Targetable Molecular Alterations Research Articles

Muscle-invasive and metastatic urothelial carcinoma of the urinary bladder : Current state of histopathologic, molecular, and immunologic prognostic and predictive factors

Muscle-invasive and metastatic urothelial carcinoma (UC) represents aheterogeneous disease entity with numerous morphological, molecular, and immunological phenotypes. This article aims to provide an overview of current histopathological, molecular, and immunological prognostic and predictive factors in muscle-invasive and metastatic UC. Muscle-invasive and metastatic UC exhibits awide range of divergent differentiations and histological subtypes. The correct diagnosis of these morphological variants is essential, as they may determine the clinical course and may also present specific and potentially therapeutically targetable molecular alterations (e.g., HER2 alterations in micropapillary UC). The morphological subtypes largely correlate with the six molecular consensus subtypes. Furthermore, morphological and molecular subtypes are associated with immunological properties that are relevant for modern immunotherapies, such as the PD-L1 status. Numerous immunotherapy studies in the setting of curatively treatable muscle-invasive UC will be reported in 2024 and 2025, likely leading to an increasing number of PD-L1 testing indications.

Non-small cell lung carcinoma with clear cell features: a clinicopathologic, immunohistochemical, and molecular study of 31 cases.

Non-small cell lung carcinoma with predominantly clear cell features is a rare histologic presentation of lung carcinoma. We have examined 31 cases of lung carcinomas showing extensive clear cell features. The patients were 10 women and 21 men aged 47-92years (mean: 70years). The tumors showed a predilection for the right upper and lower lobes and measured from 0.8 to 9.5cm (mean: 4.2cm). By immunohistochemistry, 9 cases were typed as adenocarcinoma, 19 cases as squamous cell carcinoma, and 3 showed a "null" phenotype with complete loss of markers for adenocarcinoma or squamous cell carcinoma. Most cases that typed as adenocarcinoma showed a solid growth pattern. A subset of the solid adenocarcinoma cases showed a distinctive "pseudosquamous" morphology. Next-generation sequencing was performed in 20 cases and showed a variety of molecular alterations. The most common abnormalities were found in the TP53 gene (9 cases), FGFR gene family (8 cases), KRAS (5 cases), AKT1 (5 cases), and BRAF (3 cases). Clinical follow-up was available in 21 patients; 16/21 patients died of their tumors from 6months to 12years after initial diagnosis (mean: 4.2years, median: 1.5years). Four patients were alive and well from 4 to 27years (mean: 11.5years, median: 7.5years); all were pathologic stage 1 or 2. NSCLC with clear cell features can display aggressive behavior and needs to be distinguished from various other tumors of the lung that can show clear cell morphology. The identification of targetable molecular alterations in some of these tumors may be of value for therapeutic management.

Targeted treatment in inflammatory myofibroblastic tumors in children.

10046 Background: Inflammatory myofibroblastic tumors (IMTs) and epithelioid inflammatory myofibroblastic sarcoma (EIMS)-a variant of IMT, are rare mesenchymal neoplasms in children. Surgical resection has been the mainstay of treatment, however it may cause morbidities due to the size, location, invasiveness of the tumor. With the identification of targetable molecular alterations, targeted treatment has begun to be used in inoperable/relapsed/refractory cases. Methods: Files of children with IMT diagnosed and treated between 1990-2023 were retrospectively evaluated for demographic, clinical, molecular characteristics, treatment and outcome. Results: The mean age of 8 patients (5 male, 3 female) at diagnosis was 9 years (8 months-17 years). Six had IMT and two EMS. Tumor localization was intestine, retroperitoneum, lower extremity in two patients each; liver and back in one each. None had metastatic at diagnosis. Three of the six patients (one EMS) who underwent only surgical resection had negative surgical margins (one after re-resection) and are under follow-up with no evidence of disease (NED). Molecular analysis was performed in six patients. ALK was positive in the tumor tissue of five patients. One patient with an inoperable local recurrence received chemotherapy, had a life-threatening infection and resistant hypercalcemia. The molecular analysis by next-generation sequencing revealed a YWHAE-ROS fusion and she was treated by ceritinib, after which a significant (>90%) tumor shrinkage occurred and hypercalcemia resolved. She is currently in remission and continuing treatment. The patient with a positive surgical margin experienced local and metastatic (lung, liver) recurrences during follow-up and was treated with chemotherapy containing vincristine, actinomycin-D, and cyclophosphamide, the patient died due to progressive disease. In a patient with an unresectable tumor and ALK positivity, crizotinib treatment was initiated. After a treatment duration of seven months with crizotinib, the tumor completely regressed and treatment was stopped. On follow-up, local recurrence was detected after two months of cessation of crizotinib, crizotinib was restarted, considering the infiltrative appearance of the tumor and possible morbidities if operated. Two months after readministering crizotinib, complete response was achieved once again. The patient is continuing treatment with crizotinib. Thus, 7/8 patients are alive with NED for a median of 99 (9-174) months. Conclusions: Inflammatory myofibroblastic tumor and epithelioid inflammatory myofibroblastic sarcoma are rare in children. Surgery is the mainstay of treatment. The effectiveness of chemotherapy is yet unclear despite its use in inoperable cases. Molecular analysis of tumor tissue is highly recommended as targets such as ALK rearrangements or ROS fusions may enable the use of targeted treatments with fewer side effects.

