腸癌標靶治療訣竅 多點基因檢測延存活2015-04-27 16:50:15醫師歐偉仁強調，過去研究顯示大腸直腸癌患者當中有家族病史的不超過兩成，主要成因還是年齡與飲食生活習慣所致，早期發現、早期治療，乃是良策。近來傳出多位名人罹患直腸癌的消息，大腸癌的高發生率，必須受到更多的重視。新店耕莘醫院血液腫瘤科主任歐偉仁表示，大腸癌症狀多元，除常見的消化不良、腹瀉、便祕之外，也常有大便帶血、大便解不乾淨、貧血、體重減輕等症狀。早期大腸癌以手術切除為主，再依病情決定術後是否需要輔助性治療，早期大腸癌五年存活率約60~80%；而轉移性大腸癌通常無法單純以手術根除，必須配合全身性化學治療為主，五年存活率下降到10%左右，因此必須及早發現以避免惡化。 歐偉仁說，一旦大腸癌的癌細胞轉移至其他器官時，治療大多會搭配標靶藥物，而選擇會影響到病患的存活時間。標靶治療屬於個人化醫療的一環，主要針對癌細胞的生長接受器，阻斷訊號傳遞，抑制癌細胞生長轉移；化學治療則是針對細胞分裂過程中的基因複製進行阻斷干擾，使正常細胞與癌細胞死亡，這是兩者最主要的不同。目前國內轉移性大腸癌的標靶藥物已有健保給付，歐偉仁醫師表示，以患者的基因檢測結果來選擇標靶藥物，是較佳的治療方式。 2014年8月國際著名期刊刺胳針（Lancet Oncology）所發表的研究指出，轉移性大腸癌病患若基因檢測確定為野生型，則第一線治療使用特定標靶藥物，其中位存活期可達近 29 個月；若改採「多點基因檢測」，將檢測位置增加到六個常見位置，而都沒有發生突變的話，則病患在使用特定標靶治療的中位存活期可達到 33 個月左右，4個月的差距在臨床上還是有統計意義的。因此根據基因檢測結果來用藥的個人化醫療是大腸癌的治療趨勢。 歐偉仁強調，過去研究顯示大腸直腸癌患者當中有家族病史的不超過兩成，主要成因還是年齡與飲食生活習慣所致，早期發現、早期治療，乃是良策。大腸癌的危險因子包括年齡、動物性脂肪攝取過量、肥胖、缺乏運動、抽菸以及大腸直腸癌家族史等。政府近年來大力推動糞便篩檢，遇有異常之檢驗報告，切不可諱疾忌醫，白白耽誤診治良機。（陳奕均編，文章來源：健康醫療網）【中央網路報】
Cetuximab delivers better overall survival than bevacizumab in metastatic colorectal cancer 18 Aug 2014 by ecancer reporter Janet Fricker Patients with KRAS exon 2 wild type metastatic colorectal cancer achieve longer overall survival with FOLFIRI plus cetuximab than FOLFIRI plus bevacizumab, concluded the FIRE-3 trial published in Lancet Oncology. While cetuximab and bevacizumab have both been shown to improve outcomes in patients with metastatic colorectal cancer when added to chemotherapy regimens, their comparative effectiveness when partnered with first-line fluorouracil, folinic acid, and irinotecan (FOLFIRI) is unknown. In the open-label, randomised, phase 3 FIRE- 3 trial Professor Volker Heinemann, from the University of Munich, and colleagues set out to explore whether cetuximab or bevacizumab was a more effective partner for FOLFIRI in first-line treatment of metastatic colorectal cancer. Patients were initially recruited without regard to KRAS tumour mutation status. However, following reports that cetuximab was not active in patients with tumour KRAS exon 2 mutations (codon 12 or 13) enrolment was restricted to patients without KRAS exon 2 mutations (wild type). Between January 2007 and September 2012 752 patients from 116 centres in Germany and Austria were randomly assigned to a treatment group. For the 593 patients with KRAS exon 2 wild-type tumours 297 were assigned to FOLFIRI plus cetuximab and 295 to FOLFIRI plus bevacizumab. Results showed that 184 patients in the cetuximab group (62%) achieved an objective response compared with 171 in the bevacizumab group (58%) (OR 1·18, 95% CI 0·85–1·64; p=0·18). Furthermore median progression free survival was 10 months in the cetuximab group versus10·3 months in the bevacizumab group (HR 1·06, 95% CI 0·88–1·26; p=0·55); however, median overall survival was 28·7 months in the cetuximab group compared with 25·0 months in the bevacizumab group (HR 0·77, 95% CI 0·62–0·96; p=0·017). The most common grade 3 or worse adverse events in both treatment groups were haematotoxicity (affecting 25% of cetuximab patients versus 21% of bevacizumab patients), skin reactions (affecting 26% of cetuximab patients versus 2% of bevacizumab patients) and diarrhoea (affecting 11% of cetuximab patients versus 14% of bevacizumab patients).“Our data suggest that FOLFIRI plus cetuximab should be the chosen first-line treatment regimen for patients with RAS wild-type metastatic colorectal cancer,” wrote the authors.
