bims-tumhet 2024-09-22 papers

bims-tumhet

Biomed News

on Tumor Heterogeneity

Issue of 2024‒09‒22
ten papers selected by
Sergio Marchini, Humanitas Research

Niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer: final overall survival results from the PRIMA/ENGOT-OV26/GOG-3012 trial.
The spatial multi-omics revolution in cancer therapy: Precision redefined.
Target-Enhanced Whole-Genome Sequencing (TE-WGS) Shows Clinical Validity Equivalent to Commercially Available Targeted Oncology Panel.
Identification of molecular subtypes for endometrial carcinoma using a 46-gene next-generation sequencing panel: a retrospective study on a consecutive cohort.
Ovarian Clear Cell Carcinoma: An Endometriosis-Associated Cancer with Therapeutic Challenges.
Reduction of chromosomal instability and inflammation is a common aspect of adaptation to aneuploidy.
Targeted therapy guided by circulating tumor DNA analysis in advanced gastrointestinal tumors.
Concurrent POLE hotspot mutations and mismatch repair deficiency/microsatellite instability in endometrial cancer: A challenge in molecular classification.
Atezolizumab Combined With Platinum and Maintenance Niraparib for Recurrent Ovarian Cancer With a Platinum-Free Interval >6 Months: ENGOT-OV41/GEICO 69-O/ANITA Phase III Trial.
Single-cell and Spatial Transcriptomic Analyses Implicate Formation of the Immunosuppressive Microenvironment during Breast Tumor Progression.

Ann Oncol. 2024 Sep 14. pii: S0923-7534(24)03762-1. [Epub ahead of print]

Niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer: final overall survival results from the PRIMA/ENGOT-OV26/GOG-3012 trial.

B J Monk, M P Barretina-Ginesta, B Pothuri, I Vergote, W Graybill, M R Mirza, C C McCormick, D Lorusso, R G Moore, G Freyer, R E O'Cearbhaill, F Heitz, D M O'Malley, A Redondo, M S Shahin, C Vulsteke, W H Bradley, C A Haslund, D M Chase, C Pisano, L L Holman, M J Rubio Pérez, P DiSilvestro, L Gaba, T J Herzog, I Bruchim, N Compton, L Shtessel, I A Malinowska, A González-Martín.

  BACKGROUND: The phase III PRIMA/ENGOT-OV26/GOG-3012 trial met its primary endpoint. Niraparib first-line maintenance significantly prolonged progression-free survival (PFS) among patients with newly diagnosed advanced ovarian cancer that responded to first-line platinum-based chemotherapy, regardless of homologous recombination deficiency (HRD) status. Final overall survival (OS) results are reported.PATIENTS AND METHODS: Patients were randomized 2:1 to niraparib or placebo, stratified by response to first-line treatment, receipt of neoadjuvant chemotherapy, and tumor HRD status. After reaching 60% target maturity, OS was evaluated via a stratified log-rank test using randomization stratification factors and summarized using Kaplan-Meier methodology. OS testing was hierarchical [overall population first, then the homologous recombination-deficient (HRd) population]. Other secondary outcomes and long-term safety were assessed; an updated, ad hoc analysis of investigator-assessed PFS was also conducted (cut-off date, 8 April 2024).
RESULTS: The median follow-up was 73.9 months. In the overall population, the OS hazard ratio was 1.01 [95% confidence interval (CI) 0.84-1.23; P = 0.8834] for niraparib (n = 487) versus placebo (n = 246). In the HRd (n = 373) and homologous recombination-proficient (n = 249) populations, the OS hazard ratios were 0.95 (95% CI 0.70-1.29) and 0.93 (95% CI 0.69-1.26), respectively. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 11.7% and 15.8% of niraparib patients and 37.8% and 48.4% of placebo patients in the overall and HRd populations, respectively. The 5-year PFS rate numerically favored niraparib in the overall (niraparib, 22%; placebo, 12%) and HRd populations (niraparib, 35%; placebo, 16%). Myelodysplastic syndromes/acute myeloid leukemia incidence was <2.5% (niraparib, 2.3%; placebo, 1.6%). No new safety signals were observed.
CONCLUSIONS: In patients with newly diagnosed advanced ovarian cancer at high risk of recurrence, there was no difference in OS between treatment arms. In the HRd population, patients alive at 5 years were two times as likely to be progression free with niraparib treatment than placebo. Long-term safety remained consistent with the established niraparib safety profile.

