Genetic testing guides the treatment of ALK positive lung cancer

If a doctor informs a patient that they have a mutation in the ALK gene, or ALK-positive lung cancer, understanding what this means is the critical first step. The ALK gene mutation was discovered in 2007 and is more precisely a gene rearrangement — a fusion of two genes called ALK and EML4 (Echinoderma microtubule-associated protein type 4). This abnormal fusion gene encodes an abnormal protein called tyrosine kinase, which acts as a chemical messenger sending signals to the cell growth center, driving cancer cell division and proliferation. In short, tyrosine kinase "drives" the growth of cancer, which is why mutations such as EML4-ALK are called "driver mutations."

ALK-positive lung cancer refers to lung cancer patients in whom the ALK mutation (EML4-ALK fusion gene) has been detected. This mutation occurs in 3–5% of people with non-small cell lung cancer — and while this may seem a small percentage, given the large number of lung cancer diagnoses globally, it represents a substantial patient population. This fusion gene has also been found in patients with neuroblastoma and anaplastic large cell lymphoma. Importantly, this is not an inherited mutation like BRCA1 or BRCA2 — it is an acquired mutation that occurs in some cancer cells as part of the process of cancer development, meaning it is not passed down from parents

The EML4-ALK fusion gene is most commonly found in patients with lung adenocarcinoma — a type of non-small cell lung cancer — and is rarely found in patients with lung squamous cell carcinoma or small cell lung cancer. Certain populations are more likely to carry ALK fusion genes, including young non-smokers or very light smokers, women, and individuals of East Asian ethnicity. A recent study found that nearly 50% of young patients under the age of 40 with lung cancer tested positive for the EML4-ALK fusion gene, compared to just 3–5% of lung cancer patients across all age groups.

The consensus among major institutions is that all patients with advanced adenocarcinoma should be tested for both ALK mutations and EGFR mutations, regardless of gender, smoking history, or race. ALK gene mutations are diagnosed through molecular analysis of tumor cell samples, which requires sufficient lung biopsy tissue or surgical tissue. While blood tests such as CEA (carcinoembryonic antigen) may provide indirect clues — as CEA is mostly negative in patients with ALK mutations — molecular-level genetic testing remains the gold standard and the best available diagnostic tool. Genetic testing that identifies driver mutations and guides targeted therapy is the core of precision cancer treatment, and every lung cancer patient should pursue it to obtain the most accurate and individualized treatment plan.

Although the ALK mutation in lung cancer was only discovered in 2007, FDA-approved treatments specifically targeting this mutation already exist. The primary medication is Xalkori (crizotinib), a tyrosine kinase inhibitor that adheres to the surface of lung cancer cell tyrosine kinase receptors, blocking the abnormal ALK protein. A useful way to understand the mechanism: the tyrosine kinase receptor acts as a lock, and the abnormal tyrosine kinase protein acts as a key. In ALK-mutated patients, this abnormal "key" continuously sends growth signals to cancer cells. Xalkori works by blocking the keyhole — preventing the abnormal protein from transmitting the signal for cell division, effectively stalling tumor growth.

Unfortunately, drug resistance to Xalkori almost always develops over time, even in patients who initially respond well. For those who develop resistance, additional treatment options are available. Roche's Alectinib was approved in 2013 as a treatment for ALK-positive lung cancer following resistance to crizotinib. In March 2014, Zykadia (ceritinib) was also approved by the FDA as a breakthrough treatment, with an initial response rate similar to Xalkori and the added benefit that many patients who develop resistance to Xalkori still respond to Zykadia. Clinical trials continue to study new drug treatments for patients with drug resistance, and researchers are hopeful that patients will eventually be able to receive continuous sequential drug therapies as resistance develops — treating lung cancer more like a manageable chronic disease rather than a terminal one. Finding mutant genes through genetic testing and achieving individualized treatment of lung cancer has always been the goal of oncologists worldwide.