Lung cancer, one of the cancers with the highest incidence and mortality, is often called the "number one cancer killer." According to statistics from the World Cancer Report 2020, there were about 2.207 million new cases of lung cancer worldwide, and China alone accounted for 37.0% of global lung cancer cases and 39.8% of global lung cancer deaths. Most patients have non-small cell lung cancer (NSCLC), which is already at a middle or late stage when it is found, and the five-year survival rate is very low. How to improve the quality of life of lung cancer patients has therefore become a central concern in the field.

Based on differences in histopathological features, lung cancer can be divided into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), with NSCLC accounting for about 85%–90% of all lung cancers. According to the size of the primary tumour, the status of local lymph node metastasis and whether distant metastasis has occurred, lung cancer is classified as stage I, II, III or IV, and survival rates and treatment approaches differ greatly between stages. In the past, clinical research on lung cancer focused more on the treatment of advanced (stage IV) disease; the efficacy and safety of targeted therapies directed at gene targets such as EGFR, ALK and ROS1 have been confirmed in patients with advanced NSCLC, making them standard treatment options and enabling many advanced NSCLC patients to achieve long-term survival and a better quality of life. In recent years, clinical research focused on the treatment of early (stage I) and locally advanced (stage III) lung cancer has also gradually increased, with very encouraging results. At the 2022 Annual Meeting of the European Society for Medical Oncology (ESMO), which has just concluded, data from the ADAURA study showed that adjuvant targeted therapy in patients with resected early-stage EGFR mutation-positive NSCLC produced a sustained and significant benefit in recurrence-free survival, drawing global attention once again. Diagnosis and active treatment of early lung cancer can therefore bring greater benefit to patients.

So in clinical practice, what is the post-operative survival rate among patients with early-stage lung cancer, and does a risk of recurrence remain? And what is the prognosis once recurrence occurs? Beyond the existing guideline recommendations, is adjuvant therapy necessary for patients with early-stage lung cancer? How can we improve survival while reducing the burden of medication on patients and improving their quality of life? In this issue we have invited Professor Yang Haihong of The First Affiliated Hospital of Guangzhou Medical University to share her insights and reflections with us —

Guest of This Issue:

Professor Yang Haihong

The First Affiliated Hospital of Guangzhou Medical University

Chief Physician, MD, Master's Supervisor; Council Member of the Guangzhou Anti-Cancer Association

Chair of the Molecular Targeted Therapy Committee of the Guangzhou Anti-Cancer Association

Outstanding Young Medical Talent of Guangdong Province; Member of the Cancer Immunotherapy Committee of the China Medical Education Association

Standing Committee Member of the Lung Cancer Committee of the Guangdong Women's Medical Association  Member of the Psychosomatic Medicine Branch of the Guangdong Medical Association

Her main research focus is brain and meningeal metastasis of NSCLC, the comprehensive treatment of ALK-positive lung cancer, and multidisciplinary translational research on lung cancer.

Expert Interview

Q1

What Is Your View on Current Screening and Early Diagnosis and Treatment of Lung Cancer?

Is the Proportion of Stage I Lung Cancer You See in Clinical Practice High?

What Is the Situation with Diagnosis and Treatment?     

The earlier lung cancer is screened and treated, the greater the benefit. Early interventional surgery not only improves overall survival but also lowers overall medical insurance spending and the financial pressure on patients. Chest spiral CT has now been included in the routine health check-up for people over 40, and a great many pulmonary nodules are being detected. In our thoracic surgery department, 70–80% of operable patients now present with pulmonary nodules. Judging whether a pulmonary nodule is benign or malignant, however, depends heavily on the ability and experience of the person reading the images, and real problems exist in clinical diagnosis. Besides the thin-slice spiral CT recommended by guidelines, approaches now being explored include testing for methylation of cell-free DNA in peripheral blood to determine the nature of a nodule, and in the future proteomics-based tests may also be used for early screening and early diagnosis of lung cancer. One cannot say which of these approaches is best; for doctors and patients, a method that is less invasive, simple to perform, repeatable and inexpensive is a good one. For stage I lung cancer discovered through pulmonary nodules found at check-up, treatment is still essentially surgery-based, with a five-year survival rate above 70%, and for stage Ia it can be even higher, at around 80%.

Q2

What Is the Post-Operative Treatment Situation for Stage I Lung Cancer,                           

Do Recurrence and Metastasis Occur;

Are There Sufficient Intervention or Detection Methods Available?

Are There Related Products in Clinical Use?  