Reference V Heinemann, L Fischer von Weikersthal, T Decker, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncology. Published online August 1, 2014.
Biomarkers for Screening and Follow-up for Cancer: Positives and Pitfalls The National Institute of Health (NIH) defines a biological marker (biomarker) as a biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process, or of a condition or disease. In addition to screening for disease, a biomarker may be used to evaluate how well the body responds to a treatment and can also be called a molecular marker or signature molecule. A biomarker can exist as related to DNA, RNA, micro-RNA, epigenetic changes, protein and even antibody expression. Biomarker discovery is increasing with the modern throughput of medical research in genomic and proteonomics. New biomarkers are building upon growing information at the same time that research tools are becoming cheaper and more efficient. Currently, biomarkers are routinely used to help guide treatment decisions in lung cancer, breast cancer, and colon cancer30 with simple testing of existing tumor samples. Though many biomarkers are interesting in their cell function as related to malignancy, biomarkers such as telomerase, transforming growth factors (TGFα and TGFβ) , epidermal growth factors (erbB2 and erbB3) and mucin (MUC1 and MUC2) have not shown clinical utility. Prostate specific antigen (PSA), carcinoembrionic antigen (CEA) and cancer antibody maker 125 (CA-125) have proven observational associations with malignancy but lack specificity. Moreover, a reduction in mortality has not been shown using these biomarkers. Fecal occult blood test (FOBT) is the only known protein biomarker shown to decrease cause-specific mortality in cancer screening Biomarkers have the potential to change treatment and diagnostic algorithms across a broad spectrum of patients. Risk stratification for screening might be augmented by finding biochemical signatures that recognize either a predisposition to disease alone or as a complement to existing tests. For example, particular HLA alleles in conjunction with certain human papillomaviruses can increase the risk of cervical cancer and could change the screening algorithm. Tissue biomarkers are at the forefront of discovery and investigations are ongoing regarding their prognostic value and the ability to accurately guide therapy.
Prognostic Colorectal Cancer Biomarkers Extensive CRC research over the last decade has suggested promising biomarkers. Although many biomarkers have been described, only a select few have provided prognostic data. This list includes markers such as epidermal growth factor receptor (EGFR), BRAF, tumor MSI-H expression (defects in DNA mismatch repair, MSI phenotype), 18q AI expression, p53 expression and KRAS mutation. Decisions regarding the modality and combination of treatments for CRC patients are made based on a variety of clinical factors in an effort to deliver patient-specific care proven to be efficacious without untoward adverse effects. This set of clinical factors has been revised and expanded as radiographic and laboratory techniques have improved. The physician today must decide eligibility for specific treatment based on an evolving set of diagnostic tests based on molecular profile of the patient's tumor. This profile is based on a number of mutations common to many patients which, when correlated with survival data, provide meaningful criteria for treatment decision making. Therapy targeting the epidermal growth factor receptor (EGFR) has been studied extensively for patients with metastatic CRC. In the largest experience, the addition of cetuximab to standard cytotoxic chemotherapy conferred a progression-free survival benefit but no benefit in overall survival. On further analysis, this benefit was only found in the Kirsten-RAS (KRAS) wild-type patients. This is because a mutation in the KRAS gene leads to constitutive activation of the EGFR signaling pathway, thereby abrogating any effects of upstream EGFR blockade. This finding has led to the selection of patients for EGFR blockade therapy based on KRAS status, with cetuximab only offered to those patients with no KRAS mutation in the primary tumor. In a similar fashion, a small percentage of primary CRC contains a mutation in the BRAF gene. The BRAF(V600E) mutation in CRC confers poor survival with standard chemotherapy regimens. Vemurafenib, a small molecule inhibitor of the mutant protein, was recently approved for use in patients with metastatic melanoma harboring the BRAF(V600E) mutation. Interestingly, CRC patients do not enjoy response rates similar to patients with BRAF(V600E) melanoma when given vemurafenib. The reason for this therapeutic failure was recently shown to be caused by compensatory increased signaling upstream at the level of the EGFR. By adding cetuximab for EGFR inhibition to a standard regimen of vemurafenib, a significant antitumor response was shown in vitro and in vivo40. While there are no reported results of this combination therapy in adult patients, the laboratory results are promising and may offer another option for late stage CRC patients with wild-type KRAS and the BRAF(V600E) mutation. While CRC may develop through a sequence of acquired mutations, another theory of carcinogenesis implies that microsatellite instability (MSI) may play a role. When mutations occur in mismatch repair (MMR) genes such as MSH2, MSH6 and MLH1 the tumor is referred to as mismatch repair deficient (dMMR). With the ability to repair single nucleotide polymorphisms lost, instability develops in microsatellites—sites in the genome normally comprised of dinucleotide repeats. Individual tumors can be assayed for the level of MSI and are described as MSI-High, MSI-Low, and microsatellite stable (MSS). MSI-H phenotype has been associated with improved clinical outcome (disease-free and overall survival). In addition, some published data supports the recommendation not to administer chemotherapy to Stage II patients with a MSI-H primary colon cancer. The overall predictive value of MSI-H phenotype is currently being tested in the Eastern Cooperative Oncology Group Trial 5202 (E5202) adjuvant CRC trial. This trial is specifically intended to identify patients with AJCC Stage II CRC most likely to respond to adjuvant systemic therapy. Other mutations can yield prognostic information. Tumor expression of 18q AI has been associated with decreased survival and is currently being studied in the E5202 trial35. A mutation in the tumor suppressor gene p53 has been associated with poor prognosis, including decreased disease free survival (DFS), recurrence free survival (RFS) and overall survival (OS). These validated criteria are changing the way patients are treated and also how the response to treatment is judged. Using modern molecular biology methods, findings from the laboratory are being translated to the clinic in an effort to focus therapy on patients who are most likely to benefit. As therapies become more sophisticated, the methods of patient selection must follow. In order to derive the most efficacious results from therapies with not insignificant side effects, these methods must be employed and others must be developed.
