Precision medicine-based therapies in advanced colorectal cancer: The University of California San Diego Molecular Tumor Board experience

Abstract

Treatment for advanced colorectal cancer is often limited by complex molecular profiles, which promote resistance to systemic agents and targeted monotherapies. Recent studies suggest that a personalized, combinatorial approach of matching drugs to tumor alterations may be more effective. We implemented a precision medicine strategy by forming a Molecular Tumor Board (MTB), a multidisciplinary team of clinicians, scientists, bioinformaticians and geneticists. The MTB integrated molecular profiling information and patient characteristics to develop N-of-One treatments for 51 patients with advanced colorectal cancer. All patients had metastatic disease and 63% had received ≥ 3 prior therapy lines. Overall, 34/51 patients (67%) were matched to ≥ 1 drug recommended by the MTB based on individual tumor characteristics, whereas 17/51 (33%) patients received unmatched therapies. Patients who received matched therapy demonstrated significantly longer progression-free survival (hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.21-0.81; P = 0.01) and a trend towards higher clinical benefit rates (41% vs. 18%, P = 0.058) (all multivariate) compared to patients receiving unmatched therapy. The MTB facilitated personalized matching of drugs to tumor characteristics, which was associated with improved progression-free survival in patients with advanced colorectal cancer.

Trial registration: ClinicalTrials.gov NCT02478931.

Keywords: Molecular Tumor Board; N-of-One; colorectal cancer; combinatorial treatment; precision oncology; tumor alterations.

Fig. 1

Consort diagram of 87 colorectal cancer patients presented at face‐to‐face Molecular Tumor Board (MTB) [23]. *Excluded patients were most often those who presented to the MTB for assessment of future treatment strategies, but without need for immediate treatment.

Fig. 2

Frequency of characterized genomic alterations from tissue NGS and cfDNA of colorectal cancer. (A) Alterations identified by tissue NGS (N = 47). Alterations present in ≥ 4% of patients were included. (B) Alterations identified by cell‐free DNA (N = 30). Alterations present in ≥ 3% of patients were included. Colored bars show the percent of patients with the specific type of genomic alteration for each gene. Multiple aberrations indicates that some patients harbored multiple types of alterations (e.g. mutation, deletion, insertion) within the same gene.

Fig. 3

Progression‐free survival and overall survival in matched vs. unmatched patients. (A) Progression‐free survival (PFS) in patients who received matched vs. unmatched therapy (N = 51). Median PFS: whole cohort, 3.6 months (95% CI: 2.6–4.6); matched patients, 3.9 months (95% CI: 1.3–6.5); unmatched patients, 3.1 months (95% CI: 1.6–4.7). Hazard ratio (HR) calculated by univariate Cox regression. (B) Overall survival (OS) in patients who received matched vs. unmatched therapy (N = 51). Median OS: whole cohort, 11.5 months (95% CI: 6.5–16.5); matched patients, 9.3 months (95% CI: 3.9–14.7); unmatched patients, 13.1 months (95% CI: 0–27). Hazard ratio (HR) calculated by univariate Cox regression. Notably, of the 17 unmatched patients, 4 patients died upon progression of disease from initial treatment (i.e., date of progression equals the date of death). Of the remaining 13 unmatched patients, 8 (62%) received matched targeted therapy following progression (potentially confounding the OS).

Fig. 4

Clinical benefit rate (SD ≥ 6 months/PR/CR) in matched vs. unmatched patients. Clinical benefit rate (SD ≥ 6 months/PR/CR) in patients who received matched (13/32 (41%)) vs. unmatched (3/17 (18%)) therapy (N = 49*) (P = 0.058, multivariate analysis). *Two patients were not included in this analysis because they had ongoing stable disease that was < 6 months at last follow up and hence it was too early for evaluation of this parameter.