bims-preonc 2024-11-10 papers

bims-preonc

Biomed News

on Precision oncology

Issue of 2024–11–10
fourteen papers selected by
Ankita Daiya, OneCell Diagnostics Inc.

Advances and challenges in the use of liquid biopsy in gynaecological oncology.
New Insights into Colorectal Cancer through the Lens of Precision Oncology and Personalized Medicine: Multi-Omics Helps Aging of Predisposed People.
Clinical utility of circulating tumor DNA profiling in detecting targetable fusions in non-small cell lung cancer.
Dynamics of cell-free tumor DNA correlate with early MRI response during chemoradiotherapy in rectal cancer.
Multicenter Prospective Study in HER2-Positive Early Breast Cancer for Detecting Minimal Residual Disease by Circulating Tumor DNA Analysis With Neoadjuvant Chemotherapy: HARMONY Study.
Genomes and epigenomes of matched normal and tumor breast tissue reveal diverse evolutionary trajectories and tumor-host interactions.
Comprehensive liquid biopsy analysis for monitoring NSCLC patients under second-line osimertinib treatment.
Genetic and clinical characteristics of genetic tumor syndromes in the central nervous system cancers: Implications for clinical practice.
Molecular Tumor Board of the University Medical Center Groningen (UMCG-MTB): outcome of patients with rare or complex mutational profiles receiving MTB-advised targeted therapy.
Neoadjuvant therapy in early-stage non-small cell lung cancer: A real-world analysis.
The Current Status of Comprehensive Genomic Profiling in the Management of Metastatic Castration-Resistant Prostate Cancer: A Study from a Cooperative Hospital for Cancer Genomic Medicine in Japan.
Immune checkpoint inhibitors as first-line treatment for brain metastases in stage IV NSCLC patients without driver mutations.
Tepotinib in Cholangiocarcinoma with MET Amplification: A Case Report.
Leukocytes telomere length as a biomarker of adverse drug reactions induced by Osimertinib in advanced non-small cell lung cancer.

Heliyon. 2024 Oct 30. 10(20): e39148

Advances and challenges in the use of liquid biopsy in gynaecological oncology.

Yingfeng Zhang, Libi Tian.

  Ovarian cancer, endometrial cancer, and cervical cancer are the three primary gynaecological cancers that pose a significant threat to women's health on a global scale. Enhancing global cancer survival rates necessitates advancements in illness detection and monitoring, with the goal of improving early diagnosis and prognostication of disease recurrence. Conventional methods for identifying and tracking malignancies rely primarily on imaging techniques and, when possible, protein biomarkers found in blood, many of which lack specificity. The process of collecting tumour samples necessitates intrusive treatments that are not suitable for specific purposes, such as screening, predicting, or evaluating the effectiveness of treatment, monitoring the presence of remaining illness, and promptly detecting relapse. Advancements in treatment are being made by the detection of genetic abnormalities in tumours, both inherited and acquired. Newly designed therapeutic approaches can specifically address some of these abnormalities. Liquid biopsy is an innovative technique for collecting samples that examine specific cancer components that are discharged into the bloodstream, such as circulating tumour DNA (ctDNA), circulating tumour cells (CTCs), cell-free RNA (cfRNA), tumour-educated platelets (TEPs), and exosomes. Mounting data indicates that liquid biopsy has the potential to improve the clinical management of gynaecological cancers through enhanced early diagnosis, prognosis prediction, recurrence detection, and therapy response monitoring. Understanding the distinct genetic composition of tumours can also inform therapy choices and the identification of suitable targeted treatments. The main benefits of liquid biopsy are its non-invasive characteristics and practicality, enabling the collection of several samples and the continuous monitoring of tumour changes over time. This review aims to provide an overview of the data supporting the therapeutic usefulness of each component of liquid biopsy. Additionally, it will assess the benefits and existing constraints associated with the use of liquid biopsy in the management of gynaecological malignancies. In addition, we emphasise future prospects in light of the existing difficulties and investigate areas where further research is necessary to clarify its rising clinical capabilities.

Keywords:  CTCs; Exosomes; Gynaecological cancers; Liquid biopsy; TEPs; cfRNA; ctDNA

DOI:  https://doi.org/10.1016/j.heliyon.2024.e39148
Curr Aging Sci. 2024 Nov 05.

