Dynamic circulating tumor DNA quantificaton for the individualization of non-small-cell lung cancer patients treatment

Abstract

BackgroundLiquid biopsy has evolved from being a promising line to becoming a validated approach for biomarker testing. However, its utility for individualization of therapy has been scarcely reported. In this study, we show how monitoring levels of EGFR mutation in plasma can be useful for the individualization of treatment.ResultsLongitudinal EGFR mutation levels in plasma always correlated with tumor response ascertained by RECIST criteria. Moreover, decreasing EGFR mutation levels were detected in all patients benefiting from locoregional radiotherapy, whereas the opposite occurred when a patient progressed soon after radiotherapy treatment. Similarly, increasing EGFR mutation levels anticipated disease progression after TKI dose reduction, discontinuation of treatment, or reduced bioavailability due to drug interactions. In addition, EGFR mutation levels were useful to monitor treatment outcome of new therapies and constituted a decisive factor when the clinical situation of the patient did not correlate with responses ascertained by radiologist. Finally, our results indicate that cancer associated body fluids (pleural, pericardial or cerebrospinal fluid) are certainly a suitable source for biomarker testing that can extend EGFR mutation detection to biofluids other than blood.Materials and MethodsA total of 180 serial plasma samples from 18 non-small-cell lung cancer patients who carried an activating EGFR mutation were investigated by digital PCR.ConclusionsMonitoring levels of EGFR mutation in plasma allows resolving doubts that frequently arise in daily clinical practice and constitutes a major step towards achieving personalized medicine.

The Value of Liquid Biopsies for Guiding Therapy Decisions in Non-small Cell Lung Cancer

“…Treatment response has been monitored by observing the abundance of known driver mutations, where the fluctuations of EGFR-mutant abundance in the serial plasma cfDNA samples are in accordance with the changes in tumor size assessed via imaging scans ( 60 ). In addition, longitudinal EGFR mutation levels in plasma correlated with the tumor response determined using RECIST criteria ( 12 ). In 19 patients treated with afatinib for ≥24 weeks, the number of EGFR mutant alleles detected in cfDNA via digital polymerase chain reaction (PCR) declined rapidly and markedly after treatment onset, becoming undetectable or detectable at only a low copy number (<10 copies per milliliter) at 4 weeks ( 23 ).…”

“…In addition, early progression as indicated by T790M mutation in plasma can be detected earlier than that detected in computed tomography (CT) scans. In a study of 41 patients, progression was detected from plasma samples 51 days prior to those detected in CT scans ( 12 ). Another study that enrolled 102 patients even reported an earlier detection time of 103 days ( 66 ).…”

“…ctDNA and CTCs are the most widely investigated markers in liquid biopsies of patients with cancer. In addition to blood, promising results of liquid biopsies have been obtained from other body liquids, such as saliva and urine ( 10 – 12 ).…”

Intra‐individual variation of circulating tumour DNA in lung cancer patients

“…Furthermore, if ctDNA is present after curative treatment, the risk of relapse is significantly increased (Garcia‐Murillas et al , ). Likewise, an increase in the concentration of ctDNA during ongoing treatment precedes disease progression (Demuth et al , ; Provencio et al , ; Xiong et al , ). These findings offer new hope for monitoring disease activity using ctDNA and emphasise how ctDNA may be a valuable tool in the treatment–decision pathway in the near future.…”

Clinical utility of liquid biopsy for the diagnosis and monitoring of EML4-ALK NSCLC patients

“…cfDNA profiling has proved to be useful to guide personalized treatments based on the molecular profile, for early detection of resistance mechanisms [35,36], early detection of disease recurrences, as well as tumor response to therapy monitoring [37] by means of sequential liquid biopsies. Furthermore, several studies comparing the detection of EML4-ALK translocation by formalin-fixed paraffinembedded (FFPE) tissuesand liquidbiopsy havereportedthat indeed cfDNA can be used as a surrogate of FFPE DNA [38].…”