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. 2024 Sep;131(4):676-684.
doi: 10.1038/s41416-024-02773-w. Epub 2024 Jun 22.

Treatment outcome according to genetic tumour alterations and clinical characteristics in digestive high-grade neuroendocrine neoplasms

Hege Elvebakken  1   2 , Andreas Venizelos  3 , Aurel Perren  4 , Anne Couvelard  5 , Inger Marie B Lothe  6 , Geir O Hjortland  7 , Tor Å Myklebust  8   9 , Johanna Svensson  10 , Herish Garresori  11 , Christian Kersten  12 , Eva Hofsli  13   14 , Sönke Detlefsen  15   16 , Lene W Vestermark  17 , Stian Knappskog  3   18 , Halfdan Sorbye  18   19
Affiliations

Treatment outcome according to genetic tumour alterations and clinical characteristics in digestive high-grade neuroendocrine neoplasms

Hege Elvebakken et al. Br J Cancer. 2024 Sep.

Abstract

Background: Chemotherapy has limited efficacy in advanced digestive high-grade neuroendocrine neoplasms (HG-NEN) and prognosis is dismal. Predictive markers for palliative chemotherapy are lacking, and prognostic markers are limited.

Methods: Digestive HG-NEN patients (n = 229) were prospectively included 2013-2017. Pathological re-assessment revealed 188 neuroendocrine carcinomas (NEC) and 41 neuroendocrine tumours (NET G3). Tumour-DNA was sequenced across 360 cancer-related genes, assessing mutations (mut) and copy number alterations. We linked sequencing results to clinical information and explored potential markers for first-line chemotherapy efficacy and survival.

Results: In NEC given cis/carboplatin and etoposide (PE), TP53mut predicted inferior response rate in multivariate analyses (p = 0.009) and no BRAFmut NEC showed response. In overall assessment of PE-treated NEC, no genetic alterations were prognostic for OS. For small-cell NEC, TP53mut were associated with longer OS (p = 0.011) and RB1 deletions predicted lack of immediate-progression (p = 0.003). In non-small cell NEC, APC mut were associated with immediate-progression and shorter PFS (p = 0.008/p = 0.004). For NET G3, ATRXmut, ARID1A- and ERS1 deletions were associated with shorter PFS.

Conclusion: Correlations between genetic alterations and response/immediate-progression to PE were frequent in NEC but affected PFS or OS only when subdividing for cell-type. The classification of digestive NEC into large- and small-cell seems therefore molecularly and clinically relevant.

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Conflict of interest statement

HG: Honoraria from Ipsen, Amgen, Pfizer, Bristol Meyer Squibb and Astra Zeneca, SK: Research support from AstraZeneca, Pfizer and Illumina and honoraria from AstraZeneca, Pfizer, Pierre- Fabre, Novartis, Sobi, Amgen, Sanofi Aventis and Roche, HS: Consultant/advisory board: Hutchison, Bayer, ITM, Advanced Accelerator. Lecture honoraria: Novartis, Ipsen, Bayer, SAM Nordic, Pierre Fabre. The other authors have no disclosures.

Figures

Fig. 1
Fig. 1. Top genetic alterations for digestive NEC (N = 188).
Upper panel shows the mutational burden per sample. Percentages on the right represent mutations frequency per gene. The panel under the oncoplot area is composed of two single row heatmaps showing celltype and primary tumour site.
Fig. 2
Fig. 2. Efficacy to cis/carboplatin and etoposide and survival dependent on genetic alteration and NEC celltype.
a Response to cis/carboplatin and etoposide according to TP53 status for LC-NEC (N = 61). b Immediate progression to cis/carboplatin and etoposide according to APC status for LC-NEC (N = 61). c Progression free survival (PFS) after cis/carboplatin and etoposide for LC-NEC according to APC status (N = 61). d Overall survival (OS) for SC-NEC according to TP53 status (N = 61).
See this image and copyright information in PMC

References

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