New Insights into Colorectal Cancer through the Lens of Precision Oncology and Personalized Medicine: Multi-Omics Helps Aging of Predisposed People.

Amir Bayat, Alireza Sharafshah, Farshid Sefat, Milad Rahimzadegan, Mohammad Raad, Kai-Uwe Lewandrowski.

   BACKGROUND: Recently, there has been a significant evolution in our understanding of the molecular pathways causing the genesis and progression of cancer via the inter-individual variations. Thus, one-size-fits-all methods for cancer treatment have been replaced by precision oncology (PO) targeting individual cancer symptoms, offering increased effectiveness, and decreased safety concerns and cost load.
OBJECTIVE: The identification of novel actionable indications, rapid, precise, and comprehensive detection of complex phenotypes in every individual, pioneering clinical trial projects with enhanced response feedback, and widespread availability of innovative targeted anticancer management for every patient are vital for the effective implementation of next-generation precision oncology. Additionally, the emergence of precision medicine has altered the perspective of oncologic biomarkers, drug discovery, drug development, and, improvements for cancer patients.
METHOD: This paper narratively reviewed to identify actionable abnormalities, Genomic profiling of tumors employing clinical next-generation sequencing (NGS) from both tumor tissues and liquid biopsies along with the multi-omics strategies as the key component of PO.
RESULTS: Our increasing information on tumor biology, specifically microenvironment and heterogeneity- associated data, would improve our understanding of the resistance of targeted drugs and specific mechanisms of action, as well as help enhance existing metastatic colorectal cancer (mCRC) treatment strategies.
CONCLUSION: Collectively, this paper indicated the current and innovative strategies for prognosis, diagnosis, and treatment of various cancer types based on PO overview with a groundbreaking emphasis on CRC suggesting the integrations of multi-omics, highlighting Genomics, and utilizing AL and ML algorithms with targeted therapies. Notably, these findings can help improve the life-span and ageing of the predisposed people.

Keywords:  Colorectal cancer; biomarkers.; omics; precision oncology; targeted therapy

DOI:  https://doi.org/10.2174/0118746098348122241024061610
Front Oncol. 2024 ;14 1463341

Clinical utility of circulating tumor DNA profiling in detecting targetable fusions in non-small cell lung cancer.

Young-Gon Kim, Boram Lee, Changhee Ha, Cheonghwa Lee, Hyun Ae Jung, Jong-Mu Sun, Se-Hoon Lee, Myung-Ju Ahn, Yoon-La Choi, Sehhoon Park, Jong-Won Kim.

   Introduction: Numerous studies have suggested high concordance between tissue and circulating tumor DNA (ctDNA) comprehensive genomic profiling (CGP) tests but only few of them focused on fusions. In addition, atypical breakpoints occasionally detected from DNA-based fusion detection make interpretation difficult, and their clinical significance remains unclear. This study evaluated the clinical utility of ctDNA CGP for fusion detection.
Methods: The results of ctDNA CGP tests performed on patients with stage IV non-small cell lung cancer during routine clinical care were retrospectively reviewed. The concordance between ctDNA CGP and combined tissue test results was analyzed using CGP, immunohistochemistry, fluorescence in situ hybridization, and reverse transcription polymerase chain reaction. The clinical significance of fusions detected by ctDNA CGP, including those with atypical breakpoints at the DNA level, was assessed.
Results: In total, 264 patients were tested with ctDNA CGP. Fusions were detected in 27 patients (10.2%), and the fusion drivers were RET (n=12, 4.6%), ALK (n=9, 3.4%), ROS1 (n=4, 1.5%), and FGFR2 (n=2, 0.8%). The overall prevalence of fusion in tissue CGP was comparable to that in ctDNA CGP. A total of 371 ctDNA-tissue test pairs were available, and the overall positive and negative percent agreement rates were 92.9% (13/14) and 100.0% (357/357), respectively. One ALK IHC-positive and ctDNA CGP-negative case did not respond to ALK-targeted therapy. Response to targeted therapy was assessed in 16 patients, and a partial response was achieved in all patients, including four with atypical breakpoints.
Conclusion: Fusion detection using ctDNA CGP showed high concordance with tissue tests and accuracy in predicting therapeutic responses in patients with non-small cell lung cancer. ctDNA CGP may provide an important diagnostic tool for fusion detection.

