bims-tumhet 2024-02-18 papers

bims-tumhet

Biomed News

on Tumor Heterogeneity

Issue of 2024‒02‒18
seven papers selected by
Sergio Marchini, Humanitas Research

Systematic analysis of HRD testing in ovarian cancer - development of recommendations for optimal assay performance.
The spatial structure of the tumor immune microenvironment can explain and predict patient response in high-grade serous carcinoma.
Uterine washings as a novel method for early detection of ovarian cancer: Trials and tribulations.
Screening and prevention of ovarian cancer.
Measuring the composition of the tumor microenvironment with transcriptome analysis: past, present and future.
Targeting chromosomal instability and aneuploidy in cancer.
Convergent evolution of BRCA2 reversion mutations under therapeutic pressure by PARP inhibition and platinum chemotherapy.

Mod Pathol. 2024 Feb 08. pii: S0893-3952(24)00025-5. [Epub ahead of print] 100445

Systematic analysis of HRD testing in ovarian cancer - development of recommendations for optimal assay performance.

Marcel Romey, Fiona Rodepeter, Akira Hattesohl, Kristin Kaiser, Julia Teply-Szymanski, Florian Heitz, Annette Staebler, Violeta Serra, Albert Grass, Frederik Marmé, Kirsten M Timms, Philipp Harter, Alba Llop-Guevara, Stefan Kommoss, Jelena Boekhoff, Carsten Denkert.

  HRD assays are an important element of personalized oncology in ovarian carcinomas, but the optimal tissue requirements for these complex molecular assays remain unclear. As a result, a considerable percentage of assays are not successful, leading to sub-optimal diagnoses for these patients. In this study, we have systematically analyzed tumor and tissue parameters for HRD analysis in a large cohort of real-world cancer samples. The aim of this study is to give recommendations for pathologists and gynecological oncologists for selection of tissue samples to maximize the success rate of HRD analyses. Tumor samples from 2702 patients were sent to the Institute of Pathology of the Philipps-University Marburg between October 2020 and September 2022, 2654 were analyzed using the Myriad MyChoice CDx HRD+ assay. 2396 (90.3% of 2654) were successfully tested, of which 984 (41.1% of 2396) were HRD positive and 1412 (58.9%) HRD negative. 363 (15.2%) of 2396 samples were BRCA1/2-mutated, 27 samples had a BRCA mutation and a GIS<42. 22 (0.9%) failed GIS measurement, but displayed a BRCA1/2 mutation. BRCA1/2-mutated samples showed significantly (p<0.0001) higher GIS values than those with a wild type BRCA1/2-status. Tumor cell content, tumor area, and histology significantly (p<0.0001) affected the probability of successfully analyzing a sample. Based on a systematic analysis of tumor cell content and tumor area, we recommend selecting patient high-grade serous ovarian cancer samples that display a tumor cell content ≥30% and a tumor area ≥0.5 cm2 (on their H&E) for HRD testing, to allow for optimal chances of a successful analysis and conclusive results. Considering histological and sample conditions, success rates of up to 98% can be achieved. Our comprehensive evaluation contributes to further standardization of recommendations on HRD testing in ovarian cancer, which will have a large impact on personalized therapeutic strategies in this highly aggressive tumor type.

Keywords:  BRCA; histology; homologous recombination deficiency; ovarian cancer

DOI:  https://doi.org/10.1016/j.modpat.2024.100445
bioRxiv. 2024 Jan 29. pii: 2024.01.26.577350. [Epub ahead of print]

The spatial structure of the tumor immune microenvironment can explain and predict patient response in high-grade serous carcinoma.

Lucy Van Kleunen, Mansooreh Ahmadian, Miriam D Post, Rebecca J Wolsky, Christian Rickert, Kimberly Jordan, Junxiao Hu, Jennifer K Richer, Nicole A Marjon, Kian Behbakht, Matthew J Sikora, Benjamin G Bitler, Aaron Clauset.

