bims-tumhet 2022-11-13 papers

bims-tumhet

Biomed News

on Tumor Heterogeneity

Issue of 2022–11–13
thirteen papers selected by
Sergio Marchini, Humanitas Research

Resistance to Poly (ADP-Ribose) Polymerase Inhibitors (PARPi): Mechanisms and Potential to Reverse.
Therapeutic implications of the tumor microenvironment in ovarian cancer patients receiving PD-1/PD-L1 therapy.
Management of patients with early-stage ovarian clear cell carcinoma: risk stratification and fertility conservation.
Evaluation of DNA Methylation Array for Glioma Tumor Profiling and Description of a Novel Epi-Signature to Distinguish IDH1/IDH2 Mutant and Wild-Type Tumors.
Tumor-Infiltrating Lymphocytes (TILs) in Epithelial Ovarian Cancer: Heterogeneity, Prognostic Impact, and Relationship with Immune Checkpoints.
Pan-cancer landscape of aberrant DNA Methylation across childhood Cancers: Molecular Characteristics and Clinical relevance.
The Potential of MicroRNAs as Clinical Biomarkers to Aid Ovarian Cancer Diagnosis and Treatment.
Application of NGS molecular classification in the diagnosis of endometrial carcinoma: A supplement to traditional pathological diagnosis.
Integrative Genomic Tests in Clinical Oncology.
Spatial transcriptomics with light barcodes in intact tissues.
Interplay between the DNA Damage Response and Immunotherapy Response in Cancer.
Profiling the immune landscape in mucinous ovarian carcinoma.
Overall survival with circulating tumor DNA-guided therapy in advanced non-small-cell lung cancer.

Curr Oncol Rep. 2022 Nov 08.

Resistance to Poly (ADP-Ribose) Polymerase Inhibitors (PARPi): Mechanisms and Potential to Reverse.

Christina R Washington, Kathleen N Moore.

   PURPOSE OF REVIEW: This review will focus on the most common mechanisms for poly (ADP-ribose) polymerase inhibitors' (PARPi) resistance and the main strategies for overcoming acquired or de novo PARPi resistance.
RECENT FINDINGS: Initial approvals for PARPi as part of treatment for advanced epithelial ovarian cancer (EOC) started in 2014 with patient with recurrent cancer characterized by BRCA mutations in the 3rd and 4th line and now have approvals for front-line maintenance in both the BRCA mutated and BRCAwt populations. As with all therapies, patients will eventually develop resistance to treatment. The most common mechanisms for PARPi resistance include reversion mutations, methylation events, and restoration of homologous recombination deficiency (HRD) through combinations and targeting replication stress. As more and more patients receive initial treatment (and potential retreatment with PARPi), we need to better understand the mechanisms in which tumors acquire PARPi resistance.

Keywords:  BRCA mutation; Epithelial ovarian cancer; Homologous recombination deficiency; Niraparib; Olaparib; PARP inhibitor resistance; PARP inhibitors; Restoration of homologous recombination proficiency; Rucaparib

DOI:  https://doi.org/10.1007/s11912-022-01337-6
Front Immunol. 2022 ;13 1036298

Therapeutic implications of the tumor microenvironment in ovarian cancer patients receiving PD-1/PD-L1 therapy.

Yusha Wang, Lei Zhang, Yun Bai, Li Wang, Xuelei Ma.

  Epithelial ovarian cancer (EOC) ranks as the second most common cause of gynecologic cancer death. The conventional treatment for patients with EOC is postoperative therapy along with platinum chemotherapy. However, a more efficient treatment regimen is of great need for these patients diagnosed with advanced disease (FIGO stages III-IV), whose survival is approximately 29%. Immunotherapy seems to be an encouraging therapeutic strategy for EOC. Given the crucial role in the complicated interactions between tumor cells and other cells, the tumor microenvironment (TME) influences the response to immunotherapy. In this review, we discuss feasible strategies for EOC immunotherapy by exploiting the reciprocity of cancer cells and the constituents of the TME.

Keywords:  combination therapy; immune cells; immunotherapy; stromal cells; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2022.1036298
Int J Gynecol Cancer. 2022 Nov 11. pii: ijgc-2022-003935. [Epub ahead of print]

Management of patients with early-stage ovarian clear cell carcinoma: risk stratification and fertility conservation.

