bims-tumhet 2024-06-09 papers

Issue of 2024–06–09
six papers selected by
Sergio Marchini, Humanitas Research

Cancer. 2024 Jun 02.

Clinical utility of comprehensive liquid molecular profiling in patients with advanced endometrial cancer.

Félix Blanc-Durand, Geraldine M Camilleri, Arnaud Bayle, Mihaela Aldea, Damien Vasseur, Kaissa Ouali, Judith Michels, Patricia Pautier, Claudio Nicotra, Maud Ngo-Camus, Ludovic Lacroix, Etienne Rouleau, Santiago Ponce-Aix, Antoine Italiano, Alexandra Leary.

BACKGROUND: Molecular characterization has significantly improved the management of advanced endometrial cancer (EC). It distinguishes four molecular subclasses associated with prognosis and personalized therapeutic strategies. This study assesses the clinical utility of cell-free DNA (cfDNA) profiling in EC to identify targetable alterations.
METHODS: Women with metastatic or recurrent EC were prospectively recruited within the framework of the STING trial (NCT04932525), during which cfDNA was analyzed. Genomic alterations were identified with the FoundationOne CDx assay. Each molecular report underwent review by a molecular tumor board. Alterations were categorized via the European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT).
RESULTS: A total of 61 patients were enrolled. The median age was 66.9 years, with 43% presenting frontline metastatic disease. All histologic subgroups were represented. Notably, 89% of patients yielded informative cfDNA analysis. Six tumors were classified with deficient mismatch repair/microsatellite instability (11%) and 37 as TP53 gene mutant (67%), and 12 had nonspecific molecular profiles (22%). Molecular classification based on liquid biopsy showed 87.5% accuracy in correlating with tissue results. Moreover, 65% of cases exhibited ≥1 actionable alteration, including 25% ESCAT I alterations and 13% ESCAT II alterations. Consequently, 16% of patients received a molecularly matched therapy, and presented with a 56% response rate and median progression-free survival of 7.7 months.
CONCLUSIONS: cfDNA sequencing in EC is a feasible approach that produces informative results in 89% of cases and accurately categorizes patients into the main molecular subclasses. It also reveals multiple actionable alterations, which offers the potential for personalized therapeutic strategies.

Keywords: cell‐free DNA (cfDNA); clonal hematopoiesis; endometrial cancer; molecular profile; personalized treatment

DOI: https://doi.org/10.1002/cncr.35381

Clin Cancer Res. 2024 Jun 05.

Concurrent RB1 Loss and BRCA-Deficiency Predicts Enhanced Immunological Response and Long-Term Survival in Tubo-Ovarian High-Grade Serous Carcinoma.

Flurina A M Saner, Kazuaki Takahashi, Timothy Budden, Ahwan Pandey, Dinuka Ariyaratne, Tibor A Zwimpfer, Nicola S Meagher, Sian Fereday, Laura Twomey, Kathleen I Pishas, Therese Hoang, Adelyn Bolithon, Nadia Traficante, Kathryn Alsop, Elizabeth L Christie, Eun-Young Kang, Gregg S Nelson, Prafull Ghatage, Cheng-Han Lee, Marjorie J Riggan, Jennifer Alsop, Matthias W Beckmann, Jessica Boros, Alison H Brand, Angela Brooks-Wilson, Michael E Carney, Penny Coulson, Madeleine Courtney-Brooks, Kara L Cushing-Haugen, Cezary Cybulski, Mona El-Bahrawy, Esther Elishaev, Ramona Erber, Simon A Gayther, Aleksandra Gentry-Maharaj, C Blake Gilks, Paul R Harnett, Holly R Harris, Arndt Hartmann, Alexander Hein, Joy Hendley, Brenda Y Hernandez, Anna Jakubowska, Mercedes Jimenez-Linan, Michael E Jones, Scott H Kaufmann, Catherine J Kennedy, Tomasz Kluz, Jennifer M Koziak, Björg Kristjansdottir, Nhu D Le, Marcin Lener, Jenny Lester, Jan Lubiński, Constantina Mateoiu, Sandra Orsulic, Matthias Ruebner, Minouk J Schoemaker, Mitul Shah, Raghwa Sharma, Mark E Sherman, Yurii B Shvetsov, T Rinda Soong, Helen Steed, Paniti Sukumvanich, Aline Talhouk, Sarah E Taylor, Robert A Vierkant, Chen Wang, Martin Widschwendter, Lynne R Wilkens, Stacey J Winham, Michael S Anglesio, Andrew Berchuck, James D Brenton, Ian Campbell, Linda S Cook, Jennifer A Doherty, Peter A Fasching, Renée Turzanski Fortner, Marc T Goodman, Jacek Gronwald, David G Huntsman, Beth Y Karlan, Linda E Kelemen, Usha Menon, Francesmary Modugno, Paul D P Pharoah, Joellen M Schildkraut, Karin Sundfeldt, Anthony J Swerdlow, Ellen L Goode, Anna DeFazio, Martin Köbel, Susan J Ramus, David D L Bowtell, Dale W Garsed.

