Table of Contents
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As is true of tissue specimens for most diseases, the vast majority of banked esophageal cancer samples for research are samples that were initially collected in the course of diagnosis and treatment for the indicated disease; the types of specimens, the manner of collection, and any pathological data associated them will have been guided by accepted standards of medical care and histological classification at the time the patient presented. The numeric and demographic incidence of a disease, its geographic distribution, and the pathological progression of the condition will all impact the timeframe and costs associated with procurement of research specimens. Biomedical studies that have been structured to account for these constraints will have the best chance of success. It may even be advisable to consult with biobank personnel while designing a study to help streamline the procurement process.
An alternative to using banked samples is prospective procurement, in which potential donors will be identified, informed consent gathered with IRB oversight, screenings conducted, medical histories may be taken, and specimens will then be gathered, processed and shipped in accordance with your study’s specific protocol.
Esophageal cancer (EsC) in the United States is a less common yet deadly form of cancer. The estimated number of individuals who would be diagnosed with it in 2015 was nearly 17,000, placing it as the 18th most common cancer in the US. The estimated number of deaths from esophageal cancer in 2015, however, was 15,590, and the present U.S. 5-year survival rate is just less than 18%, so most of those who will be diagnosed with it will face an extremely poor prognosis (National Cancer Institute, 2015). Part of the reason for this is that it is not usually diagnosed until it has already reached advanced stage, and esophageal cancer in advanced stage does not respond favorably to the treatment options that are available.
Regarding its global occurrence, esophageal cancer is presently the 8th most common cancer worldwide in terms of new diagnoses and resulted in 456,000 new cases in 2012, 81% of which were in less-industrialized nations (World Cancer Research Fund International, 2015).
Causes and Risk Factors
Causes and risk factors for esophageal cancer are varied and primary causes within the U.S. population include the following.
- Age – The median age of diagnosis in the U.S. is 67.
- Gender – Esophageal cancer develops in men more than four times as often as in women.
- Gastroesophageal reflux disease (GERD) – Individuals with GERD have a slightly increased risk of developing EsC. GERD can also cause Barrett’s esophagus which further increases the risk of developing EsC.
- Barrett’s esophagus – If stomach acid reflux goes on over a long period of time, the squamous cells that normally line the esophagus may end up being replaced with gland cells which are more resistant to stomach acid, and this condition is known as Barrett’s esophagus. While most individuals who have Barrett’s esophagus will not develop EsC, this condition does increase the risk of developing EsC by 50 to 100 times compared to the general population (American Cancer Society, 2015; Zhang, 2013).
- Tobacco and alcohol – These are the primary causes of the SCC type of EsC (see “Types” below).
- Obesity – Individuals who are obese have a higher risk of developing EsC, perhaps as much as three times higher or more (Zhang, 2013).
- Diet – Low intake of fruits and non-starchy vegetables with greater amounts of beta-carotene or vitamin C, high consumption of red meat, and frequent consumption of hot liquids (such as hot tea) have all been associated with a higher risk of the SCC type of EsC.
Globally, additional risk factors such as poor oral health, chewing betel, HPV (human papilloma virus), and low socioeconomic status have also been associated with higher incidence of esophageal carcinomas. (World Cancer Research Fund International, 2015; Zhang, 2013).
There are two primary histological types accounting for more than 90% of esophageal cancers: squamous cell carcinoma (SCC) and adenocarcinoma. Whereas SCC is the primary type of EsC worldwide and formerly accounted for the greater number of esophageal cancers in the US, adenocarcinoma has increased in incidence dramatically across demographic groups in the U.S. and other Western countries since the 1970’s (Lagergren, and Lagergren, 2013), especially among white patients. As of 2008, more than 60% of all esophageal cancers in the US are adenocarcinomas (Umar and Fleischer, 2008), although there is variation of relative incidence by race. Lymphomas, melanomas, and sarcomas of the esophagus are very rarely diagnosed, thus specimens of these conditions will be extremely difficult to locate.
