Prognostic molecular markers in cancer – quo vadis?

Despite the tremendous number of studies of prognostic molecular markers in cancer, only a few such markers have entered clinical practise. The lack of clinical prognostic markers clearly reflects limitations in or an inappropriate approach to prognostic studies. This situation should be of great concern for the research community, clinicians and patients. In the present review, we evaluate immunohistochemical prognostic marker studies in oral squamous cell carcinomas (OSCC) from 2006 to 2012. We comment upon general issues such as study design, assay methods and statistical methods, applicable to prognostic marker studies irrespective of cancer type. The three most frequently studied markers in OSCC are reviewed. Our analysis revealed that most new molecular markers are reported only once. To draw conclusions of clinical relevance based on the few markers that appeared in more than one study was problematic due to between‐study heterogeneity. Currently, much valuable tissue material, time and money are wasted on irrelevant studies.     

Utility of cytologic specimens in the evaluation of prognostic and predictive factors of breast cancer: current issues and future directions

Although numerous biological and molecular markers of breast cancer have been identified over the past two decades, traditional factors such as estrogen receptor (ER), progesterone receptor (PR), and HER-2 remain among the most useful indicators of prognosis and therapeutic response to treatment. These markers can be reliably evaluated in cytologic specimens, particularly in fine-needle aspirates (FNA) of primary or metastatic breast cancer. Accurate assessment of ER, PR, and HER-2 is critical in the treatment of breast cancer patients. A review of the literature, however, shows considerable interlaboratory variability in the detection of these markers and reporting of the test results. Because therapies are now being directed toward individual molecular targets, there is a need for increased standardization of such analyses. Current practices should follow consensus recommendations set by the College of American Pathologists and the American Society for Clinical Oncology, and the results should be monitored through quality-assurance programs. The utility of cytologic specimens of breast lesions is also not limited to evaluation of individual prognostic and predictive factors. Cytologic specimens have been used successfully for genomic and proteomic studies. Such investigational studies are under way and offer great potential for revolutionizing the prediction of patient outcomes and disease response to therapy, as well as assessment of risk of developing breast cancer.     

Prognosefaktoren des Prostatakarzinoms

Since several therapeutic options are currently available for clinically organ-confined prostate cancer, morphological parameters have rapidly emerged as prognostic factors to stratify patients into different therapeutic modalities. In addition to the PSA value, pathologic stage, as defined by the TNM system, Gleason grade and the surgical margin status, other markers have prognostic implications. This includes the percent pattern 4/5 cancer, tumor volume, intraductal spread, large volume perineural invasion and molecular markers. This review discusses the methods of sampling and reporting in prostate pathology with an emphasis on well established and new prognostic factors.     

Immunohistochemical markers of prognosis in non-small cell lung cancer: a review and proposal for a multiphase approach to marker evaluation

Characteristics of the tumour that affect and predict the survival outcome of patients with cancer are prognostic markers for cancer. In non-small cell lung carcinoma (NSCLC), stage is the main determinant of prognosis and the basis for deciding options for treatment. Patients with early-stage tumour are treated by complete surgical resection, which is curative in 40-70% of patients. That there are other factors important in determining the biology of these tumours, especially genes that have a role in metastasis, is indicated. Such factors could potentially be used to further classify patients into groups according to substages that may be treated differently. During the past decade, a large number of proteins that are putatively important in carcinogenesis and cancer biology have been studied for their prognostic value in NSCLC, but none of them have been proved to be sufficiently useful in clinical diagnosis. Several markers (epidermal growth factor receptor, human epidermal growth factor receptor 2, Ki-67, p53 and Bcl-2) have been studied exhaustively. Ki-67, p53 and Bcl-2 are suggested to be important but weak prognostic markers, by meta-analyses of the results. Cyclin E, vascular endothelial growth factor A, p16(INK4A), p27(kip1) and beta-catenin are promising candidates, but require further study in large randomised clinical trial samples by using standardised assays and scoring systems. Some issues and inconsistencies in the reported studies to date are highlighted and discussed. A guideline for a multi-phase approach for conducting future studies on prognostic immunohistochemistry markers is proposed here.     

