Auntie Fang is 68 years old and worked as an administrator in an institution before she retired, never smoked and none of her family members smoked.
Thirteen years ago (2004), she had a CT during a medical checkup and inadvertently “saw” a mass in her lung. The tumor in the middle lobe of the right lung had grown like a date (3*4 cm).
Auntie Fang underwent lobectomy and lymph node dissection, which was determined to be a stage IIb, low- to moderate-differentiated adenocarcinoma. Four cycles of chemotherapy (vincristine + cisplatin) were given after surgery.
In 2007, she had pain and difficulty moving her right leg and went to the hospital for an intensive CT and MRI, which showed that the lung cancer had metastasized to the femoral neck of her right leg, when no lesion was found in the lung.
On the advice of the doctor, Auntie Fang had two more cycles of chemotherapy, but her leg pain did not improve; she tried local radiotherapy, but her leg pain was better, but she still had difficulty moving around, and she felt uncomfortable in her right leg at night.
The family was desperate because of the lack of results from radiation and chemotherapy.
At this point (April 2008), the doctor suggested that since radiation and chemotherapy had failed, a new drug called gefitinib could be tried. This drug, unlike traditional chemotherapy, inhibits the epidermal growth factor receptor (EGFR) gene, a “driver gene” of lung cancer development, and “hits” the tumor like a target. The drug is called a “targeted drug” because it inhibits a “driver gene” of lung cancer – the epidermal growth factor receptor (EGFR) gene – and “hits” the tumor like a target, with little effect on normal cells.
With confidence, Auntie Fang started to take the drug, once a day, one pill, which is much easier than chemotherapy and radiation therapy. Although it was expensive, she was lucky enough to receive a charity gift of the drug six months after taking it.
After taking the drug, her bone pain was significantly reduced, and she was able to walk freely without crutches. 10 years later, she has not used any anti-tumor treatment except for gefitinib, and she is doing well, taking care of herself and going to the park.
One of the “unusual” ones: can I also “blindly” try a targeted drug?
The first time I tried a targeted drug was in 2015.
From the first EGFR-TKI (epidermal growth factor receptor-tyrosine kinase inhibitor) drug, gefitinib, which was launched in China in 2015, to oseltinib, which has just been launched, there are now at least five EGFR inhibitors for lung cancer in China, including gefitinib, erlotinib, and erlotinib in the first generation, afatinib in the second generation, and oseltinib in the third generation.
The consensus in the professional community is to check for EGFR gene mutations before taking these drugs. This is because only tumors that carry sensitive mutations will be killed by targeted drugs; if the tumor does not carry the mutation (also known as a “wild-type tumor”), the targeted drug becomes a “targetless” drug and will not be effective. This research was first discovered and reported by the team of Professor Mo Shujin from the Chinese University of Hong Kong and Professor Wu Yilong from the Guangdong Provincial People’s Hospital (IPASS study), and has since been validated by many studies in China and abroad.
How is this genetic test done? It’s very simple. Usually, when lung cancer is diagnosed, a piece of tumor tissue is taken for a “biopsy,” which is a pathological examination, and this piece of tissue can be used for genetic testing to look for EGFR and other sensitive genetic mutations through specific techniques. If the result is “positive,” that is, if it has a sensitive mutation, then targeted therapy is preferred, which is more effective than chemotherapy and has fewer side effects.
In addition to EGFR, a genetic test will describe the presence or absence of mutations in many other genes. But not all genetic mutations can be treated with targeted drugs, such as KRAS mutations, for which no drugs are currently available. Even for the EGFR gene, not all mutations have a target drug, but currently drugs are available for mutations in exons 19 and 21 (the most common), but if an insertional mutation in exon 20 occurs, there is no drug available.
It’s like a key.
It’s like a key to a lock, and some locks don’t have a key yet. So when you get the genetic test report, you need to consult with a medical professional for specific medication recommendations.
Today, there are still many patients who ask “Can I skip the genetic test and ‘blind test’ a handful of times because they lack tumor tissue specimens, or are concerned about the cost of testing?” The answer is: this approach is not advisable. The answer is: this is not advisable because the probability of success of a “blind” trial of a targeted drug is very low when the genetic status is unknown. It is likely to cost money and delay treatment.
About 30% of all lung cancer patients have EGFR mutations, and the IPASS study mentioned earlier identified a so-called “predominant population” of Asian, female, nonsmoking adenocarcinoma patients. This group has a high EGFR mutation rate of up to 60%, and Auntie Fang happens to be in this group. But even in this “advantaged group,” the professional community still does not recommend “blind” targeted therapy. The majority of male smokers with lung cancer should not take the chance to “blindly try”, but follow the doctor’s instructions to do chemotherapy may be more certain.
In addition, a hot concept in recent years is “liquid biopsy,” which means using liquid specimens for genetic testing instead of tumor tissue, including blood, pleural fluid, pericardial fluid, and even saliva and urine. In fact, due to the limitations of the existing testing technology, the sensitivity of liquid biopsy is not sufficient, and the use of tumor tissue testing is still the “gold standard” recognized by the professional community. The current international consensus is that blood, pleural fluid, and pericardial fluid should be used for EGFR genetic testing only when tumor specimens are not available.