Despite ovarian cancer being the deadliest gynecological malignancy, there has been little change to therapeutic options and mortality rates over the last three decades. Recent studies indicate that the composition of the tumor immune microenvironment (TIME) influences patient outcomes but are limited by a lack of spatial understanding. We performed multiplexed ion beam imaging (MIBI) on 83 human high-grade serous carcinoma tumors - one of the largest protein-based, spatially-intact, single-cell resolution tumor datasets assembled - and used statistical and machine learning approaches to connect features of the TIME spatial organization to patient outcomes. Along with traditional clinical/immunohistochemical attributes and indicators of TIME composition, we found that several features of TIME spatial organization had significant univariate correlations and/or high relative importance in high-dimensional predictive models. The top performing predictive model for patient progression-free survival (PFS) used a combination of TIME composition and spatial features. Results demonstrate the importance of spatial structure in understanding how the TIME contributes to treatment outcomes. Furthermore, the present study provides a generalizable roadmap for spatial analyses of the TIME in ovarian cancer research.

DOI: https://doi.org/10.1101/2024.01.26.577350
Gynecol Oncol Rep. 2024 Feb;51 101330

Uterine washings as a novel method for early detection of ovarian cancer: Trials and tribulations.

Tiffany Y Sia, Zvi Yaari, Ron Feiner, Evan Smith, Arnaud Da Cruz Paula, Pier Selenica, Sital Doddi, Dennis S Chi, Nadeem R Abu-Rustum, Douglas A Levine, Britta Weigelt, Martin Fleisher, Lakshmi V Ramanathan, Daniel A Heller, Kara Long Roche.

  Given the tubal origin of high-grade serous ovarian cancer (HGSC), we sought to investigate intrauterine lavage (IUL) as a novel method of biomarker detection. IUL and serum samples were collected from patients with HGSC or benign pathology. Although CA-125 and HE4 concentrations were significantly higher in IUL samples compared to serum, they were similar between IUL samples from patients with HGSC vs benign conditions. In contrast, CA-125 and HE4 serum concentrations differed between HGSC and benign pathology (P =.002 for both). IUL and tumor samples from patients with HGSC were subjected to targeted panel sequencing and droplet digital PCR (ddPCR). Tumor mutations were found in 75 % of matched IUL samples. Serum CA-125 and HE4 biomarker levels allowed for better differentiation of HGSC and benign pathology compared to IUL samples. We believe using IUL for early detection of HGSC requires optimization, and current strategies should focus on prevention until early detection strategies improve.

Keywords:  Early detection; Intrauterine lavage; Ovarian cancer

DOI:  https://doi.org/10.1016/j.gore.2024.101330
Med J Aust. 2024 Feb 14.

Screening and prevention of ovarian cancer.

Michail Sideris, Usha Menon, Ranjit Manchanda.

  Ovarian cancer remains the most lethal gynaecological malignancy with 314 000 cases and 207 000 deaths annually worldwide. Ovarian cancer cases and deaths are predicted to increase in Australia by 42% and 55% respectively by 2040. Earlier detection and significant downstaging of ovarian cancer have been demonstrated with multimodal screening in the largest randomised controlled trial of ovarian cancer screening in women at average population risk. However, none of the randomised trials have demonstrated a mortality benefit. Therefore, ovarian cancer screening is not currently recommended in women at average population risk. More frequent surveillance for ovarian cancer every three to four months in women at high risk has shown good performance characteristics and significant downstaging, but there is no available information on a survival benefit. Population testing offers an emerging novel strategy to identify women at high risk who can benefit from ovarian cancer prevention. Novel multicancer early detection biomarker, longitudinal multiple marker strategies, and new biomarkers are being investigated and evaluated for ovarian cancer screening. Risk-reducing salpingo-oophorectomy (RRSO) decreases ovarian cancer incidence and mortality and is recommended for women at over a 4-5% lifetime risk of ovarian cancer. Pre-menopausal women without contraindications to hormone replacement therapy (HRT) undergoing RRSO should be offered HRT until 51 years of age to minimise the detrimental consequences of premature menopause. Currently risk-reducing early salpingectomy and delayed oophorectomy (RRESDO) should only be offered to women at increased risk of ovarian cancer within the context of a research trial. Pre-menopausal early salpingectomy is associated with fewer menopausal symptoms and better sexual function than bilateral salpingo-oophorectomy. A Sectioning and Extensively Examining the Fimbria (SEE-FIM) protocol should be used for histopathological assessment in women at high risk of ovarian cancer who are undergoing surgical prevention. Opportunistic salpingectomy may be offered at routine gynaecological surgery to all women who have completed their family. Long term prospective opportunistic salpingectomy studies are needed to determine the effect size of ovarian cancer risk reduction and the impact on menopause.

