrated significant correlations between pre-surgical ctDNA tumor fractions, post-surgical plasma MRD status, and both recurrence-free survival (RFS) and overall survival (OS). Post-surgical MRD status emerged as the most significant risk factor for cancer recurrence (HR=2.17, 95% CI: 1.09-4.30, p=0.027) compared to other clinical characteristics in multivariate Cox regression analysis. Notably, MRD status showed potential as a prognostic indicator among clinically low-recurrent-risk patients, such as those with BCLC stage 0-A, CNLC stage I-II.
CONCLUSION: Evaluating personalized MRD provided crucial prognostic insights into RFS and OS. It efficiently identified patients at high risk of recurrence, even among those initially perceived as low-risk cases.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-1897
Carcinogenesis. 2024 Nov 08. pii: bgae066. [Epub ahead of print]

Redefining pancreatic cancer management with tumor-agnostic precision medicine.

Neha K Reddy, Vivek Subbiah.

  Precision oncology and tumor-agnostic drug development provide hope for enhancing outcomes among patients with pancreatic cancer. Tumor-agnostic therapies have emerged across various tumor types, driven by insights into shared biomarkers. In the case of pancreatic cancer, the prevalence of the KRAS gene mutation is noteworthy. However, there exist other actionable alterations, such as BRCA1/2 mutations and fusion genes (BRAF, FGFR2, RET, NTRK, NRG1, and ALK), which present potential targets for therapy. Notably, tumor-agnostic drugs have demonstrated efficacy in specific subsets of pancreatic cancer patients who harbor these genetic alterations. Despite the rarity of NTRK fusions in pancreatic cancer, larotrectinib and entrectinib have exhibited effectiveness in NTRK fusion-positive pancreatic cancers. Additionally, repotrectinib, a next-generation NTRK inhibitor, has shown promising activity in NTRK positive pancreatic cancer patients who have developed acquired resistance to previous NTRK inhibitors. Immune checkpoint inhibitors, such as pembrolizumab and dostarlimab, have proven to be effective in dMMR/MSI-H pancreatic cancers. Moreover, targeted therapies for BRAF V600, RET fusions, and HER2/neu overexpression have displayed promising results in specific subsets of pancreatic cancer patients. Emerging targets like NRG fusions, FGFR2 fusions, TP53 mutations, and KRAS G12C mutations present potential avenues for targeted therapy. Tumor-agnostic therapies have the potential to revolutionize pancreatic cancer treatment by focusing on specific genetic alterations. It is crucial to continue implementing comprehensive screening strategies that encompass the ability to detect all these tumor-agnostic biomarkers. This will be essential in identifying pancreatic cancer patients who may benefit from these therapies.

Keywords:  BRAF; NTRK; RET; precision oncology; tissue-agnostic; tumor-agnostic

DOI:  https://doi.org/10.1093/carcin/bgae066
Oncologist. 2024 Nov 12. pii: oyae269. [Epub ahead of print]

Genomic alterations associated with early-stage disease and early recurrence in patients with colorectal cancer.

Leontios Pappas, Julia C F Quintanilha, Richard S P Huang, Aparna R Parikh.

   BACKGROUND: The molecular characterization of early-stage (1-3) colorectal cancer (CRC) remains incomplete, as opposed to metastatic disease, where comprehensive genomic profiling (CGP) is routinely performed. This study aimed to characterize the genomics of stages 1-3 versus IV CRC, and the genomics of patients recurring within 1 year of diagnosis.
PATIENTS AND METHODS: Patients from a de-identified CRC clinico-genomic database who received Foundation Medicine testing (FoundationOne/FoundationOne CDx) during routine clinical care at approximately 280 US cancer clinics between March 2014 and June 2023 were included. Genomic alterations (GA) were compared by Fisher's exact test.
RESULTS: A total of 4702 patients were included; 1902 with stages 1-3 and 2800 with stage 4 disease. Among patients with stages 1-3 disease, 546 recurred within 1 year. Patients staged 1-3 had higher prevalence of microsatellite instability (MSI-H, 11.4% vs 4.5%, P < .001), tumor mutational burden (TMB) ≥ 10 Mut/Mb (14.6% vs 6.8%, P < .001), GA in RNF43 (11.2% vs 5.7%, P < .001), MSH6 (3.9% vs 1.7%, P < .001), MLH1 (2.3% vs 0.7%, P < .001), and MSH2 (1.5% vs 0.6%, P < .01) compared to those with stage 4 disease. Patients who recurred within 1 year had higher prevalence of MSI-H (13.2% vs 4.4%, P < .001), TMB ≥ 10 Mut/Mb (16.2% vs 6.9%, P < .001), BRAF V600E (17.2% vs 7.9%, P < .003), GA in RNF43 (13.7% vs 5.3%, P < .001), MSH6 (4.2% vs 1.6%, P = .035), and BRCA1/2 (6.2% vs 3.0%, P = .030). On recurrence, more patients received targeted therapy when CGP was performed before versus after first-line therapy (43% vs 19%, P < .001).
CONCLUSIONS: Early-stage CRC patients can have distinct genomic profiles and CGP in this population can help expand access to targeted therapies.

Keywords:  cancer recurrence; colorectal cancer; early-stage cancer; genomic alterations; molecular characterization

DOI:  https://doi.org/10.1093/oncolo/oyae269
Sci Rep. 2024 11 08. 14(1): 27296

Prognostic impact of circulating tumor DNA detection in portal and peripheral blood in resected pancreatic ductal adenocarcinoma patients.

