bims-preonc Biomed News
on Precision oncology
Issue of 2025–02–02
eightteen papers selected by
Ankita Daiya, OneCell Diagnostics Inc.
  1. Liquid Biopsy and Challenge of Assay Heterogeneity for Minimal Residual Disease Assessment in Colon Cancer Treatment.
  2. Circulating Tumor DNA as a Marker of Recurrence Risk in Stage III Colorectal Cancer: The α-CORRECT Study.
  3. Clinical value of preoperative circulating tumor DNA before surgery in patients with esophageal squamous cell carcinoma.
  4. Circulating Tumor Cell-Free DNA as Prognostic Biomarker in Non-Small Cell Lung Cancer Patients Undergoing Immunotherapy: The CORELAB Experience.
  5. Multimodal integration of blood RNA and ctDNA reflects response to immunotherapy in metastatic urothelial cancer.
  6. Analytical and Clinical Validation of the Plasma-Based Guardant360 CDx Test for Assessing HER2 (ERBB2) Mutation Status in Patients with Non-Small-Cell Lung Cancer for Treatment with Trastuzumab Deruxtecan in DESTINY-Lung01/02.
  7. Case report: Selpercatinib in the treatment of RET fusion-positive advanced lung adenocarcinoma: a challenging clinical case.
  8. Whole exome sequencing-based homologous recombination deficiency test for epithelial ovarian cancer.
  9. Radiotherapy(R) Integration(I) Strategy for Small(S)-Cell Lung Cancer in Extensive(E) Stage (RISE) with up to 10 metastases- a study protocol of a randomized phase II trial.
  10. Pembrolizumab as first-line treatment for recurrent and metastatic head and neck cancer - real-world single-centre data.
  11. Comprehensive evaluation of genomic and functional assays for homologous recombination deficiency with high-grade epithelial ovarian cancer: Platinum sensitivity and prognosis.
  12. Retraction Note: Integration of virtual reality in neurosurgical training and planning: current developments.
  13. Rebiopsy Enhances Survival with Afatinib vs. Osimertinib in EGFR Exon 19 Deletion Non-Small Cell Lung Cancer: A Multicenter Study in Taiwan.
  14. An open-label, phase IB/II study of abemaciclib with paclitaxel for tumors with CDK4/6 pathway genomic alterations.
  15. Liquid biopsy for diagnosing epithelial ovarian cancer: quantification of cell-free DNA and p53 mutational analysis.
  16. Differential response to immunotherapy in different lesions of MSI-H double primary colorectal cancer: a case report and literature review.
  17. Dihydropyrimidine enzyme activity and its effect on chemotherapy toxicity: importance of genetic testing.
  18. Adjuvant Atezolizumab for Early Triple-Negative Breast Cancer: The ALEXANDRA/IMpassion030 Randomized Clinical Trial.
  1. Genes (Basel). 2025 Jan 09. pii: 71. [Epub ahead of print]16(1):
    Liquid Biopsy and Challenge of Assay Heterogeneity for Minimal Residual Disease Assessment in Colon Cancer Treatment.
    Giovanni Crisafulli.
      This review provides a comprehensive overview of the evolving role of minimal residual disease (MRD) for patients with Colon Cancer (CC). Currently, the standard of care for patients with non-metastatic CC is adjuvant chemotherapy (ACT) for all patients with stage III and high-risk stage II CC following surgical intervention. Despite a 5-20% improvement in long-term survival outcomes, this approach also results in a significant proportion of patients receiving ACT without any therapeutic benefit and being unnecessarily exposed to the risks of secondary side effects. This underscores an unmet clinical need for more precise stratification to distinguish patients who necessitate ACT from those who can be treated with surgery alone. By employing liquid biopsy, it is possible to discern MRD enabling the categorization of patients as MRD-positive or MRD-negative, potentially revolutionizing the management of ACT. This review aimed to examine the heterogeneity of methodologies currently available for MRD detection, encompassing the state-of-the-art technologies, their respective advantages, limitations, and the technological challenges and multi-omic approaches that can be utilized to enhance assay performance. Furthermore, a discussion was held regarding the clinical trials that employ an MRD assay focusing on the heterogeneity of the assays used. These differences in methodology, target selection, and performance risk producing inconsistent results that may not solely reflect biological/clinical differences but may be the consequence of the preferential use of particular products in studies conducted in different countries. Standardization and harmonization of MRD assays will be crucial to ensure the liquid revolution delivers reliable and clinically actionable outcomes for patients.
    Keywords:  colorectal cancer; ctDNA; liquid biopsy; minimal residual disease; precision oncology
    DOI:  https://doi.org/10.3390/genes16010071
  2. J Surg Oncol. 2025 Jan 25.
    Circulating Tumor DNA as a Marker of Recurrence Risk in Stage III Colorectal Cancer: The α-CORRECT Study.
    Exact Sciences MRD Group
       BACKGROUND AND OBJECTIVES: Identification of colorectal cancer (CRC) patients at high risk of recurrence could be of substantial clinical use. We evaluated the association of ctDNA status, using a tumor-informed assay, with recurrence-free survival (RFS).
    METHODS: Stage III CRC patients were enrolled between 2016 and 2020. Tumor tissue and serial (every 3 months for years 1-3, biannually for years 4-5) blood samples were collected. Utilizing whole-exome sequencing and selection of 50-200 variants for tumor informed assays, ctDNA status was determined using plasma cell-free DNA.
