bims-tumhet 2024-01-14 papers

Issue of 2024–01–14
five papers selected by
Sergio Marchini, Humanitas Research

Histochem Cell Biol. 2024 Jan 08.

From complexity to clarity: unravelling tumor heterogeneity through the lens of tumor microenvironment for innovative cancer therapy.

Sikiru O Imodoye, Kamoru A Adedokun, Ibrahim O Bello.

Despite the tremendous clinical successes recorded in the landscape of cancer therapy, tumor heterogeneity remains a formidable challenge to successful cancer treatment. In recent years, the emergence of high-throughput technologies has advanced our understanding of the variables influencing tumor heterogeneity beyond intrinsic tumor characteristics. Emerging knowledge shows that drivers of tumor heterogeneity are not only intrinsic to cancer cells but can also emanate from their microenvironment, which significantly favors tumor progression and impairs therapeutic response. Although much has been explored to understand the fundamentals of the influence of innate tumor factors on cancer diversity, the roles of the tumor microenvironment (TME) are often undervalued. It is therefore imperative that a clear understanding of the interactions between the TME and other tumor intrinsic factors underlying the plastic molecular behaviors of cancers be identified to develop patient-specific treatment strategies. This review highlights the roles of the TME as an emerging factor in tumor heterogeneity. More particularly, we discuss the role of the TME in the context of tumor heterogeneity and explore the cutting-edge diagnostic and therapeutic approaches that could be used to resolve this recurring clinical conundrum. We conclude by speculating on exciting research questions that can advance our understanding of tumor heterogeneity with the goal of developing customized therapeutic solutions.

Keywords: Cancer stem cells; Cancer therapy; Immunotherapy; Tumor heterogeneity; Tumor microenvironment; Tumor plasticity

DOI: https://doi.org/10.1007/s00418-023-02258-6

J Clin Oncol. 2024 Jan 12. JCO2301182

Poor Concordance Between Cancer Antigen-125 and RECIST Assessment for Progression in Patients With Platinum-Sensitive Relapsed Ovarian Cancer on Maintenance Therapy With a Poly(ADP-ribose) Polymerase Inhibitor.

Gynecologic Cancer Intergroup Meta-Analysis Committee

PURPOSE: Cancer antigen-125 (CA-125) is recommended by treatment guidelines and widely used to diagnose ovarian cancer recurrence. The value of CA-125 as a surrogate for disease progression (PD) and its concordance with radiologic progression are unclear, particularly for women with platinum-sensitive relapsed ovarian cancer (PSROC) who have responded to chemotherapy and treated with maintenance poly(ADP-ribose) polymerase inhibitor (PARPi).
METHODS: In this pooled analysis of four randomized trials of maintenance PARPi or placebo (Study 19, SOLO2, ARIEL3, and NOVA), we extracted data on CA-125 PD as defined by Gynecologic Cancer InterGroup criteria and RECIST v1.1. We evaluated the concordance between CA-125 and RECIST PD and reported on the negative predictive value (NPV) and positive predictive value (PPV).
RESULTS: Of 1,262 participants (n = 818 PARPi, n = 444 placebo), 403 (32%) had CA-125 PD, and of these, 366 had concordant RECIST PD (PPV, 91% [95% CI, 88 to 93]). However, of 859 (68%) without CA-125 PD, 382 also did not have RECIST PD (NPV, 44% [95% CI, 41 to 48]). Within the treatment arms, PPV remained high (PARPi, 91% [95% CI, 86 to 94]; placebo, 91% [95% CI, 86 to 95]) but NPV was lower on placebo (PARPi, 53% [95% CI, 49 to 57]; placebo, 25% [95% CI, 20 to 31]). Of 477 with RECIST-only PD, most (95%) had a normal CA-125 at the start of maintenance therapy and the majority (n = 304, 64%) had CA-125 that remained within normal range. Solid organ recurrence without peritoneal disease was more common in those with RECIST-only PD than in those with CA-125 and RECIST PD (36% v 24%; P < .001).
CONCLUSION: In patients with PSROC treated with maintenance PARPi, almost half with RECIST PD did not have CA-125 PD, challenging current guidelines. Periodic computed tomography imaging should be considered as part of surveillance, particularly in those with a normal CA-125 at the start of maintenance therapy and on treatment.

