bims-preonc Biomed News
on Precision oncology
Issue of 2024–08–25
nine papers selected by
Ankita Daiya, OneCell Diagnostics Inc.
  1. Optimal systemic treatment and real-world clinical application of ctDNA in patients with metastatic HER2-mutant lung cancer.
  2. Tumor Board Visualization: Integrating Clinical and Laboratory Insights.
  3. Harnessing cancer genomes for precision oncology.
  4. Determinants of successful minimally invasive surgery (MIS) for resectable non-small cell lung cancer (NSCLC) after neoadjuvant therapy.
  5. Assessing actionability and incidental findings of germline variants in two precision oncology trials.
  6. Epigenetic Therapy in a Rare Ovarian Cancer - A Double-Edged Sword.
  7. Nano-mediated strategy: recent advance in the application of drug delivery systems in melanoma treatment and diagnosis.
  8. Clinical value of guideline recommended molecular targets and genome targeted cancer therapies: cross sectional study.
  9. A phase II randomized trial of talimogene laherparepvec oncolytic immunotherapy with or without radiotherapy for patients with cutaneous metastases from solid tumors.
  1. Eur J Cancer. 2024 Aug 14. pii: S0959-8049(24)00913-4. [Epub ahead of print]210 114257
    Optimal systemic treatment and real-world clinical application of ctDNA in patients with metastatic HER2-mutant lung cancer.
    Si-Yang Liu, Tatiana Erazo, Justin Jee, Andrea Arfe, Avantika Gupta, Luke R G Pike, Fernando C Santini, Bobby Daly, Adam Schoenfeld, Jordan Eichholz, Kaylie Johnson, Andres Martinez, Jane Sui, Nadeem Riaz, Jason Chang, Soo-Ryum Yang, William Travis, Maria E Arcila, Jiannan Guo, Eric Gagne, Kavita Garg, Frederick Baehner, Nancy Y Lee, Alexander Drilon, Mark G Kris, Howard I Scher, Pedram Razavi, Daniel R Gomez, David R Jones, Charles M Rudin, Sarat Chandarlapaty, James M Isbell, Bob T Li.
       INTRODUCTION: No definitive answers currently exist regarding optimal first-line therapy for HER2-mutant NSCLC. Access to rapid tissue sequencing is a major barrier to precision drug development in the first-line setting. ctDNA analysis has the potential to overcome these obstacles and guide treatment.
    METHODS: We retrospectively analyzed patients with metastatic HER2-mutant NSCLC who underwent prospective clinical ctDNA sequencing and received systemic therapy at Memorial Sloan Kettering Cancer Center (MSK) from January 2016 to September 2022. HER2 mutations were identified by next-generation sequencing through MSK-IMPACT, MSK-ACCESS or Resolution ctDx LungTM assay. Primary endpoints were time to the next treatment (TTNT) and overall survival (OS).
    RESULTS: Sixty-three patients were included in the primary analysis. Chemoimmunotherapy (33/63, 52.4 %) was the predominant first-line treatment with a median TTNT of 5.1 months (95 %CI 4.1 - 6.1) whereas 55.0 % (22/40) of patients who received second-line T-DXd obtained a median TTNT of 9.2 m (95 % CI, 0-22.2). Plasma ctDNA was tested before first-line therapy in 40 patients with a median OS of 28.0 months (95 % CI 21-34), in whom 31 patients (78.0 %) had detectable ctDNA. HER2 mutations were detected on ctDNA with a median turnaround time of 13 days, occasionally co-occurred with EGFR and MET alterations and were tracked longitudinally correlating with treatment response. Patients with detectable baseline ctDNA had significantly shorter OS (hazard ratio (HR), 5.25; 95 % CI, 1.2-23.9; p = 0.019).
    CONCLUSION: Chemoimmunotherapy remains a major treatment option for metastatic HER2-mutant NSCLC. ctDNA can rapidly detect HER2 and co-mutations, and it has the potential to guide and monitor optimal first-line therapy. As a negative prognostic biomarker, detectable ctDNA at baseline would need to be taken into account for patient selection in future studies.
    Keywords:  CtDNA; HER2 mutation; Immunotherapy; NSCLC; Targeted therapy
    DOI:  https://doi.org/10.1016/j.ejca.2024.114257
  2. Stud Health Technol Inform. 2024 Aug 22. 316 1750-1751
    Tumor Board Visualization: Integrating Clinical and Laboratory Insights.
