Molecular profile examples of specific tumours

Molecular profile: examples of specific tumours

Colorectal carcinoma In CRC, the anti-EGFR monoclonal antibodies cetuximab and panitumumab are used in combination with chemotherapy for metastatic disease. These drugs are less likely to be e ff ective if KRAS or NRAS mutations are present than if a tumour is ‘wild type’ (i.e. has no RAS mutation). Various other genetic changes assist with selection of therapy and making prognostic predictions ( Summary boxes 11.17 and 11.18 ). Molecular analysis in colorectal carcinoma /uni25CF /uni25CF Summary box 11.17 /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF Bronchial (lung) carcinoma In non-small cell lung cancer, specific EGFR mutations occur in a minority of lesions and identification predicts a response to the anti-EGFR tyrosine kinase inhibitor gefitinib, while ALK gene rearrangement predicts a response to the anaplastic lymphoma kinase (ALK) inhibitor crizotinib (see Chapter 60 ). Summary box 11.19 shows other relevant molecular changes. Summary box 11.19 Molecular and related changes in non-small cell lung carcinoma /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF Gynaecological carcinoma MMR status is increasingly important for the classification and management of ovarian and endometrial carcinomas. Other molecular changes that are important for prognosis and selection of therapy in endometrial cancer include polymerase ε (POL ε ) and TP53 abnormalities. HER2 amplification and PD-1 expression may be relevant in some settings. Classification influences prognostic predictions and now depends not only on traditional histology but also on a number of molecular changes (many of which are detectable using immunohisto - chemistr y) (see Chapter 87 ). Breast carcinoma The most important ancillary tests for breast carcinoma remain ER immunohistochemistry and HER2 testing. As for many advanced malignancies, ICIs may be useful and accordingly PD-L1 immunostaining (with the appropriate antibody clone) may help predict outcome (see Chapter 58 ). Lymphoma The distinction between benign and malignant lymphoid proliferations is sometimes di ffi cult. Clonal immunoglobulin heavy chain (IgH) gene rearrangements in B-cell proliferations and clonal T-cell receptor gene rearrangements in T-cell proliferations favour lymphoma over reactive proliferations. Identification of characteristic cytogenetic abnormalities plays an important role in diagnosis, classification and management of several haematological neoplasms. PCR-based tests help detect minimal residual disease after therapy . Gastrointestinal stromal tumour, soft-tissue tumours and malignant melanoma Most GISTs have either a KIT gene mutation or a PDGFRA gene mutation, more often the former. A few have defects in succinate dehydrogenase ( SDH ), BRAF or NF1 genes. Iden - tification of known mutations helps confirm the diagnosis. Mutational profile also helps predict clinical outcome and response to chemotherapy . For example, imatinib, a tyrosine kinase inhibitor, is a useful drug for advanced GIST but is ine ff ective in those with SDH mutations. Molecular testing assists the diagnosis and classification of many types of soft-tissue tumour. Examples include Ewing’s sarcoma and alveolar rhabdomyosarcoma, in which specific fusion genes are diagnostic. FISH testing detects c haracteristic cytogenetic changes. In metastatic malignant melanoma, specific BRAF muta - tions predict response to the BRAF kinase inhibitor vemu - rafenib. Table 11.1 outlines the clinical applications of some bio - markers in tumours.

Mismatch repair gene abnormalities Multiple considerations (see ) KRAS or NRAS mutation Predicts resistance to EGFR inhibitors Tumour mutation burden Predicts response to ICI therapy BRAF V600E mutation Poor prognosis in metastatic CRC Predictive of response to therapy NTRK fusion Uncommon (<1% CRC) Usually MSI-H Poor prognosis Speci /f_i c therapy available: tyrosine kinase inhibitors Prediction of response to tyrosine kinase therapy Mutations EGFR KRAS BRAF V600E Fusions ALK RET NTRK Prediction of response to immune checkpoint inhibitors PD-L1 expression (in a subgroup)