    RESULTS: Of 137 patients enrolled, 124 with 1029 ctDNA results were included in the analyses. Median follow-up was 4.8 years. Plasma ctDNA status was strongly associated with risk of recurrence during the surveillance period (hazard ratio (HR) 49.6, 95% CI: 16.6-148.3; p < 0.0001), and at the postsurgical (HR 9.6, 95% CI: 3.2-29.5) and postdefinitive therapy timepoints (HR: 16.7, 95% CI: 6.9-40.3). The estimated 3-year RFS for ctDNA positive and ctDNA negative patients were, respectively, 54.5% and 96.1% after surgery, and 18.2% and 90.0% after definitive therapy. Multivariable analysis indicated ctDNA but not CEA was strongly prognostic for recurrence.
    CONCLUSIONS: Our tumor-informed ctDNA assay was strongly prognostic for recurrence in patients with stage III colorectal cancer at all timepoints.
    Keywords:  colorectal cancer; ctDNA; molecular residual disease (MRD); tumor‐informed
    DOI:  https://doi.org/10.1002/jso.27989
  3. Eur J Surg Oncol. 2025 Jan 21. pii: S0748-7983(25)00053-8. [Epub ahead of print]51(5): 109625
    Clinical value of preoperative circulating tumor DNA before surgery in patients with esophageal squamous cell carcinoma.
    Ryota Kobayashi, Satoru Matsuda, Kohei Nakamura, Hirofumi Kawakubo, Keiso Ho, Yosuke Morimoto, Kazuhiko Hisaoka, Yuki Hoshi, Masashi Takeuchi, Kazumasa Fukuda, Jun Okui, Hiroshi Nishihara, Yuko Kitagawa.
       INTRODUCTION: A precise preoperative tumor monitoring method that reflects tumor burden during neoadjuvant treatment is required to guide individualized perioperative treatment strategies for esophageal squamous cell carcinoma (ESCC). This study examined the clinical significance of preoperative circulating tumor DNA (ctDNA) in the plasma of patients undergoing neoadjuvant chemotherapy (NAC) followed by esophagectomy.
    MATERIALS AND METHODS: Plasma samples were collected longitudinally for ctDNA analysis as well as genomic DNA from primary lesions from patients with histologically confirmed ESCC who received neoadjuvant chemotherapy (NAC) followed by subtotal esophagectomy. Next-generation sequencing was used to identify mutations in both the plasma and primary tumors. We evaluated the relationship between ctDNA alterations and recurrence in patients with locally advanced ESCC.
    RESULTS: Pretreatment samples from 25 patients (100 %) showed the same mutations in both ctDNA and primary tumors; therefore, they were classified as ctDNA-positive before treatment. In the cohort of 25 patients analyzed, those who tested positive for ctDNA after NAC had a significantly higher risk of recurrence; the 36-month recurrence-free survival rates were 92 % for ctDNA-negative patients and 8 % for ctDNA-positive patients (p < 0.001).
    CONCLUSIONS: Preoperative ctDNA status may be a promising prognostic biomarker that can be assessed before surgery in patients with ESCC who received NAC. Expanded cohort validation will allow for more personalized multidisciplinary treatment approaches for ESCC tailored to ctDNA analysis.
    Keywords:  Circulating tumor DNA; Esophageal squamous cell carcinoma; Liquid biopsy; Neoadjuvant chemotherapy
    DOI:  https://doi.org/10.1016/j.ejso.2025.109625
  4. Int J Mol Sci. 2025 Jan 13. pii: 611. [Epub ahead of print]26(2):
    Circulating Tumor Cell-Free DNA as Prognostic Biomarker in Non-Small Cell Lung Cancer Patients Undergoing Immunotherapy: The CORELAB Experience.
    Stefania Gelmini, Adele Calabri, Irene Mancini, Camilla Eva Comin, Valeria Pasini, Marco Banini, Vieri Scotti, Pamela Pinzani.
      The expression level of Programmed Death-Ligand 1 (PD-L1) determined by the immunohistochemical method is currently approved to test the potential efficacy of immune-checkpoint inhibitors and to candidate patients with Non-Small Cell Lung Cancer (NSCLC) for treatment with immunotherapeutic drugs. As part of the CORELAB (New prediCtivebiOmaRkers of activity and Efficacy of immune checkpoint inhibitors in advanced non-small cell Lung cArcinoma) project, aimed at identifying new predictive and prognostic biomarkers in NSCLC patients receiving immunotherapeutic drugs, we investigated the role of circulating tumor DNA (ctDNA) molecular characterization as an additional predictive biomarker. We analyzed plasma ctDNA by targeted Next Generation Sequencing in a subset of 50 patients at different time points. ctDNA content was inversely correlated with the clinical outcome both at a baseline and after 2 months of treatment. OS was significantly higher in patients with ≥50% ctDNA reduction. TP53 and KRAS were the most frequently mutated genes, and patients with KRAS and/or TP53 mutations showed worse outcomes than patients without detectable variants or with mutations in other genes. Fewer common variants were found in BRAF, EGFR, MAP2K1, MET, NRAS, and PIK3CA genes. Our data demonstrated that molecular characterization of ctDNA and also its quantitative evaluation could serve as a dynamic, real-time prognostic, and predictive biomarker, enabling regular molecular monitoring of therapy efficacy in support of other medical examinations.
    Keywords:  NGS; NSCLC; PD-L1; immunotherapy; liquid biopsy; prognostic biomarkers
    DOI:  https://doi.org/10.3390/ijms26020611
  5. JCI Insight. 2025 Jan 30. pii: e186062. [Epub ahead of print]
    Multimodal integration of blood RNA and ctDNA reflects response to immunotherapy in metastatic urothelial cancer.