Keywords:  PARP inhibitor; maintenance; niraparib; ovarian cancer; overall survival

DOI:  https://doi.org/10.1016/j.annonc.2024.08.2241
Cell Rep Med. 2024 Sep 17. pii: S2666-3791(24)00470-1. [Epub ahead of print]5(9): 101740

The spatial multi-omics revolution in cancer therapy: Precision redefined.

Yanhua Du, Xinyu Ding, Youqiong Ye.

Spatially resolved multi-omics revolutionizes cancer therapy by decoding the cellular and molecular heterogeneity of the tumor microenvironment through spatial coordinates. This commentary discusses the roles of spatial multi-omics in identifying precise therapeutic targets and predicting treatment responses while also highlighting the challenges that impede its integration into precision medicine.

DOI: https://doi.org/10.1016/j.xcrm.2024.101740
Cancer Res Treat. 2024 Sep 19.

Target-Enhanced Whole-Genome Sequencing (TE-WGS) Shows Clinical Validity Equivalent to Commercially Available Targeted Oncology Panel.

Sangmoon Lee, Jin Roh, Jun Sung Park, Islam Oguz Tuncay, Wonchul Lee, Jung-Ah Kim, Brian Baek-Lok Oh, Jong-Yeon Shin, Jeong Seok Lee, Young Seok Ju, Ryul Kim, Seongyeol Park, Jaemo Koo, Hansol Park, Joonoh Lim, Erin Connolly-Strong, Tae-Hwan Kim, Yong Won Choi, Mi Sun Ahn, Hyun Woo Lee, Seokhwi Kim, Jang-Hee Kim, Minsuk Kwon.

  Purpose: Cancer poses a significant global health challenge, demanding precise genomic testing for individualized treatment strategies. Targeted-panel sequencing (TPS) has improved personalized oncology but often lacks comprehensive coverage of crucial cancer alterations. Whole-genome sequencing (WGS) addresses this gap, offering extensive genomic testing. This study demonstrates the medical potential of WGS.Materials and Methods: This study evaluates target-enhanced WGS (TE-WGS), a clinical-grade WGS method sequencing both cancer and matched normal tissues. Forty-nine patients with various solid cancer types underwent both TE-WGS and TruSight Oncology 500 (TSO500), one of the mainstream TPS approaches.
Results: TE-WGS detected all variants reported by TSO500 (100%, 498/498). A high correlation in variant allele fractions (VAF) was observed between TE-WGS and TSO500 (r=0.978). Notably, 223 variants (44.8%) within the common set were discerned exclusively by TE-WGS in peripheral blood, suggesting their germline origin. Conversely, the remaining subset of 275 variants (55.2%) were not detected in peripheral blood using the TE-WGS, signifying them as bona fide somatic variants. Further, TE-WGS provided accurate copy number profiles, fusion genes, microsatellite instability (MSI), and homologous-recombination deficiency (HRD) scores, which were essential for clinical decision-making.
Conclusion: TE-WGS is a comprehensive approach in personalized oncology, matching TSO500's key biomarker detection capabilities. It uniquely identifies germline variants and genomic instability markers, offering additional clinical actions. Its adaptability and cost-effectiveness underscore its clinical utility, making TE-WGS a valuable tool in personalized cancer treatment.

