Serum Lactate Dehydrogenase and Gamma-Glutamyl Transferase Correlate Optimally with Nottingham Prognostic Index for Breast Cancer

doi:10.21203/rs.3.rs-4873845/v1

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Research Article

Serum Lactate Dehydrogenase and Gamma-Glutamyl Transferase Correlate Optimally with Nottingham Prognostic Index for Breast Cancer

https://doi.org/10.21203/rs.3.rs-4873845/v1

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Background

LDH and GGT have been identified as prognostic serum markers for breast cancer patients. The serum level of LDH is increased due to increased anaerobic glycolysis in malignant neoplastic conditions. GGT has also been noted to increase in circulation, indicating the extent of oxidative stress within the body. Their levels are high in advanced breast cancer patients. Moreover, in our setting, there are no serum marker data available on a routine basis for breast cancer surveillance among women orfor predicting patient prognosis. Thus, these markers can augment the available tool(s) for predicting breast cancer prognosis since they are widely available, accessible, and economically affordable.

Objective

This study aimed to assess the correlation between LDH/GGT and the NPI among women with breast cancer.

Study Methods

A cross-sectional study was conducted for 12 months. The data were collected by interviewing patients, patients’ files and from the hospital’s electronic database (Jeeva) and then completed the structured checklist. IBM SPSS version 27 was used to analyse the data. The mean, median and standard deviation were used to present numerical variables. Categorical variables are presented as frequencies or proportions. Correlations were assessed and analysed by Spearman correlation coefficient and linear regression models,while receiver operating characteristic (ROC) curves were used to determine the accuracy.

Results

The 104 patients who underwent radical mastectomy for breast cancer had a mean age of 48.51 ±12.80 years. Among them, 27 (26%) were diagnosed before 40 years of age.

With a Spearman coefficient of r=0.66 and p<0.01, a regression coefficientof b=4.21 and p<0.001, and a coefficient of determination of 28.3%, a substantial positive correlation between LDH and the NPI was found. Based on the NPI and TNM, LDH demonstrated significant predictive accuracy for the prognosis of breast cancer patients, with AUCs of 0.85 (95% CI: 0.77 - 0.92, p<0.001) and 0.87 (0.80 - 0.94, p<0.001), respectively, according to the ROC curve.

A weak positive correlation between GGT and the NPI was observed, with a Spearman coefficient of r=0.46 and p<0.01. With AUCs of 0.73 (95% CI: 0.62 ─ 0.83, p<0.001) and 0.76 (95% CI: 0.67 ─ 0.85, p<0.001) for the ROC curve, GGT showed modest predictive accuracy for the prognosis of breast cancer patients based on the NPI and TNM, respectively.

Conclusion

Preoperative serum levels of LDH and GGT can serve as predictors for breast cancer outcome for women with breast cancer undergoing modified radical mastectomy in conjunction with other potential prognostic factors.

Lactate dehydrogenase

Gamma-glutamyl transferase

Nottingham prognostic index

Correlation

Breast cancer

Breast cancer is one of the most common malignancies of solid organs among females next to cervical cancer. It affects women in high-income and low-income countries and settings. In sub-Saharan Africa, it accounts for 19.5% of all cancer types[1–4].

In addition to the available diagnostic and prognostic tools, serum biomarkers have evolved to predict breast cancer prognosis in terms of response to treatment, disease-free survival and overall survival. Among them, LDH and GGT serum levels have been tested and found useful in prognostic stratification[5–7].

LDH is present in almost all body cells but is predominantly found in the liver, kidney, breast, brain, cardiac muscles, skeletal muscles and red blood cells, particularly in the mitochondria, with a normal value in the circulation of approximately 125–220 U/L. Its main function is to reversibly catalyse the conversion of lactate to pyruvate in anaerobic respiration due to the high metabolic demand. Medical conditions such as breast malignancy, bacterial meningitis, liver disease, acute kidney injury, acute myocardial infarction, bone fracture,lyphoma and skeletal muscle trauma can lead to an increase in LDH in circulation[8].

In malignant conditions, even in the presence of oxygen, cancerous cells release larger quantities of LDH to facilitate glycolysis for producing energy and lactate to meet metabolic requirements in highly proliferating cells. This phenomenon is referred to as the Warburg effect[9].