Lung cancer can still recur even after radical surgical resection. In our conventional understanding, the cure rate for stage I lung cancer after surgical resection is very high; in particular, most patients with stage Ia disease do not need adjuvant therapy and require only regular follow-up. In clinical practice, follow-up is generally every three months for the first two years and every six months for the following three years, with an observation period of five years; if there is no recurrence, the patient is considered cured. Relying on current detection methods alone, however, 20–30% of patients still relapse, and once relapse occurs it is advanced lung cancer, with a five-year survival rate of only about 10%.

Both for us as doctors and for patients, we would like more tools to support us, so that these patients can be identified at an early stage and given more active intervention or closer follow-up. After all, among stage I lung cancer patients, 70–80% will never relapse. Blanket intervention not only creates unnecessary financial pressure; overtreatment and excessive testing also lower patients' quality of life. If we had a suitable means of further stratifying patients with early lung cancer, and could select the 20–30% at high risk of recurrence for more active follow-up and appropriate interventional treatment, we could greatly improve survival, reduce the risk of recurrence and improve quality of life. The remaining majority of patients, who are at low risk, would also see their psychological burden greatly eased. At present there are no products in clinical use for the prognosis of stage I lung cancer; there are some genetic-level products for breast cancer, but not yet for stage I lung cancer.

Q3

Do You Have Related Research? How Is It Progressing?           

On the stratified prediction of prognostic risk in stage I lung cancer that I mentioned earlier, ProteinT is currently developing such a product. Because CT has become part of the routine chest examination, 70–80% of surgical patients have stage I lung cancer; although the cure rate after surgery is high, 20–30% of patients still relapse, and relapse is a heavy blow to patients, with an unfavourable prognosis. Working at the proteomic level, this product aims to stratify patients' recurrence risk and identify those at higher risk, so that more targeted intervention can be given. A prediction model covering 500 patients has now been established, with high sensitivity and specificity, and it can effectively assist us in the auxiliary assessment of recurrence risk. The related product is now moving into clinical translation.

Q4

What Is Your View on MRD Testing for Lung Cancer Patients?        

In clinical practice, follow-up for patients with stage Ia disease is relatively lax, and they may not attend their appointments on time. By the time CT reveals a lesion, recurrence or metastasis may already have occurred. MRD testing, by detecting minimal residual disease in the blood, can find lung cancer earlier than imaging. At present, MRD follow-up is performed mainly at the level of peripheral blood DNA using NGS, with monitoring every six months. The depth of the NGS panels used in current clinical testing is, however, insufficient, and there is doubt as to whether true MRD detection can be achieved. MRD testing at the proteomic level has considerable room to grow in the future and is well worth anticipating as protein technology continues to advance; compared with genes, proteins may after all be more accurate and more stable, but a certain technical level must first be reached in order to capture the relevant proteins.

Another point concerns patients with advanced disease: after treatment with immunotherapy drugs, current imaging cannot reflect the treatment effect well. This problem did not arise with targeted drugs and chemotherapy drugs in the past, but after immunotherapy the mass may still be present, and it may not consist of tumour cells but of necrotic tumour cells or infiltration. Without surgery, current imaging cannot reveal this. This also creates difficulties for doctors in diagnosis; all we can do is ask the patient to keep observing. Today's MRD testing, however, can provide a signal from peripheral blood, complementing the shortcomings of imaging.

Q5

What Is Your View on the Prospects of Proteomics Technology?                   

There are limitations at the genetic level. For example, when a patient develops drug resistance, nothing abnormal may be found at the genetic level, yet the problem may actually lie in a protein pathway, and the genetic level cannot provide further guidance. Proteomics technology, by contrast, makes it possible to identify abnormalities in the relevant pathways. In fact, many small-molecule drugs acting on proteins already exist — for example, some drugs for diabetes and cardiovascular disease that act on the same abnormal pathways — and using them in combination may reverse drug resistance.

Overall, whether we are talking about genomics or proteomics, we must return to the disease itself; both are technical means for solving real clinical problems. I hope that in future more products will be genuinely based on the problems encountered in clinical practice, starting from real needs and solving the problems we actually face, and only being turned into products once the problem is well solved. Not products conceived out of thin air, like some on the market that merely test whether something is a tumour or not, which is meaningless to us.

As clinicians, what we care about most is whether the problems we encounter in clinical practice can be solved. If genomics, proteomics, or a combination of approaches can help us solve the difficulties we truly face, then even solving part of the problem and complementing existing treatment methods would give doctors more help and benefit more patients!