Publication: 554P KRAS-dependent and independent mechanisms of progressive disease …

blood plasma

A Kirov, Z Mihaylova, V Petrova, T Todorov, D Petkova, A Garev, A Todorova-Georgieva, 

554P KRAS-dependent and independent mechanisms of progressive disease (PD) in colorectal cancer (CRC) patients (pts) with liver metastases (LM) while monitoring on circulating cell free DNA (cfDNA)

Abstract 

Background: KRAS mutational analysis (MA) in plasma (P) cfDNA is an alternative to tissue (T) analysis with concordance rate (ConR) from 30 to 90%. The emergence of KRAS mutation (M) during the course of anti-EGFR therapy is responsible for acquired resistance (AR). We aimed to evaluate the RAS ConR between T and cfDNA in mCRC pts, and to monitor changes in RAS M status.

Methods: All blood samples were collected in cfDNA Preservative Tubes (Norgen Biotek Corp., Canada). ctDNA was extracted within 3 days after sampling, the extraction was performed by commercial kit (P/Serum cfDNA Purification Mini Kit, Norgen Biotek). KRAS (ex 2) M on P cfDNA and tumor T were detected by real-time PCR kits TheraScreen: K-RAS Mutation Kit. The other M were detected by Sanger sequencing (BigDye Terminator v3.1 Cycle Sequencing Kit – Thermo Fisher Scientific).

Results: In the ConR evaluation were enrolled prospectively 63 mCRC pts. Only LM had 52,4% (33) pts, from whom – 27,3% (9) pts had primary resectable LM. The median time from T biopsy (primary -97%) to P collection was 275, 7 days (range 26 – 1560). TMA revealed 58,7% (37) M pts from whom 78,4% (29) pts had KRAS ex.2 M. cfDNA evaluation showed the distribution of M to wild (W) – 81%/19% with KRAS ConR of 58,7%. To reduce time between T and P samples MA in the monitoring analysis were included only 31 pts who had primary unresectable LM, with baseline (b) P collection. In 5 pts with KRAS M after converting treatment, LM resection resulted in W type on consecutive cfDNAs. In responding pts (10) with W disease on bcfDNA, there was no change in MA consequently. In non-responders with W type the appearance of KRAS M was noted in 6 pts, while in the rest 3 pts PD was not correlated to KRAS M. In non-responders with KRAS M on bcfDNA (6 pts), monitoring of cfDNA revealed disappearance of KRAS M contemporary with mainly LM PD.

Conclusions: The estimated ConR between primary tumor and cfDNA KRAS MA was 58%. The emergence of KRAS M in W type pts reveled AR to anti-EGFR therapy. In pts with M KRAS on bcfDNA, liver resection in responders and LM PD in non-responders correlated with loss of KRAS M as a mechanism of AR to anti-angiogenesis treatment in the later.

Legal entity responsible for the study: Prof. Albena Parvanova Todorova-Georgieva.

Funding: Medical University Sofia.

Disclosure: All authors have declared no conflicts of interest.

Abstract 

Background: KRAS mutational analysis (MA) in plasma (P) cfDNA is an alternative to tissue (T) analysis with concordance rate (ConR) from 30 to 90%. The emergence of KRAS mutation (M) during the course of anti-EGFR therapy is responsible for acquired resistance (AR). We aimed to evaluate the RAS ConR between T and cfDNA in mCRC pts, and to monitor changes in RAS M status.

Methods: All blood samples were collected in cfDNA Preservative Tubes (Norgen Biotek Corp., Canada). ctDNA was extracted within 3 days after sampling, the extraction was performed by commercial kit (P/Serum cfDNA Purification Mini Kit, Norgen Biotek). KRAS (ex 2) M on P cfDNA and tumor T were detected by real-time PCR kits TheraScreen: K-RAS Mutation Kit. The other M were detected by Sanger sequencing (BigDye Terminator v3.1 Cycle Sequencing Kit – Thermo Fisher Scientific).

Results: In the ConR evaluation were enrolled prospectively 63 mCRC pts. Only LM had 52,4% (33) pts, from whom – 27,3% (9) pts had primary resectable LM. The median time from T biopsy (primary -97%) to P collection was 275, 7 days (range 26 – 1560). TMA revealed 58,7% (37) M pts from whom 78,4% (29) pts had KRAS ex.2 M. cfDNA evaluation showed the distribution of M to wild (W) – 81%/19% with KRAS ConR of 58,7%. To reduce time between T and P samples MA in the monitoring analysis were included only 31 pts who had primary unresectable LM, with baseline (b) P collection. In 5 pts with KRAS M after converting treatment, LM resection resulted in W type on consecutive cfDNAs. In responding pts (10) with W disease on bcfDNA, there was no change in MA consequently. In non-responders with W type the appearance of KRAS M was noted in 6 pts, while in the rest 3 pts PD was not correlated to KRAS M. In non-responders with KRAS M on bcfDNA (6 pts), monitoring of cfDNA revealed disappearance of KRAS M contemporary with mainly LM PD.

Conclusions: The estimated ConR between primary tumor and cfDNA KRAS MA was 58%. The emergence of KRAS M in W type pts reveled AR to anti-EGFR therapy. In pts with M KRAS on bcfDNA, liver resection in responders and LM PD in non-responders correlated with loss of KRAS M as a mechanism of AR to anti-angiogenesis treatment in the later.

Legal entity responsible for the study: Prof. Albena Parvanova Todorova-Georgieva.

Funding: Medical University Sofia.

Disclosure: All authors have declared no conflicts of interest.

Citation

A Kirov, Z Mihaylova, V Petrova, T Todorov, D Petkova, A Garev, A Todorova-Georgieva; 554P
KRAS-dependent and independent mechanisms of progressive disease (PD) in colorectal cancer (CRC) patients (pts) with liver metastases (LM) while monitoring on circulating cell free DNA (cfDNA), Annals of Oncology, Volume 29, Issue suppl_8, 1 October 2018, mdy281.100, https://doi.org/10.1093/annonc/mdy281.100

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