Esophageal Squamous Cell Carcinoma (ESCC)
Esophageal squamous cell carcinoma (ESCC) arises in the squamous cells that line the esophagus. This type of EsC is more common in African American men in the United States than it is in white men. It is also associated with poverty worldwide as lower socioeconomic status correlates with an increased risk of SCC (Melhado, et al. 2010). As mentioned above, tobacco and alcohol use are the primary risk factors for developing this type of esophageal cancer.
Esophageal Adenocarcinoma (EAC)
Esophageal adenocarcinomas often arise from gland cells. As gland cells are not typically part of the inner lining of the esophagus, adenocarcinomas will only develop once gland cells have replaced some of the squamous cells lining the esophagus, as happens with Barrett’s esophagus. Adenocarcinomas typically occur in the distal part of the esophagus and in the gastroesophageal junction (which includes the stomach cardia) (American Cancer Society, 2015; Zhang, 2013). They are also much more common in white men than in black men in the U.S. (Umar and Fleischer, 2008).
Esophageal cancer samples are staged using the TNM classification system of the American Joint Committee on Cancer (AJCC) which includes the histologic grade (G) of the cancer as determined by the appearance of the cancer cells under microscope. T describes the extent of primary tumor growth into the wall of the esophagus and nearby organs plus the location of the tumor in the case of ESCC, N describes the degree to which nearby lymph nodes are involved, and M describes whether the cancer has metastasized. Esophageal cancers are graded from G1 (well differentiated appearance to cells) to G4 (undifferentiated cells). Once the TNM and G categories have been determined, the cancer will be further staged and sub-staged into stages I – IV with Stage IV being the most advanced, and metastatic.
The current TNM staging was adopted by the AJCC in 2010, and reflects much finer distinctions in staging, such as differentiating between ESCC and EAC, as well as identifying additional subclassifications and reclassifying or reassigning certain conditions (National Cancer Institute, 2016). See Rice, Blackstone, and Rusch (2010) for a succinct summary of staging details. Pathology reports for specimens gathered prior to 2010 will utilize the previous staging conventions. Contemporary researchers may choose to purchase additional histological examination services from the source biobank to update the stage data, if possible, or researchers may choose to conduct this examination themselves. Researchers who wish to use a separate staging system to describe samples may need to translate the required criteria to the clinical standard to facilitate procurement services.
Genetics of Esophageal Cancer
The genetic changes associated with esophageal cancers are still not well understood, although progress has been made within the last few years in identifying genetic mutations and amplifications, chromosomal gains and losses, and other genomic and proteomic aspects of esophageal cancer that contribute to the development of a more complete picture of esophageal cancer in its various forms and manifestations. Additionally, while there are some overlapping characteristics between the two primary types of EsC—squamous cell carcinoma and adenocarcinoma, the genetics and molecular developments of the two appear to be, for the most part, discrete.
Genetic screening of esophageal cancer samples will generally be dictated by established standard of care. The more recently that samples were collected, the more likely they are to have been tested for key markers. While diagnostic and treatment protocols increasingly rely on screening for genetic markers in recent years, the number of markers that are routinely tested for will be a very limited, clinically significant subset of the known markers associated with any condition. However, a well-equipped biobank with a CLIA-certified laboratory can be contracted to perform precision screening to meet your research demands, although this will incur fees for the service. Certainly, prospective collection services will be best able to meet any unique combination of criteria or specialized collection or preservation procedures, but will greatly affect the service costs.
