Molecular Profiling Is a Necessity in Colorectal Cancer Treatment

At the 6th Annual SONO meeting, Kelley A. Rone, DNP, RN, AGNP-C, reviewed evidence supporting molecular testing in patients with colorectal cancer.

Colorectal cancer (CRC) is the most common cancer in the United States, and is the second most common cause of cancer-related death.1 However, molecular testing is drastically changing the treatment landscape and improving patient outcomes in this specialty, according to Kelley A. Rone, DNP, RN, ADNP-C.

“One of the things that is most relevant is the molecular profiling portion of cancer in general. [But] it's such a rapidly changing part of oncology, that it is sometimes hard to keep up,” Rone, who is an advanced practice nurse specializing in [gastrointestinal] GI cancers at Mayo Clinic in Phoenix, Arizona, said in an interview with Oncology Nursing News®. “As new mutations become recognized and become linked to certain treatments, that is going to change a lot of the way treatments are matched.”

Rone recently presented on advances in gastrointestinal cancers as part of the 6th Annual School of Nursing Oncology Meeting. In her talk, she highlighted the various biomarkers that patients with colorectal cancer should be tested for, and the corresponding treatment options.

“It is important for the nurses to understand the importance of testing,” Rone told Oncology Nursing News®, noting that nurses can be critical in ensuring that the appropriate tests have been ordered for different patients.

“If someone comes in and [we do not believe their cancer is] metastatic, or if the have had their prior biopsy done at an outside institution, we may not necessarily think about doing the molecular profiling. [But] sometimes myself or the clinic nurses will say to the physician: Did we do molecular profiling on this patient? Because if it hasn’t been done, we can order it,” she said.

Molecular Profiling

Mismatch repair deficiency (dMMR) and microsatellite stability testing is recommended for all patients with newly diagnosed colon cancer, regardless of disease stage.2 In addition, patients with metastatic disease should be screened for RAS, BRAF, and HER2 positivity.3

RAS mutations are the most frequently mutated oncogenes and these variants are present in 90% of pancreatic cancers, 45% of colon cancers, and 35% of lung cancers. KRAS is the most common RAS form.4 Patients with CRC must be tested for RAS prior to initiating any EGFR-inhibiting therapy, such as cetuximab (Erbitux) or panitumumab (Vectibix). Patients who present with KRAS, NRAS, or, the much less common, HRAS mutations (1.7%) should not receive anti-EGFR therapy, as these biomarkers have negative predictive value with these therapies.5-7

BRAF mutations are mutually exclusive with KRAS mutations, as they serve as the primary effector of KRAS signaling. These mutations are most likely to occur in exon 15 (V600E). Identified in approximately 10% of patients with CRC, BRAF V600E mutations account for 98% of BRAF mutations. If a molecular profile comes back as BRAF wild-type, this means that no BRAF mutation is present.8

Approximately 2% to 3% of patients with CRC will show a degree of HER2 amplification. Among patients with a KRAS/BRAF wild-type mutation, the prevalence of HER2 amplification is increased; approximately 5% of these patients will have this amplification. Uncommon among patients with NRAS, KRAS, and BRAF mutations, HER2 amplification is frequently associated with left-sided CRC. Identifying this amplification is key in determining if a patient may benefit form a HER2-directed therapy.9

Treatment

As of August 2022, patients with metastatic disease may receive a combination of bevacizumab (Avastin) plus either FOLFOX,10 FOLFIRI, or FOLFOXIRI. They may also receive any of these chemotherapies as monotherapy.

Patients with wild-type (no KRAS, NRAS, or BRAF mutations) left-sided tumors may receive monotherapy with cetuximab11 or panitumumab. They also may receive one of the anti-EGFR therapies in addition to chemotherapy (FOLFOX or FOLFIRI).12-17

Patients with dMMR and microsatellite instability–high disease are eligible for monotherapy with pembrolizumab (Keytruda), nivolumab (Opdivo), or ipilimumab (Yervoy). They may also receive dual immunotherapy with nivolumab plus ipilimumab.18-20

Patients with HER2-positive disease and no RAS or BRAF mutations may receive either a combination of trastuzumab (Herceptin) plus pertuzumab (Perjeta).21 They may also receive lapatinib (Tykerb).