Detecting Common Gene Expression Patterns in Multiple Cancer Outcome Entities

Most oncological microarray studies focus on molecular distinctions in different cancer entities. Recently, researchers started using microarrays for investigating molecular commonalities of multiple cancer types. This poses novel bioinformatics challenges.In this paper we describe a method that detects common molecular mechanisms in different cancer entities. The method extends previously described concepts by introducing Meta-Analysis Pattern Matches. In an analysis of four prognostic cancer studies, involving breast cancer, leukemia, and mesothelioma, we are able to identify 42 genes that show consistent up- or down-regulation in patients with a poor disease outcome. These genes complement the set of previously published candidates for universal prognostic markers in cancer.     

Aldehyde dehydrogenase 1 expression in cancer cells could have prognostic value for patients with non‐small cell lung cancer who are treated with neoadjuvant therapy: Identification of prognostic microenvironmental factors after chemoradiation

Prognostic factors for patients with non‐small cell lung cancer (NSCLC) who have been treated with neoadjuvant therapy have not been fully assessed. The purpose of this study was to analyze prognostic biomarkers in NSCLC after treatment with neoadjuvant therapy, with special reference to the immunophenotypes of both the cancer cells and stromal cells. A total of 52 patients with NSCLC who were treated with neoadjuvant therapy followed by complete resection were included. We examined the expressions of nine markers in the cancer cells and stromal cells. The 5‐year disease‐free survival rate of patients with high aldehyde dehydrogenase 1 (ALDH1) expression levels in their cancer cells was significantly lower than those with a low ALDH1 level (47.3% vs. 21.5%, respectively; P = 0.023). The other molecules expressed in cancer cells did not exhibit any prognostic value. In NSCLC without neoadjuvant therapy (case control, n = 104), expression of ALDH1 in cancer cells was not correlated with prognosis (P = 0.507). A multivariate analysis identified ALDH1 expression in cancer cells as significantly independent prognostic factors for disease‐free survival (P = 0.045). The current study indicated that the immunophenotypes of ALDH1 in cancer cells could have prognostic value for patients with NSCLC who are treated with neoadjuvant therapy.     

Histopathological regression of gastric adenocarcinoma after neoadjuvant therapy: a critical review

As the perioperative chemotherapy has been widely implemented on the management of gastric cancer patients, heterogeneity of clinical outcomes has been evidenced in parallel to different histopathological regression pattern of gastric cancer cells. Tumor histological response to preoperative therapy has been graded by various systems in order to categorize the amount of regressive changes induced by chemotherapy in relation to residual tumor. In this context, tumor regression grading (TRG) systems might provide important prognostic information as the variety of tumor response may imply on different clinical outcomes with impact in survival rates. Moreover, gastric cancer behavior varies enormously upon individual factors such as histological classification and tumor anatomic site of involvement that have been shown to affect the TRG interpretation. On the other hand, some studies have assessed the role of molecular markers as a predictor of tumor response to neoadjuvant chemotherapy in terms of TRG. Thus, the aim of this review is to evaluate how TRG has been interpreted in gastric cancer, discuss their clinical and prognostic relevance and also address the molecular markers involved in this process.     

放射免疫分析肿瘤标记物监护125I粒子植入肿瘤治疗随访的研究

目的:为了监护放射性125I粒子TPS植入肿瘤的治疗后的肿瘤标志物的动态水平。方法:放射性125I粒子植入治疗了153例恶性肿瘤,其中48例乳腺癌,46例前列腺癌和59例肺癌,放射免疫分析了治疗后血清CA153、PSA和CYFRA21-1的动态水平。结果:在治疗后,153例恶性肿瘤的肿瘤标记物水平明显降低,在动态观察中,10例乳腺癌治疗后明显好转的,血清CA125明显降低,10例前列腺癌治疗后恶化的,血清PSA不断增加,10例肺癌治疗后死亡的,血清CYFRA21-1明显增加。结论:放射性125I粒子植入治疗肿瘤病人血清CA153、PSA、CYFRA21-1起着重要的作用,并是理想估计疗效的有效工具。     

