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Tumour M2-pyruvate kinase: a gastrointestinal cancer markerYogesh Kumar, Niteen Tapuria, Naveed Kirmani and Brian R. Davidson Background Gastrointestinal cancer tumour markers are ethylenediaminetetraacetic acid (EDTA) plasma tumour valuable in the detection of recurrence following resection M2-pyruvate kinase were analysed together as a small or in monitoring response to chemotherapy. CEA, CA19-9, CA-50 and CA72-4 are currently available but arenonspecific and have a low sensitivity.‘Tumour M2-pyruvate Results At a diagnostic cut-off value of 15 U/ml for kinase’ was described by Eigenbrodt around 1985. In tumour M2-pyruvate kinase in EDTA plasma the sensitivity, cancers the active tetrameric form of the M2 isoenzyme of specificity, positive predictive and negative predictive value pyruvate kinase converted to an inactive dimeric form by was 57.3, 89, 85.7 and 64.8%, respectively, for colorectal direct interaction with oncoproteins to channel glucose cancers, 62.1, 89, 88 and 64%, respectively, for gastric/ carbons into DNA synthesis. This review summarizes the oesophageal cancers and 72.5, 89, 58 and 94%, current knowledge of this unique tumour marker with respectively, for pancreatic cancers. As a faecal marker for regard to its biochemistry, assay and potential use as a colorectal cancers, faecal tumour M2-pyruvate kinase has a diagnostic and screening tool in gastrointestinal cancer.
sensitivity of 73–92% at a cut-off value of 4 U/ml as against50% sensitivity for Guaiac faecal test.
Methods A literature search was conducted for entriesfrom 1980 to 2005 using PubMed and NeLH databases Conclusion Circulating tumour M2-pyruvate kinase is using tumour M2-pyruvate kinase, faecal tumour M2- more commonly elevated in oesophageal, gastric and pyruvate kinase, tumour metabolism, tumour markers and colorectal cancer patients than conventional tumour carcinoembryonic antigen as keywords. A total of 56 markers. Faecal M2-pyruvate kinase is a sensitive marker references relevant to tumour M2-pyruvate kinase were of colorectal cancer. The clinical role of tumour M2- retrieved. Eighteen references were clinical studies pyruvate kinase in gastrointestinal cancer management involving plasma/faecal tumour M2-pyruvate kinase and should be investigated in large-scale clinical trials.
gastrointestinal cancer. The remaining 38 references were Eur J Gastroenterol Hepatol 19:265–276 clinical/nonclinical trials and reviews on tumour metabolism and plasma/faecal tumour M2-pyruvate kinaseassay. Seven of the 18 clinical studies involved faecal European Journal of Gastroenterology & Hepatology 2007, 19:265–276 M2-pyruvate kinase. Three of the 11 plasma tumour Keywords: M2-pyruvate kinase, pyruvate kinase, tumour M2-pyruvate M2-pyruvate kinase studies were non-English language and were excluded. The sensitivity, specificity, positivepredictive and negative predictive value for plasma/serum Department of Surgery, Royal Free Hospital, Royal Free and University CollegeMedical School, London tumour M2-pyruvate kinase in the detection ofgastrointestinal cancer was determined for each of the Correspondence to Professor Brian R. Davidson, FRCS, MD, University remaining eight studies. Data for gastrointestinal cancer Department of Surgery, 9th Floor, Royal Free and University College Medical M2-pyruvate kinase were compared with other School of UCL, Pond Street, London NW3 2QG, UKTel: + 44 20 85273081; e-mail: b.davidson@medsch.ucl.ac.uk gastrointestinal cancer markers. Data from three of theeight studies using a diagnostic cut-off value of 15 U/ml for Received 3 March 2006 Accepted 25 August 2006 limited to detecting recurrence after surgery or monitor- Gastrointestinal (GI) cancer is one of the commonest ing response to treatment. Even the most commonly used causes of cancer death in Europe [1,2]. In the UK, GI tumour marker, carcinoembryonic antigen (CEA), has colorectal cancer accounts for 12% of all cancers. It is the been repeatedly questioned regarding its clinical useful- second most common cancer among women after breast cancer and the third most common in men after lung andprostate cancer [3]. Stomach and pancreatic cancer Tumour M2-pyruvate kinase (PK), the inactive dimeric account for 3% of all reported cases of cancer [3]. The form of the M2 isoenzyme of PK (a glycolytic pathway high mortality of GI cancers may relate to their advanced enzyme), was first described in 1985 by Eigenbrodt as a stage at diagnosis and early detection is an important way tumour characteristic metabolic marker [6–8]. Initial of reducing cancer mortality. Current tumour markers studies in patients with cancers of the lung, pancreas, have a low sensitivity for detecting cancer and their role is liver, kidney and breast showed increased activity of PK Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
266 European Journal of Gastroenterology & Hepatology 2007, Vol 19 No 3 type M2 in blood as well as cancer tissues and its role is former group is likely to have advanced disease. Serum emerging in the management of GI cancers [9–14]. It can CEA can also be increased in other forms of cancer and in be measured in both blood and faeces. The review aims multiple benign disorders [68]. A high preoperative to provide a critical review of the current literature on serum CEA level is associated with a poor outcome in tumour M2-PK as a marker of GI cancer.
