bims-tumhet 2023-11-12 papers

bims-tumhet

Biomed News

on Tumor Heterogeneity

Issue of 2023‒11‒12
thirteen papers selected by
Sergio Marchini, Humanitas Research

Methodical Manipulation of the TME in Ovarian Cancer.
Shallow whole genome sequencing approach to detect Homologous Recombination Deficiency in the PAOLA-1/ENGOT-OV25 phase-III trial.
Homologous recombination deficiency (HRD) testing on cell-free tumor DNA from peritoneal fluid.
A zero-agnostic model for copy number evolution in cancer.
Circulating tumor DNA (ctDNA): can it be used as a pan-cancer early detection test?
cGAS-STING at the crossroads in cancer therapy.
Genomic and immune signatures predict clinical outcome in newly diagnosed multiple myeloma treated with immunotherapy regimens.
Most large structural variants in cancer genomes can be detected without long reads.
FIGO 2023 endometrial cancer staging: too much, too soon?
MiR-181a targets STING to drive PARP inhibitor resistance in BRCA- mutated triple-negative breast cancer and ovarian cancer.
Pembrolizumab plus chemotherapy versus chemotherapy in untreated advanced pleural mesothelioma in Canada, Italy, and France: a phase 3, open-label, randomised controlled trial.
TGF-β, EMT, and resistance to anti-cancer treatment.
Circulating tumor DNA landscape and prognostic impact of acquired resistance to targeted therapies in cancer patients: a national center for precision medicine (PRISM) study.

Clin Cancer Res. 2023 Nov 08.

Methodical Manipulation of the TME in Ovarian Cancer.

Pamela Soberanis Pina, Amit M Oza.

The complex interplay between ovarian cancer (OC) cells and the tumor microenvironment (TME) modulates progression, with dynamic cellular interactions influenced by external modulators, including neoadjuvant chemotherapy (NACT). A recent article described the alterations within the TME following NACT, either with or without bevacizumab, in OC.

DOI: https://doi.org/10.1158/1078-0432.CCR-23-2365
Oncogene. 2023 Nov 09.

Shallow whole genome sequencing approach to detect Homologous Recombination Deficiency in the PAOLA-1/ENGOT-OV25 phase-III trial.

Celine Callens, Manuel Rodrigues, Adrien Briaux, Eleonore Frouin, Alexandre Eeckhoutte, Eric Pujade-Lauraine, Victor Renault, Dominique Stoppa-Lyonnet, Ivan Bieche, Guillaume Bataillon, Lucie Karayan-Tapon, Tristan Rochelle, Florian Heitz, Sabrina Chiara Cecere, Maria Jesús Rubio Pérez, Christoph Grimm, Trine Jakobi Nøttrup, Nicoletta Colombo, Ignace Vergote, Kan Yonemori, Isabelle Ray-Coquard, Marc-Henri Stern, Tatiana Popova.

The bevacizumab (bev)/olaparib (ola) maintenance regimen was approved for BRCA1/2-mutated (BRCAmut) and Homologous Recombination Deficient (HRD) high-grade Advanced Ovarian Cancer (AOC) first line setting, based on a significantly improved progression-free survival (PFS) compared to bev alone in the PAOLA-1/ENGOT-ov25 trial (NCT02477644), where HRD was detected by MyChoice CDx PLUS test. The academic shallowHRDv2 test was developed based on shallow whole-genome sequencing as an alternative to MyChoice. Analytical and clinical validities of shallowHRDv2 as compared to MyChoice on 449 PAOLA-1 tumor samples are presented. The overall agreement between shallowHRDv2 and MyChoice was 94% (369/394). Less non-contributive tests were observed with shallowHRDv2 (15/449; 3%) than with MyChoice (51/449; 11%). Patients with HRD tumors according to shallowHRDv2 (including BRCAmut) showed a significantly prolonged PFS with bev+ola versus bev (median PFS: 65.7 versus 20.3 months, hazard ratio (HR): 0.36 [95% CI: 0.24-0.53]). This benefit was significant also for BRCA1/2 wild-type tumors (40.8 versus 19.5 months, HR: 0.45 [95% CI: 0.26-0.76]). ShallowHRDv2 is a performant, clinically validated, and cost-effective test for HRD detection.

