PJZ_58_3_1461-1475

Introduction

Breast cancer constitutes the predominant etiology of oncological mortality among the female population in 140 out of 184 nations globally and is the most frequently diagnosed malignancy, presently accounting for one in four of all cancer diagnoses in females (Angahar, 2017; Urooj et al., 2022). It constitutes approximately 25% of cancer cases and 16% of cancer deaths among women worldwide, with peak incidence in France, Australia, Northern America, and Northern Europe, where rates are quadruple those in South-Central Asia and Middle Africa. Women in transitioned countries exhibit significantly higher incidence rates than those in developing nations i.e., 54.1/30.8 per 100,000, yet experience lower mortality rates i.e., 11.3/15.3 per 100,000 (Bray et al., 2024). According to the study conducted in 2020, the incidence of breast cancer is increasing worldwide, with 2.3 million new cases and 685,000 mortalities. The projections indicate a potential surge to 2.64 million occurrences and 1.7 million deaths by the year 2030 (Shang and Xu, 2022).

Breast cancer prevalence varies significantly across different countries and regions, influenced by socioeconomic factors and healthcare access. In Europe, the burden of breast cancer was reported at 463.2 cases per 100,000 people in 2019, which is 1.7 times the global average, with Monaco, Serbia, and Montenegro showing the highest rates (Yu et al., 2024). Each year, the American Cancer Society estimates new cancer cases and deaths in the U.S. using recent population-based data from cancer registries and mortality statistics. In 2025, projections indicate 2,041,910 new cancer cases and 618,120 cancer deaths in the United States (Siegel et al., 2025). Noteworthy geographic and temporal disparities in breast cancer mortality persist across various regions (Sun et al., 2023; Torres-Román et al., 2023), which appear to be significantly correlated with the extent of access to essential health services (Duggan et al., 2021). A considerable number of sub-Saharan African nations rank among those exhibiting the highest breast cancer mortality rates globally, indicative of inadequate healthcare infrastructure and, consequently, suboptimal survival outcomes attributable to late-stage presentations of the disease (Soerjomataram et al., 2023). In China, breast cancer was the most common female cancer in urban areas (Ong et al., 2024). While in India, 19 per 100,000 women have breast cancer, and the prevalence of incidence has escalated over the past 40 years (Rai et al., 2022). Among all the Asian nations, Pakistan has the highest risk of breast cancer development (Mubarik et al., 2019). The rate of incidence is 2.5 times higher in Pakistan than in neighboring countries such as India or Iran (Majeed et al., 2022). The number of cases in Pakistan is increasing, with 25,928 cases in 2020, representing 14% of all cancer diagnoses (Khan et al., 2024). Another study reported approximately 34,066 new cases of breast cancer with a ratio 1 in every 9 women (Iftikhar et al., 2024).

In western nations, screening initiatives have proven effective in detecting the majority of breast cancers via screening protocols rather than as a result of symptomatic presentation (Shang and Xu, 2022). Even though mortality rates from breast cancer are higher in lower and middle-income nations, there is a lack of early detection techniques, and the majority of patients with late illnesses require palliative treatment with low survival rates (Mehiret et al., 2022). Prior research has indicated that early detection of cancer is crucial for effective and appropriate treatment and has the potential to halt its progression and substantially lower the mortality rate. However, current breast diagnostic techniques, including mammography, ultrasound, and magnetic resonance imaging (MRI), exhibit several limitations that compromise their precision and efficacy. Mammography, recognized as the predominant screening technique, encounters challenges in patients with dense breast tissue, resulting in diminished sensitivity and specificity (Grigoryants et al., 2023). Ultrasound is an operator-dependent tool that may yield false positives, especially in younger women. MRI is sensitive but costly and less accessible, limiting its use in widespread screening. Current techniques also pose a risk due to ionizing radiation, particularly for younger women and those at elevated risk (Devi and Anandhamala, 2018; Abdul-Halim et al., 2021). Furthermore, the discomfort linked to mammography, particularly from breast compression, can discourage regular screening among women (Abeelh and AbuAbeileh, 2024).

