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E-Poster Display

430P - Serial ctDNA (circulating tumour DNA) for detection of genomic changes during neoadjuvant chemoradiotherapy (NACRT) in locally advanced rectal cancer (LARC)

Date

17 Sep 2020

Session

E-Poster Display

Presenters

Cha Len Lee

Citation

Annals of Oncology (2020) 31 (suppl_4): S409-S461. 10.1016/annonc/annonc270

Authors

C.L. Lee1, S. Toomey1, B. O'Neill2, B.T. Hennessy1

Author affiliations

  • 1 Molecular Medicine, Rcsi, Medical Oncology, D09YD60 - Dublin/IE
  • 2 St Luke’s Radiation Oncology Network (slron), Beamount Hospital & St Luke’s Hospital, Rathgar, Dublin/IE
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Abstract 430P

Background

ctDNA can be useful in mapping evolving mutations during NACRT to diagnosis residual disease and guide adaptive therapies in resistant patients (pts) without pCR.

Methods

Pilot study of 10 LARC pts enrolled on CTRIAL-IE 12-38 TRI-LARC (NCT02151019) trial and received NACRT. Tumour tissues(ts) with plasma samples were taken at baseline, on-treatment and post-operation (post-op). Ts DNA was sent for targeted sequencing with AgilentTM ClearSeq Panel. ctDNA was genotyped for mutations in NRAS, KRAS, EGFR, PIK3CA and BRAF genes.

Results

3 pts had pCR and 7 had non-pCR. Post-op ts were available in 6 non-pCR pts. Compared to baseline ts, 50% (3/6) post-op ts showed no residual mutations, followed by 17% (1/6) had alterations and 33% (2/6) had no changes. The alterations were ATRX gain with SMAD4 and KRAS losses. ctDNA detected more synchronous mutations than ts. Extra mutations in NRAS/KRAS were seen in 6/10 pts’ ctDNA taken at baseline, with MAF 0.83 [0.3-1.4]. Mutations in BRAFV600E and PIK3CA were seen in 1/10 and 5/10 pts' ctDNA, respectively. Concordance between ctDNA and ts is 40%. Post-operatively, non-pCR patients have ctDNA with median MAF 1.20±0.99 vs pCR pts 0.60±0 (p=0.74). Table: 430P

Genetic mutation landscape in ts at various timepoints. Tumour response according to Mandard Score. Among pts with non-pCR, mutations seen in baseline ts include NRAS/KRAS in 86% (6/7), FBXW7 in 29% (2/7), MAPK2K1 in 14% (1/7), SMAD4 in 14% (1/7), ATRX in 14% (1/7) and DDX3X in 14% (1/7) No BRAF mutation detected in any ts. NM=no mutations; NS=no sample available.

Patients (Treatment Response) 20 (TRG1) 26 (TRG1) 11 (TRG1) 17 (TRG2) 18 (TRG3) 41 (TRG3) 3 (TRG2) 27 (TRG4) 28 (TRG4) 19 (TRG5)
Baseline ts
NRAS61 ERBB4232 APC1367 APC1114 NRAS61 MAP2K157 APC1367 NRAS13 FBXW7385 APC876
PIK3CA 546 APC1367 TP53266 APC1356 FBXW7333 KRAS12 CHD7287 KRAS12 KRAS13
SLCO1B1 489 TP53248 ATM3028 APC1309 TP53273 ERBB3583 TP53245 TP53213
KRAS12 DDX3X66 TP53199
ATRX494 SMAD4496
Week 3 ts
NRAS61 ERBB4232 NS NS NM MAP2K157 NS NS FBXW7385 NS
SLCO1B1 489 APC1367 KRAS12
TP53248
Post-op ts
pCR pCR pCR NM NM NM APC1367 NRAS13 FBXW7385 NS
ATRX1739 CHD7287 KRAS12
ERBB3583 TP53245

Conclusions

Serial ctDNA can identify intratumoural heterogeneity and potentially elucidate driver mutations implicated in chemoradioresistance. We are analysing mutations of interest in ERBB, SMAD4, FBXW7 and ATRX genes.

Clinical trial identification

NCT02151019 (CTRIAL-IE 12-38 TRI-LARC clinical trial).

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Northeast Cancer Research and Education Trust (NECRET), St Luke’s Institute of Cancer Research (SLICR) and the Ronnie Cox Award (Cancer Research Ireland).

Disclosure

All authors have declared no conflicts of interest.

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