Keywords:  circulating-tumor DNA; comprehensive genomic profiling; ctDNA; gene fusion; non-small cell lung cancer

DOI:  https://doi.org/10.3389/fonc.2024.1463341
Radiat Oncol. 2024 Nov 06. 19(1): 153

Dynamics of cell-free tumor DNA correlate with early MRI response during chemoradiotherapy in rectal cancer.

Kerstin Clasen, Cihan Gani, Leon Schuetz, Stephan Clasen, Nadja Ballin, Irina Bonzheim, Michael Orth, Stephan Ossowski, Olaf Riess, Maximilian Niyazi, Christopher Schroeder, Olga Kelemen.

   BACKGROUND: In locally advanced rectal cancer, the prediction of tumor response during and after neoadjuvant treatment remains challenging. In terms of organ preservation, adaptive radiotherapy, and intensified (total) neoadjuvant therapies, biomarkers are desirable for patient stratification.
METHODS: In 16 patients, weekly blood samples (n = 86) to detect cell-free tumor DNA (ctDNA) during long-course neoadjuvant chemoradiotherapy were analyzed. Data were correlated with initial tumor volumes, MRI response in week 2 and 5 of radiotherapy as well as with pathologic tumor response after resection and outcome parameters.
RESULTS: Most patients showed decreasing ctDNA during the course of radiochemotherapy. However, we found heterogenous dynamics of ctDNA and could identify three groups: (1) decline (2) no clear decline and/or late shedding (3) persistence of ctDNA. In seven patients we could detect significant amounts of ctDNA in week 5 or week 6 of treatment. In our pilot cohort, we did not find significant correlations of ctDNA dynamics with pathologic response or outcome parameters. However, patients with distinct decline of ctDNA had larger tumor volumes prior to treatment, and MRI imaging in week 2 and 5 revealed bigger absolute decrease of tumor volumes. If significant levels of ctDNA were found in week 5 and / or 6, patients showed less absolute tumor volume decrease in week 2 and 5.
CONCLUSIONS: Weekly measurement of ctDNA during radiochemotherapy is feasible and might represent a promising biomarker. Bigger initial primary tumors showed different ctDNA shedding profiles compared with smaller primary tumors and correlations of ctDNA dynamics with early imaging response were found.

Keywords:  Adaptive radiotherapy; Biomarker; Imaging; Magnetic resonance imaging; NGS; cfDNA; ctDNA

DOI:  https://doi.org/10.1186/s13014-024-02540-4
Breast Cancer (Auckl). 2024 ;18 11782234241288671

Multicenter Prospective Study in HER2-Positive Early Breast Cancer for Detecting Minimal Residual Disease by Circulating Tumor DNA Analysis With Neoadjuvant Chemotherapy: HARMONY Study.

Momoko Tokura, Mark Malalay Ando, Yuki Kojima, Rui Kitadai, Shu Yazaki, Cyrielle Marie N Atutubo, Rubi K Li, Minda Z Perez, Agnes E Gorospe, Manuelito A Madrid, Mel Valerie C Ordinario, Marcelo Severino B Imasa, Kazuki Sudo, Tatsunori Shimoi, Akihiko Suto, Shinji Kohsaka, Ryunosuke Machida, Ryo Sadachi, Masayuki Yoshida, Yasushi Yatabe, Tomomi Hata, Kenichi Nakamura, Kan Yonemori, Sho Shiino.

