Foreword For reprint orders, please contact: [email protected]
Biomarkers: a framework driving advances in oncology “…two principal axioms have prevailed among clinical oncologists: earlier treatment of metastatic disease does not significantly prolong DFI and/or overall survival; any biochemical and/or instrumental tool for postoperative monitoring of disease-free breast cancer patients is cost/benefit unfavorable.”
Keywords: biomarkers • cancer • diagnosis • prediction of response • prognosis
Nowadays, it is clear that cancer is a very complex disease. Basic research, mainly genetics and molecular biology, provides insights for better comprehension of the pathological mechanisms giving origin and sustaining tumor growth; these advances move on and are continuously refined. On the other hand, diagnosis, prognosis and treatment are three main fields of clinical medicine that take advantage from progress in basic research. Increasingly, biomarkers are an example of this translational medicine and are the framework driving the progression in clinical practice, as is clear in this thematic issue devoted to ‘Biomarkers in gastrointestinal and endocrine-dependent tumors’. In the issue the reader will find all the three principal clinical application of biomarkers: diagnosis, prognosis and prediction of response to treatment, the latter enabling so-called ‘personalized medicine’ that is the gold standard of any specialty in medicine. Biomarkers for diagnosis The research paper entitled ‘Usefulness of an individual reference limit (IRL) for early diagnosis of metastatic breast cancer during post-operative follow-up’ [1] defines criteria to calculate the cutoff value and critical change in order to utilize the serum CEA-TPA-CA 15.3 tumor marker panel at the best for early detection of metastatic disease during postoperative monitoring of disease-free breast
10.2217/BMM.15.7 © 2015 Future Medicine Ltd
cancer patients. During a mean follow-up of 3.7 years, 93% sensitivity, 97.6% specificity and a rate of false warning signals per year of 9 per 100 patients are demonstrated. The authors conclude that when adopting the new elaborated criteria, the serum CEATPA-CA15.3 tumor marker panel is a highly accurate tool for early detection of metastatic disease. The authors are cautious and clearly state that the underlined limitations of the study recommend large prospective randomized trials to confirm the shown data. In spite of this, they consider the proposed tool a promising premise for postoperative monitoring based only on the use of the serum tumor marker panel every 3 months, physical examination every 6 months and radiological examinations carried out in patients suspected of relapse due to clinical symptoms and/or with the serum CEA-TPA-CA15.3 panel. Moreover, the authors state that a favorable cost/benefit ratio of this type of follow-up could be expected as serum tumor markers are easily repeatable, cheap and harmless. Doubtless this paper is an effort to bring, following two decades of deadlock, a breakthrough in the field. In fact, current guidelines recommend postoperative breast cancer monitoring based only on physical examination and annual mammography [2–4] , a policy that is the consequence of two randomized prospective trials published in the early 1990s which demonstrated no significant benefit
Biomark. Med. (2015) 9(4), 303–306
Andrea Nicolini Department of Oncology, University of Pisa, Via Roma 67, 56126 Pisa, Italy andrea.nicolini@ med.unipi.it
part of
ISSN 1752-0363
303
Foreword Nicolini from earlier detection of recurrences through intensive instrumental–biochemical postoperative monitoring [5,6] when compared with follow-up conducted only with history and physical examination. In both prospective and randomized trials only CEA, among serum tumor markers, was regularly measured and no criteria other than the cutoff provided by the used commercial kit were adopted. Since then, two principal axioms have prevailed among clinical oncologists: earlier treatment of metastatic disease does not significantly prolong the disease-free interval and/or overall survival; any biochemical and/or instrumental tool for postoperative monitoring of disease-free breast cancer patients is cost/benefit unfavorable.
“…when the expression of PTEN and KRAS, BRAF and PIK3CA were considered simultaneously, up to 70% of patients who were unlikely to respond to anti-EFGR therapies could be identified. In particular, the probability of response was high among patients with no alteration (defined as quadruple-negative subgroup).
