More than 1.2 million new cases of colorectal cancer (CRC) occur globally each year, resulting in about 600,000 deaths. CRC remains the third most commonly diagnosed cancer in both men and women in the United States; estimated new cases in 2015 will reach 132,700.
Unfortunately, the majority of CRC cases continue to elude early detection. About 50% of CRC patients are diagnosed at advanced tumor stages. Such patients have poor prognoses. Earlier diagnoses, and better prognoses, may be attained by means of early screening for CRC. Implementing such screening has become one of the greatest public health challenges over the last 50 years.
A means of reliably predicting gene expression profiles (GEPs) for those who will develop CRC has proven hard to develop. And questions about the ultimate clinical utility of predictive tests for Stage II patients who require chemotherapy remain, even as companies continue to introduce new tests.
Historically, CRCs have been considered a single disease entity that shares the same cause, clinical characteristics, and treatment outcomes. But analysis of precursor lesions and hereditary forms of the disease has revealed CRC to be a complex and heterogeneous disorder that occurs relatively rarely in a hereditary form. The disease more commonly occurs sporadically.
Colorectal tumors arise through a gradual series of histological changes, the so-called adenoma-carcinoma sequence, with each change accompanied by a genetic alteration in a specific oncogene or tumor suppressor gene. Mutations in the adenomatous polyposis coli (APC) gene are not only responsible for familial adenomatous polyposis (FAP), but also play a rate-limiting role in the majority of sporadic colorectal cancers.
FAP arises as a result of a germline mutation on chromosome 5q21. Individuals who inherit a mutant APC gene have a high likelihood of developing colonic adenomas. The risk is estimated to be more than 90%. Characterized by hundreds of adenomatous colorectal polyps, the disease inevitably progresses to colorectal cancer, and it occurs in patients aged 35 to 40, on average.
About 75% of patients with CRC have sporadic disease with no apparent evidence of having inherited the disorder; the remaining 25% of patients have a family history of CRC that suggests a hereditary contribution, common exposures to carcinogens among family members, or a combination of both.
To date at least three distinct molecular pathways to CRC have been described: the conventional suppressor pathway characterized by mutations in APC and exemplified by FAP; the serrated pathway characterized by aberrant cytosine-guanosine island methylation; and the hereditary microsatellite instability pathway found in Lynch syndrome, with different genes being mutated or altered in carcinomas arising via the same genetic pathway.
Gene Expression Profiles
About 20% of patients with Stage II CRC experience a relapse after surgery. Current clinical-pathologic stratification factors do not allow clear identification of these high-risk patients. Over a dozen different GEP tests have been developed for use as prognostic markers in Stage II colon cancer. These assays are intended to help identify patients with Stage II colon cancer who are at high risk for recurrent disease and are candidates for adjuvant chemotherapy.
To date, no gene expression test for evaluation of prognosis in Stage II colon cancer has been cleared for marketing by the FDA. These tests are offered as laboratory-developed assays in clinical laboratory improvement amendment (CLIA)-licensed laboratories operated by each company and currently do not require FDA premarket review as a result of enforcement discretion.
Several tests have undergone evaluation and continue to be evaluated in multiple validation studies, including ColonPRS® and Signal ColonPRS® (Signal Genetics), Coloprint® (Agendia), Genefx Colon® (Precision Therapeutics), OncoDefender™-CRC (Everist Genomics), and Oncotype DX® colon cancer test (Genomic Health).
Independent validation studies ranging in size from 33 to 1,436 patients have been reported on some of these assays. Depending on the manufacturing process, GEPs may be marketed as either in vitro devices or laboratory-developed tests (LDTs). In the latter case, GEPs are used solely within a particular lab and are not distributed or sold to any other labs or healthcare facilities. As a result, GEPs marketed as LDTs may enter the U.S. market with analytical validation under laboratory regulations imposed by CLIA but without evidence of clinical validity or utility.
Two examples of CLIA LDTs are Oncotype Dx, a 12-gene RT-PCR assay, and Coloprint, an 18-gene microarray. Both tests are intended to predict the development of distant metastasis of patients with Stage II colon cancer and facilitate the identification of patients who may be safely managed without chemotherapy.
Oncotype Dx was developed by evaluating 761 colon cancer-related genes in 1,851 patients with resected colon cancer in four large development studies. These development studies led to the definition of the test’s 12-gene panel (which includes 7 cancer-related genes and 5 reference genes) as well as the Recurrence Score® (RS) algorithm. The test, which was prospectively validated in the QUASAR validation study, generates a score that predicts the risk of recurrence for individuals with Stage II or Stage III colon cancer.
Investigators at the Mayo Clinic and other institutions prospectively evaluated the impact of RS results on physician recommendations regarding the use of adjuvant chemotherapy in T3 stage (according to the tumor, node, and metastasis [TNM] system), mismatch repair-proficient (MMR-P) Stage II colon cancer patients. For each patient, the investigators compared the physician’s recommended postoperative treatment plan of observation, fluoropyrimidine monotherapy, or combination therapy with oxaliplatin before and after the RS.
Of 141 T3 MMR-P patients eligible for the primary analysis, treatment recommendations changed for 63 (45%; 95% confidence interval: 36–53%), with intensity decreasing for 47 patients (33%) and increasing for 16 (11%). Recommendations for chemotherapy decreased from 73 patients (52%) to 42 (30%).