    Sandra van Wilpe, Davide Croci, Sara S Fonseca Costa, Iris Baw Te Paske, Sofie H Tolmeijer, Jolique van Ipenburg, Leonie I Kroeze, Simona Pavan, Sylvain Monnier-Benoit, Guido Coccia, Noushin Hadadi, Irma M Oving, Tineke J Smilde, Theo van Voorthuizen, Marieke Berends, Mira D Franken, Marjolijn Jl Ligtenberg, Sahar Hosseinian Ehrensberger, Laura Ciarloni, Pedro Romero, Niven Mehra.
       BACKGROUND: Previously, we demonstrated that changes in circulating tumor DNA (ctDNA) are promising biomarkers for early response prediction (ERP) to immune checkpoint inhibitors (ICI) in metastatic urothelial cancer (mUC). In this study, we investigated the value of whole blood immunotranscriptomics for ERP-ICI and integrated both biomarkers into a multimodal model to boost accuracy.
    METHODS: Blood samples of 93 patients were collected at baseline and after 2-6 weeks of ICI for ctDNA (N=88) and immunotranscriptome (N=79) analyses. ctDNA changes were dichotomized into increase or no increase, the latter including patients with undetectable ctDNA. For RNA model development, the cohort was split into a discovery (N=29), test (N=29) and validation set (N=21). Finally, RNA- and ctDNA-based predictions were integrated in a multimodal model. Clinical benefit (CB) was defined as progression-free survival beyond 6 months.
    RESULTS: Sensitivity (SN) and specificity (SP) of ctDNA increase for predicting non-CB (N-CB) was 59% and 92%, respectively. Immunotranscriptome analysis revealed upregulation of T-cell activation, proliferation and interferon signalling during treatment in the CB group, contrary to N-CB patients. Based on these differences a 10-gene RNA model was generated, reaching a SN and SP of 73% and 79% in the test and 67% and 67% in the validation set for predicting N-CB. Multimodal model integration led to superior performance with a SN and SP of 79% and 100% in the validation cohort.
    CONCLUSION: The combination of whole blood immunotranscriptome and ctDNA in a multimodal model showed promise for ERP-ICI in mUC and accurately identified patients with N-CB.
    TRIAL REGISTRATION: 2016-3060, 2020-6778FUNDING. Eurostars grant E! 114908 - PRECISE, Paul Speth Foundation (Bullseye project).
    Keywords:  Bioinformatics; Cancer immunotherapy; Immunology; Oncology; Urology
    DOI:  https://doi.org/10.1172/jci.insight.186062
  6. J Mol Diagn. 2025 Feb;pii: S1525-1578(24)00307-6. [Epub ahead of print]27(2): 119-129
    Analytical and Clinical Validation of the Plasma-Based Guardant360 CDx Test for Assessing HER2 (ERBB2) Mutation Status in Patients with Non-Small-Cell Lung Cancer for Treatment with Trastuzumab Deruxtecan in DESTINY-Lung01/02.
    Zhenhao Qi, Shinya Tokuhiro, Justin I Odegaard, Sara Wienke, Maha Karnoub, Wenqin Feng, Ryota Shiga, Egbert F Smit, Yasushi Goto, Adrianus J De Langen, Koichi Goto, Kaline Pereira, Shirin Khambata-Ford.
      This study demonstrates the analytical and clinical validity of the approved (United States and Japan) plasma-based Guardant360 companion diagnostic (CDx) test for selecting patients with human epidermal growth factor receptor 2 (HER2 [ERBB2])-mutated (HER2m) non-small-cell lung cancer (NSCLC) for trastuzumab deruxtecan (T-DXd) treatment. Concordance between the Guardant360 CDx test and the plasma-based AVENIO ctDNA Expanded Kit Assay (AVENIO), as well as the tissue-based clinical trial assays (CTAs) was investigated. Clinical utility was assessed by comparing T-DXd clinical efficacy results of patients in DESTINY-Lung01/02 who tested positive for HER2 mutations using the Guardant360 CDx test to benchmark efficacy results from DESTINY-Lung01/02. Finally, concordance between the Guardant360 CDx test and the tissue-based Oncomine Dx Target (ODxT) test was explored. High concordance was observed between the Guardant360 CDx test versus AVENIO [positive percent agreement (PPA), 98.8%; negative percent agreement (NPA), 91.5%] and CTAs (DESTINY-Lung01 Cohort 2-PPA, 91.0%; NPA, 100%; DESTINY-Lung02 arm 1-PPA, 86.0%; NPA, 100%). Confirmed objective response rates were similar in patients with HER2m NSCLC identified by the Guardant360 CDx test and by CTAs. There was a high level of agreement between the Guardant360 CDx test and the ODxT test. The Guardant360 CDx test demonstrated analytical and clinical validity for identifying patients with HER2m NSCLC for T-DXd therapy; results support plasma-based testing when tissue-based testing is not feasible.
    DOI:  https://doi.org/10.1016/j.jmoldx.2024.11.006
  7. Front Oncol. 2024 ;14 1500449
    Case report: Selpercatinib in the treatment of RET fusion-positive advanced lung adenocarcinoma: a challenging clinical case.
    Raffaella Pagliaro, Paola Maria Medusa, Fabiana Vitiello, Luigi Aronne, Susan F M Campbell, Fabio Perrotta, Andrea Bianco.