LDH causes malignant cells to resist the immune response by inhibiting CD8 + T cells and activating natural killer (NK) cells by increasing the expression of vascular endothelial growth factor.

Furthermore, LDH promotes angiogenesis within the tumor, facilitating the migration and metastasis of tumor cells[10]. A pretreatment LDH level of approximately 244 U/L and above has been noted to indicate poor prognosis among breast cancer patients[11].

GGT is a membrane-bound enzyme that catalyzes the catabolism of reduced glutathione to cysteine and glycine in Meister’s glutamyl cycle. As a result, it delivers cysteine for the intracellular synthesis of glutathione, which is a powerful antioxidant that plays a role in protecting cells from injury caused by oxygen-free radicals. The level of GGT in circulation indicates the extent of oxidative stress/imbalance in the body. Its normal level in circulation is approximately 0–29 U/L. It is potentially found in the liver, pancreas, heart and kidney. Conditions that have been documented to cause GGT elevation include cholestasis, malignancy, alcoholic liver disease, pancreatitis, heart failure and diabetes mellitus[12].

The amount of circulating GGT is directly proportional to the turnover rate of malignant cells. The serum levels of GGT provide enlightenment on the extent of apoptosis and oxidative stress in patients with breast cancer.Studies have shown that GGT can predict the disease progression rate, response to chemotherapy and overall survival of patients with this disease[10, 13]. In breast cancer patients, those with pretreatment serum levels of GGT ≥ 29 U/L have been noted to have unfavourable outcomes[14, 15].

Among the models that have been validated, the Nottingham Prognostic Index (NPI), which was devised by Galea in 1982, can still predict outcomes in independent populations by comparing predicted and observed outcomes. In this study, it was used as the gold standard for categorizing patients to assess serum markers' accuracy in predicting nonmetastatic breast cancer patient's prognosis[16–23].

Moreover, in our setting, we do not have any serological or serum markers that are routinely measured during breast cancer surveillance and prognosis stratification[24].

TNM staging has been used for decision-making and even for determining the prognosis of patients before intervention; however, patients with similar TNM stages may have different prognoses[25].

There is a need to augment the available serum markers, particularly LDH and GGT, which have been found to correlate with pathological parameters such as tumour grade, number of positive nodes for the tumour, molecular subtypes and response to either adjuvant or palliative chemotherapy[26].

Tests for LDH and GGT are widely available, easy to perform and relatively inexpensive. The correlation of these markers(enzymes) with pathological parameters that we obtain only after surgery could augment clinical TNM staging and immunohistochemical markers in the prognostic stratification of patients before initiating any treatment.Some studies have reported that postoperative levels of LDH and GGT measured at certain intervals can be used to predict disease recurrence.Signficanly elevated levels of such markers may be an alarming sign of local recurrence or distant metastasis[27–29].

A prospective cross-sectional study was conducted at Muhimbili National Hospital in the Department of Surgery.

We aimed to determine the correlation between LDH/GGT and the NPI among women with breast cancer. We also aimed to determine the predictive accuracy of LDH and GGT for prognosis based on the NPI and clinical TNM stages in patients who underwent modified radical mastectomy for breast cancer.

Study area

This study was conducted at Muhimbili National Hospital. This is a National Referral Hospital, University teaching hospital, and research centre located in Dar es Salaam, Tanzania.

The Department of Surgery has 20 qualified surgeons who perform mastectomies regularly, and there are 5 attending oncologists from the Department of Clinical Oncology. Patients with stage II to III breast cancer are attended asoutpatients and admitted one or two days before surgery for preparation. On average, 49 women with breast neoplastic conditions at various clinical stages are admitted monthly, and among them, 16 (32.2%) undergo a mastectomy on an elective basis.

Sample size estimation and selection

The sample size was estimated by the OpenEpi formula as described in Kelsey[30]. The study only included those who had epithelial non metastatic malignant breast tumors undergoing modified radical mastectomy.

A total sample of 104 patients was selected, and the results were used to determine the correlation between the markers and the NPI at a power of 80%, margin of error of less than 5% and confidence interval of 95%.

From April 2023 to March 2024, a nonprobability convenient sampling technique was applied. During the study, 104 women with a histological diagnosis of breast cancer in the surgical ward who were scheduled for modified radical mastectomy were studied after providing consent.