   Background: Biomarkers to predict the recurrence risk are required to optimize perioperative treatment. Adjuvant chemotherapy for patients with human epidermal growth factor 2-positive (HER2-positive) early breast cancer is decided by pathological responses of neoadjuvant chemotherapy (NAC). However, whether pathological responses are appropriate biomarkers is unclear. Currently, there are several studies using minimal residual disease (MRD) as a predictor of prognosis in solid tumors. However, there is no standard method for detecting MRD.
Objectives: This study aimed at prospectively evaluating the relationship between MRD detection and recurrence in Asian patients with HER2-positive early breast cancer.
Design: Prospective, observational, single-group, and exploratory. This study will include 60 patients from 2 institutions in Japan and the Philippines. The invasive disease-free survival (IDFS) rates of the MRD-positive and MRD-negative groups are compared in patients with HER2-positive early breast cancer who undergo surgery after receiving NAC.
Methods and analysis: Circulating tumor DNA (ctDNA) levels of patients will be evaluated 6 times: before NAC, after NAC, after surgery, and annually after surgery for 3 years. We will analyze the genetic profile of blood and tissue samples using the Todai OncoPanel (TOP) and the methylation level of DNA. The primary endpoint is IDFS. Secondary endpoints include overall survival (OS) and disease-free survival (DFS). Patient enrollment began in June 2022, and new participants are still being recruited.
Ethics: This study has been approved by the National Cancer Center Hospital Certified Review Board in March 2022 and has been approved by the Research Ethics Board of the participating center.
Discussion: Our findings will contribute to determining whether MRD detection using TOP is useful for predicting the recurrence of HER2-positive early breast cancer. If this is proven, MRD detected by TOP could be used in the future as a biomarker to assist in the de-/escalation of treatment strategies in the next interventional trial, thereby avoiding overtreatment in patients at low risk, and in the addition of intensive treatment modalities for those in patients at high risk.

Keywords:  Asia; HER2-positive breast cancer; Todai OncoPanel; ctDNA; ctRNA; minimal residual disease

DOI:  https://doi.org/10.1177/11782234241288671
Am J Hum Genet. 2024 Oct 29. pii: S0002-9297(24)00374-4. [Epub ahead of print]

Genomes and epigenomes of matched normal and tumor breast tissue reveal diverse evolutionary trajectories and tumor-host interactions.

Bin Zhu, Avraam Tapinos, Hela Koka, Priscilla Ming Yi Lee, Tongwu Zhang, Wei Zhu, Xiaoyu Wang, Alyssa Klein, DongHyuk Lee, Gary M Tse, Koon-Ho Tsang, Cherry Wu, Min Hua, Chad A Highfill, Petra Lenz, Weiyin Zhou, Difei Wang, Wen Luo, Kristine Jones, Amy Hutchinson, Belynda Hicks, Montserrat Garcia-Closas, Stephen Chanock, Lap Ah Tse, David C Wedge, Xiaohong R Yang.

  Normal tissues adjacent to the tumor (NATs) may harbor early breast carcinogenesis events driven by field cancerization. Although previous studies have characterized copy-number (CN) and transcriptomic alterations, the evolutionary history of NATs in breast cancer (BC) remains poorly characterized. Utilizing whole-genome sequencing (WGS), methylation profiling, and RNA sequencing (RNA-seq), we analyzed paired germline, NATs, and tumor samples from 43 individuals with BC in Hong Kong (HK). We found that single-nucleotide variants (SNVs) were common in NATs, with one-third of NAT samples exhibiting SNVs in driver genes, many of which were present in paired tumor samples. The most frequently mutated genes in both tumor and NAT samples were PIK3CA, TP53, GATA3, and AKT1. In contrast, large-scale aberrations such as somatic CN alterations (SCNAs) and structural variants (SVs) were rarely detected in NAT samples. We generated phylogenetic trees to investigate the evolutionary history of paired NAT and tumor samples. They could be categorized into tumor only, shared, and multiple-tree groups, the last of which is concordant with non-genetic field cancerization. These groups exhibited distinct genomic and epigenomic characteristics in both NAT and tumor samples. Specifically, NAT samples in the shared-tree group showed higher number of mutations, while NAT samples belonging to the multiple-tree group showed a less inflammatory tumor microenvironment (TME), characterized by a higher proportion of regulatory T cells (Tregs) and lower presence of CD14 cell populations. In summary, our findings highlight the diverse evolutionary history in BC NAT/tumor pairs and the impact of field cancerization and TME in shaping the genomic evolutionary history of tumors.

Keywords:  Chinese; breast cancer; cancer genomics; clonal evolution; normal tissues adjacent to the tumor; omics analyses; whole-genome sequencing

DOI:  https://doi.org/10.1016/j.ajhg.2024.10.005
Front Oncol. 2024 ;14 1435537

Comprehensive liquid biopsy analysis for monitoring NSCLC patients under second-line osimertinib treatment.

