Assessment of Molecular Relapse Detection in Early-Stage Breast Cancer

Abstract

IMPORTANCE Current treatment cures most cases of early-stage, primary breast cancer. However, better techniques are required to identify which patients are at risk of relapse.OBJECTIVE To assess the clinical validity of molecular relapse detection with circulating tumor DNA (ctDNA) analysis in early-stage breast cancer. DESIGN, SETTING, AND PARTICIPANTSThis prospective, multicenter, sample collection, validation study conducted at 5 United Kingdom medical centers from November 24, 2011, to October 18, 2016, assessed patients with early-stage breast cancer irrespective of hormone receptor and ERBB2 (formerly HER2 or HER2/neu) status who were receiving neoadjuvant chemotherapy followed by surgery or surgery before adjuvant chemotherapy. The study recruited 170 women, with mutations identified in 101 patients forming the main cohort. Secondary analyses were conducted on a combined cohort of 144 patients, including 43 patients previously analyzed in a proof of principle study.INTERVENTIONS Primary tumor was sequenced to identify somatic mutations, and personalized tumor-specific digital polymerase chain reaction assays were used to monitor these mutations in serial plasma samples taken every 3 months for the first year of follow-up and subsequently every 6 months. MAIN OUTCOMES AND MEASURESThe primary end point was relapse-free survival analyzed with Cox proportional hazards regression models. RESULTSIn the main cohort of 101 female patients (mean [SD] age, 54 [11] years) with a median follow-up of 35.5 months (interquartile range, 27.9-43.0 months), detection of ctDNA during follow-up was associated with relapse (hazard ratio, 25.2; 95% CI, 6.7-95.6; P < .001). Detection of ctDNA at diagnosis, before any treatment, was also associated with relapse-free survival (hazard ratio, 5.8; 95% CI, 1.2-27.1; P = .01). In the combined cohort, ctDNA detection had a median lead time of 10.7 months (95% CI, 8.1-19.1 months) compared with clinical relapse and was associated with relapse in all breast cancer subtypes. Distant extracranial metastatic relapse was detected by ctDNA in 22 of 23 patients (96%). Brain-only metastasis was less commonly detected by ctDNA (1 of 6 patients [17%]), suggesting relapse sites less readily detectable by ctDNA analysis. CONCLUSIONS AND RELEVANCEThe findings suggest that detection of ctDNA during follow-up is associated with a high risk of future relapse of early-stage breast cancer. Prospective studies are needed to assess the potential of molecular relapse detection to guide adjuvant therapy.

Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer

“…14). Garcia-Murillas and colleagues (2019) did not compute clinical sensitivity at postoperative but stated that most patients who experienced recurrence did not have an initial MRDþ test at postoperative (15). Meanwhile, Coombes and colleagues reported higher sensitivity in the first postoperative sample tested per patient but this was later for most patients, up to 3 years after completion of adjuvant chemotherapy (13).…”

“…Recent studies have shown that liquid biopsies can detect minimal residual disease (MRD) in multiple cancer types (8)(9)(10)(11)(12) including breast (13)(14)(15), by tracking tumor mutations in circulating cell-free DNA (cfDNA). However, in these previous studies, clinical sensitivity has been limited at the early postoperative time points, at which treatment decisions are typically made, and the lead time prior to clinical presentation of overt metastatic disease has been relatively short.…”

Utility of Circulating Tumor DNA for Detection and Monitoring of Endometrial Cancer Recurrence and Progression

“…As with CTCs, numerous methods are available for total cfDNA extraction from both serum and plasma, with studies illustrating that several pre-analytical factors affect yield and downstream analysis post-venepuncture, including the blood tube used, number of centrifugation steps, centrifugal speed, cfDNA extraction method, and ctDNA detection methods [19][20][21]. Methods employed for detection of ctDNA depend upon the question being asked, with whole genome/exome next generation sequencing (NGS) being performed to obtain a global view of genomic changes associated with disease progression [22,23] (however, this is hampered by low sensitivity), targeted sequencing to obtain higher sensitivity (1 ctDNA molecule in 1000 cfDNA molecules) in a smaller number of genes [6,15,17,24,25], or digital droplet PCR (ddPCR) (usually analysis of one or two mutations to a sensitivity of one in 100,000) to detect early stage disease [14,26]. To date, only a handful of ctDNA tests have been approved by the U.S Food and Drug Administration (FDA) for use in metastatic and locally advanced NSCLC, and HR+, HER2-negative, advanced breast cancer in progression on or after endocrine therapy.…”

Liquid Biopsy in Breast Cancer

“…According to smaller trials the circulating DNA may also contribute to risk stratification in the follow-up of asymptomatic patients 43 , 44 , 45 , 46 . In a group of 101 women Garcia-Murillas et al were able to establish that serial ctDNA measurements can predict the risk of recurrence 44 . Blood tests were repeated every 3 months in the first year and then every 6 months for 5 years.…”

“…Kleineren Studien zufolge kann auch die zirkulierende DNA zur Risikostratifizierung der asymptomatischen Patientin während der Nachsorge beitragen 43 , 44 , 45 , 46 . So konnten Garcia-Murillas et al an einem Kollektiv von 101 Frauen zeigen, dass serielle Messungen der ctDNA das Rezidivrisiko voraussagen können 44 . Blutentnahmen erfolgten im 1.…”