Charlotte Maulat, Cindy Canivet, Bastien Cabarrou, Anne Pradines, Janick Selves, Anne Casanova, Aurélia Doussine, Naïma Hanoun, Emmanuel Cuellar, Paul Boulard, Nicolas Carrère, Louis Buscail, Barbara Bournet, Fabrice Muscari, Pierre Cordelier.

  In PDAC patients, ctDNA detection's prognostic significance needs validation especially in resected patients. This study investigated ctDNA kinetics in portal and peripheral blood before and after resection, and whether tissue mobilization during surgery influences ctDNA detection. In this single-center prospective cohort, portal and peripheral blood were drawn during pancreaticoduodenectomy before and after tissue mobilization, during 12 postoperative months and were associated with overall survival (OS), recurrence-free survival (RFS) and CA19-9 (secondary endpoints). Tumor mutations were identified using next-generation-sequencing and ctDNA detected by digital droplet PCR. From 2018 to 2022, 34 patients were included. The 2-year RFS and OS were 47.6%(95%CI[29.5; 63.6]) and 65.7%(95%CI[46.5; 79.4]) respectively. Intraoperatively, ctDNA detection in portal or peripheral blood was associated with worse RFS (HR[95%CI]3.26[1.26; 8.45],p = 0.010) and OS (HR[95%CI]5.46[1.65;18.01],p = 0.002). Portal vein sampling did not improve ctDNA detection. CtDNA levels were increased by 2.5-fold (p = 0.031) in peripheral blood after tissue mobilization but not significantly linked to RFS or OS. Detecting ctDNA intraoperatively was correlated with poorer RFS (HR [95% CI] 3.26 [1.26;8.45], p = 0.010) and 0S (HR [95% CI] 5.46 [1.65;18.01], p = 0.002). Portal vein sampling did not improve ctDNA detection. Tissue mobilization increases ctDNA levels. Intraoperative detection of ctDNA is associated with a worse prognosis.

Keywords:  Circulating tumor DNA; Liquid biopsy; Overall survival; Pancreatic ductal adenocarcinoma; Recurrence-free survival; Tissue mobilization

DOI:  https://doi.org/10.1038/s41598-024-76903-y
BJC Rep. 2024 Feb 13. 2(1): 12

Incidental finding of leukaemia in circulating tumour DNA- the importance of a molecular tumour board.

Justin Mencel, Neha Rayarel, Paula Proszek, Paul Carter, Andy Feber, Sanjay Popat, Terri P McVeigh, Angela George, Alan Dunlop, Katy Hardy, Ian Chau, David Cunningham, Darina Kohoutova, Richard Lee, Sunil Iyengar, Naureen Starling.

As the use of liquid biopsies are increasing across multiple indications in cancer medicine, the detection of incidental findings on circulating tumour DNA is of increasing importance. We report the finding of leukaemia detected in a patient who underwent plasma-based circulating tumour DNA next generation screening as part of a screening liquid biopsy study. A BRAF V600E mutation detected was deemed pathogenic following discussion at a molecular tumour board, and recommendation of further investigations led to the diagnosis of an occult haematological malignancy. We report the importance of molecular tumour board discussion and recommendations in the identification of incidental, pathogenic findings on circulating tumour DNA.

DOI: https://doi.org/10.1038/s44276-023-00034-6
Mol Cytogenet. 2024 Nov 14. 17(1): 28

Precision oncology platforms: practical strategies for genomic database utilization in cancer treatment.

Antonia A Gazola, William Lautert-Dutra, Leticia Frohlich Archangelo, Rodolfo B Dos Reis, Jeremy A Squire.

  In recent years, the expansion of molecularly targeted cancer therapies has significantly advanced precision oncology. Parallel developments in next-generation sequencing (NGS) technologies have also improved precision oncology applications, making genomic analysis of tumors more affordable and accessible. Targeted NGS panels now enable the rapid identification of diverse actionable mutations, requiring clinicians to efficiently assess the predictive value of cancer biomarkers for specific treatments. The urgency for timely and accurate decision-making in oncology emphasizes the importance of reliable precision oncology software. Online clinical decision-making tools and associated cancer databases have been designed by consolidating genomic data into standardized, accessible formats. These new platforms are highly integrated and crucial for identifying actionable somatic genomic biomarkers essential for tumor survival, determining corresponding drug targets, and selecting appropriate treatments based on the mutational profile of each patient's tumor. To help oncologists and translational cancer researchers unfamiliar with these tools, we review the utility, accuracy, and comprehensiveness of several commonly used precision medicine software options currently available. Our analysis categorized selected genomic databases based on their primary content, utility, and how well they provide practical guidance for interpreting somatic biomarker data. We identified several comprehensive, mostly open-access platforms that are easy to use for genetic biomarker searches, each with unique features and limitations. Among the precision oncology tools we evaluated, we found MyCancerGenome and OncoKB to be the first choice, offering comprehensive, accurate up-to-date information on the clinical significance of somatic mutations. To illustrate the application of these precision oncology tools in clinical settings, we evaluated three case studies to see how use of the platforms could have influenced treatment planning. Most of the precision oncology software evaluated could be easily streamlined into clinical workflows to provide updated information on approved drugs and clinical trials related the actionable mutations detected. Some platforms were very intuitive and easy to use, while others, often developed in smaller academic settings, were more difficult to navigate and may not be updated consistently. Future enhancements, incorporating artificial intelligence algorithms, are likely to improve integration of the platforms with diverse big data sources, enabling more accurate predictions of potential therapeutic responses.