Patients with nonepithelial breast tumors, clinical stage IV disease, or features of hepatobiliary disease (jaundiced, dilated biliary duct or identified focal biliary pathology from radiological metastatic workups, particularly thoracoabdominal CT scans) were not enrolled in the study. Patients with coexisting lymphoma, musculoskeletal trauma within 7 days, heart failure, myocardial infarction, renal failure or diabetes mellitus identified during routine preoperative physician review were also not enrolled in the study.

Data collection methods and measurement

Sociodemographic data, including age, menopausal status, age at diagnosis, and history of neoadjuvant therapy, were obtained by interviewing the study participants[31, 32].

The clinical TNM stage, as per the American Joint Committee on Cancer (AJCC), 8th edition, was established from a physical examination. A thorough assessment of the affected breast was performed for all participants. Features of skin involvement, such as ulceration, peaud’s orange and satellite nodules and inflammation, were noted during the inspection. For participants who had undergone breast imaging, the size of the tumor was recorded from a mammogram or breast ultrasound report. For those with a palpable lump(s) and who had not undergone any imaging, the size was estimated by palpating the affected breast. For all patients, the greatest dimension was considered, and the largest lump was considered in the case of multiple lumps. Through palpation and radio imaging reports, if any, the status of regional lymph nodes was determined and recorded[33–36].

Since the study involved patients undergoing modified radical mastectomy, patients with distant metastasis were excluded based on clinical features and metastatic radio imaging, particularly thoracoabdominal CT, which is currently recommended[37, 38]. However, chest X-ray and abdominal ultrasound were used for patients in the early stages of the disease[39].

Blood sample collection

For all study participants blood specimen was collected and alaysed within 24 hours before surgery.Aseptic precautions were taken, and approximately 3 ml of blood was collected from the antecubital vein of each subject into a red top bottle. To avoid hemolysis that may result in increased LDH, the specimen was sent to the laboratory immediately after collection for analysis.

After allowing the blood sample to clot, the serum was extracted by centrifuging it at 3000 rpm for approximately 10 minutes. Before analysis, the serum samples were stored at -20°C. By catalyzing the reaction between pyruvate and NADH to form NAD and lactate and measuring the absorbance at 340 nm, the amount of LDH in the serum was measured by employing a Stat Fax 3300 semiautomated analyser (USA).

Similarly, the amount of 5-amino-2-nitrobenzonate generated during the catalytic reaction of L-glutamyl-3carboxy-4-nitroanilide with glycylglycine at 405 nm was used to evaluate the level of GGT with a semi-automated analyser (Stat Fax 3300, USA) and analytical reagent kits from Analyticon Biotechnologies AG Muhlenberg, Germany. The results were saved in U/L and uploaded to the hospital's electronic database (Jeeva). The cut-off values were 280 U/L for LDH and 30 U/L for GGT[11, 14, 15].

Histopathology data

The histological type and immunohistochemical results (PR, ER, HER2, and Ki-67) were obtained postoperatively. Tumor grade was determied by using Nottingham Criteria as recommended by the National Comprehensive Cancer Network and stipulated by the College of American Pathologists.The status of the margins, pathological tumor size and a number of positive regional lymph nodes were obtained postoperatively on the entire tissue submitted[40]. All these data were found on the histopathology report by searching the hospital database (Jeeva) using the patient’s file number. A senior pathologist was contacted to review and report on the missing parameters from the histopathology reports for a few patients, and the NPI was calculated from the formula NPI=(0.2 x S) + N + G, where

S-Pathological size of the tumor in centimetres

N-positive lymph node for the tumor where 0 nodes = 1, 1–3 nodes = 2, > 3 nodes = 3

G-Tumor grade: Grade I = 1, Grade II = 2, Grade III = 3

whereby NPI ≤ 5.4 was considered to be favourable and NPI > 5.4) was considered to be unfavouable[41–43].

Data handling and analysis

The data for each participant were correctly entered into an adapted European Society of Medical Oncology (ESMO) checklist before analysis. The data were analysed using version 27 of the IBM SPSS. Correlations were assessed using simple linear regression by determining the Spearman correlation coefficient. The ability of LDH and GGT to predict the outcome of women with breast cancer based on the NPI and clinical TNM stage was assessed using a binary logistic regression model, and the accuracy was determined by the area under the curve (AUC) of the receiver operating characteristic (ROC) curve.

