Review Outlines Advancements in Precision Therapy for Metastatic Lung Cancer

In a new review published in The American Journal of the Medical Sciences, researchers outlined how targeted therapies and personalized medicine offer potential in redefining molecular lung cancer care.

Lung cancer is the leading cause of cancer death in the United States and is often diagnosed in the metastatic setting where it is incurable, authors explained, adding that nearly 30% of these cases might be driven by mutations that promote tumor growth and proliferation.

Although completion of low dose computed tomography screening for those at high-risk of lung cancer (ie, smokers or older individuals) will serve to improve mortality rates, estimates indicate that 10% to 20% of all new lung cancer diagnoses in the country are among individuals with no smoking history and thus fall outside current screening guidelines.

For some patients with the disease, recent developments in oral therapies have led to the replacement of cytotoxic chemotherapy with these treatments as the front-line standard of care.

In addition, because some patients with non-small cell lung cancer (NSCLC) may have an actionable mutation making them a candidate for these therapies, “understanding the biology of the patient’s tumor represents one of the best opportunities for personalized medicine currently known,” authors wrote.

A total of 7 known genetic alterations have targeted therapies approved for treatment of lung cancer in the first-line setting. These are most commonly observed when a patient has a history of adenocarcinoma, “but testing should be considered on all tissue types as mutations can be found in tumors of squamous or large cell histology, though less frequently,” researchers stressed.

Mutations can be identified via immunohistochemistry, fluorescence in situ hybridization, and by DNA sequencing with polymerase chain reaction, with the use of next-generation sequencing (NGS) becoming a promising tool to detect and report multiple mutations and fusions. NGS can be more cost-effective than the previously mentioned methodologies and oftentimes has superior sensitivity and specificity, according to authors.

Recommendations currently support the use of NGS when testing patients with NSCLC, while the method can also detect rare or emerging biomarkers to better guide clinical trial enrollment.

Liquid biopsy, or testing for actionable mutations in blood samples, also serves as a promising step forward in diagnosing molecular lung cancer. This mode has “improved the ability to characterize the molecular profile of cancers, especially in instances where there is inadequate tumor tissue for comprehensive biomarker analysis, and may allow for less invasive ways to monitor for recurrence of disease or development of new resistance mutations,” researchers said.

However, tissue biopsy may remain necessary in instances of low volume metastatic disease; for example, when the cancer is confined to the thorax.

Several expert panels also endorse testing for driver mutations in advanced stages of NSCLC, although this practice is not universally performed, with research showing patients with low socioeconomic status less likely to receive mutational testing or receive treatment with a targeted therapy.

“Racial disparities also exist, with Black and Hispanic individuals receiving lower rates of molecular testing than their White counterparts with lung cancer, despite data suggesting that some mutations may occur with higher frequency in Black patients,” investigators explained.

With regard to specific actionable targets in NSCLC, mutations in the epidermal growth factor receptor (EGFR) are the most studied and most prevalent. Data show that in the United States, 17% to 25% of new NSCLC cases have this mutation and it is more commonly found in non-smokers, patients with Asian ethnicity, and women.

This mutation was also the first to have a targeted drug for treatment developed. In comparison with chemotherapy, EGFR inhibitors consistently demonstrated milder toxicity profiles and improved quality of life among patients.

In addition to EGFR mutations, studies have also identified mutations in the anaplastic lymphoma kinase (ALK) in NSCLC, with ALK gene rearrangements present in up to 5% of patients and more common in younger individuals and those with no history of tobacco abuse.

The remaining genetic alterations identified in this disease are:

• Kirsten rat sarcoma viral oncogene or KRAS
• BRAF mutation
• V600E mutation
• Splice site mutations in the MET oncogene
• Gene fusions involving the neurotrophic receptor tyrosine kinase (NTRK)
• ROS proto-oncogene 1 (ROS-1)
• RET, a proto-oncogene
• Mutations in the human epidermal growth factor receptor 2 (HER2 or ERBB2)

“Less than 15% of all lung cancer diagnoses are made in patients younger than age 50, but in this group the incidence of driver mutations may increase by nearly 60%,” a finding that leads to unique challenges when it comes to treating younger patients with lung cancer.

For example, this patient population may be more vulnerable to financial and psychosocial obstacles compared with their older counterparts. Younger patients are also more likely to lack health insurance at the time of diagnosis, while additional challenges like fertility concerns may be present.

“It is paramount that for any patient with a new diagnosis of advanced NSCLC, especially young patients without significant smoking history, testing for driver mutations on both tumor tissue and potentially on peripheral blood is conducted,” researchers concluded.

“With the proper diagnostic approach to comprehensive testing, providers can seek to improve both quality and duration of life for their patients with a new lung cancer diagnosis.”

Reference

Quinn ZL, Barta JA, Johnson JM. Molecular lung cancer: how targeted therapies and personalized medicine are re-defining cancer care. Am J Med Sci. Published online April 21, 2022. doi:10.1016/j.amjms.2022.04.019