bims-preonc Biomed News
on Precision oncology
Issue of 2025–01–12
thirteen papers selected by
Ankita Daiya, OneCell Diagnostics Inc.
  1. The promises and perils of circulating tumor DNA for monitoring immunotherapy response in non-small cell lung cancer.
  2. Comprehensive Genome Profiling-Initiated Tumor-Informed Circulating Tumor DNA Monitoring for Patients With Advanced Cancer.
  3. Comparative analysis of EGFR mutations in circulating tumor DNA and primary tumor tissues from lung cancer patients using BEAMing PCR.
  4. Longitudinal genomic profiling using liquid biopsies in metastatic nonsquamous NSCLC following first line immunotherapy.
  5. Diagnosis of Leptomeningeal Disease in Diffuse Midline Gliomas by Detection of H3F3A K27M Mutation in Circulating Tumor DNA of Cerebrospinal Fluid.
  6. Monitoring of Circulating Tumor DNA and Indication of De-Escalation Adjuvant Targeted Therapy for EGFR-Mutated NSCLC After Complete Resection.
  7. Treatment for low-grade and high-grade endometrial carcinoma after recurrence/relapse before the molecular targeted therapy era: A retrospective, propensity score-matched cohort study.
  8. Use of scalp cooling therapy in patients with breast or gynecological cancers undergoing chemotherapy may be associated with a higher risk of systemic recurrence.
  9. A Hitchhiker's Guide Toward CSF Biomarkers for Neuro-Oncology.
  10. Melanoma's New Frontier: Exploring the Latest Advances in Blood-Based Biomarkers for Melanoma.
  11. EML4-ALK-Positive Ovarian Cancer With Intracranial Metastasis Responds to Lorlatinib: A Case Report and Literature Review.
  12. Primary Intracranial Sarcoma, DICER1-Mutant, With Prominent Chondroid Differentiation: Case Report and Summary of Reported Patients in Literature.
  13. An acquired CCDC6::RET gene fusion as resistance mechanism for Osimertinib in exon 21 EGFR(L858R)-mutated non-small cell lung cancer and its successful management with Osimertinib and Selpercatinib: a case report and review of literature.
  1. Explor Target Antitumor Ther. 2024 ;5(6): 1365-1372
    The promises and perils of circulating tumor DNA for monitoring immunotherapy response in non-small cell lung cancer.
    Brandon Joseph Hebert, James Bradley.
      There has been a rapid expansion of immunotherapy options for non-small cell lung cancer (NSCLC) over the past two decades, particularly with the advent of immune checkpoint inhibitors. Despite the emerging role of immunotherapy in adjuvant and neoadjuvant settings though, relatively few patients will respond to immunotherapy which can be problematic due to expense and toxicity; thus, the development of biomarkers capable of predicting immunotherapeutic response is imperative. Due to the promise of a noninvasive, personalized approach capable of providing comprehensive, real-time monitoring of tumor heterogeneity and evolution, there has been wide interest in the concept of using circulating tumor DNA (ctDNA) to predict treatment response. Although the use of ctDNA to detect actionable mutations such as EGFR is now integral in the standard of care for patients with NSCLC, several large studies have also shown its potential as a biomarker of immunotherapeutic response. Ongoing ctDNA interventional clinical trials, such as the BR.36 trial, will help to clarify the potential role of ctDNA for therapeutic guidance. Despite the promise of this technology, there are many limitations and considerations that clinicians need to be aware of prior to widespread implementation in clinical practice, such as the effect of underlying comorbidities, ctDNA fraction, stage of underlying malignancy, and concordance between aberrations detected in ctDNA and tumor tissue.
    Keywords:  Circulating tumor DNA; cancer; liquid biopsy; lung cancer; non-small cell lung cancer
    DOI:  https://doi.org/10.37349/etat.2024.00280
  2. Cancer Sci. 2025 Jan 05.
    Comprehensive Genome Profiling-Initiated Tumor-Informed Circulating Tumor DNA Monitoring for Patients With Advanced Cancer.
    Taiga Sasaki, Hayato Hiraki, Akiko Yashima-Abo, Hiromi Nagashima, Fumitaka Endo, Mizunori Yaegashi, Shimpei Miura, Keiko Obata, Naoki Yanagawa, Hiroaki Itamochi, Hidekazu Shirota, Takeshi Iwaya, Satoshi S Nishizuka.