Aliki Ntzifa, Theodoros Marras, Galatea Kallergi, Athanasios Kotsakis, Vasilis Georgoulias, Evi Lianidou.

   Background: The heterogeneous and complex genetic landscape of NSCLC impacts the clinical outcomes of patients who will eventually develop resistance to osimertinib. Liquid biopsy (LB) analysis as a minimally invasive approach is a key step to efficiently identify resistance mechanisms and adjust to proper subsequent treatments.
Materials and methods: In the present study, we combined plasma-cfDNA and CTC analysis from 30 NSCLC patients in samples collected before treatment and at the progression of disease (PD). We detected molecular alterations at the DNA mutation (EGFR, PIK3CA, KRAS G12C, BRAF V600E), DNA methylation (RASSF1A, BRMS1, FOXA1, SLFN1, SHISA3, RARβ,, WIF-1, RASSF10 and APC), gene expression (CK-19, CK-18, CK-8, AXL, TWIST-1, PD-L1, PIM-1, Vimentin, ALDH-1, and B2M) and chromosomal level (HER2 and MET amplification) as possible resistance mechanisms and druggable targets. We also studied the expression of PD-L1 in single CTCs using immunofluorescence.
Results: In some cases, T790M resistance EGFR mutation was detected at baseline in CTCs but not in the corresponding plasma cfDNA. PIK3CA mutations were detected only in plasma-cfDNA but not in corresponding CTCs. KRAS G12C and BRAF V600E mutations were not detected in the samples analyzed. MET amplification was detected in the CTCs of two patients before treatment whereas HER2 amplification was detected in the CTCs of three patients at baseline and in one patient at PD. DNA methylation analysis revealed low concordance between CTCs and cfDNA, indicating the complementary information obtained through parallel LB analysis. Results from gene expression analysis indicated high rates of vimentin-positive CTCs detected at all time points during osimertinib. Moreover, there was an increased number of NSCLC patients at PD harboring CTCs positive in PD-L1. AXL and PIM-1 expression detected in CTCs during treatment suggesting new possible therapeutic strategies.
Discussion: Our results reveal that comprehensive liquid biopsy analysis can efficiently represent the heterogeneous molecular landscape and provide prominent information on subsequent treatments for NSCLC patients at PD since druggable molecular alterations were detected in CTCs.

Keywords:  CTC; NSCLC; ctDNA; liquid biopsy; osimertinib; resistance

DOI:  https://doi.org/10.3389/fonc.2024.1435537
iScience. 2024 Nov 15. 27(11): 111073

Genetic and clinical characteristics of genetic tumor syndromes in the central nervous system cancers: Implications for clinical practice.

Chuanwei Wang, Jian Chen, Yanzhao Wang, Ningning Luo, Tiantian Han, Xiangyu Yin, Yunjie Song, Dongsheng Chen, Jie Gong.

  Recognizing individuals with Genetic tumor syndromes (GTS) in the primary central nervous system (CNS) tumors is crucial for optimizing proper genetic counseling and improving therapeutics and clinical care. We retrospectively analyzed the GTS in a Chinese CNS tumor cohort and examined the molecular characteristics and their clinical significance for diagnostic and therapeutic purposes. Our study identified 34 categories of GTS in 258 patients with CNS tumors. The gene with the highest germline pathogenic or likely pathogenic mutation frequency was TP53, followed by MSH2, NF1, and BRCA2. The top five GTS in CNS tumors showed high genetic heterogeneity GTS analysis reclassifies CNS tumors as "NEC." 53.88% of patients diagnosed with GTS harbor potential precision oncology therapy target mutations. The results of our study deepen our understanding of CNS tumors, provide a reference direction for the future design of clinical trials, and further expect to improve disease entire process management in CNS tumors.

Keywords:  Clinical genetics; Disease; Genomics

DOI:  https://doi.org/10.1016/j.isci.2024.111073
ESMO Open. 2024 Nov 04. pii: S2059-7029(24)01736-8. [Epub ahead of print]9(11): 103966

Molecular Tumor Board of the University Medical Center Groningen (UMCG-MTB): outcome of patients with rare or complex mutational profiles receiving MTB-advised targeted therapy.