Sociodemographic characteristics

The mean age of the patients selected to participate in this research was 48.51 (± 12.80) years.60 patients (57.7%) had between 41–60 years and 21 patients (20.2%) had age between 21–40 years. Among them, 94 individuals (90.4%) had completed formal education, whereas 10 individuals (9.5%) had not received formal education. A total of 54 (51.9%) patients had public patient bills. The remaining patients were either insured or private at the same time. Of the total participants, 77 (74%) had a breast cancer diagnosis at the age of 40 years or older. Table 1

Table 1

Socio-demographic characteristics of women with breast cancer at MNH, N = 104
Variable	Mean \(\:\pm\:\) SD	Frequency (%)
Age (years)	48.51 (\(\:\pm\:\)12.80)
Age at diagnosis
< 40 years		27 (26.00 )
≥ 40 years		77 (74.0 0 )
Level of education
No formal education		10 ( 9.60)
Formal education		94 ( 90.40)
Billing Category
Public		54 (51.90 )
Private/ Insured		50 (48.10 )

Preoperative characteristics

Fifty-three patients, or 51% of the total, were postmenopausal. Regarding the clinical stage, 57 individuals (54.80%) had stage III disease, 46 individuals (44.20%) had stage II disease, and 1 individual (1.0%) had stage I disease. Forty-four patients (42.30%) had high LDH levels (> 280 U/L), with a median of 240.5 (195.50, 357.75). With a median score of 31.99 (24.30, 47.57), elevated GGT (> 30 U/L) was identified in 62 (59.60%) patients.

Postoperative characteristics

Among the histological types, invasive ductal carcinoma accounted for 89 (85.60%) of the cases, followed by invasive lobular carcinoma 12 (11.50%) and indeterminate 3 (2.90%). Luminal A comprised 56 (54%) of the patients, followed by triple negative 19(18%), luminal B 14 (13%), and Her 2 enriched 6 (6%).

In this study there was no significant variation of LDH and GGT among different molecular subtypes and NPI groups.

NPI of women for breast cancer

Following histopathological evaluation, the data (pathological tumor size, histological grade, and the number of lymph nodes containing a tumor) were used to calculate the NPI. The mean NPI was 4.89 ± 2.11. Of those evaluated, 62 (59.62%) had a favourable prognosis, and 42 (40.38%) had an unfavourable prognosis. Table 2

Table 2

Clinicopathological characteristics of women with breast cancer at MNH, N = 104
Variable	Mean \(\:\pm\:\) SD	Median (IQR)	Frequency (%)
Menopausal status
Premenopausal			51 ( 49.00 )
Post-menopausal			53 ( 51.00 )
Clinical TNM stage
Early stage ( stage 2)			47 ( 45.20)
Advanced stage ( stage 3)			57 ( 54.80)
NAT
Yes			36 (34.6)
No			68 (65.4)
LDH		240.5 (195.50, 357.75)
LDH Level
Normal or Low (≤ 280 U/L)			60 ( 57.70)
High (> 280 U/L)			44 (42.30)
GGT		31.99 (24.30,47.57)
GGT Level
Normal or Low (≤ 30U/L)			42 (40.40)
High (> 30 U/L )			62 (59.60)
Histological type
Ductal			89 (85.60)
Lobular			12 (11.50)
Other			3 (2.90)
Molecular subtype
Luminal A			56(54)
Luminal B			14(13)
HER 2 Enriched			6(6)
Triple Negative			19(18)
Unkown			9(9)
NPI	4.89 ± 2.11
NPI Category
Favourable (≤ 5.4)			62 ( 59.60)
Unfavourable (> 5.4)

Correlation between LDH and the NPI

To determine whether there is a relationship between the LDH level and the NPI among breast cancer patients, a correlation test was performed. There is a significant positive correlation, as demonstrated by the Spearman correlation coefficient, r = 0.660, p < 0.01

To assess whether there was any degree of dependence of the NPI on changes in LDH, a linear regression analysis was also carried out. After deriving the statistical model y = 3.49 + 4.21 * x, it was determined that the two variables had a positive relationship with a regression coefficient of b = 4.21, p < 0.001. This model shows that the increase in LDH by 4.21 then NPI is increased by one value. Figure 1.

