Improving Risk Assessment for Stage I Colorectal Cancer
Summary
Background
Colorectal cancer is the second leading cause of cancer-related death in the US. It affects men and women equally. Approximately one-third of patients diagnosed with colon cancer will die from the disease.
The majority of colon cancers develop through an orderly sequence of histopathologic stages. This begins with the normal colonic epithelium, which advances to an adenoma, and concludes with the development of an invasive carcinoma driven by the expansion of progressive genetic mutations. In patients without inherited genetic defects (sporadic cancer) this process evolves over 10 years.
Cancer prognosis is dependent on burden of disease (stage) at diagnosis. For instance, patients with stage I have the best prognosis versus those with stage IV having the worst. Patients with stage I colon cancer usually have 100% survival at one and two years from diagnosis, although some may relapse during surveillance, and the survival drops with continued follow up. Traditionally these patients do not receive adjuvant therapy (chemotherapy following curative surgery) since the prognosis is excellent. However, we have identified patients with sporadic stage I colon cancer who developed rapid recurrence following which, the prognosis was poor and all of them died due to metastatic disease.
Models to identify patients whose prognosis is poor despite an early anatomic stage exist. One such example in stage II colon cancer is a detailed pathologic assessment. For instance: lymph vascular invasion, peri-neural invasion, T4 disease, obstruction and perforation. The other example for good prognosis in stage II colon cancer is loss of mismatch repair gene(s), which is a good prognostic feature and a poor predictive feature for chemotherapy. Additionally for those with stage II disease and average risk, Oncotype Dx™ is a test based on gene expression, which is used to construct a “recurrence score”, which is used to further inform if chemotherapy may be of benefit. This test is prognostic, not predictive of response to therapy.
Statement of potential impact – Currently, there are no tests available to identify patients with stage I colon cancer who may have a tendency to recur after surgical resection. An assay to address this unmet medical need would help to save lives. Stage I colon cancer is a heterogeneous disease and there is mounting evidence indicating there is no one-size-fits-all answer for who may benefit from post-surgical treatment (ie, chemotherapy).
Aim 1 – Collection of Tissue Samples and Histopathologic Analysis
Tissue samples from six (6) patients with sporadic stage I colorectal cancer, who recurred quickly and died, have already been identified with detailed clinical data. We will review and possibly repeat aspects of the initial histopathologic analyses in preparation for advanced molecular profiling.
Aim 2 – Multi-modality Deep Sequencing via Advanced Next Generation Sequencing (NGS)
A variety of NGS modalities will be employed to examine tumor and normal tissue for the assessment of DNA mutational status, copy number variability, gene and transcript assessment via RNA-seq, and epigenetics via reduced representation bisulfite sequencing (RRBS). Advanced bioinformatics will be utilized by integrating data within and between samples for pattern identification.
Keywords:
- colon cancer
- risk assessment
- molecular profiling