DOI: https://doi.org/10.1038/s41388-023-02839-8
Mol Cancer. 2023 Nov 06. 22(1): 178

Homologous recombination deficiency (HRD) testing on cell-free tumor DNA from peritoneal fluid.

Cyril Roussel-Simonin, Felix Blanc-Durand, Roseline Tang, Damien Vasseur, Audrey Le Formal, Laure Chardin, Elisa Yaniz, Sébastien Gouy, Amandine Maulard, Stéphanie Scherier, Claire Sanson, Ludovic Lacroix, Sophie Cotteret, Lea Mauny, François Zaccarini, Etienne Rouleau, Alexandra Leary.

  BACKGROUND: Knowing the homologous recombination deficiency (HRD) status in advanced epithelial ovarian cancer (EOC) is vital for patient management. HRD is determined by BRCA1/BRCA2 pathogenic variants or genomic instability. However, tumor DNA analysis is inconclusive in 15-19% of cases. Peritoneal fluid, available in > 95% of advanced EOC cases, could serve as an alternative source of cell-free tumor DNA (cftDNA) for HRD testing. Limited data show the feasibility of cancer panel gene testing on ascites cfDNA but no study, to date, has investigated HRD testing.METHODS: We collected ascites/peritoneal washings from 53 EOC patients (19 from retrospective cohort and 34 from prospective cohort) and performed a Cancer Gene Panel (CGP) using NGS for TP53/HR genes and shallow Whole Genome Sequencing (sWGS) for genomic instability on cfDNA.
RESULTS: cfDNA was detectable in 49 out of 53 patients (92.5%), including those with limited peritoneal fluid. Median cfDNA was 3700 ng/ml, with a turnaround time of 21 days. TP53 pathogenic variants were detected in 86% (42/49) of patients, all with HGSOC. BRCA1 and BRCA2 pathogenic variants were found in 14% (7/49) and 10% (5/49) of cases, respectively. Peritoneal cftDNA showed high sensitivity (97%), specificity (83%), and concordance (95%) with tumor-based TP53 variant detection. NGS CGP on cftDNA identified BRCA2 pathogenic variants in one case where tumor-based testing failed. sWGS on cftDNA provided informative results even when tumor-based genomic instability testing failed.
CONCLUSION: Profiling cftDNA from peritoneal fluid is feasible, providing a significant amount of tumor DNA. This fast and reliable approach enables HRD testing, including BRCA1/2 mutations and genomic instability assessment. HRD testing on cfDNA from peritoneal fluid should be offered to all primary laparoscopy patients.

Keywords:  Ascites; HRD; Ovarian cancer; ctDNA; shallowWGS

DOI:  https://doi.org/10.1186/s12943-023-01864-1
PLoS Comput Biol. 2023 Nov 09. 19(11): e1011590

A zero-agnostic model for copy number evolution in cancer.

Henri Schmidt, Palash Sashittal, Benjamin J Raphael.