colorectal cancer [66,69–74]. Unfortunately, no clinicalbenefit has been demonstrated by the use of adjuvant chemotherapy based solely on increased preoperativeCEA concentration [5]. Elevated CEA levels following A literature search was conducted for the period from bowel cancer resection is also correlated with an adverse 1980 to 2005 using PubMed and NeLH databases using outcome [5]. In a landmark study Moertel et al. [75] the following keywords: tumour M2-pyruvate kinase, demonstrated that CEA monitoring following bowel faecal tumour M2-pyruvate kinase, tumour metabolism, cancer resection had a 59% sensitivity rate for recurrence, tumour markers and carcinoembryonic antigen. A total of but with a 16% false-positive rate. In a randomized 56 references relevant to tumour M2-PK were retrieved.
prospective study, Ohlsson et al. [76] showed no Thirty-eight references were reviews, book chapters and difference in 5-year survival rate or cancer-specific bibliographic links from the reviews on tumour M2-PK survival rates between an intensive CEA-based follow- biochemistry, assay and measurement [6–11,13–44].
up and a group with no follow-up. Recent meta-analyses Eighteen references were the clinical trials involving of randomized trials suggest that intensive CEA, com- circulating/faecal tumour M2-PK and GI cancer [12,45– puted tomography scan and colonoscopy-based post- 61]. Seven of these 18 clinical studies were related to operative surveillance improves 5-year survival rates by faecal tumour M2-PK in GI cancer [49,53–58]. Of the approximately 10% compared with less intensive follow- remaining 11 studies for plasma/serum tumour M2-PK, up [77–79]. Current guidelines by the National Institute three studies were in non-English language and have for Clinical Excellence, therefore, recommend the been excluded [59–61]. Full papers on eight studies with measurement of CEA along with serial imaging following serum/plasma tumour M2-PK and GI cancer were reviewed [12,45–48,50–52]. The sensitivity, specificity,positive predictive value (PPV) and negative predictivevalue (NPV) were calculated for tumour M2-PK for individual GI cancer types and in comparison with other This is an oligosaccharide related to the Lewis A blood cancer markers. Three [46,48,50] of the eight studies, group substance [4]. It has been proposed as a sensitive which all used the same diagnostic cut-off value of marker for pancreatic, gastric and hepatobiliary malig- 15 U/ml for EDTA plasma tumour M2-PK, were used for a nancies [81]. CA19-9 is elevated in nearly 80% of small meta-analysis. Only one full published English advanced pancreatic cancer patients. The false-positive language paper [55] on faecal tumour M2-PK is available.