Molecular profile: examples of specific tumours

Colorectal carcinoma In CRC, the anti-EGFR monoclonal antibodies cetuximab and panitumumab are used in combination with chemotherapy for metastatic disease. These drugs are less likely to be e ff ective if KRAS or NRAS mutations are present than if a tumour is ‘wild type’ (i.e. has no RAS mutation). Various other genetic changes assist with selection of therapy and making prognostic predictions ( Summary boxes 11.17 and 11.18 ). Molecular analysis in colorectal carcinoma /uni25CF /uni25CF Summary box 11.17 /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF Bronchial (lung) carcinoma In non-small cell lung cancer, specific EGFR mutations occur in a minority of lesions and identification predicts a response to the anti-EGFR tyrosine kinase inhibitor gefitinib, while ALK gene rearrangement predicts a response to the anaplastic lymphoma kinase (ALK) inhibitor crizotinib (see Chapter 60 ). Summary box 11.19 shows other relevant molecular changes. Summary box 11.19 Molecular and related changes in non-small cell lung carcinoma /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF Gynaecological carcinoma MMR status is increasingly important for the classification and management of ovarian and endometrial carcinomas. Other molecular changes that are important for prognosis and selection of therapy in endometrial cancer include polymerase ε (POL ε ) and TP53 abnormalities. HER2 amplification and PD-1 expression may be relevant in some settings. Classification influences prognostic predictions and now depends not only on traditional histology but also on a number of molecular changes (many of which are detectable using immunohisto - chemistr y) (see Chapter 87 ). Breast carcinoma The most important ancillary tests for breast carcinoma remain ER immunohistochemistry and HER2 testing. As for many advanced malignancies, ICIs may be useful and accordingly PD-L1 immunostaining (with the appropriate antibody clone) may help predict outcome (see Chapter 58 ). Lymphoma The distinction between benign and malignant lymphoid proliferations is sometimes di ffi cult. Clonal immunoglobulin heavy chain (IgH) gene rearrangements in B-cell proliferations and clonal T-cell receptor gene rearrangements in T-cell proliferations favour lymphoma over reactive proliferations. Identification of characteristic cytogenetic abnormalities plays an important role in diagnosis, classification and management of several haematological neoplasms. PCR-based tests help detect minimal residual disease after therapy . Gastrointestinal stromal tumour, soft-tissue tumours and malignant melanoma Most GISTs have either a KIT gene mutation or a PDGFRA gene mutation, more often the former. A few have defects in succinate dehydrogenase ( SDH ), BRAF or NF1 genes. Iden - tification of known mutations helps confirm the diagnosis. Mutational profile also helps predict clinical outcome and response to chemotherapy . For example, imatinib, a tyrosine kinase inhibitor, is a useful drug for advanced GIST but is ine ff ective in those with SDH mutations. Molecular testing assists the diagnosis and classification of many types of soft-tissue tumour. Examples include Ewing’s sarcoma and alveolar rhabdomyosarcoma, in which specific fusion genes are diagnostic. FISH testing detects c haracteristic cytogenetic changes. In metastatic malignant melanoma, specific BRAF muta - tions predict response to the BRAF kinase inhibitor vemu - rafenib. Table 11.1 outlines the clinical applications of some bio - markers in tumours.

Mismatch repair gene abnormalities Multiple considerations (see ) KRAS or NRAS mutation Predicts resistance to EGFR inhibitors Tumour mutation burden Predicts response to ICI therapy BRAF V600E mutation Poor prognosis in metastatic CRC Predictive of response to therapy NTRK fusion Uncommon (<1% CRC) Usually MSI-H Poor prognosis Speci /f_i c therapy available: tyrosine kinase inhibitors Prediction of response to tyrosine kinase therapy Mutations EGFR KRAS BRAF V600E Fusions ALK RET NTRK Prediction of response to immune checkpoint inhibitors PD-L1 expression (in a subgroup)