Keywords:  Biomarkers; Cancer; Mutations; Precision medicine; Whole genome sequencing

DOI:  https://doi.org/10.4143/crt.2024.114
ESMO Open. 2024 Sep 16. pii: S2059-7029(24)01480-7. [Epub ahead of print]9(10): 103710

Identification of molecular subtypes for endometrial carcinoma using a 46-gene next-generation sequencing panel: a retrospective study on a consecutive cohort.

Q Guo, S Tang, X Ju, Z Feng, Z Zhang, D Peng, F Liu, H Du, J Wang, Y Zhang, G Wang, Z Zhang, S Cai, Y Diao, Y Zhong, X Wu, X Zhou, H Wen.

  BACKGROUND: Traditional classification tools for endometrial carcinoma (EC), such as DNA sequencing, immunohistochemistry (IHC), or PCR, are cumbersome and time-consuming. Large next-generation sequencing (NGS) panels have simplified testing but are expensive. In this study, we propose a concise NGS panel as an effectively viable approach for classifying EC.MATERIALS AND METHODS: We retrospectively enrolled a consecutive EC cohort of hysterectomy with bilateral salpingo-oophorectomy from Fudan University Shanghai Cancer Center between 2020 and 2022. A 46-gene NGS panel was utilized to identify POLE exonuclease domain mutations, microsatellite instability-high (MSI-H), TP53 mutations, and other clinically relevant targets.
RESULTS: Tumor tissue samples from 331 EC patients were evaluated, with 284 (85.8%) cases classified as endometrioid endometrial carcinoma. The median follow-up time was 32.6 months (n = 303), during which 23 patients experienced recurrence or disease progression. Using the concise NGS panel, patients were stratified into four molecular subgroups according to the World Health Organization classification criteria: POLE mut (n = 47; 14.2%), mismatch repair deficiency (dMMR) (n = 79; 23.9%), non-specific molecular profile (n = 148; 44.7%), and abnormal p53 expression (p53 abn) (n = 57; 17.2%). POLE mut displayed the most favorable prognosis, while p53 abn had the worst prognosis (P < 0.001). The concordance between NGS and IHC was 91.8% (269/293) for detecting MMR status and 65.3% (201/308) for detecting p53 status. Patients detected solely by NGS had significantly worse prognosis than those detected solely by IHC, indicating higher accuracy of the NGS panel. With the molecular subtyping information, adjuvant treatment plans for 19.6% of patients could potentially be altered, mainly concentrated in the POLE mut and p53 abn subtypes. This panel also aids targeted therapy and poly (ADP-ribose) polymerase (PARP) inhibitor-related gene mutation detection, as well as auxiliary genetic screening.
CONCLUSION: Our study demonstrates that the concise NGS panel is an effective 'one-stop' strategy for precisely classifying EC with high clinical availability.

Keywords:  NGS panel; adjuvant treatment; endometrial carcinoma; molecular subgroups

DOI:  https://doi.org/10.1016/j.esmoop.2024.103710
Cold Spring Harb Perspect Med. 2024 Sep 16. pii: a041315. [Epub ahead of print]

Ovarian Clear Cell Carcinoma: An Endometriosis-Associated Cancer with Therapeutic Challenges.

Ruby Yun-Ju Huang, Jimmy Jin-Che Lin.

Ovarian clear cell carcinoma (OCCC) is a histological subtype of epithelial ovarian cancer with distinct pathological features, molecular profiles, and biological functions. OCCC has high incidence rates in East Asia compared to the Western hemisphere and Europe and is associated with endometriosis. With its relative resistance to conventional treatment regimens and the worst stage-adjusted prognosis among ovarian cancer subtypes, there is an urgent need to optimize therapeutic options and to improve patient outcomes. To achieve this goal, better patient stratification strategies are required. These strategies could derive from comprehensive and in-depth multidimensional analysis of tumor heterogeneity. Understanding intertumor heterogeneity could assist us in stratifying OCCC patients based on features that are prognostic or predictive. Recent genomic, epigenomic, and transcriptomic profiling analyses allow us to provide an integrative perspective on the diverse heterogeneity in OCCC that could pave the way for novel translational research and clinical development in the future.