rates, however, are also high at 20–30% in benign The rest of the data on faecal tumour M2-PK was hepatobiliary and pancreatic diseases [82]. Other benign obtained from two clinical trials [49,58], two published conditions associated with elevated CA19-9 levels include abstracts [53,54] and two German studies with English pneumonia, pleural effusion, renal failure and systemic lupus erythematosus (SLE) [81]. Recent reviews andmulticentre studies [83,84] have questioned the clinicalsignificance of elevated levels of CA19-9. Confident Current gastrointestinal tumour markers – roles discrimination between benign and malignant disease cannot be made on the basis of a solitary elevated CA19-9 ( > 33 U/ml) measurement [84]. Elevated levels are This glycoprotein has a structural similarity to the associated with advanced disease at presentation and with disease progression during follow-up [83]. The (ICAM)-1 and ICAM-2 [62,63], suggesting a role in clinical role of the tumour markers CEA and CA19-9 in GI cancer invasion and dissemination [64,65]. It can be cancer diagnosis and management is limited and new measured in the serum and its clinical use has been investigated in GI cancers. It is less frequently elevatedin early stage (Duke’s A and B) colon cancers, the stagesat which early detection is most likely to result in curative surgery. In a study by Wang et al. [66] the proportion of The term tumour metabolome (in analogy to tumour patients with increased serum CEA concentration genome and tumour proteome) was coined by Mazurek ( > 5 ng/ml) in Duke’s A and Duke’s B stage disease and Eigenbrodt in 2001 for the metabolic characteristics were 25 and 39%, respectively, compared with 71% in of tumour cells [19,20,24]. In differentiated cells glucose Duke’s C stage. As pointed out by Fletcher [67,68], is mainly converted to pyruvate via glycolysis and sensitivity in symptomatic individuals is likely to be thereafter to CO2 and water or lactate depending on higher than in the asymptomatic individuals, because the Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Tumour M2-pyruvate kinase Kumar et al. 267 The final reaction of glycolysis is catalysed by the highly regulated enzyme, PK. This enzyme mediates thetransfer of high energy phosphate of phosphoenolpyr- uvate (PEP) to generate ATP and pyruvate in differ- entiated cells. PK has different isoenzymes. L-PK ispresent in tissues with gluconeogenesis such as the liver and kidney, R-PK is present in erythrocytes and M1-PK isfound in tissues requiring large amounts of energy such as the brain and muscle [6,7,13,25,41]. M2-PK is present in all proliferating cells such as embryonic and adult stemcells, but especially in tumour cells. M2-PK can occur in ahighly active tetrameric form with high affinity for its substrate PEP and in an inactive dimeric form with a low affinity to PEP [6–8,18–20,24,26,41]. The tetrameric form is associated with other glycolytic enzymes within the so-called glycolytic enzyme complex which leads to a [7,13,18,25,41]. In tumour cells the dimeric form is always predominant and has therefore been labelled astumour M2-PK [7,18,24,26,37] (Fig. 1). The dimeric form switches to the tetrameric form with high levels of fructose 1,6 bi-phosphates in tumour cells [18]. During tumourogenesis, different tissues with totally different basic metabolism, for example, liver and brain, shift to thesame metabolic phenotype [18]. The common result is increased glycolysis, glutaminolysis, expansion of phos- phometabolites and a shift of metabolism to the synthesisof nucleic acids, amino acids and phospholipids [6–8,18–20,26,29,38,41,85]. Energy production is facilitated by an alternative pathway called glutaminolysis [28] (degrada- tion of the amino acid glutamine to lactate), which depends on an adequate oxygen supply and high NAD(P) levels [6,18,21,41]. In the absence of oxygen, M2-PK is reactivated to the tetrameric form by high bi-phosphate levels and glutaminolysis is inhibited, thereby switching M2-PK may act as a sensor of the tumour metabolomeallowing the tumour cells to adapt to varying oxygen andnutrient supply. Although tumour cells are able tocompensate for nutrient starvation for a while, if NAD(P) levels are low then both glycolysis and glutaminolysis are inhibited and tumour apoptosis occurs [18]. A similar M2-pyruvate kinase (M2-PK) in normal proliferating cells and cancer mechanism for tumour cell apoptosis is induced by cells. The tetrameric form is predominantly present in normal cells chemotherapeutic drugs in which decreased NAD(P) while the dimeric form is predominant in cancer cells. Reproduced levels result in the inability of tumour cells to recycle M2-PK is a target of different oncoproteins with totally Quantification of tumour M2-pyruvate kinase pp60v-src kinase [30] and HPV-16 E7 [22]. The pp60v- Tumour M2-PK can be detected by a highly sensitive src kinase phosphorylates M2-PK in tyrosine. The E7 enzyme-linked immunosorbent assay (ELISA), which oncoprotein of the human papilloma virus type 16 allows the quantitative measurement of tumour M2-PK directly binds to M2-PK. Thus the tetrameric form of in EDTA-plasma samples. The test is based on two M2-PK is dissociated to the dimeric form during monoclonal antibodies, which specifically react with transformation of normal cells to oncoprotein-expressing tumour M2-PK and do not cross-react with the other isoforms of PK (types L, R and M1) [31,32,86]. Tumour Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
268 European Journal of Gastroenterology & Hepatology 2007, Vol 19 No 3 M2-PK is adsorbed onto microtitre wells coated with a Factors affecting tumour M2-pyruvate kinase specific monoclonal antibody. It is quantified after incubation with a biotinylated second monoclonal anti- body and with streptavidine–peroxidase conjugate [86].
