Category Archives: Mutations

Neratinib for breast cancer – the key is managing gastrointestinal toxicity

Neratinib is an irreversible tyrosine-kinase inhibitor of EGFR (epidermal growth factor receptor), as well as HER1, HER2, and HER4. It is being developed for patients with breast cancer. It blocks many signal transduction pathways that result in proliferation and invasion, leading to cell cycle arrest and apoptosis. (Figures 1 and 2). Continue reading

CDKN2A Mutation Shortens Survival in Melanoma Patients

Individuals that carry mutations to the CDKN2A tumor suppressor gene have 65-fold increased risk of developing melanoma and a lifetime penetrance of melanoma of 60-90%. In a new study by researchers from the Karolinska University Hospital in Sweden, individuals who had inherited CDKN2A mutations were on average 10 years younger at their melanoma diagnosis than the non-mutated familial melanoma cases. Continue reading

Mechanisms of Melanoma Resistance to PD-1 Checkpoint Inhibition

It is estimated that about 40 percent of patients with advanced melanoma, the deadliest form of skin cancer, will initially respond to an immunotherapy, but about a quarter of those 40 percent will relapse within three years of treatment. In order to identify the mechanisms by which resistance to PD-1 inhibition is mediated, UCLA researchers studied biopsies of melanoma tumors taken before and after treatment with Keytruda (pembrolizumab) in patients whose cancer had returned. Continue reading

Intra-tumor heterogeneity leads to sampling bias and biomarker failure – Conor McAuliffe, Contributor

A growing understanding of genetic variation both between histologically similar tumors from different patients and within individual tumors themselves is shedding light on the difficulties in treating cancer and developing biomarkers to diagnose it. It has long been known that a single tumor displays differences in morphology, nuclear shape, proliferation, and proportions of constituent cell types. However, these differences may be only be the “tip of the iceberg” as vast genetic and epigenetic variations that underlie them have been discovered between and within tumors. Continue reading

Rociletinib for Resistant Non-Small Cell Lung Cancer Patients with EGFR T790M Mutation – Anthony J. Meglio, Contributor

There are two major subtypes of lung cancer: Non-Small Cell Lung Cancer (NSCLC), which accounts for 85% of all cases,  and Small Cell Lung Cancer (SMLC).  About 60% of NSCLC are unresectable at diagnosis, hence, the poor prognosis – ten to twelve months survival when treated with platinum-based chemotherapy.  Treatment options are evaluated based on the histologic subtype and the presence of mutations to determine the the best combination of molecular therapies for treatment. Ten to twenty percent of patients with NSCLC have a mutated epidermal growth factor receptor, most commonly. a deletion in the in-frame of exon 19 (around amino acid 747 to 752) or a L858R point mutation of exon 21. On June 1, 2016, the FDA approved the first blood test (liquid biopsy) companion diagnostic to determine whether these mutations are present. Continue reading

Saliva Test to Detect EGFR Mutations and Guide Therapy in Lung Cancer

A new technology called electric field–induced release and measurement (EFIRM) is able to detect biomarkers in saliva for non-small cell lung cancer (NSCLC). The test detects circulating tumor DNA (ctDNA). It is able to detect actionable EGFR (epidermal growth factor receptor) mutations in NSCLC patients with 100% concordance with biopsy-based genotyping, Dr Wong (study author) said, and it can detect the most common EGFR gene mutations that are treatable with TKIs (tyrosine kinase inhibitors), such as gefitinib (Iressa, AstraZeneca Pharmaceuticals LP) or erlotinib (Tarceva, Genentech/Roche). Continue reading

Additional Drivers and Pathways in Basal Cell Carcinoma

The Sonic hedgehog (Hh) pathway is known to be important in basal cell carcinoma (BCC), which as an extremely common skin cancer that only rarely invades and metastasizes. An approved drug for patients with advanced BCC, Vismodegib (Erivedge), interferes with the Hedgehog pathway. The Patched (12 membrane-spanning receptor protein) normally disables Smoothened (7 membrane-spanning protein) rendering it functionally inert. This maintains transcription factor Gli in a cleaved state, acting as a transcriptional repressor. When Hedgehog proteins bind to Patched, Smoothened is released and protects Gli from cleavage. Uncleaved Gli travels to the nucleus and is an inducer of transcription, increasing Cyclin D1 and stimulating the cell cycle (proliferation). Vismodegib blocks the actions of Smoothened. It is administered orally in 150 mg capsules.

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Priority Review for Potent Novel Therapy for Chronic Lymphocytic Leukemia (CLL)

Venetoclax is a novel cancer therapy being developed by Roche and AbbVie. The U.S. FDA has accepted the New Drug Application and granted Priority Review and Breakthrough Therapy Designation for venetoclax for the treatment of people with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy, including those with 17p deletion. Continue reading

Biomarkers for Wnt activation Predict For HER-2(-) Breast Cancer and NSCLC Response to Vantictumab

OncoMed is developing several compounds that target Wnt and Notch pathways, which are important in cancer and cancer stem cell maintenance, survival, and proliferation. Biomarkers for response of Her-2-negative breast cancer and non-small cell lung cancer (NSCLC) following treatment with Vantictumab, anti-Wnt monoclonal antibody, have been developed. Continue reading