BackgroundThird-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as osimertinib are the last line of targeted treatment of metastatic non-small-cell lung cancer (NSCLC) EGFR-mutant harboring T790M. Different mechanisms of acquired resistance to third-generation EGFR-TKIs have been proposed. It is therefore crucial to identify new and effective strategies to overcome successive acquired mechanisms of resistance.MethodsFor Amplicon-seq analysis, samples from the index patient (primary and metastasis lesions at different timepoints) as well as the patient-derived orthotopic xenograft tumors corresponding to the different treatment arms were used. All samples were formalin-fixed paraffin-embedded, selected and evaluated by a pathologist. For droplet digital PCR, 20 patients diagnosed with NSCLC at baseline or progression to different lines of TKI therapies were selected. Formalin-fixed paraffin-embedded blocks corresponding to either primary tumor or metastasis specimens were used for analysis. For single-cell analysis, orthotopically grown metastases were dissected from the brain of an athymic nu/nu mouse and cryopreserved at −80°C.ResultsIn a brain metastasis lesion from a NSCLC patient presenting an EGFR T790M mutation, we detected MET gene amplification after prolonged treatment with osimertinib. Importantly, the combination of capmatinib (c-MET inhibitor) and afatinib (ErbB-1/2/4 inhibitor) completely suppressed tumor growth in mice orthotopically injected with cells derived from this brain metastasis. In those mice treated with capmatinib or afatinib as monotherapy, we observed the emergence of KRAS G12C clones. Single-cell gene expression analyses also revealed intratumor heterogeneity, indicating the presence of a KRAS-driven subclone. We also detected low-frequent KRAS G12C alleles in patients treated with various EGFR-TKIs.ConclusionAcquired resistance to subsequent EGFR-TKI treatment lines in EGFR-mutant lung cancer patients may induce genetic plasticity. We assess the biological insights of tumor heterogeneity in an osimertinib-resistant tumor with acquired MET-amplification and propose new treatment strategies in this situation.

Purpose: Treatment options for advanced cholangiocarcinoma are limited and prognosis is poor. Cholangiocarcinomas are highly heterogeneous at the molecular level, with divergent patterns between intrahepatic and extrahepatic forms, intrahepatic being particularly rich in actionable alterations. We compared survival in patients with advanced cholangiocarcinoma harboring alterations matched to targeted drugs, with patients harboring nonactionable alterations. Experimental Design: Patients with cholangiocarcinoma treated between 2011 and 2020 at one institution, with available molecular analyses, were retrospectively reviewed. Genomic alteration actionability was classified according to the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) and correlated with efficacy endpoints. Results: Of 327 patients included, 78.9% had intrahepatic cholangiocarcinoma, 97.9% had received chemotherapy for metastatic disease. Actionable molecular alterations per ESCAT were identified in 184 patients (56.3%), including IDH1 mutations and FGFR2 fusions (23.1% and 8.0% of patients with intrahepatic cholangiocarcinoma, respectively). Median overall survival in 50 patients with ESCAT I-IV alterations who received matched therapy (48 with intrahepatic cholangiocarcinoma) was 22.6 months [95% confidence interval (CI), 20.1–32.8], compared with 14.3 months (95% CI 11.9–18.1) in 130 patients without actionable ESCAT alterations (HR, 0.58; 95% CI, 0.40–0.85; P = 0.005). Among patients receiving matched targeted therapy, median progression-free survival was longer for patients with alterations classified as ESCAT I-II compared with ESCAT III-IV (5.0 vs. 1.9 months; HR, 0.36; 95% CI, 0.15–0.87; P = 0.02). Conclusions: ESCAT represents a tool to guide clinicians in fine-tuning use of molecular profiling data to choose matched targeted therapies. Our data demonstrate that targeted treatment administered per alteration actionability according to ESCAT is associated with improved survival in cholangiocarcinoma, particularly in ESCAT I-II intrahepatic cholangiocarcinoma.

Gastric and gastro-oesophageal junction cancer (GC) represents a worldwide problem, this being the fifth most common malignancy. The fragility of patients with GC together with the aggressiveness of this tumour makes it as one of the most difficult neoplasias to manage. This article summarises the main strategies for treating patients with GC. Correct assessment of patients with GC requires a multidisciplinary evaluation and close follow-up. For patients with resectable tumours, perioperative chemotherapy should be always considered, especially in the neoadjuvant setting given its capacity for tumour downstaging and eradication of micro-metastases. In the metastatic setting, first-line and second-line treatment improve survival and quality of life in patients with GC. In this setting, only trastuzumab as first-line therapy in patients with human epidermal growth factor receptor 2 positive tumours and ramucirumab as second-line therapy have demonstrated a clear survival improvement. The lack of adequate biomarker selection and the intrinsic heterogeneity of these tumours have jeopardised the possible usefulness of many other targeted agents. Finally, when considering GC carcinogenesis as a multiple stepwise process from initial inflammation starting in the gastric epithelia, immune checkpoint inhibitors may improve the survival of these patients, although the optimal setting for their activity has yet to be fully elucidated.

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Heat shock proteins (HSPs) are molecular chaperones that maintain proteins in their correct conformation to ensure stability and protect carcinoma cells from apoptosis. HSP90 inhibitors (HSP90i) block multiple targets simultaneously, and despite responses in a selected population, no HSP90i have yet been approved. We present a patient with a lung tumor with an exceptional response to cisplatin/gemcitabine in combination with HSP90i, which nowadays continues with HSP90i maintenance after three years. Whole-exome sequencing of the lung tumor unveiled a BRCA1/2 deficiency mutational signature, and mutation analysis confirmed a germline BRCA1 mutation. The striking efficacy of HSP90i plus chemotherapy vs chemotherapy alone was reproduced in a patient-derived xenograft (PDX) model from a breast cancer patient with a BRCA1 mutation (mean tumor volume [SD], No. of tumors: vehicle 8.38 [7.07] mm3, n = 3; HSP90i 4.18 [1.93] mm3, n = 5; cisplatin plus gemcitabine 3.31 [1.95] mm3, n = 5; cisplatin plus gemcitabine plus HSP90i 0.065 [0.076] mm3, n = 6). This case and the PDX demonstrate the efficacy for therapeutic inhibition of HSP90 in a BRCA-mutated patient, opening a new potential avenue for better identifying patients who might benefit most from HSP90i.