SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women 12%) will develop invasive breast cancer during their lifetime. Approximately 279,100 new cases of invasive breast cancer will be diagnosed in 2020 and about 42,690 individuals will die of the disease largely due to metastatic recurrence. Recurrent disease can occur early, but majority of patients with hormone receptor-positive breast cancer may develop recurrent disease decades, following their initial diagnosis. Once a diagnosis of metastatic breast cancer is established, it is generally incurable.
Systemic recurrence likely arises from micrometastatic disease present at initial diagnosis, which is undetectable by imaging or conventional blood tests. Adjuvant systemic therapy is recommended to eradicate micrometastatic disease and reduce the risk of cancer recurrence. However, current clinical tools are not accurate in identifying which patients would benefit from adjuvant systemic therapy and further are unable to, in real-time, predict whether the recommended therapies have achieved their therapeutic objective. Therefore, more sensitive techniques to detect micrometastatic disease are needed, so that patients receive the most appropriate and optimal therapy, with improved outcomes.
Recently published studies have shown that detection of circulating tumor DNA (ctDNA) in the peripheral blood may identify patients at risk of relapse following definitive therapy using digital droplet Polymerase Chain Reaction (ddPCR) assays. ctDNA refers to DNA fragments that are shed into the bloodstream by cancer cells after apoptosis or necrosis. The clinical sensitivity of this technique however is limited at the early postoperative time points, at which treatment decisions are usually made, and the lead time prior to clinical manifestation of overt metastatic disease has been relatively short. This is because presently available techniques track one or few mutations and are unable to detect MRD when the fraction of cancerous cell free DNA (cfDNA) in the bloodstream is low.
The authors developed an ultrasensitive blood test for tracking hundreds of patient-specific mutations, to detect Minimal Residual Disease (MRD), with a 1,000-fold lower error rate than conventional sequencing, to identify patients who might benefit from additional systemic treatment or de-escalation of therapy. The authors performed Whole-Exome Sequencing (WES) to define several hundred mutations from each patient’s tumor, and to limit potential errors, selected somatic SNVs (Single Nucleotide Variants) to track, using duplex sequencing in cfDNA and employing strict criteria. The detection of 2 or more mutations in a cfDNA sample was considered MRD-positive and any mutations found in a patient’s own genomic DNA was excluded.
For this study, the authors identified 142 patients who had been treated for Stage 0-III breast cancer with curative intent surgery, had postoperative blood and plasma samples available. Overall, 92% of patients received either neoadjuvant, or adjuvant chemotherapy, 76% received adjuvant endocrine therapy and 73% received adjuvant radiation treatment. Approximately 2% of patients had Stage 0 disease, 23% had Stage I, 48% had Stage II, and 27% had Stage III breast cancer at diagnosis. The MRD levels were tracked post-op (median 3.5 months) and 1 year out (median 14.2 months). The patients were monitored for distant recurrences for up to 13 years. A median of 57 mutations were targeted in each patient, identified via Whole-Exome Sequencing of primary tumor tissue and genomic DNA from whole blood. About 78% of patients had post-op samples available, while 86% had 1-year samples. The Primary objective of this study was to determine the predictive power of MRD testing and associated lead time to recurrence, in patients treated for early-stage breast cancer.
The median lead time (the time from a positive test to diagnosis of metastatic disease) between the first MRD-positive result and disease recurrence was 18.9 months in the patients with the most mutations tracked. This is significantly longer than what has been seen in prior studies. Distant disease recurrence was shown to be more likely if MRD was detected at the 1-year mark (HR=20.8; P<0.0001) compared with the post-op setting. Among these patients, the positive and negative predictive values for distant recurrence, was 0.70 and 0.77, respectively. Overall, the clinical sensitivities were 81% in patients with newly diagnosed metastatic breast cancer, 23% in the post-op setting, and 19% at the one year in early stage disease, and highest among patients with the most tumor mutations available to track. The authors noted that their testing methodology was 100-fold more sensitive than ddPCR, when tracking 488 mutations.
It was concluded that the ultrasensitive blood test developed by investigators for Minimal Residual Disease (MRD) could identify survivors who might benefit from additional systemic treatment versus de-escalation. MRD detection was strongly associated with distant recurrence and provided significant lead time to recurrence, enabling early therapeutic intervention in patients who may otherwise develop metastatic recurrence. The authors recommended that future blood-based Whole-Genome Sequencing assays should aim for extra sensitivity, to identify enough mutations to track in all patients.
Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer. Parsons HA, Rhoades J, Reed SC, et al. Clin Can Res. DOI: 10.1158/1078-0432.CCR-19-3005. Published June 2020.