bims-preonc 2024-12-22 papers

bims-preonc

Biomed News

on Precision oncology

Issue of 2024–12–22
seventeen papers selected by
Ankita Daiya, OneCell Diagnostics Inc.

Application of Circulating Tumor DNA in the Auxiliary Diagnosis and Prognosis Prediction of Glioma.
Cerebral spinal fluid analyses and therapeutic implications for leptomeningeal metastatic disease.
ctDNA/MRD Testing for Colon Cancer: A Work in Progress or Ready for Prime-Time Standard of Care?
Circulating tumor DNA-guided treatment decision in metastatic castration-resistant prostate cancer patients: a cost-effectiveness analysis.
Minimal residual disease in colorectal cancer. Tumor-informed versus tumor-agnostic approaches: unraveling the optimal strategy.
Circulating Tumor DNA (ctDNA) Dynamics Predict Early Response to Treatment in Metastasized Gastroesophageal Cancer (mGEC) After 2 Weeks of Systemic Treatment.
Patterns of genomic instability in > 2000 patients with ovarian cancer across six clinical trials evaluating olaparib.
If it is a solid tumor target, then it may be a hematologic cancer target: Bridging the great divide.
Clinical outcomes of patients with EGFR-mutated NSCLC developing interstitial lung disease during first-line osimertinib therapy: a sub-analysis of the Reiwa study.
Integration of personalised ultrasensitive ctDNA monitoring of patients with metastatic breast cancer to reduce imaging requirements.
Implementation of Universal Germline Genetic Testing Into Standard of Care for Patients With Prostate Cancer: The Time Is Now.
Quantification of PD-L1 expression and tumor mutational burden in biologically distinct advanced pancreatic cancers responding to pembrolizumab: case reports.
[The role of clonal hematopoiesis in the molecular diagnostics of solid tumors].
Analytical Validation and Performance Evaluation of Amplicon-Based Next-Generation Sequencing Assays for Detecting ERBB2 and Other Gene Amplifications in Solid Tumors.
Case report: Favorable efficacy of combined afatinib and anlotinib treatment in a lung adenocarcinoma patient harboring uncommon EGFR L858M/L861R mutations.
Microsatellite instability and high tumor mutational burden detected by next generation sequencing are concordant with loss of mismatch repair proteins by immunohistochemistry.
Decoding the Clinical and Molecular Signatures of EGFR Common, Compound, and Uncommon Mutations in Non-Small Cell Lung Cancer.

Cell Mol Neurobiol. 2024 Dec 18. 45(1): 6

Application of Circulating Tumor DNA in the Auxiliary Diagnosis and Prognosis Prediction of Glioma.

Ying Lu, Zhouyu Wang, Danmeng Zhang, Ningning Luo, Hui Yang, Dongsheng Chen, Haixin Huang.

  Glioma is the most common primary malignant brain tumor. Despite significant advances in the past decade in understanding the molecular pathogenesis of this tumor and exploring therapeutic strategies, the prognosis of patients with glioma remains poor. Accurate diagnosis of glioma is very important for the treatment and prognosis. Although the gold-standard method for the diagnosis and prognosis prediction of patients with glioma is tissue biopsy, it still has many limitations. Liquid biopsy can provide information on the auxiliary diagnosis and prognosis of gliomas. In this review, we summarized the application of cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) in the auxiliary diagnosis and prognosis of glioma. The common methods used to detect ctDNA in gliomas using samples including blood and cerebrospinal fluid (CSF) and the detection techniques for ctDNA, including droplet digital PCR (ddPCR) and next-generation sequencing (NGS), were discussed. Detection of ctDNA from plasma of patients with brain tumors remains challenging because of the blood-brain barrier (BBB). CSF has been proposed as a medium for ctDNA analysis in brain tumors, and mutation detection using plasma ctDNA was less sensitive than CSF ctDNA sequencing. Moreover, ongoing relevant clinical studies were summarized. Finally, we discussed the challenges, and future directions for the studies on ctDNA in glioma.

Keywords:  Auxiliary diagnosis; CtDNA; Glioma; Next-generation sequencing; Prognosis

DOI:  https://doi.org/10.1007/s10571-024-01515-z
J Neurooncol. 2024 Dec 20.

Cerebral spinal fluid analyses and therapeutic implications for leptomeningeal metastatic disease.

Jie Wei Zhu, Megan Shum, Maleeha A Qazi, Arjun Sahgal, Sunit Das, Matthew Dankner, Ines Menjak, Mary Jane Lim-Fat, Katarzyna J Jerzak.