Beryl Manning-Geist, Sushmita Gordhandas, Anjelica Hodgson, Qin C Zhou, Alexia Iasonos, Dennis S Chi, Lora Ellenson, Carol A Aghajanian, Nadeem R Abu-Rustum, Mario Leitao, Kara Long, Maria M Rubinstein, Yukio Sonoda, Kaled Alektiar, Britta Weigelt, Oliver Zivanovic, Rachel N Grisham.

   OBJECTIVE: We sought to describe clinicopathologic and treatment factors associated with oncologic outcomes in patients with early-stage ovarian clear cell carcinoma undergoing complete staging and in a sub-set of these patients undergoing fertility-conserving surgery.
METHODS: We retrospectively identified patients with ovarian clear cell carcinoma initially treated at our institution from January 1, 1996 to March 31, 2020. Survival was estimated using Kaplan-Meier curves and compared by log-rank test. Survival-associated variables were identified by Cox proportional hazards regression.
RESULTS: Of 182 patients, mismatch repair and p53 protein expression were assessed by immunohistochemistry on 82 and 66 samples, respectively. There were no significant differences in progression-free survival or overall survival between mismatch repair-deficient (n=6, including 4 patients with Lynch syndrome; 7.3%) and mismatch repair-proficient patients, whereas aberrant p53 expression (n=3; 4.5%) was associated with worse progression-free (p<0.001) and overall survival (p=0.01). Patients with stage IA/IC1 disease had a 95% 5-year overall survival rate (95% CI 88% to 98%); patients with stage IC2/IC3 disease had a similar 5-year overall survival rate (76%; 95% CI 54% to 88%) to that of patients with stage IIA/IIB disease (82%; 95% CI 54% to 94%). There was no difference in 5-year overall survival in patients with stage IA/IC1 undergoing chemotherapy versus observation (94% vs 100%). Nine patients underwent fertility-sparing surgery and none experienced recurrence. Of five patients who pursued fertility, all had successful pregnancies.
CONCLUSIONS: In patients with completely staged ovarian clear cell carcinoma, those with stage IA/IC1 disease have an excellent prognosis, regardless of chemotherapy. Aberrant p53 expression may portend worse outcomes. Additional investigation is warranted on the safety of fertility conservation in patients with stage IA/IC1 disease.

Keywords:  ovarian cancer

DOI:  https://doi.org/10.1136/ijgc-2022-003935
Genes (Basel). 2022 Nov 09. pii: 2075. [Epub ahead of print]13(11):

Evaluation of DNA Methylation Array for Glioma Tumor Profiling and Description of a Novel Epi-Signature to Distinguish IDH1/IDH2 Mutant and Wild-Type Tumors.

Laila C Schenkel, Joseph Mathew, Hal Hirte, John Provias, Guillaume Paré, Michael Chong, Daria Grafodatskaya, Elizabeth McCready.

  Molecular biomarkers, such as IDH1/IDH2 mutations and 1p19q co-deletion, are included in the histopathological and clinical criteria currently used to diagnose and classify gliomas. IDH1/IDH2 mutation is a common feature of gliomas and is associated with a glioma-CpG island methylator phenotype (CIMP). Aberrant genomic methylation patterns can also be used to extrapolate information about copy number variation in a tumor. This project's goal was to assess the feasibility of DNA methylation array for the simultaneous detection of glioma biomarkers as a more effective testing strategy compared to existing single analyte tests.
METHODS: Whole-genome methylation array (WGMA) testing was performed using 48 glioma DNA samples to detect methylation aberrations and chromosomal gains and losses. The analyzed samples include 39 tumors in the discovery cohort and 9 tumors in the replication cohort. Methylation profiles for each sample were correlated with IDH1 p.R132G mutation, immunohistochemistry (IHC), and previous 1p19q clinical testing to assess the sensitivity and specificity of the WGMA assay for the detection of these variants.
RESULTS: We developed a DNA methylation signature to specifically distinguish a IDH1/IDH2 mutant tumor from normal samples. This signature is composed of 11 CpG sites that were significantly hypermethylated in the IDH1/IDH2 mutant group. Copy number analysis using WGMA data was able to identify five of five positive samples for 1p19q co-deletion and was concordant for all negative samples.
CONCLUSIONS: The DNA methylation signature presented here has the potential to refine the utility of WGMA to predict IDH1/IDH2 mutation status of gliomas, thus improving diagnostic yield and efficiency of laboratory testing compared to single analyte IDH1/IDH2 or 1p19q tests.

