Sequential Genomic Testing Could Reveal Efficacy, Patterns of Resistance in Metastatic CRC

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The use of genetic testing by way of tumor tissue analysis combined with liquid biopsy monitoring at different time points throughout the disease progression of colorectal cancer may help optimize treatment selection.

Heinz-Josef Lenz, MD

The use of genetic testing by way of tumor tissue analysis combined with liquid biopsy monitoring at different time points throughout the disease progression of colorectal cancer (CRC) may help optimize treatment selection. It is also important to consider germline testing if patients are young or have a family history to capture genetic predisposition which can impact treatment decisions and surveillance such as Mismatch Repair orBRCA.

Recent data from meta-analyses have shown a strong inclination towards improved results when patients were treated based on molecular profiling with targeted therapies, with longer progression-free survival (PFS) and increases in response rates. This coupled with more targeted agents available than ever before motion toward progress in the space of personalized medicine.

"The number of targeted therapies on the market is expected to grow and accelerate in the future," Heinz-Josef Lenz, MD, professor of medicine and preventative medicine as well as associate director for Clinical Science at the USC Norris Comprehensive Cancer Center at the University of Southern California, Los Angeles, said during a virtual presentation organized by Medical Oncology Association of Southern California. "This will provide new treatment options and more benefit to patients when therapies are being personalized based on tumor profiling and liquid biopsies."

With mutational testing, biomarkers may also facilitate precision therapy selection in patients who do not harbor an actionable mutation and are slated to receive standard-of-care targeted agents for their disease. However, challenges exist to using mutational information for prognosis and treatment selection.

Heterogeneity of individual tumors and the variability of biomarker detection by tumor sampling are existing barriers to detecting actionable and prognostic mutations. Therefore, liquid biopsies that detect circulating tumor (ct)DNA and RNA released into the blood stream offer a viable alternative to tissue testing in that cancer-relevant mutations can be tracked over time with a series of blood draws.

"Routine liquid biopsy assessment can effectively identify mechanisms of resistance across different tumor types and treatments," Lenz wrote in his presentation.

Biomarkers for Standard Agents

Sequencing for ctDNA has shown that acquired resistance mutations to anti-EGFR antibodies, such as acquiredRASmutations and subclonal mutations in theEGFRectodomain, may experience clonal decay, potentiating re-challenge with EGFR-targeted therapy.2This evolution demonstrates a growing necessity for ctDNA tracking as a resource for therapy selection.Patients with CRC grouped by consensus molecular subtype (CMS) have demonstrated different rates of median overall survival (OS) when all other treatment factors have been controlled for.

In an analysis of the CALGB/SWOG 80405 trial in which the patients with KRAS wild-type disease did not show benefit with either cetuximab (Erbitux) or bevacizumab (Avastin) added to chemotherapy for the treatment of CRC,3 upregulation of WNT and MYC downstream targets5 experienced the greatest survival benefit; whereas patients with CMS1 disease had the worst survival clinically.4 CMS1 tumors are characterized by expression of genes associated with diffuse immune infiltration and strong immune evasion pathways that are associated with microsatellite instability.4,5

Targeted Therapy for Actionable Mutations

Similarly, next-generation sequencing (NGS) has demonstrated that certain novel mutated genes are associated with survival and response to targeted therapies. Results of an analysis of the same trial presented at the European Society for Medical Oncology 2019 Congress indicated that mutant GRM3 (HR, 2.34; 95% CI, 1.09-5.02; P = .028) and wild-type LRP1B (HR, 0.55; 95% CI, 0.32-0.97; P = .041) were prognostic of survival benefit with bevacizumab therapy. When cetuximab (Erbitux) was compared against bevacizumab (Avastin), decreased OS efficacy was associated with mutations in RNF43 (adjusted HR, 2.38; 95% CI, 1.22-4.63; interaction P = .0003) and ARID1A (adjusted HR, 2.29; 95% CI, 1.27-4.13; interaction P = .014).6 Certain biomarkers, such as HER2 and BRAF, continue to show benefit of using targeted therapies for the treatment of tumors with associated overexpression.