”
Indeed the paper by Nicolini et al. challenge the caveats and reopens the discussion on criteria that should be adopted for an appropriate use of serum tumor markers in breast cancer postoperative monitoring. Biomarkers for prognosis The two review articles in this issue by Duffy [7] and Voudsadakis [8] respectively give an exhaustive updating on the current availability and reliability of prognostic biomarkers in colorectal cancer (CRC) while the research paper by Lippert proposes C-type natriuretic peptide (CNP) and CNP precursor (proCNP) as new potential prognostic markers in prostate cancer. The Duffy review article focuses on stage II CRC patients, a stage of disease that has long remained a gray zone as to whether these patients should or should not receive adjuvant treatment. In fact, while it is clearly established that stage I patients do not need and stage III patients do need this complementary therapy, data suggest that a very small subpopulation of stage II CRC patients, about 4%, could potentially benefit from adjuvant chemotherapy. Therefore, prognostic factors helpful to better identify those in this stage II of disease who should or should not be submitted to adjuvant treatment are mandatory. Microsatellite instability (MSI) has been discussed as a crucial investigation to solve this issue. It occurs when cells exhibit one or more alleles with different numbers of repeats and can be due to germline loss of function in the mismatch repair genes, thus having a genetic or sporadic origin. Some studies have demonstrated that MSI is associated with favorable outcome
304
Biomark. Med. (2015) 9(4)
in patients with CRC including those with stage II disease. Conversely other studies demonstrate no benefit from adjuvant 5-FU-based chemotherapy in patients with the same stage II disease and MSI. At present in stage II CRC patients, MSI drives the decision-making process regarding requirements for adjuvant chemotherapy. Although CEA is a more conventional marker, worse outcomes have been observed in CRC patients with high preoperative serum CEA levels. Therefore, this marker can provide further information to select high-risk stage II CRC patients. The review article by Voutsadakis [8] focuses on the pathogenic lesions of CRC and the regulation of pluripotency network. After having reminding the reader of the model proposed by Fearon and Vogelstein [9] of the two principal pathways leading to transformation of colonic epithelium, the article begins a long detailed discussion on activating mutations in different molecular pathways mainly β-catenin accounting for different molecular lesions in CRCs. These form part of important regulatory pathways of oncogenesis that are intertwined in the regulation of pluripotency networks. The influence of β-catenin activating mutations on pluripotency also depends on the specific cellular context and co-factors present as CBP, while pluripotency genes such as oct-4 and c-myc are among β-catenin/ CBP targets. Given the principal role that pluripotency factors play in the molecular lesions of CRC, results of some studies on their prognostic relevance are summarized. Patients with tumors with higher Sox2 staining by immunoistochemistry-developed metastases more frequently in the lymph nodes and liver. Similarly, in rectal cancer, higher mRNA levels of Oct4 and Sox2 in residual tumors after preoperative chemoradiotherapy were associated with higher rates of metastases. High LIN28B expression observed by immunohistochemistry in tumor tissue correlated with both decreased overall survival and recurrence-free survival in patients with stage I and II CRC. Conversely, patients with KLF4-positive tumors observed by immunohistochemical staining and those with c-myc overexpression had significant better survival. However, in another study the positive effect of increased c-myc mRNA levels on survival was lost in tumors with concomitant p53 mutations. These observations cause the author to state that a “multiple platform may provide a more robust prognostic tool” and that there is a need for “a combined evaluation of the global status of the pluripotency and carcinogenesis networks in order to assess the prognosis.” As an example, the Oncotype Dx test is mentioned. This test includes an evaluation of the mRNA of seven genes (and five control genes) to e stimate recurrence risk. Finally, in the research paper by Lippert et al. [10] , the prostate tissue gene expression of CNP and the