MOTIVATION: New low-coverage single-cell DNA sequencing technologies enable the measurement of copy number profiles from thousands of individual cells within tumors. From this data, one can infer the evolutionary history of the tumor by modeling transformations of the genome via copy number aberrations. Copy number aberrations alter multiple adjacent genomic loci, violating the standard phylogenetic assumption that loci evolve independently. Thus, specialized models to infer copy number phylogenies have been introduced. A widely used model is the copy number transformation (CNT) model in which a genome is represented by an integer vector and a copy number aberration is an event that either increases or decreases the number of copies of a contiguous segment of the genome. The CNT distance between a pair of copy number profiles is the minimum number of events required to transform one profile to another. While this distance can be computed efficiently, no efficient algorithm has been developed to find the most parsimonious phylogeny under the CNT model.RESULTS: We introduce the zero-agnostic copy number transformation (ZCNT) model, a simplification of the CNT model that allows the amplification or deletion of regions with zero copies. We derive a closed form expression for the ZCNT distance between two copy number profiles and show that, unlike the CNT distance, the ZCNT distance forms a metric. We leverage the closed-form expression for the ZCNT distance and an alternative characterization of copy number profiles to derive polynomial time algorithms for two natural relaxations of the small parsimony problem on copy number profiles. While the alteration of zero copy number regions allowed under the ZCNT model is not biologically realistic, we show on both simulated and real datasets that the ZCNT distance is a close approximation to the CNT distance. Extending our polynomial time algorithm for the ZCNT small parsimony problem, we develop an algorithm, Lazac, for solving the large parsimony problem on copy number profiles. We demonstrate that Lazac outperforms existing methods for inferring copy number phylogenies on both simulated and real data.

DOI: https://doi.org/10.1371/journal.pcbi.1011590
Crit Rev Clin Lab Sci. 2023 Nov 07. 1-13

Circulating tumor DNA (ctDNA): can it be used as a pan-cancer early detection test?

Michael J Duffy, John Crown.

  Circulating tumor DNA (ctDNA, DNA shed by cancer cells) is emerging as one of the most transformative cancer biomarkers discovered to-date. Although potentially useful at all the phases of cancer detection and patient management, one of its most exciting possibilities is as a relatively noninvasive pan-cancer screening test. Preliminary findings with ctDNA tests such as Galleri or CancerSEEK suggest that they have high specificity (> 99.0%) for malignancy. Their sensitivity varies depending on the type of cancer and stage of disease but it is generally low in patients with stage I disease. A major advantage of ctDNA over existing screening strategies is the potential ability to detect multiple cancer types in a single test. A limitation of most studies published to-date is that they are predominantly case-control investigations that were carried out in patients with a previous diagnosis of malignancy and that used apparently healthy subjects as controls. Consequently, the reported sensitivities, specificities and positive predictive values might be lower if the tests are used for screening in asymptomatic populations, that is, in the population where these tests are likely be employed. To demonstrate clinical utility in an asymptomatic population, these tests must be shown to reduce cancer mortality without causing excessive overdiagnosis in a large randomized prospective randomized trial. Such trials are currently ongoing for Galleri and CancerSEEK.

Keywords:  cancer; ctDNA; early diagnosis; liquid biopsy; screening

DOI:  https://doi.org/10.1080/10408363.2023.2275150
Crit Rev Oncol Hematol. 2023 Nov 04. pii: S1040-8428(23)00282-2. [Epub ahead of print] 104194

cGAS-STING at the crossroads in cancer therapy.

Rui Wang, Aashiq Hussain, Quanquan Guo, Meimei Ma.

  DNA is highly immunogenic, both exogenous and endogenous DNA can activate the pathogen-associated molecular pattern (PAMP) and danger-associated molecular pattern (DAMP), respectively, and hence activate the evolutionarily conserved cGAS-STING pathway for inflammatory responses. The cGAS-STING signaling pathway plays a very important role in the pathogenesis and progression of neoplastic diseases. For cancer therapy, there are some discrepancies on whether cGAS-STING should be inhibited or activated. Deregulated cGAS-STING signaling pathway might be the origin and pathogenesis of tumor, understanding and modulating cGAS-STING signaling holds great promise for cancer therapy. In this review article, we discuss the molecular mechanisms underlying cGAS-STING deregulation, highlighting the tumor inhibiting and promoting roles and challenges with cGAS-STING agonists in the context of cancer therapies.

Keywords:  Agonist; Antagonist; Innate immunity; STING; Tumorigenesis; cGAS

DOI:  https://doi.org/10.1016/j.critrevonc.2023.104194
Nat Cancer. 2023 Nov 09.