PROGNOSTIC VALUE OF ANGIOGENESIS IN OPERABLE NON-SMALL CELL LUNG CANCER

Tumour angiogenesis is an important factor for tumour growth and metastasis. Although some recent reports suggest that microvessel counts in non-small cell lung cancer are related to a poor disease outcome, the results were not conclusive and were not compared with other molecular prognostic markers. In the present study, the vascular grade was assessed in 107 (T1,2–N0,1) operable non-small cell lung carcinomas, using the JC70 monoclonal antibody to CD31. Three vascular grades were defined with appraisal by eye and by Chalkley counting: high (Chalkley score 7–12), medium (5–6), and low (2–4). There was a significant correlation between eye appraisal and Chalkley counting ( P <0·0001). Vascular grade was not related to histology, grade, proliferation index (Ki67), or EGFR or p53 expression. Tumours from younger patients had a higher grade of angiogenesis ( P =0·05). Apart from the vascular grade, none of the other factors examined was statistically related to lymph node metastasis ( P <0·0001). A univariate analysis of survival showed that vascular grade was the most significant prognostic factor ( P =0·0004), followed by N-stage ( P =0·001). In a multivariate analysis, N-stage and vascular grade were not found to be independent prognostic factors, since they were strongly related to each other. Excluding N-stage, vascular grade was the only independent prognostic factor ( P =0·007). Kaplan–Meier survival curves showed a statistically significant worse prognosis for patients with high vascular grade, but no difference was observed between low and medium vascular grade. These data suggest that angiogenesis in operable non-small cell lung cancer is a major prognostic factor for survival and, among the parameters tested, is the only factor related to cancer cell migration to lymph nodes. The integration of vascular grading in clinical trials on adjuvant chemotherapy and/or radiotherapy could substantially contribute in defining groups of operable patients who might benefit from cytotoxic treatment.     

A model building exercise of mortality risk for Taiwanese women with breast cancer

Background  

The accurate estimation of outcome in patients with malignant disease is an essential component of the optimal treatment, decision-making and patient counseling processes. The prognosis and disease outcome of breast cancer patients can differ according to geographic and ethnic factors. To our knowledge, to date these factors have never been validated in a homogenous loco-regional patient population, with the aim of achieving accurate predictions of outcome for individual patients. To clarify this topic, we created a new comprehensive prognostic and predictive model for Taiwanese breast cancer patients based on a range of patient-related and various clinical and pathological-related variables.     

Prognostic and predictive molecular markers in DCIS: a review

Eighteen percent of all new breast cancers detected on screening mammography are ductal carcinoma in situ (DCIS), a preinvasive lesion that is highly curable. However, some women with DCIS will develop life-threatening invasive breast cancer. Because the determinants of invasive recurrence are unknown, all women with DCIS require the same treatment (usually with surgery and radiation). Therefore, there is a need to identify biologic markers and create a profile that will provide prognostic information that is more accurate than the currently used van Nuys Index to predict invasive recurrence. In the present review, we examined the many biologic markers studied in breast cancer, describe their main biologic role and their expression in DCIS, and review the various studies regarding their ability to serve as prognostic factors in breast cancer with an emphasis on predicting invasive recurrence in patients with DCIS. This review covers established markers, namely, ER, PR and HER2/neu, that are used routinely to make treatment decisions as well as investigative biologic factors involved in cell proliferation, cell cycle regulation, extracellular molecules, factors involved in extracellular matrix degradation, and angiogenesis. However, controversies exist regarding the value of these prognostic factors, their interrelationship, and their advantages over morphologic evaluation.     

Gene expression profiling in breast cancer: towards individualising patient management

Breast cancer is a complex and clinically heterogeneous disease. The increase in knowledge of breast cancer biology has led to a number of clinical advances in the treatment of breast cancer, most notably the implementation of widespread mammography screening and advances in adjuvant treatment of early-stage disease. In the last 20 years, arrays of potential prognostic and/or predictive markers of breast cancer have been analysed. However, relatively few have proven to be clinically useful. To date, the only widely accepted markers for routine use in breast cancer are the oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor, HER-2 (c-erbB2/neu). Expression microarray technology and laser capture microdissection have now been employed to further our understanding of the molecular pathogenesis of breast cancer. Recently reported advances in array technology and RNA amplification methods are having a considerable impact in this field, allowing the analysis of pre-malignant and pre-invasive lesions. A number of studies have identified prognostic and predictive gene 'signatures', whose prediction of disease outcome and response to treatment is superior to conventional prognostic indicators. Despite major technological advances, a number of confounding issues remain concerning the potential clinical utility of gene expression profiling, including differences in study design, patient selection, array technology, chemistry, and methods of analysis. It seems likely, however, that following careful 'hypothesis driven' validation studies and clinical trials, expression profiling will be applied in the future to identify patient-specific disease profiles and provide rationale for individualised treatment. This review focuses on the current use and future potential of microarray profiling in breast cancer.     

