Is genetic testing (liquid biopsy) reliable? Which lung cancers require genetic testing?

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In recent years, the term "genetic testing" has frequently appeared in our lives. More and more people are using genetic testing to understand their health conditions, prevent diseases and plan their health. At the same time, there are also many people who are curious about this new technology. Genetic testing, what exactly is it? Should I get genetic testing for lung cancer? Which lung cancers require or are suitable for genetic testing? These are the questions that this article focuses on.

Genetic testing is a technique for detecting genetic material (DNA, RNA) through blood, other body fluids or cells. It involves taking oral mucous membrane cells, blood or other tissue cells shed by the subject, amplifying their genetic information, and then testing the genetic material information in the subject's sample through specific equipment to analyze the various genes or genetic mutations it contains.

Human tumors are very different, and even for the same type of tumor, the treatment effect and method should be different from person to person, and this kind of different disease treatment method is called "individualized treatment". Therefore, in the process of cancer treatment, only by treating the same disease differently and implementing individualized treatment, can we choose the appropriate drugs for different types of patients. Therefore, the detection of amplification/mutation/expression of specific genes in tumors can be used to tailor the most suitable treatment plan for each patient.

Although factors such as smoking and environmental pollution play an important role in the development of lung cancer, genetic mutations play a major role in the development of lung cancer. Medical research has confirmed that lung cancer occurs due to the accumulation of mutations in dozens of genes (including oncogenes, oncogenes, etc.) in the body, combined with the stimulation of environmental carcinogenic factors.A 2017 article published in the prestigious journal Science states that 33.4% of lung cancer occurs from random mutations in somatic cells, 66.1% from environmental factors, and only 0.5% from genetic factors. Random mutation means what we usually call "luck", which means that even if you live a very healthy life, you can still develop lung cancer due to "bad luck".

Although lung cancer chemotherapy has been developed for decades with many updates, it has now entered a bottleneck period with very limited improvement in overall effectiveness. Until the advent of targeted therapeutic drugs brought light to the treatment of lung cancer. Currently the most widely known are the use of EGFR-TKI drugs such as Eressa, Troche or Kemena have made the treatment of lung adenocarcinoma much more effective. The main principle of action of these drugs is to target the EGFR on the surface of lung cancer cells to exert anti-cancer effects.

Why do I need genetic testing before targeted lung cancer treatment?

The initial use of targeted drugs in lung cancer treatment was a bumpy ride: first, the definitive international study (the First-SIGNAL study) showed that targeted therapy combined with chemotherapy did not increase efficacy compared to chemotherapy alone; furthermore, the ISEL study showed that even when compared to placebo, targeted drugs did not prolong patient survival. These studies pretty much cut off targeted therapy drugs for lung cancer. But careful researchers found a strange phenomenon: targeted therapy drugs were almost ineffective in Western populations, but showed miraculous results in Eastern populations, significantly prolonging survival. The scientists eventually found the reason through genetic testing, it turns out that the probability of EGFR mutation in the Chinese population is about 40%, while the United States is only 2% to 10%, and then through clinical trials (IPASS study) to confirm the survival benefit of targeted drug treatment for people with EGFR mutation than chemotherapy.

Immunotherapy, represented by anti-PD-1 drugs, has also emerged in recent years as a major breakthrough in the field of lung cancer treatment. It works by blocking the PD-1/PD-L1 signaling pathway in tumor cells and activating the body's own immune cells, "T cells", to restore their ability to fight cancer, thereby killing tumor cells. To work, this treatment relies on genetic testing to determine the expression of PD-L1 on the surface of tumor cells. In one study, anti-PD-1 drugs did not have a significant advantage over chemotherapy for lung cancer patients with PD-L1 expression >1%, while another study (KEYNOTE-024 phase III clinical trial) found that anti-PD-1 drugs (pabumab) were significantly more effective than chemotherapy in lung cancer patients with PD-L1 expression ≥50%. Therefore, the well-known NCCN guidelines also recommend anti-PD-1 drugs (pabumumab) as first-line treatment for lung cancer patients with PD-L1 expression ≥50%.

If targeted therapy or immunotherapy is the new weapon in the treatment of lung cancer, then genetic testing is the aiming device of this weapon. Targeted drugs are missing the aimer, and targeting without the aimer is blind. Then it will definitely not hit properly.

So, which lung cancer patients actually need genetic testing?

First, the primary purpose of genetic testing is to guide targeted therapies, and genetic testing is required for anyone considering targeted therapies. Although some studies of genetic testing to guide chemotherapy drug selection have been reported, there is still a lack of high-quality clinical evidence that needs to be treated with caution. Patients with advanced lung adenocarcinoma require genetic testing to guide the selection of targeted agents according to the recommendations of the NCCN guidelines.

In contrast, the preferred treatment modality for patients with early to mid-stage lung cancer is a combination of surgical treatment combined with postoperative adjuvant therapy. There is no evidence to prove the benefit of postoperative targeted therapy for stage I lung cancer. A recent high-quality clinical study conducted by Chinese scholar Professor Yilong Wu showed that stage II-III EGFR mutation-positive lung cancer patients can benefit from postoperative targeted therapy, and it is significantly better than postoperative adjuvant chemotherapy. Therefore, postoperative genetic testing is recommended for patients with stage II-III lung adenocarcinoma to guide the dosing of next adjuvant therapy.

Due to the low EGFR mutation rate of approximately 2.7% in patients with squamous lung cancer and the fact that even patients with squamous lung cancer with EGFR mutations are not as sensitive to EGFR-TKI-targeted drugs as adenocarcinoma. There is no clinical evidence that patients with EGFR mutation-positive squamous lung cancer benefit from EGFR-TKI-targeted drugs. Therefore, genetic testing for EGFR is not recommended for all patients with squamous lung cancer, although it is still relevant for some patients with advanced squamous lung cancer. Based on the Cancer Genome Atlas, 96% of 178 squamous lung cancer samples had genomic abnormalities, and two targeted drugs, ramolutumab and Necitumumab, have been approved in combination with chemotherapeutic agents for the treatment of squamous lung cancer. In addition, patients with squamous lung cancer can undergo genetic testing for PD-L1 to determine the availability of anti-PD-1 immunotherapeutic agents.

So does a patient need to be genetically tested again if they are resistant to a targeted therapy drug?

The answer is yes. Resistance to targeted drugs is also a result of genetic mutations at work. Genetic mutations change during the course of tumor treatment, so genetic testing is theoretically required before each phase of targeted therapy to guide drug selection. Studies have shown that approximately 50% of EGFR-TKI resistant patients have T790 mutations and that the use of a third generation TKI drug, Theresa (AZD9291), is effective in overcoming this resistance.

In short, people who intend to use targeted therapies or apply immunotherapy drugs are the right people for genetic testing. Like targeting, genetic testing is the "aiming device" for the target.

Note: Reprinted from a 2017 science article by Dr. Jigang Dai of Good Doctor Online

Is genetic testing (liquid biopsy) reliable? Which lung cancers require genetic testing?