Assessing the Small Cell Lung Cancer Treatment Landscape - Episode 5

Small Cell Lung Cancer Genomics

Kristie L. Kahl: Where are we in terms of identifying genomic profiles in small cell lung cancer?

Wade T. Iams, MD: We understand the typical mutations of small cell lung cancer at the moment. One of the issues with understanding what mutations lead to small cell lung cancer is they tend to be, for the most part, fundamentally different. For example, the mutations that lead to non-small cell lung cancer. What I mean by that is mutations that we've identified as most common in people with small cell lung cancer, tend to be breakdowns in the normal regulation of cell growth. And they allow a variety of mutations to result in cancer, as opposed to many of the mutations we've identified in non-small cell lung cancer are 1 mutation that drives cancer. And it tends to be more linear for some people with non-small cell lung cancer than mutations in small cell lung cancer. And the reason that's important is it impacts our ability to make specific treatment recommendations. So, there's a cohort of individuals with non-small cell lung cancer, in whom we identify that 1 mutation that lead to cancer, we develop a pill for it, we block it and we can control the cancer very well. In small cell lung cancer, it's more of a loss of the gatekeepers of normal cell growth. And many mutations that contribute to cancer end up playing a role and it's very difficult to develop a pill that can thereby control small cell lung cancer, when there tends to be so many that are contributing at every individual.

Kristie L. Kahl: Are we seeing any challenges in this area because genomic profiling and small cell lung cancer is on the difficult side?

Wade T. Iams, MD: Yes, the other dimension and difficulty of identifying mutations in small cell lung cancer are very practical logistical factors. Small cell lung cancer tends to grow very rapidly, so much so that when we take a biopsy of it, some of it is dying. And it's a little counterintuitive to think, “My very aggressive cancer when we take a biopsy, and most of it’s dead.” But it's actually dead cells because of how rapidly it's growing, even outgrowing its blood and nutrition supply, is growing that rapidly. So small cell lung cancer is difficult to sample, and thereby, to learn more about it as a field over the last 5 to 10 years, we've done a very good job of putting together big series, but it takes many institutions all around the world, because it's difficult to have enough small cell lung cancer tumor to study. And then when we get into clinical trials, that makes it difficult to make linkages between the mutations in each individual and their responses to treatment. When for big groups of patients, we just can't even assess their mutations. And we have to presume, based on the other studies, of big groups of people that the mutational profile probably looks like the typical mutational profile. But for a big group of people, we just can't get enough tumor tissue to do thorough testing.

Kristie L. Kahl: Are there currently any known genomic alterations associated with small cell lung cancer?

Wade T. Iams, MD: Yes, the 2 most common are TP53 – that's the name of a gene that helps regulate normal cell growth – and RB1 – that's the name of another gene that also helps regulate cell growth. When we look at mutations associated with small cell lung cancer, those 2 are far and away the most common, and I would put at the highest level of cancer of small cell lung cancer-associated mutations. And then there are a handful of others that come in at what would be a second tier, but not common enough that I think it's critical to go through each 1 of those here.

Kristie L. Kahl: From a genomic standpoint, what do we have to look forward to in this space when it comes to small cell lung cancer?

Wade T. Iams, MD: Because of the difficulty of targeting 1 specific mutation in individuals with small cell lung cancer, where there are typically many, many mutations that are contributing to that cancer and that individual, the way that the field is headed is trying to categorize those mutational profiles. So instead of saying, there are 20 mutations contributing to this person’s small cell lung cancer, let's develop a pill for 1 of the mutations and see if it works. We're trying to categorize small cell lung cancer and say, “How can we link the typical profiles that are coming up in individuals?” And, for subgroup categorization, that's emerging from some really amazing science being done to research patients with small cell lung cancer. And we're trying to then say, not can this 1 pill apply to this 1 mutation, but is this pill more effective in this category of patients with small cell lung cancer? So we weren't able to drill down to just 1 mutation and a pill mentality and small cell lung cancer, but we're trying to have a more individual informed approach starting with categories.