INTRODUCTION
In recent decades, the prevalence of carcinogenic diseases has surged, with approximately 1.9 million new cancer cases and 0.6 million deaths reported annually in the United States alone[1]. This signifies an 18% increase in cases and a 3% rise in deaths compared to statistics from a decade ago, posing significant concerns for public health globally, especially in developed countries[2]. Despite advancements in cancer diagnosis and treatment methods, the numbers have either stabilized or increased over the past decade. Successful treatment hinges on early detection, but conventional diagnostic procedures are often invasive, time-consuming, and uncomfortable, prompting a growing demand for fast, accurate, and painless diagnostic and treatment methodologies[2].
Non-invasive Exhaled Breath Analysis Analyzing metabolites in the human body, particularly through non-invasive exhaled breath analysis, emerges as a promising solution to current diagnostic challenges. The history of breath analysis, dating back to a groundbreaking work of Pauling et al[3], reveals the detection of over 200 volatile organic compounds (VOCs) in exhaled air. These VOCs, defined as organic compounds with a boiling point below 250 °C, show potential as biomarkers for various diseases, including cancer[2]. They can interact with biological tissues and be expelled from the interior of the organism, where they are created directly from metabolomic processes to the exterior, due to their peculiarities. They can be incredibly useful and instructive in the field of carcinogenic biomarkers in this way[4]. A biomarker is described as a “biological molecule found in blood, body fluids, or tissues that is a sign of a normal or abnormal process, health condition, or disease” by the National Cancer Institute. Their use in assessing cancer diseases, however, has not been limited to diagnosis. Indeed, biomarkers have been addressed and thoroughly explored in terms of their applicability for risk assessment, health state screening, prognosis prediction, therapy response evaluation, and pathology progression tracking[2,4]. While most of these metabolites are not yet clinically validated, their potential, documented in numerous scientific publications, is expected to lead to certification in the near future[2]. However, a known issue in breath analysis is the lack of consensus on standardized methodologies to eliminate ambient air factors. Studies on container suitability for breath sample collection underscore the need for further research on the impact of exogenous factors[5]. Caution is advised in subtracting VOCs from breathed air without reliable toxicokinetic models for VOC absorption and elimination from ambient air, considering significant variations in ambient air VOCs[2]. Certain diseases can lead to the production of VOCs through metabolic processes within tumor cells and surrounding tissues reacting to the presence of cancer. Examples include lipid peroxidation of polyunsaturated fatty acids, resulting in the production of saturated hydrocarbons such as ethane and pentane, which are expelled in increased quantities during stress[6]. While some methylated hydrocarbons have been identified in breath, their full diagnostic potential remains unclear[2]. Despite the known origins of these compounds, only a limited number of VOCs have received official approval as disease biomarkers, according to the Food and Drug Administration (FDA). Approved compounds include ethanol, hydrogen, nitric oxide, carbon monoxide, 13CO2, and branched hydrocarbons, serving as biomarkers for various conditions such as alcohol intoxication, carbohydrate metabolism, asthma, neonatal jaundice, Helicobacter pylori infection, and organ transplant rejection, respectively[2]. The confirmation of this burgeoning scientific field’s clinical promise is inextricably tied to technology breakthroughs that enable the execution of reproducible tests. This progress is facilitated by the use of highly precise and sensitive analytical instruments, including gas chromatography-ion mobility spectrometry (GC-IMS)[7], GC-mass spectrometry (GC-MS)[8], GC-GC-time-of-flight-mass spectrometry (GCxGC-TOF-MS)[9], proton transfer reaction-mass spectrometry (PTR-MS)[10], selected ion flow-tube mass spectrometry (SIFT-MS)[11], and electronic noses (e-noses)[12]. While the specifics of the analytical processes are outside the scope of this editorial, it is worth noting that the expansion and optimization of detection resources has resulted in a greater capacity for recognizing substances in breath, reaching 3500 VOCs[2]. Diagnosis of Cancer VOCs studied as biomarkers for diagnosing of several malignant diseases, including breast, colorectal, gastric, lung, prostate, and squamous cell cancers. Additionally, it addresses five other cancers, bladder, liver, ovarian, pancreatic, and thyroid, as future perspectives due to the potential discovery of new VOCs in breath[2,6]. Lung cancer, often associated with risky behaviors like smoking, is a leading cause of death, particularly among men. The text explores various techniques and devices that offer alternatives to invasive histological