bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2024–05–12
two papers selected by
Sergio Marchini, Humanitas Research
  1. MITO END-3: Efficacy of Avelumab immunotherapy according to molecular profiling in first-line endometrial cancer therapy.
  2. Molecular landscape and clinical implication of CCNE1-amplified esophagogastric cancer.
  1. Ann Oncol. 2024 May 02. pii: S0923-7534(24)00128-5. [Epub ahead of print]
    MITO END-3: Efficacy of Avelumab immunotherapy according to molecular profiling in first-line endometrial cancer therapy.
    S Pignata, D Califano, D Lorusso, L Arenare, M Bartoletti, U De Giorgi, C Andreetta, C Pisano, G Scambia, D Lombardi, A Farolfi, S Cinieri, A Passarelli, V Salutari, C De Angelis, C Mignogna, D Priolo, E D Capoluongo, S Tamberi, G L Scaglione, V Arcangeli, R De Cecio, G Scognamiglio, F Greco, A Spina, M Turinetto, D Russo, V Carbone, C Casartelli, C Schettino, F Perrone.
       BACKGROUND: Immunotherapy combined with chemotherapy significantly improves progression-free survival compared to first-line chemotherapy alone in advanced endometrial cancer, with a much larger effect size in microsatellite-instability high (MSI-H) cases. New biomarkers might help to select patients that may have benefit among those with a microsatellite-stable (MSS) tumor.
    METHODS: In a pre-planned translational analysis of the MITO END-3 trial, we assessed the significance of genomic abnormalities in patients randomized to standard carboplatin/paclitaxel without or with avelumab.
    RESULTS: Out of 125 randomized patients, 109 had samples eligible for next-generation sequencing (NGS) analysis, and 102 had MSI tested. According to The Cancer Genome Atlas (TCGA), there were 29 cases MSI-H, 26 MSS TP53 wild-type (wt), 47 MSS TP53 mutated (mut), and one case with POLE mutation. Four mutated genes were present in more than 30% of cases: TP53, PIK3CA, ARID1A, and PTEN. Eleven patients (10%) had a BRCA1/2 mutation (five in MSI-H and six in MSS). High TMB (≥10 Muts/Mb) was observed in all MSI-H patients, in four out of 47 MSS/TP53 mut, and no case in the MSS/TP53 wt category. The effect of avelumab on progression-free survival significantly varied according to TCGA categories, being favorable in MSI-H and worst in MSS/TP53 mut (P interaction=0.003); a similar non-significant trend was seen in survival analysis. ARID1A and PTEN also showed a statistically significant interaction with treatment effect, which was better in the presence of the mutation (ARID1A P interaction=0.01; PTEN P interaction=0.002).
    CONCLUSION: The MITO END-3 trial results suggest that TP53 mutation is associated with a poor effect of avelumab, while mutations of PTEN and ARID1A are related to a positive effect of the drug in patients with advanced endometrial cancer.
    Keywords:  Avelumab; Cancer Genome Atlas; Chemotherapy; Endometrial Cancer; Next Generation Sequencing
    DOI:  https://doi.org/10.1016/j.annonc.2024.04.007
  2. Cancer Res Commun. 2024 May 08.
    Molecular landscape and clinical implication of CCNE1-amplified esophagogastric cancer.
    Naryan Rustgi, Sharon Wu, Timothy Samec, Phillip Walker, Joanne Xiu, Emil Lou, Sanjay Goel, Anwaar Saeed, Ryan H Moy.
      Cyclin E overexpression as a result of CCNE1 amplification is a critical driver of genomic instability in gastric cancer, but its clinical implication is largely unknown. Thus, we integrated genomic, transcriptomic, and immune profiling analysis of 7,083 esophagogastric tumors and investigated the impact of CCNE1 amplification on molecular features and treatment outcomes. We identified CCNE1 amplification in 6.2% of esophageal adenocarcinoma samples, 7.0% of esophagogastric junction carcinoma, 4.2% of gastric adenocarcinoma samples, and 0.8% of esophageal squamous cell carcinoma. Metastatic sites such as lymph node and liver showed an increased frequency of CCNE1 amplification relative to primary tumors. Consistent with a chromosomal instability phenotype, CCNE1 amplification was associated with decreased CDH1 mutation and increased TP53 mutation and ERBB2 amplification. We observed no differences in immune biomarkers such as PD-L1 expression and tumor mutational burden comparing CCNE1-amplified and non-amplified tumors, although CCNE1 amplification was associated with changes in immune populations such as decreased B cells and increased M1 macrophages from transcriptional analysis. Real-world survival analysis demonstrated that patients with CCNE1-amplified gastric cancer had worse survival after trastuzumab for HER2-positive tumors, but better survival after immunotherapy. These data suggest that CCNE1-amplified gastric cancer has a distinct molecular and immune profile with important therapeutic implications, and therefore further investigation of CCNE1 amplification as a predictive biomarker is warranted.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-23-0496
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