Keywords:  Actionable mutations; Artificial intelligence; Big data integration; Cancer biomarkers; Chemotherapy; DNA mutational analysis; Oncogenes; Oncology software; Personalized cancer treatment; Tumor suppressor genes

DOI:  https://doi.org/10.1186/s13039-024-00698-w
Clin Cancer Res. 2024 Nov 14.

A Phase III Randomized Trial of Integrated Genomics and Avatar Models for Personalized Treatment of Pancreatic Cancer: the AVATAR Trial.

Francesca Sarno, Jair Tenorio, Sofia Perea, Laura Medina, Roberto Pazo-Cid, Ignacio Juez, Rocio Garcia-Carbonero, Jaime Feliu, Carmen Guillen-Ponce, Pedro P Lopez-Casas, Carmen Guerra, Yolanda Duran, Jose Francisco López-Acosta, Carolina Alonso, Estrella Esquivel, Ana Dopazo, Dipikaa Akshinthala, Senthil K Muthuswamy, Pablo Lapunzina, Bruno Bockorny, Manuel Hidalgo.

PURPOSE: Pancreatic adenocarcinoma (PDAC) has limited treatment options. We compared the efficacy of comprehensive precision medicine against the conventional treatment in PDAC.
METHODS: Phase III trial of advanced PDAC where patients were randomized (1:2) to a conventional treatment treated at physician's discretion (arm A), or to precision medicine (arm B). Subjects randomized to arm B underwent a tumor biopsy for whole exome sequencing (WES) and to generate avatar mouse models and patient derived organoids for phenotypic drug screening, with final treatment recommended by molecular tumor board. The primary objective was median overall survival (OS).
RESULTS: 137 patients were enrolled with 125 randomized, 44 to arm A and 81 to Arm B. WES was performed in 80.3% (65/81) patients of arm B, with potentially actionable mutations detected in 21.5% (14/65). Experimental models were generated in 16/81 patients (19.8%). Second-line treatment was administered to 39 patients in the experimental arm, but only 4 (10.2%) received personalized treatment, while 35 could not be receive matched therapy due to rapid clinical deterioration, delays in obtaining study results or absence of actionable targets. Median OS was 8.7 and 8.6 months (p=0.849) and median progression-free survival was 3.8 and 4.3 months (p=0.563) for the conventional and experimental arms, respectively. Notably, the four patients who received personalized treatment had median OS of 19.3 months.
CONCLUSIONS: Personalized medicine was challenging to implement in most patients with PDAC, limiting the interpretation of intention to treat analysis. Survival was improved in the subset of patients who did receive matched therapy.

DOI: https://doi.org/10.1158/1078-0432.CCR-23-4026
Neuron. 2024 Nov 06. pii: S0896-6273(24)00733-5. [Epub ahead of print]

Glioblastoma functional heterogeneity and enrichment of cancer stem cells with tumor recurrence.

Xuanhua P Xie, Mungunsarnai Ganbold, Jing Li, Michelle Lien, Mollie E Chipman, Tao Wang, Chenura D Jayewickreme, Alicia M Pedraza, Tejus Bale, Viviane Tabar, Cameron Brennan, Daochun Sun, Roshan Sharma, Luis F Parada.

  Glioblastoma (GBM) is an incurable disease with high intratumoral heterogeneity. Bioinformatic studies have examined transcriptional heterogeneity with differing conclusions. Here, we characterize GBM heterogeneity and highlight critical phenotypic and hierarchical roles for quiescent cancer stem cells (qCSCs). Unsupervised single-cell transcriptomic analysis of patient-derived xenografts (PDXs) delineates six GBM transcriptional states with unique tumor exclusive gene signatures, five of which display congruence with central nervous system (CNS) cell lineages. We employ a surrogate tumor evolution assay by serial xenograft transplantation to demonstrate faithful preservation of somatic mutations, transcriptome, and qCSCs. PDX chemotherapy results in CSC resistance and expansion, also seen in recurrent patient GBM. In aggregate, these novel GBM transcriptional signatures exclusively identify tumor cells and define the hierarchical landscape as stable biologically discernible cell types that allow capture of their evolution upon recurrence, emphasizing the importance of CSCs and demonstrating general relevance to all GBM.

Keywords:  F3 receptor; cancer stem cells; chemoresistance; glioblastoma; heterogeneity; hierarchy; patient-derived xenograft; recurrence; single-cell RNA sequencing; temozolomide

DOI:  https://doi.org/10.1016/j.neuron.2024.10.012
Clin Cancer Res. 2024 Nov 08.

A tumor-naive ctDNA assay detects minimal residual disease in resected stage II or III colorectal cancer and predicts recurrence: subset analysis from the GALAXY study in CIRCULATE-Japan.

Yoshiaki Nakamura, Kristiyana Kaneva, Christine Lo, Daniel Neems, Jonathan E Freaney, Hala Boulos, Seung Won Hyun, Farahnaz Islam, Jason Yamada-Hanff, Terri M Driessen, Anne Sonnenschein, Dana F DeSantis, Daisuke Kotani, Jun Watanabe, Masahito Kotaka, Saori Mishima, Hideaki Bando, Kentaro Yamazaki, Hiroya Taniguchi, Ichiro Takemasa, Takeshi Kato, Chithra Sangli, Robert Tell, Richard Blidner, Takayuki Yoshino, Kate Sasser, Eiji Oki, Halla Nimeiri.