V D de Jager, P Plomp, M S Paats, S van Helvert, A Ter Elst, A van den Berg, H J Dubbink, W H van Geffen, L Zhang, L E L Hendriks, T J N Hiltermann, B I Hiddinga, L B M Hijmering-Kappelle, M Jalving, J Kluiver, B Koopman, M van Kruchten, E M J van der Logt, B Piet, J van Putten, B H Reitsma, S R Rutgers, M de Vries, J A Stigt, M R Groves, W Timens, S M Willems, L C van Kempen, E Schuuring, A J van der Wekken.

   PURPOSE: Molecular tumor boards (MTBs) are considered beneficial for treatment decision making for patients with cancer with uncommon, rare, or complex mutational profiles. The lack of international MTB guidelines results in significant variation in practices and recommendations. Therefore, periodic follow-up is necessary to assess and govern MTB functioning. The objective of this study was to determine the effectiveness of MTB treatment recommendations for patients with rare and complex mutational profiles as implemented in the MTB of the University Medical Center Groningen (UMCG-MTB) in 2019-2020.
PATIENTS AND METHODS: A retrospective follow-up study was carried out to determine the clinical outcome of patients with uncommon or rare (combinations of) molecular aberrations for whom targeted therapy was recommended as the next line of treatment by the UMCG-MTB in 2019 and 2020.
RESULTS: The UMCG-MTB recommended targeted therapy as the next line of treatment in 132 of 327 patients: 37 in clinical trials, 67 in the on-label setting, and 28 in the off-label setting. For on- and off-label treatment recommendations, congruence of recommended and received treatment was 85% in patients with available follow-up (67/79). Treatment with on-label therapy resulted in a response rate of 50% (21/42), a median progression-free survival (PFS) of 6.3 months [interquartile range (IQR) 2.9-14.9 months], and median overall survival (OS) of 15.8 months (IQR 6.4-34.2 months). Treatment with off-label therapy resulted in a response rate of 53% (8/15), a median PFS of 5.1 months (IQR 1.9-7.3 months), and a median OS of 17.7 months (IQR 5.1-23.7 months).
CONCLUSION: Treatment with MTB-recommended next-line targeted therapy for patients with often heavily pretreated cancer with rare and complex mutational profiles resulted in positive overall responses in over half of patients. Off-label use of targeted therapies, for which there is sufficient rationale as determined by an MTB, is an effective treatment strategy. This study underlines the relevance of discussing patients with rare and complex mutational profiles in an MTB.

Keywords:  clinical decision making; molecular pathology; molecular tumor board; precision oncology; real-world data; targeted therapy

DOI:  https://doi.org/10.1016/j.esmoop.2024.103966
Lung Cancer. 2024 Oct 24. pii: S0169-5002(24)00531-2. [Epub ahead of print]198 107997

Neoadjuvant therapy in early-stage non-small cell lung cancer: A real-world analysis.

Leyla Ay, Daniel Steiner, Hannah Fabikan, Oliver Illini, Dagmar Krenbek, Thomas Klikovits, Michal Benej, Klaus Kirchbacher, Stefan Watzka, Arschang Valipour, Maximilian Hochmair.

   BACKGROUND: Phase 3 trials of neoadjuvant immunotherapy-based regimens have shown promising outcomes in patients with resectable non-small cell lung cancer (NSCLC). However, real-world data on treatment regimens with combined chemoimmunotherapy, patient profiles, and clinical outcomes in those patients are limited.
METHODS: This dual-center registry-based study describes clinical patterns and outcomes of using neoadjuvant platinum-based chemoimmunotherapy in patients with resectable NSCLC. The main objective was to evaluate the proportion of patients receiving local therapy after chemoimmunotherapy. Further objectives include pathological outcome, disease-free survival (DFS), and overall survival (OS). Histological samples underwent next-generation sequencing (NGS).
RESULTS: Seventy-two patients (median age 64.5 years (interquartile range (IQR), 59-69); 40.3 % women) were included. Prior to initiation of therapy, NGS was available in 90.3 %. Median follow-up time from date of diagnosis was 374 days (IQR, 241-605). After neoadjuvant therapy, 46 patients underwent surgery and 23 radiotherapy, resulting in 69 patients receiving local therapy. Out of 46 patients who underwent surgery, 22 had pathological complete remission (PR), 11 major PR, and 12 minor PR. DFS (95 % confidence interval (CI)) in 43 (out of 46) surgical patients with R0 resection was 98 % (93-100), 98 % (93-100) and 81 % (57-100) after 180, 360 and 720 days, respectively. OS (95 % CI) was 97 % (94-100), 90 % (82-99) and 90 % (82-99), after 180, 360 and 720 days, respectively.
CONCLUSION: Following neoadjuvant chemoimmunotherapy, the majority of resectable early-stage NSCLC patients could undergo local therapy in routine clinical practice. This was associated with favorable DFS and OS.