   PURPOSE: To review applications of cerebral spinal fluid (CSF) biomarkers for the diagnosis, monitoring and treatment of leptomeningeal metastatic disease (LMD) among patients with metastatic solid tumors.
METHODS: A narrative review identified original research related to CSF biomarkers among patients with metastatic solid tumors and LMD. Pre-clinical research (e.g. studies conducted in animal models) was not included. A descriptive analysis of literature was undertaken, with a focus on clinical applications related to the diagnosis, monitoring and treatment of LMD.
RESULTS: The low cellularity of CSF in comparison to plasma is an advantage for liquid biopsy, given that circulating tumor DNA (ctDNA) is not significantly diluted by genomic DNA from non-cancer cells. This results in higher variant allelic frequencies and increased sensitivity in detecting ctDNA compared to plasma. However, the clinical significance of positive ctDNA and/or circulating tumor cells (CTCs) in the CSF, particularly in the absence of other signs of LMD (either clinical and/or radiological), remains unclear. While the use of CSF liquid biopsy to monitor treatment response is promising, this approach requires prospective validation using larger sample sizes prior to adoption in routine clinical care. Discovery efforts involving proteomics and metabolomics have potential to identify proteins involved in the regulation of energy metabolism, vasculature, and inflammation in LMD, which in turn, may offer insights into novel treatment approaches.
CONCLUSION: CSF liquid biopsy should be incorporated in prospective studies for patients with LMD to validate promising diagnostic and/or predictive biomarkers of treatment response, as well as new therapeutic targets.

Keywords:  Biomarkers; Cerebral spinal fluid; Circulating tumor cells; Circulating tumor DNA; Leptomeningeal metastatic disease; Liquid biopsy

DOI:  https://doi.org/10.1007/s11060-024-04902-0
J Natl Compr Canc Netw. 2024 12;pii: e247049. [Epub ahead of print]22(10):

ctDNA/MRD Testing for Colon Cancer: A Work in Progress or Ready for Prime-Time Standard of Care?

Bennett A Caughey, Aparna R Parikh.

In patients with surgically resectable colon cancer (CC), clinicopathologic characteristics translate into cancer staging and predict recurrence risk. Adjuvant chemotherapy reduces the risk of recurrence and is offered to high-risk patients. However, some patients are inevitably overtreated or undertreated; better risk stratification is necessary to improve outcomes after surgery. Circulating tumor DNA (ctDNA)-based minimum residual disease (MRD) assays sequence plasma cell-free DNA for tumor DNA to predict the presence of otherwise subclinical malignancy. Studies have demonstrated that detectable ctDNA after surgery for CC predicts a high rate of recurrence and improves prognostication. Recent clinical trials show promise for using ctDNA to guide therapy, in particular standard-risk stage II CC. Large, randomized studies evaluating ctDNA-guided adjuvant chemotherapy versus standard of care in stage III CC are ongoing. Current data are insufficient to recommend routine use of ctDNA to guide adjuvant chemotherapy in resectable stage III CC.

DOI: https://doi.org/10.6004/jnccn.2024.7049
Ther Adv Med Oncol. 2024 ;16 17588359241305084

Circulating tumor DNA-guided treatment decision in metastatic castration-resistant prostate cancer patients: a cost-effectiveness analysis.

Catharina J P Op 't Hoog, Sabien J E Bosman, Emmy Boerrigter, Niven Mehra, Inge M van Oort, Nielka P van Erp, Wietske Kievit.

   Background: The androgen receptor pathway inhibitors (ARPI), abiraterone acetate and enzalutamide, are commonly used in first-line treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). However, early resistance to ARPI treatment occurs frequently. Traditionally, the response is evaluated 3-6 months after the start of treatment. However, recent findings indicate that by detecting circulating tumor DNA (ctDNA) at baseline and 4 weeks after ARPI treatment initiation, patients with a nondurable response can be identified after 4 weeks of treatment, enabling an early switch to alternative treatments.
Objective: This study aims to evaluate the cost-effectiveness of ctDNA-guided treatment switch after 4 weeks of ARPI therapy in mCRPC patients compared to standard of care.
Design: A cost-effectiveness analysis.
Methods: A cost-effectiveness analysis was conducted by creating a Markov state transition model to simulate progression, mortality, and treatment costs over a 5-year time horizon comparing ctDNA-guided care versus standard of care. The outcomes measured were incremental treatment costs per life-years and quality-adjusted life-years (QALYs) gained.
Results: The analysis showed an incremental cost-effectiveness ratio of €65,400.86 per QALY gained and an incremental net monetary benefit of €2716.62. Thereby, the use of ctDNA-guided treatment was cost-effective in comparison to standard care in 74% of the simulations using a willingness-to-pay threshold of €80,000 per QALY gained.
Conclusion: Our study demonstrated the cost-effectiveness of using a ctDNA-guided early therapy switch in non-responders after only 4 weeks of first-line ARPI therapy in mCRPC patients. This paves the way for implementing ctDNA-guided treatment decisions in clinical practice.

Keywords:  androgen receptor pathway inhibitors; biomarkers; chemotherapy; circulating tumor DNA (ctDNA); cost-effectiveness analysis; health services research; hormone therapy; liquid biopsy; prostate cancer

DOI:  https://doi.org/10.1177/17588359241305084
Ann Oncol. 2024 Dec 13. pii: S0923-7534(24)04981-0. [Epub ahead of print]

Minimal residual disease in colorectal cancer. Tumor-informed versus tumor-agnostic approaches: unraveling the optimal strategy.