PURPOSE: Analysis of circulating tumor DNA (ctDNA) may enable early identification of patients likely to relapse, presenting an opportunity for early interventions and improved outcomes. Tumor-naïve plasma-only approaches for molecular residual disease (MRD) assessment accelerate turnaround time, enabling rapid treatment decisions and ongoing surveillance.
EXPERIMENTAL DESIGN: Plasma samples were obtained from 80 study participants with stage II or III colorectal cancer (CRC) selected from CIRCULATE-Japan GALAXY. MRD status was assessed using a tumor-naïve ctDNA assay (xM) that integrates methylation and genomic variant data, delivering a binary call. MRD was assessed at 4 weeks post-surgery (landmark timepoint (LMT)) using methylation and genomic variant data and longitudinally (median 22.1 months) using only methylation data.
RESULTS: At LMT, 69/80 study participants were evaluable (36 recurrent; 33 non-recurrent). Of recurrent study participants, 22/36 had detectable ctDNA (MRD+) at LMT and 29/33 non-recurrent study participants had undetectable ctDNA (MRD-), yielding clinical sensitivity of 61.1% and specificity of 87.9%. Additionally, 74 study participants were evaluable for longitudinal performance with a clinical sensitivity of 83.3% and specificity of 89.5%. Median lead time from first MRD+ result to recurrence was 4.77 months overall, and 5.30 months for study participants with no adjuvant treatment. At 12 weeks post-surgery, MRD status strongly correlated with disease-free survival (DFS) [adj. HR 9.69], outperforming carcinoembryonic antigen (CEA) correlation [HR 2.13].
CONCLUSIONS: This tumor-naïve MRD assay demonstrated clinically meaningful performance at LMT and longitudinally, accurately predicting clinical recurrence. MRD status was a stronger prognostic biomarker to DFS compared to standard of care CEA.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-2396
BMC Cancer. 2024 Nov 14. 24(1): 1403

Molecular profiling reveals novel therapeutic targets and clonal evolution in ovarian clear cell carcinoma.

Angel Chao, Chen-Yang Huang, Willie Yu, Chiao-Yun Lin, Hao Lin, An-Shine Chao, Cheng-Tao Lin, Hung-Hsueh Chou, Kuang-Gen Huang, Huei-Jean Huang, Ting-Chang Chang, Steven G Rozen, Ren-Chin Wu, Chyong-Huey Lai.

   BACKGROUND: Ovarian clear cell carcinoma (OCCC) has a disproportionately high incidence among women in East Asia. Patients diagnosed with OCCC tend to experience worse clinical outcomes than those with high-grade serous carcinoma (HGSC) at advanced stages. The unfavorable prognosis of OCCC can be partly attributed to its frequent resistance to conventional chemotherapy. Within a precision medicine framework, we sought to provide a comprehensive molecular characterization of OCCC using whole-exome sequencing to uncover potential molecular targets that may inform novel therapeutic strategies.
METHODS: We performed whole-exome sequencing analysis on tumor-normal paired samples from 102 OCCC patients. This comprehensive genomic characterization of a substantial cohort of OCCC specimens was coupled with an analysis of clonal progression.
RESULTS: On analyzing 102 OCCC samples, ARID1A (67%) and PIK3CA (49%) emerged as the most frequently mutated driver genes. We identified tier 1 or 2 clinically actionable molecular targets in 40% of cases. This included DNA mismatch repair deficiency (n = 1), as well as BRCA2 (n = 1), PIK3CA (n = 36), KRASG12C (n = 1), and ATM (n = 4) mutations. Furthermore, 45% of OCCC samples displayed ARID1A biallelic loss. Interestingly, we identified previously unreported mutations in the 5' untranslated region of the TERT gene that harbored an adverse prognostic significance. Clock-like mutational processes and activated APOBECs were major drivers of somatic point mutations. Mutations arising from DNA mismatch repair deficiency were uncommon. Reconstruction of clonal evolution revealed that early genetic events likely driving tumorigenesis included mutations in the ARID1A, PIK3CA, TERT, KRAS, and TP53 genes.
CONCLUSIONS: Our study provides a comprehensive characterization of the genomic landscape and clonal evolution in OCCC within a substantial cohort. These findings unveil potentially actionable molecular alterations that could be leveraged to develop targeted therapies.

Keywords:   TERT mutation; Clinical actionability; Clonal evolution; Mutational signature; Ovarian clear cell carcinoma; Whole-exome sequencing

DOI:  https://doi.org/10.1186/s12885-024-13125-5
Ann Med. 2024 Dec;56(1): 2426770

Comparison of androgen receptor mutation detection between plasma extracellular vesicle DNA and cell-free DNA and its relationship to prostate cancer prognosis.

Ting Ding, Xiao Li, Longlong Zhang, Zhen Wei, Chaoliang Xiong, Hong Wang, Xiaoke Hao, Xianfei Zeng.

   BACKGROUND: In liquid biopsy, mutation detection is primarily performed using cell-free DNA (cfDNA). However, the numerous advantages of extracellular vesicle (EV) DNA for mutation detection have gradually garnered the attention of researchers in recent years. This study aimed to compare the differences between EV DNA and cfDNA in mutation detection and explore the role of plasma androgen receptor (AR) mutations in the prognosis of prostate cancer (PCa).
METHODS: We compared the biological characteristics of plasma extracellular vesicle DNA (p-EV DNA) and cfDNA by capillary electrophoresis and concentration detection. Subsequently, we performed pan-oncogene-targeted sequencing in paired tissue and plasma samples from five patients with PCa to verify the feasibility of mutation detection using p-EV DNA and cfDNA. Further, we conducted AR mutation detection in expanded samples to compare the differences between EV DNA and cfDNA in mutation detection and to analyse their role in PCa.
RESULTS: p-EV DNA fragments were larger than plasma cell-free DNA (p-cfDNA) fragments; however, there was no significant difference in their concentrations in the plasma of patients with PCa. Feasibility analysis revealed that major mutations associated with PCa detected in tissue samples could be identified in both p-EV DNA and p-cfDNA. Advantage comparison found that, although cfDNA could detect more mutations, AR mutations in EV DNA were more strongly associated with a poor prognosis of PCa than cfDNA.
CONCLUSION: Mutation detection using either EV DNA or cfDNA is both feasible in PCa liquid biopsies, and EV DNA AR mutations have an advantage in prognostic assessment for PCa. This study lays the foundation for future research on EV DNA-related biomarkers.