IMPRESS-Norway: improving public cancer care by implementing precision medicine in Norway; inclusion rates and preliminary results.

In Norway, comprehensive molecular tumour profiling is implemented as part of the public healthcare system. A substantial number of tumours harbour potentially targetable molecular alterations. Therapy outcomes may improve if targeted treatments are matched with actionable genomic alterations. In the IMPRESS-Norway trial (NCT04817956), patients are treated with drugs outside the labelled indication based on their tumours molecular profile. IMPRESS-Norway is a national, prospective, non-randomised, precision cancer medicine trial, offering treatment to patients with advanced-stage disease, progressing on standard treatment. Comprehensive next-generation sequencing, TruSight Oncology 500, is used for screening. Patients with tumours harbouring molecular alterations with matched targeted therapies available in IMPRESS-Norway, are offered treatment. Currently, 24 drugs are available in the study. Primary study endpoints are percentage of patients offered treatment in the trial, and disease control rate (DCR) defined as complete or partial response or stable disease in evaluable patients at 16 weeks (W16) of treatment. Secondary endpoint presented is DCR in all treated patients. Between April 2021 and October 2023, 1,167 patients were screened, and an actionable mutation with matching drug was identified for 358 patients. By the data cut off 186 patients have initiated treatment, 170 had a minimum follow-up time of 16 weeks, and 145 also had evaluable disease. In patients with evaluable disease, the DCR was 40% (58/145). Secondary endpoint analysis of DCR in all treated patients, showed DCR of 34% (58/170). Precision cancer medicine demonstrates encouraging clinical effect in a subset of patients included in the IMPRESS-Norway trial.

Myxoid Inflammatory Myofibroblastic Sarcoma: Clinicopathologic Analysis of 25 Cases of a Distinctive Sarcoma With Deceptively Bland Morphology and Aggressive Clinical Behavior.

The number of recognized sarcoma types harboring targetable molecular alterations continues to increase. Here we present 25 examples of a distinctive myofibroblastic tumor, provisionally termed "myxoid inflammatory myofibroblastic sarcoma," which might be related to inflammatory myofibroblastic tumor, and which occurred in 13 males (52%) and 12 females at a median age of 37 years (range: 7 to 79 years). Primary tumor sites were peritoneum (18 patients; 72%), paratesticular (2; 8%), chest wall (1), upper extremity (1), esophagus (1), retroperitoneum (1), and uterus (1). Nine peritoneal tumors (50%) were multifocal at presentation; all other tumors were unifocal. Tumors showed bland-to-mildly-atypical neoplastic myofibroblasts in a myxoid stroma, with prominent inflammatory infiltrates in 22 cases (88%). Most tumors showed delicate branching stromal vessels like those of myxoid liposarcoma, and most showed infiltrative growth through non-neoplastic tissue. Immunohistochemistry demonstrated expression of SMA (19/25 tumors; 76%), desmin (13/22; 59%), and CD30 (5/11; 45%), while ALK was expressed in 1 tumor (of 25; 4%) that was negative for ALK rearrangement. Sequencing of 11 tumors showed seven to harbor tyrosine kinase fusions (4 PDGFRB , 2 PML :: JAK1 , 1 SEC31A :: PDGFRA ). Two instead harbored hot spot KRAS mutations (G12V and Q61H), and 2 were negative for known driving alterations. Clinical follow-up was available for 18 patients (72%; median: 2.7 years; range: 4 mo-12.3 years). Nine patients (50%) were alive with no evidence of disease, 5 (28%) died of disease, and 4 (22%) were alive with disease. Seven patients (39%) experienced peritoneal relapse or distant metastasis. Two patients showed disease progression on conventional, nontargeted chemotherapy. The patient whose tumor harbored SEC31A :: PDGFRA was treated after multiple relapses with imatinib and sunitinib therapy, with progression-free periods of 5 and 2 years, respectively. Despite its bland appearance, myxoid inflammatory myofibroblastic sarcoma harbors a significant risk for disseminated disease, particularly when it occurs in the peritoneum. Targeted therapy could be considered for patients with disseminated disease.

