Molecular profiling of 6,892 colorectal cancer samples suggests different possible treatment options specific to metastatic sites

Abstract

Metastatic colorectal cancer (mCRC) carries a poor prognosis with an overall 5-year survival of 13.1%. Therapies guided by tumor profiling have suggested benefit in advanced cancer. We used a multiplatform molecular profiling (MP) approach to identify key molecular changes that may provide therapeutic options not typically considered in mCRC. We evaluated 6892 mCRC referred to Caris Life Sciences by MP including sequencing (Sanger/NGS), immunohistochemistry (IHC) and in-situ hybridization (ISH). mCRC metastases to liver, brain, ovary or lung (n = 1507) showed differential expression of markers including high protein expression of TOPO1 (52%) and/or low RRM1 (57%), TS (71%) and MGMT (39%), suggesting possible benefit from irinotecan, gemcitabine, 5FU/capecitabine and temozolomide, respectively. Lung metastases harbored a higher Her2 protein expression than the primary colon tumors (4% vs. 1.8%, p = 0.028). Brain and lung metastases had higher KRAS mutations than other sites (65% vs 59% vs 47%, respectively, p = 0.07, <0.01), suggesting poor response to anti-EGFR therapies. BRAF-mutated CRC (n = 455) showed coincident high protein expression of RRM1 (56%), TS (53%) and low PDGFR (22%) as compared with BRAF wild-type tumors. KRAS-mutated mCRC had higher protein expression of c-MET (47% vs. 36%) and lower MGMT (56% vs. 63%), suggesting consideration of c-MET inhibitors and temozolomide. KRAS-mutated CRC had high TUBB3 (42% vs. 33%) and low Her2 by IHC (0.5%) and HER2 by FISH (3%, p <0.05). CRC primaries had a lower incidence of PIK3CA and BRAF mutations in rectal cancer versus colon cancer (10% and 3.3%, respectively). MP of 6892 CRCs identified significant differences between primary and metastatic sites and among BRAF/KRAS sub-types. Our findings are hypothesis generating and need to be examined in prospective studies. Specific therapies may be considered for different actionable targets in mCRC as revealed by MP.

Keywords: APC; BRAF; Cox2; ERCC1; Her2; KRAS; TP53; Topo1; c-MET; colorectal cancer; irinotecan; metastasis; molecular profiling; oxaliplatin; peritoneal cancer; precision medicine.

Figure 1.

Percentage breakdowns by primary and metastasis. Green: biomarker expressions associated with benefit of therapies that are statistically significantly higher than the primary CRC; Red: biomarker expressions associated with benefit of therapies that are statistically significantly lower than the primary CRC. The numbers in parentheses are NOT statistically significantly different from the primary CRC.

Figure 2.

Odds ratio of biomarker comparisons in 7 metastases. Shown are biomarkers that are significantly differentially distributed between the metastases and primary (all p < 0.05 by 2-tailed Fisher-Exact test.) Bladder metastasis was also investigated however no significant differences in biomarker distribution were found and is therefore not included here. Odds ratios were calculated as (Biomarker positive N in metastasis / Biomarker negative N in metastasis) / (Biomarker positive N in primary/Biomarker negative N in primary).

Figure 3.

Differential molecular profiling results by: 4A. KRAS mutation status 4B. BRAF mutation status.

Figure 4.

Comparison of metastases with primary tumors from 43 paired samples.