       Background: Rearranged during transfection (RET) fusions represent a distinct molecular subset of non-small cell lung cancer (NSCLC) with targeted therapeutic potential. Selpercatinib, a highly selective RET inhibitor, has demonstrated efficacy in various solid tumors harboring RET alterations. Here, we present a case highlighting the use and clinical outcomes of selpercatinib in a patient diagnosed with advanced lung adenocarcinoma harboring a RET fusion.
    Case presentation: A 59-year-old woman with a history of stage IV lung adenocarcinoma harboring a KIF5B-RET fusion presented with disease progression following first-line chemo-immunotherapy. Selpercatinib was initiated as a targeted therapy, leading to a notable radiographic response and clinical improvement. The patient experienced a significant reduction in tumor burden and reported improved symptom control, with no significant adverse effects during the 21-month follow-up period.
    Conclusions: This case highlights the efficacy and tolerability of selpercatinib in treating advanced lung adenocarcinoma with a RET fusion. The observed clinical response supports the early use of selpercatinib as a targeted therapy for RET fusion-positive NSCLC, including in patients with compromised general and respiratory conditions, especially in cases refractory to conventional treatments. Long-term follow-up studies are warranted to validate these findings and assess the durability of responses.
    Keywords:  RET fusion; lung adenocarcinoma; precision medicine; selpercatinib; targeted therapy
    DOI:  https://doi.org/10.3389/fonc.2024.1500449
  8. J Ovarian Res. 2025 Jan 30. 18(1): 19
    Whole exome sequencing-based homologous recombination deficiency test for epithelial ovarian cancer.
    Ying-Cheng Chiang, Hsien-Neng Huang, Kuan-Ting Kuo, Wuh-Liang Hwu, Po-Han Lin.
       BACKGROUND: The homologous recombination deficiency (HRD) test is an important tool for identifying patients with epithelial ovarian cancer (EOC) benefit from the treatment with poly(adenosine diphosphate-ribose) polymerase inhibitor (PARPi). Using whole exome sequencing (WES)-based platform can provide information of gene mutations and HRD score; however, the clinical value of WES-based HRD test was less validated in EOC.
    METHODS: We enrolled 40 patients with EOC in the training cohort and 23 in the validation cohort. The WES-based HRD score was calculated using the scarHRD software. We first evaluated the concordance of the HRD status defined by the Myriad MyChoice CDx and then assessed the value of HRD on clinical prognosis in patients with EOC.
    RESULTS: The HRD score defined by the WES-based test was positively correlated with that of the Myriad MyChoice® CDx test (r = 0.82, p < 0.01) in the training cohort. In compared to HRD status of Myriad test, the sensitivity, specificity, positive predictive value, and negative predictive value of the WES-based HRD test were 93.5% (29/31), 77.8% (7/9), 93.5% (29/31), and 77.8% (7/9), respectively. Patients with positive HRD status defined by WES-based scarHRD test and Myriad MyChoice® CDx test were both highly associated with platinum sensitive response (both Fisher's exact test, p = 0.002) as well as the superior progression-free survival (both log-rank p = 0.002). The multi-variate Cox regression model incorporated with optimal debulking surgery showed that the recurrence risk was decreased in the patients with positive HRD status, either defined by Myriad MyChoice® CDx test (Hazard ratio (HR) 0.33, 95% confidence interval (CI) 0.14-0.79, p = 0.013) or WES-based test Myriad MyChoice® CDx test (HR 0.34, 95% CI 0.14-0.80, p = 0.014). Nine patients had mutations in the genes involved in HR DNA repair, and all of them were positive for HRD. In the validation group, 23 patients were defined as positive HRD by WES-based testing. Six positive HRD patients and 5 negative HRD patients received maintenance PARPi. The median responsive interval of PARPi was 17 months in positive HRD patients and 3 months in negative HRD patients.
    CONCLUSION: The WES-based test is a potential option for determining the HRD status in EOC patients, and desires for further validation in large-scale cohorts.
    Keywords:  Epithelial ovarian cancer; Homologous recombination deficiency test; Whole-exome sequencing; scarHRD
    DOI:  https://doi.org/10.1186/s13048-024-01565-3
  9. BMC Cancer. 2025 Jan 24. 25(1): 142
    Radiotherapy(R) Integration(I) Strategy for Small(S)-Cell Lung Cancer in Extensive(E) Stage (RISE) with up to 10 metastases- a study protocol of a randomized phase II trial.
    Łukasz Kuncman, Jacek Fijuth, Damian Tworek, Ewa Sierko, Paweł Cisek, Michał Masłowski, Maja Lisik-Habib, Magdalena Orzechowska, Katarzyna Galwas-Kliber, Adam Antczak, Izabela Chmielewska, Barbara Ziółkowska, Marta Kurczewska-Michalak, Wojciech Kuźnicki, Nina Jędrzejczak, Kinga Ranoszek, Mateusz Bilski.
       BACKGROUND: The current standard of care (SoC) for patients with extensive-disease small-cell lung cancer (ED-SCLC) is chemo-immunotherapy. The efficacy of radiotherapy (RT) for chest consolidation has been established for patients with ED-SCLC who have responded to chemotherapy. There is a lack of data on incorporating RT as chest consolidation and metastasis-directed therapy for ED-SCLC. The RISE (Radiotherapy for Extensive-Stage Small-Cell Lung Cancer) study aims to evaluate the effectiveness of different RT strategies for residual lesions for patients with ED-SCLC who receive chemo-immunotherapy.