Targeting KRAS in Pancreatic Ductal Adenocarcinoma: The Long Road to Cure.

Pancreatic ductal adenocarcinoma (PDAC) remains an important cause of cancer-related mortality, and it is expected to play an even bigger part in cancer burden in the years to come. Despite concerted efforts from scientists and physicians, patients have experienced little improvement in survival over the past decades, possibly because of the non-specific nature of the tested treatment modalities. Recently, the discovery of potentially targetable molecular alterations has paved the way for the personalized treatment of PDAC. Indeed, the central piece in the molecular framework of PDAC is starting to be unveiled. KRAS mutations are seen in 90% of PDACs, and multiple studies have demonstrated their pivotal role in pancreatic carcinogenesis. Recent investigations have shed light on the differences in prognosis as well as therapeutic implications of the different KRAS mutations and disentangled the relationship between KRAS and effectors of downstream and parallel signaling pathways. Additionally, the recognition of other mechanisms involving KRAS-mediated pathogenesis, such as KRAS dosing and allelic imbalance, has contributed to broadening the current knowledge regarding this molecular alteration. Finally, KRAS G12C inhibitors have been recently tested in patients with pancreatic cancer with relative success, and inhibitors of KRAS harboring other mutations are under clinical development. These drugs currently represent a true hope for a meaningful leap forward in this dreadful disease.

Cancer broncho-pulmonaire : Quel bilan moléculaire ?: Lung Cancer: what do we propose for molecular testing?

The identification of targetable molecular alterations is now required before starting any treatment of patients with non-small cell lung cancer, particularly for non-squamous. Molecular diagnosis is mainly realized on tissue samples but analyzing circulating tumor DNA is also a valuable tool in the daily practice. The diversification of therapeutic targets requires the use of various molecular biology techniques adapted to the search for targets on DNA (point mutations, small deletions / insertions, gene amplification) but also on RNA (fusion transcript, exon skipping). In addition to new generation sequencing, many targeted techniques are also proposed by laboratories. The choice of technologies must be made according to the criteria of exhaustiveness of the results, analytical sensitivity, delay of results and cost. For this, a close discussion with clinicians and pathologists is essential.1877-1203/© 2023 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Targetable Molecular Alterations in the Treatment of Biliary Tract Cancers: An Overview of the Available Treatments.

Biliary tract cancers (BTCs) are rare tumours, most often diagnosed at an unresectable stage, associated with poor prognosis, with a 5-year survival rate not exceeding 10%. Only first- and second-line treatments are well codified with the combination of cisplatin-gemcitabine chemotherapy and immunotherapy followed by 5-FU and oxaliplatin chemotherapy, respectively. Many studies have shown that BTC, and more particularly intrahepatic cholangiocarcinoma (iCCA), have a high rate of targetable somatic alteration. To date, the FDA has approved several drugs. Ivosidenib targeting IDH1 mutations, as well as futibatinib and pemigatinib targeting FGFR2 fusions, are approved for pre-treated advanced CCA. The combination of dabrafenib and trametinib are approved for BRAFV600E mutated advanced tumours, NTRK inhibitors entrectinib and larotrectinib for tumours bearing NTRK fusion and prembrolizumab for MSI-H advanced tumours, involving a small percentage of BTC in these three settings. Several other potentially targetable alterations are found in BTC, such as HER2 mutations or amplifications or KRASG12C mutations and mutations in genes involved in DNA repair mechanisms. This review aims to clarify the specific diagnostic modalities for gene alterations and to summarize the results of the main trials and developments underway for the management of advanced BTC with targetable alterations.

Developments in targeted therapy & immunotherapy-how non-small cell lung cancer management will change in the next decade: a narrative review.