Molecular profile: examples of specific tumours

Colorectal carcinoma In CRC, the anti-EGFR monoclonal antibodies cetuximab and panitumumab are used in combination with chemotherapy for metastatic disease. These drugs are less likely to be e ff ective if KRAS or NRAS mutations are present than if a tumour is ‘wild type’ (i.e. has no RAS mutation). Various other genetic changes assist with selection of therapy and making prognostic predictions ( Summary boxes 11.17 and 11.18 ). Molecular analysis in colorectal carcinoma /uni25CF /uni25CF Summary box 11.17 /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF Bronchial (lung) carcinoma In non-small cell lung cancer, specific EGFR mutations occur in a minority of lesions and identification predicts a response to the anti-EGFR tyrosine kinase inhibitor gefitinib, while ALK gene rearrangement predicts a response to the anaplastic lymphoma kinase (ALK) inhibitor crizotinib (see Chapter 60 ). Summary box 11.19 shows other relevant molecular changes. Summary box 11.19 Molecular and related changes in non-small cell lung carcinoma /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF Gynaecological carcinoma MMR status is increasingly important for the classification and management of ovarian and endometrial carcinomas. Other molecular changes that are important for prognosis and selection of therapy in endometrial cancer include polymerase ε (POL ε ) and TP53 abnormalities. HER2 amplification and PD-1 expression may be relevant in some settings. Classification influences prognostic predictions and now depends not only on traditional histology but also on a number of molecular changes (many of which are detectable using immunohisto - chemistr y) (see Chapter 87 ). Breast carcinoma The most important ancillary tests for breast carcinoma remain ER immunohistochemistry and HER2 testing. As for many advanced malignancies, ICIs may be useful and accordingly PD-L1 immunostaining (with the appropriate antibody clone) may help predict outcome (see Chapter 58 ). Lymphoma The distinction between benign and malignant lymphoid proliferations is sometimes di ffi cult. Clonal immunoglobulin heavy chain (IgH) gene rearrangements in B-cell proliferations and clonal T-cell receptor gene rearrangements in T-cell proliferations favour lymphoma over reactive proliferations. Identification of characteristic cytogenetic abnormalities plays an important role in diagnosis, classification and management of several haematological neoplasms. PCR-based tests help detect minimal residual disease after therapy . Gastrointestinal stromal tumour, soft-tissue tumours and malignant melanoma Most GISTs have either a KIT gene mutation or a PDGFRA gene mutation, more often the former. A few have defects in succinate dehydrogenase ( SDH ), BRAF or NF1 genes. Iden - tification of known mutations helps confirm the diagnosis. Mutational profile also helps predict clinical outcome and response to chemotherapy . For example, imatinib, a tyrosine kinase inhibitor, is a useful drug for advanced GIST but is ine ff ective in those with SDH mutations. Molecular testing assists the diagnosis and classification of many types of soft-tissue tumour. Examples include Ewing’s sarcoma and alveolar rhabdomyosarcoma, in which specific fusion genes are diagnostic. FISH testing detects c haracteristic cytogenetic changes. In metastatic malignant melanoma, specific BRAF muta - tions predict response to the BRAF kinase inhibitor vemu - rafenib. Table 11.1 outlines the clinical applications of some bio - markers in tumours.

Mismatch repair gene abnormalities Multiple considerations (see ) KRAS or NRAS mutation Predicts resistance to EGFR inhibitors Tumour mutation burden Predicts response to ICI therapy BRAF V600E mutation Poor prognosis in metastatic CRC Predictive of response to therapy NTRK fusion Uncommon (<1% CRC) Usually MSI-H Poor prognosis Speci /f_i c therapy available: tyrosine kinase inhibitors Prediction of response to tyrosine kinase therapy Mutations EGFR KRAS BRAF V600E Fusions ALK RET NTRK Prediction of response to immune checkpoint inhibitors PD-L1 expression (in a subgroup)