Gene mutations and copy number alterations of EGFR, KRAS and MET
Inventors
Kopetz, Scott • Talasaz, AmirAli
Assignees
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Publication Number
US-12319968-B2
Publication Date
2025-06-03
Expiration Date
Abstract
Sequence variants and copy number variations in the EGFR, KRAS and MET genes are biomarkers for resistance to anti-EGFR therapies for cancer. This disclosure provides methods of detecting these biomarkers and using them in the diagnosis and treatment of cancer.
Core Innovation
The invention relates to biomarkers and diagnostic assessment of cancers by detecting EGFR, KRAS, and MET sequence variants and copy number alterations, including in cell-free DNA. Sequence variants are assessed for EGFR ectodomain variants, such as T130A, and for KRAS codon variants including G12C, G12R, G13D, and Q61H.
The problem addressed is managing diagnosis, prognosis, and therapy selection in cancers where detection of EGFR and related molecular alterations indicates resistance to anti-EGFR therapy. In particular, in metastatic colorectal cancer, the document states that resistance is indicated by the presence of the specified EGFR alterations and that this supports ceasing or reducing anti-EGFR treatment or switching to non-anti-EGFR therapy.
The invention includes methods that obtain sequence data from a sample comprising cell-free DNA, a tumor sample, or blood and determine whether cancer comprises cancer cells having an EGFR nucleotide sequence variant encoding a T130A-EGFR variation. The described approach integrates variant detection and copy number determination to inform treatment selection.
Claims Coverage
The partial claims provided include two independent claims. Across the independent claims, there is a common inventive focus on identifying an EGFR nucleotide sequence variant encoding EGFR comprising a T130A variation and using that determination to guide initiation of a therapy other than anti-EGFR therapy, including after prior anti-EGFR therapy.
Treating cancer with non-anti-egfr therapy when egfr t130a is present
A method of treating a cancer in a subject by administering a cancer treatment other than an anti-EGFR therapy, wherein the cancer comprises cancer cells, the cancer cells comprising an EGFR nucleotide sequence variant that encodes EGFR comprising a T130A variation.
Determining egfr t130a-egfr variation from sample sequence data and commencing alternative therapy
A method comprising determining that the cancer comprises cancer cells having at least one EGFR nucleotide sequence variant encoding an EGFR comprising a T130A-EGFR variation by obtaining sequence data from a sample comprising cell free DNA, a tumor sample, or a blood sample and commencing a therapy other than anti-EGFR therapy, or an alternative therapy following previous anti-EGFR therapy.
The claim coverage centers on detecting an EGFR nucleotide sequence variant encoding an EGFR comprising a T130A variation from sample-derived sequence data and using that result to commence a therapy that is explicitly other than anti-EGFR therapy, including as an alternative following prior anti-EGFR therapy.
Stated Advantages
Indicates resistance to anti-EGFR therapy in cancers, particularly metastatic colorectal cancer.
Supports ceasing or reducing anti-EGFR treatment or switching to non-anti-EGFR therapy.
Supports diagnosis, prognosis, and therapy selection by using detected EGFR, KRAS, and MET sequence variants and copy number alterations, including in cell-free DNA.
Documented Applications
Guiding diagnosis, prognosis, and therapy selection in cancers, especially metastatic colorectal cancer, where detection of EGFR alterations indicates resistance to anti-EGFR therapy and supports switching to non-anti-EGFR therapy.
Monitoring and detection example using cfDNA sequencing from CRC patients after EGFR mAb progression, showing newly detected KRAS mutations and associated gene amplification.
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