The adoption of targeted therapy and immunotherapy has revolutionised the treatment landscape of non-small cell lung cancer. For early staged disease, incorporation of targeted therapy and immunotherapy has recently been demonstrated to reduce recurrence. Development of targeted therapies in advanced lung cancer is driven by advanced genomic sequencing techniques, better understanding of drug resistance mechanisms, and improved drug designs. The list of targetable molecular alteration is continuously expanding, and next generation molecular therapies have shown promise in circumventing drug resistance. Lung cancer patients may achieve durable disease control with immune checkpoint inhibitors however most patients develop immunotherapy resistance. A wide spectrum of resistance mechanisms, ranging from impaired T-cell activation, presence of coinhibitory immune checkpoints, to immunosuppressive tumour microenvironment, have been proposed. A multitude of novel immunotherapy strategies are under development to target such resistance mechanisms. This review aims to provide a succinct overview in the latest development in targeted therapy and immunotherapy for NSCLC management. We searched all original papers and reviews on targeted therapy and immunotherapy in non-small cell lung cancer (NSCLC) using PubMed in June 2022. Search terms included "non-small cell lung cancer", "targeted therapy", "immunotherapy", "EGFR", "ALK", "ROS1", "BRAF V600E", "MET", "RET", "KRAS", "HER2", "ERBB2", "NRG1", "immune checkpoint", "PD-1", "PD-L1", "CTLA4", "TIGIT", "VEGF", "cancer vaccine", "cellular therapy", "tumour microenvironment", "cytokine", and "gut microbiota". We first discuss the incorporation of targeted therapy and immunotherapy in early staged NSCLC. This includes the latest clinical data that led to the approval of neoadjuvant immunotherapy, adjuvant immunotherapy and adjuvant targeted therapy for early staged NSCLC. The second section focuses on targeted therapy in metastatic NSCLC. The list of targetable alteration now includes but is not limited to EGFR, ALK, ROS1, BRAF V600E, MET exon 14 skipping, RET, KRAS G12C, HER2 and NRG1. Potential drug resistance mechanisms and novel therapeutics under development are also discussed. The third section on immunotherapy in metastatic NSCLC, covers immunotherapy that are currently approved [anti-PD-(L)1 and anti-CTLA4], and agents that are under active research (e.g., anti-TIGIT, cancer vaccine, cellular therapy, cytokine and other TME modulating agents). This review encompasses the latest updates in targeted therapy and immunotherapy in lung cancer management and discusses the future direction in the field.

Anaplastic thyroid cancer cells upregulate mitochondrial one-carbon metabolism to meet purine demand, eliciting a critical targetable vulnerability

Anaplastic thyroid cancer (ATC) is one of the most aggressive and lethal tumor types, characterized by loss of differentiation, epithelial-to-mesenchymal transition, extremely high proliferation rate, and generalized resistance to therapy. To identify novel relevant, targetable molecular alterations, we analyzed gene expression profiles from a genetically engineered ATC mouse model and from human patient datasets, and found consistent upregulation of genes encoding enzymes involved in the one-carbon metabolic pathway, which uses serine and folates to generate both nucleotides and glycine.Genetic and pharmacological inhibition of SHMT2, a key enzyme of the mitochondrial arm of the one-carbon pathway, rendered ATC cells glycine auxotroph and led to significant inhibition of cell proliferation and colony forming ability, which was primarily caused by depletion of the purine pool. Notably, these growth-suppressive effects were significantly amplified when cells were grown in the presence of physiological types and levels of folates. Genetic depletion of SHMT2 dramatically impaired tumor growth in vivo, both in xenograft models and in an immunocompetent allograft model of ATC.Together, these data establish the upregulation of the one-carbon metabolic pathway as a novel and targetable vulnerability of ATC cells, which can be exploited for therapeutic purposes.

A radiomic-based predictive model of lung adenocarcinoma brain metastases and molecular subtypes.