Keywords:  Mass screening; Ovarian neoplasms; Preventive medicine

DOI:  https://doi.org/10.5694/mja2.52227
Future Oncol. 2024 Feb 16.

Measuring the composition of the tumor microenvironment with transcriptome analysis: past, present and future.

Han Zhang, Xinghua Lu, Binfeng Lu, Giuseppe Gullo, Lujia Chen.

  Interactions between tumor cells and immune cells in the tumor microenvironment (TME) play a vital role the mechanisms of immune evasion, by which cancer cells escape immune elimination. Thus, the characterization and quantification of different components in the TME is a hot topic in molecular biology and drug discovery. Since the development of transcriptome sequencing in bulk tissue, single cells and spatial dimensions, there are increasing methods emerging to deconvolute and subtype the TME. This review discusses and compares such computational strategies and downstream subtyping analyses. Integrative analyses of the transcriptome with other data, such as epigenetics and T-cell receptor sequencing, are needed to obtain comprehensive knowledge of the dynamic TME.

Keywords:  TME subtype; bulk-RNAseq; cell-cell network; deconvolution; immune phenotype; immunotherapy; scRNAseq; spatial transcriptome; tumor microenvironment

DOI:  https://doi.org/10.2217/fon-2023-0658
Trends Pharmacol Sci. 2024 Feb 13. pii: S0165-6147(24)00022-1. [Epub ahead of print]

Targeting chromosomal instability and aneuploidy in cancer.

Sugandha Bhatia, Kum Kum Khanna, Pascal H G Duijf.

  Cancer development and therapy resistance are driven by chromosomal instability (CIN), which causes chromosome gains and losses (i.e., aneuploidy) and structural chromosomal alterations. Technical limitations and knowledge gaps have delayed therapeutic targeting of CIN and aneuploidy in cancers. However, our toolbox for creating and studying aneuploidy in cell models has greatly expanded recently. Moreover, accumulating evidence suggests that seven conventional antimitotic chemotherapeutic drugs achieve clinical response by inducing CIN instead of mitotic arrest, although additional anticancer activities may also contribute in vivo. In this review, we discuss these recent developments. We also highlight new discoveries, which together show that 25 chromosome arm aneuploidies (CAAs) may be targetable by 36 drugs across 14 types of cancer. Collectively, these advances offer many new opportunities to improve cancer treatment.

Keywords:  CRISPR; aneuploidy; cancer; chromosomal instability; genomic instability; oncology

DOI:  https://doi.org/10.1016/j.tips.2024.01.009
NPJ Precis Oncol. 2024 Feb 14. 8(1): 34

Convergent evolution of BRCA2 reversion mutations under therapeutic pressure by PARP inhibition and platinum chemotherapy.

Charlotte S Walmsley, Philip Jonsson, Michael L Cheng, Sean McBride, Christopher Kaeser, Herbert Alberto Vargas, Vincent Laudone, Barry S Taylor, Rajya Kappagantula, Priscilla Baez, Allison L Richards, Anne Marie Noronha, Dilmi Perera, Michael Berger, David B Solit, Christine A Iacobuzio-Donahue, Howard I Scher, Mark T A Donoghue, Wassim Abida, Alison M Schram.

Reversion mutations that restore wild-type function of the BRCA gene have been described as a key mechanism of resistance to Poly(ADP-ribose) polymerase (PARP) inhibitor therapy in BRCA-associated cancers. Here, we report a case of a patient with metastatic castration-resistant prostate cancer (mCRPC) with a germline BRCA2 mutation who developed acquired resistance to PARP inhibition. Extensive genomic interrogation of cell-free DNA (cfDNA) and tissue at baseline, post-progression, and postmortem revealed ten unique BRCA2 reversion mutations across ten sites. While several of the reversion mutations were private to a specific site, nine out of ten tumors contained at least one mutation, suggesting a powerful clonal selection for reversion mutations in the presence of therapeutic pressure by PARP inhibition. Variable cfDNA shed was seen across tumor sites, emphasizing a potential shortcoming of cfDNA monitoring for PARPi resistance. This report provides a genomic portrait of the temporal and spatial heterogeneity of prostate cancer under the selective pressure of a PARP inhibition and exposes limitations in the current strategies for detection of reversion mutations.

DOI: https://doi.org/10.1038/s41698-024-00526-9