Genomic and immune signatures predict clinical outcome in newly diagnosed multiple myeloma treated with immunotherapy regimens.

Francesco Maura, Eileen M Boyle, David Coffey, Kylee Maclachlan, Dylan Gagler, Benjamin Diamond, Hussein Ghamlouch, Patrick Blaney, Bachisio Ziccheddu, Anthony Cirrincione, Monika Chojnacka, Yubao Wang, Ariel Siegel, James E Hoffman, Dickran Kazandjian, Hani Hassoun, Emily Guzman, Sham Mailankody, Urvi A Shah, Carlyn Tan, Malin Hultcrantz, Michael Scordo, Gunjan L Shah, Heather Landau, David J Chung, Sergio Giralt, Yanming Zhang, Arnaldo Arbini, Qi Gao, Mikhail Roshal, Ahmet Dogan, Alexander M Lesokhin, Faith E Davies, Saad Z Usmani, Neha Korde, Gareth J Morgan, Ola Landgren.

Despite improving outcomes, 40% of patients with newly diagnosed multiple myeloma treated with regimens containing daratumumab, a CD38-targeted monoclonal antibody, progress prematurely. By integrating tumor whole-genome and microenvironment single-cell RNA sequencing from upfront phase 2 trials using carfilzomib, lenalidomide and dexamethasone with daratumumab ( NCT03290950 ), we show how distinct genomic drivers including high APOBEC mutational activity, IKZF3 and RPL5 deletions and 8q gain affect clinical outcomes. Furthermore, evaluation of paired bone marrow profiles, taken before and after eight cycles of carfilzomib, lenalidomide and dexamethasone with daratumumab, shows that numbers of natural killer cells before treatment, high T cell receptor diversity before treatment, the disappearance of sustained immune activation (that is, B cells and T cells) and monocyte expansion over time are all predictive of sustained minimal residual disease negativity. Overall, this study provides strong evidence of a complex interplay between tumor cells and the immune microenvironment that is predictive of clinical outcome and depth of treatment response in patients with newly diagnosed multiple myeloma treated with highly effective combinations containing anti-CD38 antibodies.

DOI: https://doi.org/10.1038/s43018-023-00657-1
Nat Genet. 2023 Nov 09.

Most large structural variants in cancer genomes can be detected without long reads.

Zi-Ning Choo, Julie M Behr, Aditya Deshpande, Kevin Hadi, Xiaotong Yao, Huasong Tian, Kaori Takai, George Zakusilo, Joel Rosiene, Arnaud Da Cruz Paula, Britta Weigelt, Jeremy Setton, Nadeem Riaz, Simon N Powell, Klaus Busam, Alexander N Shoushtari, Charlotte Ariyan, Jorge Reis-Filho, Titia de Lange, Marcin Imieliński.

Short-read sequencing is the workhorse of cancer genomics yet is thought to miss many structural variants (SVs), particularly large chromosomal alterations. To characterize missing SVs in short-read whole genomes, we analyzed 'loose ends'-local violations of mass balance between adjacent DNA segments. In the landscape of loose ends across 1,330 high-purity cancer whole genomes, most large (>10-kb) clonal SVs were fully resolved by short reads in the 87% of the human genome where copy number could be reliably measured. Some loose ends represent neotelomeres, which we propose as a hallmark of the alternative lengthening of telomeres phenotype. These pan-cancer findings were confirmed by long-molecule profiles of 38 breast cancer and melanoma cases. Our results indicate that aberrant homologous recombination is unlikely to drive the majority of large cancer SVs. Furthermore, analysis of mass balance in short-read whole genome data provides a surprisingly complete picture of cancer chromosomal structure.

DOI: https://doi.org/10.1038/s41588-023-01540-6
Int J Gynecol Cancer. 2023 Nov 07. pii: ijgc-2023-004981. [Epub ahead of print]

FIGO 2023 endometrial cancer staging: too much, too soon?