Gene variants and mutations – ADH and ALDH2 gene variants have been associated with increased risk of ESCC (Zhang, 2013). A recent study newly identified several mutations in ESCCs and also confirmed some mutations that had already been identified. The eleven mutated genes found to have the highest frequencies in ESCC, according to their study, were TP53, TTN, MLL2, MUC16, SYNE1, FAT1, CSMD3, GPR98, LRP1B, PCLO, and XIRP2, all with roughly 10% or greater frequency. Recurrent focal somatic copy number variations (SCNVs) of the following genes were also found: CCND1, EGFR, MYC, KRAS, CDKN2A, and FGFR1 (Lin, et al. 2014). Additionally, inactivating mutations of NOTCH1—a potential tumor suppressor gene of the esophagus—have been identified in 21% of ESCCs and were found to be more frequent in North American than in Chinese ESCCs. The study also implicated NOTCH3, FBXW7, KIF16B, KIF21B, and MYCBP2 in ESCC (Agrawal, et al. 2012). Another study identified eight significantly mutated genes in ESCC, some of which had already been identified: TP53, RB1, PIK3CA, NOTCH1, NFE2L2, ADAM29, and FAM135B. The miRNA MIR548K was also found to enhance malignant phenotypes of ESCC. Additionally, the histone regulator genes MLL2 (KMT2D), ASH1L, MLL3 (KMT2C), SETD1B, CREBBP, and EP300 were found to be frequently altered in ESCC (Song, et al. 2014).
miRNA – miRNAs that have been found to be consistently upregulated in ESCC include miR-21, miR-25, miR-10b, and miR-151. Downregulated miRNAs in ESCC include miR-27b, miR-99a, miR-100, miR-125b, miR-133a, miR-133b, miR-143, miR-145, miR-203, miR-205, and miR-375 (Jian, et al. 2013).
While only a minority of individuals with Barrett’s esophagus (BE) will develop esophageal adenocarcinoma, BE remains the greatest (perhaps single) risk factor for developing EAC. Many researchers have, therefore, investigated the links and differences between the two. While several studies have shown that there is an accumulation of genetic abnormalities from Barrett’s esophagus to adenocarcinoma (Rygiel, et al. 2008; Jankowski, et al. 1999), other studies have found evidence that some mutations present in EACs were already present in benign precursor lesions associated with Barrett’s esophagus, suggesting that many of the genetic abnormalities of EACs do originate with BE (Levine, et al. 2013; Agrawal, et al. 2012). The following paragraphs provide some information on the genetics of EAC, some of which are linked to genetic developments in BE.
Gene variants and mutations – TP53 (p53) mutations have been identified in a high percentage of esophageal adenocarcinomas (e.g. 73%, Agrawal, et al. 2012). There also appears to be a general increase in the frequency of TP53 mutations from benign Barrett’s esophagus mucosa to lower to higher grade dysplasia to EAC (Jankowski, et al. 1999). The MET oncogene has been reported to be amplified in 2% – 10% of EACs and present in more advanced stage tumors (Forde and Kelly, 2013). Additionally, a study published in 2013 identified 26 significantly mutated genes in EAC, five of which—TP53, CDKN2A, SMAD4, ARID1A and PIK3CA—had already been identified in relation to EAC, but the rest—genes that include SPG20, TLR4, ELMO1 and DOCK2—were newly implicated in EAC (Dulak, et al. 2013). Other genes that may be involved in EAC have been found by identifying chromosomal loci that harbor genetic variants (see “Chromosomal aberrations” below).
Chromosomal aberrations – Loss of chromosome 18q has been reported in as much as 70% of esophageal adenocarcinomas. Two tumor suppressor genes are located in that region—DCC and SMAD4. Abnormalities there have also been found in a significant percentage of those with Barrett’s esophagus (Chang, et al. 2010). Amplifications (copy gains) of the loci 8q24 (c-myc), 20q13, and EGFR have been identified in 18%, 13%, and 11%, respectively, of EACs and high-grade dysplastic Barrett’s esophagus samples (Rygiel, et al. 2008). In a 2013 study, researchers looked at Barrett’s esophagus and esophageal adenocarcinoma as if they represented a single phenotype, and they identified three new loci harboring genetic variants associated with both Barrett’s esophagus and esophageal adenocarcinoma. These three loci were 1) 19p13, the most significantly associated, in the CRCT1 region that encodes CREB-regulated transcription coactivator; 2) 9q22 in the BARX1 region that encodes a transcription factor that is important in esophageal specification; and 3) 3p14 near the FOXP1 transcription factor which regulates esophageal development. The study also extended to the putative tumor suppressor gene FOXF1 at 16q24 which had previously been associated with Barrett’s esophagus, and they found that it was also associated with an increased risk of esophageal adenocarcinoma (Levine, et al. 2013). Other genetic abnormalities that have been implicated in EAC include loss of heterozygosity at VHL (chromosome 3p), APC (chromosome 5q), CDKN2 (chromosome 9p), and the retinoblastoma gene (Rb) (chromosome 13q) (Jankowski, et al. 1999).
