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Fabiana Letizia Cecere
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MS08 - Management of Thymic Carcinoma (ID 71)
- Event: WCLC 2019
- Type: Mini Symposium
- Track: Thymoma/Other Thoracic Malignancies
- Presentations: 1
- Now Available
- Moderators:Enrico Ruffini, Giovannella Palmieri
- Coordinates: 9/09/2019, 14:00 - 15:30, Seoul (2007)
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MS08.04 - Novel Biomarkers for Thymic Carcinoma (Now Available) (ID 3484)
14:00 - 15:30 | Author(s): Fabiana Letizia Cecere
- Abstract
- Presentation
Abstract
Thymic carcinoma (TC), the rarer among Thymic Epithelial Tumors (TET), occur with an incidence rate of 0.2-0.5/million/yr. Difficulties in the evaluation of molecular aspects derive from the extreme rarity of these tumors. The Squamous cell carcinoma (SQCC) is the most frequently analyzed, however the other rarer histotypes could differ both in molecular pathogenesis and in clinical behaviour. The Cancer Genome Atlas Thymoma study (TCGA-THYM) in a series of ten TC cases including four SQCC, four undifferentiated carcinoma and both one large cell neuroendocrine carcinoma as well as one TC, NOS, identified a few genes rarely mutated, including KIT, HRAS, NRAS and TP53, reflecting the low mutational burden of these tumors (1). In the last years, only a limited number of TC has been investigated by other groups and only a limited number of relevant alterations has been identified. In addition to genomic events, however, epigenetic factors could contribute to TET carcinogenesis. Wang et al. in 2014 performed targeted sequencing of 197 cancer-associated genes in 78 advanced-stage TET patients, including 47 TC and 31 thymoma (THYM) cases. They reported that TC showed a higher incidence of somatic non-synonymous mutations than THYM. Moreover, they found that mutations of epigenetic regulatory genes involved in chromatin modification pathways are common in TC in comparison to THYM (2).
In the last years we have been interested in the characterization of genomic and epigenetic findings related to TET development. In our earlier microRNA (miR) study, we reported, among other findings, preliminary data on mature microRNAs differentially expressed in TC vs THYM, as revealed by microarray-based unsupervised clustering analysis. Among the differentially expressed miRs, 3 were validated by RT-qPCR (miR128, miR142-5p and miR-181c-5p) (3). By a different approach, we analyzed by Next Generation Sequencing (NGS) thirteen TC cases and one Atypical Type A thymoma case. The tissues derived from Formalin-fixed, paraffin embedded (FFPE) material including biopsies/surgical specimens of tumors and a single case of matched peritumoral thymus. The percentage of neoplastic cells was not < 70-80% of total cells. The DNA was extracted using the QIAcube and QIAamp DNA FFPE Tissue Kit (Qiagen, Valencia, CA) from microdissected 5 μm FFPE tissue sections. The NGS platform Ion S5 (Thermofisher) and the Ion AmpliSeq™Cancer Hotspot Panel v2 were used. This panel is designed to amplify 207 amplicons covering over 2,800 COSMIC mutations from 50 oncogenes and tumor suppressor genes. Libraries from Ion AmpliSeq Cancer Hotspot Panel v2 were prepared and sequenced by Ion Chef and S5 system. Data analysis was conducted by using the dedicated Ion Reporter Software. Among other genomic variants (polymorphysms and mutations were found in four cases), in one out of these four TC cases a KIT mutation (c.1900C>T; p.R634W, exon 13), already reported in TC, was identified. Moreover, a further KIT mutation ( c.1718C>T p.P573L, exon11) was found in a second case. In addition, a missense TP53 mutation ( c.824G>T; p.C275F), occurring in exon 8, was observed in a single case of TC, NOS. The patient harbouring a TC with this TP53 mutation had a R0 robotic-assisted thymectomy of a pT2 Thymic carcinoma (according to the 8th TNM edition), and after adjuvant chemotherapy and radiotherapy is alive and in complete remission with a follow-up of 22 months . The recent case of Atypical Type A thymoma showed a NOTCH1 c.4732_4734delGTG p.V1578del in exon 26 of uncertain significance.
Basing on the relatively few cases reported in the literature, analyzed by different techniques for their genomic alterations, it appears that the mutation status of TC is highly heterogeneous. In the cases examined so far by NGS we didn’t find recurrent genetic aberrations, but a variety of alterations. Each case, with the panel available, revealed either polymorphisms or, in few cases, mutations in cancer-associated genes, both oncogenic and oncosuppressor. Among the genes involved, both the KIT reported variants could be considered relevant for targeted therapy. Moreover, the tumor suppressor gene TP53 is already known for its importance and frequency of mutations particularly in TC. Moreira et al reported recurrent TP53 mutations with unfavorable prognostic value (4). The TP53 mutation found in one of our cases (previously reported in cases of SQCC of upper respiratory tract, in lung, head & neck and esophageal carcinoma) affects, among others, the DNA damage repair, the cell cycle and the apoptosis pathways. In human thymus, the Notch pathway, activated in thymic EC, is crucial to T cell differentiation; moreover the Notch signaling is also involved in hematological and in solid tumors. The NOTCH1 c.4732_4734delGTG p.V1578del in exon 26 we reported in a Atypical case A thymoma was already described in lymphoid tissues. The clinical and prognostic value of the genomic alterations we observed needs to be definied.