W Glenn McCluggage, Tjalling Bosse, C Blake Gilks, Brooke E Howitt, Jessica N McAlpine, Marisa R Nucci, Joseph T Rabban, Naveena Singh, Karen L Talia, Carlos Parra-Herran.

  An updated International Federation of Gynecology and Obstetrics (FIGO) staging system for endometrial carcinoma was introduced in June 2023. The new system represents a significant departure from traditional endometrial and other gynecological carcinoma staging systems which are agnostic of parameters such as tumor type, tumor grade, lymphovascular space invasion, and molecular alterations. The updated system, which incorporates all of these 'non-anatomical' parameters, is an attempt to make staging more personalized and relevant to patient prognostication and management, and to align with the European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology (ESGO/ESTRO/ESP) risk stratification. Herein, we present a critical review of the new staging system and discuss its advantages and disadvantages. The authors propose that the new FIGO staging system should be first appraised at a multi-institutional and global level with the input of all relevant societies (gynecology, pathology, gynecologic oncology, medical oncology, radiation oncology) to understand the impact, scope, and supporting evidence of the proposed changes. Such a process is fundamental to produce a robust system that pathologists and treating clinicians can adopt.

Keywords:  AJCC; FIGO; TNM; endometrial cancer; endometrial carcinoma; stage; staging system

DOI:  https://doi.org/10.1136/ijgc-2023-004981
Cell Biosci. 2023 Nov 06. 13(1): 200

MiR-181a targets STING to drive PARP inhibitor resistance in BRCA- mutated triple-negative breast cancer and ovarian cancer.

Matias A Bustos, Takamichi Yokoe, Yoshiaki Shoji, Yuta Kobayashi, Shodai Mizuno, Tomohiro Murakami, Xiaoqing Zhang, Sreeja C Sekhar, SooMin Kim, Suyeon Ryu, Matthew Knarr, Steven A Vasilev, Analisa DiFeo, Ronny Drapkin, Dave S B Hoon.

  BACKGROUND: Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved for the treatment of BRCA-mutated breast cancer (BC), including triple-negative BC (TNBC) and ovarian cancer (OvCa). A key challenge is to identify the factors associated with PARPi resistance; although, previous studies suggest that platinum-based agents and PARPi share similar resistance mechanisms.METHODS: Olaparib-resistant (OlaR) cell lines were analyzed using HTG EdgeSeq miRNA Whole Transcriptomic Analysis (WTA). Functional assays were performed in three BRCA-mutated TNBC cell lines. In-silico analysis were performed using multiple databases including The Cancer Genome Atlas, the Genotype-Tissue Expression, The Cancer Cell Line Encyclopedia, Genomics of Drug Sensitivity in Cancer, and Gene Omnibus Expression.
RESULTS: High miR-181a levels were identified in OlaR TNBC cell lines (p = 0.001) as well as in tumor tissues from TNBC patients (p = 0.001). We hypothesized that miR-181a downregulates the stimulator of interferon genes (STING) and the downstream proinflammatory cytokines to mediate PARPi resistance. BRCA1 mutated TNBC cell lines with miR-181a-overexpression were more resistant to olaparib and showed downregulation in STING and the downstream genes controlled by STING. Extracellular vesicles derived from PARPi-resistant TNBC cell lines horizontally transferred miR-181a to parental cells which conferred PARPi-resistance and targeted STING. In clinical settings, STING levels were positively correlated with interferon gamma (IFNG) response scores (p = 0.01). In addition, low IFNG response scores were associated with worse response to neoadjuvant treatment including PARPi for high-risk HER2 negative BC patients (p = 0.001). OlaR TNBC cell lines showed resistance to platinum-based drugs. OvCa cell lines resistant to platinum showed resistance to olaparib. Knockout of miR-181a significantly improved olaparib sensitivity in OvCa cell lines (p = 0.001).
CONCLUSION: miR-181a is a key factor controlling the STING pathway and driving PARPi and platinum-based drug resistance in TNBC and OvCa. The miR-181a-STING axis can be used as a potential marker for predicting PARPi responses in TNBC and OvCa tumors.