    METHODS: A total of 165 patients with ED-SCLC will be recruited, with 55 patients assigned to each of the three study arms. Patients with stabilization or partial regression, according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, during chemo-immunotherapy will be included. • Arm I will serve as the control group, comprising patients who continue SoC of programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1) immunotherapy (durvalumab or atezolizumab) following platinum-based chemo-immunotherapy. • Arm II will receive the SoC with consolidative RT to the chest area and potentially, according to palliative indications to metastatic lesions, delivered in 30 Gy in 3-Gy fractions. • Arm III will receive SoC with RT of 45 Gy in 3-Gy fractions to the chest area and stereotactic body radiotherapy (SBRT) with 24 Gy in 8-Gy fractions to the metastatic lesions. Blood samples for circulating tumor DNA (ctDNA) will be collected before RT, during each week of treatment, and at the time of disease progression. The primary endpoint is progression-free survival (PFS) based on RECIST 1.1 or patient death. 1. Secondary endpoints are OS, treatment toxicity (frequency of G3 toxicity according to CTCAE v.5.0), area of progression (primary tumor localization/new lesions), Overall response rate (ORR), and the response rate in non-irradiated lesions.
    DISCUSSION: The study population of patients with ED-SCLC has a poor prognosis. Dose-escalated chest RT and SBRT (for up to 10 metastases) administered with modern techniques offer the possibility to improve OS and PFS.
    TRIAL REGISTRATION: Clinicaltrials.gov NCT06529081 (Registered 26th Jul 2024).
    Keywords:  Chemotherapy; Immunotherapy; Lung cancer; Oligometastatic disease; Radiotherapy
    DOI:  https://doi.org/10.1186/s12885-025-13552-y
  10. Acta Oncol. 2025 Jan 28. 64 143-146
    Pembrolizumab as first-line treatment for recurrent and metastatic head and neck cancer - real-world single-centre data.
    Bogdana Patachi, Kristian H Jensen, Anita Gothelf, Mogens Bernsdorf, Jeppe Friborg, Claus A Kristensen.
       BACKGROUND AND PURPOSE: The randomised clinical trial KEYNOTE-048 has demonstrated a significant increase in survival for patients with head and neck cancer treated with pembrolizumab with or without chemotherapy. The purpose of the present retrospective study was to investigate whether survival in a group of consecutive patients treated at our department was comparable to the results from KEYNOTE-048.
    PATIENTS/MATERIAL AND METHODS: Seventy-six patients initiated treatment with pembrolizumab ± platinum/5-FU between July 2020 and May 2022. Baseline characteristics were collected, response rates and survival times were calculated and compared to those published from KEYNOTE-048.
    RESULTS AND INTERPRETATION: Fifty-one percent of patients had locoregional recurrence and 47% had distant metastases. Median progression-free survival was 5.5 months, and median overall survival (OS) was 12.3 months in the total cohort. OS was significantly higher for patients with combined positive score (CPS) ≥20 (14.6 months) than for patients with CPS 1-19 (7.3 months) (p = 0.04). There was no significant difference in survival times between patients ± 65 years of age or between patients with locoregional disease versus distant metastases. In conclusion, the results from KEYNOTE-048 were corroborated in a consecutive cohort of patients treated at Rigshospitalet, Copenhagen, Denmark.
    DOI:  https://doi.org/10.2340/1651-226X.2025.42128
  11. Int J Gynecol Cancer. 2025 Jan;pii: S1048-891X(24)01979-0. [Epub ahead of print]35(1): 100031
    Comprehensive evaluation of genomic and functional assays for homologous recombination deficiency with high-grade epithelial ovarian cancer: Platinum sensitivity and prognosis.
    Zheng Feng, Changbin Zhu, Xiaotian Zhang, Zhan Huang, Xingzhu Ju, Qinhao Guo, Xing Li, Xiaohua Wu, Hao Wen.
       OBJECTIVE: Homologous recombination deficiency assays, guiding treatment of poly (adenosine diphosphate ribose) polymerase inhibitors, are increasingly applied in clinics. This study aimed to evaluate the predictive performance of homologous recombination deficiency status at genomic and functional perspective on the efficacy of platinum-based chemotherapy in ovarian cancer.
    METHODS: Between 2016 and 2019, 134 patients with high-grade ovarian cancer were retrospectively analyzed. Formalin-fixed paraffin-embedded tissues were subjected to DNA sequencing using the AmoyDx HRD Complete Panel. The genomic scar score and the genomic instability score were calculated based on copy number variation events. Furthermore, the RAD51 and SLFN11 protein levels in tumors were assessed by immunohistochemistry.
    RESULTS: Of all patients, 106 of 134 (79.1%) were homologous recombination deficiency (genomic scar score)-positive, with a higher platinum sensitivity rate than those who were homologous recombination deficiency (genomic scar score)-negative (78.3% vs 57.1%, p = .023). Similarly, 104 of 134 (77.6%) were homologous recombination deficiency (genomic instability score)-positive, with increased platinum sensitivity compared with homologous recombination deficiency (genomic instability score)-negative (77.9% vs 60.0%, p = .049). The overall concordance rate of homologous recombination deficiency status defined by the 2 scores was 98.5%. Genomic scar score and genomic instability score determined homologous recombination deficiency-positive statuses correlated with better progression-free survival (p = .0019, p = .0041) and overall survival (p = .018, p = .031). Patients with nuclear RAD51-loss or SLFN11-positive expression were likely to be homologous recombination deficiency-positive by genomic scar score/genomic instability score (94.1% and 97.6%; 94.1% and 95.2%, respectively). Patients with nuclear RAD51-loss and SLFN11-positive expression had better overall survival than those with RAD51-positive and SLFN11-negative expression. Among homologous recombination deficiency statuses, RAD51 and SLFN11 expressions, homologous recombination deficiency (genomic scar score)-positive was most associated with progression-free survival and platinum sensitivity. Multivariate regression analysis showed that homologous recombination deficiency (genomic scar score)-positive status was a good prognostic factor, implying a higher possibility of platinum sensitivity.