Keywords:  1p19q co-deletion; IDH1/IDH2 epi-signature; glioma; whole-genome methylation array

DOI:  https://doi.org/10.3390/genes13112075
Cancers (Basel). 2022 Oct 29. pii: 5332. [Epub ahead of print]14(21):

Tumor-Infiltrating Lymphocytes (TILs) in Epithelial Ovarian Cancer: Heterogeneity, Prognostic Impact, and Relationship with Immune Checkpoints.

Delphine Hudry, Solenn Le Guellec, Samuel Meignan, Stéphanie Bécourt, Camille Pasquesoone, Houssein El Hajj, Carlos Martínez-Gómez, Éric Leblanc, Fabrice Narducci, Sylvain Ladoire.

  Epithelial ovarian cancers (EOC) are often diagnosed at an advanced stage with carcinomatosis and a poor prognosis. First-line treatment is based on a chemotherapy regimen combining a platinum-based drug and a taxane-based drug along with surgery. More than half of the patients will have concern about a recurrence. To improve the outcomes, new therapeutics are needed, and diverse strategies, such as immunotherapy, are currently being tested in EOC. To better understand the global immune contexture in EOC, several studies have been performed to decipher the landscape of tumor-infiltrating lymphocytes (TILs). CD8+ TILs are usually considered effective antitumor immune effectors that immune checkpoint inhibitors can potentially activate to reject tumor cells. To synthesize the knowledge of TILs in EOC, we conducted a review of studies published in MEDLINE or EMBASE in the last 10 years according to the PRISMA guidelines. The description and role of TILs in EOC prognosis are reviewed from the published data. The links between TILs, DNA repair deficiency, and ICs have been studied. Finally, this review describes the role of TILs in future immunotherapy for EOC.

Keywords:  epithelial ovarian cancer (EOC); high-grade serous ovarian cancer (HGSOC); immune checkpoint inhibitors; peritoneum; tumor microenvironment; tumor-infiltrating lymphocytes (TILs)

DOI:  https://doi.org/10.3390/cancers14215332
Exp Hematol Oncol. 2022 Nov 08. 11(1): 89

Pan-cancer landscape of aberrant DNA Methylation across childhood Cancers: Molecular Characteristics and Clinical relevance.

Zheng Dong, Hongyu Zhou.

  Aberrant DNA methylation (DNAm) is an important epigenetic regulator in various cancers. Pan-cancer DNAm analyses have investigated the potential common mechanisms of DNAm in tumorigenesis. However, these pan-cancer studies focused on adult cancers rather than pediatric cancers, which may have distinct pathology and treatment responses. Here, we performed a pan-cancer analysis of genome-wide DNAm in over 2,000 samples from nine pediatric cancers to elucidate the DNAm landscape of pediatric cancers. We identified 217,586 differentially methylated CpG sites (DMCs) in pediatric cancers, with a tendency toward hypermethylation as opposed to hypomethylation (P = 0.02). Amongst them, 75.65% also presented DNAm alterations in adult cancers. In nine pediatric cancers, we defined 54 shared DMCs (SDMCs), which were also observed in at least one adult cancer type. Furthermore, methylation patterns in SDMCs influenced the transcription of several genes (MEIS1, MIA3, PCDHAC2, SH3BP4, and ATP8B1) involved in well-known cancer-related pathways and cancer hallmarks (FDR < 0.05). Moreover, SDMCs were significantly associated with patient survival, and this association was independent of sex, age, and tumor stage (P < 0.05). Interestingly, SDMCs could affect patient survival not only in the nine pediatric cancers that were used to identify SDMCs but also in other untested pediatric cancers (P < 0.05). Collectively, our data depicts a comprehensive landscape of aberrant DNA methylation in pediatric cancers, which is partly similar to that of adult cancers. We also suggest a potential clinical application of SDMCs as biomarkers for the prognosis of pediatric cancer.

Keywords:  Adult cancer; And ATP8B1; DNA methylation; MEIS1; MIA3; PCDHAC2; Pan-cancer; Patient survival; Pediatric cancer; SH3BP4

DOI:  https://doi.org/10.1186/s40164-022-00339-1
Genes (Basel). 2022 Nov 07. pii: 2054. [Epub ahead of print]13(11):

The Potential of MicroRNAs as Clinical Biomarkers to Aid Ovarian Cancer Diagnosis and Treatment.

Molly Davies, Matthew G Davey, Nicola Miller.

