Molecular Subtypes Make SCLC Treatment a Dynamic Practice


In an interview with Targeted Oncology, Penn Medicine’s Qian Wang, MD, MPH, gives an in-depth overview of the molecular targets in the small cell lung cancer field.

Male lung cancer biopsy respiratory system in x-ray. 3d render | Lungs | Image Credit: © Vector Market -

Lungs | Image Credit: © Vector Market -

Today, oncologists have a better understanding of the various subtypes of small cell lung cancer (SCLC) compared with previous years. Research has discovered new biomarkers to develop therapies for SCLC, and such therapies appear successful. However, more information is needed about the molecular landscape, according to Qian Wang, MD, MPH.

“This field is a rapidly evolving field. There are many, many biomarkers have been discovered and have been validated,” explained Wang, clinical instructor of Medicine, Rutgers Robert Wood Johnson Medical School and physician at Penn Medicine, in an interview with Targeted Oncology™.

Wang did explain, however, that much of the research has not been validated. Most studies on molecular targets are in the early stages and cannot inform therapeutic research or treatment in the clinical setting.

In the interview, Wang discussed molecular subtypes of SCLC and how to approach research to better treat patients with SCLC in the future.

TARGETED ONCOLOGY: What can you share about the changing incidence of small cell lung cancer among patients both globally and in the United States?

Wang: We know that small cell lung cancer accounts for about 50% of all lung cancer cases. Most of the epidemiological studies combine a small cell and non–small cell lung cancer as 1 group. So, in the data, the incidence and mortality data are combined.

From the Global Cancer Statistics 2020, we know that lung cancer remains the most common cancer in males, and the third most common cancer in females. It continues to be a leading cause of cancer-related death in males and second for females. In 2020, there were about 1.4 million lung cancer cases in males globally, and about .8 million lung cancer cases in females. Among those, approximately about 15% of them are small cell lung cancers.

Smoking is the predominant cause of lung cancer, especially for small cell lung cancer, so the incidence and mortality lags about 20 to 30 years behind the trends in smoking rates. It dates back to the 1960s, including in the [United States] and some other countries around the world. Once they started the Tobacco Control Program in the late 1990s and 1980s, the smoking incidence and the lung cancer incidence started to downtrend, including small cell lung cancer.

Can you discuss the key risk factors associated with SCLC?

As I mentioned, smoking is the most predominant risk factor for small cell lung cancer. This is more important for small cell lung cancer than other lung cancer, because about 95% of small cell lung cancer can be attributed to smoking, and this number is cited as lower for non–small cell lung cancer. In non–small cell lung cancer, we know up to 25% can be non-smoking related, but I think another important thing to note is that we have several smoking metrics to assess the effect of smoking on lung cancer risks, including small cell lung cancer.

What is known to us is the pack years, which is packs per day, the intensity times duration, and how long have been smoked. But studies have shown that those 2 factors contribute differently. For example, for total, or equal total exposure or pack years, smoking at a lower intensity over a longer period leads to a higher risk of lung cancer, including small cell lung cancer, compared with smoking at a higher intensity over a shorter time. This means that the duration probably contributes to more lung cancer risk than the intensity.

The other important thing is to be aware is the age at initiation and studies have shown that people who smoked early are at a much higher risk of developing small cell lung cancer than those who started later. This is a more prominent or more problematic or more significant for small cell lung cancer.

Lastly, I think we are seeing more e-cigarettes and vaping. The data have shown that from 2013 to 2020, the e-cigarettes users has almost tripled from 21 million to 68 million. Among them, about half of them are younger individuals. There are some early studies have shown that e-cigarettes produce more carcinogens such as the formaldehyde, compared with the traditional cigarettes. Also, those who smoke e-cigarettes are more likely smoke real cigarettes later in life. I think this is more problematic for younger people or younger individuals, when they start to smoke e-cigarettes or vape.

There are some other risk factors including occupational or environmental exposure I want to point out, especially a residential radon exposure. This has been found to link to a higher risk of small cell lung cancer. There are other environment exposures such as indoor and outdoor air pollutants.

Can you discuss molecular pathology in this patient population? What does research suggest regarding different molecular pathways in SCLC development?