Keywords:  AR mutations; Liquid biopsy; cell-free DNA; extracellular vesicle DNA; prostate cancer

DOI:  https://doi.org/10.1080/07853890.2024.2426770
Front Cell Dev Biol. 2024 ;12 1449543

The role of STK11/LKB1 in cancer biology: implications for ovarian tumorigenesis and progression.

Jian Kang, Stefano Gallucci, Junqi Pan, Jonathan S Oakhill, Elaine Sanij.

  STK11 (serine-threonine kinase 11), also known as LKB1 (liver kinase B1) is a highly conserved master kinase that regulates cellular metabolism and polarity through a complex signaling network involving AMPK and 12 other AMPK-related kinases. Germline mutations in LKB1 have been causatively linked to Peutz-Jeghers Syndrome (PJS), an autosomal dominant hereditary disease with high cancer susceptibility. The identification of inactivating somatic mutations in LKB1 in different types of cancer further supports its tumor suppressive role. Deleterious mutations in LKB1 are frequently observed in patients with epithelial ovarian cancer. However, its inconsistent effects on tumorigenesis and cancer progression suggest that its functional impact is genetic context-dependent, requiring cooperation with other oncogenic lesions. In this review, we summarize the pleiotropic functions of LKB1 and how its altered activity in cancer cells is linked to oncogenic proliferation and growth, metastasis, metabolic reprogramming, genomic instability, and immune modulation. We also review the current mechanistic understandings of this master kinase as well as therapeutic implications with particular focus on the effects of LKB1 deficiency in ovarian cancer pathogenesis. Lastly, we discuss whether LKB1 deficiency can be exploited as an Achilles heel in ovarian cancer.

Keywords:  LKB1; STK11; cancer biology; cancer signaling; immunotherapy; metabolism; ovarian cancer; targeted therapy

DOI:  https://doi.org/10.3389/fcell.2024.1449543
Front Immunol. 2024 ;15 1462496

Genomic instability as a driver and suppressor of anti-tumor immunity.

Marta Requesens, Floris Foijer, Hans W Nijman, Marco de Bruyn.

  Genomic instability is a driver and accelerator of tumorigenesis and influences disease outcomes across cancer types. Although genomic instability has been associated with immune evasion and worsened disease prognosis, emerging evidence shows that genomic instability instigates pro-inflammatory signaling and enhances the immunogenicity of tumor cells, making them more susceptible to immune recognition. While this paradoxical role of genomic instability in cancer is complex and likely context-dependent, understanding it is essential for improving the success rates of cancer immunotherapy. In this review, we provide an overview of the underlying mechanisms that link genomic instability to pro-inflammatory signaling and increased immune surveillance in the context of cancer, as well as discuss how genomically unstable tumors evade the immune system. A better understanding of the molecular crosstalk between genomic instability, inflammatory signaling, and immune surveillance could guide the exploitation of immunotherapeutic vulnerabilities in cancer.

Keywords:  MMRd; cGAS-STING; chromosomal instability; genomic instability; immune evasion; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3389/fimmu.2024.1462496
Methods Mol Biol. 2025 ;2866 265-286

How Have Massively Parallel Sequencing Technologies Furthered Our Understanding of Oncogenesis and Cancer Progression?

Diogo Ann Onuselogu, Saskia Benz, Suparna Mitra.

  Massively parallel sequencing technologies have been a boon to many fields of biological science, including oncology. Cancer is an umbrella term for many diseases featuring abnormal cellular growth due to genetic and epigenetic aberrations. Advances in sequencing technology allow for interrogation of the DNA and RNA of cancer cells and other cells in the tumor microenvironment down to a single-base resolution. However, these strides come after a rich history of ground-breaking biological assays, like the discovery of the Philadelphia chromosome in the context of leukemia. Many specific genetic and epigenetic modifications have been implicated in oncogenesis, cancer progression, and response to treatment. Sequencing technologies have also helped to associate populations of bacteria in the microbiome to cancer development and prognosis. However, all this new information, especially when procured via high-throughput methods, comes at the cost of being more computationally and staff-resource intensive. There is also more risk to the privacy of the individuals with sequenced genomes. Notwithstanding, the overall benefit of sequencing technologies can greatly outweigh the risks with careful advancements and continued focus on the goal: helping those affected by cancer via precision medicine. Cancer biology has been and will continue to be elucidated by sequencing innovations in ways unimaginable without it.

Keywords:  Cancer; Modern history; Next-generation sequencing; Oncogenesis; Technology

DOI:  https://doi.org/10.1007/978-1-0716-4192-7_15
Sci Rep. 2024 11 08. 14(1): 27257

More subtle microsatellite instability better predicts fluorouracil insensitivity in colorectal cancer patients.

Kaname Miyashita, Seijiro Shioi, Tatsuhiro Kajitani, Yumiko Koi, Mototsugu Shimokawa, Akitaka Makiyama, Shinya Oda, Taito Esaki.

