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Page 2 of 13 Udukala et al. J Cancer Metastasis Treat 2020;6:25 I http://dx.doi.org/10.20517/2394-4722.2020.45

Conclusion: This feasibility study, comprising 33 non-small cell lung cancer patients and 20 apparently healthy
subjects, clearly demonstrated the feasibility of minimally invasive early diagnosis of non-small cell lung cancer,
starting with stage I.

Keywords: Non-small cell lung cancer, lung cancer diagnosis, protease activity, liquid biopsies, iron/iron oxide
nanoparticles, significance table, multivariate model

INTRODUCTION
Lung cancer is the second most common cancer in men and women. For 2020, a total of 228,820 new
cases are estimated. For both genders, lung cancer is on top of the cancer mortality ranking in the US, and
[1]
135,720 cancer mortalities are anticipated this year . Approximately 13% of all lung cancers are small cell
lung cancers (SCLC), and 84% are non-small cell lung cancers (NSCLC). Here, we focus on the detection
of NSCLC by means of optical nanobiosensors capable of determining the activity of signature proteases
in serum. In Figure 1, the 5-year survival of NSCLC patients as a function of cancer stage at the time of
lung cancer diagnosis is shown. The staging system used for NSCLC in this report is the American Joint
Committee on Cancer (AJCC) TNM system, which is based on the size and extent of the main tumor (T),
[2]
the spread to nearby lymph nodes (N), and the metastasis to distant sites (M) . It is clearly discernible
that the 5-year survival rate significantly decreases if the cancer is diagnosed late. This implies that early
detection of cancer saves lives. On the basis of the 5-year survival statistics of NSCLC, we conservatively
estimate that about 30 percent of mortalities could be prevented if NSCLC were routinely detected at stage 1
[3]
(combined T1a, T1b, and T1c) instead at stages 2 or 3, when it is currently diagnosed . The optical
nanobiosensors developed in the Bossmann group feature sub-femtomolar limits of detection, thereby
[4-7]
permitting the diagnosis of NSCLC by means of a liquid biopsy utilizing the serum of cancer patients .
Liquid biopsies
In 2000, Veridex introduced the first commercially available liquid biopsy assay, the CELLSEARCH®

[8]
CTCtest . In 2016, the Food and Drug Administration (FDA) approved the cobas® epidermal growth
factor receptor (EGFR) Mutation Test for determination of the EGFR gene mutation in blood from lung
[9]
cancer patients . Commercially available liquid biopsies consist in the detection of circulating tumor cells
(CTCs), tumor-derived exosomes, circulating cell-free DNA (cfDNA), microRNA (miRNA), signaling
[10]
proteins and metabolic enzymes (proteases and kinases) . Virtually all companies in this field, among
[11]
[14]
[13]
[12]
them Personal Genome Diagnostics , Genomic Health , Myriad Genetics , Guardant Health and
[15]
Pathway Genomics rely on PCR to detect genetic mutations, and various RNAs that are overexpressed
in tumors [11-15] . CancerSEEK evaluated the plasma levels of 8 cancer-indicating proteins and the presence
of mutations in 2,001 genomic positions for detecting 8 solid tumor types, among them pancreatic cancer
with an overall percentage of cancer detection of 62% at > 99% specificity . DETECT-A (detecting cancers
[16]
earlier through elective mutation-based blood collection and testing) was able to detect 26 cancers by
means of a liquid biopsy (nine lung cancers, six ovarian cancers and two colorectal cancers). Seventeen (65%)
[17]
of the 26 cancers were localized or regional, including five patients with stage I tumors . The GRAIL
technology looks at differences in DNA methylation between cancerous and healthy cells. It is capable of
detecting > 50 different cancers from one liquid biopsy and has a very low false positive rate. Regardless of
the cancer detection technology used, it is of vital importance to detect cancers at AJCC stage I or earlier
[17]
to maximize cancer survival . GRAIL is promising early detection capability, because changes in DNA
methylation occur early in cancer [18,19] . As for all approaches, including the optical nanobiosensors for
protease activity profiling discussed here, future comparative clinical trials will permit a true comparison of
genomic vs. other methods of early cancer detection.