future science group
Biomarkers: a framework driving advances in oncology
CNP receptor (NPR-B) in more advanced prostate cancer were observed to be significantly reduced. In addition, when the seminal plasma concentrations of proCNP were compared with final histopathology and biochemical outcome in patients with clinically localized prostate cancer, a higher concentration of seminal proCNP occurred with more extensive tumor growth concomitant with an increased risk of recurrence. Based on these findings, the authors point out a potential role of proCNP in seminal plasma as a marker for staging and prognosis. Considering some limitations of the study underlined by the authors (andropause, inadequate material from some prostate biopsies) the potential use of CNP as a prognostic marker in prostate cancer warrants further studies and comparison with conventional serum prostate-specific antigen. Biomarkers predictive of response to treatment In the two articles by Duffy et al. [7] and Caiazza et al. [11] the predictive role of the Ras gene in targeting EGFR in metastatic CRC is discussed. Indeed, monoclonal antibodies (mAbs) specific for EGFR, particularly cetuximab and panitumumab, are currently among common targeted therapies and one example of the clear efforts to move toward personalized therapy. A great deal of scientific literature has centered on this issue and both authors provide useful updates. Based on the seminal finding that KRAS mutation status was highly predictive of resistance to anti-EGFR mAbs, it was initially stated that therapy using anti-EGFR mAbs should be recommended only for metastatic CRC patients with wild-type (wt) KRAS. However, successive studies uncovered the relevance of other genes of the same family as NRAS in addition to molecular alterations of the downstream activated pathway including BRAF. Once activated, RAS phosphorylates BRAF, which in turn activates a sequential cascade leading to MAPK-mediated regulation of transcription factors and modulation of gene expression. While mutation at exon 2 in KRAS was the first mutation found to be associated with lack of response to anti-EGFR antibodies, other mutations in this gene in addition to in the related NRAS gene were also found to predict resistance. Thus, from December 2013, the European Commission has amended the product information for cetuximab, updating the indication for the treatment of patients from wt-KRAS to the broader wt-RAS. Besides, as the absence of a BRAF mutation increases the chance of clinical benefit from cetuximab therapy, testing for BRAF mutations is becoming part of routine clinical management of metastatic CRC patients in some centers.
future science group
Foreword
In the article by Caiazza et al. data from a recent meta-analysis are also reported, concluding that there was an association between PIK3CA mutations and a decreased objective response to cetuximab in wt-KRAS patients. PI3K can be activated directly by RAS and somatic mutations in the PIK3CA gene are reported in 15–20% of CRCs. Moreover, the prevalence of PTEN inactivation in CRC is higher than that of PIK3CA mutations. Therefore, the overlapping pattern of expression of these molecular alterations supports the use of multiple biomarkers instead of studying each individually. For confirmation, the author mentions a retrospective analysis where, when the expression of PTEN and KRAS, BRAF and PIK3CA were considered simultaneously, up to 70% of patients who were unlikely to respond to anti-EFGR therapies could be identified. In particular, the probability of response was high among patients with no alteration (defined as quadruple-negative subgroup). Epiregulin (EREG) and amphiregulin (AREG), two ligands of the four members of the EGFR family, seem to be additional predictive biomarkers in metastatic CRC. In fact, tumors expressing high levels of EREG and AREG were observed to be more likely respond to cetuximab and, more recently, high mRNA levels of AREG were predictive of longer survival in patients with wt-KRAS but not in KRAS mutant tumors.
“These observations cause the author to state
that a ‘multiple platform may provide a more robust prognostic tool’ and that there is a need for ‘a combined evaluation of the global status of the pluripotency and carcinogenesis networks in order to assess the prognosis.