Finally, patients with NTRK fusion positive disease, with no evidence of RAS or BRAF mutations, may receive larotrectinib (Vitrakvi) or entrectinib (Rozlytrek).22

References

  1. Rone KA. Advances in gastrointestinal cancers: shifting evidence into practice. Presented at: 6th Annual School of Nursing Oncology™; July 29-30, 2022; San Diego, CA.
  2. Kawakami H, Zaanan A, Sinicrope FA. Microsatellite instability testing and its role in the management of colorectal cancer. Curr Treat Options Oncol. 2015;16(7):30. doi:10.1007/s11864-015-0348-2
  3. Dienstmann R, Salazar R, Tabernero J. Molecular subtypes and the evolution of treatment decisions in metastatic colorectal cancer. Am Soc Clin Oncol Educ Book. 2018;38:231-238. doi:10.1200/EDBK_200929
  4. Porru M, Pompili L, Caruso C, Biroccio A, Leonetti C. Targeting KRAS in metastatic colorectal cancer: current strategies and emerging opportunities. J Exp Clin Cancer Res. 2018;37(1):57. doi:10.1186/s13046-018-0719-1
  5. Allegra CJ, Rumble RB, Hamilton SR, et al. Extended RAS gene mutation testing in metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy: American Society of Clinical Oncology Provisional Clinical Opinion Update 2015. J Clin Oncol. 2016;34(2):179-185. doi:10.1200/JCO.2015.63.9674
  6. Al-Shamsi HO, Alhazzani W, Wolff RA. Extended RAS testing in metastatic colorectal cancer-Refining the predictive molecular biomarkers. J Gastrointest Oncol. 2015;6(3):314-321. doi:10.3978/j.issn.2078-6891.2015.016
  7. Gong J, Cho M, Fakih M. RAS and BRAF in metastatic colorectal cancer management. J Gastrointest Oncol. 2016;7(5):687-704. doi:10.21037/jgo.2016.06.12
  8. Larki P, Gharib E, Yaghoob Taleghani M, Khorshidi F, Nazemalhosseini-Mojarad E, Asadzadeh Aghdaei H. Coexistence of KRAS and BRAF mutations in colorectal cancer: a case report supporting the concept of tumoral heterogeneity. Cell J. 2017;19(suppl 1):113-117. doi:10.22074/cellj.2017.5123
  9. Sandhu J, Wang C, Fakih M. Clinical response to T-DM1 in HER2-amplified, KRAS-mutated metastatic colorectal cancer. J Natl Compr Canc Netw. 2020;18(2):116-119. doi:10.6004/jnccn.2019.7371
  10. Emmanouilides C, Sfakiotaki G, Androulakis N, et al. Front-line bevacizumab in combination with oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: a multicenter phase II study. BMC Cancer. 2007;7:91. doi:10.1186/1471-2407-7-91
  11. Venook AP, Niedzwiecki D, Lenz HJ, et al. Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients With KRAS wild-type advanced or metastatic colorectal cancer: a randomized clinical trial. JAMA. 2017;317(23):2392-2401. doi:10.1001/jama.2017.7105
  12. Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(10):1065-1075. doi:10.1016/S1470-2045(14)70330-4
  13. Martín-Martorell P, Roselló S, Rodríguez-Braun E, Chirivella I, Bosch A, Cervantes A. Biweekly cetuximab and irinotecan in advanced colorectal cancer patients progressing after at least one previous line of chemotherapy: results of a phase II single institution trial. Br J Cancer. 2008;99(3):455-458. doi:10.1038/sj.bjc.6604530
  14. Peeters M, Price TJ, Cervantes A, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28(31):4706-4713. doi:10.1200/JCO.2009.27.6055
  15. Cremolini C, Loupakis F, Antoniotti C, et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol. 2015;16(13):1306-1315. doi:10.1016/S1470-2045(15)00122-9
  16. Van Cutsem E, Tejpar S, Vanbeckevoort D, et al. Intrapatient cetuximab dose escalation in metastatic colorectal cancer according to the grade of early skin reactions: the randomized EVEREST study. J Clin Oncol. 2012;30(23):2861-2868. doi:10.1200/JCO.2011.40.9243
  17. Van Cutsem E. Optimizing administration of epidermal growth factor receptor-targeted agents in the treatment of colorectal cancer. Clin Colorectal Cancer. 2007;6(suppl 2):S60-S65. doi:10.3816/ccc.2007.s.004
  18. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509-2520. doi:10.1056/NEJMoa1500596
  19. Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18(9):1182-1191. Published correction appears in Lancet Oncol. 2017;18(9):e510.
  20. Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36(8):773-779. doi:10.1200/JCO.2017.76.9901
  21. Meric-Bernstam F, Hurwitz H, Raghav KPS, et al. Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol. 2019;20(4):518-530. doi:10.1016/S1470-2045(18)30904-5
  22. Sartore-Bianchi A, Trusolino L, Martino C, et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016;17(6):738-746. Published correction appears in Lancet Oncol. 2016;17(10):e420].