    Akhila Abdulnazar, Markus Kreuzthaler, Stefan Schulz, Barbara Prietl, Laurin Herbsthofer.
      We present a data visualization tool for tumor boards, merging clinical with molecular and multi-omics data to refine precision oncology decisions. The tool offers a holistic patient perspective, facilitating personalized treatment strategies. By integrating clinical and laboratory datasets, it enables intuitive navigation through complex information. Clinicians are supported in their decision-making by user-friendly visualizations. Future studies are needed to evaluate its real-world impact and usability in precision oncology settings.
    Keywords:  Oncology; data visualization; precision medicine
    DOI:  https://doi.org/10.3233/SHTI240767
  3. Nat Genet. 2024 Aug 20.
    Harnessing cancer genomes for precision oncology.
    Stephen J Chanock.
      
    DOI:  https://doi.org/10.1038/s41588-024-01879-4
  4. J Thorac Cardiovasc Surg. 2024 Aug 19. pii: S0022-5223(24)00696-2. [Epub ahead of print]
    Determinants of successful minimally invasive surgery (MIS) for resectable non-small cell lung cancer (NSCLC) after neoadjuvant therapy.
    Ngoc-Quynh Chu, Kay See Tan, Joe Dycoco, Prasad S Adusumilli, Manjit S Bains, Matthew J Bott, Robert J Downey, Katherine D Gray, James Huang, James M Isbell, Daniela Molena, Smita Sihag, Gaetano Rocco, David R Jones, Bernard J Park, Valerie W Rusch.
       OBJECTIVE: MIS (VATS, RATS) for pulmonary resection is standard in early stage NSCLC as it is associated with better perioperative outcomes than thoracotomy. MIS for resection of more advanced NSCLC (Stages IB-IIIB) treated with neoadjuvant therapy has been utilized. However, the determinants of success are not well-defined.
    METHODS: A single institution retrospective review of a prospectively maintained database was conducted, querying for patients with clinical Stage IB-IIIB NSCLC who had resection after neoadjuvant systemic therapy without radiation from 2013-2022. Patients were grouped by surgical approach, open vs. MIS. Successful MIS was defined by no conversion, R0 resection, and no major (≥grade 3) morbidity. Analyses by intent-to-treat assessed outcomes by Wilcoxon rank sum test and Fisher's exact test. (MVA identified variables that contributed to successful MIS resection.
    RESULTS: Of 627 eligible patients, 360 (57%) had open and 267 (43%) had MIS procedures. Most patients (79.1%) received neoadjuvant platinum-based chemotherapy, and 21.9% were treated with immunotherapy or targeted therapy alone or combined with chemotherapy. Among MIS resections, 179 (67%) were performed by VATS and 88 (33%) by RATS. The conversion rate was 16% (n=43). Successful MIS resection was achieved in 77% of patients. MVA showed that pre-treatment clinical N stage was a significant determinant of success, but not pre-treatment clinical T stage or type of neoadjuvant therapy.
    CONCLUSION: Following neoadjuvant systemic therapy for clinical stage IB-IIIB NSCLC, MIS resection can be successfully accomplished and should be considered in appropriate patients. Presence of pre-treatment nodal disease is associated with higher odds of conversion, major morbidity, and incomplete resection.
    Keywords:  Minimally invasive surgery; lung cancer; neoadjuvant therapy
    DOI:  https://doi.org/10.1016/j.jtcvs.2024.08.012
  5. Eur J Cancer. 2024 Aug 03. pii: S0959-8049(24)00912-2. [Epub ahead of print]210 114256
    Assessing actionability and incidental findings of germline variants in two precision oncology trials.
    Maria Baz Ibrahim, Yahia Adnani, Gérôme Jules Clément, Ludovic Lacroix, Yohann Loriot, Benjamin Besse, Christophe Massard, Etienne Rouleau.
       INTRODUCTION: High-throughput sequencing techniques have revolutionized oncology. Paired germline-tumor DNA analysis has emerged as a comprehensive strategy to uncover actionable alterations in advanced cancer patients (ACP) enrolled in precision oncology trials. However, challenges persist in variant interpretation and managing incidental germline findings.
