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Atocha Romero
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FP12 - Tumor Biology and Systems Biology - Basic and Translational Science (ID 188)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Tumor Biology and Systems Biology - Basic and Translational Science
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP12.01 - Circulating Tumor DNA to the Identification of EGFR Positive NSCLC Long-Term Survivors (ID 3013)
00:00 - 00:00 | Author(s): Atocha Romero
- Abstract
Introduction
Survival data supports the use of first-line osimertinib as standard of care for EGFR positive non-small lung cancer (NSCLC). However, it remains unclear whether upfront osimertinib is superior to sequential first- or second-generation tyrosine kinase inhibitor (TKI) followed by osimertinib for all patients. The impossibility of predicting which patients are at high risk of progression constitutes a major limitation of the sequential TKI approach.
Methods
Seven hundred and forty-five plasma samples from 192 stage IV, EGFR positive NSCLC patients who were treated with first-line TKI were analysed by digital PCR.
Results
Patients with EGFR sensitizing mutations in plasma with mutant allele frequency (MAF) <7% before treatment initiation had median OS 37.9 months (25.3-NR), compared 17.5 (95%CI: 11.3-25.5) months for patients with MAF≥7% (adjusted HR=0.43; 95%CI: 0.25-0.76, respectively). OS was achieved with 53.1% of the patients treated with a 2nd line treatment other than osimertinib. In the multivariable analysis, undetectable levels of circulating tumour DNA (ctDNA) after 3 and 6 months of treatment were associated with improved PFS and OS (P<0.001 in all cases). Patients who became ctDNA negative after 3 or 6 months of treatment with MAF<7% at diagnosis had more than two-thirds lower risk of progression and death compare to the rest of patients (adjusted HR=0.28; 95%CI: 0.17-0.46 and HR=0.24; 95%CI: 0.12-0.48 for PFS and OS, respectively).
Conclusion
Pre-treatment ctDNA levels identify patients at low risk of progression and death who could benefit from sequential TKI treatment. Information regarding EGFR sensitizing mutation clearance could improve patient selection.
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P60 - Tumor Biology and Systems Biology - Basic and Translational Science - Immune Bio (ID 198)
- Event: WCLC 2020
- Type: Posters
- Track: Tumor Biology and Systems Biology - Basic and Translational Science
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P60.07 - TMB and Selected Mutations in Resectable Stage IIIA NSCLC Patients Receiving Neo-Adjuvant Chemo-Immunotherapy from NADIM Trial (ID 2142)
00:00 - 00:00 | Author(s): Atocha Romero
- Abstract
Introduction
Tumor Mutational Burden (TMB) assessment and identification of specific mutations associated to anti-PD1 blockade therapy resistance have become a novel approach to predict the clinical benefit to anti-PD1/PDL1 therapy. However, the clinical relevance of these parameters in terms of pathological response and PFS in neo-adjuvant chemo-immunotherapy has not been established. To answer this question we analysed samples from the NADIM study (NCT03081689), in which resectable stage IIIA NSCLC patients were treated with neoadjuvant chemo-immunotherapy with Nivolumab.
Methods
Pretreatment TMB, defined as the number of nonsynonymous variants (missense and nonsense single nucleotide variants (SNVs)), plus insertion and deletion variants (INDELs) detected per megabase (Mb) of exonic sequence, was estimated from 27 patients that had enough diagnostic material for next generation sequencing using the Oncomine Tumor mutation Load assay (ThermoFisher) following manufacturer’s instructions. The panel covers 1.7 Mb of 409 genes with known cancer associations. Regarding pathological responses, patients were classified into 3 groups: pathologic complete response (pCR) (0% viable tumour at any localization tested), major pathologic response (MPR, <10% viable tumour) and pathologic incomplete response (pIR) (>10% of viable tumour). At data analysis, median follow-up time was 22.7 months.