”
Another important predictive field of biomarkers is those that forecast the likelihood of toxicity. Two such markers are available for treatments used in CRC: dihydropyrimidine dehydrogenase for predicting toxicity from fluoropyrimidines and uridine diphosphate glucuronyltransferase 1A1*28 (UGT1A1*28) for predicting toxicity from irinotecan. Both tests are described in the article by Duffy et al. Esophageal cancer (EC) is characterized by high mortality rates and complete surgical removal is the only possible cure for resectable disease. Before surgery, an increasing number of patients receive neoadjuvant therapy, which thus far has been recognized as one of the curative modalities for this type of cancer. However, no accurate biological factor predicting responsiveness to chemotherapy is known. Therefore, defining a circulating predictive marker, which can be easily measured by objective methods is desirable and of particular importance. In the interesting research paper by Ilhan-Mutlu et al. [12] , pretreatment levels of coagula-
www.futuremedicine.com
305
Foreword Nicolini tory and immune response factors were assessed in 84 EC patients receiving neoadjuvant therapy and findings were correlated with tumor regression, clinicopathological parameters, prognosis and survival. Higher plasma fibrinogen and peripheral blood platelet count levels in addition to C-reactive protein in EC patients were significantly associated with better histological response to neoadjuvant treatment. Plasma fibrinogen levels remained as a significant independent factor influencing tumor regression. The authors comment that this might indicate that the evaluated parameters serve as markers for the immune system, which might
be activated during the neoadjuvant course and play a role for the good response.
References
6
Rosselli Del Turco M, Palli D, Cariddi A, Ciatto S, Pacini P, Distante V. Intensive diagnostic follow-up after treatment of primary breast cancer. A randomized trial. National Research Council Project on Breast Cancer follow-up. JAMA 271(20), 1593–1597 (1994).
7
Duffy MJ. Personalised treatment for patients with colorectal cancer: role of biomarkers. Biomarkers Med. 9(4), 337–347 (2015).
8
Voutsadakis IA. Pluripotency transcription factors in the pathogenesis of colorectal cancer and implication for prognosis. Biomarkers Med. 9(4), 349–361 (2015).
9
Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 61(5), 759–767 (1990).
10
Lippert S, Iversen P, Brasso K, Goetze JP. C-type natriuretic peptide and its precursor: potential markers in human prostate cancer. Biomarkers Med. 9(4), 319–326 (2015).
1
Nicolini A, Ferrari P, Fulceri F, Carpi A, Rossi G. An individual reference limit (IRL) for “early” diagnosis of metastatic breast cancer during post-operative follow-up. Biomarkers Med. 9(4), 307–317 (2015).
2
Bast RC Jr, Ravdin P, Hayes DF American Society of Clinical Oncology Tumor Markers Expert Panel. et al.; 2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology. J. Clin. Oncol. 19(6), 1865–1878 (2001); Erratum in: J. Clin. Oncol. 19(21), 4185–4188 (2001); J. Clin. Oncol. 20(8), 2213 (2002).
3
306
Smith TJ, Davidson NE, Schapira DV et al. American Society of Clinical Oncology 1998 update of recommended breast cancer surveillance guidelines. J. Clin. Oncol. 17(3), 1080–1082 (1999).
Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
4
Khatcheressian JL, Wolff AC, Smith TJ et al. American Society of Clinical Oncology. American Society of Clinical Oncology 2006 update of the breast cancer follow-up and management guidelines in the adjuvant setting. J. Clin. Oncol. 24(31), 5091–5097 (2006).
11
Caiazza F, Elliot L, Fennelly D, Sheahan K, Doherty GA, Ryan EJ. Targeting EGFR in metastatic colorectal cancer beyond the limitations of KRAS status: alternative biomarkers and therapeutic strategies. Biomarkers Med. 9(4), 363–375 (2015).
5
Ghezzi P, Magnanini S, Rinaldini M GIVIO Investigators. et al.; Impact of follow-up testing on survival and healthrelated quality of life in breast cancer patients. A multicenter randomized controlled trial. JAMA 271(20), 1587–1592 (1994).
12
Ilhan-Mutlu A, Starlinger P, Perkmann T, Schoppmann F, Preusser M, Birner P. Plasma fibrinogen and blood platelet counts are associated with response to neoadjuvant therapy in esophageal cancer. Biomarkers Med. 9(4), 327–335 (2015).
