MedGen

Neonatal nephrocutaneous inflammatory syndrome (NNCIS) is an autosomal recessive disorder characterized by intrauterine growth retardation and premature birth, fragile infection-prone skin, and nephromegaly with tubular dysfunction. Some patients have chronic diarrhea, and necrotizing enterocolitis with intestinal perforation has been observed. Other features include facial dysmorphisms and cardiac anomalies. Most patients require ventilatory and circulatory support at birth, exhibit failure to thrive, experience recurrent infections with sepsis as a common complication, and die within 6 months (Mazurova et al., 2020; Labbouz et al., 2023). Reviews Takeichi and Akiyama (2021) reviewed published reports of patients with mutation in the EGFR gene, whose features included intrauterine growth restriction; thin, translucent, and fragile skin (14 of 15 cases); skin desquamation (10 of 17 cases); ichthyosis (9 of 17 cases); recurrent skin infections and sepsis (9 of 12 cases); nephromegaly (10 of 16 cases); and congenital heart defects (7 of 17 cases). Other observed features included erythroderma, tubulopathy, necrotizing enterocolitis/intestinal perforation, cryptorchidism, hyperimmunoglobulin E, and dentinogenesis imperfecta. Almost all children died within 2.5 years after birth. The authors suggested that EGFR-associated systemic inflammatory diseases should be considered a part of the clinical spectrum of 'autoinflammatory keratinization diseases' (AiKDs). [from OMIM]

Panitumumab is a monoclonal antibody used for the treatment of metastatic colorectal cancer (mCRC). Panitumumab is an epidermal growth factor receptor (EGFR) antagonist, which works by blocking the growth of cancer cells. It is administered every 14 days as an intravenous (IV) infusion, often with chemotherapy. Panitumumab is approved for first-line therapy with folinic acid, fluorouracil, and oxaliplatin (FOLFOX) and as monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy. The location of the primary tumor correlates whether an individual with mCRC is likely respond to anti-EGFR therapy. Individuals with left-sided tumors are more likely to respond well to anti-EGFR therapy and have a better prognosis. Individuals with right-sided tumors have a worse prognosis and respond poorly to anti-EGFR therapy. However, only the genetic variation status of the tumor, and not the location of the tumor, is discussed in the FDA drug label’s dosing recommendations. Resistance to panitumumab is associated with specific RAS mutations. The RAS is a family of oncogenes that includes the KRAS and NRAS genes. When mutated, these genes have the ability to transform normal cells into cancerous cells by providing a continual growth stimulus to cells. The KRAS mutations are particularly common, being detectable in 40% of metastatic colorectal tumors. The KRAS mutations often lead to constitutive activation of the EGFR and are associated with resistance to anti-EGFR drugs such as panitumumab. Mutations in NRAS and another gene, BRAF, have also been associated with poor response to anti-EGFR therapy. The 2017 FDA-approved label states that panitumumab is indicated for wild-type RAS (no mutations in either KRAS or NRAS) mCRC. The label states that an FDA-approved test must be used to confirm the absence of RAS mutations before starting panitumumab, and that panitumumab is not indicated for the treatment of individuals with colorectal cancer with RAS mutations (in either NRAS or KRAS), or when the RAS genetic variation status is unknown. Similarly, the 2015 Update from the American Society of Clinical Oncology (ASCO) states that anti-EGFR therapy should only be considered for the treatment of individuals whose tumor is determined to not have variations detected after extended RAS testing. The 2020 National Comprehensive Cancer Network (NCCN) guideline also strongly recommends KRAS/NRAS genotyping of tumor tissue in all individuals with mCRC. In addition, the guideline states the V600E mutation in the BRAF gene makes a response to panitumumab highly unlikely, unless given with a BRAF inhibitor. [from Medical Genetics Summaries]

Cetuximab is a monoclonal antibody used in the treatment of metastatic colorectal cancer (mCRC) and cancer of the head and neck. Cetuximab is an epidermal growth factor receptor (EGFR) antagonist, which works by blocking the growth of cancer cells. It is administered as a weekly intravenous (IV) infusion, but in practice, is often given every other week to coincide with chemotherapy (for example, FOLFIRI or FOLFOX). Cetuximab has several off-label uses as well, which include non-small cell lung cancer, squamous cell carcinoma of the skin, and Menetrier’s disease. Interestingly, for colorectal cancer, the location of the primary tumor influences whether an individual with mCRC will respond to anti-EGFR therapy, and influences prognosis. Individuals with left-sided tumors are more likely to respond well to anti-EGFR therapy and have a better prognosis. Individuals with right-sided tumors have a worse prognosis and respond poorly to anti-EGFR therapy. However, currently only the mutation status of the tumor, and not the location of the tumor, is discussed in the drug label’s dosing recommendations. Resistance to cetuximab is associated with specific RAS mutations. The RAS family of oncogenes includes the KRAS and NRAS genes. When mutated, these genes have the ability to transform normal cells into cancerous cells. The KRAS mutations are particularly common, being detectable in 40% of metastatic colorectal tumors. The KRAS mutations often lead to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway and are associated with resistance to anti-EGFR drugs such as cetuximab. In addition, mutations in NRAS and another gene, BRAF, have been associated with poor response to anti-EGFR therapy; however, BRAF mutation does not explicitly preclude anti-EGFR therapy. Combination therapies targeting both BRAF and EGFR have shown to improve survival for individuals with wild-type RAS and mutant BRAF. The 2018 FDA-approved drug label for cetuximab states that for mCRC, cetuximab is indicated for K- and N-RAS wild-type (no mutation), EGFR-expressing tumors. The label states that an FDA-approved test must be used to confirm the absence of a RAS mutation (in either KRAS or NRAS) prior to starting cetuximab. While the FDA label also states that EGFR expression should also be confirmed by an approved test prior to starting therapy for mCRC, this is largely not implemented in practice, nor is it recommended by professional oncology society guidelines. Similarly, the 2015 Update from the American Society of Clinical Oncology (ASCO) states that anti-EGFR therapy should only be considered for the treatment of individuals whose tumor is determined to not have mutations detected after extended RAS testing. The 2020 National Comprehensive Cancer Network (NCCN) guideline also strongly recommends KRAS/NRAS genotyping of tumor tissue in all individuals with mCRC. In addition, the guideline states the V600E mutation in the BRAF gene makes a response to cetuximab (and panitumumab) highly unlikely unless given a BRAF inhibitor. [from Medical Genetics Summaries]