DOI: https://doi.org/10.1101/cshperspect.a041315
EMBO Rep. 2024 Sep 18.

Reduction of chromosomal instability and inflammation is a common aspect of adaptation to aneuploidy.

Dorine C Hintzen, Michael Schubert, Mar Soto, René H Medema, Jonne A Raaijmakers.

  Aneuploidy, while detrimental to untransformed cells, is notably prevalent in cancer. Aneuploidy is found as an early event during tumorigenesis which indicates that cancer cells have the ability to surmount the initial stress responses associated with aneuploidy, enabling rapid proliferation despite aberrant karyotypes. To generate more insight into key cellular processes and requirements underlying adaptation to aneuploidy, we generated a panel of aneuploid clones in p53-deficient RPE-1 cells and studied their behavior over time. As expected, de novo-generated aneuploid clones initially display reduced fitness, enhanced levels of chromosomal instability (CIN), and an upregulated inflammatory response. Intriguingly, after prolonged culturing, aneuploid clones exhibit increased proliferation rates while maintaining aberrant karyotypes, indicative of an adaptive response to the aneuploid state. Interestingly, all adapted clones display reduced CIN and reduced inflammatory signaling, suggesting that these are common aspects of adaptation to aneuploidy. Collectively, our data suggests that CIN and concomitant inflammation are key processes that require correction to allow for fast proliferation in vitro. Finally, we provide evidence that amplification of oncogenic KRAS can promote adaptation.

Keywords:  Adaptation; Aneuploidy; Chromosomal Instability; Inflammation

DOI:  https://doi.org/10.1038/s44319-024-00252-0
Nat Med. 2024 Sep 16.

Targeted therapy guided by circulating tumor DNA analysis in advanced gastrointestinal tumors.

Yoshiaki Nakamura, Hiroshi Ozaki, Makoto Ueno, Yoshito Komatsu, Satoshi Yuki, Taito Esaki, Hiroya Taniguchi, Yu Sunakawa, Kensei Yamaguchi, Ken Kato, Tadamichi Denda, Tomohiro Nishina, Naoki Takahashi, Taroh Satoh, Hisateru Yasui, Hironaga Satake, Eiji Oki, Takeshi Kato, Takashi Ohta, Nobuhisa Matsuhashi, Masahiro Goto, Naohiro Okano, Koushiro Ohtsubo, Kentaro Yamazaki, Riu Yamashita, Naoko Iida, Mihoko Yuasa, Hideaki Bando, Takayuki Yoshino.

Although comprehensive genomic profiling has become standard in oncology for advanced solid tumors, the full potential of circulating tumor DNA (ctDNA)-based profiling in capturing tumor heterogeneity and guiding therapy selection remains underexploited, marked by a scarcity of evidence on its clinical impact and the assessment of intratumoral heterogeneity. The GOZILA study, a nationwide, prospective observational ctDNA profiling study, previously demonstrated higher clinical trial enrollment rates using liquid biopsy compared with tissue screening. This updated analysis of 4,037 patients further delineates the clinical utility of ctDNA profiling in advanced solid tumors, showcasing a significant enhancement in patient outcomes with a 24% match rate for targeted therapy. Patients treated with matched targeted therapy based on ctDNA profiling demonstrated significantly improved overall survival compared with those receiving unmatched therapy (hazard ratio, 0.54). Notably, biomarker clonality and adjusted plasma copy number were identified as predictors of therapeutic efficacy, reinforcing the value of ctDNA in reflecting tumor heterogeneity for precise treatment decisions. These new insights into the relationship between ctDNA characteristics and treatment outcomes advance our understanding beyond the initial enrollment benefits. Our findings advocate for the broader adoption of ctDNA-guided treatment, signifying an advancement in precision oncology and improving survival outcomes in advanced solid tumors.