Carbon metabolism is a key aspect of reprogramming tumor metabolism (Fig. 1), as it provides energy and building blocks for tumor growth and survival (Lane et al., 2020). Normal cells predominantly utilize oxidative phosphorylation (OXPHOS) to generate 36 ATP molecules per glucose. This mechanism entails the thorough oxidation of glucose to carbon dioxide and water, thereby optimizing energy yield (Kubicka et al., 2021). Carbon dioxide (CO2) is a byproduct of the citric acid cycle, which is essential for OXPHOS (Liao, 2017). On the other hand, cancerous cells demonstrate the Warburg effect, preferentially utilizing glycolysis even when oxygen is available. This metabolic adaptation leads to the generation of lactic acid rather than carbon dioxide, yielding merely 2 ATP molecules for each glucose molecule consumed. The transition towards glycolysis facilitates the biosynthetic pathways required for the production of nucleic acids, proteins, and lipids, which are essential for expedited cellular proliferation (Liao, 2017; Kubicka et al., 2021). CO2 can enhance cancer therapies by influencing tumor microenvironment, oxygen release, and blood pH, and potentially optimizing cellular mechanisms through hypercapnia and modulating metabolic pathways (Gaspary et al., 2024). Stable isotopes including 13C-labeled glutamine or glucose can be used to study carbon metabolism, to track the fate and flux of carbon atoms in various metabolic pathways (Dong, 2020). The alterations in different metabolic processes, such as glycolysis, krebs cycle, amino acid metabolism, pentose phosphate pathway, can be intimated by 13C isotopes in the variety of tumors. The identification of metabolic biomarkers and therapeutic targets for tumor metabolism reprogramming can also be identified using 13C isotopes (Han et al., 2021). Significance of carbon isotopes in breast cancer has garnered substantial scholarly interest, particularly in interpreting tumor metabolism and treatment efficacy. Analysis on employing naturally occurring carbon isotopes have elucidated distinctive metabolic signatures that differentiate healthy breast tissues from cancerous tissues, especially focusing lipid metabolism and urea cycle (Illa et al., 2016).

Data collection for this systematic review was searched through Reference Citation Analysis (RCA), ScienceDirect, Research Gate, Web of Science, and PubMed databases using keywords i.e., breast cancer, signs and symptoms, stages of breast cancer, risk factors, 13C isotope and diagnostic strategies, and evaluated the content of the articles. After assessing the articles, we selected 117 publications out of 1148 (Fig. 2).

STAGING AND CLASSIFICATION OF BREAST CANCER

Breast cancer staging is a critical process that determines the extent of cancer spread, guides treatment decisions, and predicts patient outcomes. The staging and classification of breast cancer are determined based on tumor size, lymph node involvement, metastatic activity, or specific biomarkers (Jacene et al., 2024) (Table I). This data is crucial for determining prognosis and selecting appropriate treatment strategies to manage the breast cancer (Singh et al., 2024; Afzal and Vahdat, 2024). Early-stage breast cancer is often curable with localized treatments, while advanced stages require systemic therapies. The 5-year survival rate for early-stage breast cancer is significantly higher than for metastatic disease (Loibl et al., 2024; Trayes and Cokenakes, 2021). Advances in precision medicine have integrated molecular and genetic data into the staging process, enabling more accurate prognostication and tailored therapies (Afzal and Vahdat, 2024; Singh et al., 2024).

Stage 0

Stage 0, or ductal carcinoma in situ (DCIS), is a non-invasive breast cancer that indicates that malignant cells have emerged within the breast tissue; however, they have not yet disseminated to adjacent tissues, lymph nodes, or distant organs (Trayes and Cokenakes, 2021). According to Breast Cancer Research Foundation (2024), principally, this stage is asymptomatic, while in rare cases, the patient may feel a lump or have nipple discharge (Hanna et al., 2019). For treating this stage, surgical choices include lumpectomy or mastectomy, and research shows that many patients with DCIS are recommended and accept surgery (Pico et al., 2023). Proton therapy has been investigated as a treatment option, demonstrating feasibility and low toxicity in initial trials for patients in early-stage breast cancer (Freedman et al., 2024). Endocrine therapy may be added for ER-positive patients (Jha and Dhale, 2024). According to the American Cancer Society (2016), the five-year survival rate for individuals diagnosed with stage 0 is nearly 100%. However, if this stage is left untreated, around 40% of cases may advance to invasive breast carcinoma (Cowell et al., 2013).

