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Poster Discussion – Gastrointestinal tumours, colorectal

2951 - Impact of clonality and DNA repair mutations on plasma tumor mutation burden (pTMB) and immunotherapy efficacy in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) in CCTG CO.26


29 Sep 2019


Poster Discussion – Gastrointestinal tumours, colorectal


Jonathan Loree


Annals of Oncology (2019) 30 (suppl_5): v198-v252. 10.1093/annonc/mdz246


J.M. Loree1, D.J. Jonker2, H. Feilotter3, H.F. Kennecke4, P.Z. Brohawn5, K. Banks6, K. Quinn7, D. Tu8, C. O'Callaghan8, E.X. Chen9

Author affiliations

  • 1 Medical Oncology, BC Cancer, V5Z 4E6 - Vancouver/CA
  • 2 Department Of Medicine, Division Of Medical Oncology, Ottawa Hospital Research Institute, University of Ottawa, K1H8L6 - Ottawa/CA
  • 3 Pathology And Molecular Medicine, Queen's University, K7L 3N6 - Kingston/CA
  • 4 Hematology-oncology, Virginia Mason Medical Center, 98101 - Seattle/US
  • 5 Research & Development, MedImmune, 20878 - Gaithersburg/US
  • 6 Medical Affairs, Guardant Health, 94063 - Redwood City/US
  • 7 Bioinformatics, Guardant Health, 94063 - Redwood City/US
  • 8 Cctg Trials Unit, Queen's University, K7L 3N6 - Kingston/CA
  • 9 Medical Oncology, University Health Network, M5G 2C1 - Toronto/CA


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Abstract 2951


We previously showed pTMB selects patients (pts) deriving benefit from PD-L1 and CTLA-4 inhibition with durvalumab and tremelimumab (D+T) compared to best supportive care (BSC) in refractory mCRC in CCTG CO.26.


We investigated somatic variants contributing to pTMB in MSS pts using cell-free DNA (cfDNA) analysis performed with the GuardantOMNITMassay (2.1Mb) on 166 pts from CO.26.


Median pTMB was 16.3 mutations/megabase (mts/Mb). Using a minimum p-value approach, pts with pTMB>28 mts/Mb (21% of MSS pts) had the greatest overall survival (OS) benefit for D + T (HR 0.34, 90% CI 0.18-0.63, p-interaction=0.070) and worse OS in the BSC arm (HR 2.59, 90% CI 1.46-4.62). Of 4044 mts detected, 2718 (67.2%) were subclonal (<10% of max detected mutant allele frequency [MAF]). Anti-EGFR exposure associated with more mts per pt (median 28.5 vs 15.5, P < 0.0001), higher proportion of subclonal mts (78.3% vs 53.7%, P < 0.0001) and higher median pTMB compared to RAS mt pts with no prior anti-EGFR (24.9 vs 13.4 mts/Mb, P < 0.0001). After removing subclonal mts from pTMB calculation, median pTMB decreased to 5.8 mts/Mb. This clonal pTMB remained predictive of D+T improving OS (HR 0.19, 90% CI 0.08-0.45, p-interaction=0.039) when pTMB>10.6 mts/Mb (14.1% pts). Similarly, pTMB calculated using only subclonal mts associated with D+T OS benefit (HR 0.32, 90% CI 0.16-0.67, p-interaction=0.057). Though many genes were associated with pTMB and improved efficacy (see Table), only BRCA1 mts predicted treatment effect (p-interaction=0.035). Most DNA repair mts were subclonal and not associated with increased clonal pTMB.Table:


Gene MutationMedian pTMB MT vs WTMedian Clonal pTMB MT vs WTHR (90% CI, p) Among Pts with Selected MT
MSS Study Population (n = 166)16.3 (95% CI: 14.4-20.1)5.8 (95% CI: 4.8-5.8)0.66 (0.49-0.89, 0.024)
BRCA1 (n = 21)23.0 vs 15.3 (P = 0.0006)5.8 vs 5.8 (P = 0.64)0.20 (0.07-0.58, 0.013)
BRCA2 (n = 29)28.9 vs 14.6 (P < 0.0001)5.8 vs 5.8 (P = 0.52)0.39 (0.18-0.85, 0.047)
ATM (n = 31)31.6 vs 13.9 (P < 0.0001)6.7 vs 4.8 (P = 0.023)0.66 (0.37-1.18, 0.24)
Polymerase E/D1/Q/H (n = 20)36.4 vs 14.7 (P < 0.0001)5.3 vs 5.8 (P = 0.57)0.95 (0.44-2.05, 0.91)
TP53 (n = 126)17.2 vs 13.1 (P = 0.024)4.8 vs 6.7 (P = 0.017)0.63 (0.45-0.88, 0.024)
MMR Gene without MSI (n = 31)24.9 vs 14.6 (P < 0.0001)5.8 vs 5.8 (P = 0.85)0.38 (0.17-0.85, 0.050)


Both clonal and subclonal mts causing an elevated pTMB associated with benefit from D+T and mts in select DNA repair genes may correlate with benefit. cfDNA provides an opportunity to evaluate tumor evolution potentially missed in archival tissue.

Clinical trial identification


Editorial acknowledgement

Legal entity responsible for the study

Canadian Cancer Trials Group.


Canadian Cancer Society.


P.Z. Brohawn: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. K. Banks: Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment: Guardant Health. K. Quinn: Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment: Guardant Health. All other authors have declared no conflicts of interest.

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