miRNA – miRNAs that have been found to be consistently upregulated in EAC include miR-21, miR-192, and miR-194. Downregulated miRNAs in EAC include miR-27b, miR-99a, miR-100, miR-125b, miR-203, miR-205, and let-7c. It has also been reported that there appears to be a gradual increase or decrease in the expression of miR-21, miR-192, miR-203, miR-205, and let-7c from normal squamous epithelium to Barrett’s esophagus to esophageal adenocarcinoma (Jian, et al. 2013).
EAC & ESCC genetics – commonalities
While EAC and ESCC are in many respects two different types of cancer, there are at least two genetic aberrations exhibited in both of them. miR-21 has been found to be upregulated in both EAC and ESCC. It regulates quite a few genes involved in apoptosis, cellular survival, and cell invasiveness. Some of the genes that it regulates are the tumor-suppressor genes TPM1, PTEN, SERPINB5, and PDCD4 (Jian, et al. 2013). The most frequently mutated gene in both EAC and ESCC is TP53, which has been found mutated in as much as 73% of EACs and 92% of ESCCs (Agrawal, et al. 2012).
Diagnosis and Treatments
The following tests are available to determine if a patient has esophageal cancer and to detect how far it may have spread.
- CT scan
- PET scan
Biopsy – One or more of the following can be used to obtain tissue samples. Such samples will be preserved according to the demands of the intended diagnostic assay, and will be stored in accordance with legal requirements and industry best practices. Often, biopsies will include varying amounts of normal adjacent tissue (NAT).
- Endoscopic ultrasound (EUS) or endosonography
- Video endoscopy
- Bronchoscopy – for examination of the trachea and bronchi
- Laryngoscopy – for examination of the larynx
- Thoracoscopy – for biopsy of the lymph nodes inside the chest and abdomen
HER2 Testing: The physician may also have a tissue sample tested for excess amounts of the HER2 protein.
The treatments given to an individual esophageal cancer patient depend on the stage of their cancer as well as their overall health. A very useful summary of the most frequently performed treatments at each stage of ESC compiled by the NIH National Cancer Institute can be found at http://www.cancer.gov/types/esophageal/hp/esophageal-treatment-pdq#section/_44 (National Cancer Institute, 2016). Researchers are encouraged to consider these practices while structuring your study, e.g. which stages are most likely to be naïve for chemotherapy or radiation therapy at time of surgery.
For very early stage esophageal cancers, endoscopic treatments can be beneficial. Some of them improve a patient’s ability to swallow; endoscopic mucosal resection (EMR) is used to remove abnormal tissue; photodynamic therapy can destroy some of the cancer.
Stage 0, I, and II esophageal cancers, as well as most stage III ECs, are potentially resectable. The standard therapy for resectable cancers is neoadjuvant chemotherapy or chemoradiotherapy followed by surgery (Shridhar, et al. 2013; Purwar, et al. 2014). Cancers that have grown into critical structures such as the spine, trachea, or aorta, or that have spread to distant lymph nodes or other organs are unresectable. A primary therapy option for these cancers is concurrent chemoradiotherapy (Kato & Nakajima, 2013; American Cancer Society, 2015). Most esophageal carcinomas are diagnosed when the cancer is advanced and incurable (Jian, et al. 2013; Kyrgidis, et al. 2005).