    CONCLUSION: Genomic scar score, given by AmoyDx HRD Complete Panel, was most associated with the efficacy of platinum treatment in patients with high-grade ovarian cancer. Validation is warranted via prospective studies.
    Keywords:  RAD51; genomic scar score; homologous recombination deficiency; ovarian cancer; platinum sensitivity; survival
    DOI:  https://doi.org/10.1016/j.ijgc.2024.100031
  12. Neurosurg Rev. 2025 Jan 31. 48(1): 146
    Retraction Note: Integration of virtual reality in neurosurgical training and planning: current developments.
    Mayur Wanjari, Gaurav Mittal, Roshan Prasad, Lakshya Choudhary, Tangmi Djabo Eric Adrien.
      
    DOI:  https://doi.org/10.1007/s10143-025-03315-5
  13. Curr Oncol. 2025 Jan 10. pii: 36. [Epub ahead of print]32(1):
    Rebiopsy Enhances Survival with Afatinib vs. Osimertinib in EGFR Exon 19 Deletion Non-Small Cell Lung Cancer: A Multicenter Study in Taiwan.
    Jerry Shu-Hung Kuo, Cheng-Yu Chang, Shih-Chieh Chang, Yu-Feng Wei, Chung-Yu Chen.
       BACKGROUND: Afatinib and Osimertinib are first-line treatments for EGFR-mutated advanced non-small cell lung cancer (NSCLC), but their comparative efficacies and the patient groups that benefit the most remain unclear. This multicenter retrospective study evaluated the efficacy of first-line Afatinib and Osimertinib in NSCLC patients with EGFR 19del and no brain metastases at diagnosis.
    METHODS: The primary endpoints were time on treatment (ToT) and overall survival (OS). Survival analyses were performed for three groups: Afatinib followed by Osimertinib, Afatinib followed by other therapies, and Osimertinib (alone or followed by other therapies). Rebiopsy practices, including T790M mutation detection, were also analyzed in patients with disease progression on Afatinib.
    RESULTS: Among 97 Afatinib-treated and 60 Osimertinib-treated patients, Osimertinib showed a significantly longer ToT (23.3 vs. 16.5 months; p = 0.007). Median OS was numerically higher for Afatinib with sequential Osimertinib (40.5 vs. 34.6 months for Osimertinib; p = 0.473). Osimertinib demonstrated advantages, with fewer brain metastases upon progression and fewer adverse effects. In the Afatinib group, 64% of patients with disease progression underwent rebiopsy, with 39% testing positive for T790M mutation and subsequently receiving Osimertinib. Rebiopsy was most frequently performed on the lung parenchyma using non-surgical methods.
    CONCLUSIONS: In this real-world study, Osimertinib achieved a significantly longer ToT compared to Afatinib in NSCLC patients with EGFR 19del and no brain metastases. The sequential use of Afatinib followed by Osimertinib showed a trend toward improved OS, highlighting the importance of rebiopsy for identifying T790M mutations to guide subsequent therapy.
    Keywords:  Afatinib; EGFR mutation; Osimertinib; lung cancer; rebiopsy
    DOI:  https://doi.org/10.3390/curroncol32010036
  14. ESMO Open. 2025 Jan 27. pii: S2059-7029(24)01877-5. [Epub ahead of print]10(2): 104106
    An open-label, phase IB/II study of abemaciclib with paclitaxel for tumors with CDK4/6 pathway genomic alterations.
    K H Kim, C Park, S-H Beom, M H Kim, C G Kim, H R Kim, M Jung, S J Shin, S Y Rha, H S Kim.
       BACKGROUND: Disruption of cyclin D-dependent kinases (CDKs), particularly CDK4/6, drives cancer cell proliferation via abnormal protein phosphorylation. This open-label, single-arm, phase Ib/II trial evaluated the efficacy of the CDK4/6 inhibitor, abemaciclib, combined with paclitaxel against CDK4/6-activated tumors.
    PATIENTS AND METHODS: Patients with locally advanced or metastatic solid tumors with CDK4/6 pathway aberrations were included. Based on phase Ib, the recommended phase II doses were determined as abemaciclib 100 mg twice daily and paclitaxel 70 mg/m2 on days 1, 8, and 15, over 4-week-long cycles. The primary endpoint for phase II was the overall response rate (ORR). The secondary endpoints included the clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety. Tissue-based next-generation sequencing and exploratory circulating tumor DNA analyses were carried out.
    RESULTS: Between February 2021 and April 2022, 30 patients received abemaciclib/paclitaxel (median follow-up: 15.7 months), and 27 were included in the efficacy analysis. CDK4/6 amplification (50%) and CCND1/3 amplification (20%) were common activating mutations. The ORR was 7.4%, with two partial responses, and the CBR was 66.7% (18/27 patients). The median OS and PFS were 9.9 months [95% confidence interval (CI) 5.7-14.0 months] and 3.5 months (95% CI 2.6-4.3 months), respectively. Grade 3 adverse events (50%, 21 events) were mainly hematologic. Genetic analysis revealed a 'poor genetic status' subgroup characterized by mutations in key signaling pathways (RAS, Wnt, PI3K, and NOTCH) and/or CCNE amplification, correlating with poorer PFS.