Tumour M2-PK levels in EDTA plasma have been found The mean intra-assay coefficient of variance (CV) is 3.5% to be elevated in bacterial infection as opposed to severe and the mean interassay coefficient of variance is 5.3% sepsis and polytrauma [35]. Other benign conditions [33,34]. A reference concentration of r 15.0 U/ml in reported to have tumour M2-PK elevations include: EDTA plasma corresponds to a specificity of 90% for a rheumatic diseases [16], diabetic nephropathy [15], control group of patients without cancer (n = 393) [34] chronic cardiac failure [36], inflammatory bowel disease (Fig. 2). A study involving 695 healthy controls showed a [48] and acute and chronic pancreatitis [45]. Plasma specificity of 95% at a diagnostic cut-off value of 17.5 U/ tumour M2-PK, at cut-off value of 25 U/ml is elevated in ml in EDTA-plasma samples [17]. The tumour M2-PK 39% of patients with diabetic nephropathy [15]. In concentration in these healthy individuals ranged from 2 chronic cardiac failure (CCF), the median tumour M2-PK to 30 U/ml with a median value of 6 U/ml. Tumour M2-PK level in plasma of patients with NYHA grade-2 disease concentrations have been shown to be affected by was 24 U/ml, with grade-3 disease was 30 U/ml and with haemolysis of blood samples (median value: 50.5 U/ml), grade-4 disease was 46 U/ml. The diagnostic cut-off value icterus (median value: 39.1 U/ml) and lipaemia (median for CCF was 5 U/ml. How often it was elevated in both value: 30.8 U/ml). A correlation with the severity of these controls and patients with CCF was not mentioned in conditions, however, has not been reported [17].
this study [36]. The mechanism suggested for the rise inplasma tumour M2-PK value in patients with heart disease was the increased glycolysis to meet the Tumour M2-PK can be measured in stool by a similar metabolic demand related to the increased ventilation ELISA technique using the same monoclonal antibody as and neurohormonal activation, for example, seen in CCF.
used in the serum/plasma assay. A reference concentra- An alternative explanation was that the increased tion of 4 U/ml corresponds to a specificity of 83% for a bilirubin and triglycerides levels commonly observed in control group of individuals aged 50 to 89 years [44]. The CCF patients had caused analytical interference with the intra-assay mean CV was 7.9% and the interassay mean tumour M2-PK assay. These postulations were not investigated although the authors had ruled out the Distribution of tumour M2-PK (M2-pyruvate kinase) levels in 393 noncancer controls with 90% of subjects had tumour M2-PK levels below 15 U/ml (data obtained by personal communication with ScheBo Biotech, Giessen, Germany).
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Tumour M2-pyruvate kinase Kumar et al. 269 impaired renal function seen in CCF as a cause of tumour M2-PK has a higher sensitivity than plasma elevated plasma tumour M2-PK levels [36]. Oehler et al.
tumour M2-PK in determining cancer stage in colorectal [35] studied the expression of PK type M2 in neutrophils of polytrauma patients. Using Western blotting foridentifying M2-PK expression, they noticed strong expression of M2-PK in 62% of polytrauma patients as The level of tumour M2-PK in blood can be influenced compared with none of the healthy volunteers. Oremek by the mechanical stress of shaking the sample, the type et al. [16] showed elevated levels of plasma tumour of anticoagulant (EDTA, heparin, citrate), duration M2-PK (diagnostic cut-off 17.5 U/ml) in different types of before the blood sample is centrifuged and the tempera- rheumatic diseases. It was elevated in 82% of rheumatoid ture at which the centrifuged sample is stored. Hugo et al.
arthritis patients, 82% of seronegative spondyloarthritis [33] observed a high reproducibility of tumour M2-PK patients and 63% of patients with collagen disorders. The levels in EDTA plasma but not with serum or citrated/ overall median value of plasma tumour M2-PK in heparinized plasma blood samples from 10 healthy rheumatic diseases was 26 U/ml. Plasma tumour M2-PK volunteers. Shaking or leaving the samples at room (diagnostic cut-off 15 U/ml) was elevated in 68% of temperature for several hours before centrifugation led patients with inflammatory bowel disease with a median to a 2–3-fold increase of tumour M2-PK in serum and value of 12 U/ml [48], 68% of patients with acute heparin-plasma samples. In contrast, the quantification in pancreatitis with a median value of 22 U/ml and 67% of EDTA plasma and citrate plasma was absolutely stable patients with chronic pancreatitis with a median value of after 24 h [33]. Lymphocytes were found to be a potential 11 U/ml (cut-off 8.9 U/ml) [45]. These levels were source for the increased concentration in serum and significantly higher than the median levels in respective citrate plasma [33]. After centrifugation the EDTA- controls. The cause of this rise in tumour M2-PK value plasma sample is stable for 3 days at 41C or for up to 1 with benign disease has not been elucidated in any of year at – 201C [56,57]. No known factors are found that these studies. The mechanism suggested is an increased can interfere with the faecal tumour M2-PK levels.
