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T. Muley
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P1.15 - SCLC/Neuroendocrine Tumors (ID 701)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.15-011 - Longitudinal Mutation Monitoring in Plasma Without Matching Tumor Tissue by Deep Sequencing in Small Cell Lung Cancer (SCLC) (ID 9622)
09:30 - 09:30 | Author(s): T. Muley
- Abstract
Background:
SCLC is a devastating cancer with poor overall survival. Mutation profiles and treatment regimens differ significantly from non-small cell lung cancer (NSCLC). Here we demonstrate feasibility of monitoring patients with SCLC by deep sequencing from only 2 ml of plasma, without prior knowledge of the tumor tissue mutations relative to CT imaging.
Method:
Cell free DNA (cfDNA) was isolated from 64 longitudinal plasma samples (2ml) from 23 subjects with advanced SCLC using the cobas® cfDNA Sample Preparation Kit. The AVENIO ctDNA Surveillance kit (RUO, Roche, Pleasanton, CA, USA) with 197 genes detects SNVs, fusions, CNVs and InDels, and was used for sequencing the cfDNAs. Library preparation with 10-50ng cfDNA yielded a mean pre-capture library yield of 1,728ng. Mean % reads on-target was 65% with a mean deduped coverage of 3,397 fold. CT scans were reviewed to assess disease burden.
Result:
47 longitudinal plasma samples from 8 subjects were successfully analyzed without access to matched tumor tissue. Sixteen subjects with only one baseline plasma sample were excluded from further analysis. Subjects had 3-10 longitudinal plasma samples. Somatic variants were detected with allele frequency (AF) of >0.5% to 30% and 60-90% if they were present in cfDNA from at least three different time points. Germline variants were identified and removed if AFs were 40-60%, and >90%. All variants with frequencies >1% in ExAC were removed. Somatic variants were identified in TP53 (5), APC (2), NPAP1 (2), MKRN3 (2), BRAF, NFE2L2, CDKN2A, TIAM1, LRRTM1, NYP2, FAM135B, FAM71B, PIK3CG, KEAP1, DCAF12L1, PCDH15, EGFLAM. Tracking somatic variants in the longitudinal plasma samples allowed monitoring of treatment response at the molecular level for 6 of 8 subjects. In one subject with 10 longitudinal plasma samples mutations in five different genes were tracked at 1-3% AF before rising to 5- 20% at month 8 and 12-55% at month 9. Molecular progression was detected 1 month earlier than clinical progression by CT. Another subject had a TP53 splice mutation over 10 time points and through 3 lines of treatment and AF correlated with clinical response as measured by imaging.
Conclusion:
Subjects with advanced SCLC and mixed SCLC/NSCLC can be monitored at the mutation level using molecular barcoded duplex sequencing in longitudinal plasma samples. 2ml of plasma yielded sufficient cfDNA for testing with the Surveillance kit. Somatic mutation monitoring is possible without matching tumor tissue samples where longitudinal mutation profiles correlate with clinical response by CT imaging.
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P3.05 - Early Stage NSCLC (ID 721)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Early Stage NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.05-007 - Potential of CYFRA 21-1 and CEA to Predict Adjuvant Chemotherapy Benefit in Early-Stage Squamous Cell Lung Cancer (ID 9303)
09:30 - 09:30 | Author(s): T. Muley
- Abstract
Background:
Tumor markers (TMs), cytokeratin 19 fragment (CYFRA 21-1) and carcinoembryonic antigen (CEA), which have demonstrated prognostic value in early-stage non-small cell lung cancer (NSCLC), may also predict which patients are suitable candidates for adjuvant chemotherapy (adCHT).
Method:
Presurgical serum samples collected during an observational study of patients with stage I-II NSCLC were analyzed for CYFRA 21-1 and CEA via electrochemiluminescence immunoassay (Elecsys[®]; Roche Diagnostics). Recurrence-free survival (RFS) was analyzed using Kaplan Meier methods and a Cox proportional hazards model. A TM-based risk score was generated with RFS as the endpoint and the log10 of CYFRA 21-1 and CEA values as independent risk predictors. RFS was compared for patients who received adCHT versus surgery alone, with patients stratified as high versus low risk based on pathological disease stage (I vs II), the TM-based risk score, and clinical characteristics (age, gender, smoking status, disease stage, Eastern Cooperative Oncology Group performance status).