We know that small cell lung cancer is known for a loss of 2 tumor suppressor genes. One is called RB1, and the other one is called TP53. About 90% of small lung cancer cases have loss of those 2 genes. There are also other gene changes that have been found in small cell lung cancer, including the NOTCH gene family, MYC gene family and some epigenetic-related gene changes, such as the CREBBP, and EP300.

In terms of its molecular sub classification, we're learning more and more that small cell lung cancer is not just 1 entity. There are different subtypes based on its gene expression and molecular markers. So far, there are several of them. There is small cell lung cancer type A, which is known for expression of the ASCL1 gene. There is also type N, type P, and type Y. Most recently, studies have shown there is another subtype called small cell lung cancer I, which indicates inflammation. Research shows that small cell lung cancer type I may have a better response to immunotherapy. This is a rapidly evolving field.

Can you discuss blood-based biomarkers as potential tools for early detection of SCLC?

This field is also a rapidly evolving field. Many biomarkers have been discovered and have been validated. In our article, we primarily looked at the blood-based biomarkers, including their circulating tumor cells. I think before we discuss biomarkers, it's important to know they are there probably 5 phases of biomarker development for any biomarker in cancer screening. The phase 1 is to discover such a biomarker, and a phase 2 is to assess or to validate, and whether this biomarker can detect the index cancer, and the phase 3 is using a retrospective study designed to assess whether this biomarker can develop or can detect preclinical cancer. The phase 4 is to use a prospective study designed to look at the future of those cancers are detected. Then the last phase is a phase 5, which we call the cancer control phase. The goal in phase 5 is to look at whether this biomarker is reducing lung cancer burden or cancer burden.

For all the biomarkers we have summarized in our paper, most of them are in phase 2 or phase 3, and they're sort of in their early phase. Therefore, none of them has been really incorporated in clinical decision making or been used to guide our decisions.

The first biomarker I would like to discuss is the circulating tumor cells. A lot of times tumors shed their cells into the bloodstream. Then small cell lung cancer is the 1 that tends to shed, and studies showing that in about 90% of small cell lung cancer patients, [we] can detect the cells in their blood. That makes it promising, and several of the phase 2 or phase 3 clinical validation studies have shown a promising sensitivity and specificity. I think the caveat is that a lot of those studies are quite small and primarily focused on non–small cell lung cancer, or a very small proportion of small cell lung cancer patients. Some other biomarkers that we included in our paper, including the microRNAs and proteins, demonstrated exciting sensitivity and specificity. Some of them are approaching to 90% to 100%, in terms of sensitivity. But again, those were conducted in small studies, only a small proportion of small cell lung cancer cases were included. I think it does have its limitations.

What are the next steps for research on this subject? Where do you think the SCLC field is headed, in general?

In small cell lung cancer, the prognosis remains poor despite that we have many newer treatments. In recent years, especially for extensive-stage small cell lung cancer, the 2-year overall survival rate was about 7% to 8%, and the median survival was about a couple of months, 7 months. I think to reduce the small cell lung cancer burden, there is room for improvement.

First, when you look at what would be the best strategy to reduce the small cell lung cancer burden, that would be smoking cessation, because we know smoking accounts for 95% of small cell lung cancers, although globally, there are many efforts have been made to improve smoking cessation programs or tobacco control programs. But we know that there are significant geographic variations, or gender, or age variations in terms of who smokes, and where is the highest smoking prevalence? I think we need more targeted effort for those who continue to smoke or target effort in tobacco control.

Secondly, is for its early detection, although we have summarized that there are several promising biomarkers, they're in very early phases, and they are studied in different patient populations, and use in different techniques to mirror those biomarkers. Those studies are mostly case-controlled studies or retrospective cohort studies. We do need more efforts to research in identifying a biomarker that can be universally measured, that we have larger studies to look at its outcomes for longer durations follow-up.

Lastly, we need better understanding of the molecular landscape of small cell lung cancer. Knowing more the subtypes of small cell lung cancer, it can help us understand the resistance mechanism of therapeutic agent, who is better with treatment, or who are those that develop resistance quickly. That can also help us to develop better drugs.


Wang Q, Gumus ZH, Colarossi C, et al. SCLC: Epidemiology, risk factors, genetic susceptibility, molecular pathology, screening, and early detection. J Thorac Oncol. 2023;18(1):31-46. doi:10.1016/j.jtho.2022.10.002

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