The coefficient of determination, R², was found to be 0.283, p < 0.001. This implies that LDH alone could predict the NPI by 28.3%.

In addition, ANOVA was performed, and a significant difference in the variance in LDH levels was observed between patients who had favourable NPIs (variance = 913.5) and those who had unfavourable NPIs (variance = 1348.6).

The mean LDH varied significantly between the favourable and unfavourable NPI groups. The mean LDH of patients with an NPI > 5.4 was 491.5 (95% CI: 419.4–563.6), while the mean LDH of patients with an NPI ≤ 5.4 was 229.4 (95% CI: 170.0 − 288.7, p < 0.001 and F = 31). Figure 2.

Simple Boxplot of LDH by NPI Category

Correlation between GGT and the NPI

The Spearman correlation coefficient was computed to determine whether there was a correlation between GGT and the NPI. There is a relatively weak positive correlation, r = 0.455, between the two, despite a substantial association, p < 0.01.

Furthermore, an analysis of variance was conducted, and it was found that there was an insignificant difference in the variance of GGT levels between the two groups. The mean GGT did not differ significantly between the favourable and unfavourable NPI groups. Patients with an NPI > 5.4 had a mean GGT of 175.72 (95% CI: 53.72–297.67), while those with an NPI ≤ 5.4 had an average GGT of 32.87 (95% CI: -67.50 ─ 133.25), p = 0.148 and F = 2.17. Figure 3

Simple Boxplot of GGT by NPI Category

The accuracy of LDH and GGT in predicting breast cancer prognosis based on the NPI

The ability of LDH and GGT to predict the outcome of women with breast cancer based on the NPI was determined using the ROC curve. The areas under the curve were 0.845 (0.766–0.923, 95% CI, p < 0.001) and 0.725 (0.623–0.827, 95% CI, p < 0.001), respectively. Figure 4

The accuracy of LDH and GGT in predicting breast cancer prognosis based on TNM staging

Based on the clinical TNM stage, LDH and GGT can correctly categorise women with breast cancer into favourable and unfavourable groups. The area under the curve (AUC) was computed and found to be 0.870 (0.801–0.939, 95% CI, p < 0.001) and 0.759 (0.665–0.852, 95% CI, p < 0.001). Figure 5

Using the Youden index, the optimal effectiveness of the markers for patient classification was also assessed. Only LDH showed statistical significance, with an index of 58% for the NPI and 65% for the clinical TNM stage. For GGT, where an index of 44% for NPI and 45% for TNM was noted, it was comparatively insignificant. Table 3

Table 3

Prognostic accuracy and precision values for LDH and GGT
Biomarker	Cutpoint	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)	Youden’s Index	AUC	95%CI	Metric score	P-value
NPI status
LDH	270.00	80.95	77.42	70.83	85.71	0.58	0.845	0.766 -0.923	1.58	0.000
GGT	39.00	61.90	82.26	70.27	76.12	0.44	0.725	0.623–0.827	1.44	0.000
Clinical stage status
LDH	231.00	82.46	82.98	85.45	79.59	0.65	0.870	0.801–0.939	1.65	0.000
GGT	38.60	57.89	87.23	84.62	63.08	0.451	0.759	0.665–0.852	1.45	0.000

The purpose of this study was to ascertain whether there was a correlation between LDH/GGT and the Nottingham Prognostic Index in breast cancer patients. The correlation between LDH and the NPI suggested that high levels of lactate release in highly malignant breast cancer cells are indicative of a predictive value for the lactate concentration in breast cancer.

While lactate serves as an energy source for advancing epithelial cancer cells, excessive lactate concentrations seriously impair macrophage function by reducing the generation of natural killer cells and causing T cells to undergo apoptosis. The study revealed a statistically significant difference (p < 0.001) in the means of LDH between individuals with a favourable NPI and those with an unfavourable NPI. This observation aligns with the physiological reaction of lactate to malignant neoplasms described earlier. A strong positive correlation was observed between LDH and the NPI, with a Spearman correlation value of r = 0.66 and p = 0.01; the mean NPI was 4.89 ± 2.11.