Stage I

This stage is characterized by a neoplasm that measures less than 2 cm in diameter. Furthermore, this neoplasm has not disseminated to the lymphatic nodes or to other systems (Stage 1A) or has only developed micrometastases in 1-3 lymph nodes located in the axillary region (Stage 1B), (Mitsuk, 2016). Common symptoms include a palpable lump, changes in breast shape or size, and nipple discharge. However, many patients are asymptomatic, detected through screening mammography (Hadar et al., 2024). Recent research has shown notable progress in treatment options and outcomes for this early stage of breast cancer. Treatment involves surgery (lumpectomy or mastectomy) with or without radiation. Moreover, depending on the tumor biology and the patient’s preferences, systemic therapies (chemotherapy, hormone therapy, or targeted therapy) are suggested (Jha and Dhale, 2024; White et al., 2024). Survival rates for this stage differ markedly based on tumor biology. Stage I triple-negative tumors have a five-year survival rate of about 85%. Conversely, hormone receptor-positive show significantly higher survival rates, between 94% and 99% (Waks and Winer, 2019).

Stage II

Stage IIA and IIB are distinct stages of a tumor. Stage IIA refers to neoplasm with metastasis to three lymph nodes in the axillary region, minor metastatic deposits in mammary glands, or exceeds 2 cm but is less than 5 cm without metastasis. Stage IIB describes a tumor exceeding 2 cm but less than 5 cm with no metastasis, limited metastasis in three lymph nodes, or a tumor exceeding 5 cm without metastasis (DePolo, 2024). Nausea, diarrhea, low appetite, general pain and constipation are the main symptoms in this stage (Kaufmann et al., 2023). At this stage, prognosis and treatment strategies are crucial to enhancing patient outcomes. According to the research patients generally opt for radiation therapy or chemotherapy. Whereas, some patients prioritise mastectomy, especially those residing farther from the hospitals (Perry et al., 2023). The recommendation of systemic therapies including chemotherapy, hormonal therapy, or targeted therapy is based on patient’s preference and tumor biology (Jha and Dhale, 2024; White et al., 2024). The overall survival rates for stage II were observed to be 5 years (96%) and 10 years (87.1%), (Saghir et al., 2023). In comparison, the study conducted in Bangladesh reported the survival rate of 36.1% over 10 years (Nahar et al., 2023). The recurrence rate varies according to the lymph node involvement and treatment strategies, also impacting the patients’ outcome; 2% for stage IIA and 3.5% for stage IIB. The continuous monitoring and preventive measures are important because the survivors of stage I and II breast cancer are at higher risk of second primary malignany (Schumacher et al., 2022).

Stage III

Locally advanced breast cancer stages (IIIA, IIIB, and IIIC) are non-metastatic (Trayes and Cokenakes, 2021). and encompasses tumors exceeding 5 cm. It has significant involvement of regional lymph node, direct invasion of the chest wall or skin, inoperable tumors without distant metastases, and inflammatory breast cancer (Maughan et al., 2010). According to Breast Cancer Research Foundation (2024), the symptoms include swollen red breasts with thickened skin, a large lump in the breast that feels attached to the chest wall, and a lump in the armpits and base of the neck (Maria, 2024). During the preoperative phase, adjuvant endocrine therapy (ET) or immunotherapies are used when tumors express estrogen or progesterone receptors. Preoperative chemotherapy is the only option for triple-negative tumors (Trayes and Cokenakes, 2021; Marques et al., 2024). The surgical phase presents two alternatives that exhibit comparable survival outcomes: a lumpectomy accompanied by radiation therapy, provided that the neoplasm can be entirely removed with favorable aesthetic results or a mastectomy. Additionally, a sentinel lymph node biopsy is conducted when there is an indication of potential nodal involvement (Trayes and Cokenakes, 2021; Retamales et al., 2024). The postoperative period encompasses radiotherapy, hormonal treatment, immune-modulatory therapy, and cytotoxic chemotherapy. It is imperative to provide postoperative bisphosphonates to women who have reached menopause (Trayes and Cokenakes, 2021). A study by Saghir et al. (2023) reported an overall survival rate of 88.3% at 5 years and 68.7% at 10 years. Recurrence rates vary significantly; overall, 30% of patients experienced recurrence within 10 years, with a notable prevalence of distant metastases (D’Oronzo et al., 2021).

