Genetics of rectal cancer and novel therapies: primer for radiologists

Abstract

Rectal cancer accounts for one-third of newly diagnosed colorectal cancer cases. Given its anatomical location and risk for local recurrence, a multidisciplinary treatment program including surgery, radiation therapy, and chemotherapy has demonstrated improved outcomes in localized disease. Genetic analysis has become part of the standard approach for management of advanced disease and new trials are considering tailored therapies for locally advanced disease. This review describes molecular subsets of colorectal cancer; implications for clinical management, including patterns of metastatic spread and response to therapies; and emerging matched therapies. During the last decade, significant biological differences have been noted based on colorectal cancer primary location and here we focus on rectal cancers and relevant markers for this disease. As more treatment for localized rectal cancer is shifted to the neoadjuvant setting and more targeted regimens are developed for metastatic disease, radiologists will increasingly see patients defined by molecular subsets and their awareness of the genetics of rectal cancer will help further refine our understanding of this disease.

Keywords: Genomics; Next-generation sequencing; Rectal cancer; Targeted therapy.

Figure 1.. Genomic instability pathways in colorectal cancer.

Abbreviation: CIN, chromosomal instability; MSI, microsatellite instability; CIMP, CpG island methylator phenotype; LOH, loss of heterozygosity; MMR, mismatch repair; GA, genomic alteration.

Figure 2.. Serial rectal MRIs during total neoadjuvant therapy for locally advanced KRAS G12D rectal cancer.

(Left) Baseline axial T2-weighted image shows large circumferential tumor with surrounding lymph nodes. (Center) Post-induction chemotherapy axial T2-weighted image shows moderate response with decreased tumor size but persistent tumor extending through mesorectum to contact the right seminal vesicle (arrow). (Right) Post-chemoradiotherapy axial T2-weighted image shows new edema of the rectal wall (long arrow) with little to no decrease in tumor in prior location (arrow).

Figure 3.. Sankey diagram describing relative flow of first site of metastasis from colorectal cancer according to different primary tumor location.

Abbreviation: Gyn, ovaries, fallopian tubes, uterus, cervix, and vagina; PAO, peritoneum, abdominal wall or omentum. Asterisk indicates a statistically significant difference (P<0.05).

Figure 4.. CT imaging from a patient with resected MSI-H sigmoid colon cancer with a local recurrence.

(Left) Axial contrast enhanced CT scan at level of anastomosis revealing circumferential recurrent tumor (arrow). (Right) Axial contrast enhanced CT scan at level of anastomosis post Pembrolizumab treatment for 10 weeks showing complete normalization of anastomosis.