1) Radovich M, et al., The integrated genomic landscape of thymic epithelial tumors - Cancer Cell, 2018 Feb 12;33(2):244-258
2) Wang Y, et al., Mutations of epigenetic regulatory genes are common in thymic carcinomas - Sci Rep. 2014 Dec 8;4:7336
3) Ganci F, et al., MicroRNAs Expression Profiling of Thymic Epithelial Tumors - Lung Cancer 2014, 85 (2) 197–204
4) Moreira AL, et al, Massively parallel sequencing identifies recurrent mutations in TP53 in thymic carcinoma associated with poor prognosis - J Thorac Oncol. 2015 Feb;10(2):373-80
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P1.03 - Biology (ID 161)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.03-14 - HLA-E and FAT1 in Head and Neck and Lung Cancer. The Effect of Osimertinib or Olmutinib with Artesunate (Dihydroartemisinin) (ID 912)
09:45 - 18:00 | Author(s): Fabiana Letizia Cecere
- Abstract
Background
Cisplatin and cetuximab have little effect in head and neck squamous cell carcinoma (HNSCC) and lung squamous cell carcinoma (LSCC). HLA-E expression suppressed the cetuximab effect and HLA-E is overexpressed in both HNSCC and LSCC. In addition, FAT1 inactivating mutations are present in 30% of HNSCCs and 19% of LSCCs. Dihydroartemisinin (DHA) inhibits STAT3 and increases cisplatin effect in HNSCC. Osimertinib and olmutinib increase intracellular accumulation of doxorubicin by blocking the efflux function of ABC transporters. We posit that osimertinib or olmutinib, plus DHA, could have activity in the HNSCC cell lines, FaDu and CAL27, with loss of FAT1 expression.
Method
Osimertinib and olmutinib plus DHA were tested in the FaDu and CAL27 cell lines. Tumor cell proliferation assays (MTTs) and mouse xenografts were performed, and western blotting analysis was carried out. FaDu CTXR clone #3 (cetuximab-resistant, a gift from Bhola) and SCCNC4 (EGFR exon 20 S768_D770 dup, a gift from Hermsen) were also examined.
Result
1. DHA decreased HLA-E protein levels in a dose dependent manner in the FaDu CTXR.
2. DHA was able to induce the expression of FAT1 in FaDu and CAL27 cells.
3. Osimertinib plus DHA had a synergistic effect (<1, Combination index (CI)=0.468 and 0.593 in FaDu and CAL27, respectively). Olmutinib with DHA was also synergistic (CI=0.773 and 0.762 in FaDu and CAL27).
4. Osimertinib plus DHA was validated in vivo in FaDu and CAL27 mice xenografts with significant tumor regression.
5. Osimertinib plus DHA suppress the expression of onco-effectors: STAT3, Src, YAP and AXL.
6. Osimertinib plus DHA was also synergistic in SCCNC4 (CI=0.596).
Conclusion
The findings indicate that DHA can revert resistance to cetuximab by repressing the expression of HLA-E. The combination of DHA plus osimertinib was active in the parental FaDu, but not in FaDu CTXR. For tumors with lack of FAT1 expression, the use of DHA reactivates FAT1 and YAP1 inhibition was noted. DHA has been tested for the treatment of systemic lupus erythematosus (SLE), orally, daily for 2 years. The results encourage development of clinical trials with DHA to re-sensitize HNSCC and LSCC cells to cetuximab-based therapy.
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P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.01-15 - Phase II Single Arm Study of CABozantinib in Non-Small Cell Lung Cancer Patients with MET Deregulation (CABinMET) (ID 2637)
10:15 - 18:15 | Author(s): Fabiana Letizia Cecere
- Abstract
Background
Mesenchymal-Epithelial Transition gene (MET) amplification and exon 14 skipping mutations are established oncogenic drivers in non-small cell lung cancer (NSCLC), both occurring in about 4% of cases. In patients with MET amplified or mutated lung cancer, oral MET tyrosine kinase inhibitors (TKI) showed promising activity. The American Food and Drug Administration has recently granted crizotinib a breakthrough therapy designation for MET exon 14 mutation positive NSCLC. Cabozantinib is a novel oral inhibitor of MET and other receptor tyrosine kinases that has shown preliminary activity in MET deregulated NSCLC patients pretreated with crizotinib, although definitive data on its therapeutic role are still missing.