or cytological methods for the diagnosis of lung cancer. These methods include thermo-desorption GC-MS, electronic nose, colorimetric sensor arrays, magnetic nanoparticles, photoacoustic spectroscopy, IMS, PTR-MS, and Fourier transform-ion cyclotron resonance-mass spectrometry (FT-ICR-MS). The aim is to achieve a rapid and accurate diagnosis of lung cancer. Several studies that have identified specific VOCs as potential biomarkers, using various analytical techniques such as GC-MS and electronic noses. These VOCs show promise in differentiating between healthy individuals and those with lung cancer. The overall goal is to develop non-invasive methods for diagnosing lung cancer, improving the efficiency and accuracy of the diagnostic process[13,14]. Breast cancer, a prevalent and deadly carcinoma in women, with a focus on the potential use of VOCs as biomarkers for non-invasive and painless screening. Current screening methods are often invasive, leading to delayed diagnoses. Various studies have employed techniques such as GC-MS, Fourier-transform infrared spectroscopy, and electronic noses to analyze breath and identify VOCs associated with breast cancer[15]. Gastric cancer diagnosis often involves invasive and painful procedures. Various studies have explored VOCs in saliva and exhaled breath as potential indicators of gastric cancer. Specific VOCs, such as ethanol, 2-propanol, acetone, and acetaldehyde, have been identified with high accuracy in distinguishing between healthy individuals and gastric cancer patients[16]. Colorectal cancer (CRC) is a significant health concern with high incidence and mortality rates. Detecting CRC in advanced stages underscores the need for rapid and precise diagnostic tools. VOCs have shown promise in CRC diagnosis. Studies by Altomare et al[17] identified VOC patterns distinguishing CRC patients from healthy individuals with high sensitivity and specificity. Other researchers highlighted specific VOCs as potential biomarkers. Overall, VOCs offer a promising avenue for non-invasive CRC diagnosis[2]. Prostate cancer diagnosis is challenging, often identified late with limited cure options. Current invasive methods prompt the need for faster, more accurate diagnostics. The disease, causing thousands of annual deaths, requires improved approaches (12000 and 34700 estimated deaths in the United Kingdom and United States in 2023). While urinary VOCs have been explored, breath biomarkers for prostate cancer offer untapped potential[2]. Waltman et al[18] used an electronic nose to detect VOC patterns in breath, successfully distinguishing prostate cancer patients from healthy volunteers with 75% accuracy, 84% sensitivity, and 70% specificity. In recent research, Maiti et al[19] identified six key VOCs in breath samples from prostate cancer patients and healthy subjects, emphasizing their significance in diagnosis. Head and neck cancer (HNC), specifically squamous cell carcinoma, poses challenges in diagnosis and treatment due to its critical location. Detecting HNC early is crucial to avoid invasive treatments affecting essential functions. VOCs have shown potential as biomarkers for rapid and accurate HNC diagnosis. Studies using electronic nose devices and GC-MS reveal distinct VOC patterns in breath, enabling differentiation between healthy individuals and HNC patients. While promising, further research and advancements in techniques are needed for the certification and clinical implementation of breath biomarkers in HNC diagnosis[2]. Diagnosis of Pancreatic Cancer One of the most difficult tumors to diagnose is pancreatic cancer. The majority of patients receive their diagnosis in the latter stages of the illness, when there is already very little hope for recovery[6]. In order to address this problem, new methods that guarantee a quicker and more precise pathology detection need to be investigated and their heterogeneity researched. The VOCs seen in pancreatic cancer patients’ urine have been explored as possible biomarkers to help identify the disease. However, breath VOCs have not gotten the same level of scrutiny. Markar et al[20] evaluated the usefulness of breath analytes for pancreatic cancer diagnosis. Exhaled breath analysis using a GC-MS instrument was performed on 132 participants (57 pancreatic cancer patients and 75 healthy persons). Twelve VOCs [1-butanol, amylene hydrate, tetradecane, undecane, benzaldehyde, acetoin, 1-(methylthio)-propane, n-hexane, isopropyl alcohol, acetone, pentane, and formaldehyde] were found as possible biomarkers in the breath among the 66 detected analytes[20]. Princivalle et al[21], on the other hand, were able to identify between pancreatic patients (65 individuals) and healthy volunteers (102 persons) using a pattern of 10 VOCs with sensitivity and specificity values of 100% and 84%, respectively. n-heptane, toluene, benzene, n-propanol, isoprene, acetone, ethanol, acetonitrile, butanone, and methanol were discovered as possible biomarkers for pancreatic cancer detection[21]. More than a dozen VOCs have been identified as being of particular relevance in the discovery of breath biomarkers for pancreatic cancer.