Stage IV

Stage IV of breast cancer is marked by metastatic cancer, and the tumor can be of any size (Grobler et al., 2023). Metastatic breast cancer is extensively recognized for its poor prognosis in contrast to non-metastatic breast cancer. The most prevalent sites are bone, liver, lung, and brain (Gerratana et al., 2015). Patients commonly experience symptoms such as pain, fatigue, and complications arising from metastasis, which may require palliative care (Maughan et al., 2010). The therapeutic approach for metastatic breast cancer is customized, with the principal objectives being the extension of life expectancy and the alleviation of symptoms (Mitsuk, 2016). The treatment approach typically includes a combination of therapies (Schumacher et al., 2022). Systemic therapy constitutes the principal intervention for stage IV breast carcinoma, encompassing endocrine therapy, chemotherapy, and targeted therapy. Currently, there exists a lack of standardized guidelines for the management of stage IV breast carcinoma subsequent to multiple lines of treatment. Prospective investigations have produced incongruous findings concerning the potential survival benefits associated with the surgical intervention of the primary tumor (Zheng et al., 2021; Jha and Dhale, 2024). Recurrence rates can differ, with a reported 2-year recurrence rate of 11.8% following surgery. Factors like lymph node involvement and tumor characteristics significantly determine survival outcomes (Kumilau et al., 2022). The median overall survival (OS) is roughly 3 years, with a 5-year survival rate estimated at about 25% (Grobler et al., 2023).

INDICATORS TO IDENTIFY BREAST CANCER

The onset of breast cancer is characterized by the emergence of malignant cellular formations within breast tissue, frequently manifesting as palpable lumps or masses. Empirical observations indicate that breast lumps constitute the most prevalent clinical manifestation associated with breast cancer. A research investigation revealed that merely 50.5% of participants possessed knowledge that a breast lump serves as an alarming indicator, thereby highlighting a considerable deficiency in public awareness (Coleman, 2017). Such awareness is of paramount importance, as the early identification of breast lumps can facilitate prompt diagnosis and subsequent therapeutic intervention. Other symptoms may include a change in breast size and shape due to thickening or swelling, redness or decoloration, nipple retraction, pain in the breast or nipple, dimpled skin as well as unusual warmth in one breast with the presence of discharge from the nipple (Galamba, 2024). Individuals with advanced breast cancer experience various symptoms that negatively impact their quality of life and physical capabilities. Metastatic disease primarily affects the bone, lungs, liver, and brain. Clinical manifestations of advanced breast cancer include pain, fractures, pleural effusions, and ascites. Oncological emergencies related to these metastatic sites may consist of hypercalcemia, spinal cord compression, superior vena cava obstruction, and increased intracranial pressure (Shewbridge et al., 2024). Previous researches underscore the significance of awareness concerning these indicators, particularly within demographic groups characterized by lower screening frequencies. Moreover, the affective and cognitive dimensions associated with the identification of symptoms have been acknowledged, as postponements in pursuing assistance frequently correspond with insufficient awareness of indicative signals (Quaife et al., 2014).