  Ovarian cancer is a commonly diagnosed malignancy in women. When diagnosed at an early stage, survival outcomes are favourable for the vast majority, with up to 90% of ovarian cancer patients being free of disease at 5 years follow-up. Unfortunately, ovarian cancer is typically diagnosed at an advanced stage due to the majority of patients remaining asymptomatic until the cancer has metastasised, resulting in poor outcomes for the majority. While the molecular era has facilitated the subclassification of the disease into distinct clinical subtypes, ovarian cancer remains managed and treated as a single disease entity. MicroRNAs (miRNAs) are small (19-25 nucleotides), endogenous molecules which are integral to regulating gene expression. Aberrant miRNA expression profiles have been described in several cancers, and have been implicated to be useful biomarkers which may aid cancer diagnostics and treatment. Several preliminary studies have identified candidate tumour suppressor and oncogenic miRNAs which may be involved in the development and progression of ovarian cancer, highlighting their candidacy as oncological biomarkers; understanding the mechanisms by which these miRNAs regulate the key processes involved in oncogenesis can improve our overall understanding of cancer development and identify novel biomarkers and therapeutic targets. This review highlights the potential role of miRNAs which may be utilised to aid diagnosis, estimate prognosis and enhance therapeutic strategies in the management of primary ovarian cancer.

Keywords:  biomarkers; miRNA; non-coding RNA; ovarian cancer; personalised medicine

DOI:  https://doi.org/10.3390/genes13112054
Cancer Med. 2022 Nov 07.

Application of NGS molecular classification in the diagnosis of endometrial carcinoma: A supplement to traditional pathological diagnosis.

Qunxian Rao, Jianwei Liao, Yangyang Li, Xin Zhang, Guocai Xu, Changbin Zhu, Shengya Tian, Qiuhong Chen, Hui Zhou, Bingzhong Zhang.

   OBJECTIVE: This study aims to demonstrate the advantages of NGS molecular classification in EC diagnosis and to assess whether molecular classification could be performed on curettage specimens and its concordance with subsequent hysterectomy specimens.
METHODS: 80 patients with hysterectomy specimens and 35/80 patients with paired curettage specimens were stratified as POLE mut, MSI-H, TP53 wt, or TP53 abn group by NGS panel. Histotype, tumor grade, IHC results, and other pathological details were taken from original pathological reports.
RESULTS: The correlation analysis of 80 patients with hysterectomy specimens between NGS molecular classification and clinicopathological characters displayed that the POLE mut group was associated with EEC (87.5%) and TP53 abn subtype was correlated to a later stage (Stage II-IV, 47.6%), G3 (76.2%), serous histology (61.9%) and myometrial invasion ≥50% (47.6%). A favorable concordance (31/32, 96.9%) was shown in MSI analysis and MMR IHC results, and the agreement rate of p53 IHC and TP53 mutation was 81.5% (53/65). Compared with the p53 IHC abnormal group, the TP53 mutation group had a higher correlation with high-risk factors. A high level of concordance (31/35, 88.0%) of NGS molecular classification was achieved between curettage specimens and hysterectomy specimens while grade and histotype (including unclassified group) from curettage specimens and hysterectomy specimens showed only moderate levels of agreement, 54.3% (19/35) and 68.6% (24/35), respectively.
CONCLUSION: NGS molecular classification achieved on curettage samples showed high concordance with the final hysterectomy specimens, demonstrating superior to the conventional pathological assessment of grade and histotype and potential utilization in clinical practice.

Keywords:  NGS; curettage; endometrial cancer; hysterectomy; molecular classification

DOI:  https://doi.org/10.1002/cam4.5363
Int J Mol Sci. 2022 Oct 28. pii: 13129. [Epub ahead of print]23(21):

Integrative Genomic Tests in Clinical Oncology.

Evgeny Imyanitov, Anna Sokolenko.