According to the regression coefficient (b = 4.21.5), there was a one-point increase in the probability of an unfavourable prognosis for every fourfold increase in LDH. Individuals with LDH levels ≥ 280 U/L are more likely to have greater NPIs, which is associated with a worse prognosis[44]. According to the linear regression model, the coefficient of determination was 0.283, which indicates that LDH alone can distinguish between breast cancer patients with favourable and unfavourable prognoses with an accuracy of approximately 28.3%. An increased lactate concentration was correlated with a poorer NPI but is also a sensitive marker of tumor grade, according to a study by Cheung SM et al. The two parameters showed a significant correlation, with p = 0.0495 [45–49].

Additionally, we investigated whether lactate could accurately classify breast cancer patients with favourable and unfavourable prognoses based on the NPI. The sensitivity was 80.95%, and the specificity was 77.42%. Its discriminatory capacity is useful, with an AUC of 0.85. According to our research, women with breast cancer who have a lactate level greater than 270 U/L are at risk for an unfavourable prognosis.

Our results are in line with those of a different study by He J et al. that evaluated the predictive power of the lactate-to-albumin ratio for disease-free survival in nonmetastatic breast cancer patients[45]. The lactate-to-albumin ratio, with an area under the curve (AUC) of 0.709, a sensitivity of 94.1%, and a specificity of 38.5%, is an independent predictor of prognosis in patients with breast cancer. The fact that their study included only Caucasian women and included the patients' patterns of dietary status might account for the discrepancy in specificity[50–52].

Furthermore, it has been observed that lactate can distinguish between locally advanced disease and early disease. Fifty-eight per cent of the individuals in our study had locally advanced disease. This might be explained by the low level of education, ignorance, and the state of the economy in our area. Although this study included only one patient with stage I disease, the accuracy of LDH in properly classifying breast cancer patients with favourable and unfavourable prognoses based on clinical stage was also assessed and noted to be significantly helpful (AUC = 0.870). Serum lactate levels were compared in previous research at different stages of the disease. The results of the interstage comparison showed that there was a significant increase between stages II, III and IV but not between stages I and II [10, 26, 53].

On the other hand, a high/rapid turnover of malignant cells releases enzymes into the bloodstream, which in turn reflects the tumor burden, leading to elevated serum GGT. The measured serum GGT and NPI in the current investigation showed an unremarkable correlation, with a Spearman correlation coefficient of r = 0.455. This is in contrast to findings from earlier research by Mohammed Saheb SK and Abdalla M Jarari et al., where GGT levels in the blood were considerably greater in breast cancer patients than in controls.

During the progression stage, particularly across stages III and IV, the amount of this specific enzyme noticeably increased. Since our study included only patients in the nonmetastasizing group and other studies included patients in the stage IV group, where the correlation was highly significant, it is possible that this accounts for the discrepancy between the findings of the two studies[54, 55].

Based on the clinical TNM stage, the efficacy of GGT in classifying patients with breast cancer into early and locally advanced disease groups was also evaluated. With 57.9% sensitivity and 87.2% specificity, the AUC was 0.759. These results are in line with those of another study conducted by Mohammed SSK et al., in which the activity of serum GGT was found to significantly increase between stage II and stage IV patients, but an interstage comparison revealed a nonsignificant increase between stages I and II[10].

Based on the NPI and cTNM, we evaluated the accuracy of GGT in classifying women with breast cancer into favourable and unfavourable groups in our study based on the NPI and clinical TNM stages. Its specificity and sensitivity were determined to be 62%, 82%, and 58%, 87%, respectively. Its discriminatory capacity/utility was somewhat limited, with AUCs of 0.73 and 0.76, respectively. These results imply that the enzyme may be used as a predictive marker in breast cancer patients concerning their tumour load.

The distinction between our study's cut-off values and those of the other research it cited was also clearly visible. The values for LDH were 270 U/L and 231 U/L for the NPI and clinical TNM stages, respectively, whereas the value for GGT was 39 U/L for both[14, 15].

Lastly, in this study, there was no significant variation in LDH and GGT levels across molecular subtypes and histological types. In contrast to our study, another research done by Dennison JB et al showed significantly elevated enzymes in Triple Negative and HER-2 enriched groups as well as undiffentiated types of breast cancer[56, 57].

Strengths and limitations of the study

The testing of easy, affordable, and accessible markers (enzymes) in breast cancer, which is practically a public health challenge, is one of this study's many remarkable strengths.