B Martínez-Castedo, D G Camblor, J Martín-Arana, J A Carbonell-Asins, B García-Micó, V Gambardella, M Huerta, S Roselló, D Roda, F Gimeno-Valiente, A Cervantes, N Tarazona.

   BACKGROUND: Circulating tumor DNA (ctDNA) analysis has emerged as a minimally invasive tool for detecting minimal residual disease (MRD) in colorectal cancer (CRC) patients. This enables dynamic risk stratification, earlier recurrence detection, and optimized post-surgical treatment. Two primary methodologies have been developed for ctDNA-based MRD detection: tumor-informed strategies, which identify tumor-specific mutations through initial tissue sequencing to guide ctDNA monitoring, and tumor-agnostic approaches, which utilize predefined panels to detect common cancer-associated genomic or epigenomic alterations directly from plasma without prior tissue analysis. The debate over which is superior in terms of sensitivity, specificity, cost-effectiveness, and clinical feasibility remains unresolved.
DESIGN: This review summarizes studies published up to November 2024, exploring the utility and performance of tumor-informed and tumor-agnostic approaches for ctDNA analysis in CRC. We evaluate the strengths and limitations of each methodology, focusing on sensitivity, specificity, and clinical outcomes.
RESULTS: Both strategies demonstrate clinical utility in postoperative risk stratification and guiding adjuvant chemotherapy decisions in CRC patients. Tumor-informed approaches generally exhibit superior sensitivity and specificity for recurrence prediction, attributed to their personalized tumor profile designs. However, these methods are limited by the need for prior tissue sequencing and higher associated costs. In contrast, tumor-agnostic approaches offer broader applicability due to their reliance on plasma-only analysis, although with relatively lower sensitivity. Technological advancements, including fragmentomics and multi-omic integrations, are expanding the capabilities of ctDNA-based MRD detection, enhancing the performance of both approaches.
CONCLUSIONS: While tumor-informed strategies currently offer higher precision in MRD detection, tumor-agnostic approaches are gaining traction due to their convenience and improving performance metrics. The integration of novel technologies in ongoing clinical trials may redefine the optimal approach for MRD detection in CRC, paving the way for more personalized and adaptive patient management strategies.

Keywords:  Circulating tumor DNA; Colorectal cancer; Minimal residual disease; Tumor-agnostic approach; Tumor-informed approach

DOI:  https://doi.org/10.1016/j.annonc.2024.12.006
Cancers (Basel). 2024 Nov 26. pii: 3960. [Epub ahead of print]16(23):

Circulating Tumor DNA (ctDNA) Dynamics Predict Early Response to Treatment in Metastasized Gastroesophageal Cancer (mGEC) After 2 Weeks of Systemic Treatment.

Stefan Tatalovic, Bernhard Doleschal, Alexander Kupferthaler, Stephan Grundner, Jonathan Burghofer, Gerald Webersinke, Simon Schwendinger, Emina Jukic, Johannes Zschocke, Lorenz Danhel, Antonia Kirchweger, Lukas Havranek, Demetre Shalamberidze, Daniel Rezaie, Matthias Biebl, Holger Rumpold, Patrick Kirchweger.

  mGEC is associated with poor overall survival (OS) of approximately 4-10 months. CtDNA is emerging as a promising prognostic biomarker with high potential for early relapse detection. However, until now, there was little knowledge on serial ctDNA detection and its impact on early treatment evaluation and prognosis in mGEC.
METHODS: ctDNA detection (ddPCR) was carried out serially in 37 matched tissue (NGS) patients with mGEC prior to systemic treatment initiation and every two weeks thereafter until restaging (n = 173 samples). The results have been correlated with response to treatment (restaging CT), overall survival (OS), and progression-free survival (PFS).
RESULTS: The pretherapeutic detection rate was 77.8%. Response to treatment assessment was correct in 54.2% (pretherapeutically pos./neg.) and 85.7% (dynamics at week 4). Moreover, a decline in ctDNA (MAF in %) below 57.1% of the pretherapeutic value after 2 weeks of systemic treatment was accompanied by a sensitivity of 57.1% and a specificity of 90% (AUC = 0.73) for correct restaging assessment (response evaluation by CT after 3 months) evaluating 76.5% of patients correctly after only 2 weeks. In contrast to mere pretherapeutic ctDNA positivity (p = 0.445), a decline in ctDNA dynamics to under 57.1% of its initial value was significantly associated with OS (4.1 (95% Cl 2.1-6.1) vs. 13.6 (95% CI 10.4-16.6) months, p < 0.001) and PFS (3.2 (1.9-4.5) vs. 9.5 (95% CI 5.5-13.5) months, p = 0.001) after two weeks of treatment. Additionally, the change in detectability from positive pretherapeutic levels to negative during treatment was associated with similar survival as for patients who were always regarded as ctDNA-negative (9.5 (95%Cl 0.4-18.5) vs. 9.6 (95%Cl 1.3-17.9)). The absence of becoming undetectable was associated with worse survival (4.7 months).
CONCLUSIONS: ctDNA is a promising additional biomarker allowing for early evaluation of response to treatment and saving unevaluated treatment time for patients with mGEC, and could allow for an early change in treatment with anticipated prognostic benefit in the future.