RISK FACTORS

Breast cancer is influenced by various factors, encompassing modifiable and non-modifiable elements. Gender, age, early onset or late cessation of menstruation, family medical history, absence of pregnancies, large breasts, and genetic susceptibility (mutations in the BRCA gene) are integral components of the non-modifiable risk factors (Ibarra-Cuevas et al., 2024; Admoun et al., 2022). Conversely, modifiable risk factors are associated with obesity, poor dietary habits, sedentary lifestyle, alcohol consumption, smoking, usage of birth control pills, and hormone replacement therapy (Admoun et al., 2022). Furthermore, environmental factors play a significant role, as exposure to endocrine-disrupting substances originating from various sources like plastics, cosmetics, detergents, and atmospheric pollutants contribute to the susceptibility to breast cancer (Akanji et al., 2022).

Decreased oxygen concentrations, which fall below the thresholds necessary for sustaining standard metabolic processes and physiological function within tissues (hypoxia), represent a significant oncogenic risk factor commonly observed in cases of breast carcinoma (Tutzauer et al., 2022). Women with a history of breast cancer are at a higher risk of developing the disease again. Either the same breast or a different breast could be the site of the second breast cancer. Moreover, women with ductal carcinoma in situ or lobular carcinoma in situ breast cancers are more likely to experience a recurrence, even though most of them do not (Buist et al., 2018).

DIFFERENTIAL DIAGNOSIS

Diagnostic strategies

Different diagnostic strategies, including a range of non-invasive and invasive modalities, can be used for breast cancer detection (Obeagu and Obeagu, 2024). Imaging modalities such as mammography, ultrasound, magnetic resonance imaging (MRI), positron emission tomography (PET), histopathology facilitates to acquire breast images (Chowdhury et al., 2024). Despite the higher specificity of traditional techniques i.e. mamography, they may have lower sensitivity in particular populations, especillay those with denser breast tissues (Abiramasundari et al., 2024).

Biopsy

Different types of biopsies can be used to detect breast cancer includes core biopsy (Poort et al., 2022), lymph node biopsy (Wang et al., 2019), and needle aspiration (Wang et al., 2020). Cells or tissue samples are taken during the biopsy procedure and analysed in the laboratory to detect the cancerous cells in the patient. The choice of biopsy technique is dependent on the lesion’s palpability. Ultrasound or mammography may be utilized by the physician to locate the area for assessment (Poort et al., 2022). This method has a 94% accuracy rate. The cumulative probability over a ten-year period that a woman will receive at least one false-positive biopsy is estimated to be between 4.8% and 9.4% (Sandbank et al., 2022).

Ultrasound

An ultrasound employs high-frequency acoustic waves to visualize anatomical structures. It is essential for determining if a breast mass is a neoplasm or cyst. Additionally, ultrasound aids practitioners in accurately locating biopsy sites. Ultrasound assessments may be performed on women with advanced breast cancer to assess potential hepatic metastasis (Wang et al., 2019). Despite its advantages in specificity, it has a lower sensitivity (61%) and frequently underestimates tumor size (67.7%) (Alotaibi et al., 2024).

Mammography

Diagnostic mammography constitutes a radiographic procedure that generates an image of the breast by applying minimal radiation exposure. This modality investigates further unanticipated results from a clinical examination of breast or mammography. Additionally, mammography may be utilized concurrently with a biopsy to delineate an anomalous region (Chang et al., 2022). Mammography, while the predominant screening method, has been shown to overestimate tumor sizes in 41.9% of cases and often fails to detect malignancies in dense breast tissue (Mansour et al., 2024).

Magnetic resonance imaging (MRI)

Breast magnetic resonance imaging is a non-invasive diagnostic technique that uses low-energy radiofrequency waves and a magnetic field to obtain detailed images of the breast’s anatomical structure (Graves and Zhu, 2015). The application of MRI is particularly beneficial for quantifying the dimensions of neoplastic growths and for detecting metastatic lesions in female patients with a prior diagnosis of breast cancer. Neoplasms measuring 2 cm or less than this, have been consistently and precisely identified and quantified using MRI techniques. Conversely, larger breast tumors frequently suffer from overestimation due to the presence of aberrant breast tissue surrounding the actual lesion, which may consequently result in increased mastectomy rates (Bhushan et al., 2021). Although demonstrating the highest sensitivity (72.2%) and accuracy (86.9%), MRI still presents challenges, particularly its ability to reflect tumor size in all cases accurately (Alotaibi et al., 2024).