      In Japan, comprehensive genome profiling (CGP) as a companion diagnostic (CDx) has been covered by public insurance since June 2019, but the proportion of patients with cancer who actually received drug therapy based on CGP data is low. In the present study, we attempted to use CGP as a starting point for tumor-informed circulating tumor DNA (ctDNA) monitoring. We retrospectively validated 219 patients with malignant tumors who underwent CGP at Iwate Medical University Hospital between October 2019 and April 2023 in terms of patient demographics, genetic analysis, drug recommendations, and drug administration rate. The 219 cancer cases analyzed by CGP for 27 target organs, including prostate (n = 27, 12.3%), colorectal (n = 25, 11.4%), lung (n = 19, 8.7%), and other neoplasms (n = 148, 67.6%). Among the cohort, only 14 cases (6.4%) subsequently were able to undertake the recommended action by Molecular Tumor Board. Of patients who underwent ctDNA monitoring based on somatic mutations identified by CGP (n = 11), clinical validity was confirmed in terms of early relapse prediction (n = 5, 45.5%), treatment response evaluation (n = 10, 90.9%), and no relapse/regrowth corroboration (n = 2, 18.2%) whereas 90.9% (n = 10) of patients obtained information with at least one source of the clinical validity. Although the current rate of CGP contributing to a drug recommendation is low, CGP results can be an alternate resource for tumor-informed longitudinal ctDNA monitoring to provide information concerning early relapse prediction, treatment response evaluation, and no relapse/regrowth corroboration.
    Keywords:  Digital PCR; comprehensive genome profiling; tumor‐informed ctDNA monitoring
    DOI:  https://doi.org/10.1111/cas.16446
  3. Sci Rep. 2025 Jan 08. 15(1): 1252
    Comparative analysis of EGFR mutations in circulating tumor DNA and primary tumor tissues from lung cancer patients using BEAMing PCR.
    Duhita Mirikar, Nandini Banerjee, Kumar Prabhash, Rajiv Kumar Kaushal, Vanita Naronha, C S Pramesh, George Karimundackal, Amit Joshi, Swapnil Rane, Ranjan Basak.
      In this study, we measured human epidermal growth factor receptor (EGFR) mutations in both tissue and circulating tumor DNA (ctDNA) by using beads, emulsions, amplifications and magnetic polymerase chain reaction (BEAMing PCR). Noninvasive mutation detection by assessing circulating tumor DNA (ctDNA) offers many advantages over tumor biopsy. One hundred non-small cell lung cancer (NSCLC) patients were enrolled, and both preoperative plasma samples and formalin-fixed and paraffin-embedded (FFPE) samples were collected for the study. The EGFR mutation status was determined by BEAMing PCR in ctDNA. Real-time quantitative PCR (qPCR) data were collected from our hospital database (EMR-qPCR, Electronic Medical Records) for comparative analysis. Additionally, qPCR was also performed on FFPE tissues using a Diatech EGFR qPCR kit. The concordance rates were 98.8%, 98.9% and 95.5% for exons 19, 20 and 21, respectively, when the BEAMing data were compared with the EMR-qPCR data. Additionally, when the BEAMing and Diatech qPCR data were compared, 90%, 100%, 96% and 98% of the genes were obtained for exons 19, 20, 21 (L858R) and 21 (L861Q), respectively. For both comparisons, Cohen's kappa agreement was significant. The advantage of BEAMing is its ability to identify mutated DNA sequences in cancer cells in the background of normal cell DNA contamination. This could be useful for disease monitoring and progression.
    Keywords:  BEAMing ; EGFR; NSCLC; ctDNA; qPCR
    DOI:  https://doi.org/10.1038/s41598-025-85160-6
  4. NPJ Precis Oncol. 2025 Jan 08. 9(1): 5
    Longitudinal genomic profiling using liquid biopsies in metastatic nonsquamous NSCLC following first line immunotherapy.
    Haolun Ding, Min Yuan, Yaning Yang, Xu Steven Xu.