glycolysis to meet the metabolic demand related to the Excessive dilution of stool can lower the faecal M2-PK stress of trauma and inflammatory reaction [45]. No level. Therefore, a formed stool sample should always be correlation between plasma tumour M2-PK levels and the analysed. Undiluted stool extracts can be stored at 4–81C severity activity index or C-reactive protein levels was for 1 day or up to 4 weeks at – 201C without losing their found in these inflammatory conditions [48]. Cross- reactivity of monoclonal antibodies with the tetramericform of M2-PK cannot explain these results as the two monoclonal antibodies used in these studies are highly There have been no GI cancer studies so far correlating specific to the dimeric form. The level of tumour M2-PK M2-PK levels with the tumour size, grade and histological in EDTA plasma should therefore be interpreted with type. In renal cell carcinoma (RCC) patients (n = 40), a caution in patients with these benign conditions.
significant correlation was found between serum tumourM2-PK and RCC grade (50% in G1-RCC, 70% in G2- Tumour M2-pyruvate kinase levels and tumour stage RCC and 86% in G3-RCC) [37]. No correlation was As with most tumour markers, the concentration of found between serum tumour M2-PK levels and histo- tumour M2-PK tends to increase with disease stage.
logical type or tumour diameter. Similarly in lung cancer Zhang et al. [46] showed an increase in plasma tumour neither plasma tumour M2-PK nor immunohistochemical M2-PK levels with increasing tumour stage in gastric staining showed significant correlation with the histo- [compared with tumour node metastasis (TNM) stage], logical type or differentiation of cancer but the concen- colorectal (compared with Duke’s stage) and pancreatic tration of tumour M2-PK in EDTA plasma correlated well cancers (compared with TNM stage) [45]. The level of tumour M2-PK in patients with pancreatic cancer(n = 60) differed significantly between those with stage I–II disease and those with distant metastasis (stage IV).
Among non-GI cancers the association between tumour Faecal M2-pyruvate kinase in screening for M2-PK levels and disease stage has also been found [24,37,40]. In lung tumours the sensitivity of tumour M2- Following the completion of a pilot project based on PK was observed to be 28% in stage I, increasing centres in Scotland (Fife, Tayside and Grampian) and progressively to 73% in stage IV. A similar correlation is England (Coventry and Warwickshire) in which around seen in renal cancer staging (Robson staging) with serum/ 120 000 patients aged 50–69 years old were enrolled [88], EDTA plasma tumour M2-PK increasing in sensitivity the UK Department of Health announced the introduc- from 60% in stages I and II to 100% in stage IV. Faecal tion of national colorectal cancer screening, which will levels of tumour M2-PK showed a strong correlation with begin to be ‘rolled out’ from 2006 in England for men and TNM and Duke’s staging in colorectal cancer [87]. Faecal women aged 60–69 and from March 2007 in Scotland for Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
270 European Journal of Gastroenterology & Hepatology 2007, Vol 19 No 3 those aged 50–74 years [89]. Under these programmes Koss et al. [53] found a specificity of 92%. At a cut-off of patients will be offered a guaiac faecal occult blood 4 U/ml McLoughlin et al. [54] found a similarly high (FOB) test every 2 years, with positive FOB test results sensitivity of 95%. These studies also looked at the being further investigated by diagnostic colonoscopy. A sensitivity for the detection of polyps, finding a similar approach is also currently being assessed in sensitivity of 63% for adenoma [54], 63% for polyps Australia [90]. Randomized trials of screening by FOB > 1 cm [53] and 25% for polyps < 1 cm [53]. One study test have been shown to reduce the disease-specific has compared faecal tumour M2-PK with a guaiac and an mortality by 15–18% although screening for cancer immunological FOB test [57]. Sensitivity of the guaiac remains controversial owing to the large number of FOB test was only 27% for colorectal cancer and 10% for false-positive results [88,91,92]. The data from the polyps, whereas it was 77 and 48%, respectively, for faecal Nottingham study showed a positive predictive value of tumour M2-PK and 91 and 19%, respectively, for the only 12% (false-positive rate 88%) for colorectal cancer in immunological FOB test. Specificity was 89, 72 and 94%, individuals who underwent subsequent colonoscopy after respectively. Small meta-analyses of studies with faecal FOB test [91]. Sigmoidoscopy, colonoscopy or combina- tumour M2-PK reported an overall sensitivity of 77.9% for tions are the other current practices of searching for and the detection of colorectal cancer and specificity ranging removing adenomatous polyps to prevent colorectal from 74.3 to 83.3%. Overall sensitivity for adenomatous cancer [93], but they are limited by poor patient polyps was 45.9%, increasing to 61.1% for those > 1 cm [56]. No randomized trial has been found to be [94,95]. Therefore newer screening tools for colorectal comparing faecal M2-PK with FOB test or colonoscopy cancer are under evaluation and may take their place in as a screening tool in terms of efficacy, cost effectiveness, future guidelines. Hardt et al. [49,58] showed that tumour feasibility and reducing the cancer-related mortality.