    METHODS: We conducted a study involving 288 ACP from MOSCATO (NCT01566019) and MATCHR (NCT02517892) trials to assess germline variants impacting cancer-related genes. Germline DNA sequencing was performed using a panel of 250 cancer-related genes, and the results were discussed during tumor molecular board sessions.
    RESULTS: Germline pathogenic variants (PV) were classified according to the ESCAT classification. Lung cancer (36.8 %), followed by prostate (18.4 %) and breast cancer (17.7 %), comprised the most prevalent tumor types. PVs were found in 12.5 % of patients. Most PVs were classified as ESCAT X (63.9 %), highlighting limited therapeutic actionability. Notably,2 % of patients had actionable variants (ESCAT I-A/II-A). Incidental findings included 7.3 % of patients with PVs in cancer-predisposition genes, with 2.4 % having very high-risk potential, necessitating mandatory oncogenetic counseling. Nearly one in five patients (21.9 %) had at least one VUS.
    DISCUSSION: Our study underscores the significance of germline sequencing in identifying actionable alterations and the need for improved variant interpretation as well as pretest counseling plans in precision oncology trials.
    Keywords:  Basket trial; Germline DNA variants; Incidental variants; Precision oncology; Targeted therapy
    DOI:  https://doi.org/10.1016/j.ejca.2024.114256
  6. N Engl J Med. 2024 Aug 22. 391(8): 770-772
    Epigenetic Therapy in a Rare Ovarian Cancer - A Double-Edged Sword.
    Charles Hsu, Jason A Konner, Mrinal M Gounder.
      
    DOI:  https://doi.org/10.1056/NEJMc2407971
  7. Biomed Mater. 2024 Aug 21. 19(5):
    Nano-mediated strategy: recent advance in the application of drug delivery systems in melanoma treatment and diagnosis.
    Yinan Wang, Yuan Tian, Liwei Jia, Shujun Xu, Xin Meng.
      Melanoma is a common malignant tumor, with a five-year mortality rate as high as 62% in cases of metastatic melanoma according to cancer statistics (2024). In recent years, the focus of melanoma research has predominantly centered on immunotherapy and targeted therapy, grappling with challenges such as resistance and immunogenicity. The discovery of nanoparticles (NPs) has brought nano-delivery systems to the forefront of melanoma diagnosis and treatment. Although certain NPs, like liposomes, have gained clinical approval, utilizing most nano-delivery systems for melanoma diagnosis and treatment remains largely exploratory. The inherent limitations of NPs present a major obstacle to their clinical translation. By selecting suitable nanocarriers and functionalizing NPs to optimize nano-delivery systems, and combining these systems with other therapies, it is possible to reduce the systemic toxicity and resistance associated with conventional therapies and the NPs themselves. This optimization could significantly improve the effectiveness of nano-delivery systems in the early detection and timely treatment of melanoma. However, there have been few reviews on the optimization of NPs and the combined application of other therapies in the treatment and diagnostic application of melanoma in the past three years. This review summarizes the latest applications of nano-delivery systems in the diagnosis and treatment of melanoma over the past three years, including innovations and achievements in both preclinical and clinical studies, offering new perspectives on their potential and future application prospects. It integrates clinical data and patent information, highlights trends in nano-delivery system development, and offers new insights into their clinical translation. Additionally, it discusses the challenges and opportunities of nano-delivery systems in melanoma treatment, providing a foundation for advancing their application in diagnosis, treatment, and clinical translation.
    Keywords:  applications; diagnosis and therapy; drug delivery; melanoma; nanoparticles
    DOI:  https://doi.org/10.1088/1748-605X/ad6dc3
  8. BMJ. 2024 Aug 20. 386 e079126
    Clinical value of guideline recommended molecular targets and genome targeted cancer therapies: cross sectional study.
    Ariadna Tibau, Thomas J Hwang, Jerry Avorn, Aaron S Kesselheim.
       OBJECTIVE: To assess the clinical benefit and actionability of molecular targets for genome targeted cancer drugs recommended for clinical practice by the National Comprehensive Cancer Network (NCCN).
    DESIGN: Cross sectional study.
    PARTICIPANTS/SETTING: Genome targeted cancer drugs recommended by NCCN guidelines in the advanced setting.
