Biomarkers detecting minimal residual disease in solid tumors: what do they mean in the clinical management of patients?

Abstract

After curative resection of the primary tumor in nonmetastatic cancer, there are three questions to be answered. First, is adjuvant therapy necessary to decrease the risk of future relapse? Second, if so, what therapy? And third, how to monitor the response? The decision to use adjuvant therapy is based on the clinical-pathological findings of the primary tumor stage according to the TNM classification, tumor differentiation and vascular, lymphatic and/or perineural infiltration. Patients are classified according to the risk of relapse and based on the results of large double-blinded randomized trials assigned to adjuvant therapy (chemotherapy, radiotherapy, immunotherapy or hormonal therapy as monotherapy or in combination). Adjuvant therapy may be nonspecific such as chemotherapy with/without radiotherapy or specific. Specific therapy is based on the characteristics of the primary tumor; examples are trastuzumab for HER2-positive breast cancer, tamoxifen for estrogen receptor positive breast cancer [1]. In colon cancer, the determination of tumor gene status for RAS and BRAF is done individually or as part of next-generation sequencing or the use of microsatellite instability or mismatch repair testing [2]. In patients with advanced non-small-cell lung cancer, EGFR mutation testing, ALK testing and PD-L1 testing (category 1 based evidence), BRAF and ROS1 testing are utilized to determine specific therapies [3]. The third question is how to monitor treatment, as imaging studies are intially negative for disseminated cancer and follow-up is based on detecting treatment failure and the appearance of metastasis. The level of prostate-specific antigen after primary treatment is used as a serum biomarker to determine the need for treatment and to monitor treatment response in non-metastatic cancer only in prostate cancer. The rational for the use of adjuvant therapy is that the presence of occult cancer cells, which have dissemination prior to surgery, will cause future relapse and their elimination will improve disease-specific survival.These occult cancer cells are termed minimal residual disease (MRD). To detect MRD there are three forms, the detection of circulating tumor cells (CTCs), detection of disseminated tumor cells or micro-metastasis in bone marrow (DTCs) and circulating tumor DNA. Each method has its pitfalls. CTC detection is method dependent; those based on enrichment using EpCAM such as CellSearch R © do not detect EpCAM-negative CTCs, such as those that have undergone the epithelial–mesenchyme transition and can be found in benign disease [4–7]. Those based on cell size or density, such as Oncoquick R ©, Screencell R © or ISET R ©, do not detect cell clusters or CTCs smaller than 8 μm. DTCs are detected in bone marrow aspirates or biopsies and identified using immunocytochemistry or RT-PCR, which is a more invasive procedure, but serious adverse events are reported in only 0.07% of cases [8]. Both CTCs and DTCs are detected with increasing frequency with higher stage nonmetastatic cancer and their presence is associated with a worse prognosis [8–12]. More recently, the circulating tumor-free DNA (tfDNA) has been used as a measure of MRD. At present, only the detection of tumor-specific mutations on cell-free DNA indicates the presence of tfDNA. In cancer patients, a major source of tfDNA is from necrotic or apoptotic tumor cells, a minor component is that secreted from viable cancer cells, however there is no form of distinguishing between tfDNA from live or dying/dead tumor cells [13].