  Many clinical decisions in oncology practice rely on the presence or absence of an alteration in a single genetic locus, be it a pathogenic variant in a hereditary cancer gene or activating mutation in a drug target. In addition, there are integrative tests that produce continuous variables and evaluate complex characteristics of the entire tumor genome. Microsatellite instability (MSI) analysis identifies tumors with the accumulation of mutations in short repetitive nucleotide sequences. This procedure is utilized in Lynch syndrome diagnostic pipelines and for the selection of patients for immunotherapy. MSI analysis is well-established for colorectal malignancies, but its applications in other cancer types lack standardization and require additional research. Homologous repair deficiency (HRD) indicates tumor sensitivity to PARP inhibitors and some cytotoxic drugs. HRD-related "genomic scars" are manifested by a characteristic pattern of allelic imbalances, accumulation of deletions with flanking homology, and specific mutation signatures. The detection of the genetic consequences of HRD is particularly sophisticated and expensive, as it involves either whole genome sequencing (WGS) or the utilization of large next-generation sequencing (NGS) panels. Tumor mutation burden (TMB) can be determined by whole exome sequencing (WES) or middle-throughput NGS multigene testing. Although TMB is regarded as an agnostic indicator of tumor sensitivity to immunotherapy, the clinical utility of this test is proven only for a few cancer types.

Keywords:  homologous repair deficiency; integrative tests; microsatellite instability; tumor mutation burden

DOI:  https://doi.org/10.3390/ijms232113129
Nat Biotechnol. 2022 Nov;40(11): 1575

Spatial transcriptomics with light barcodes in intact tissues.

Alexandra Despang.

DOI: https://doi.org/10.1038/s41587-022-01577-8
Int J Mol Sci. 2022 Nov 01. pii: 13356. [Epub ahead of print]23(21):

Interplay between the DNA Damage Response and Immunotherapy Response in Cancer.

Elizabeth Chun Yong Lee, Jessica Sook Ting Kok, Bin Tean Teh, Kah Suan Lim.

  Genome instability and immune evasion are both defining hallmarks of cancer. Tumorigenesis is frequently initiated when there is DNA damage to a proto-oncogene or tumor suppressor gene and DNA repair mechanisms are lost or insufficient to correct the damage; immune evasion then prevents the host immune system from recognizing these transformed cells. Therapies targeting genomic instability and immune evasion have been effectively used to treat cancer. Genotoxic therapies such as chemoradiation have been employed in cancer treatments for several decades, while immunotherapy is a relatively new class of cancer therapy that has led to disease regression even in patients with advanced cancer. Several recent studies have shown synergy between both classes of therapy targeting these two defining hallmarks of cancer, and different mechanisms are proposed to be involved. Here, we review the different classes of DNA damage, their links to cancer, and their contribution to immunotherapy responses, as well as the different models that are currently being used to study tumor-immune interactions.

Keywords:  DNA repair; cancer; genome instability; immunotherapy

DOI:  https://doi.org/10.3390/ijms232113356
Gynecol Oncol. 2022 Nov 08. pii: S0090-8258(22)01899-6. [Epub ahead of print]168 23-31

Profiling the immune landscape in mucinous ovarian carcinoma.

Nicola S Meagher, Phineas Hamilton, Katy Milne, Shelby Thornton, Bronwyn Harris, Ashley Weir, Jennifer Alsop, Christiani Bisinoto, James D Brenton, Angela Brooks-Wilson, Derek S Chiu, Kara L Cushing-Haugen, Sian Fereday, Dale W Garsed, Simon A Gayther, Aleksandra Gentry-Maharaj, Blake Gilks, Mercedes Jimenez-Linan, Catherine J Kennedy, Nhu D Le, Anna M Piskorz, Marjorie J Riggan, Mitul Shah, Naveena Singh, Aline Talhouk, Martin Widschwendter, David D L Bowtell, Francisco J Candido Dos Reis, Linda S Cook, Renée T Fortner, María J García, Holly R Harris, David G Huntsman, Anthony N Karnezis, Martin Köbel, Usha Menon, Paul D P Pharoah, Jennifer A Doherty, Michael S Anglesio, Malcolm C Pike, Celeste Leigh Pearce, Michael L Friedlander, Anna DeFazio, Brad H Nelson, Susan J Ramus.