    CONCLUSION: Abemaciclib and paclitaxel showed moderate clinical benefits for CDK4/6-activated tumors. We identified a poor genetic group characterized by bypass signaling pathway activation and/or CCNE amplification, which negatively affected treatment response and survival. Future studies with homogeneous patient groups are required to validate these findings.
    Keywords:  CDK4/6; abemaciclib; paclitaxel
    DOI:  https://doi.org/10.1016/j.esmoop.2024.104106
  15. Int J Gynecol Cancer. 2025 Jan;pii: S1048-891X(24)01493-2. [Epub ahead of print]35(1): 100022
    Liquid biopsy for diagnosing epithelial ovarian cancer: quantification of cell-free DNA and p53 mutational analysis.
    Shalini Rajaram, Aanchal Varma, Bindiya Gupta, Rajarshi Kar, Vinod Kumar Arora, Sandhya Jain, Lakhwinder Singh.
       OBJECTIVE: To isolate and quantify cell-free DNA, analysis for p53 mutations, and correlation with tumor burden in women with epithelial ovarian cancer compared with benign and borderline epithelial ovarian tumors.
    METHODS: In this case-control study, plasma samples of eligible women collected 1 hour before surgery and based on final histopathology, women with epithelial ovarian cancer recruited as cases and borderline, and benign ovarian tumors as controls. Cell-free DNA extracted from plasma serum and quantified using Nanodrop Spectrophotometer. Amplification refractory mutation system-based polymerase chain reaction was used to detect point mutation in exon 8, codon 239 of p53 using primer pairs. p53 immunostaining was performed on tissue samples.
    RESULTS: A total of 40 women (20 cases of epithelial ovarian cancer and 10 each of benign and borderline ovarian tumors [controls]) were included in a 2:1:1 ratio. The mean cell-free DNA amount was 1330 ± 1705.4 ng/mL in women with epithelial ovarian cancer compared with 748.5 ± 444.8 and 448.5 ± 203.9 ng/mL in benign and borderline ovarian tumors, respectively (p = .023). In those with high-grade serous ovarian cancer, it was 2640 ± 2450.6 ng/mL compared with 600 ± 316.7 and 652.5 ± 158.9 ng/mL in low-grade serous and mucinous ovarian cancer, respectively (p = .006). In stage I and II ovarian cancer, these were 502.5 ± 134.4 and 330 ± 296.9 ng/mL, respectively, compared with 1655 ± 1924.8 ng/mL in stage III disease (p = .004). A total of 11 (55%) women with epithelial ovarian cancer harbored mutation in exon 8, codon 239 of p53 compared with 2 (20%) each in benign and borderline ovarian tumors (p = 0.07). Fair agreement was noted between cell-free DNA p53 mutation and abnormal tissue p53 staining on immunohistochemistry (κ = 0.41).
    CONCLUSION: Cell-free DNA amount was higher in women with epithelial ovarian cancer than women with benign and borderline ovarian tumors, with higher levels in advanced stage and high-grade serous carcinoma sub-type. Cell-free DNA p53 mutational analysis yielded fair concordance with tumor tissue p53 immunohistochemical results.
    Keywords:  Carcinoma; Ovarian Cancer; Ovarian Epithelial; Pathology; Surgery
    DOI:  https://doi.org/10.1016/j.ijgc.2024.100022
  16. AME Case Rep. 2025 ;9 17
    Differential response to immunotherapy in different lesions of MSI-H double primary colorectal cancer: a case report and literature review.
    Zhigui Guo, Dan Hong, Yaning Wei, Yue Huo, Shenyong Su, Yan Shi, Lin An, Kunjie Wang, Yajing Su, Zhiyu Wang.
       Background: Mucinous adenocarcinoma is a rare type of colorectal cancer (CRC) associated with poor prognosis, particularly when it includes signet ring cell components. Furthermore, its rate of microsatellite instability-high (MSI-H) is significantly higher compared to non-mucinous adenocarcinoma. Immunotherapy has emerged as the standard treatment for MSI-H metastatic CRC (mCRC). In the KEYNOTE-177 trial, for individuals with advanced CRC exhibiting MSI-H or mismatch repair deficiency (dMMR), treatment with pembrolizumab as a single agent demonstrated a superior outcome compared to standard systemic chemotherapy. The study revealed a notably higher objective response rate (43.8% versus 33.1%) and an extended progression-free survival duration (16.5 versus 8.2 months). These findings imply that pembrolizumab may be regarded as a front-line treatment option for patients with advanced CRC who have MSI-H/dMMR status.
    Case Description: The patient with double primary CRC, both of which were identified as MSI-H through next generation sequencing (NGS). Following a regimen of immunotherapy-based combination therapy, the rectal lesion achieved a complete clinical response (cCR), while the colon lesion displayed continued progression, indicating primary resistance to treatment.
    Conclusions: Specific histological subtypes of CRC, such as mucinous adenocarcinoma, might adversely affect the efficacy of immunotherapy, resulting in primary treatment resistance. Consequently, in the case of this particular cancer subtype, local surgical resection may be a more appropriate treatment strategy.
    Keywords:  Colorectal cancer (CRC); case report; immunotherapy; microsatellite instability-high (MSI-H); mucinous adenocarcinoma
    DOI:  https://doi.org/10.21037/acr-24-137
  17. Cancer Chemother Pharmacol. 2025 Jan 18. 95(1): 26
    Dihydropyrimidine enzyme activity and its effect on chemotherapy toxicity: importance of genetic testing.
    Alexia Shamaei Zadeh, Danielle Roberts, Abby Williams, Deepali Pandey, John L Villano.