      Tumor genomic profiling is often limited to one or two timepoints due to the invasiveness of tissue biopsies, but longitudinal profiling may provide deeper clinical insights. Using ctDNA data from IMpower150 study, we examined genetic changes in metastatic non-squamous NSCLC post-first-line immunotherapy. Mutations were most frequently detected in TP53, KRAS, SPTA1, FAT3, and LRP1B at baseline and during treatment. Mutation levels rose prior to radiographic progression in most progressing patients, with specific mutations (SPTA1, STK11, KEAP1, SMARCA4, TBX3, CDH2, and MLL3) significantly enriched in those with progression or nondurable response. However, ctDNA's role in detecting hyperprogression and pseudoprogression remains uncertain. STK11, SMARCA4, KRAS, SLT2, and KEAP1 mutations showed the strongest correlation with poorer overall survival, while SMARCA4, STK11, SPTA1, TBX3, and KEAP1 mutations correlated with shorter progression-free survival. Overall, longitudinal liquid biopsy profiling provided valuable insights into lung cancer biology post-immunotherapy, potentially guiding personalized therapies and future drug development.
    DOI:  https://doi.org/10.1038/s41698-024-00797-2
  5. Pediatr Blood Cancer. 2025 Jan 09. e31535
    Diagnosis of Leptomeningeal Disease in Diffuse Midline Gliomas by Detection of H3F3A K27M Mutation in Circulating Tumor DNA of Cerebrospinal Fluid.
    Satoshi Shibuma, Jotaro On, Manabu Natsumeda, Akihide Koyama, Haruhiko Takahashi, Jun Watanabe, Masaki Mitobe, Satoshi Nakata, Yuki Tanaka, Yoshihiro Tsukamoto, Masayasu Okada, Junichi Yoshimura, Mari Tada, Hiroshi Shimizu, Soichi Oya, Junko Murai, Kouichirou Okamoto, Hiroyuki Kawashima, Akiyoshi Kakita, Makoto Oishi.
       INTRODUCTION: Leptomeningeal disease (LMD) in diffuse midline gliomas (DMGs) can lead to devastating symptoms such as severe pain, urinary incontinence, and tetraparesis, with limited treatment options. We determined whether detecting H3F3A K27M-mutant droplets in cerebrospinal fluid (CSF) circulating tumor deoxyribonucleic acid (ctDNA) could be a biomarker for detecting LMD in DMGs.
    METHODS: Twenty-five CSF samples were obtained from 22 DMG patients. Histological confirmation of H3F3A K27M mutation was obtained in 10 (45.5%) cases. ctDNA was extracted from CSF, and H3F3A K27M-mutant and wildtype droplets were detected using digital droplet polymerase chain reaction (ddPCR). LMD was diagnosed by CSF cytology and pre- and post-contrast head and spine magnetic resonance (MR) imaging.
    RESULTS: The number of H3F3A K27M-mutant droplets (median 27 [range: 1-379] vs. median 0 [range: 0-1]; p < 0.0001) and variant allele frequency (VAF) (median 48.9% [range: 7.5%-87.5%] vs. median 0.0% [range: 0.0%-50.0%]; p < 0.0001) were significantly higher in the LMD/early-LMD group compared to no-LMD group. In two cases (Cases 4 and 11) without clinical evidence of LMD, multiple H3F3A K27M-mutant droplets were detected in CSF ctDNA. In those cases, extensive spinal dissemination was detected 6 months after the initial liquid biopsy. One case (Case 15) with high Schlafen11 (SLFN11) expression responded well to treatment for LMD and survived for 532 days after the diagnosis of LMD.
    CONCLUSION: This study provides evidence that detecting H3F3A K27M-mutant droplets in CSF ctDNA is diagnostic for LMD and is more sensitive than traditional methods such as CSF cytology and MR imaging.
    Keywords:  diffuse midline glioma; droplet digital PCR; leptomeningeal disease; liquid biopsy
    DOI:  https://doi.org/10.1002/pbc.31535
  6. JTO Clin Res Rep. 2025 Jan;6(1): 100758
    Monitoring of Circulating Tumor DNA and Indication of De-Escalation Adjuvant Targeted Therapy for EGFR-Mutated NSCLC After Complete Resection.
    Song Dong, Bingfa Yan, Si-Yang Liu, Xuan Gao, Hui-Zhao Hong, Hong-Ji Li, Wei Gao, Hong-Hong Yan, Si-Yang Maggie Liu, Hai-Yan Tu, Yi Pan, Qing Zhou, Xue-Ning Yang, Xue-Feng Xia, Xin Yi, Wen-Zhao Zhong, Yi-Long Wu, Jia-Tao Zhang.
       Introduction: EGFR tyrosine kinase inhibitor (TKI) is the standard adjuvant treatment for patients with stages IB to IIIA EGFR-mutated NSCLC. Nevertheless, adapting this approach to include a molecular residual disease (MRD)-guided de-escalation strategy warrants further investigation.