Keywords:  Chemoimmunotherapy; Consolidation therapy; NSCLC; Neoadjuvant therapy; Resection rate; Surgery; Survival

DOI:  https://doi.org/10.1016/j.lungcan.2024.107997
J Nippon Med Sch. 2024 ;91(5): 472-479

The Current Status of Comprehensive Genomic Profiling in the Management of Metastatic Castration-Resistant Prostate Cancer: A Study from a Cooperative Hospital for Cancer Genomic Medicine in Japan.

Jun Akatsuka, Go Kimura, Mami Takadate, Sayuri Hiraoka, Tomoko Sahara, Takuma Iwai, Hiroya Hasegawa, Hikaru Mikami, Kotaro Obayashi, Hayato Takeda, Yuki Endo, Yuka Toyama, Yoichiro Yamamoto, Takeshi Yamada, Yukihiro Kondo.

   BACKGROUND: Several effective treatment modalities against metastatic castration-resistant prostate cancer (mCRPC) are available; however, an unmet clinical need persists for mCRPC treatment because resistance to these therapies is inevitable. This study aimed to evaluate the status of comprehensive genomic profiling (CGP) and its impact on subsequent treatments for patients with mCRPC at our hospital.
METHODS: Between December 2020 and August 2023, we assessed 41 patients with mCRPC who underwent CGP testing at the Nippon Medical School Hospital. The testing comprised FoundationOne® CDx for 30 patients and FoundationOne® Liquid CDx for 11 patients, following the procedures outlined by the Japanese Urological Association.
RESULTS: CGP testing was successfully conducted in 40 out of 41 patients (97.6%), which resulted in the identification of 140 actionable genomic alterations. The most common alteration was TP53 in 12 patients (30.0%). Twenty-three patients (57.5%) with druggable gene alterations were identified; 21 were recommended for clinical trials, four for patient-proposed healthcare services, and six for insurance-covered drugs. Consequently, genotype-matched therapy with insurance-covered drugs was administered to five patients (12.5%) with a BRCA2 mutation. Notably, none of the patients underwent clinical or prospective trials based on patient-suggested medical services.
CONCLUSIONS: Our results offer insights into the real-world application of CGP testing for patients with mCRPC at a cooperative hospital for cancer genomic medicine in Japan. Thus, urologists require a comprehensive understanding of the current status of CGP testing to enhance mCRPC management.

Keywords:  metastatic castration-resistant prostate cancer; next-generation sequencing; prostate cancer

DOI:  https://doi.org/10.1272/jnms.JNMS.2024_91-512
Cancer Lett. 2024 Nov 01. pii: S0304-3835(24)00712-2. [Epub ahead of print]606 217317

Immune checkpoint inhibitors as first-line treatment for brain metastases in stage IV NSCLC patients without driver mutations.

Guillermo Suay, Juan-Carlos Garcia-Cañaveras, Francisco Aparisi, José Garcia, Oscar Juan-Vidal, Agustín Lahoz.