Comparative oncology of lung tumors

Toxicologic pathologists need to understand the comparative oncology of lung tumors because lung cancer is a common and serious cancer in the human population. Lung cancer in humans is known to be caused by cigarette smoke and a number of other carcinogens in the environment. Animal studies are needed to elucidate possible interactions with other potential carcinogens in environmental or occupational settings. In addition, knowledge of dose-response relationships and potential synergistic effects are needed to minimize harmful effects. Understanding the pathogenesis of common lung tumors will also aid in the prevention, diagnosis and treatment of the disease. Toxicologic pathologists need to remember several important points about lung tumors. The lung cancer response varies among species. Important factors in this variation are the nature of the administered carcinogen, the tissue dose of the carcinogen, the mode of exposure, the sensitivity of the test animal species and the similarity to the human response. Studies of molecular changes are important new tools to understanding lung carcinogenesis. For example, the molecular changes in lung tumors of mice and humans have a number of similarities that may be important in evaluating the significance of compound-induced lung tumors in mice.     

Prognosis in systemic lupus erythematosus

Conclusions In SLE, morbidity is universal and fatality is significant. One cannot learn too much about the prognostic markers for this disorder. The identification by means of renal biopsy of subclasses of lupus nephritis spurred the development of new treatment regimens that have improved outcomes. While proliferative nephritis remains a marker of serious renal involvement, the newer indices that attempt to quantify the activity and chronicity of the renal lesion, as well as greater awareness of the importance of tubulointerstitial involvement and improvement in the amount of subendothelial electron-dense deposits with therapy, will likely permit further fine-tuning of the treatment of individual patients with lupus nephritis.Neuropsychiatric involvement in SLE is another major determinant of financial costs, morbidity and death. Unfortunately, our knowledge of the prognostic markers for this more heterogeneous group of manifestations is less advanced than for lupus renal involvement. Additional studies are needed urgently to determine the factors that predict the subsequent development of the different forms of neuropsychiatric lupus. The determinants will likely differ among the various forms of neuropsychiatric lupus, thereby permitting different preventative or treatment regimens to be developed.The role of social factors, particularly socioeconomic status, has attracted attention in the United States. The lessons are likely applicable elsewhere. Additional studies to identify social factors that can be modified may bring tangible benefits to SLE patients in this decade.Although not universally accepted, it does appear that as more SLE patients survive the acute disease, there is an inordinately high risk of developing vascular diseases, including coronary artery disease, stroke and peripheral vascular disease. As with neuropsychiatric lupus, the determinants may differ depending on the specific vascular disease. Better knowledge of these determinants will permit a further improvement in the overall prognosis for patients with SLE.     

The reporting of prostate cancer on needle biopsy: prognostic and therapeutic implications and the utility of diagnostic markers

Prostate needle biopsy remains the gold standard for diagnosing prostate cancer. Prostate cancer on needle biopsy can be evaluated by numerous techniques of quantifying tumour extent, Gleason score, and the presence of perineural invasion (PNI). These modalities can help clinicians in assessing the risk of extraprostatic disease, progression likelihood, and in helping men with prostate cancer choose among therapeutic options. This review details the information that should be included in the routine pathology report. Recent advances in molecular biology of prostate carcinogenesis have identified many molecular markers for prostate cancer. While several are extremely promising as diagnostic immunohistochemical markers, other prognostic markers are not yet ready to be used in routine practice until they are validated by large prospective studies.     

Predictive and prognostic markers for invasive breast cancer

Breast cancer is one of the most serious carcinomas among women worldwide, yet there are now encouraging signs that improvements in the mortality rate may be possible. The use of hormone therapy and chemotherapy has been widely accepted as treatment for breast cancer. Predictive factors can be used to predict response or lack of response to a particular therapy, and prognostic factors can be useful in making decisions about which patients should receive adjuvant therapy. Histopathology remains the universal basis of diagnosis, with the identification of new surrogate markers for potential new treatments. These are aimed at blocking tumor cell proliferation, neutralizing growth factors, stimulating apoptosis and blocking metastasis, and represent an integral part of new approaches for improving clinical management of patients with breast cancer. We review the standard predictive and prognostic factors that are routinely available today, and also describe some of the new, potential markers that are currently under investigation.     