Keywords:  ctDNA; esophageal cancer; gastric cancer; liquid biopsy

DOI:  https://doi.org/10.3390/cancers16233960
Genome Med. 2024 Dec 18. 16(1): 145

Patterns of genomic instability in > 2000 patients with ovarian cancer across six clinical trials evaluating olaparib.

Alan Barnicle, Isabelle Ray-Coquard, Etienne Rouleau, Karen Cadoo, Fiona Simpkins, Carol Aghajanian, Alexandra Leary, Andrés Poveda, Stephanie Lheureux, Eric Pujade-Lauraine, Benoit You, Jonathan Ledermann, Ursula Matulonis, Charlie Gourley, Kirsten M Timms, Zhongwu Lai, Darren R Hodgson, Cathy E Elks, Simon Dearden, Coumaran Egile, Pierre Lao-Sirieix, Elizabeth A Harrington, Jessica S Brown.

   BACKGROUND: The introduction of poly(ADP-ribose) polymerase (PARP) inhibitors represented a paradigm shift in the treatment of ovarian cancer. Genomic data from patients with high-grade ovarian cancer in six phase II/III trials involving the PARP inhibitor olaparib were analyzed to better understand patterns and potential causes of genomic instability.
PATIENTS AND METHODS: Homologous recombination deficiency (HRD) was assessed in 2147 tumor samples from SOLO1, PAOLA-1, Study 19, SOLO2, OPINION, and LIGHT using next-generation sequencing technology. Genomic instability scores (GIS) were assessed in BRCA1 and/or BRCA2 (BRCA)-mutated (BRCAm), non-BRCA homologous recombination repair-mutated (non-BRCA HRRm), and non-HRRm tumors.
RESULTS: BRCAm was identified in 1021/2147 (47.6%) tumors. BRCAm tumors had significantly higher GIS than non-BRCAm tumors (P < 0.001) and high biallelic loss (815/838; 97.3%) regardless of germline (658/672; 97.9%) or somatic (101/108; 93.5%) BRCAm status. In non-BRCA HRRm tumors (n = 121) a similar proportion were HRD-positive (GIS ≥ 42: 55/121; 45.5%) relative to HRD-negative (GIS < 42: 52/121; 43.0%). GIS was highly variable in non-BRCA HRRm (median 42 [interquartile range (IQR) 29-58]) and non-HRRm (n = 1005; median 32 [IQR 20-55]) tumors. Gene mutations with high GIS included HRR genes BRIP1 (median 46 [IQR 41-58]), RAD51C (median 58 [IQR 48-66]), RAD51D (median 62 [IQR 54-69]), and PALB2 (median 64 [IQR 58-74]), and non-HRR genes NF1 (median 49 [IQR 25-60]) and RB1 (median 55 [IQR 30-71]). CCNE1-amplified and PIK3CA-mutated tumors had low GIS (CCNE1-amplified: median 24 [IQR 18-29]; PIK3CA-mutated: median 32 [IQR 14-52]) and were predominantly non-BRCAm.
CONCLUSIONS: These analyses provide valuable insight into patterns of genomic instability and potential drivers of HRD, besides BRCAm, in ovarian cancer and will help guide future research into the potential clinical effectiveness of anti-cancer treatments in ovarian cancer, including PARP inhibitors as well as other precision oncology agents.
TRIAL REGISTRATION: The SOLO1 trial was registered at ClinicalTrials.gov (NCT01844986) on April 30, 2013; the PAOLA-1 trial was registered at ClinicalTrials.gov (NCT02477644) on June 18, 2015 (retrospectively registered); Study 19 was registered at ClinicalTrials.gov (NCT00753545) on September 12, 2008 (retrospectively registered); the SOLO2 trial was registered at ClinicalTrials.gov (NCT01874353) on June 7, 2013; the OPINION trial was registered at ClinicalTrials.gov (NCT03402841) on January 3, 2018; the LIGHT trial was registered at ClinicalTrials.gov (NCT02983799) on November 4, 2016.

Keywords:  Genomic instability; Olaparib; Ovarian cancer; Translational research

DOI:  https://doi.org/10.1186/s13073-024-01413-5
Med. 2024 Dec 06. pii: S2666-6340(24)00444-6. [Epub ahead of print]

If it is a solid tumor target, then it may be a hematologic cancer target: Bridging the great divide.

Jacob J Adashek, Javier L Munoz, Razelle Kurzrock.