  Immune checkpoint inhibitors (ICI) therapy with or without chemotherapy has been established as the first-line treatment for patients with non-oncogene addicted advanced Non-Small Cell Lung Cancer (NSCLC). Yet some clinical settings, such as the treatment sequence in patients with brain metastases, have barely been evidenced. Although ICIs cannot directly cross the blood-brain barrier (BBB), evidence suggests that BBB damage could allow ICIs into the central nervous system, or that they can have an indirect effect on the tumor immune microenvironment (TIME) and cause an anti-tumor response. Pivotal phase III trials have included a highly selected population but offer few data on these patients. Here we first review how ICIs can indirectly shape the brain metastases microenvironment through different mechanisms, and some possible causes of ICIs resistance. We also analyze the evidence reported in pivotal phase III trials and phase II trials focused on NSCLC brain metastases for first-line treatment, and the evidence for upfront or delayed local brain therapy. Finally, we discuss the best evidence-based approach to treat NSCLC patients with brain metastases and propose future research.

Keywords:  Immunotherapy; Metastatic NSCLC; Radiotherapy; brain metastases treatment; immune checkpoint inhibitors

DOI:  https://doi.org/10.1016/j.canlet.2024.217317
Onco Targets Ther. 2024 ;17 857-861

Tepotinib in Cholangiocarcinoma with MET Amplification: A Case Report.

Yen-Hao Chen, Yu-Ting Huang, Fang-Ying Kuo.

  Cholangiocarcinoma is a malignant tumor that affects the bile ducts and is usually aggressive with poor prognosis. The treatment of cholangiocarcinoma depends on the stage and location of the tumor as well as the patient's overall health status. Systemic therapy, such as chemotherapy using gemcitabine and cisplatin, is the first choice for patients with cholangiocarcinoma who were inoperable. After no response to first-line chemotherapy, second-line chemotherapy or targeted therapy focusing on signaling pathway inhibition are subsequent treatment. The present report described a case of cholangiocarcinoma involving bilateral lobes of liver. He received one cycle of chemotherapy with gemcitabine plus cisplatin and exhibited rapid progression. Next-generation sequencing was performed, and the results showed that MET amplification had a gene copy number of 68. After that, he underwent tepotinib and tumor shrinkage occurred. After a follow‑up period of 12 months, the treatment response was partial response, and the benefit of tepotinib is ongoing. The development of precision medicine has expanded the paradigm of targeted therapies to increasingly favorable options in the second line and beyond, and prolong overall survival. Detecting druggable mutations (mutations potentially amenable to treatment with) for identifying a landscape of therapeutic options is imperative for managing cholangiocarcinoma.

Keywords:  MET amplification; NGS; cholangiocarcinoma; tepotinib

DOI:  https://doi.org/10.2147/OTT.S483155
Sci Rep. 2024 11 03. 14(1): 26543

Leukocytes telomere length as a biomarker of adverse drug reactions induced by Osimertinib in advanced non-small cell lung cancer.

Narumol Trachu, Thanyanan Reungwetwattana, Jennis Meanwatthana, Chonlaphat Sukasem, Teerapat Majam, Wacharapol Saengsiwaritt, Jiraphun Jittikoon, Wanvisa Udomsinprasert.

  This study aimed to measure relative telomere length (RTL) in blood leukocytes of advanced-stage NSCLC patients either with or without Osimertinib-induced ADRs and determine whether RTL could serve as a biomarker of Osimertinib-induced ADRs. Blood leukocytes RTL were measured in 63 advanced-stage NSCLC patients and 62 age-matched healthy controls using real-time polymerase chain reaction. In patients with advanced-stage NSCLC, RTL was significantly shorter than that in healthy controls (P < 0.001). Compared to patients without ADRs and those with mild/moderate ADRs, patients with severe ADRs exhibited significantly decreased RTL (P < 0.001, P < 0.001, respectively). ROC curve analysis uncovered a diagnostic value of RTL as a biomarker of Osimertinib-induced ADRs (AUC = 1.000, P < 0.001). Kaplan-Meier analysis revealed a significant association between shorter RTL and increased cumulative incidence of Osimertinib-induced ADRs in patients with advanced-stage NSCLC (P < 0.001). Shorter RTL in blood leukocytes would reflect the occurrence of Osimertinib-induced ADRs and might emerge as a promising biomarker for identifying advanced-stage NSCLC patients who are at risk of experiencing Osimertinib-induced ADRs, particularly those with severe ADRs.

Keywords:  Biomarker; Non-small cell lung cancer; Osimertinib; Osimertinib-induced adverse drug reactions; Telomere length

DOI:  https://doi.org/10.1038/s41598-024-77935-0