Results
Median TMB was 5.89 (range 1.68 – 73.95). No differences in TMB value between histologies (adenocarcinoma vs squamous cell), smoking status (former vs current), age or sex were observed. Somatic mutations were identified in lung cancer driver genes such as TP53, KRAS, EGFR, CDKN2A, NOTCH1, BRAF and in specific genes associated with resistance to immunotherapy such as STK11, KEAP1, and RB1. No genomic alterations in ALK, ROS1, PTEN or ERBB2 were found.
Based on literature, a poor prognosis mutation signature (presence of EGFR, STK11, KEAP1 or RB1 mutations) was generated. A third of the sequenced patients (9/27) harboured at least one mutation in one of these genes.
Pathological response data was available from 23 out of 27 patients sequenced. Both the TMB value and the presence of these resistance mutations were not associated with the degree of pathological response.
Regarding PFS, TMB alone was not predictive of disease progression using different thresholds. However, the presence of these resistance mutations was associated with shorter PFS (log-rank p-value=0.032). The median PFS for mutated patients was 21.4 months (95% CI 16-26 months) while median PFS was not reached in non-mutated patients.
Additionally, the combination of this mutational signature with TMB (absence of resistance mutations and TMB-Higher than median) was able to distinguish patients that strongly benefit from this therapy. Although the median PFS was not reached in both groups yet, statistically significant differences were observed (log-rank p-value=0.046). PFS at 18 and 24 months was 100% (95% CI not estimable) for Non-mutated patients with TMB-High vs 70% (95% CI 50-89%) and 58% (95% CI 35-81%) for the rest of patients (mutated patients plus Non-mutated patients with TMB-Low).
Conclusion
TMB did not predict benefit from chemo-immunotherapy induction in our cohort. However, the presence of EGFR/STK11/KEAP1/RB1 mutations alone, or in combination with TMB, may help identify patients that unlikely benefit from neo-adjuvant chemo-immunotherapy
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P84 - Targeted Therapy - Clinically Focused - ALK (ID 261)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P84.14 - Identification of Mechanisms of Resistance to ALK Inhibitors. Next-Generation Sequencing-Based Liquid Biopsy Profiling. (ID 3612)
00:00 - 00:00 | Presenting Author(s): Atocha Romero
- Abstract
Introduction
Despite impressive and durable responses, patients treated with ALK inhibitors (ALK-Is) ultimately progress. We investigated potential resistance mechanisms in a series of ALK-positive non-small cell lung cancer (NSCLC) patients progressing on different types of ALK-Is.
Methods
26 plasma and 2 cerebrospinal fluid samples collected upon disease progression to an ALK-I, from 24 advanced ALK-positive NSCLC patients, were analyzed by next-generation sequencing (NGS). A tool to retrieve variants at the ALK locus was developed.
Results
61 somatic mutations were detected in 14 genes: TP53, ALK, PIK3CA, SMAD4, MAP2K1 (MEK1) FGFR2, FGFR3, BRAF, EGFR, IDH2, MYC, MET, CCND3 and CCND1. Overall, We identified at least one mutation in ALK locus in 10 (38.5%) plasma samples, being the G1269A and G1202R mutations the most prevalent among patients progressing to first- and second-generation ALK-I treatment, respectively. An exon 19 deletion in EGFR was identified in a patient showing primary resistance to ALK-I. Likewise, the G466V mutation in BRAF and the F129L mutation in MAP2K1 (MEK1) were identified as the underlying mechanism of resistance in three patients who gained no or little benefit from second-line treatment with an ALK-I. Putative ALK-I resistance mutations were also found in PIK3CA and IDH2. Finally, a c-MYC gain, along with a loss of CCND1 and a FGFR3, were detected in a patient progressing on a first-line treatment with crizotinib.
Conclusion
NGS analysis of liquid biopsies upon disease progression identified putative ALK-I resistance mutations in most cases, being a valuable approach to devise therapeutic strategies upon ALK-I failure.