PURPOSE: To evaluate RB1 expression and survival across ovarian carcinoma histotypes, and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC).
EXPERIMENTAL DESIGN: RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 primary HGSC to characterize tumors with concurrent BRCA-deficiency and RB1 loss.
RESULTS: RB1 loss was associated with longer OS in HGSC, but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared to patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA-deficiency correlated with transcriptional markers of enhanced interferon response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1.
CONCLUSIONS: Co-occurrence of RB1 loss and BRCA-deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

DOI: https://doi.org/10.1158/1078-0432.CCR-23-3552

Med Genet. 2023 Dec;35(4): 201-235

The changing face of circulating tumor DNA (ctDNA) profiling: Factors that shape the landscape of methodologies, technologies, and commercialization.

Abel J Bronkhorst, Stefan Holdenrieder.

Liquid biopsies, in particular the profiling of circulating tumor DNA (ctDNA), have long held promise as transformative tools in cancer precision medicine. Despite a prolonged incubation phase, ctDNA profiling has recently experienced a strong wave of development and innovation, indicating its imminent integration into the cancer management toolbox. Various advancements in mutation-based ctDNA analysis methodologies and technologies have greatly improved sensitivity and specificity of ctDNA assays, such as optimized preanalytics, size-based pre-enrichment strategies, targeted sequencing, enhanced library preparation methods, sequencing error suppression, integrated bioinformatics and machine learning. Moreover, research breakthroughs have expanded the scope of ctDNA analysis beyond hotspot mutational profiling of plasma-derived apoptotic, mono-nucleosomal ctDNA fragments. This broader perspective considers alternative genetic features of cancer, genome-wide characterization, classical and newly discovered epigenetic modifications, structural variations, diverse cellular and mechanistic ctDNA origins, and alternative biospecimen types. These developments have maximized the utility of ctDNA, facilitating landmark research, clinical trials, and the commercialization of ctDNA assays, technologies, and products. Consequently, ctDNA tests are increasingly recognized as an important part of patient guidance and are being implemented in clinical practice. Although reimbursement for ctDNA tests by healthcare providers still lags behind, it is gaining greater acceptance. In this work, we provide a comprehensive exploration of the extensive landscape of ctDNA profiling methodologies, considering the multitude of factors that influence its development and evolution. By illuminating the broader aspects of ctDNA profiling, the aim is to provide multiple entry points for understanding and navigating the vast and rapidly evolving landscape of ctDNA methodologies, applications, and technologies.

Keywords: Liquid biopsy; cell-free DNA; circulating tumor DNA; liquid profiling; precision medicine

DOI: https://doi.org/10.1515/medgen-2023-2065

Lancet Oncol. 2024 Jun 03. pii: S1470-2045(24)00102-5. [Epub ahead of print]

A manifesto for improving cancer detection: four key considerations when implementing innovations across the interface of primary and secondary care.

Anna Dowrick, Sue Ziebland, Tanvi Rai, Claire Friedemann Smith, Brian D Nicholson.

Improving cancer outcomes through innovative cancer detection initiatives in primary care is an international policy priority. There are unique implementation challenges to the roll-out and scale-up of different innovations, requiring synchronisation between national policy levers and local implementation strategies. We draw on implementation science to highlight key considerations when seeking to sustainably embed cancer detection initiatives within health systems and clinical practice. Points of action include considering the implications of change on the current configuration of responsibility for detecting cancer; investing in understanding how to adapt systems to support innovations; developing strategies to address inequity when planning innovation implementation; and anticipating and making efforts to mitigate the unintended consequences of innovation. We draw on examples of contemporary cancer detection issues to illustrate how to apply these recommendations to practice.

DOI: https://doi.org/10.1016/S1470-2045(24)00102-5

Clin Cancer Res. 2024 Jun 02.