There are many other people who have negative genetic test results, do they need to try targeted drugs? The answer is: not recommended. As mentioned earlier, many studies at home and abroad have well demonstrated that only patients with EGFR-sensitive mutations benefit from targeted therapy; patients without mutations are less than 10% effective and less effective than chemotherapy, so it is not recommended.
“Unusual” #2: Gefitinib worked for 10 years, can I be so lucky?
The first time I took gefitinib, it worked for 10 years.
Targeted therapy is good, but the biggest problem is drug resistance, especially with a generation of targeted drugs, and usually after a period of time (9-13 months on average), the original lesion expands or new metastases appear, which often means that the tumor is resistant and the targeted drug has failed. This often means that the tumor is resistant to the drug and the targeted drug has failed. Those who still take the drug for 10 years are rare like Auntie Fang. The first time I saw this, I was able to get to the bottom of it.
This is a question that the professional community does not yet have a definitive answer to.
The team of Professor Yilong Wu found that the “abundance” of mutated genes – that is, the proportion of tumor cells carrying the mutation to all tumor cells – has an important impact on the duration of targeted drug efficacy. The team found that the “abundance” of mutated genes – that is, the proportion of tumor cells carrying the mutation to all tumor cells – has a significant impact on the length of time that targeted drugs are effective. Another expert in the field of lung cancer, Professor Tension of the Cancer Hospital of Sun Yat-sen University, also found that mixing in other mutations may affect the duration of efficacy.
In addition to the drugs themselves, the patient’s own positive and optimistic mental state and scientific and careful family care can help maintain good immune function and give us the upper hand against the tumor.
Not so lucky, what should I do?
There are very few “lucky” people like Auntie Fang. Most patients who take a generation of targeted drugs become resistant to them after a few months to a year or two, so what should I do?
The cause of tumor resistance is still an open question, but some mechanisms have been identified. For example, some tumor cells develop new genetic mutations that evade the targeted drugs. This is like tumor growth needs an “engine” (driver gene), the targeted drugs can make this engine “shut down”, but the cunning tumor quickly find a new “engine”. We need to find out who this new engine is and then design new targeted drugs to destroy it.
The T790M mutation in the EGFR gene is one such new “engine” that causes about 50% of the resistance to a generation of targeted drugs, and the third-generation targeted drug, axitinib, which has just been introduced in China, is a tool to specifically “extinguish” the T790M “engine. “The first generation of T790M is the most important one.
So drug resistance is not something to be afraid of, and once it happens, doctors usually recommend taking another biopsy, doing a genetic analysis, and choosing a new targeted drug for the emerging mutation information. The so-called devil is one foot high, the road is one foot high, for several common variants, such as T790M, C-MET gene amplification, EGFR gene amplification, etc., there are already targeted drugs on the market at home and abroad. There are also some genetic variants for which no new drugs are available yet, but some are already in clinical trials and doctors will recommend appropriate patients to try them.
Some patients who have developed resistance to targeted drugs have been genetically tested again and no new “engine” has been found, so they can’t use the targeted drugs. The new genetic test did not find a new “engine”, so there is no way to use the targeted drug. Does this mean that there is no cure? No, it doesn’t! In fact, classical chemotherapy is still an option as long as the body type allows. And clinical studies have shown that patients who have had both targeted therapy and chemotherapy actually survive the longest, longer than those who have had only one or the other, which seems to be a reward for the indomitable tumor fighters.
Professor Yilong Wu’s team has done studies describing three scenarios after targeted therapy resistance and the corresponding responses by physicians.
Local progression:
Most lesions remain stable, and only a few progress. At this point, you can continue to take the original targeted drug and do local treatment of the progressed site, such as minimally invasive surgery, radiation therapy, radiofrequency ablation, etc.
slow progression:
The lesion grows gradually, but very slowly, sometimes only a few millimeters in six months, and causes no symptoms, so the doctor will usually “keep it quiet” and recommend continuing to take the original drug and monitoring the disease closely without rushing to increase the dose or change the regimen.
Outbreak progression:
The tumor is progressing fully, growing rapidly, and causing significant discomfort. In this case, it is usually time to change the drug. If there is no appropriate targeted agent, the doctor will consider whether chemotherapy is possible.
In short, having lung cancer is like a head-to-head battle between us and the tumor, and the battlefield changes frequently, sometimes we win the initiative, sometimes it gets the upper hand. In this tough and protracted battle, trust in science, trust in doctors, perseverance and resistance to the end, the flower of life is wounded but not thankful, will be the highest reward for us.
Disclaimer:
Tumor disease and treatment options are extremely complex, and treatment should be fully individualized, and this case does not represent a treatment decision for a “similar patient. Please seek professional advice from your supervising physician regarding your specific treatment plan.