DOI: https://doi.org/10.1038/s41591-024-03244-8
Gynecol Oncol. 2024 Sep 13. pii: S0090-8258(24)01115-6. [Epub ahead of print]191 1-9

Concurrent POLE hotspot mutations and mismatch repair deficiency/microsatellite instability in endometrial cancer: A challenge in molecular classification.

Sara Moufarrij, Andrea Gazzo, Satshil Rana, Pier Selenica, Nadeem R Abu-Rustum, Lora H Ellenson, Ying L Liu, Britta Weigelt, Amir Momeni-Boroujeni.

  OBJECTIVE: Endometrial carcinoma (EC) has different molecular subtypes associated with varied prognosis. We sought to characterize the molecular features of ECs with POLE hotspot mutations and concurrent mismatch repair (MMR) deficiency/high microsatellite instability (MSI).METHODS: We identified POLE-mutated (POLEmut), MMR-deficient (MMRd)/MSI-high (MSI-H), or combined POLEmut/MMRd ECs subjected to clinical tumor-normal panel sequencing between 2014 and 2023. Clonality of somatic mutations, MSI scoring, tumor mutational burden (TMB), proportion of somatic insertions and deletions (indels), and single base substitution (SBS) mutational signatures were extracted.
RESULTS: We identified 41 ECs harboring POLE exonuclease domain hotspot mutations, 138 MMRd and/or MSI-H ECs, and 14 POLEmut/MMRd ECs. Among the 14 POLEmut/MMRd ECs, 11 (79 %) exhibited clonal POLE hotspot mutations; 4 (29 %) had a dominant POLE-related mutational signature, 4 (29 %) displayed dominant MMRd-related signatures, and 6 (43 %) had mixtures of POLE, aging/clock, MMRd, and POLEmut/MMRd-related SBS mutational signatures. The number of single nucleotide variants was higher in POLEmut/MMR-proficient (MMRp) and in POLEmut/MMRd ECs compared to POLE wild-type (wt)/MMRd EC (both p < 0.001). Small indels were enriched in POLEwt/MMRd ECs (p < 0.001). TMB was highest in POLEmut/MMRd EC compared to POLEmut/MMRp and POLEwt/MMRd ECs (both p < 0.001). Of 14 patients with POLEmut/MMRd EC, 21 % had a recurrence, versus 10 % of those with POLEmut/MMRp EC. Similar findings were noted in 3 POLEmut ECs in patients with Lynch syndrome; akin to somatic POLEmut ECs, these tumors had high TMB.
CONCLUSION: POLEmut/MMRd ECs may be genetically distinct. Further studies are needed to assess the impact on outcomes and treatment response within this population.

Keywords:  Endometrial cancer; MMR-deficiency; Molecular subtypes; Mutational signatures; POLE; Tumor mutational burden

DOI:  https://doi.org/10.1016/j.ygyno.2024.09.008
J Clin Oncol. 2024 Sep 18. JCO2400668

Atezolizumab Combined With Platinum and Maintenance Niraparib for Recurrent Ovarian Cancer With a Platinum-Free Interval >6 Months: ENGOT-OV41/GEICO 69-O/ANITA Phase III Trial.

Antonio González-Martín, María Jesús Rubio, Florian Heitz, René Depont Christensen, Nicoletta Colombo, Toon Van Gorp, Margarita Romeo, Isabelle Ray-Coquard, Lydia Gaba, Alexandra Leary, Luis Miguel De Sande, Coriolan Lebreton, Andrés Redondo, Michel Fabbro, Maria-Pilar Barretina Ginesta, Philippe Follana, J Alejandro Pérez-Fidalgo, Manuel Rodrigues, Ana Santaballa, Renaud Sabatier, Maria José Bermejo-Pérez, Jean-Pierre Lotz, Beatriz Pardo, Gloria Marquina, Luisa Sánchez-Lorenzo, María Quindós, Purificación Estévez-García, Eva Guerra Alía, Luis Manso, Victoria Casado, Stefan Kommoss, Germana Tognon, Stéphanie Henry, Ilan Bruchim, Ana Oaknin, Frédéric Selle.