Personalized circulating tumor DNA for monitoring disease status in head and neck squamous cell carcinoma.

Glenn J Hanna, Michael J Dennis, Nicole Scarfo, Michelle S Mullin, Rosh K V Sethi, Kartik Sehgal, Donald J Annino, Laura A Goguen, Robert I Haddad, Roy B Tishler, Danielle N Margalit, Ravindra Uppaluri, Jonathan D Schoenfeld, Eleni M Rettig.

BACKGROUND: Many patients with locoregionally advanced HPV-negative head and neck squamous cell carcinoma (HNSCC) relapse. Circulating tumor (ct)DNA has the potential to identify minimal residual disease, but its clinical utility for virus-negative HNSCC is not well understood.
METHODS: We retrospectively evaluated a personalized, commercial ctDNA assay (Signatera™, Natera) during clinical care of patients treated for predominantly newly diagnosed HPV-negative HNSCC. Signatera™ utilizes 16-plex PCR from matched tumor and blood. Objectives were to understand ctDNA detectability and correlate changes post-treatment with disease outcomes.
RESULTS: Testing was successful in 100/116 (86%) patients (median age: 65, 68% male, 65% smokers); testing failed in 16 (14%) due to insufficient tissue. Oral cavity (55, 47%) tumors were most common; most had stage III-IV disease (82, 71%) while 17 (15%) had distant metastases. Pre-treatment, 75/100 patients with successful testing (75%) had detectable ctDNA (range: 0.03-4049.69 MTM/mL). No clinical features predicted ctDNA detectability or levels (multivariate analysis). At median follow-up of 5.1 months (range: 0.2-15.1), 55 (55%) had >1 test result (range: 1-7; 194 samples). Of 55, 17 (31%) remained ctDNA positive after starting treatment. Progression-free survival was significantly worse for patients who were ctDNA positive vs. negative post-treatment (HR 7.33, 95%CI 3.12-17.2, p<0.001); 1-year overall survival was 89.1% vs. 100%, respectively (HR 7.46, 95%CI 0.46-119.5; p=0.155).
CONCLUSIONS: Tumor-informed ctDNA testing is feasible in non-viral HNSCC. ctDNA positivity is an indicator of disease progression and associated with inferior survival. Further research is warranted to understand whether ctDNA may be leveraged to guide therapy in HNSCC.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-0590

Clin Cancer Res. 2024 Jun 03.

Early evaluation of risk stratification and clinical outcomes for patients with advanced breast cancer through combined monitoring of baseline circulating tumor cells and DNA.

Qiang Zhang, Zheng Cai, Lorenzo Gerratana, Andrew A Davis, Paolo D'Amico, Akhil Chawla, Saya Jacob, Youbin Zhang, Jianhua Jiao, Weijun Qin, Carolina Reduzzi, Lisa Flaum, Ami Shah, William Gradishar.

PURPOSE: Early evaluation of tumor heterogeneity related to metastasis and outcomes is a major challenge in the management of advanced BCa in the clinic. Here we introduce the value of baseline CTCs and ctDNA to early differentiate clinical stages, tumor heterogeneity, and prognosis.
EXPERIMENTAL DESIGN: We enrolled 254 stage IV and 38 stage III BCa patients and examined the baseline levels of CTCs, CTC-clusters, and plasma ctDNA before initiating therapies. Outcome including PFS, and OS were evaluated.
RESULTS: The baseline CTCs for stage IV patients were approximately 9.5 times higher than those detected in stage III patients. Baseline CTC counts with a cutoff of 5 were significantly associated with prognosis. Within each stage, patients with <5 CTCs had longer PFS. Stage III patients with no CTCs exhibited the longest survival compared to patients with ≥1 CTC. CTC-clusters were only found in stage IV patients, among whom 15 stage IV patients with ≥5 CTC-clusters had the worst PFS compared to the 239 stage IV patients with <5 CTC-clusters. Similar outcomes were observed in 28 out of 254 stage IV patients who had at least 1 CTC-cluster detected, as these patients had shorter PFS. The major differences in ctDNA mutations between stage III and stage IV BCa were in PIK3CA and ESR1, which were associated with specific organ metastasis and worse outcomes.
CONCLUSIONS: Assessing the baseline levels of CTCs, CTC-clusters, and mutational ctDNA profile could reliably aid in differentiation of clinical stage and early prediction of metastasis and outcomes in advanced BCa.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-0535