2014 Background: Non-small cell lung cancer (NSCLC) comprises the largest portion of brain metastases (BM) from solid cancer with 40% of patients developing BM during the course of their disease. There are currently no reliable prediction tools for identifying patients at risk for BM, especially in the early-stage setting where MRI screening is not performed. Furthermore, in the later stage setting, brain MRI are only performed annually. Therefore, there is a critical need to identify high-risk patients for BM that could benefit from MRI surveillance. Methods: We identified 162 lung adenocarcinoma (LUAD) patients with (N = 66) or without (N = 96) BM that had treatment-naïve CT scans with a segmentable lesion. The tumor, surrounding ground glass opacity and necrosis were segmented via 3D slicer to create a volume of interest for radiomic texture analysis and 400 features were extracted. The Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression feature selection method was used to select the most relevant features and models were built using the machine learning method XGBoost classifier. Training and testing sets with random splitting was used for cross validation. We report the accuracy, sensitivity, specificity, and area under the curve (AUC) for each model. Results: Among the extracted features that LASSO deemed as most discriminative for development of BM, we identified the most relevant features using XGBoost that predicted BM with 79% accuracy, 83% sensitivity, 72% specificity, and 79% AUC ( p= 0.01) in the overall population. The addition of ground glass opacity and necrosis to the model did not significantly improve performance. Furthermore, the model distinguished those with metachronous vs synchronous BM with 84% accuracy, 83% sensitivity, 86% specificity, and 83% AUC ( p = 0.04). Our model held up across molecular subtypes ( EGFR and KRAS mutant). Importantly, the model was predictive in early-stage patients with 92% accuracy, 96% sensitivity, 83% specificity, and 95% AUC ( p= 0.0005). Moreover, our model predicted for high vs. low overall survival, and was BM-specific as it was not predictive of other sites of metastases. We further developed a model from the CT features that correctly classified KRAS mutant vs. KRAS wild type LUAD with 77% accuracy, 73% sensitivity, 80% specificity, and 80% AUC ( p= 0.002). Conclusions: Utilizing a radiomics approach, we were able to predict BM from primary lung CT features including in stage I and II disease, predict synchronous vs metachronous BM, and distinguish distinct molecular LUAD subtypes. We are currently validating our BM prediction model in a large independent cohort and developing models to classify targetable LUAD-BM molecular alterations utilizing brain MRI scans. These studies will identify patients that require MRI surveillance in the early-stage setting and more intensive surveillance in the late-stage setting for BM.

Clinical utility of plasma ctDNA sequencing in metastatic urothelial carcinoma.

4576 Background: Genomic stratification may help to improve the management of patients with metastatic urothelial cancer (mUC) given the recent identification of targetable molecular alterations in this disease. However, collecting tissue samples in mUC remains challenging. We assessed the clinical utility of plasma circulating tumor DNA (ctDNA) sequencing in mUC. Methods: mUC patients were prospectively enrolled in the STING trial (NCT04932525) whereby ctDNA was profiled using the FoundationOne Liquid CDx Assay (324 genes, tumor mutational burden [TMB], microsatellite instability status). Each individual genomic report was reviewed and discussed weekly by a multidisciplinary tumor board (MTB). Actionable targets were classified by ESCAT tier leading to molecular-based treatment suggestions whenever it was possible. Results: Between January 2021 and June 2022, 140 mUC patients underwent molecular profiling. Median time to assay results was 20 days. ctDNA abundance was correlated with number of prior lines and number of metastatic sites. ctDNA analysis reproduces the somatic genomic landscape reported by previous tissue-based cohorts. Concordance for serial tumor tissue was moderate (r=0.545 CI95: [0.121-0.801], p= 0.016). At least one actionable target was detected in 63 patients (45 %) with a total of 35 actionable alterations including TMB high (≥12 mutations/Mb) (N= 39, 21.1%), FGFR3 (N= 20, 10.8%) and HRD alterations (N= 14, 7.6%). The MTB recommended a matched therapy for 63 patients (45.0%). In total, 8 patients (5.7 %) were treated with an overall response rate of 50% (95%: 15.70-84.30) and a median PFS of 5.2 months (CI95%: 4.1 - NR). FGFR3 alterations were associated with lower progression-free survival in patients treated with immunotherapy. Conclusions: Overall, our analysis demonstrates that genomic profiling with a large panel of ctDNA in mUC is a reliable and feasible approach to timely initiate genotype-matched therapies. Clinical trial information: NCT04932525 .

Clinical implications of molecular alterations in intraductal carcinoma of the prostate.