    Methods: From January 2019 to December 2022, 71 patients with stages I to III NSCLC and EGFR (exon 19 deletion or L858R) mutations were enrolled in this observational study. A total of 375 blood samples were analyzed using the MRD_Navigator assay. Among them, 27 patients suspended EGFR TKI treatment based on undetectable MRD and were thus included in the adaptive, de-escalation group.
    Results: Overall, the sensitivity of longitudinal MRD was 86.2%. Only four patients (11.8%) recurred with longitudinal undetectable MRD, indicating a negative predictive value of 88.2%. Of the patients who had detectable MRD after surgery, nine subsequently received EGFR TKI treatment, with only one (11.1%) achieving persistent circulating tumor DNA clearance post-EGFR TKI. Furthermore, 22 patients with stages IB to III disease who had previously suspended their TKI treatment based on undetectable MRD were included in the adaptive group, with an average duration of TKI 3.9 (range: 0-35.0) months. The 2-year disease-free survival rate of these 22 patients was 80.2%, and the median was not reached. Five patients (n = 5 of 22, 22.7%) had disease recurrence during the period of drug cessation but were stable under EGFR TKI treatment until the latest follow-up. Two patients remained in complete remission.
    Conclusions: Our initial findings underscore the potential of an adaptive, de-escalation approach to adjuvant EGFR TKIs based on circulating tumor DNA-MRD monitoring.
    Keywords:  Circulating tumor DNA; De-escalation therapy; Epidermal growth factor receptor; Molecular residual disease; Non–small cell lung cancer
    DOI:  https://doi.org/10.1016/j.jtocrr.2024.100758
  7. J Obstet Gynaecol Res. 2025 Jan;51(1): e16197
    Treatment for low-grade and high-grade endometrial carcinoma after recurrence/relapse before the molecular targeted therapy era: A retrospective, propensity score-matched cohort study.
    Masao Okadome, Kenzo Sonoda, Rina Nagayama, Toshiaki Saito, Kumi Shimamoto, Ai Nio, Yu Yoshida, Ayano Tsubomi, Shinichiro Yamaguchi, Kazuya Ariyoshi.
       AIM: To compare the prognosis of low-grade endometrial carcinoma (LG-EC) with that of high-grade endometrial carcinoma (HG-EC) after first recurrence/relapse before the molecular targeted therapy era.
    METHODS: Recurrent/relapsed endometrial cancer was diagnosed in 155 women at our hospital between January 26, 1999 and February 26, 2019. Fifty of these women received paclitaxel-carboplatin, two received doxorubicin-cisplatin, and one received docetaxel-carboplatin as postoperative chemotherapy. Two women who did not receive postoperative chemotherapy received paclitaxel-carboplatin for their first recurrence/relapse. The prognosis in these 55 women was retrospectively investigated using propensity score matching.
    RESULTS: Twenty-five women had LG-EC and 30 had HG-EC. Cox proportional hazards analysis identified response to chemotherapy for the first recurrence/relapse to be a statistically significant determinant of progression-free survival and HG-EC to be a significant determinant of overall survival. After propensity score matching, median overall survival was better in women with LG-EC than in those with HG-EC (82 months [95% CI 27-not reached] vs. 31 months [95% CI 2-47], p = 0.0127). Three women survived for at least 10 years without recurrence after completion of treatment. The interval between postoperative chemotherapy and first recurrence was more than 6 months. The recurrences resolved after multimodal treatment or aggressive chemotherapy followed by 5-12 cycles of chemotherapy other than paclitaxel-carboplatin if received postoperatively.
    CONCLUSIONS: The prognosis was poorer in patients with recurrent/relapsed HG-EC than in those with recurrent/relapsed LG-EC before the molecular targeted therapy era. There were no long-term recurrence-free survivors after repeat paclitaxel-carboplatin chemotherapy.
    Keywords:  carboplatin/cisplatin/docetaxel/doxorubicin/paclitaxel; combined modality therapy; high‐grade/low‐grade endometrial neoplasms; prognosis; propensity score
    DOI:  https://doi.org/10.1111/jog.16197
  8. Support Care Cancer. 2025 Jan 05. 33(1): 70
    Use of scalp cooling therapy in patients with breast or gynecological cancers undergoing chemotherapy may be associated with a higher risk of systemic recurrence.
    Kadri Altundag.
      
    DOI:  https://doi.org/10.1007/s00520-025-09151-z
  9. Neuro Oncol. 2024 Dec 30. pii: noae276. [Epub ahead of print]
    A Hitchhiker's Guide Toward CSF Biomarkers for Neuro-Oncology.