Biomark. Med. (2015) 9(4)
future science group
Biomarkers: a framework driving advances in oncology “…two principal axioms have prevailed among clinical oncologists: earlier treatment of metastatic disease does not significantly prolong DFI and/or overall survival; any biochemical and/or instrumental tool for postoperative monitoring of disease-free breast cancer patients is cost/benefit unfavorable.”
Keywords: biomarkers • cancer • diagnosis • prediction of response • prognosis
Nowadays, it is clear that cancer is a very complex disease. Basic research, mainly genetics and molecular biology, provides insights for better comprehension of the pathological mechanisms giving origin and sustaining tumor growth; these advances move on and are continuously refined. On the other hand, diagnosis, prognosis and treatment are three main fields of clinical medicine that take advantage from progress in basic research. Increasingly, biomarkers are an example of this translational medicine and are the framework driving the progression in clinical practice, as is clear in this thematic issue devoted to ‘Biomarkers in gastrointestinal and endocrine-dependent tumors’. In the issue the reader will find all the three principal clinical application of biomarkers: diagnosis, prognosis and prediction of response to treatment, the latter enabling so-called ‘personalized medicine’ that is the gold standard of any specialty in medicine. Biomarkers for diagnosis The research paper entitled ‘Usefulness of an individual reference limit (IRL) for early diagnosis of metastatic breast cancer during post-operative follow-up’ [1] defines criteria to calculate the cutoff value and critical change in order to utilize the serum CEA-TPA-CA 15.3 tumor marker panel at the best for early detection of metastatic disease during postoperative monitoring of disease-free breast
10.2217/BMM.15.7 © 2015 Future Medicine Ltd
cancer patients. During a mean follow-up of 3.7 years, 93% sensitivity, 97.6% specificity and a rate of false warning signals per year of 9 per 100 patients are demonstrated. The authors conclude that when adopting the new elaborated criteria, the serum CEATPA-CA15.3 tumor marker panel is a highly accurate tool for early detection of metastatic disease. The authors are cautious and clearly state that the underlined limitations of the study recommend large prospective randomized trials to confirm the shown data. In spite of this, they consider the proposed tool a promising premise for postoperative monitoring based only on the use of the serum tumor marker panel every 3 months, physical examination every 6 months and radiological examinations carried out in patients suspected of relapse due to clinical symptoms and/or with the serum CEA-TPA-CA15.3 panel. Moreover, the authors state that a favorable cost/benefit ratio of this type of follow-up could be expected as serum tumor markers are easily repeatable, cheap and harmless. Doubtless this paper is an effort to bring, following two decades of deadlock, a breakthrough in the field. In fact, current guidelines recommend postoperative breast cancer monitoring based only on physical examination and annual mammography [2–4] , a policy that is the consequence of two randomized prospective trials published in the early 1990s which demonstrated no significant benefit
Biomark. Med. (2015) 9(4), 303–306
Andrea Nicolini Department of Oncology, University of Pisa, Via Roma 67, 56126 Pisa, Italy andrea.nicolini@ med.unipi.it
part of
ISSN 1752-0363
303
Foreword Nicolini from earlier detection of recurrences through intensive instrumental–biochemical postoperative monitoring [5,6] when compared with follow-up conducted only with history and physical examination. In both prospective and randomized trials only CEA, among serum tumor markers, was regularly measured and no criteria other than the cutoff provided by the used commercial kit were adopted. Since then, two principal axioms have prevailed among clinical oncologists: earlier treatment of metastatic disease does not significantly prolong the disease-free interval and/or overall survival; any biochemical and/or instrumental tool for postoperative monitoring of disease-free breast cancer patients is cost/benefit unfavorable.
“…when the expression of PTEN and KRAS, BRAF and PIK3CA were considered simultaneously, up to 70% of patients who were unlikely to respond to anti-EFGR therapies could be identified. In particular, the probability of response was high among patients with no alteration (defined as quadruple-negative subgroup).