Tumor-agnostic US Food and Drug Administration approvals are transforming oncology. They include larotrectinib/entrectinib/repotrectinib (NTRK fusions), selpercatinib (RET fusions), dabrafenib/trametinib (BRAFV600E mutations), pembrolizumab/dostarlimab (microsatellite instability), pembrolizumab (high tumor mutational burden), and trastuzumab deruxtecan (HER2 3+ expression) (all solid cancers). Pemigatinib is approved for FGFR1-rearranged myeloid/lymphoid neoplasms. The genomically driven tissue-agnostic approach has a strong biological rationale (cancer is a disease of the genome), yields remarkably high response rates, and provides drug access to patients with an unmet need (rare/ultra-rare malignancies). Despite the solid tumor focus, both solid and hematologic cancers can harbor identical driver molecular abnormalities and respond to cognate therapies. For example, BRAFV600E and IDH1/2 mutations; ALK, FGFR, and NTRK fusions; PD-L1 amplification; and CD70 antigens are druggable in both solid and blood malignancies by gene-/immune-targeted therapies/chimeric antigen receptor T cells. Future biomarker-based tissue-agnostic basket studies/approvals should bridge the great divide and include both solid and hematologic cancers.

DOI: https://doi.org/10.1016/j.medj.2024.11.003
Jpn J Clin Oncol. 2024 Dec 20. pii: hyae178. [Epub ahead of print]

Clinical outcomes of patients with EGFR-mutated NSCLC developing interstitial lung disease during first-line osimertinib therapy: a sub-analysis of the Reiwa study.

Takayuki Kobayashi, Kageaki Watanabe, Yukio Hosomi, Kiyotaka Yoh, Kazuhiro Usui, Kazuma Kishi, Go Naka, Shu Tamano, Kohei Uemura, Hideo Kunitoh.

   INTRODUCTION: Osimertinib-induced interstitial lung disease in untreated EGFR-mutated, advanced non-small cell lung cancer is being reported at a higher rate in Japan than elsewhere. However, data on the interstitial lung disease incidence during first-line osimertinib therapy and the course of lung cancer treatments administered after interstitial lung disease onset in the real-world setting are scarce.
MATERIALS AND METHODS: The present study reviewed the data from the Reiwa study, a multicentric, observational study examining the efficacy and safety of first-line osimertinib therapy in the clinical setting. Patients with EGFR-mutated non-small cell lung cancer who began osimertinib therapy between September 2018 and August 2020 were enrolled and followed until August 2022.
RESULTS: Among 583 patients receiving first-line osimertinib therapy, 75 (12.8%) had interstitial lung disease development, and 18 (3.0%) had at least grade 3 interstitial lung disease. Fifty-nine patients (78%) received some form of treatment following interstitial lung disease onset. An epidermal growth factor receptor-tyrosine kinase inhibitor rechallenge was performed in 31 patients (41%), with 18 (24%) receiving osimertinib again. Interstitial lung disease recurred in five (28%) of these 18 patients, none of 13 patients receiving another type of tyrosine kinase inhibitor, and seven (25%) of 28 patients receiving chemotherapy and/or immune checkpoint inhibitor therapy. The median overall survival after the initial osimertinib therapy was 38.4 months and 12.2 months for patients with interstitial lung disease grade 1-2 and grade 3-4, respectively (hazard ratio: 0.37; 95% confidence interval: 0.20-0.70; P = 0.002).
CONCLUSION: Patients with interstitial lung disease grade 3-4 had poorer survival during the first-line osimertinib therapy. A substantial risk of interstitial lung disease recurrence was associated with post-osimertinib therapy. Trial registration code: UMIN000038683.

Keywords:  EGFR; interstitial lung disease; non-small cell lung cancer; osimertinib; post-osimertinib therapy

DOI:  https://doi.org/10.1093/jjco/hyae178
Int J Cancer. 2024 Dec 18.

Integration of personalised ultrasensitive ctDNA monitoring of patients with metastatic breast cancer to reduce imaging requirements.

Pia Mouhanna, Anders Ståhlberg, Daniel Andersson, Ahmed Albu-Kareem, Ellinor Elinder, Olle Eriksson, Amy Kavanagh, Anikó Kovács, Karolina F Larsson, Barbro Linderholm, Monika Uminska, Tobias Österlund, Sacha J Howell, Maria Ekholm.

