Last fall, a consortium of more than 300 researchers from The Cancer Genome Atlas (TCGA) Research Network published the results of their large-scale genetic analysis of squamous cell lung cancer in the journal Nature.1 The study, the first of its kind, compared the tumor cells from 178 untreated patients with squamous cell lung cancer to their healthy cells. The investigators found that over 60% of the tumors had genomic alterations in “targetable” signal transduction genes, and 90% showed mutations in TP53, a gene that regulates the cell cycle and functions as a tumor suppressor to prevent cancer from developing. They also identified previously unreported loss-of-function mutations of the HLA-A gene in the tumors. HLA (human leukocyte antigen) helps the immune system distinguish the body’s own proteins from proteins made by foreign invaders.
The findings from the study suggest that treatment strategies utilizing customized immunotherapies could be an effective tool in treating squamous cell lung carcinoma, which kills about 50,000 people a year and is second in frequency to adenocarcinoma of the lung. While adenocarcinoma of the lung is the most common type of lung cancer found in nonsmokers, over 90% of squamous cell lung carcinomas are found in smokers and former smokers.
The ASCO Post talked with the study’s lead author, Matthew L. Meyerson, MD, PhD, Director of the Center for Cancer Genome Discovery at the Dana-Farber Cancer Institute, Professor of Pathology at Harvard Medical School, and Senior Associate Member of the Broad Institute of MIT and Harvard Medical School, Boston, about the study results and what they could mean for more effective lung cancer therapies.
Significant Findings
Please talk about some of the major findings from The Cancer Genome Atlas Research Network study of squamous cell lung carcinoma.
One of the significant findings of this study was that there are a large number of potentially actionable genomic alterations in squamous cell lung cancer, many of which had not been previously described. They include mutations in the PI3 kinase pathway, particularly in the catalytic gene PIK3CA and in the PTEN tumor-suppressor gene.
Also, we found amplification of receptor tyrosine kinases, including EGFR, ERBB2, and FGFR1, and overexpression of the AKT3 gene. These are all classic signal transduction alterations, and over 60% of the cases of squamous cell carcinomas in the study harbored one of these targetable alterations.
Existing Treatments
Are there drugs currently available that can target some of these pathways?
Yes. We’ve seen a real profusion of targeted therapies directed against mutant EGFR, ALK translocations, ROS1 translocations, and RET translocations in adenocarcinoma of the lung. Several of those drugs are already approved, and more are in clinical trials. There was not previously the notion that the signal transduction inhibitors would be an effective treatment for squamous cell lung carcinoma, but now we know that a large number of alterations can be considered for clinical trials.
We also found mutations in the kinase domain of EGFR in 2 out of the 178 cases tested. While it’s a very small number, traditionally people always test lung adenocarcinoma for EGFR mutations, and if 1% of patients with squamous cell lung cancer might be treatable with already approved EGFR inhibitors, it seems valuable to test those patients for EGFR mutations as well.
Clinical Trials and Genomic Profiling
If cancer is now considered a genetic disease rather than a disease of a specific organ, how will it change the way drugs are tested in clinical trials, and how will you get enough patients to enroll in those trials?
In order to get patients enrolled in appropriate clinical trials, every patient should be tested in a comprehensive way for the potentially actionable genomic alteration in their tumors. We know that there are about 200,000 new cases of lung cancer each year, and between 25% and 30% of them are squamous cell lung cancer. That means there are 50,000 to 60,000 new cases of squamous cell lung cancer every year. Imagine that there is a mutation present in 2% of those patients. That would mean there are 1,000 to 1,200 new patients every year who can be tested in clinical trials with a targeted therapy, providing you do the genomic profiling to identify those patients.
The Lung Cancer Mutation Consortium, which comprises 16 cancer institutions nationwide, is designed to accrue patients with non–small cell lung cancers and match their tumor type with trials testing targeted therapies. The initial trials are focusing on lung adenocarcinoma, but there is an effort to eventually expand accrual to include patients with squamous cell lung carcinoma.
In addition, we are going to start seeing clinical trials stratified not only by disease type, but for alterations in specific genes as well. So you might have a specific trial for patients with a BRAF gene mutation or an FGFR3 gene mutation that might span different cancer types.
Are lung cancer tumors now routinely genomically tested to determine the most effective therapy for each patient?
At the Dana-Farber Cancer Institute, all patients with lung cancer are being tested for a number of major actionable gene alterations. And I think this is also true at the institutions in the Lung Cancer Mutation Consortium. I don’t know if it is happening at community oncology practices, but I think all patients with non–small cell lung cancer should be tested for mutations and other genomic alterations, especially patients who are nonsmokers, because they are the most likely to have actionable alterations in their genomes.
Looking Ahead
How might your findings benefit patients with lung cancer in the future?
In 2004, our group at Dana-Farber, as well as other groups, discovered EGFR mutations in lung cancer, and I think that started the paradigm of testing patients for gene mutations and using targeted therapies against those mutations. We have seen patients benefit enormously from EGFR inhibitors and more recently from ALK inhibitors. These findings have really changed our view of lung cancer, and we have gone from seeing advanced disease as an almost intractable disease to a situation where there is hope for every patient with lung cancer.
But there still is no cure?
Yes, that’s true. But in addition to what we have already discussed, there is another area that is beginning to show promise in lung cancer treatment, especially for squamous cell lung cancer, and it is with drugs that affect immune system regulation, such as anti-PD1 or anti-PDL1 antibodies. In our study, we found loss-of-function mutation in the HLA-A gene, which encodes major histocompatibility complex class 1. These mutations downregulate the immune response, so it suggests that the squamous cell lung cancers are somehow using downregulation of the immune response as a mechanism of tumor progression.
This is interesting because the squamous cell lung cancers are responding to drugs like anti-PD1 antibodies. That suggests the squamous cell lung cancers may be trying to avoid an immune response because the immune response keeps the cancer in check. It is consistent with the observation that antibodies such as anti-PD1 or anti-PDL1 appear to be effective in the treatment of squamous cell lung cancer.
The other interesting feature of squamous cell lung cancers is that they have a very high mutation rate. That means that they have a lot of mutations in many, many different proteins, and these proteins could create neoantigens or neoepitopes that could be recognized by the immune system. So the loss-of-function mutation in HLA-A provides more evidence that patients with squamous cell lung cancer may have underlying immune control of their cancers, and there may be some benefit achieved with immune system therapy.
A related point is this: Now that we have the concept of genomic stratification to help identify patients who will benefit from targeted therapy, we may also use genomic analysis to help identify patients who will benefit from immunomodulatory therapy. Another important suggestion of this study is that our findings are not limited to squamous cell lung cancer, but can be applied to all types of lung cancer.
I’m confident that in the future, therapies will become more targeted and effective and that it will be possible to cure all lung cancers. ■
Disclosure: Dr. Meyerson is an inventor of the patent on using the EGFR gene for cancer diagnosis and is the founder of Foundation Medicine, a cancer diagnostics company.
Reference
1. The Cancer Genome Atlas Research Network: Comprehensive genomic characterization of squamous cell lung cancers. Nature 489:519-525, 2012.
