Despite low individual recurrence rates, the vast number of women diagnosed with early-stage breast cancer means they account for most deaths. The annual proportion of deaths from stage 2 disease rose from 26% to 40%, while stage 1 accounts for another 23%. This highlights the need for better monitoring, like ctDNA, in this population.
In neoadjuvant breast cancer treatment, patients with residual cancer post-therapy remain at high risk of recurrence (10-20%) even if their ctDNA tests are negative. This finding suggests that the physical presence of residual disease is a critical factor, and ctDNA status alone cannot justify forgoing additional adjuvant therapy in this cohort.
Hematologic cancers often have a single, common genetic marker per disease, enabling MRD detection with simple PCR for decades. Solid tumors are genetically diverse, lacking a universal marker. This required developing personalized, multi-probe assays like Signatera to track unique mutations, explaining the field's more recent progress.
Dr. Pusztai clarifies the ctDNA lexicon: "Molecular relapse" is when a supposedly cured patient turns ctDNA positive during surveillance. "Molecular progression" is when a metastatic patient on therapy develops new resistance mutations detectable in ctDNA before clinical progression. This specific terminology is key for precise clinical decision-making.
The next wave of ctDNA research focuses on de-escalation. Trials like SIGNAL ER101 and an Alliance cooperative group study will test withholding intensive adjuvant treatments (like CDK4/6 inhibitors) in high-risk, ctDNA-negative patients, initiating therapy only if they turn positive later. This could spare many from toxicity and cost.
The original Signatera assay used 16 personalized probes based on whole-exome sequencing to find ctDNA. The next-generation version, based on whole-genome sequencing, expands this to 64 probes. This is expected to significantly increase sensitivity, detect molecular relapse earlier, and provide a longer window for clinical intervention.