  Circulating tumour DNA (ctDNA) is an emerging biomarker for monitoring cancers. The personalised disease monitoring in metastatic breast cancer (PDM-MBC) study is an ongoing study instigated to evaluate ctDNA as a biomarker to individualise imaging requirements in patients with MBC. Patients receiving first-line endocrine therapy (aromatase inhibitor + cyclin-dependent kinase 4/6 inhibitor) had plasma samples collected pre-treatment, weeks 2 and 4, and concurrently with imaging until progressive disease (PD). Here, we apply an experimental analytical workflow for ultrasensitive ctDNA analysis, utilising personalised ctDNA panels designed from mutations identified in tumour tissue, and present results for 24 patients. Twenty patients (83%) had detectable ctDNA pre-treatment. The median progression-free survival was 25.6 months, and 13 patients experienced PD, with rising ctDNA detected at or prior to PD in 12 patients (92%). If imaging had been omitted until the detection of rising ctDNA for at least one mutation, 68% (n = 71) of the scans performed amongst ctDNA-positive patients would have been avoided. Our results demonstrate that integration of personalised ctDNA monitoring of patients with MBC has potential to substantially reduce the imaging needs in patients showing ctDNA response to treatment.

Keywords:  breast cancer; ctDNA; imaging; liquid biopsy; precision medicine

DOI:  https://doi.org/10.1002/ijc.35292
JCO Oncol Pract. 2024 Dec 19. OP2400626

Implementation of Universal Germline Genetic Testing Into Standard of Care for Patients With Prostate Cancer: The Time Is Now.

Neal Shore, Sarah M Nielsen, Edward D Esplin, Emmanuel S Antonarakis, Pedro C Barata, Tomasz M Beer, Himisha Beltran, Alan Bryce, Michael S Cookson, E David Crawford, Tanya B Dorff, Daniel J George, Elisabeth I Heath, Brian T Helfand, Maha Hussain, Rana R Mckay, Alicia K Morgans, Michael J Morris, Channing J Paller, Ashley E Ross, Oliver Sartor, John Shen, Paul Sieber, Matthew R Smith, David R Wise, Andrew J Armstrong.

Indications for and implications of germline genetic testing (GGT) in patients with prostate cancer have expanded over the past decade, particularly related to precision therapies and management. GGT has become the standard of care for many cancers such as breast, ovarian, colorectal, pancreatic, and metastatic prostate cancer, and it is imperative that patients be offered timely and equitable access to testing as it can inform patient-physician shared decision making for management of the current cancer as well as anticipatory guidance for disease progression. Additionally, GGT guides screening for and prevention of secondary malignancies for the patient and cascade testing for at-risk family members. Here, we present data supporting the notion that clinicians should offer all patients with prostate cancer the opportunity to undergo comprehensive GGT for pathogenic germline variants known to be associated with familial cancer and/or known to have implications for treatment and management.

DOI: https://doi.org/10.1200/OP-24-00626
Front Immunol. 2024 ;15 1452543

Quantification of PD-L1 expression and tumor mutational burden in biologically distinct advanced pancreatic cancers responding to pembrolizumab: case reports.

Kevin Y Li, Andrew M Lowy, Paul Fanta.

   Background: The advent of checkpoint therapy is one of the most important recent advancements in cancer therapy. Though checkpoint therapy is a mainstay in some cancers, it has been largely ineffective in treating cancers of the pancreas. Pancreatic ductal adenocarcinoma and pancreatic neuroendocrine tumors are seldom responsive to checkpoint inhibition.
Case presentations: Here we present two cases of advanced pancreatic cancers that either failed to respond or recurred following conventional treatments. Tissue from each tumor was sequenced and analyzed for PD-L1 expression. Each patient was started on checkpoint blockade after assessing for a predictive biomarker, either the combined positive score or the tumor mutational burden. In each case, checkpoint blockade led to durable radiographic responses.
Conclusions: We therefore propose that it is reasonable to assess combined positive score and tumor mutational burden in refractory or recurrent pancreatic cancers when initiation of ICB is being considered.

Keywords:  CPS; TMB; immunotherapy; pancreatic adenocarcinoma; pancreatic neuroendocrine tumor

DOI:  https://doi.org/10.3389/fimmu.2024.1452543
Magy Onkol. 2024 Dec 10. 68(4): 351

[The role of clonal hematopoiesis in the molecular diagnostics of solid tumors].

Zoltán Őrfi, Attila Kállai, Dóra Csabán, Nóra Meggyesi, Mariann Nagy-Schwendtner, József Harasztdombi, Béla Kajtár, Andrea Ceglédi, Árpád Bátai, Attila Tordai, Péter Reményi, Gábor Mikala, Zoltán Ungvári, Hajnalka Andrikovics.

This review presents the latest molecular genetic diagnostic and clinical aspects related to clonal hematopoiesis of indeterminate potential (CHIP). CHIP belongs to the continuously expanding group of pre-cancerous conditions, increasingly recognized in routine patient care due to the development of molecular diagnostic tools and the increase in life expectancy. The incidence of CHIP mutations increases with age (1-2% in individuals aged 50 years, 15-45% in those aged 80 years). According to international studies, 5-8% of examinations performed on solid tumors may contain erroneous results due to the presence of leukocytes. This rate increases to 10-15% in case of liquid biopsy samples. To avoid misleading diagnostic results, it is recommended to perform comparative analysis of samples from different tissue origins, blood/tumor sample pairs. The authors illustrate CHIP-related alterations affecting targeted therapies for solid tumors (e.g. KRAS, ATM, IDH1, TP53). The impact of CHIP on the detection of germline genetic alterations is also discussed.
Cancers (Basel). 2024 Nov 23. pii: 3927. [Epub ahead of print]16(23):

Analytical Validation and Performance Evaluation of Amplicon-Based Next-Generation Sequencing Assays for Detecting ERBB2 and Other Gene Amplifications in Solid Tumors.