Not many targeted therapies are available for esophageal cancer. For patients who overexpress the HER2 protein on their cancer cells, physicians may prescribe the drug trastuzumab (Herceptin®). HER2 is overexpressed in 12%-14% of esophageal adenocarcinomas (rarely in ESCCs) (Forde & Kelly, 2013). A drug called Ramucirumab can be used to treat cancers that begin in the gastroesophageal junction. Ramucirumab is a monoclonal antibody that inhibits VEGF from signaling the formation of new blood vessels; thus it can slow or stop the growth and spread of cancer (American Cancer Society, 2015).
Trends in Standard Care Looking Forward
It is hoped that research will lead to new therapies and diagnostic and prognostic tools for esophageal cancer. EGFR (epidermal growth factor receptor), c-MET (mesenchymal-epithelial transition factor), VEGF (vascular endothelial growth factor), AXL (a receptor tyrosine kinase that has been implicated in esophageal adenocarcinoma), and aurora kinase A (AURKA, found to be amplified and/or overexpressed frequently in EAC) have all been identified as potential therapeutic targets for esophageal cancer. In particular, bevacizumab—which targets VEGF—has had positive effects on esophageal cancer patients in phase III clinical trials (Belkhiri & El-Rifai, 2015), indicating that it may not be long before it becomes an approved therapy for esophageal cancer.
Additionally, sentinel lymph node biopsies are routinely used in breast cancers and malignant melanomas, and some researchers advocate that it become standard of care in esophageal cancer (Thompson, Bartholomeusz, & Jamieson, 2011).
Considerations for Researchers using Esophageal Cancer Samples
For banked specimens, it is always important to note the differences in purpose for specimen collection between treatment needs and research aims. For example, while the ideal research design would incorporate a closely matched, normal sample to use as a control, there is generally no clinical compunction to resect healthy functioning tissue from a patient under medical care. Histologically normal tissue are therefore most likely to be sourced as normal adjacent (NAT) or postmortem samples. Where research design demands strictly defined procedures and specimen criteria, a prospective collection process may be the solution.
Clinically-collected tissues must be retained for mandatory retention period – often 10 years – after which they may legally be utilized for research purposes, under the supervision of designated institutional review boards (IRB) and after having been fully de-identified by appropriately credentialed third-party intermediaries. The U.S. Code of Federal Regulations governing protection of human subjects, including the collection, storage, use and disposal of human tissue specimens, are embodied in Title 45 CFR 46, available for review online at http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html. Given the retention timeframes involved, banked archival specimens will reflect the statistical distribution of the indication roughly a decade ago. In the case of ESC, the changing relative incidences of EAC vs ESCC and the lower prevalence in more developed regions should be taken into consideration.
As esophageal cancer is not a particularly common cancer in the United States and historically was not usually detected until it is in advanced stage, and early stage esophageal cancer samples were hard to come by. Increased frequency of endosopic examinations for GERD cases is leading to improved early detection and availability of biopsies but early stage or pre-cancerous cases are generally not resected. In general, advanced stage esophageal cancer samples should be easier to obtain. Any pathological reports that are associated with the specimen will most likely reflect past conventions in staging and classification, thus it is recommended that researchers gain some familiarity with prior staging systems, or consider re-staging by a qualified pathologist.
For esophageal cancer samples collected prospectively, plan ahead as collection times can exceed several months or even years depending on your inclusion and exclusion criteria. Biomarker information is initially only available if it was collected as part of standard care at the time of treatment. Data mining fees may apply.
Lab-Ally and its partners have the capability to perform molecular characterization of specimens, but this can be extremely expensive, as a client would need to pay for the examination of all samples tested, including those that do not match the specified criteria. A better alternative may be to purchase sections only for a statistically suitable number of cases, screen them in your own lab using your preferred assay or a third-party, high volume genetic screening service, then request the blocks of interest.
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