  Microsatellite instability (MSI) is now widely used as an indispensable biomarker. However, the relationship between MSI-H (high) and defective DNA mismatch repair (MMR) is not as straightforward as has been expected. Genome-edited cells carrying Lynch syndrome mutations do not exhibit drastic MSI typical in MSI-H (i.e. Type B) but more subtle MSI (i.e. Type A). In this study, we explored a connection between Type A MSI and 5-fluorouracil (5-FU) resistance in colorectal cancer patients. Using our precision and high-resolution MSI assay technique, tumour microsatellites were analysed in 30 colorectal cancer patients treated with FOLFOX or CAPOX. Among 30 tumours, eleven (37%) were judged as Type A MSI-positive. In Type A MSI+ tumours, the patient response to fluoropyrimidine and oxaliplatin was significantly poor (Fisher's exact test, p = 0.021). Accordingly, median PFS and OS were significantly poor in Type A+ patients (log-rank test, p < 0.001/p = 0.009). Type A MSI was an independent predictor of patient prognosis in this pilot cohort (Cox regression analysis, p = 0.003). Thus, more subtle Type A MSI better predicts fluoropyrimidine insensitivity in colorectal cancer patients, which may shed light on a hitherto overlooked connection between the MSI phenotypes and drug resistance in human cancer.

Keywords:  5-fluorouracil (5-FU); Colorectal cancer; DNA mismatch repair (MMR); Drug resistance; Fluoropyrimidine; Microsatellite instability (MSI)

DOI:  https://doi.org/10.1038/s41598-024-77770-3
Eur J Cancer. 2024 Oct 31. pii: S0959-8049(24)01715-5. [Epub ahead of print]213 115108

Prospective study on Oncotype DX® assay to assess recurrence risk in early ER-positive HER2-negative breast cancer patients with uncertain biological behavior by standard parameters and its impact on treatment recommendation: The POST trial.

Luca Livraghi, Francesca Martella, Matteo Ghilli, Catia Angiolini, Simonetta Magnanini, Erica Moretti, Carmelo Bengala, Emanuela Risi, Elena Molinara, Ilaria Pazzagli, Luca Malorni, Sara Donati, Stefano Gabellini, Angelo Martignetti, Piergiorgio Giannessi, Giuseppina Sanna, Leonardo Barellini, Chiara Biagioni, Luca Boni, Simonetta Bianchi, Manuela Roncella, Laura Biganzoli.

   BACKGROUND: Data published in 2015 showed that patients with early breast cancer (EBC) and a low-risk (LR) Recurrence Score® (RS) result by the 21-gene Oncotype DX® assay ("the test") did not derive benefit from adding chemotherapy (CT) to endocrine therapy (HT), while those with a high-risk (HR) RS result did. However, the role of CT remained uncertain in patients with intermediate-risk (IR) cancers. We designed a study to assess the test's ability to categorize patients with EBC with uncertain biological behavior into the groups (LR and HR) for which the value of additional chemotherapy was defined.
METHODS: The POST trial was a multicenter, prospective cohort study conducted in 14 Breast Centers of the Tuscany region of Italy. Consecutive patients with pT1-2 pN0-N1mi hormone receptor-positive/HER2-negative EBC and uncertain biological behavior based on standard parameters were enrolled. Patients were categorized based on RS results into LR, IR, and HR groups if RS result was < 11, 11-25, and > 25, respectively. Treatment recommendations by multidisciplinary meeting assessed before and after RS results were available.
RESULTS: Of 246 tested samples, 78 were classified as LR or HR, with most of the patients (65.4 %) being at IR. Following test results, the recommendation changed in 15.9 % of cases. Among patients initially recommended for CT or for discussion about the role of CT, respectively 64.3 % and 75.9 % ultimately received recommendation for HT alone.
CONCLUSIONS: Our study suggests that RS results can refine treatment decisions for patients with EBC exhibiting uncertain biological behavior initially recommended or considered for CT. (250/250).

Keywords:  Adjuvant; Breast neoplasms / drug therapy; Breast neoplasms / pathology; Chemotherapy; Clinical decision-making; Gene expression profiling

DOI:  https://doi.org/10.1016/j.ejca.2024.115108
Mol Diagn Ther. 2024 Nov 08.

Extracellular Histones Profiles of Pediatric H3K27-Altered Diffuse Midline Glioma.

Diana Buzova, Lucia Lisa Petrilli, Jan Frohlich, Desislava K Tsoneva, Salvatore Daniele Bianco, Maria Rita Braghini, Anna Alisi, Angela Mastronuzzi, Jan Cerveny, Tommaso Mazza, Maria Vinci, Manlio Vinciguerra.