Putative Colorectal Cancer Stem Cell-Associated Biomarkers The methods of patient stratification based on tumor mutation status have resulted in significant advances for patients with CRC; however, in order to expand upon these advances new criteria must be developed to further stratify patients. The precise cell of origin of CRC remains unknown. Recently, compelling evidence has emerged in support of the cancer stem cell (CSC) hypothesis in several solid organ epithelial malignancies including CRC. The theory of the cancer stem cell was originally proposed by Cohnheim in 1875.This theory encompassed four principles: 1. A number of external or internal insults, such as radiation, injury, or carcinogens, may result in genetic damages in the stem cells; 2. Each damaged stem cell gives rise to a morphologically distinct type of tumor; 3. All the cells within a given tumor share the same profile at different stages of progression; 4. Different tumors from different stem cells have different genetic and biochemical profiles. Following this, the theory of clonal evolution was introduced by Nowell in 1976 stating, 1. A number of external or internal stem cell insults, such as radiation, injury,or carcinogens, may result in genetic damages in stem cells; 2. A genetically damaged stem cell gives rise to a morphological distinct type of tumor; 3. New cell clones constantly emerge from the same tumor; 4. Only the more aggressive ones with growth advantages progress, and from which, new clones emerge. Currently, both of which have been supported by several lines of evidence. The CSC hypothesis posits that CSC's are responsible for tumor initiation, metastases and resistance to treatment leading to disease relapse following surgery and/or chemoradiotherapy. The traditional, stochastic model of tumorigenesis suggests that all cells within a tumor are capable of tumor initiation and propagation. The CSC hypothesis proposes a hierarchical model, in which only a small fraction of cells (CSC) are capable of tumor propagation56. The CSC hypothesis therefore raises questions regarding current diagnostic and therapeutic modalities, suggesting that the CSC is a rational target for the development of more efficacious screening, early detection, prevention, treatment and surveillance modalities and interventions. Based on the tenets of the CSC hypothesis, identification, proper selection, characterization, testing, biological implications and validation of CRC derived CSC (CRCSC) are imperative for improving early detection, screening, risk stratification prognostication and individualized prediction of treatment response. Properties that define potential CSC's are: [1] self-renewal; [2] the capacity for differentiation (allowing for recapitulation of all cell types of the original tumor); [3] tumor initiating capacity; and, [4] asymmetric cell division via non-random chromosomal co-segregation. Investigators have used these properties and various membrane and cytoplasmic markers to isolate putative CRCSC: CD133, CD24, CD29, CD44, CD166 (ALCAM), EpCAM, Lgr5, ALDH1A1 and ALDH1B1. These markers represent all reported CRCSC. Despite the potential of CRCSC's to be utilized as clinically relevant biomarkers, little is known about the prognostic value of non-CD133 CRCSC markers. Notwithstanding, the CSC hypothesis may herald a paradigm shift in screening and early detection in CRC once the precise role of CRCSC markers is further established. Therefore, we hypothesize that CRCSC markers can be used as biomarkers to predict disease progression, and identify patients at risk for recurrence. Two fundamental issues regarding colorectal carcinogenesis remain unanswered. First, the level of differentiation in the initiating neoplastic cell has not been well described i.e. colonic stem cell vs. differentiated mature colonic mucosal epithelial cell. Second, since tumors are well known to be composed of a heterogeneous group of cells, the specific identity of tumor cells that lead to lymph-node involvement, and metastatic disease is not well characterized. Recently, attempts to address both of these issues pragmatically, which are critical to our understanding of tumor biology, have resulted in the description of cancer stem cells. While the stochastic model of tumorigenesis holds that every cell within the tumor population is capable of tumor initiation and propagation, the cancer stem cell model proposes that only a small fraction of cells possess the ability to initiate cancer growth and promote metastatic dissemination. We posit that only stem cells possess the potential for unlimited proliferation, multi-lineage differentiation, and colonization at new sites, and thus, represent the most likely precursor for invasive and metastatic CRC. Therefore, these cells require much further attention and introspection.
Reference: J Cancer 2013; 4(3):241-250
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