13C mass spectrometry

The majority of cancer diagnoses rely on histological evaluations. Histopathological evaluations requires considerable expertise and knowledge of both clinical and pathological aspects. Because it is often challenging to differentiate early-stage cancers within biopsy samples using the conventional histopathological techniques (Tseng et al., 2023; Schlageter et al., 2014). Consequently, errors in diagnostic pathology can result in inappropriate patient management including treatment delays or incorrect regimens (Clary et al., 2002; Raab et al., 2005). Isotope ratio mass spectrometry (IRMS) facilitates the detection of malignancy with improved sensitivity and specificity, thus overcoming the constraints of existing detection modalities. Mass spectrometry can detect the alterations in metabolic pathways associated with cancer by examining the isotopic composition of biological samples. This nuclear methodology detetcted the increased expression of ornithine decarboxylase in cancer cell lines by measuring the amount of 13CO2 produced because of the enzyme-mediated degradation of 13C ornithine in cancerous tissues (Jaenisch et al., 2016).

The use of metabolic alterations as a biomarkers for disease prgression is also demonstrated by Guenther et al. (2015) illustrating the value of desorption ionization mass spectrometry in spatially resolved metabolic phenotyping of breast cancer. Ornithine decarboxylase may be a diagnostic or predictive biomarker for cancers and its activity has been employed to evaluate the progression of cancer (Hoshino et al., 2007; Geerts et al., 2010; Samoylenko et al., 2021). Furthermore, several researches have reported the elevated level of ornithine decarboxylase in cancers assessed by mRNA expression, immunohistochemistry, and radiometric liquid scintillation spectrometry at different sites such as colon (Hu et al., 2005), breast (Capellen et al., 2021), esophagus (He et al., 2017), and stomach (McNamara et al., 2021). Despite that, isotope ratio mass spectrometry has an advantage over mRNA expression, immuhistochemistry and radiometry due to the application of stable isotope, direct analysis of generated 13CO2, and exceptionally low 13CO2 detection limit in headspace. Isotope ratio mass spectrometry measured the 13CO2 which is directly produced when ornithine decarboxylase reacts with stable isotope. Mass spectrometry serves as an effective adjunct to radiometry for the identifcation of resilient radionuclides (Hou and Roos, 2008). Employing the optimal counting technique for a given hazard is essential because of the possible health effects of radioactive substance releases (Gonzales et al., 2005).

BREAST CANCER BIOMARKERS

The role of biomarkers in breast cancer management is well-established. Biomarkers are crucial in healthcare for their ability to provide insights into disease diagnosis, prognosis, treatment response, and personalized medicine. They enable early detection, intervention, and improved patient outcomes, reducing costs and guiding treatment decisions (Das et al., 2023). Breast cancer biomarkers can be broadly categorized into genetic (includes mutations in genes such as BRCA 1, BRCA 2, PIK3CA, and TP53) and protein (includes HER 2, estrogen receptors (ER), progesterone receptors (PR) and Ki-67) biomarkers, each offering unique insights into the disease’s biology and clinical management (Tarighati et al., 2023; Yang et al., 2023).