    Cecile Riviere-Cazaux, Michael B Keough, Jeffrey A Zuccato, Rahul Kumar, Sebastian Schulz, Arthur E Warrington, Michael W Ruff, Benjamin M Ellingson, Nader Sanai, Jian L Campian, Sani H Kizilbash, Ian F Parney, Gelareh Zadeh, Mustafa Khasraw, Tobias Kessler, Ugur Sener, Daniel P Cahill, Alireza Mansouri, Terry C Burns.
      Cerebrospinal fluid (CSF) has emerged as a valuable liquid biopsy source for glioma biomarker discovery and validation. CSF produced within the ventricles circulates through the subarachnoid space, where the composition of glioma-derived analytes is influenced by the proximity and anatomical location of sampling relative to tumor, in addition to underlying tumor biology. The substantial gradients observed between lumbar and intracranial CSF compartments for tumor-derived analytes underscore the importance of sampling site selection. Moreover, radiographic features, such as tumor-CSF contact and blood-brain barrier (BBB) disruption, are critical covariates that may affect biomarker detectability and the abundance of plasma-derived analytes in CSF, respectively. Longitudinal intracranial CSF sampling, enabled by access devices like Ommaya reservoirs, may offer a window into treatment response and disease progression, though variability in analyte yield, sample volumes, and the dynamic effects of surgical resection pose challenges. This review critically evaluates the anatomic, radiographic, and longitudinal factors that impact glioma CSF biomarker abundance. Practical considerations for longitudinal CSF biobanking, including access device placement and collection, are also reviewed. Key takeaways and recommendations for CSF glioma biomarker discovery and validation are provided based on our collective experience, along with resources for investigators aiming to develop CSF biobanking at their institutions.
    Keywords:  biomarker; cerebrospinal fluid; glioma; monitoring; neuro-oncology
    DOI:  https://doi.org/10.1093/neuonc/noae276
  10. Cancers (Basel). 2024 Dec 18. pii: 4219. [Epub ahead of print]16(24):
    Melanoma's New Frontier: Exploring the Latest Advances in Blood-Based Biomarkers for Melanoma.
    Ivana Prkačin, Mislav Mokos, Nikola Ferara, Mirna Šitum.
      Melanoma is one of the most malignant cancers, and the global incidence of cutaneous melanoma is increasing. While melanomas are highly prone to metastasize if diagnosed late, early detection and treatment significantly reduce the risk of mortality. Identifying patients at higher risk of metastasis, who might benefit from early adjuvant therapies, is particularly important, especially with the advent of new melanoma treatments. Therefore, there is a pressing need to develop additional prognostic biomarkers for melanoma to improve early stratification of patients and accurately identify high-risk subgroups, ultimately enabling more effective personalized treatments. Recent advances in melanoma therapy, including targeted treatments and immunotherapy, have underscored the importance of biomarkers in determining prognosis and predicting treatment response. The clinical application of these markers holds the potential for significant advancements in melanoma management. Various tumor-derived genetic, proteomic, and cellular components are continuously released into the bloodstream of cancer patients. These molecules, including circulating tumor DNA and RNA, proteins, tumor cells, and immune cells, are emerging as practical and precise liquid biomarkers for cancer. In the current era of effective molecular-targeted therapies and immunotherapies, there is an urgent need to integrate these circulating biomarkers into clinical practice to facilitate personalized treatment. This review highlights recent discoveries in circulating melanoma biomarkers, explores the challenges and potentials of emerging technologies for liquid biomarker discovery, and discusses future directions in melanoma biomarker research.
    Keywords:  LDH; S100B; biomarkers; cell-free DNA; cell-free RNA; circulating tumor DNA; circulating tumor cells; liquid biopsy; melanoma; tumor-educated platelets
    DOI:  https://doi.org/10.3390/cancers16244219
  11. Clin Case Rep. 2025 Jan;13(1): e70043
    EML4-ALK-Positive Ovarian Cancer With Intracranial Metastasis Responds to Lorlatinib: A Case Report and Literature Review.
    Qiongqian Li, Tongze Cai, Xiaoming Zheng, Shunrong Zhang, Chanjuan Li, Huang Tang, Zhiyong Yu, Jianlong Zhou.