       PURPOSE: Patients with partial or complete DPD deficiency have decreased capacity to degrade fluorouracil and are at risk of developing toxicity, which can be even life-threatening.
    CASE: A 43-year-old man with moderately differentiated rectal adenocarcinoma on capecitabine presented to the emergency department with complaints of nausea, vomiting, diarrhea, weakness, and lower abdominal pain for several days. Laboratory findings include grade 4 neutropenia (ANC 10) and thrombocytopenia (platelets 36,000). Capecitabine is used as a component of first-line adjuvant therapy by approximately 2 million patients worldwide each year. Capecitabine is metabolized to fluorouracil via the enzyme dihydropyrimidine dehydrogenase (DPD). With worsening pancytopenia and diarrhea, genetic testing for DPD deficiency was sent. Prompt treatment with uridine triacetate was initiated for presumed DPD deficiency. Unfortunately, he passed away from an infectious complication and was later confirmed to have a heterozygous DPYD*2A mutation.
    DISCUSSION: Our case demonstrates uneven testing guidelines for DPD prior to initiating 5-FU chemotherapy, appropriateness of treating with uridine triacetate, and analysis of next-generation sequencing (NGS) on tumor samples and co-incidentally obtaining germline DPD deficiency status. Our case also highlights the severe clinical impact of having DPD deficiency even with early uridine triacetate therapy.
    CONCLUSION: It is our recommendation to perform DPD deficiency in curative intent cancer treatment and this information can increasingly be obtained in standard tumor NGS profiling, a growing norm in medical oncology.
    Keywords:  5-Fluorouracil; Capecitabine; Chemotoxicity; DPYD*2A mutation; Dihydropyrimidine dehydrogenase
    DOI:  https://doi.org/10.1007/s00280-024-04740-x
  18. JAMA. 2025 Jan 30.
    Adjuvant Atezolizumab for Early Triple-Negative Breast Cancer: The ALEXANDRA/IMpassion030 Randomized Clinical Trial.
    Michail Ignatiadis, Andrew Bailey, Heather McArthur, Sarra El-Abed, Evandro de Azambuja, Otto Metzger, Stephen Y Chui, Max Dieterich, Thomas Perretti, Esther Shearer-Kang, Luciana Molinero, Günther G Steger, Jacek Jassem, Soo Chin Lee, Michaela Higgins, Jose Zarba, Marcus Schmidt, Henry Gomez, Angel Guerrero Zotano, Luca Moscetti, Joanne Chiu, Elisabetta Munzone, Noa Efrat Ben-Baruch, Emilio Bajetta, Shinji Ohno, Seock-Ah Im, Gustavo Werutsky, Einav Nili Gal-Yam, Xavier Gonzalez Farre, Ling-Ming Tseng, William Jacot, Oleg Gluz, Zhimin Shao, Yaroslav Shparyk, Anastasia Zimina, Eric Winer, David A Cameron, Giuseppe Viale, Shigehira Saji, Richard Gelber, Martine Piccart.
       Importance: Triple-negative breast cancer is an aggressive subtype with a high incidence in young patients, a high incidence in non-Hispanic Black women, and a high risk of progression to metastatic cancer, a devastating sequela with a 12- to 18-month life expectancy. Until recently, one strategy for treating early-stage triple-negative breast cancer was chemotherapy after surgery. However, it was not known whether the addition of immune therapy to postsurgery chemotherapy would be beneficial.
    Objective: To evaluate the addition of immune therapy in the form of atezolizumab to postoperative chemotherapy in patients with the high-risk triple-negative breast cancer subtype.
    Design, Setting, and Participants: In this open-label international randomized phase 3 trial conducted in more than 330 centers in 31 countries, patients undergoing surgery as initial treatment for stage II or III triple-negative breast cancer were enrolled between August 2, 2018, and November 11, 2022. The last patient follow-up was on August 18, 2023.
    Interventions: Patients were randomized (1:1) to receive standard chemotherapy for 20 weeks with (n = 1101) or without (n = 1098) the immune therapy drug atezolizumab for up to 1 year.
    Main Outcomes and Measures: The primary end point was invasive disease-free survival (time between randomization and invasive breast cancer in the same or opposite breast, recurrence elsewhere in the body, or death from any cause).
    Results: The median age of enrolled patients was 53 years and most self-reported as being of Asian or White race and neither Latino nor Hispanic ethnicity. The study independent data monitoring committee halted enrollment at 2199 of 2300 planned patients. All patients stopped atezolizumab following a planned early interim and futility analysis. The trial continued to a premature final analysis. With invasive disease-free survival events in 141 patients (12.8%) treated with atezolizumab-chemotherapy and 125 (11.4%) with chemotherapy alone (median follow-up, 32 months), the final stratified invasive disease-free survival hazard ratio was 1.11 (95% CI, 0.87-1.42; P = .38). Compared with chemotherapy alone, the regimen of atezolizumab plus chemotherapy was associated with more treatment-related grade 3 or 4 adverse events (54% vs 44%) but similar incidences of fatal adverse events (0.8% vs 0.6%) and adverse events leading to chemotherapy discontinuation. Chemotherapy exposure was similar in the 2 treatment groups.
    Conclusions and Relevance: The addition of the immune therapy drug atezolizumab to chemotherapy after surgery did not provide benefit among patients with triple-negative breast cancer who are at high risk of recurrent disease.
    Trial Registration: ClinicalTrials.gov Identifier: NCT03498716.
    DOI:  https://doi.org/10.1001/jama.2024.26886
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