BACKGROUND: Diffuse midline glioma, H3 K27-altered (DMG) is a fatal tumour that arises in the midline structures of the brain. When located in the pons, it is more commonly referred to as diffuse intrinsic pontine glioma (DIPG). DMG/DIPG is usually diagnosed when children are < 10 years, and it has a median overall survival of < 12 months after diagnosis. Radiological imaging is still the gold standard for DIPG diagnosis while the use of biopsy procedures led to our knowledge on its biology, such as with the identification of the canonical histone H3K27M mutation. However, the need to improve survival encourages the development of non-invasive, fast and inexpensive assays on biofluids for optimizing molecular diagnoses in DMG/DIPG. Here, we propose a rapid, new, imaging and epigenetics-based approach to diagnose DMG/DIPG in the plasma of paediatric patients.
METHODS: A total of 20 healthy children (mean age: 10.5 years) and 24 children diagnosed with DMG/DIPG (mean age: 8.5 years) were recruited. Individual histones (H2A, H2B, H3, H4, macroH2A1.1 and macroH2A1.2), histone dimers and nucleosomes were assayed in biofluids by means of a new advanced flow cytometry ImageStream(X)-adapted method.
RESULTS: We report a significant increase in circulating histone dimers and tetramers (macroH2A1.1/H2B versus control: p value < 0.0001; macroH2A1.2/H2B versus control: p value < 0.0001; H2A/H2B versus control: p value < 0.0001; H3/H4 versus control: p value = 0.008; H2A/H2B/H3/H4 versus control: p value < 0.0001) and a significant downregulation of individual histones (H2B versus control: p value < 0.0001; H3 versus control: p value < 0.0001; H4 versus control: p value < 0.0001). Moreover, histones were also detectable in the cerebrospinal fluid (CSF) of patients with DMG/DIPG and in the supernatant of SF8628, OPBG-DIPG002 and OPBG-DIPG004 DMG/DIPG cell lines, with patterns mostly similar to each other, but distinct compared to blood plasma.
CONCLUSIONS: In summary, we identified circulating histone signatures able to detect the presence of DMG/DIPG in biofluids of children, using a rapid and non-invasive ImageStream(X)-based imaging technology, which may improve diagnosis and benefit the patients.

DOI: https://doi.org/10.1007/s40291-024-00754-6
Pathologie (Heidelb). 2024 Nov 13.

Leveraging homologous recombination deficiency for sarcoma : Unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcoma.

Lara Planas-Paz, Chantal Pauli.

   BACKGROUND: Homologous recombination deficiency (HRD) in tumors correlates with poor prognosis and metastases development. Determining HRD is of major clinical relevance as it can be treated with PARP inhibitors (PARPi). HRD remains poorly investigated in sarcoma, a rare and heterogeneous cancer of mesenchymal origin.
OBJECTIVE: We aimed (i) to investigate predictive biomarkers of HRD in several independent sarcoma cohorts using a cross-functional strategy by combining genomic, transcriptomic and phenotypic approaches and (ii) to evaluate the therapeutic potential of PARPi and DNA damage response (DDR)-based therapies ex vivo.
MATERIALS AND METHODS: We performed a comprehensive genomic and transcriptomic characterization of sarcoma using datasets from The Cancer Genome Atlas (TCGA) and Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and our own bone and soft tissue sarcoma cohorts. We evaluated PARP1/2 and WEE1 inhibition ex vivo in patient-derived sarcoma cell models as monotherapy and in combination with chemotherapeutic agents to identify synergistic effects.
RESULTS: Firstly, we identified genomic traits of HRD in a subset of sarcomas associated with molecular alterations in homologous recombination repair (HRR) pathway genes and high chromosomal instability. Secondly, we identified and validated distinct SARC-HRD transcriptional signatures that predicted sensitivity to PARPi. Finally, we showed functional defects in HRR in sarcoma cells that were associated with functional dependency towards PARPi and WEE1i and support the clinical use of RAD51 as a predictive biomarker for PARPi sensitivity.
CONCLUSION: We provide a personalized oncological approach to potentially improve the treatment of sarcoma patients. We encourage the evaluation of gene expression signatures to enhance the identification of patients who might benefit from DDR-based therapies.

Keywords:  Cancer organoids; Combination therapy; DNA damage response; PARPi; Precision oncology

DOI:  https://doi.org/10.1007/s00292-024-01381-y
United European Gastroenterol J. 2024 Nov 14.

Pancreatic Neuroendocrine Neoplasms: Classification and Novel Role of Endoscopic Ultrasound in Diagnosis and Treatment Personalization.

Matteo Tacelli, Stefano Partelli, Massimo Falconi, Paolo Giorgio Arcidiacono, Gabriele Capurso.

  The incidence and prevalence of pancreatic neuroendocrine neoplasms are steadily increasing. These tumors are highly heterogeneous, with treatment options ranging from observation to surgery, and various medical therapies. The choice of treatment is influenced by factors such as tumor stage, grade (proliferative activity), and the presence of hormone-related syndromes. Endoscopic ultrasound (EUS) is becoming increasingly valuable for assessing pancreatic neuroendocrine neoplasms, offering detailed morphological, vascular, and functional information through techniques such as contrast enhancement and elastography. It also allows biopsies that are useful for both histopathological and molecular analyses. These tumors are highly heterogeneous, with treatment options ranging from observation to various medical therapies and surgery. Recent data suggest that small, non-functioning PanNENs with low proliferation rates may be safely monitored, whereas more aggressive or functioning tumors typically require surgery. EUS-guided ablation is a promising alternative for patients with functional pancreatic neuroendocrine neoplasms who are unsuitable for surgery, although randomized trials are needed. In non-resectable pancreatic neuroendocrine neoplasms, treatment options include somatostatin analogs, targeted therapies (e.g., everolimus, sunitinib), chemotherapy, and radioligand therapy. This review discusses key factors in planning personalized treatment strategies for pancreatic neuroendocrine neoplasms.

Keywords:  Pancreatic Ductal Adenocarcinoma; Temozolomide; capecitabine; chemotherapy; endoscopic ultrasound; everolimus; neuroendocrine tumors; pancreatic neuroendocrine neoplasm

DOI:  https://doi.org/10.1002/ueg2.12710
Mol Biol Rep. 2024 Nov 11. 51(1): 1141

Evaluation of ploidy and the DNA index by flow cytometry in central nervous system tumors: a review.