Moreover, studies on prognostice and predictive biomarkers suggest that a deeper understanding of metabolic substrates such as 13C could significantly improve their predictive accuracy (Nicolini et al., 2018). Combining advanced imaging technologies with biomarker analysis is considered essential for the early detection of breast cancer (Ginsburg et al., 2020). Supporting this approach, Pashayan et al. (2020) emphasized the need for personalized early detection strategies, advocating the inclusion of metabolic biomarkers in screening programs. Their consensus highlighted that metabolic signatures, potentially measurable using 13C isotopes, could be instrumental in designing targeted prevention measures for high-risk groups. Research on serum biomarkers has highlighted their effectiveness in the early detection of malignancy. According to Kazarian et al. (2017), 13C-based metabolic profiling may offer non-invasive biomarkers for the detection of early breast cancer. In addition, the prospective developments in blood-based biomarkers highlight their potential to support non-invasive and early detection techniques. Although many biomarkers have already been identified, incorporating metabolic profiles derived from 13C isotope analysis could greatly enhance the accuracy and reliability of blood tests in diagnosing breast cancer at an early stage (Loke, 2018).

13C NATURAL ABUNDANCE AS A DIAGNOSTIC BIOMARKER

13C isotopic natural abundance has been investigated in biological samples as a possible diagnostic marker for breast cancer detection (Tea et al., 2016). This method involves analyzing the ratios of carbon isotope in tumor and contrasted with those in normal tissues. Due to changes in metabolic pathways including glycolysis, tricarboxylic acid cycle (TCA) and lipid metabolism, cancer cells tend to display unique 13C/12C ratios. These variations occur because enzymatic reactions often favor the lighter isotope, i.e. 12C, leading to measurable differences. These isotopic changes are frequently measured using non-invasive techniques such as isotope ratio mass spectrometry (IRMS) and compound-specific isotope analysis (CSIA), offering comprehensive insights into tumor metabolism. Notably, the carbon isotope patterns in breast cancer tissues have been found to differ markedly from those in non-cancerous tissues, showing their probability as a biomarker for early diagnosis and metabolic profiling (Holland et al., 2021; Tea et al., 2021; Tea and Tcherkez, 2017).

13C metabolism

The stable isotope tracing combined with metabolic profiling highlights the importance of glucose metabolism in activated CD8+ T cells. Tumor microenvironments may be reflected in metabolic alterations suggesting the potential application of 13C for the detection of cancer and explaining the metaolic processes in tumor cells (Ma et al., 2019). A study on the oxygen-depleted cellular environment in malignancy elucidates the molecular mechanisms that govern tumor survival in low oxygen environemnts such as glycolysis, lipid metabolism, angiogenesis, immune tolerance and therapy resistance. Since it enables the development of diagnostic tools for early detection by tracking metabolic changes in hypoxic malignancies by using the 13C isotopes, the afformentioned knowledge is crucial when analyzing the stable isotopes function. The improved therapeutic efficacy depends on early detection of breast cancer, while survival probabilities increases with innovative techniques such as 13C signatures, labeling and imaging technologies. The need for improved patient treatment selection through biomarker identification is highlighted by the examination of the molecular classification of triple negative breast cancer (TNBC). The diversity of breast cancer, particularly in TNBC, emphasizes the significance of metabolic pathway comprehension and its impact on tumor dynamics (Garrido-Castro et al., 2019). Dai et al. (2016) further elucidated cancer hallmarks and molecular variations in breast cancer, proposing that unique metabolic reprogramming may characterize different subtypes, potentially influenced by 13C substrates.

13C metabolic reprogramming

Cancer cells undergo metabolic reprogramming foucsed by researchers to identify the aterations responsible for rapid growth and tumor progression (Schiliro and Firestein, 2021). Several metabolic pathways are believed to contribute in tumor spread and expansion, where 13C substrate may play a major role in promoting these pathways. Research suggests that adipocyte-derived fatty acids play a significant role in stimulating breast cancer cell growth and migration, suggesting a strong link between lipid metabolism and cancer progression (Balaban et al., 2017). Understanding the behavior of metabolic compounds like 13C within the tumor microenvironment is further aided by the investigation of circulating microRNA as non-invasive markers in breast cancer. Since microRNAs can influence metabolic activity, they might provide valuable insignts about metabolic status of tumors and their responsiveness to particular biochemical substrates (Cortez et al., 2012).