In the phase II HERACLES trial of trastuzumab (Herceptin) plus lapatinib (Tykerb) in HER2-amplified,KRASexon 2 wildtype in metastatic (m)CRC that was resistant to standard therapies, demonstrating an objective response rate (ORR) of 35% and a disease control rate of 78%. Of the 849 patients screened for the trial, 46 (5.4%) were positive for HER2.7

In an interim report of the phase II MyPathway basket trial, trastuzumab plus pertuzumab (Perjeta) in patients with HER2-amplified or -overexpressed mCRC produced an ORR of 38.2% with a median response duration of 10.3 months. In patients with wild-typeKRAS, the ORR was 52% whereas no responses were seen in patients with mutantKRAS.8

More recently, data from the BEACON CRC trial ofBRAF-mutant CRC treated with encorafenib (Braftovi) and binimetinib (Mektovi) plus cetuximab indicated that substantial improvements in ORR and PFS over historical standard of care.9Although not yet approved, data from this trial has led to the National Comprehensive Cancer Network including the combination in their guidelines as therapy for patients who harbor aBRAFV600E mutation.10

To actively utilize these data for the treatment of patients, Lenz recommended performing tumor tissue testing at the time of diagnosis and again at the time of growth, with active monitoring by way of liquid biopsies. Patient-level data by these methods has potential to reveal an innate predisposition to certain outcomes.


  1. Heinz-Josef Lenz. Update on molecular targeted therapies for mCRC. Presented at: Annual Education Symposium of the Medical Oncology Association of Southern California; Huntington Beach, CA; March 14, 2020.
  2. Parseghian CM, Loree JM, Morris VK, et al. Anti-EGFR-resistant clones decay exponentially after progression: implications for anti-EGFR re-challenge.Ann Oncol. 2019;30(2):243-249. doi:10.1093/annonc/mdy509
  3. Venook AP, Niedzwiecki D, Lenz HJ, et al. Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients withKRASwild-type advanced or metastatic colorectal cancer: a randomized clinical trial. JAMA. 2017;317(23):2392-240 doi:10.1001/jama.2017.7105
  4. Lenz H-J, Ou F-S, Venook AP, et al. Impact of consensus molecular subtyping (CMS) on overall survival (OS) and progression free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB/SWOG 80405 (Alliance).J Clin Oncol. 2017;35(suppl 15;abstr 3511). doi: 10.1200/JCO.2017.35.15_suppl.3511
  5. Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer.Nat Med. 2015;21(11):1350-1356. doi: 10.1038/nm.3967
  6. Innocenti F, Rashid N, Wancen M, et al. Next-generation sequencing (NGS) in metastatic colorectal cancer (mCRC): novel mutated genes and their effects on response to therapy (Alliance).Ann Oncol. 2019;30(suppl 5; abstr 524O). doi: 10.1093/annonc/mdz246
  7. Siena S, Sartore-Bianchi A, Lonardi S, et al. Trastuzumab and lapatinib in HER2-amplified metastatic colorectal cancer patients (mCRC): The HERACLES trial.J Clin Oncol. 2015;33(suppl 15;abstr 3508). doi: 10.1200/JCO.2015.33.15_suppl.3508
  8. Hurwitz H, Singh Raghav KP, Burris HA, et al. Pertuzumab + trastuzumab for HER2-amplified/overexpressed metastatic colorectal cancer (mCRC): Interim data from MyPathway.J Clin Oncol. 2017;35(suppl 4;abstr 676). doi: 10.1200/JCO.2017.35.4_suppl.676
  9. Cutsem EV, Cuyle P-J, Huijberts S, et al. BEACON CRC study safety lead-in (SLI) in patients withBRAFV600E metastatic colorectal cancer (mCRC): Efficacy and tumor markers.J Clin Oncol. 2018;36(suppl 4S;abstr 627). doi: 10.1200/JCO.2018.36.4_suppl.627
  10. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Colon cancer. Version 2.2020. March 3, 2020. NCCN website. Accessed March 4, 2020.
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