Ekaterina Olkhov-Mitsel, Danny Chan, Kenneth J Craddock, August Lin, Grace Luk, Rashmi S Goswami, Hong Wang, Anna Plotkin, Sharon Nofech-Mozes, David M Hwang, Weei-Yuarn Huang.

   BACKGROUND: Targeted next-generation sequencing (NGS) panels are increasingly being utilized to identify actionable gene amplifications (copy number > 4) among solid tumors.
METHODS: This study validated the analytical performance of two amplicon-based NGS assays, the Oncomine Comprehensive Panel (OCAv3) and the Oncomine Focus Assay (OFA), for detecting gene amplification in formalin-fixed paraffin-embedded (FFPE) tumors of varying cellularity. OCAv3 was assessed for amplification detection in 756 FFPE samples comprising various tumor types.
RESULTS: We demonstrated that with standardized quality control metrics, including median absolute pairwise difference score, these assays can achieve a near-perfect positive predictive value, although their sensitivity for detecting amplifications significantly decreased in tumors with cellularity below 30%. Stratifying tumor cellularity into 10-30%, 31-60%, and 61-95% groups revealed significantly higher gene amplification detection rates in the 31-60% and 61-95% groups versus the 10-30% group (20.6% and 26.7% vs. 9.2%, p < 0.0001). When considering all detected gene amplifications, the average amplification calling per sample was nearly five-fold lower in the 10-30% group versus the 61-95% group (0.11 vs. 0.52; p < 0.0001). To further investigate the analytic performance of OCAv3 in detecting ERBB2 amplification, we analyzed a cohort of 121 uterine carcinomas with confirmed ERBB2 status by HER2 IHC or FISH, in which a threshold incorporating amplifications and tumor cellularity achieved 79% sensitivity and 100% specificity, potentially eliminating the need for FISH analysis in 34% of equivocal cases. In a separate validation cohort, similar analytical performance was observed, with the threshold demonstrating consistent sensitivity and specificity.
CONCLUSIONS: This study highlights the strengths and limitations of amplicon-based NGS assays in detecting amplifications using real-world data.

Keywords:  ERBB2 amplification; amplicon based next-generation sequencing; amplicon-based panels; copy number variation; fluorescence in situ hybridization; gene amplification; molecular pathology; solid tumors

DOI:  https://doi.org/10.3390/cancers16233927
Front Pharmacol. 2024 ;15 1437086

Case report: Favorable efficacy of combined afatinib and anlotinib treatment in a lung adenocarcinoma patient harboring uncommon EGFR L858M/L861R mutations.

Yueming He, Yitao Wu, Rongqi He, Meng Xu, Heshan Chen, Yiran Meng, Liuqing Zheng, Li Wang.

  Targeted therapy has significantly prolonged survival of non-small cell lung cancer (NSCLC) patients carrying common EGFR mutations, but the standard care for patients with rare mutations has not been well established. Here, we report a 65-year-old female diagnosed with stage IIIC lung adenocarcinoma located in the right inferior lobe, harboring uncommon EGFR L858M/L861R mutations. Remarkably, 24 days post-treatment of afatinib and anlotinib, chest CT scans demonstrated significant shrinkage of primary lesion, indicating a partial response. Except for mild hand-foot syndrome and diarrhea, no other severe adverse symptoms were observed throughout treatment. The patient, now on combination therapy for exceeding 12 months, exhibits further decreased tumor size and a high quality of life. This case underscores the importance of precise molecular diagnosis in guiding therapeutic strategies and provides a valuable reference for clinical decision-making in EGFR-positive NSCLC cases with atypical mutations.

Keywords:  EGFR L858M/L861R; afatinib; anlotinib; non-small cell lung cancer; rare mutations

DOI:  https://doi.org/10.3389/fphar.2024.1437086
Cancer Genet. 2024 Dec 15. pii: S2210-7762(24)00155-8. [Epub ahead of print]290-291 44-50

Microsatellite instability and high tumor mutational burden detected by next generation sequencing are concordant with loss of mismatch repair proteins by immunohistochemistry.

Richard K Yang, Hector Alvarez, Antony San Lucas, Sinchita Roy-Chowdhuri, Asif Rashid, Hui Chen, Leomar Y Ballester, Keith Sweeney, Mark J Routbort, Keyur P Patel, Rajyalakshmi Luthra, L Jeffrey Medeiros, Gokce A Toruner.