M2-PK can be detected in the faeces of GI cancerpatients. Symptomatic patients undergoing colonoscopy Plasma M2-pyruvate kinase in detection of different for various reasons had faecal tumour M2-PK measured.
The faecal level of tumour M2-PK was higher in patients In this review we analysed the data of eight clinical with histology proven colorectal cancers as compared with studies related to tumour M2-PK and GI cancer [12,45– controls (non cancer patients). The sensitivity of faecal 48,50–52]. The diagnostic cut-off values for tumour M2- tumour M2-PK at a cut-off value of 4 U/ml was 73% with PK used in these studies ranged from 8.9 to 28 U/ml.
a specificity of 78%. The false-positive rate was 15%. This Three studies [46,48,50] used the same cut-off value of low false-positive rate, however, should be viewed with 15 U/ml for tumour M2-PK in EDTA plasma and were caution when comparing it with the high false-positive chosen for meta-analysis of histologically proven GI rate for Haemoccult faecal blood test used in the Nottingham study and the Danish trial which were basedon a large asymptomatic population [91,92]. Faecal tumour M2-PK levels were higher with more advanced Three studies (one prospective and two retrospective) disease. The sensitivity increased from 57% in case of T1 were found related to histologically proven oesophageal cancer, 78% in T4 and 90% in patients with distant cancer [47,48,50]. One study combined data for gastric metastasis [55]. Two recent studies also showed a high and oesophageal cancer [48]. The plasma tumour M2-PK sensitivity (92%) of faecal tumour M2-PK for detecting concentration in oesophageal cancer ranged from 3.2 to colorectal cancer [53,54]. Using a cut-off of 3.33 U/ml, 397 U/ml with a mean value of 42 U/ml. The controls Studies comparing the tumour markers: tumour M2-PK, CEA, CA19-9 and CA72-4 in oesophageal cancers CEA, carcinoembryonic antigen; PPV, positive predictive value; NPV, negative predictive value; M2-PK, M2-pyruvate kinase.
aThe specificity of CEA, CA72-4 and CA19-9 was not stipulated in these studies.
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Tumour M2-pyruvate kinase Kumar et al. 271 used in these studies were nonmalignant disease 15 U/ml in three of the studies, 19.8 U/ml in one study patients. The mean control value was 9.3 U/ml. The [47] and 22 U/ml in another [12] with specificity ranging diagnostic cut-off value of 15 U/ml (published cut-off) from 89 to 95%. When data from the three gastric cancer was used in two of the studies [48,50] with a specificity studies with the same diagnostic cut-off level for plasma of 89%, whereas the other study [47] used 19.8 U/ml cut- tumour M2-PK are analysed, 211 patients with 221 off value with a specificity of 95%. When data from the controls have been evaluated giving an overall sensitivity two oesophageal cancer studies with the same diagnostic of 64%, specificity of 89%, PPV of 85% and NPV of 72%.
cut-off level for plasma tumour M2-PK are analysed, 107 The sensitivity, PPV and NPV of CA72-4 (35–91, 14–95 patients with 201 controls have been evaluated with an and 34–100%, respectively) are superior to CEA (24–38, overall sensitivity of 59%, specificity of 89%, PPV of 74% 6–80, and 44–99%, respectively) and CA19-9 (33–49, 3.8– and NPV of 80%. The overall sensitivity, PPV and NPV of 93, and 52–99%, respectively). The efficacy of tumour plasma tumour M2-PK was higher as compared with M2-PK (57–67, 10–94 and 44–99%, respectively) was those of CEA (14–25%, 45–75% and 49–78%, respec- comparable. The range of values is the least and the best tively), CA72-4 (12–53%, 38–92% and 62–64%, respec- value for sensitivity, PPV, and NPV for these tumour tively) and CA19-9 (28–43%, 54–86% and 54–80%, markers in the five studies. Owing to different cut-off respectively). The range represents the lowest and the values, the data from the individual studies could not be highest value for these tumour markers in the three combined. The specificity of CEA, CA72-4 and CA19-9 in studies. Because of different cut-off values the data from these studies was again not stipulated. Low sensitivity the individual studies could not be combined. The and PPV was found in one study [12] which used serum specificity of CEA, CA72-4 and CA19-9 was not clearly tumour M2-PK rather than EDTA plasma and a high diagnostic cut-off. The cut-off values of CEA, CA19-9and CA72-4 in this study were historical.