Vascular invasion is an adverse prognostic factor in resected non–small‐cell lung cancer

Lung cancer is a leading cause of death, and there is a need for better prognostic factors in treatment decisions. Vascular invasion is a known negative prognosticator, but it is not clear how to evaluate this feature. Here, we studied the prevalence and prognostic impact of blood and lymphatic vascular invasion (BVI, LVI), tumour grade, necrosis, inflammation and pleural invasion on cancer‐specific survival (LCSS) and time to recurrence (TTR) in non–small‐cell lung cancer (NSCLC). A total of 438 patients surgically treated for NSCLC (1993–2010) were examined, including 213 adenocarcinomas (AC), 135 squamous cell carcinomas (SCC) and 90 other NSCLC. BVI and LVI were found in 25% and 21% of the cases, with reduced LCSS and TTR for both markers in AC and SCC (p < 0.005 for all). BVI and LVI remained independent prognostic factors for LCSS and TTR in separate multivariate models for AC and SCC. Combined BVI/LVI (7%) showed significantly reduced LCSS and TTR (p < 0.001), also by multivariate analysis. Our results support that BVI and LVI are valuable for prognostic staging. Vascular invasion identifies a group of patients at higher risk of recurrence and lung cancer–related death, and this could influence stratification of patients for treatment and follow‐up.     

Applications of molecular diagnostics: solid tumor genetics can determine clinical treatment protocols.

Solid tumor diagnosis is now entering an era in which molecular genetics plays an important role. Clinical trials have shown different responses to various therapies that correlate with molecular alterations. Biological determinants related to treatment response markers aimed at individualized therapies are being defined and implemented. Patients are now being treated based on the profile of molecular genetic alterations in individual tumors. Protocols based on molecular markers will increase the chances for cure by opting for the right management approach. They also will improve, in most situations, the quality of life of patients with cancer, for example by facilitating organ preservation strategies. The molecular characterization therefore has an important prognostic and practical role in diagnosis.     

Modern classification of breast cancer: should we stick with morphology or convert to molecular profile characteristics

Breast cancer represents a heterogeneous group of tumors with varied morphologic and biological features, behavior, and response to therapy. The present routine clinical management of breast cancer relies on the availability of robust prognostic and predictive factors to support decision making. Breast cancer patients are stratified into risk groups based on a combination of classical time-dependent prognostic variables (staging) and biological prognostic and predictive variables. Staging variables include tumor size, lymph node stage, and extent of tumor spread. Classical biological variables include morphologic variables such as tumor grade and molecular markers such as hormone receptor and human epidermal growth factor receptor 2 status. Although individual molecular markers were introduced in the field of breast cancer management many years ago, the concept of molecular classification was raised after the introduction of global gene expression profiling and the identification of multigene classifiers. Although there is no doubt that gene expression profiling technology has revolutionized the field of breast cancer research and have been widely expected to improve breast cancer prognostication, the unprecedented speed of progress and publicity associated with the introduction of these commercially-based multigene classifiers should not lead us to expect this technology to replace the classical classification systems. These multigene classifiers have the potential to complement traditional methods through provision of additional biological prognostic and predictive information in presently indeterminate risk groups. Here we present updated information on the present clinical value of classical clinicopathologic factors, molecular taxonomy, and multigene classifiers in routine patients management and provide some critical views and practical expectations.     

The role of molecular biology in detection and monitoring of prostate cancer

The study of molecular markers in various types of human carcinomas, as well as in carcinoma of prostate, is focused on genes responsible for the formation of carcinoma. Mutation, amplification or other changes in these genes or in their protein products are being examined and compared with traditional prognostic markers. These genes can be characterized as oncogenes, tumor suppressor genes or genes for other significant cell functions. However, studies are often limited by heterogenity and multifocality of tumors, especially in prostate cancer. In this review, we offer a survey of some of the most frequent diagnostic and prognostic parameters of molecular biology research in relation to prostate cancer.