  Impairment of DNA mismatch repair function in neoplasms can be assessed by DNA-based methods to assess for high microsatellite instability (MSI-High) or immunohistochemical (IHC) analysis to assess for deficiency of mismatch repair proteins (dMMR). Neoplasms with mismatch repair deficiency often have high tumor mutational burden (TMB-High). MSI-High, dMMR, and TMB-High are all histology agnostic biomarkers for potential therapy using immune checkpoint inhibitors (ICI). In this single center, retrospective study, our primary aim was to assess if NGS-based positive TMB/MSI findings are concordant with patient matched concurrent MMR IHC studies. In addition, we determined if positive TMB/MSI findings are attributable to genetic/epigenetic alterations of MMR genes. Finally, we explored potential associations between IHC, TMB and MSI findings and specific tumor types We screened 4,258 patients in our database who had tumor-normal-testing with our institutional high-throughput NGS-based CLIA assay between Apr 1, 2021-August 31, 2022 for TMB and MSI. We identified 65 patients who had neoplasms with documented TMB-High/MSI-High (n = 59) or TMB-High/MSI-Undetermined (n = 6) results as well as concurrent IHC results for MMR proteins [colorectal (n = 25), endometrial (n = 28), prostatic (n = 7), urothelial (n = 3), other (n = 5)]. The concordance between positive NGS TMB/MSI and MMR results was 98 %. Genetic/epigenetic alterations of MMR genes were documented in 78 % of the neoplasms. IHC studies for dMMR proteins revealed loss of MLH1/PMS2 (n = 33), MSH2/MSH6 (n = 14), MLH1/MSH2/PMS2 (n = 1), MLH1 (n = 1), MSH2 (n = 2), MSH6 (n = 6) and PMS2 (n = 6). All six prostatic neoplasms with dMMR had loss of MSH2/MSH6 (p < 0.0001). We conclude that neoplasms with positive results for TMB/MSI are highly concordant with positive dMMR results. Genetic/epigenetic alterations in the MMR genes are an underlying reason for most positive findings. The association of MSH2/MSH6 loss with prostatic neoplasms is of in-terest, but sample size is limited, and further studies are warranted to address this association.

Keywords:  Immunohistochemistry; Microsatellite instability; Mismatched repair deficiency; Next generation sequencing; Solid tumors

DOI:  https://doi.org/10.1016/j.cancergen.2024.12.002
J Thorac Oncol. 2024 Dec 16. pii: S1556-0864(24)02531-0. [Epub ahead of print]

Decoding the Clinical and Molecular Signatures of EGFR Common, Compound, and Uncommon Mutations in Non-Small Cell Lung Cancer.

Daniele Tavernari, Maxime Borgeaud, Ximeng Liu, Parikh Kaushal, Xiuning Le, Giovanni Ciriello, Alfredo Addeo.

   INTRODUCTION: Epidermal growth factor receptor (EGFR) mutations are key oncogenic drivers in lung adenocarcinoma (LUAD), predominantly affecting Asian, non-smoking, and female populations. While common mutations, such as exon 19 deletions and L858R, respond well to tyrosine kinase inhibitors (TKIs), uncommon EGFR mutations and compound variants exhibit variable treatment responses. This study aims to compare clinical characteristics and molecular profiles of patients with common, uncommon, and compound EGFR mutations, assessing their implications for therapy outcomes.
METHODS: We analyzed a multi-cohort genomic dataset of 19,163 LUAD patients (5,212 with EGFR mutations), categorizing mutations into common, uncommon, and compound classes. Patient demographics, mutational signatures, and tumor microenvironment factors were assessed, with particular attention to smoking status and concomitant alterations in KRAS and TP53. Treatment outcomes were analyzed by time under treatment as a surrogate measure of TKI efficacy.
RESULTS: Uncommon EGFR mutations, comprising 8.9% of EGFR-altered cases, were significantly more frequent among smokers and associated with tobacco-related mutational signatures. Compared to common EGFR-mutant cases, tumors harboring uncommon EGFR mutations showed higher rates of EGFR amplifications, KRAS and TP53 mutations. Uncommon mutations also exhibited higher tumor mutational burden (TMB) and distinct transcriptional profiles linked to cell cycle activity. Median time on treatment with TKIs was notably shorter in patients with uncommon mutations (4.1 months) compared to those with common and compound mutations (10.9 and 12.4 months, respectively).
CONCLUSIONS: This study underscores the clinical and molecular heterogeneity of EGFR mutation classes in LUAD, highlighting the unique profile of uncommon mutations, particularly their association with smoking and co-mutations in KRAS and TP53. Comprehensive molecular testing, including next-generation sequencing, is crucial to identify these uncommon mutations and inform therapeutic decisions. Further investigation into the role of immunotherapy in patients with uncommon EGFR mutations is warranted given the tobacco-related molecular signatures and high TMB associated with this subgroup.

Keywords:  Compound EGFR mutations; Non-Small-Cell Lung Cancer; Uncommon EGFR mutations

DOI:  https://doi.org/10.1016/j.jtho.2024.12.012