”
Indeed the paper by Nicolini et al. challenge the caveats and reopens the discussion on criteria that should be adopted for an appropriate use of serum tumor markers in breast cancer postoperative monitoring. Biomarkers for prognosis The two review articles in this issue by Duffy [7] and Voudsadakis [8] respectively give an exhaustive updating on the current availability and reliability of prognostic biomarkers in colorectal cancer (CRC) while the research paper by Lippert proposes C-type natriuretic peptide (CNP) and CNP precursor (proCNP) as new potential prognostic markers in prostate cancer. The Duffy review article focuses on stage II CRC patients, a stage of disease that has long remained a gray zone as to whether these patients should or should not receive adjuvant treatment. In fact, while it is clearly established that stage I patients do not need and stage III patients do need this complementary therapy, data suggest that a very small subpopulation of stage II CRC patients, about 4%, could potentially benefit from adjuvant chemotherapy. Therefore, prognostic factors helpful to better identify those in this stage II of disease who should or should not be submitted to adjuvant treatment are mandatory. Microsatellite instability (MSI) has been discussed as a crucial investigation to solve this issue. It occurs when cells exhibit one or more alleles with different numbers of repeats and can be due to germline loss of function in the mismatch repair genes, thus having a genetic or sporadic origin. Some studies have demonstrated that MSI is associated with favorable outcome
304
Biomark. Med. (2015) 9(4)
in patients with CRC including those with stage II disease. Conversely other studies demonstrate no benefit from adjuvant 5-FU-based chemotherapy in patients with the same stage II disease and MSI. At present in stage II CRC patients, MSI drives the decision-making process regarding requirements for adjuvant chemotherapy. Although CEA is a more conventional marker, worse outcomes have been observed in CRC patients with high preoperative serum CEA levels. Therefore, this marker can provide further information to select high-risk stage II CRC patients. The review article by Voutsadakis [8] focuses on the pathogenic lesions of CRC and the regulation of pluripotency network. After having reminding the reader of the model proposed by Fearon and Vogelstein [9] of the two principal pathways leading to transformation of colonic epithelium, the article begins a long detailed discussion on activating mutations in different molecular pathways mainly β-catenin accounting for different molecular lesions in CRCs. These form part of important regulatory pathways of oncogenesis that are intertwined in the regulation of pluripotency networks. The influence of β-catenin activating mutations on pluripotency also depends on the specific cellular context and co-factors present as CBP, while pluripotency genes such as oct-4 and c-myc are among β-catenin/ CBP targets. Given the principal role that pluripotency factors play in the molecular lesions of CRC, results of some studies on their prognostic relevance are summarized. Patients with tumors with higher Sox2 staining by immunoistochemistry-developed metastases more frequently in the lymph nodes and liver. Similarly, in rectal cancer, higher mRNA levels of Oct4 and Sox2 in residual tumors after preoperative chemoradiotherapy were associated with higher rates of metastases. High LIN28B expression observed by immunohistochemistry in tumor tissue correlated with both decreased overall survival and recurrence-free survival in patients with stage I and II CRC. Conversely, patients with KLF4-positive tumors observed by immunohistochemical staining and those with c-myc overexpression had significant better survival. However, in another study the positive effect of increased c-myc mRNA levels on survival was lost in tumors with concomitant p53 mutations. These observations cause the author to state that a “multiple platform may provide a more robust prognostic tool” and that there is a need for “a combined evaluation of the global status of the pluripotency and carcinogenesis networks in order to assess the prognosis.” As an example, the Oncotype Dx test is mentioned. This test includes an evaluation of the mRNA of seven genes (and five control genes) to e stimate recurrence risk. Finally, in the research paper by Lippert et al. [10] , the prostate tissue gene expression of CNP and the