PURPOSE: To evaluate atezolizumab combined with platinum-based chemotherapy (CT) followed by maintenance niraparib for late-relapsing recurrent ovarian cancer.METHODS: The multicenter placebo-controlled double-blind randomized phase III ENGOT-OV41/GEICO 69-O/ANITA trial (ClinicalTrials.gov identifier: NCT03598270) enrolled patients with measurable high-grade serous, endometrioid, or undifferentiated recurrent ovarian cancer who had received one or two previous CT lines (most recent including platinum) and had a treatment-free interval since last platinum (TFIp) of >6 months. Patients were stratified by investigator-selected carboplatin doublet, TFIp, BRCA status, and PD-L1 status in de novo biopsy and randomly assigned 1:1 to receive either atezolizumab or placebo throughout standard therapy comprising six cycles of a carboplatin doublet followed (in patients with response/stable disease) by maintenance niraparib until progression. The primary end point was investigator-assessed progression-free survival (PFS) per RECIST v1.1.
RESULTS: Between November 2018 and January 2022, 417 patients were randomly assigned (15% BRCA-mutated, 36% PD-L1-positive, 66% TFIp >12 months, 11% previous poly [ADP-ribose] polymerase inhibitor after frontline CT, and 53% previous bevacizumab). Median follow-up was 28.6 months (95% CI, 26.6 to 30.5 months). Atezolizumab did not significantly improve PFS (hazard ratio, 0.89 [95% CI, 0.71 to 1.10]; P = .28). Median PFS was 11.2 months (95% CI, 10.1 to 12.1 months) with atezolizumab versus 10.1 months (95% CI, 9.2 to 11.2 months) with standard therapy. Subgroup analyses generally showed consistent results, including analyses by PD-L1 status. The objective response rate (ORR) was 45% (95% CI, 39 to 52) with atezolizumab and 43% (95% CI, 36 to 49) with standard therapy. The safety profile was as expected from previous experience of these drugs.
CONCLUSION: Combining atezolizumab with CT and maintenance niraparib for late-relapsing recurrent ovarian cancer did not significantly improve PFS or the ORR.

DOI: https://doi.org/10.1200/JCO.24.00668
J Immunol. 2024 Sep 16. pii: ji2400025. [Epub ahead of print]

Single-cell and Spatial Transcriptomic Analyses Implicate Formation of the Immunosuppressive Microenvironment during Breast Tumor Progression.

Fengfeng Cai, YuanYuan Li, Hui Liu, Judong Luo.

Ductal carcinoma in situ and invasive ductal carcinoma represent two stages of breast cancer progression. A multitude of studies have shown that genomic instability increases during tumor development, as manifested by higher mutation and copy number variation rates. The advent of single-cell and spatial transcriptomics has enabled the investigation of the subtle differences in cellular states during the tumor progression at single-cell level, thereby providing more nuanced understanding of the intercellular interactions within the solid tumor. However, the evolutionary trajectory of tumor cells and the establishment of the immunosuppressive microenvironment during breast cancer progression remain unclear. In this study, we performed an exploratory analysis of the single-cell sequencing dataset of 13 ductal carcinoma in situ and invasive ductal carcinoma samples. We revealed that tumor cells became more malignant and aggressive during their progression, and T cells transited to an exhausted state. The tumor cells expressed various coinhibitory ligands that interacted with the receptors of immune cells to create an immunosuppressive tumor microenvironment. Furthermore, spatial transcriptomics data confirmed the spatial colocalization of tumor and immune cells, as well as the expression of the coinhibitory ligand-receptor pairs. Our analysis provides insights into the cellular and molecular mechanism underlying the formation of the immunosuppressive landscape during two typical stages of breast cancer progression.

DOI: https://doi.org/10.4049/jimmunol.2400025