Keywords:  BRCA1/2 mutations; DNA damage; Extracellular microvesicles; Ovarian cancer; PARPi; STING; TMEM173; Triple-negative breast cancer; miR-181a-5p

DOI:  https://doi.org/10.1186/s13578-023-01151-y
Lancet. 2023 Nov 03. pii: S0140-6736(23)01613-6. [Epub ahead of print]

Pembrolizumab plus chemotherapy versus chemotherapy in untreated advanced pleural mesothelioma in Canada, Italy, and France: a phase 3, open-label, randomised controlled trial.

Quincy Chu, Francesco Perrone, Laurent Greillier, Wei Tu, Maria Carmela Piccirillo, Federica Grosso, Giuseppe Lo Russo, Marie Florescu, Manlio Mencoboni, Alessandro Morabito, Fabiana Letizia Cecere, Giovanni Luca Ceresoli, David E Dawe, Paolo Andrea Zucali, Maria Pagano, John R Goffin, Myriam Locatelli Sanchez, Cesare Gridelli, Gerard Zalcman, Xavier Quantin, Virginie Westeel, Piera Gargiulo, Sara Delfanti, Dongsheng Tu, Christopher W Lee, Natasha Leighl, Joana Sederias, Pamela Brown-Walker, Yiwen Luo, Sylvie Lantuejoul, Ming-Sound Tsao, Arnaud Scherpereel, Penelope Bradbury, Scott A Laurie, Lesley Seymour.

BACKGROUND: Pleural mesothelioma usually presents at an advanced, incurable stage. Chemotherapy with platinum-pemetrexed is a standard treatment. We hypothesised that the addition of pembrolizumab to platinum-pemetrexed would improve overall survival in patients with pleural mesothelioma.METHODS: We did this open-label, international, randomised phase 3 trial at 51 hospitals in Canada, Italy, and France. Eligible participants were aged 18 years or older, with previously untreated advanced pleural mesothelioma, with an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned (1:1) to intravenous chemotherapy (cisplatin [75 mg/m2] or carboplatin [area under the concentration-time curve 5-6 mg/mL per min] with pemetrexed 500 mg/m2, every 3 weeks for up to 6 cycles), with or without intravenous pembrolizumab 200 mg every 3 weeks (up to 2 years). The primary endpoint was overall survival in all randomly assigned patients; safety was assessed in all randomly assigned patients who received at least one dose of study therapy. This trial is registered with ClinicalTrials.gov, NCT02784171, and is closed to accrual.
FINDINGS: Between Jan 31, 2017, and Sept 4, 2020, 440 patients were enrolled and randomly assigned to chemotherapy alone (n=218) or chemotherapy with pembrolizumab (n=222). 333 (76 %) of patients were male, 347 (79%) were White, and median age was 71 years (IQR 66-75). At final analysis (database lock Dec 15, 2022), with a median follow-up of 16·2 months (IQR 8·3-27·8), overall survival was significantly longer with pembrolizumab (median overall survival 17·3 months [95% CI 14·4-21·3] with pembrolizumab vs 16·1 months [13·1-18·2] with chemotherapy alone, hazard ratio for death 0·79; 95% CI 0·64-0·98, two-sided p=0·0324). 3-year overall survival rate was 25% (95% CI 20-33%) with pembrolizumab and 17% (13-24%) with chemotherapy alone. Adverse events related to study treatment of grade 3 or 4 occurred in 60 (27%) of 222 patients in the pembrolizumab group and 32 (15%) of 211 patients in the chemotherapy alone group. Hospital admissions for serious adverse events related to one or more study drugs were reported in 40 (18%) of 222 patients in the pembrolizumab group and 12 (6%) of 211 patients in the chemotherapy alone group. Grade 5 adverse events related to one or more drugs occurred in two patients on the pembrolizumab group and one patient in the chemotherapy alone group.
INTERPRETATION: In patients with advanced pleural mesothelioma, the addition of pembrolizumab to standard platinum-pemetrexed chemotherapy was tolerable and resulted in a significant improvement in overall survival. This regimen is a new treatment option for previously untreated advanced pleural mesothelioma.
FUNDING: The Canadian Cancer Society and Merck & Co.