5024 Background: Intraductal carcinoma of the prostate (IDC-P) is a recent addition to the 2016 WHO classification system and little is known about the nature of its true incidence and biology. Clinically, it has been observed to be associated with higher grade group tumors and a more aggressive disease course with a high risk of local recurrence and distant metastasis. However, the molecular underpinnings which define IDC-P are not well elucidated. Initial case series with molecular profiling have suggested an enrichment of alterations in DNA damage/repair (DDR), PI3K, WNT and MAPK pathways. We now present comprehensive molecular profiling data from the largest cohort of IDC-P reported to date in order to better characterize this relatively new histologic entity. Methods: Eligible patients included those with radical prostatectomy tumor tissue labeled as IDC-P on testing requisition with available tissue-based DNA and RNA sequencing utilizing a commercially available CLIA-certified assay (Caris Life Sciences). Prostatic tumor specimens were analyzed using NextGen DNA sequencing (NextSeq, 592 genes and NovaSeq, WES). Digitized H&E slides underwent central pathological review by a board certified pathologist (SW) specializing in genitourinary malignancies to confirm presence of intraductal histology according to the 2022 WHO classification. Results: 31 of 44 submitted cases were confirmed to be IDC-P on central review. Median age of patients was 64 yrs (range 44-79). The majority of cases (26/31 - 84%) were Grade Group 5 and all were Grade Group 3 or higher. Overall the most frequently detected alterations were in TP53 (39%), TMPRSS2 fusion (39%), FOXA1 (16%), CDK12 (10%), PIK3CA (10%), SPOP (10%), ATM (7%), AKT1 (7%) and RB1 (5%). The most commonly altered pathways were in cell cycle regulators (50%), DDR ( BRCA1/2, ATM, CDK12) (23%), and PI3K/AKT/MTOR (23%) and WNT (10%). The FOXA1 mutation rate in this cohort was higher compared to the localized prostate cancer cohort from the TCGA (16% - 5/31 vs 6% - 82/1325). In the IDC-P cohort, there were no tumors which demonstrated mismatch-repair deficiency (dMMR) or microsatellite instability and none of the profiled tumors had a high tumor mutational burden (≥10 mutations/megabase). Conclusions: This data suggests that IDC-P harbors targetable molecular alterations in DDR genes ( BRCA1/2 and CDK12) with approved targeted agents (e.g. PARP inhibitors). These findings should underscore the importance of germline and somatic mutation testing when IDC-P is identified. We also found enrichment of oncogenic FOXA1 mutations in IDC-P which are associated with prostate cancer progression, castrate-resistance and an unfavorable prognosis. Further efforts are ongoing to expand this cohort of IDC-P cases and compare them with a matched cohort of pure adenocarcinoma cases and will include analysis of key RNA expression signatures.

IMPRESS-Norway: Improving public cancer care by implementing precision cancer medicine in Norway.

e15188 Background: Precision cancer medicine is evolving rapidly, with new drugs and biomarkers being developed. Advanced molecular diagnostics is a prerequisite for using some of the drugs, which might be approved on small or large subsets of patients. Drugs targeting a specific pathway or gene aberration, might be efficient in other tumour types harbouring the same molecular alteration, but not yet tried in randomized trials due to limited number of patients. This indicates that patients might benefit drugs that are on the market, not available for patients outside the existing indication. Methods: In this national-wide, investigator-initiated, prospective, open-label, non-randomized combined basket- and umbrella-trial, patients are enrolled into multiple parallel treatment cohorts. Patients with progressive disease on standard therapy, are eligible. Each cohort is defined by the patient’s tumour type, molecular profile, and study drug. Treatment outcome in each cohort is assessed by using a Simon two-stage-like ‘admissible’ monitoring plan to identify evidence of clinical activity. All drugs available in IMPRESS-Norway have regulatory approval and are funded by pharmaceutical companies. Currently, 21 drugs are provided by six different pharmaceutical companies, and we are in process to acquire additional drugs for patients in this study. Molecular diagnostics with the TSO-500 gene panel are funded by the public health care system. In addition, patients included are offered analyses of circulating tumour DNA (ctDNA). The primary objective is to evaluate clinical benefit of treatment at 16 weeks of treatment, defined as complete response, partial response, or stable disease. Results: IMPRESS-Norway opened for accrual at April 1st 2021. As of January 24, 2023, tumour cells from 791 patients with advanced cancer, have been analysed with TSO-500, and 662 patients had been discussed at the national molecular tumour board. 150 patients (23%) were allocated to therapy in different treatment-cohorts in IMPRESS-Norway, and 11% were referred to other ongoing clinical studies or early access programs. Extended and updated data and frequency of targetable molecular alteration will be presented. Conclusions: Patients with advanced cancer progressing on standard treatment are referred to treatment in IMPRESS-Norway after advanced molecular diagnostics. Genetic alterations indicating benefit of the drugs currently available in the study, are detected in 23% of 662 evaluated patients. Clinical trial information: NCT04817956 .

Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma: Real-life Data on Liver Disease, Treatment and Prognosis.

Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) have common features and differences. This real-life study investigated their characteristics, treatment modalities, and prognoses. This retrospective comparative study was performed in 1,075 patients seen at one tertiary center between January 2008 and December 2020. Overall survival (OS) was estimated by the Kaplan-Meier method. Subclassification of iCCAs after histological and radiological review, and molecular profiling was performed. HCCs patients were more likely to have early-stage disease than iCCA patients. iCCA patients were more likely to be female, especially those patients without cirrhosis (43% vs. 17%). Cirrhosis was prominent among HCC patients (89% vs. 34%), but no difference in underlying liver disease among cirrhotic patients was found. OS of HCC patients was 18.4 (95% CI: 6.4, 48.3) months, that of iCCA patients was 7.0 (95% CI: 3.4, 20.1) months. OS of Barcelona Clinic Liver Cancer C HCC patients was 7.8 (95% CI: 4.3, 14.2) months, that of advanced/metastatic iCCA patients was 8.5 (95% CI: 5.7, 12.3) months. In patients treated with sorafenib, OS was longer in HCC patients who received subsequent tyrosine kinase inhibitor therapies. No significant OS difference was found between iCCA patients with and without cirrhosis or according to histological subtype. A targetable molecular alteration was detected in 50% of the iCCA patients. In this French series, cirrhosis was common in iCCA, which showed etiological factors comparable to those of HCC, implying a distinct oncogenic pathway. Both entities had a dismal prognosis at advanced stages. However, systemic therapies sequencing in HCC and molecular profiling in iCCA offer new insights.

Lack of correlation between MET and PD-L1 expression in non-small cell lung cancer revealed by comparative study of matched biopsies and surgical resection samples

IntroductionBoth MET expression and the PD-L1 tumor proportion score (TPS) are companion diagnostics for treatment of advanced non-small cell lung carcinoma (aNSCLC) patients. We evaluated the rate of correlation between MET expression and the PD-L1 TPS in matched biopsies and surgically resected specimens from NSCLC patients. Patients and MethodsThis retrospective analysis assessed the prevalence and correlation between MET expression (SP44 clone) and the PD-L1 TPS (22C3 clone) by immunohistochemistry together with molecular alterations determined by targeted next-generation sequencing in matched lung biopsy and surgically lung resected specimens from 70 patients with NSCLC. ResultsThe study found a significant correlation between the MET H-score in surgical samples and matched biopsies (P-value < 0.0001), as well as between the PD-L1 TPS in paired biopsies and surgical samples (P-value < 0.0001). However, there was no significant correlation between the MET H-score or expression subgroups and the PD-L1 TPS in both types of paired samples (P-value = 0.47, and P-value = 0.90). The MET H-score was significantly higher in adenocarcinoma compared to squamous cell carcinoma (P-value < 0.0001). A mutational analysis showed that the MET H-score was significantly higher in NSCLC cases with targetable molecular alterations (P-value = 0.0095), while no significant correlation was found for the PD-L1 TPS. ConclusionsOur study found no significant correlation between PD-L1 and MET expression in samples from NSCLC patients, highlighting the importance of personalized treatment strategies based on individual expression profiles. These findings provide valuable insight into the development of effective immunotherapy and targeted therapy for NSCLC patients.

A molecular guide to systemic therapy in salivary gland carcinoma.

Salivary gland carcinomas (SGC) are a rare and variable group of head and neck cancers with historically poor response to cytotoxic chemotherapy and immunotherapy in the recurrent, advanced, and metastatic settings. In the last decade, a number of targetable molecular alterations have been identified in SGCs including HER2 upregulation, androgen receptor overexpression, Notch receptor activation, NTRK gene fusions, and RET alterations which have dramatically improved treatment outcomes in this disease. Here, we review the landscape of precision therapy in SGC including current options for systemic management, ongoing clinical trials, and promising future directions.

Clinical management of molecular alterations identified by high throughput sequencing in patients with advanced solid tumors in treatment failure: Real-world data from a French hospital.