HYPERPOLARIZED 13C MAGNETIC RESONANCE IMAGING

An increasingly crucial factor of cancer research is the metabolic profile of tumors, assessed by using carbon isotope analysis. The precision of early diagnostic techniques could be enhance by using hyperpolarized imaging techniques to detect specific metabolic alterations in breast cancer tissues. This advanced type of metabolic imaging complements the conventional imaging techniques, and provide a more comprehensive approach to understanding tumor biology (Woitek and Brindle, 2023). Unlike normal cells, cancer cells exhibit distinct metabolic behaviors, especially in the processing of glucose. Hyperpolarized 13C nuclear magnetic resonance (NMR) have shown notable shifts in glucose metabolism within the breast cancer cell cultures, shedding light on the underlying metabolic reprogramming that drives tumor development (Harris et al., 2013).

This method uses hyperpolarization to increase the MRI sensitivity, allowing real time observation of metabolic processes and labels naturally occurring molecules,like pyruvate, with the 13C isotope (Von Morze and Merritt, 2019; Arponen et al., 2023). Once the hyperpolarized 13C-pyruvate is introduced into the body, it is rapidly take up and metabolized by cancer cells, providing valuable insight into their metabolic behavior. The cancer cells tend to convert pyruvate into lactate at an accelerated rate because of the Warburg effect. This metabolic shift can captured by hyperpolarized 13C MRI by visualizing the exchange of the 13C-label between the pyruvate and lactate. The 13C-label exchange is significantly higher in more aggressive breast tumors and is closely associated with the elevated levels of monocarboxylate transporter 1 (MCT1) and lactate dehydrogenase (LDH) (Arponen et al., 2023; Woitek and Brindle, 2023). This imaging approach has also been utilized to track early metabolic alterations in tumors undergoing neoadjuvant chemotherapy. Compared to traditional imaging modalities, hyperpolarized 13C MRI offers real-time insight into tumor metabolism, enabling earlier cancer diagnosis and more precise monitoring of treatment response (Von Morze and Merritt, 2019; Arponen et al., 2023).

KNOWLEDGE GAPS AND FUTURE RESEARCH DIRECTIONS

Even though our understanding of breast cancer has advanced significantly, there is a crtical need for more research examining the interaction of genetic and environmental factors in various populations. Despite advancements in diagnostic methodologies and understanding breast cancer staging, knowledge gaps persist, including the need for standardized protocols and comparative effectiveness studies across diverse healthcare environments. Further research should focus on assessing the efficacy of diverse diagnostic approaches, including computer-aided detection, across diverse patient demographics. Genetic and molecular factors influence breast cancer staging and therapeutic responses. Understanding genetic susceptibilities and environmental influences could lead to tailored treatment. Liquid biopsies and minimally invasive methodologies require further scrutiny for reliability and applicability. The use of 13C in breast cancer identification is promising, but longitudinal studies are needed to track metabolic changes over treatment to understand their correlation with clinical outcomes. The role of 13C in distinguishing between breast cancer subtypes and its applicability in diverse populations is also under-explored. Future research should integrate 13C MRI with other imaging modalities and biomarkers for a more comprehensive approach to diagnosis and treatment. Applying metabolic profiling in breast cancer diagnosis and treatment is crucial for improving patient outcomes.

CONCLUSION

In conclusion, targeted interventions, improved screening protocols and comprehensive education on risk factors are essential for reducing the burden of breast cancer and improving patient outcomes. The utilization of ¹³C isotopes during preliminary identification of breast cancer represents a burgeoning domain. Contemporary investigations suggest that hyperpolarized ¹³C MRI may provide valuable insights into the aggressiveness of tumors, while avant-garde detection methodologies are being formulated to augment the sensitivity associated with biomarker identification. Nonetheless, significant deficiencies exist in comprehending the fundamental mechanisms and their integration with pre-existing diagnostic paradigms. Subsequent research endeavors should focus on rectifying these deficiencies, thereby ultimately facilitating more efficacious early detection strategies in managing breast cancer.

Declarations

Generative AI and AI-assisted technology statement

The authors declare that no generative AI tools were used in this manuscript.

Statement of conflict of interest

The authors have declared no conflict of interest.

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