Gastric cancer (Table 2)Five studies (two prospective and three retrospective) were reviewed with data relevant to histology proven Seven studies (six prospective and one retrospective) gastric cancer and tumour M2-PK [12,46–48,50]. One analysed tumour M2-PK in histologically proven pancrea- study combined data for gastric and oesophageal cancers tic cancer [12,45,47,48,50–52]. One study used serum [48]. Serum tumour M2-PK measurement rather than tumour M2-PK measurement [12]. The plasma/serum EDTA-plasma concentration was measured in one study levels of tumour M2-PK in pancreatic cancer patients [12]. Tumour M2-PK levels in gastric cancer ranged from ranged from 0.1 to 195 U/ml with median level of 33 U/ml 2 to 965 U/ml with mean value of 43 U/ml. The controls which was significantly higher than the median level in used in these studies were mainly healthy donors. The controls (9 U/ml). The controls used in some of the mean control value of tumour M2-PK was 9.3 U/ml. The studies were healthy blood donors [12,48,51], whereas diagnostic cut-off value for tumour M2-PK in plasma was other studies used noncancer individuals as controls Studies comparing the tumour markers: TuM2-PK, CEA, CA19-9, CA72-4 and CA50 in gastric cancers CEA, carcinoembryonic antigen; PPV, positive predictive value; NPV, negative predictive value; M2-PK, M2-pyruvate kinase.
aThe specificity of CEA, CA72-4 and CA19-9 was not stipulated in these studies.
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272 European Journal of Gastroenterology & Hepatology 2007, Vol 19 No 3 Studies comparing the tumour markers: tumour M2-PK, CEA, CA19-9, CA72-4 and CA50 in pancreatic cancers CEA, carcinoembryonic antigen; PPV, positive predictive value; NPV, negative predictive value; M2-PK, M2-pyruvate kinase.
aThe specificity of CEA, CA72-4 and CA19-9 was not stipulated in these studies.
bBenign pancreatic disease (acute or chronic pancreatitis), cystic neoplasms, neuroendocrine tumours of pancreas, other abdominal malignancies and healthy controls.
[12,45,46,50,52]. The diagnostic cut-off value for tumour tumour M2-PK in controls was 9.6 U/ml. The diagnostic M2-PK was between 8.9 and 28 U/ml. The diagnostic cut- cut-off used in these studies was either 15 or 19.8 U/ml in off value for tumour M2-PK in plasma was 15 U/ml in two EDTA plasma. Three studies used 15 U/ml cut-off level studies [48,50]. When data from the pancreatic cancer [46,48,50] and included 251 patients with colorectal studies using the same diagnostic cut-off level of 15 U/ml cancer and 221 controls with a sensitivity of 57%, for plasma tumour M2-PK are analysed, 40 patients with specificity of 89%, PPV of 86% and NPV of 65%. The 201 controls have been evaluated giving a sensitivity of overall specificity of tumour M2-PK ranged from 89 to 72%, specificity of 89%, PPV of 58% and NPV of 94%. The 95% with sensitivity, PPV and NPV (48–76%, 81–97% and overall sensitivity, specificity, PPV and NPV for tumour M2- 35–87%, respectively. Tumour M2-PK was better com- PK was (66–85%, 41–95%, 32–62% and 61–97%, respec- pared with CEA (sensitivity 34–71%, PPV 80–95% and tively. This was comparable with those of CA19-9 (28–85%, NPV 30–84%) and CA19-9 (sensitivity 27–55%, PPV 50– 73–95%, 40–86% and 54–97%, respectively). The range of 95% and NPV 29–77%). The range of values is the least values is the lowest and the highest value for sensitivity, and the best value for sensitivity, PPV and NPV for these PPV and NPV for these tumour markers in all the seven tumour markers in the four studies. The specificity of studies. Owing to different cut-off values the data from the CEA and CA19-9 was not clarified in all four studies.