      We report a case showing that lorlatinib is effective in treating EML4-ALK-positive low-grade serous ovarian cancer (LGSO) with intracranial metastasis. This may be the first clinical evidence of LGSO benefit from ALK inhibitors, to provide evidence for the use of ALK inhibitors in more ovarian cancer patients with EML4-ALK fusion and promoting new ideas for the study of EML4-ALK targets in ovarian cancer.
    Keywords:  EML4‐ALK fusion gene; intracranial metastasis; lorlatinib; ovarian cancer
    DOI:  https://doi.org/10.1002/ccr3.70043
  12. Int J Surg Pathol. 2025 Jan 07. 10668969241300502
    Primary Intracranial Sarcoma, DICER1-Mutant, With Prominent Chondroid Differentiation: Case Report and Summary of Reported Patients in Literature.
    Kinnari Karia, Kathryn L Eschbacher.
      Primary intracranial sarcoma, DICER1-mutant, included as a new diagnostic entity in the 2021 WHO Classification of Central Nervous System Tumors, is a rare, but aggressive neoplasm generally identified in the supratentorial forebrain. The prognostic implications of these uncommon tumors and optimal treatment strategy remain unclear. A 19-year-old woman was found unresponsive after reporting a severe headache. CT demonstrated an intra-axial, mass-like hemorrhage in the left temporal lobe which was subsequently resected. A review of the electronic medical record, histologic characterization by hematoxylin and eosin-stained sections and a targeted panel of immunohistochemical stains, and molecular characterization was pursued. The tumor was pleomorphic and demonstrated varying cellularity. The tumor cells had hyperchromatic nuclei with a spindled to round appearance. Numerous mitoses, interspersed islands of mature hyaline cartilage, and scattered eosinophilic globules associated with cells with marked nuclear atypia were noted. The tumor cells were positive for desmin, myogenin, and SMSA (focal) and negative for other lineage markers, suggestive of a mesenchymal neoplasm with myogenic differentiation. Next-generation sequencing revealed DICER1 (E1705K and P1805fs) and KRAS (Q61H) variants; the composite methylation profile prompted a final diagnosis of primary intracranial sarcoma, DICER1-mutant. This lesion underscores the histologic and immunophenotypic variability of these rare tumors. Notable features include prominent cartilaginous islands, retained H3K27me3 expression, prominent expression of desmin, and the presence of the unique DICER1 P1805fs variant, which has not previously been reported in this tumor type. We compile the molecular and immunohistochemical findings of all primary intracranial sarcomas, DICER1-mutant to date.
    Keywords:  CNS neoplasm; DICER1 mutant; DICER1 syndrome; neuropathology; primary intracranial sarcoma
    DOI:  https://doi.org/10.1177/10668969241300502
  13. J Chemother. 2025 Jan 05. 1-6
    An acquired CCDC6::RET gene fusion as resistance mechanism for Osimertinib in exon 21 EGFR(L858R)-mutated non-small cell lung cancer and its successful management with Osimertinib and Selpercatinib: a case report and review of literature.
    Maud Lormans, Peter Van Haecke, Ingel Demedts.
      Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are the recommended front-line therapy for treatment-naïve patients with advanced stage EGFR mutated Non-Small Cell Lung Cancer (NSCLC), with better tolerance and outcomes compared to chemotherapy. However, patients inevitably develop resistance to EGFR-TKI. The extent of progression free survival depends on intrinsic or acquired on-target/off-target mechanisms of EGFR-TKI resistance. Overcoming these acquired rearrangements remains challenging in modern precision medicine. In case of disease progression during treatment with an EGFR-TKI, rebiopsy is recommended to search for a potential resistance mechanism. However, the therapeutic potential of these resistance mechanisms represents an unmet need in thoracic oncology. CasePresentation: We present a case of a 78-year-old woman with stage IVB EGFR-mutated NSCLC in whom an acquired RET Gene Fusion was identified as the EGFR-independent resistance mechanism. Additionally, a combined therapy of Osimertinib and Selpercatinib showed a durable oncological response with 14 months of progression free survival in the absence of adverse events. Conclusion: Addition of Selpercatinib to Osimertinib in an EGFR-mutated NSCLC patient with an acquired RET fusion was well tolerated and created a clinical benefit. Further prospective investigation into these novel combination strategies is needed as resistance mechanisms could serve as possible targets for new therapy approaches.
    Keywords:  EGFR-mutation; Non-small cell lung cancer; Osimertinib; RET-fusion; Selpercatinib
    DOI:  https://doi.org/10.1080/1120009X.2024.2445909
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