    MAIN OUTCOME MEASURES: Molecular target actionability was assessed using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT). Clinical benefit of genome targeted oncology therapies was evaluated using the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS). Molecular targets at ESCAT category level I associated with studies showing substantial clinical benefit by ESMO-MCBS (grades 4-5) were designated as high benefit, and those linked to studies achieving an ESMO-MCBS grade of 3 were categorized as being of promising but unproven benefit.
    RESULTS: 411 recommendations related to 74 genome targeted drugs targeting 50 driver alterations were examined. Most recommendations (346/411; 84%) were associated with clinical trials of various phases, but 16% (65/411) relied on only case reports or pre-clinical studies. However, clinical trials mostly comprised phase I or phase II (271/346; 78%), single arm (262/346; 76%) studies. The primary endpoint assessed in most trials was overall response rate (271/346; 78%) rather than survival. ESCAT tier I targetability encompassed 60% (246/411) of target recommendations, 35% (142/411) were classified as tier II or III, and 6% (23/411) had their relevance yet to be determined (tiers IV to X). When ESMO-MCBS was applied to 267 scorable trials, only 12% (32/267) showed substantial clinical benefit (grades 4-5) and 45% (121/267) were grade 3. When both frameworks were combined, 12% (32/267) of trials supported a determination of high benefit and 33% (88/267) indicated promising but unproven benefit. Of the 118 interventions endorsed by NCCN authors as preferred, 62 (53%) applied to treatments with high or promising but unproven benefit.
    CONCLUSION: According to the ESCAT and ESMO-MCBS frameworks, about one eighth of genome based treatments for solid cancer were rated as likely to offer a high benefit to patients, whereas around a third were identified as offering a promising but unproven substantial benefit. Ensuring that NCCN recommendations are aligned with expected clinical benefits is crucial for promoting informed, evidence based, genomic guided treatment decisions.
    DOI:  https://doi.org/10.1136/bmj-2023-079126
  9. Radiother Oncol. 2024 Aug 17. pii: S0167-8140(24)00748-5. [Epub ahead of print] 110478
    A phase II randomized trial of talimogene laherparepvec oncolytic immunotherapy with or without radiotherapy for patients with cutaneous metastases from solid tumors.
    Christopher A Barker, Sandra P D'Angelo, Gloria Wasilewski, Alexa M Steckler, Ming Lian, Zhigang Zhang, Paul B Chapman, Alexander N Shoushtari, Charlotte E Ariyan.
       BACKGROUND: Cutaneous metastases (CMs) are a manifestation of advanced cancer and can be treated with oncolytic immunotherapy. Laboratory studies suggest radiotherapy (RT) may facilitate response to immunotherapy. We hypothesized that oncolytic immunotherapy with talimogene lapherparepvec (T-VEC, an oncolytic immunotherapy that expresses granulocyte-macrophage colony stimulating factor) and RT would produce response in non-targeted metastases.
    METHODS: A randomized phase 2 trial of T-VEC+/-RT was conducted. Eligible patients had ≥ 1 CM from a solid tumor amenable to T-VEC and RT and another measurable metastasis. Tumor and overall response was assessed using modified World Health Organization (mWHO) criteria. Adverse events and quality of life (QOL) were characterized using CTCAE v4.0 and Skindex-16, respectively. Correlative analyses of tumor genomics and immune system were performed.
    RESULTS: 19 patients were randomized to receive T-VEC (n = 9) or T-VEC+RT (n = 10). One patient in each arm demonstrated complete response in the largest non-targeted metastasis. The trial was closed after the first stage of enrollment because of no overall mWHO responses, slow accrual and the COVID19 pandemic. AEs were consistent with prior reports of T-VEC. Skin related QOL was poor before and after treatment. Median progression free survival was 1.2 and 2.5 months in the T-VEC and T-VEC+RT arms; median overall survival was 4.9 and 17.3 months in the T-VEC and T-VEC+RT arms. Analyses of peripheral blood cells and cytokines demonstrated responders exhibited several outlying lymphocyte and cytokine parameters.
    CONCLUSIONS: Low overall response rate, slow accrual, and the COVID19 pandemic led to closure of this trial. Responses in non-injected and non-irradiated metastases were infrequent.
    Keywords:  Cutaneous metastases; Cutaneous metastasis; Immunotherapy; Oncolytic immunotherapy; Radiation therapy; Radiotherapy; T-VEC; TVEC; Talimogene laherparepvec; Viral immunotherapy
    DOI:  https://doi.org/10.1016/j.radonc.2024.110478
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