Nevertheless, it has its drawbacks as well. The fact that our study involved a single site, had a limited sample size and was conveniently sampled all contribute to selection bias, which limits the ability of the study to be broadly applied.

Furthermore, Since immunohistochemical (IHC) markers are not covered by the National Health Insurance, few participants did not pay for them on time; hence, their results were missing at the time of analysis.

There is sufficient evidence to conclude that there is a significant correlation between LDH/GGT and NPI. Even though these enzyme markers only have unspecific diagnostic value, the preoperative serum levels of Lactate Dehydrogenase and Gamma glutamyl Transpeptidase stand as useful predictors of outcomes for women with breast cancer undergoing radical mastectomy in conjunction with other potential prognostic tools. Nonetheless, to validate these findings, further multicenter follow-up studies on disease free survival and disease specific overall survival with larger sample sizes must be performed.

LDH=Lactate Dehydrogenase

GGT=Gamma-Glutamyl Transferase

MNH=Muhimbili National Hospital

TNM=Primary Tumor,Regional lymph node(s),Distant metastasis

AUC=Area under the curve

ROC-Receicer operating curve

NPI=Notthingham Prognostic Index

IBM SPSS=International Bussiness Machine Statistical Product and Service Solution

ER=Estogen receptor

PR=Progestrone receptor

HER=Human epidermal receptor

MUHAS=Muhimbili University of Health and Allied Sciences

Ethical approval and Consent to participate

The Muhimbili University of Health and Allied Sciences Institutional Review Board approved the study protocol (IRB-MUHAS REF.No.DA.282/298/01.C/1845.

The Muhimbili National Hospital Research and Consultancy Department was approached for permission before any data were collected (REF.No.MNH/CRTCU/Perm/2023/488). Before taking part, each participant in this academic study provided written consent. All ethical principles were followed throughout the investigation. The research was completed while maintaining the confidentiality of participants' identities and other pertinent personal information.

Consent for publication

Not applicable

Availability of data and materials

All research materials pertinent to this study are accessible and will be handed down by the relevant author upon justifiable request.

Competing interests

The author declares neither financial nor non-financial interests that may be relevant to this study.

Funding

No funds were received for this paper.

Authors’ contributions

The primary researcher, Sylvery Mwesige, wrote the research proposal, collected data and produced a full-text paper and manuscript. He has access to all of the study's data.
Victor Meza Kyaruzi had an impact on the design of the research as well as its statistical analysis.
Mabula Daud Mchembe and Mungeni Misidai were supervisors of the study. They took part in the proposal development and proofreading of the manuscript.
Ally Mwanga played an administrative role and offered material and technical support.

Acknowledgement

I extend my profound appreciation to the patients who enthusiastically became part of the research we conducted. I am grateful to pathologist Dr Idd Shabani for his invaluable contribution. I also express my profound appreciation and heartfelt gratitude to the entire faculty in the Department of Surgery at the MUHAS and MNH for their unwavering support and passionate mentorship in producing this paper.

Authors’ information

SM is a resident pursuing a Master's Degree in Surgery. This study was carried out as a dissertation.
VMK is the Executive Director of the Evidence-Based Scientific Consortium's Research Division.
MM, a young surgeon and a lecturer in the Department of Surgery at MUHAS.
MDM is a Professor in the Department of Surgery at MUHAS. He is an outstanding researcher with tremendous experience.
AM is the Head of the Department and a Senior Surgeon in Gastroenterology and Hepatology. He is passionate about clinical research and makes an outstanding research mentor.

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Serum Lactate Dehydrogenase and Gamma-Glutamyl Transferase Correlate Optimally with Nottingham Prognostic Index for Breast Cancer

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Abstract

Figures

Introduction

Materials and Research Methods

Study area

Sample size estimation and selection

Data collection methods and measurement

Blood sample collection

Histopathology data

Data handling and analysis

Results

Sociodemographic characteristics

Preoperative characteristics

Postoperative characteristics

NPI of women for breast cancer

Correlation between LDH and the NPI

Simple Boxplot of LDH by NPI Category

Correlation between GGT and the NPI

Simple Boxplot of GGT by NPI Category

The accuracy of LDH and GGT in predicting breast cancer prognosis based on the NPI

The accuracy of LDH and GGT in predicting breast cancer prognosis based on TNM staging

Discussion

Strengths and limitations of the study

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1