future science group
Biomarkers: a framework driving advances in oncology
CNP receptor (NPR-B) in more advanced prostate cancer were observed to be significantly reduced. In addition, when the seminal plasma concentrations of proCNP were compared with final histopathology and biochemical outcome in patients with clinically localized prostate cancer, a higher concentration of seminal proCNP occurred with more extensive tumor growth concomitant with an increased risk of recurrence. Based on these findings, the authors point out a potential role of proCNP in seminal plasma as a marker for staging and prognosis. Considering some limitations of the study underlined by the authors (andropause, inadequate material from some prostate biopsies) the potential use of CNP as a prognostic marker in prostate cancer warrants further studies and comparison with conventional serum prostate-specific antigen. Biomarkers predictive of response to treatment In the two articles by Duffy et al. [7] and Caiazza et al. [11] the predictive role of the Ras gene in targeting EGFR in metastatic CRC is discussed. Indeed, monoclonal antibodies (mAbs) specific for EGFR, particularly cetuximab and panitumumab, are currently among common targeted therapies and one example of the clear efforts to move toward personalized therapy. A great deal of scientific literature has centered on this issue and both authors provide useful updates. Based on the seminal finding that KRAS mutation status was highly predictive of resistance to anti-EGFR mAbs, it was initially stated that therapy using anti-EGFR mAbs should be recommended only for metastatic CRC patients with wild-type (wt) KRAS. However, successive studies uncovered the relevance of other genes of the same family as NRAS in addition to molecular alterations of the downstream activated pathway including BRAF. Once activated, RAS phosphorylates BRAF, which in turn activates a sequential cascade leading to MAPK-mediated regulation of transcription factors and modulation of gene expression. While mutation at exon 2 in KRAS was the first mutation found to be associated with lack of response to anti-EGFR antibodies, other mutations in this gene in addition to in the related NRAS gene were also found to predict resistance. Thus, from December 2013, the European Commission has amended the product information for cetuximab, updating the indication for the treatment of patients from wt-KRAS to the broader wt-RAS. Besides, as the absence of a BRAF mutation increases the chance of clinical benefit from cetuximab therapy, testing for BRAF mutations is becoming part of routine clinical management of metastatic CRC patients in some centers.
future science group
Foreword
In the article by Caiazza et al. data from a recent meta-analysis are also reported, concluding that there was an association between PIK3CA mutations and a decreased objective response to cetuximab in wt-KRAS patients. PI3K can be activated directly by RAS and somatic mutations in the PIK3CA gene are reported in 15–20% of CRCs. Moreover, the prevalence of PTEN inactivation in CRC is higher than that of PIK3CA mutations. Therefore, the overlapping pattern of expression of these molecular alterations supports the use of multiple biomarkers instead of studying each individually. For confirmation, the author mentions a retrospective analysis where, when the expression of PTEN and KRAS, BRAF and PIK3CA were considered simultaneously, up to 70% of patients who were unlikely to respond to anti-EFGR therapies could be identified. In particular, the probability of response was high among patients with no alteration (defined as quadruple-negative subgroup). Epiregulin (EREG) and amphiregulin (AREG), two ligands of the four members of the EGFR family, seem to be additional predictive biomarkers in metastatic CRC. In fact, tumors expressing high levels of EREG and AREG were observed to be more likely respond to cetuximab and, more recently, high mRNA levels of AREG were predictive of longer survival in patients with wt-KRAS but not in KRAS mutant tumors.
“These observations cause the author to state
that a ‘multiple platform may provide a more robust prognostic tool’ and that there is a need for ‘a combined evaluation of the global status of the pluripotency and carcinogenesis networks in order to assess the prognosis.