Result:
227 patients were included (stage I: 69%; male: 67%; median age: 65 years; adenocarcinoma [ADC]: 47%, squamous-cell carcinoma [SCC]: 40%, mixed histology: 13%); 70 received adCHT (84% with a platinum-based regimen). Median follow-up was 58.8 months. Median RFS for all patients was 76.3 months (81.0 and 68.6 months for ADC and SCC, respectively). All high-risk patients, defined by TMs or clinical characteristics (but not stage alone), had a worse prognosis, irrespective of treatment received. A similar pattern was seen in patients with SCC, whereas stage and clinical characteristics (but not TMs) were prognostic in patients with ADC. All high-risk patients (defined by any method) derived an RFS benefit from adCHT versus surgery alone (stage HR 2.7, p = 0.002; TMs HR 2.1, p = 0.018; clinical characteristics HR 3.2, p = 0.001). However, in all low-risk patients, RFS was similar regardless of whether they received adCHT or not. High-risk SCC patients also derived an RFS benefit from adCHT versus surgery alone (stage HR 4.9, p = 0.004; TMs HR 9.4, p = 0.002; clinical characteristics HR 9.0, p = 0.003), whereas those with low-risk SCC did not. In patients with ADC, none of the methods used were able to predict which patients might benefit from adCHT.
Conclusion:
Baseline CYFRA 21‑1 and CEA levels may provide further information beyond clinical characteristics that could help clinicians to decide which patients with early-stage SCC should receive adCHT. Further evaluation of these biomarkers is warranted.
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P3.05-008 - Potential of CYFRA 21-1 and HE4 to Detect Recurrence in Patients with Early-Stage Lung Adenocarcinoma (ID 9876)
09:30 - 09:30 | Author(s): T. Muley
- Abstract
Background:
The Tumor markers (TMs) cytokeratin 19 fragment (CYFRA 21-1) and human epididymis protein 4 (HE4) have each been shown to be useful in diagnosis, prognosis and monitoring of NSCLC, but their combination has not been investigated. The objective of this analysis was to evaluate the ability of CYFRA 21-1 and HE4 to predict relapse in patients with adenocarcinoma (ADC).
Method:
In an observational study of adult patients with stage I-IIIA ADC, serum samples were prospectively collected prior to surgery and during follow-up at 3, 6, 12, 18 and 24 months and then every 6-12 months up to 5 years post-R0 resection. Patients could receive an adjuvant therapy of either radiotherapy or chemotherapy (not both) according to their clinical situation and local best practice. In a post hoc analysis, CYFRA 21-1 and HE4 levels from these samples were measured via electrochemiluminescence immunoassay (Elecsys[®]; Roche Diagnostics). All cases of disease recurrence were verified by imaging. The diagnostic performance of CYFRA 21-1, HE4 and their combination was assessed by the Receiver Operating Characteristic (ROC) and corresponding area under the curve (AUC). The combination of both TMs was based on the weighted sum of the logarithmized (base 10) markers. Weights were derived from a logistic regression model which included the log10 of CYFRA 21-1 and HE4 as independent variables and relapse (yes/no) as a dependent variable.
Result:
117 patients were included in the post hoc analysis (stage I/II/IIIA: 64%/21%/15%; male: 55%; median age: 63 years), providing a total of 623 TM measurements. All patients had received surgery for ADC; 34 patients (29%) also received adjuvant chemotherapy and 16 patients (14%) received radiation. Blood samples were collected for a median follow-up of 37 months. At this timepoint, 31 patients (26%) had experienced disease recurrence. Median recurrence-free survival was 80.2 months. Both CYFRA 21‑1 and HE4 were able to detect recurrence (AUC and corresponding 95% confidence interval [CI]): 76.6% [66.9–86.3%] and 73.7% [64.1–83.4%], respectively), but this increased with the combination (AUC 79.0%, 95% CI 69.4–88.6%). At a sensitivity of 80%, the respective specificities (95% CI) for CYFRA 21‑1, HE4 and the combination were 56.0% (51.9–60.1%), 49.1% (45.0–53.2%), and 70.1% (66.2–73.7%).
Conclusion:
Serial measurements of serum CYFRA 21‑1 and HE4 levels could provide a valuable alternative method for follow-up monitoring and recurrence detection in patients with early-stage ADC, which would trigger imaging if elevated.
