Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with the 2019 ASCO Annual Meeting but not presented at the Meeting, can be found online only.
CDKN2A/B gene loss and MDM2 alteration as a potential molecular signature for hyperprogressive disease in advanced NSCLC: A next-generation-sequencing approach.
Metastatic Non-Small Cell Lung Cancer
Lung Cancer—Non-Small Cell Metastatic
2019 ASCO Annual Meeting
J Clin Oncol 37, 2019 (suppl; abstr e20628)
Author(s): Raffaele Giusti, Marco Mazzotta, Marco Filetti, Daniele Marinelli, Arianna Di Napoli, Stefania Scarpino, Giorgia Scafetta, Monica Mei, Andrea Vecchione, Luigi Ruco, Paolo Marchetti; Sant'Andrea Hospital, Rome, Italy; Sapienza University of Rome, Rome, Italy; Universita Studi Roma-Sapienza, Roma, Italy; Sapienza - Università di Roma, Rome, Italy; Azienda Ospedaliera-Universitaria Sant'Andrea, Rome, Italy; Sapienza University, Department of Clinical and Molecular Medicine, Rome, Italy; Department of Oncology-Pathology Sant’Andrea University Hospital, Rome, Italy; Azienda Ospedaliera Sant'Andrea, Rome, Italy; Department of Medical Oncology Sant’Andrea University Hospital, Rome, Italy
Background: Hyperprogressive disease (HPD) incidence ranges from 8% to 21% in patients treated with anti-PD-1/PD-L1 mAbs in NSCLC and is associated with poor survival. Previously published data underlined a link between HPD across different cancers types and specific genetic alterations, such as MDM2 amplification and EGFR aberrations. We present a single-center cohort of patients with NSCLC and PD-L1 > 50% treated with 1st-line pembrolizumab. We performed NGS, IHC and FISH analysis to evaluate genetic correlations with the clinical phenotype. Methods: Clinical data from 20 patients with diagnosis of advanced NSCLC treated with 1stline immunotherapy pembrolizumab were retrospectively collected. HPD was defined by Time to Treatment Failure ≤2 months and raising in Tumor Burden ≥50% compared with basal CT-scan. MDM2 amplification was investigated by FISH on FFPE tissue sections using the MDM2/CON12 break apart FISH Probe. Positive cases were defined as those with > 10% positive tumor cells. We performed IHC for MDM2 protein on FFPE tissue sections. The staining was semiquantitatively graded for the intensity as: 0, negative; 1+, weak positive; 2+, moderately positive; 3+, strongly positive, and for the extent as 0–< 1% (negative), 1–50% (focal), and > 50% (diffuse). We also performed NGS analysis (FoundationOne CDX, Foundation Medicine Inc.) on 324 preidentified genes. Results: We identified 5 cases of HPD; all five cases showed MDM2amplification by FISH analysis and a focal protein expression by IHC with the strongest nuclear staining observed in the cases showing a higher degree of MDM2 amplification (8/9 dots) and a weaker expression in those with a lower MDM2amplification (4/5 dots). NGS analysis showed MDM2amplification in 1/5 HPD patient and a loss of CDKN2A/B in 4/5 patients. None of the non-HPD patients had IHC expression of MDM2 or amplification of the gene. Among the non-HPD patients no genetic alterations regarding MDM2 and/or CDKN2A/B were found on NGS analysis. Conclusions: Our data suggest a potential role of CDKN2A/B gene loss and alteration of MDM2 on the establishment of HPD in NSCLC patients treated with immunotherapy. Because the HPD logic is not yet clear, more data is needed to better understand the link between this genomic signature and the development of HPD.