In the context of personalized medicine, screening patients to identify targetable molecular alterations is essential for therapeutic decisions such as inclusion in clinical trials, early access to therapies, or compassionate treatment. The objective of this study was to determine the real-world impact of routine incorporation of FoundationOne analysis in cancers with a poor prognosis and limited treatment options, or in those progressing after at least one course of standard therapy. A FoundationOneCDx panel for solid tumor or liquid biopsy samples was offered to 204 eligible patients. Samples from 150 patients were processed for genomic testing, with a data acquisition success rate of 93%. The analysis identified 2419 gene alterations, with a median of 11 alterations per tumor (range, 0-86). The most common or likely pathogenic variants were on TP53, TERT, PI3KCA, CDKN2A/B, KRAS, CCDN1, FGF19, FGF3, and SMAD4. The median tumor mutation burden was three mutations/Mb (range, 0-117) in 143 patients with available data. Of 150 patients with known or likely pathogenic actionable alterations, 13 (8.6%) received matched targeted therapy. Sixty-nine patients underwent Molecular Tumor Board, which resulted in recommendations in 60 cases. Treatment with genotype-directed therapy had no impact on overall survival (13 months vs. 14 months; p = 0.95; hazard ratio = 1.04 (95% confidence interval, 0.48-2.26)]. This study highlights that an organized center with a Multidisciplinary Molecular Tumor Board and an NGS screening system can obtain satisfactory results comparable with those of large centers for including patients in clinical trials.

Advances in the Management of Central Nervous System Metastases in Non-Small Cell Lung Cancer.

Central nervous system (CNS) metastases are common among patients with non-small cell lung cancer (NSCLC). While the presence of brain metastases has historically portended poor prognosis, recent advances in local and systemic therapies have greatly improved outcomes for NSCLC patients with CNS involvement. Stereotactic radiology surgery (SRS) has emerged as an effective radiotherapy technique with fewer toxicities compared to whole brain radiotherapy (WBRT). Furthermore, multi-generation tyrosine kinase inhibitors (TKIs) with CNS overall response rates (ORR) of up to 70-80% are now an accepted first-line approach for a subset of advanced NSCLC patients with targetable molecular alterations. In addition, while the CNS was once considered an immunologic sanctuary site, growing evidence shows that immune checkpoint inhibitors (ICIs) can induce durable responses in brain metastases as well. Ongoing efforts to optimize CNS metastases management are necessary to refine multimodal treatment approaches and develop new therapeutics with better CNS penetrance.

Molecular profiling of male breast cancer by multigene panel testing: Implications for precision oncology.

Compared with breast cancer (BC) in women, BC in men is a rare disease with genetic and molecular peculiarities. Therapeutic approaches for male BC (MBC) are currently extrapolated from the clinical management of female BC, although the disease does not exactly overlap in males and females. Data on specific molecular biomarkers in MBC are lacking, cutting out male patients from more appropriate therapeutic strategies. Growing evidence indicates that Next Generation Sequencing (NGS) multigene panel testing can be used for the detection of predictive molecular biomarkers, including Tumor Mutational Burden (TMB) and Microsatellite Instability (MSI). In this study, NGS multigene gene panel sequencing, targeting 1.94 Mb of the genome at 523 cancer-relevant genes (TruSight Oncology 500, Illumina), was used to identify and characterize somatic variants, Copy Number Variations (CNVs), TMB and MSI, in 15 Formalin-Fixed Paraffin-Embedded (FFPE) male breast cancer samples. A total of 40 pathogenic variants were detected in 24 genes. All MBC cases harbored at least one pathogenic variant. PIK3CA was the most frequently mutated gene, with six (40.0%) MBCs harboring targetable PIK3CA alterations. CNVs analysis showed copy number gains in 22 genes. No copy number losses were found. Specifically, 13 (86.7%) MBCs showed gene copy number gains. MYC was the most frequently amplified gene with eight (53.3%) MBCs showing a median fold-changes value of 1.9 (range 1.8-3.8). A median TMB value of 4.3 (range 0.8-12.3) mut/Mb was observed, with two (13%) MBCs showing high-TMB. The median percentage of MSI was 2.4% (range 0-17.6%), with two (13%) MBCs showing high-MSI. Overall, these results indicate that NGS multigene panel sequencing can provide a comprehensive molecular tumor profiling in MBC. The identification of targetable molecular alterations in more than 70% of MBCs suggests that the NGS approach may allow for the selection of MBC patients eligible for precision/targeted therapy.