318MO - Circulating tumour DNA (ctDNA) dynamics, CEA and sites of recurrence for the randomised DYNAMIC study: Adjuvant chemotherapy (ACT) guided by ctDNA analysis in stage II colon cancer (CC)

Background

In the primary analysis of DYNAMIC, a randomised phase II study in patients (pts) with stage II CC, a ctDNA-guided approach versus standard management reduced ACT use without compromising recurrence-free survival (RFS). Notably, after ACT with oxaliplatin doublet or fluoropyrimidine alone, the 3-year RFS for ctDNA-positive pts in the ctDNA-guided group was 86.4%. Here we explore the relationship between post-op ctDNA and sites of recurrence, post-ACT ctDNA status and relapse, and the performance of post-op and post-ACT CEA from the same blood samples.

Methods

For ctDNA-positive pts at 4 and/or 7 weeks after surgery (post-op), post-ACT ctDNA results (collected 4 weeks after completing ACT) were correlated with recurrence status, as were post-op and post-ACT CEA results for all pts. Post-op ctDNA status and sites of recurrence were explored. A tumour-informed personalised assay was used to assess ctDNA.

Results

Of 291 ctDNA-guided pts, recurrence was seen in 23 (7.9%). Post-op ctDNA was negative in all 8 pts with locoregional relapse only, whereas 8 of 15 with distant relapse had a positive post-op ctDNA (P = 0.02). Of the 45 pts (15%) with a positive post-op ctDNA, post-ACT ctDNA was available in 38. 2 of 31 (6.5%) who converted to ctDNA negative after ACT recurred, compared to 5 of 7 (71%) who remained ctDNA positive (HR 17.3, 95% CI 3.3 - 90.2; P < 0.001). Median time to recurrence was 5 months (1 - 39 months) for post-ACT ctDNA-positive pts. Post-op CEA was elevated in 11 of 240 (4.6%) that were ctDNA-negative post-op, one (9%) of whom recurred, whereas 14 of 229 (6.1%) with a normal CEA recurred (P = 0.947). Post-ACT CEA was elevated in 3 of 28 (11%) pts with available CEA who converted from ctDNA positive post-op to ctDNA negative post-ACT, none of whom recurred, whereas 1 of 25 (4%) with a normal CEA recurred (P = 0.729).

Conclusions

For stage II CC pts, ctDNA analysis is more sensitive for predicting distant than locoregional recurrences. ctDNA clearance can be achieved with ACT in a high proportion of those with an initial positive post-op ctDNA and predicts for excellent outcome. In ctDNA-negative pts, CEA lacks sensitivity and specificity as a marker of recurrence risk.

Clinical trial identification

ACTRN12615000381583.

Editorial acknowledgement

Legal entity responsible for the study

The Walter and Eliza Hall Institute of Medical Research.

Funding

Australian National Health and Medical Research Council, The Virginia and D.K. Ludwig Fund for Cancer Research, The Conrad R. Hilton Foundation, The Sol Goldman Charitable Trust, John Templeton Foundation, NIH, the Marcus Foundation.

Disclosure

J. Tie: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Pierre Fabre, Inivata; Financial Interests, Personal, Invited Speaker: Servier, Merck Serono; Financial Interests, Personal, Other, Consultancy: Haystack Oncology. J. Cohen: Financial Interests, Personal, Officer: Haystack Oncology. R. Wong: Financial Interests, Personal, Advisory Board, Advisory Board - OG cancer 21/03/2022: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board, Advisory Board - CRC 22/03/2022: Merck Serono; Non-Financial Interests, Principal Investigator, Payments to Monash University ECRU: AstraZeneca, Merck Sharpe Dohme, AstraZeneca; Non-Financial Interests, Principal Investigator, Payment to Monash University ECRU (final payment June 2020): Merck Serono. L.G. Horvath: Financial Interests, Personal, Advisory Board, Honorarium donated back to Chris O'Brien Lifehouse (My hospital): Imagion Biosystems; Financial Interests, Personal, Invited Speaker, No payment: ANZUP (Australia and New Zealand Urogenital and Prostate) Clinical Trials Group; Financial Interests, Personal, Stocks/Shares, Stock options: Imagion Biosystems; Financial Interests, Personal, Stocks/Shares: My Emergency Doctor; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Invited Speaker, MK7684-001MK3475-991: MSD; Financial Interests, Institutional, Invited Speaker, AMG160 Phase I AMG509 Phase I: Amgen; Financial Interests, Institutional, Invited Speaker, 9785-CL-0335 (ARCHES): Astellas; Financial Interests, Institutional, Invited Speaker, SHR3680-002: Jiangsu Hengrui Medicines; Financial Interests, Institutional, Invited Speaker, C344102: Pfizer; Financial Interests, Institutional, Invited Speaker, JPCM: Eli-Lilly; Financial Interests, Institutional, Invited Speaker, DASL-HiCAP: ANZUP; Financial Interests, Institutional, Invited Speaker, GALAHADACIS Prevalence: Janssen-Cilag; Financial Interests, Institutional, Invited Speaker, GSK204697: GlaxoSmithKline; Financial Interests, Institutional, Invited Speaker, XL184-021: Exelexis; Financial Interests, Institutional, Invited Speaker, BGB-A317BGB-283BGB-A317-290: Beigene; Financial Interests, Institutional, Invited Speaker, FPT155-001: Five Prime; Financial Interests, Institutional, Invited Speaker, AB928CSP0003: ARCUS; Financial Interests, Institutional, Invited Speaker, ENZAMETENZARAD: ANZUP; Financial Interests, Institutional, Invited Speaker, ATG-017: Antagene. C.S. Karapetis: Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, BMS, Ipsen, Eli Lilly, Eisai, Roche, Takeda, Beigene; Financial Interests, Institutional, Invited Speaker: Takeda, Roche, Mirati, Daiichi Sankyo; Non-Financial Interests, Member: Medical Oncology Group of Australia, American Society of Clinical Oncology. N. Papadopoulos: Financial Interests, Personal, Advisory Role: Thrive Earlier Detection, Haystack Oncology, Neophore, Personal Genome Diagnostics, CAGE Pharma; Financial Interests, Personal, Stocks/Shares: Exact Science, Haystack Oncology, Neophore, Personal Genome Diagnostics, CAGE Pharma. C. Tomasetti: Financial Interests, Personal and Institutional, Royalties: exact sciences; Financial Interests, Personal, Advisory Board: prognomiQ; Financial Interests, Personal, Advisory Role: Bayer AG. K. Kinzler: Financial Interests, Personal, Advisory Role: Thrive Earlier Detection, Haystack Oncology, Neophore, Personal Genome Diagnostics, CAGE Pharma; Financial Interests, Personal, Stocks/Shares: Exact Science, Haystack Oncology, Neophore, Personal Genome Diagnostics, CAGE Pharma. B. Vogelstein: Financial Interests, Personal, Advisory Role: Thrive Earlier Detection, catalio capital management, Neophore, CAGE Pharma; Financial Interests, Personal, Stocks/Shares: Exact Science, catalio capital management, Neophore, Personal Genome Diagnostics, CAGE Pharma; Financial Interests, Personal, Advisory Role, Peter MacCallum Cancer Centre: Personal Genome Diagnostics. P. Gibbs: Financial Interests, Personal, Advisory Role: Haystack; Financial Interests, Personal, Speaker’s Bureau: MSD; Financial Interests, Personal, Advisory Board: Pierre faber, MSD; Financial Interests, Research Grant: BMS. All other authors have declared no conflicts of interest.