Method
CABinMET (NCT03911193) is a phase II, single arm, multicenter study assessing the efficacy of cabozantinib in subject with MET amplification or MET exon 14 skipping mutation pretreated or not with MET inhibitors. The primary endpoint of the trial is overall response rate. Secondary efficacy endpoints are progression free survival, overall survival and disease control rate. Main inclusion criteria include histologically/cytologically confirmed diagnosis of advanced stage NSCLC, presence of MET exon 14 skipping mutation or MET amplification (MET/CEP7 ratio ≥2.2 on FISH analysis) on archival formalin-fixed paraffin-embedded (FFPE) tumor tissue or circulating tumor DNA, measurable disease, ECOG PS 0-1, at least 1 prior line of standard therapy, adequate organ function. Patients with co-existent driver events or with symptomatic brain metastases are excluded from the trial. Cabozantinib is administered orally at 60 mg once daily until disease progression, patient refusal or unacceptable toxicity. Disease is assessed every 8 weeks. Exploratory biomarker analyses are conducted on archival FFPE tumor tissue and on blood samples collected at baseline, at the time of the first disease assessment and at progression.
Result
The study is currently running in 9 Italian centers. Recruitment started in September 2018 and 6 of the planned 25 patients have been enrolled.
Conclusion
Enrollment will be completed in 24 months.
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P2.04 - Immuno-oncology (ID 167)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.04-79 - High Rate of Immune Related Pneumonitis in Lung Cancer Patients Treated with Anti PD-1 Antibodies (ID 1061)
10:15 - 18:15 | Author(s): Fabiana Letizia Cecere
- Abstract
Background
Treatment with anti PD-1/PD-L1 antibodies has demonstrated survival improvement in several malignancies, including non small cell lung cancer (NSCLC), but these therapies are not exempt from risks. Meta-analysis and clinical trials have reported immune related (ir) pneumonitis of any grade in 3-5% of patients treated with anti PD-1/PD-L1 antibodies, including grade 3 or higher in 0.8% to 1.8% of patients.
Method
We have retrospectively reviewed clinical reports from 125 cancer patients treated at our center with anti PD-1/PD-L1 antibodies (55 were treated with nivolumab, 27 with pembrolizumab, 33 with atezolizumab, 6 with avelumab, and 4 with durvalumab) from January 2016 to January 2019.
Result
Nineteen patients (15.2%) developed ir pneumonitis. Four (21%) patients had recurrent pneumonitis during tapering corticoesteroid dose after an initial improvement and finally died. Patient characteristics are summarized in Table 1. Median time to pneumonitis was 4 months (m) (range 1m to 9m). Twelve patients (9.6% %) had grade 3-5 and 7 patients (5.6 %) grade 1-2 pneumonitis. Nine (7.2 %) patients died from ir pneumonitis, including 4 patients with no tumor progression (1 had received only one cycle, and 3 patients had ongoing tumor response at 10m+, 12m+ and 30m+). Ir pneumonitis was more frequent with nivolumab (any grade 21.8 %, grade 3 or higher 18.2 %, including 7 fatal cases-12.7%-), while no patient treated with atezolizumab developed pneumonitis (Table 2).
Table 1 Total 19 Gender
Women, n (%)
7 (36,8%)
Age
Median (range)
63,4 (51-82)
Cancer type, n (rate)
NSCLC Adenoca
NSCLC Squamous
SCLC
Mesothelioma
13 (68,4 %)
4 (21%)
1 (5,3%)
1 (5,3%)
Line of therapy, n (rate)
Adjuvant
First line
Second or further line
1 (5,2 %)
8 (42,1%)
10 (52,6%)
Tumor Response, n (rate)
CR
PR
SD
PD
NE
2 (10,5%)
8 (42,1%)
5 (26,3%)
3 (15,8%)
1 (5,2%)
table 2 Drug,n patients treated Any Grade, n (%) Grade 3-5, n (%) Grade 5, n (%) Nivolumab, 55 12 (21,8%) 10 (18,2%) 7 (12,7%) Pembrolizumab, 27 3 (11,1%) 1 (3,7%) 1 (3,7%) Atezolizumab, 33 0 0 0 Durvalumab, 4 2 (50%) 0 0 Avelumab, 6 2 (33,3%) 1 (16,7%) 1 (16,7%) Total, 125 19 (15,2%) 12 (9,6%) 9 (7,2%)
Conclusion
In our experience, ir pneumonitis rate with anti PD-1/PD-L1 antibodies in lung cancer patients was 15.2%, including 7.2% of fatal complications. It suggests that previous clinical trials could have under diagnosed this serious complication. Further studies must be performed in order to specifically assess the rate of pneumonitis in patients treated with anti PD-1 and anti PD-L1 antibodies in lung cancer patients.