DOI: https://doi.org/10.1200/JCO.23.01182

Pathology. 2023 Dec 12. pii: S0031-3025(23)00310-0. [Epub ahead of print]

Predictive and prognostic biomarkers in female genital tract tumours: an update highlighting their clinical relevance and practical issues.

Richard Wing-Cheuk Wong, Annie N Y Cheung.

The evaluation of biomarkers by molecular techniques and immunohistochemistry has become increasingly relevant to the treatment of female genital tract tumours as a consequence of the greater availability of therapeutic options and updated disease classifications. For ovarian cancer, mutation testing for BRCA1/2 is the standard predictive biomarker for poly(ADP-ribose) polymerase inhibitor therapy, while homologous recombination deficiency testing may allow the identification of eligible patients among cases without demonstrable BRCA1/2 mutations. Clinical recommendations are available which specify how these predictive biomarkers should be applied. Mismatch repair (MMR) protein and folate receptor alpha immunohistochemistry may also be used to guide treatment in ovarian cancer. In endometrial cancer, MMR immunohistochemistry is the preferred test for predicting benefit from immune checkpoint inhibitor (ICI) therapy, but molecular testing for microsatellite instability may have a supplementary role. HER2 testing by immunohistochemistry and in situ hybridisation is applicable to endometrial serous carcinomas to assess trastuzumab eligibility. Immunohistochemistry for oestrogen receptor and progesterone receptor expression may be used for prognostication in endometrial cancer, but its predictive value for hormonal therapy is not yet proven. POLE mutation testing and p53 immunohistochemistry (as a surrogate for TP53 mutation status) serve as prognostic markers for favourable and adverse outcomes, respectively, in endometrial cancer, especially when combined with MMR testing for molecular subtype designation. For cervical cancer, programmed death ligand 1 immunohistochemistry may be used to predict benefit from ICI therapy although its predictive value is under debate. In vulvar cancer, p16 and p53 immunohistochemistry has established prognostic value, stratifying patients into three groups based on the human papillomavirus and TP53 mutation status of the tumour. Awareness of the variety and pitfalls of expression patterns for p16 and p53 in vulvar carcinomas is crucial for accurate designation. It is hoped that collaborative efforts in standardising and optimising biomarker testing for gynaecological tumours will contribute to evidence-based therapeutic decisions.

Keywords: Biomarker; cervical cancer; endometrial cancer; ovarian cancer; vulvar cancer

DOI: https://doi.org/10.1016/j.pathol.2023.10.013

Cureus. 2023 Dec;15(12): e50176

Liquid Biopsy: An Evolving Paradigm for Non-invasive Disease Diagnosis and Monitoring in Medicine.

Kanishk K Adhit, Anil Wanjari, Sharanya Menon, Siddhaarth K.

Liquid biopsy stands as an innovative instrument in the realm of precision medicine, enabling non-invasive disease diagnosis and the early detection of cancer. Liquid biopsy helps in the extraction of circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and cell-free DNA (cfDNA) from blood samples and other body fluids, thereby facilitating disease diagnosis and prediction of high-risk patients. Various techniques such as advanced sequencing methods and biomarker-based cell capture have led to the isolation and study of the different biomarkers such as ctDNA, cfDNA, and CTCs. These biopsies also have immense potential in the early detection and diagnosis of various diseases across all medical specialties, prediction and screening of high-risk cases, and detection of different immune response patterns in response to infectious diseases, and also help in predicting treatment outcomes. Although liquid biopsy has the potential to disrupt the field of medical diagnosis, it is met by various challenges such as limited tumor-derived components, less specificity, and inadequate advancement in methods to isolate biomarkers. Despite all these challenges, liquid biopsies provide the potential to become a minimally invasive method of diagnosis that would facilitate real-time monitoring of patients, which differentiates them from traditional tissue biopsies. This article aims to provide a complete overview of the current technologies, different biomarkers, and body fluids that can be used in liquid biopsy and its clinical applications and the potential impact that liquid biopsy holds in the field of precision medicine, facilitating early diagnosis and prompt management of various diseases and cancers.

Keywords: cell-free dna; circulating exosomes; circulating tumor cells (ctcs); ctdna; liquid biopsy; precision medicine

DOI: https://doi.org/10.7759/cureus.50176