”
Another important predictive field of biomarkers is those that forecast the likelihood of toxicity. Two such markers are available for treatments used in CRC: dihydropyrimidine dehydrogenase for predicting toxicity from fluoropyrimidines and uridine diphosphate glucuronyltransferase 1A1*28 (UGT1A1*28) for predicting toxicity from irinotecan. Both tests are described in the article by Duffy et al. Esophageal cancer (EC) is characterized by high mortality rates and complete surgical removal is the only possible cure for resectable disease. Before surgery, an increasing number of patients receive neoadjuvant therapy, which thus far has been recognized as one of the curative modalities for this type of cancer. However, no accurate biological factor predicting responsiveness to chemotherapy is known. Therefore, defining a circulating predictive marker, which can be easily measured by objective methods is desirable and of particular importance. In the interesting research paper by Ilhan-Mutlu et al. [12] , pretreatment levels of coagula-
www.futuremedicine.com
305
Foreword Nicolini tory and immune response factors were assessed in 84 EC patients receiving neoadjuvant therapy and findings were correlated with tumor regression, clinicopathological parameters, prognosis and survival. Higher plasma fibrinogen and peripheral blood platelet count levels in addition to C-reactive protein in EC patients were significantly associated with better histological response to neoadjuvant treatment. Plasma fibrinogen levels remained as a significant independent factor influencing tumor regression. The authors comment that this might indicate that the evaluated parameters serve as markers for the immune system, which might
be activated during the neoadjuvant course and play a role for the good response.
References
6
Rosselli Del Turco M, Palli D, Cariddi A, Ciatto S, Pacini P, Distante V. Intensive diagnostic follow-up after treatment of primary breast cancer. A randomized trial. National Research Council Project on Breast Cancer follow-up. JAMA 271(20), 1593–1597 (1994).
7
Duffy MJ. Personalised treatment for patients with colorectal cancer: role of biomarkers. Biomarkers Med. 9(4), 337–347 (2015).
8
Voutsadakis IA. Pluripotency transcription factors in the pathogenesis of colorectal cancer and implication for prognosis. Biomarkers Med. 9(4), 349–361 (2015).
9
Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 61(5), 759–767 (1990).
10
Lippert S, Iversen P, Brasso K, Goetze JP. C-type natriuretic peptide and its precursor: potential markers in human prostate cancer. Biomarkers Med. 9(4), 319–326 (2015).
1
Nicolini A, Ferrari P, Fulceri F, Carpi A, Rossi G. An individual reference limit (IRL) for “early” diagnosis of metastatic breast cancer during post-operative follow-up. Biomarkers Med. 9(4), 307–317 (2015).
2
Bast RC Jr, Ravdin P, Hayes DF American Society of Clinical Oncology Tumor Markers Expert Panel. et al.; 2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology. J. Clin. Oncol. 19(6), 1865–1878 (2001); Erratum in: J. Clin. Oncol. 19(21), 4185–4188 (2001); J. Clin. Oncol. 20(8), 2213 (2002).
3
306
Smith TJ, Davidson NE, Schapira DV et al. American Society of Clinical Oncology 1998 update of recommended breast cancer surveillance guidelines. J. Clin. Oncol. 17(3), 1080–1082 (1999).
Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
4
Khatcheressian JL, Wolff AC, Smith TJ et al. American Society of Clinical Oncology. American Society of Clinical Oncology 2006 update of the breast cancer follow-up and management guidelines in the adjuvant setting. J. Clin. Oncol. 24(31), 5091–5097 (2006).
11
Caiazza F, Elliot L, Fennelly D, Sheahan K, Doherty GA, Ryan EJ. Targeting EGFR in metastatic colorectal cancer beyond the limitations of KRAS status: alternative biomarkers and therapeutic strategies. Biomarkers Med. 9(4), 363–375 (2015).
5
Ghezzi P, Magnanini S, Rinaldini M GIVIO Investigators. et al.; Impact of follow-up testing on survival and healthrelated quality of life in breast cancer patients. A multicenter randomized controlled trial. JAMA 271(20), 1587–1592 (1994).
12
Ilhan-Mutlu A, Starlinger P, Perkmann T, Schoppmann F, Preusser M, Birner P. Plasma fibrinogen and blood platelet counts are associated with response to neoadjuvant therapy in esophageal cancer. Biomarkers Med. 9(4), 327–335 (2015).
Biomark. Med. (2015) 9(4)
future science group
