Biomarker testing for treatment of metastatic colorectal cancer: role of the pathologist in community practice

Abstract

The past decade has been marked by significant advancements in the treatment of patients with metastatic colorectal cancer (mCRC), including the approval of novel biologic agents such as the angiogenesis inhibitors bevacizumab and afibercept and the epidermal growth factor receptor monoclonal antibodies (mAbs) cetuximab and panitumumab. Cetuximab was recently approved by the US Food and Drug Administration in combination with FOLFIRI (irinotecan, 5-fuorouracil, leucovorin) for the first-line treatment of patients with KRAS mutation-negative (wild-type) tumors as determined by an FDA-approved companion diagnostic. It was the first FDA approval in mCRC requiring use of a diagnostic test that is predictive of response prior to initiation of frontline therapy. The approval highlights the need for reflexive KRAS mutation testing at diagnosis to accurately determine all available treatment options. Although KRAS testing has been used by pathologists in mCRC for several years, accurate and timely reporting of test results and open communication with medical oncologists is even more essential to ensure appropriate first-line treatment selection and avoid any treatment delays. Consequently, it is critical that pathologists are highly trained and educated on KRAS testing methodology and the pros and cons of the various methods available. In this review, we discuss the development of KRAS as a biomarker in mCRC and key topics of concern to the pathologist who works with the oncologist in the community setting, including specimen preparation, KRAS testing methods, and reporting of test results. In this era of personalized medicine, pathologist education and communication with oncologists on biomarkers is paramount for optimal patient care.

Amplification efficiency and thermal stability of qPCR instrumentation: Current landscape and future perspectives

“…More recently, Qiagen received FDA approval of a therascreen® KRAS RGQ PCR kit, paired with a colorectal cancer drug. KRAS mutations occur in ~40% of colorectal cancer patients ( 7 , 8 ). Therefore, screening patients by PCR will detect the most frequent mutations in the KRAS gene and should aid with the selection of therapeutic interventions.…”

Use of the QIAGEN GeneReader NGS system for detection of KRAS mutations, validated by the QIAGEN Therascreen PCR kit and alternative NGS platform

“…They are found in 70-90% of pancreatic cancers [1, 2], 30-50% of colorectal cancers [3–5] and 10-30% of Non-Small Cell Lung Cancers (NSCLC) [6–8]. Several methods have been developed for the detection of KRAS mutations, each with specific advantages and limitations [5, 9, 10]. …”

“…It has greatly improved sensitivity over Sanger sequencing, and has been approved by the Food and Drug Administration (FDA) [9] for colorectal cancer patient stratification. Pyrosequencing also offers an attractive alternative to Sanger due to its fast turnaround time (TAT) and lower sensitivity threshold, even in tissues with low tumor cell content [5].…”

Validation of targeted next-generation sequencing forRASmutation detection in FFPE colorectal cancer tissues: comparison with Sanger sequencing and ARMS-Scorpion real-time PCR

“…It has greater sensitivity for detecting low-level mutations compared with that of Sanger sequencing, and it has been Food and Drug Administration (FDA) approved for KRAS mutation detection using DNA extracted from formalin-fixed paraffin-embedded (FFPE) colorectal adenocarcinoma tissue. 8 However, the Therascreen assay was designed to only detect specific somatic mutations in exon 2 of the KRAS oncogene. 9 Moreover, the traditional methods are especially costly and time consuming for expanded RAS mutation or multiplex genetic testing.…”