Combination Targeted Therapies may Improve Outcomes in Advanced Non-Small Cell Lung Cancer (NSCLC)

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Highlights:

• Targeted therapies to treat non-small cell lung cancer act on specific molecular targets to prevent the proliferation of the cancer cells
• The treatment of advanced non-small cell lung cancers with an EGRF inhibitor was complicated by the appearance of new genetic mutations in a study
• New guidelines may be required with respect to the use of targeted treatments to treat cancers

Recent research reveals that multiple genes may drive a non-small cell cancer of the lung and genetic changes may occur during the treatment with targeted therapy, which could make the treatment ineffective. The research was published in Nature Genetics. Cancer treatments have moved much beyond the conventional surgery, radiotherapy and chemotherapy. Drugs have been developed that target certain abnormal proteins in the cancer cells and prevent their proliferation. The drugs target proteins that are either excessive in the cancer cells, or are a result of a mutant gene in the cancer cells. Such treatment, called targeted therapy, has the advantage of a better effect on the cancer and lesser side effects on the other parts of the body.

It has been assumed that a single gene is responsible for driving a particular type of cancer. Treatment that is targeted against the particular gene is used to treat the cancer.

When targeted treatment is used to treat advanced non-small cell lung cancer the patient responds initially, but often the cancer recurs. To understand the reason for this, scientists studied the genes from the blood samples from more than 2000 patients with advanced stage non-small cell lung cancer. Among these, the cancers from 1122 patients had the mutated epidermal growth factor receptor (EGRF) gene while the cancers from 944 patients did not have the abnormal gene. The scientists also studied the genetic changes that took place in the cancer of a patient (who received targeted therapy) sequentially on seven different occasions.

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The scientists found that

• More than 90 percent cases of the cancer had additional genes along with the EGRF mutation that could be responsible for driving the cancer. The number of these mutations was even as high as 13.
• Mutations in the TP53 gene were noted in more than 50 percent of the cancers. The TP53 gene controls the production of the p53 protein, a protein that suppresses cancer. Therefore mutations in the gene have been associated with cancer.
• Other genetic mutations that were noted involved the receptor tyrosine kinases, RAS-MAP kinase, PI3 kinase, Wnt/beta-catenin, as well as in the genes involved in cell division, epigenetic modifications, DNA repair, and cellular signaling pathways.
• Some patients with an EGRF mutation who received targeted treatment developed additional mutations that worsened the prognosis for the patients.

The scientists therefore suggest that non-small cell lung cancer is driven by multiple genes rather than a single gene. Thus, targeting a single gene is unlikely to be a complete response since alternate genes may drive the cancer.

The exposure to only one targeted drug could also result in resistance due to the possible development of additional mutations, which could make treatment even more difficult and leave no options for the patient.

To overcome such problems, the scientists suggest targeting multiple proteins through a combination of targeted treatments rather than using a single drug. Another approach would be to monitor the tumor genes during treatment of the cancer and change the treatment according to the genetic changes.

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About Non-small Cell Lung Cancer

Non-small cell lung cancer is the most common type of lung cancer  accounting for around 80 to 85 percent of cases. It includes adenocarcinoma, squamous cell carcinoma, and large cell carcinoma, along with other rarer cancers. Smoking is a prominent risk factor for lung cancer. Symptoms of the cancer may include cough with blood-tinged sputum, chest pain, shortness of breath, hoarseness and weight loss. The cancer can spread to distant organs like the liver, bone and brain. Treatment is with surgery, radiation, chemotherapy, targeted therapies and immunotherapy.

Targeted therapies used for the treatment of non-small cell lung cancers include the

• Angiogenesis inhibitors (drugs that prevent proliferation of blood vessels) that include bevacizumab and ramucirumab
• Epidermal growth factor receptor (EGRF) inhibitors
• Drugs that target abnormal ALK protein that include crizotinib, ceritinib, alectinib and brigatinib
• BRAF inhibitor dabrafenib
• MEK inhibitor trametinib.

The EGRF inhibitors include

• Erlotinib, afatinib and gefitinib
• EGRF inhibitors that also target cells with the T750M mutation i.e. osimertinib
• EGRF inhibitor used in squamous cell non-small cell lung cancer i.e. necitumumab.

Reference:

1. Blakely CM et al. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nature Genetics 2017;  doi:10.1038/ng.3990
2. Targeted Cancer Therapies - (https://www.cancer.gov/about-cancer/treatment/types/targeted-therapies/targeted-therapies-fact-sheet)

Source-Medindia