QualTek is committed to offering sensitive and accurate companion IHC and molecular diagnostic testing for KRAS, as well as BRAF and PI3KCA, as prerequisite to anti-EGFR therapy, to ensure only patients who will respond to such treatment will benefit

The overwhelming majority of somatic mutations in KRAS result render it constitutively active. Activating mutations in KRAS have been observed at high frequency in a variety of tumor types (~20% of all solid tumors) and are associated with poor prognosis. In metastatic colorectal cancer (mCRC), for example, KRAS mutations are observed in ~40% of all tumors, occurring most frequently in codons 12 and 13 (~98.5% of observed point mutations).

EGFR is a clinically validated therapeutic target for mCRC, and several other cancer types including non-small cell lung cancer, squamous cell carcinoma of the head and neck, pancreatic cancer and breast cancer. EGFR is overexpressed in up to 80% of mCRC, however anti–EGFR monoclonal antibodies show little to no clinical benefit in patients harboring activating point mutations of KRAS.

Retrospectively, KRAS biomarker data (specifically, genetic stratification correlating mutation status with therapeutic response) has been approved by the US Food and Drug Administration (FDA) Oncologic Drug Advisory Committee (ODAC) for inclusion in drug labeling such that anti–EGFR monoclonal antibodies are used only in those individuals (~60%) whose tumors harbor the wildtype (i.e., non-mutated) KRAS gene.

Even so, a large proportion of patients with wildtype KRAS still do not respond to EGFR-targeted therapy, thereby implicating aberrant functional or nonfunctional mutations of other genes downstream of KRAS and EGFR on clinical decision making.

The identification of other molecular markers involved in the resistance to anti-EGFR antibodies should allow the development of new therapies that target 'escape mechanisms' used by tumors to circumvent a pharmacologically blocked EGFR-KRAS pathway.

Of the other potential targets, BRAF is also a negative prognostic marker for mCRC. Activating BRAF mutations, particularly at codon 600, are generally mutually exclusive to KRAS mutations in mCRC, as well as being a frequent cause of cutaneous melanomas (~60%) and present in ~50% papillary thyroid cancers. Pharmacologic inhibition of BRAF does restore sensitivity to anti-EGFR monoclonal antibodies in colorectal cancer cell lines.

Moreover, exon 9 (codon 542 and 545) and exon 20 mutations (codon 1047) in subunit A of PI3K (PI3KCA) are shown to co-segregate with KRAS or BRAF changes in mCRC, and are alone responsible for refractory effects of EGFR inhibitors in ~30% mCRC with wildtype KRAS/BRAF. PI3K plays an important role in several other receptor-mediated signaling pathways, with PI3KCA mutations causative for up to ~30% endometrial and ~40% breast carcinomas; acquired resistance to EGFR-targeted drugs in breast-cancer cells often involves activation of the IGF1R-PI3KCA pathway. Overamplification of P13KCA is also prevalent in cervical (~70%), squamous cell lung (~60%) and ovarian (~30%) carcinomas.

While clinical testing has typically been restricted to the identification of

KRAS, BRAF and PI3KCA mutations involving only a few allele changes

in the genes, technological advances make more comprehensive assessments

of gene alterations now feasible, allowing also for widespread adoption of

broader molecular testing beyond these most commonly mutated targets.

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