Fernandez-Sanchez David, Ramirez-Corona Juan Antonio, Perez-Becerra Jose de Jesus, Santana-Bejarano Uriel Francisco, Santana-Hernandez Jennifer, Corona-Rivera Alfredo, Rodriguez-Machuca Victor Ulises, Bobadilla-Morales Lucina.

  Research on central nervous system tumors (CNSTs) has a significant impact on the diagnosis and prognosis of patients. Currently, CNSTs are classified according to the schema proposed by the World Health Organization (WHO), which considers clinical, histopathological, and molecular characteristics, highlighting the importance of tumor biology for accurate diagnosis and optimal treatment approaches. Despite these advances, assessing DNA ploidy-a marker of tumor aggressiveness-remains complex in CNSTs. This review investigates the utility of DNA index (DNAi) and DNA ploidy analysis by flow cytometry in diagnosing CNSTs and prognosing their outcomes. We systematically reviewed studies in the PubMed database from 1990 to the present using the keywords "DNA Index", "Brain", "Flow cytometry", and "Ploidy". We identified 151 studies, 36 of which met our inclusion criteria. We found considerable variation in sample sizes and methodological variation across the studies. Discrepancies between the reported DNAi and ploidy values were observed. Aneuploidy is generally associated with more aggressive tumors, although exceptions exist. Higher DNAi levels correlate with increased malignancy, notably in glioblastomas, astrocytomas, and meningiomas, whereas diploid astrocytomas and oligodendrogliomas are associated with shorter survival rates. DNA ploidy assessment via flow cytometry could predict CNST behavior, yet methodological issues with tissue selection, adequate control samples, and technique variability remain. DNAi and ploidy assessments show promise as prognostic markers in CNSTs. However, the standardization of flow cytometry protocols and alignment with the current WHO classification schema are essential steps to integrate ploidy analysis in routine CNST assessment.

Keywords:  CNST; DNA index; Flow cytometry; Ploidy

DOI:  https://doi.org/10.1007/s11033-024-10095-6
Breast. 2024 Nov 03. pii: S0960-9776(24)00165-6. [Epub ahead of print]78 103834

Olaparib monotherapy in advanced triple-negative breast cancer patients with homologous recombination deficiency and without germline mutations in BRCA1/2: The NOBROLA phase 2 study.

Alfonso Cortés, Elena López-Miranda, Adela Fernández-Ortega, Vicente Carañana, Sonia Servitja, Ander Urruticoechea, Laura Lema-Roso, Antonia Márquez, Alexandros Lazaris, Daniel Alcalá-López, Leonardo Mina, Petra Gener, Jose Rodríguez-Morató, Gabriele Antonarelli, Antonio Llombart-Cussac, José Pérez-García, Javier Cortés.

   PURPOSE: To evaluate olaparib in advanced triple negative breast cancer (TNBC) patients with homologous recombination deficiency (HRD) and no germline BRCA1/2 mutations (gBRCA1/2mut).
METHODS: NOBROLA (NCT03367689) is a single-arm, open-label, multicenter, phase IIa trial, enrolling adult patients with advanced TNBC without gBRCA1/2mut and with HRD, who were treated with olaparib. The primary endpoint was clinical benefit rate (CBR) per RECIST v.1.1.
RESULTS: Six of 114 patients were eligible and received olaparib. Median follow up was 8.5 months. CBR and overall response rate (ORR) were 50 % (95 % CI, 11.8-88.2).
CONCLUSIONS: The observed results could prompt further investigation.
TRIAL: ClinicalTrials.gov identifier NCT03367689.

Keywords:  Germline BRCA1/2 mutations; Homologous recombination deficiency; Olaparib; PARP inhibitors; Triple-negative breast cancer

DOI:  https://doi.org/10.1016/j.breast.2024.103834
J Clin Med. 2024 Oct 31. pii: 6546. [Epub ahead of print]13(21):

Drug Survival and Clinical Course of Patients with Cancer Treated with Biologic Therapy for Psoriasis.

Nicole Macagno, Luca Mastorino, Michela Ortoncelli, Silvia Borriello, Chiara Astrua, Anna Verrone, Elena Stroppiana, Paolo Dapavo, Niccolò Siliquini, Simone Ribero, Pietro Quaglino.

  Background/Objectives: Patients with treated solid tumors (TST) are a highly heterogeneous and difficult-to-treat population due to the risk of disease progression/recurrence or infection. Methods: We conducted an observational, retrospective, single-center study at the Dermatology Clinic of Turin with a focus on the special population of cancer patients with psoriasis treated with biologics. Results: As of July 2023, 52 psoriatic patients with a prior/concomitant history of malignancy had taken biologic drugs. The median age was 67 years, and the median age of cancer onset was 55 years. The most common tumors were gastrointestinal cancer and melanoma. After the tumor diagnosis, 61% received an anti-IL17 drug; 37 patients continued the initiated biologic therapy, while 12 switched drugs due to secondary inefficacy. The estimated biologic DS was 55.6% at 50 months. Evidence suggests that IL-17 is a key pathogenic factor involved in tumorigenesis, resulting in a lower risk of malignancies in subjects managed with IL-17 inhibitors. Similarly, IL-23 plays a role in suppressing innate immunity and promoting tumor and metastases development. This is a consistent real-life case series that support the use of biologic drugs in patients with TST. Conclusions: IL-23 and IL-17 inhibitors, being immunomodulators rather than immunosuppressants, may be a safe option for patients in an active oncological setting and for immune-correlated adverse events.

Keywords:  PASI; biologics; cancer; oncology; psoriasis; safety; tumor

DOI:  https://doi.org/10.3390/jcm13216546