   OBJECTIVE: Mucinous ovarian carcinoma (MOC) is a rare histotype of ovarian cancer, with low response rates to standard chemotherapy, and very poor survival for patients diagnosed at advanced stage. There is a limited understanding of the MOC immune landscape, and consequently whether immune checkpoint inhibitors could be considered for a subset of patients.
METHODS: We performed multicolor immunohistochemistry (IHC) and immunofluorescence (IF) on tissue microarrays in a cohort of 126 MOC patients. Cell densities were calculated in the epithelial and stromal components for tumor-associated macrophages (CD68+/PD-L1+, CD68+/PD-L1-), T cells (CD3+/CD8-, CD3+/CD8+), putative T-regulatory cells (Tregs, FOXP3+), B cells (CD20+/CD79A+), plasma cells (CD20-/CD79a+), and PD-L1+ and PD-1+ cells, and compared these values with clinical factors. Univariate and multivariable Cox Proportional Hazards assessed overall survival. Unsupervised k-means clustering identified patient subsets with common patterns of immune cell infiltration.
RESULTS: Mean densities of PD1+ cells, PD-L1- macrophages, CD4+ and CD8+ T cells, and FOXP3+ Tregs were higher in the stroma compared to the epithelium. Tumors from advanced (Stage III/IV) MOC had greater epithelial infiltration of PD-L1- macrophages, and fewer PD-L1+ macrophages compared with Stage I/II cancers (p = 0.004 and p = 0.014 respectively). Patients with high epithelial density of FOXP3+ cells, CD8+/FOXP3+ cells, or PD-L1- macrophages, had poorer survival, and high epithelial CD79a + plasma cells conferred better survival, all upon univariate analysis only. Clustering showed that most MOC (86%) had an immune depleted (cold) phenotype, with only a small proportion (11/76,14%) considered immune inflamed (hot) based on T cell and PD-L1 infiltrates.
CONCLUSION: In summary, MOCs are mostly immunogenically 'cold', suggesting they may have limited response to current immunotherapies.

Keywords:  Immune infiltrate; Mucinous ovarian carcinoma; Rare histotype

DOI:  https://doi.org/10.1016/j.ygyno.2022.10.022
Nat Med. 2022 Nov 10.

Overall survival with circulating tumor DNA-guided therapy in advanced non-small-cell lung cancer.

Justin Jee, Emily S Lebow, Randy Yeh, Jeeban P Das, Azadeh Namakydoust, Paul K Paik, Jamie E Chaft, Gowtham Jayakumaran, A Rose Brannon, Ryma Benayed, Ahmet Zehir, Mark Donoghue, Nikolaus Schultz, Debyani Chakravarty, Ritika Kundra, Ramyasree Madupuri, Yonina R Murciano-Goroff, Hai-Yan Tu, Chong-Rui Xu, Andrés Martinez, Clare Wilhelm, Jesse Galle, Bobby Daly, Helena A Yu, Michael Offin, Matthew D Hellmann, Piro Lito, Kathryn C Arbour, Marjorie G Zauderer, Mark G Kris, Kenneth K Ng, Juliana Eng, Isabel Preeshagul, W Victoria Lai, John J Fiore, Afsheen Iqbal, Daniela Molena, Gaetano Rocco, Bernard J Park, Lee P Lim, Mark Li, Candace Tong-Li, Madhawa De Silva, David L Chan, Connie I Diakos, Malinda Itchins, Stephen Clarke, Nick Pavlakis, Adrian Lee, Natasha Rekhtman, Jason Chang, William D Travis, Gregory J Riely, David B Solit, Mithat Gonen, Valerie W Rusch, Andreas Rimner, Daniel Gomez, Alexander Drilon, Howard I Scher, Sohrab P Shah, Michael F Berger, Maria E Arcila, Marc Ladanyi, Ross L Levine, Ronglai Shen, Pedram Razavi, Jorge S Reis-Filho, David R Jones, Charles M Rudin, James M Isbell, Bob T Li.

Circulating tumor DNA (ctDNA) sequencing guides therapy decisions but has been studied mostly in small cohorts without sufficient follow-up to determine its influence on overall survival. We prospectively followed an international cohort of 1,127 patients with non-small-cell lung cancer and ctDNA-guided therapy. ctDNA detection was associated with shorter survival (hazard ratio (HR), 2.05; 95% confidence interval (CI), 1.74-2.42; P < 0.001) independently of clinicopathologic features and metabolic tumor volume. Among the 722 (64%) patients with detectable ctDNA, 255 (23%) matched to targeted therapy by ctDNA sequencing had longer survival than those not treated with targeted therapy (HR, 0.63; 95% CI, 0.52-0.76; P < 0.001). Genomic alterations in ctDNA not detected by time-matched tissue sequencing were found in 25% of the patients. These ctDNA-only alterations disproportionately featured subclonal drivers of resistance, including RICTOR and PIK3CA alterations, and were associated with short survival. Minimally invasive ctDNA profiling can identify heterogeneous drivers not captured in tissue sequencing and expand community access to life-prolonging therapy.

DOI: https://doi.org/10.1038/s41591-022-02047-z