DOI: https://doi.org/10.1016/S0140-6736(23)01613-6
Semin Cancer Biol. 2023 Nov 07. pii: S1044-579X(23)00133-5. [Epub ahead of print]97 1-11

TGF-β, EMT, and resistance to anti-cancer treatment.

Xuecong Wang, Pieter Johan Adam Eichhorn, Jean Paul Thiery.

  Transforming growth factor-β (TGF-β) signaling regulates cell-specific programs involved in embryonic development, wound-healing, and immune homeostasis. Yet, during tumor progression, these TGF-β-mediated programs are altered, leading to epithelial cell plasticity and a reprogramming of epithelial cells into mesenchymal lineages through epithelial-to-mesenchymal transition (EMT), a critical developmental program in morphogenesis and organogenesis. These changes, in turn, lead to enhanced carcinoma cell invasion, metastasis, immune cell differentiation, immune evasion, and chemotherapy resistance. Here, we discuss EMT as one of the critical programs associated with carcinoma cell plasticity and the influence exerted by TGF-β on carcinoma status and function. We further explore the composition of carcinoma and other cell populations within the tumor microenvironment, and consider the relevant outcomes related to the programs associated with cancer treatment resistance.

Keywords:  Chemotherapy resistance; EMT; Immune evasion; Partial EMT; TGF-β

DOI:  https://doi.org/10.1016/j.semcancer.2023.10.004
Mol Cancer. 2023 Nov 04. 22(1): 176

Circulating tumor DNA landscape and prognostic impact of acquired resistance to targeted therapies in cancer patients: a national center for precision medicine (PRISM) study.

Arnaud Bayle, Laila Belcaid, Lola-Jade Palmieri, Diego Teysonneau, Sophie Cousin, Mariella Spalato-Ceruso, Mihaela Aldea, Damien Vasseur, Melissa Alame, Laura Blouin, Isabelle Soubeyran, Claudio Nicotra, Maud Ngocamus, Antoine Hollebecque, Yohann Loriot, Benjamin Besse, Ludovic Lacroix, Etienne Rouleau, Fabrice Barlesi, Fabrice Andre, Antoine Italiano.

  BACKGROUND: Despite the effectiveness of the various targeted therapies currently approved for solid tumors, acquired resistance remains a persistent problem that limits the ultimate effectiveness of these treatments. Polyclonal resistance to targeted therapy has been described in multiple solid tumors through high-throughput analysis of multiple tumor tissue samples from a single patient. However, biopsies at the time of acquired resistance to targeted agents may not always be feasible and may not capture the genetic heterogeneity that could exist within a patient.METHODS: We analyzed circulating tumor DNA (ctDNA) with a large next-generation sequencing panel to characterize the landscape of secondary resistance mechanisms in two independent prospective cohorts of patients (STING: n = 626; BIP: n = 437) with solid tumors who were treated with various types of targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies and hormonal therapies.
RESULTS: Emerging alterations involved in secondary resistance were observed in the plasma of up 34% of patients regardless of the type of targeted therapy. Alterations were polyclonal in up to 14% of patients. Emerging ctDNA alterations were associated with significantly shorter overall survival for patients with some tumor types.
CONCLUSION: This comprehensive landscape of genomic aberrations indicates that genetic alterations involved in secondary resistance to targeted therapy occur frequently and suggests that the detection of such alterations before disease progression may guide personalized treatment and improve patient outcome.

Keywords:  Next-generation sequencing; Resistance biomarkers; Targeted therapy; ctDNA

DOI:  https://doi.org/10.1186/s12943-023-01878-9