individual studies could not be combined. The specificityof CEA and CA19-9 was not clarified in five studies Combining tumour M2-pyruvate kinase with other [12,47,48,50,51]. The low specificity of tumour M2-PK level in one study may be due to use of patients with acute Combining tumour M2-PK with the conventional tumour pancreatitis, chronic pancreatitis, cystic tumours and markers increases its diagnostic efficacy, as shown in neuroendocrine tumours of pancreas, various benign three studies [45,50,52]. In oesophageal cancer combin- digestive disorders and other abdominal malignancies as ing tumour M2-PK with CEA increases the sensitivity, controls [45]. The low cut-off value (8.9 U/ml) used in this PPV and NPV from 59, 76 and 77%, respectively, to 65, 78 study may also contribute to the low specificity.
and 80%, respectively. In gastric cancer it increased from67, 84 and 74%, respectively, to 82, 87 and 97%, respectively, when tumour M2-PK was combined with Four studies (two prospective and two retrospective) CA72-4. Similarly, in pancreatic cancer an increase in evaluated tumour M2-PK and colorectal cancer patients sensitivity, PPV and NPV was seen from 73, 54 and 95%, [46–48,50]. The level of plasma tumour M2-PK in respectively, to 96, 61 and 99%, respectively, when colorectal cancer patients was in the range of 2–986 U/ tumour M2-PK was combined with CA19-9. In colorectal ml with a mean value of 44 U/ml. The controls used in cancer combining tumour M2-PK with CEA increases the these studies were either healthy blood donors or sensitivity, PPV and NPV from 50, 83 and 60%, patients with nonmalignant disease. The mean value of respectively, to 67, 87 and 70%, respectively.
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Tumour M2-pyruvate kinase Kumar et al. 273 Studies comparing the tumour markers: tumour M2-PK, CEA and CA19-9 in colorectal cancer CEA, carcinoembryonic antigen; PPV, positive predictive value; NPV, negative predictive value; M2-PK, M2-pyruvate kinase.
aThe specificity of CEA, CA72-4 and CA19-9 was not stipulated in these studies.
Combining tumour M2-PK with other GI cancer markers GI, gastrointestinal; M2-PK, M2-pyruvate kinase; NPV, negative predictive value; PPV, positive predictive value.
Plasma tumour M2-pyruvate kinase levels in post- lung cancer patients, plasma tumour M2-PK concentra- tion reflected the course of the disease and correlated Only one study has been found assessing tumour M2-PK well with tumour progression or remission following levels and the response to therapy as far as GI cancers are concerned. Ventrucci et al. [45] showed a rise in plasmatumour M2-PK levels shortly (within 2 weeks) afterpancreaticoduodenectomy for pancreatic cancers. This immediate postoperative rise was attributed to acceler- Tumour M2-PK can be quantified in blood with a ated glycolysis due to healing [35]. Only one study has specificity of 90–95% at a diagnostic cut-off value of been found so far monitoring the serum tumour M2-PK 15–17.5 U/ml and in stool with a specificity of 83–95% at levels after the resection of cancer. In this study, with a cut-off value of 3.33–4 U/ml. The stability of tumour only six patients followed after renal cell carcinoma M2-PK is best in EDTA plasma for 24 h at room resection, tumour M2-PK normalized 11 weeks after temperature and is not influenced by any mechanical surgery and showed rising levels 2 months before stress. The quantification in blood/stool is by highly computed tomography detected recurrence [37]. In sensitive ELISA using two monoclonal antibodies specific studies with advanced breast and lung cancer patients to tumour M2-PK. It can be elevated in benign tumour M2-PK levels in plasma decreased within 4 weeks conditions including chronic cardiac failure, diabetic after the start of palliative chemotherapy and rose again nephropathy, rheumatic diseases, inflammatory bowel with disease progression [9,39]. In another study with disease and pancreatitis. The inclusion of these benign Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
274 European Journal of Gastroenterology & Hepatology 2007, Vol 19 No 3 conditions as noncancer controls can result in false- 9 Hoopmann M, Warm M, Mallmann P, Thomas A, Gohring UJ, Schondorf T.
positive rates ranging from 38 to 82%. Studies in gastric, Tumor M2 pyruvate kinase: determination in breast cancer patients receivingtrastuzumab therapy. Cancer Lett 2002; 187:223–228.
colorectal and pancreatic cancer show a good correlation 10 Schneider J, Neu K, Grimm H, Velcovsky HG, Weisse G, Eigenbrodt E.
between plasma/faecal tumour M2-PK and disease stage Tumor M2-pyruvate kinase in lung cancer patients: immunohistochemical [45,46,50,55]. Although no prospective data are available detection and disease monitoring. Anticancer Res 2002; 22:311–318.
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