NEW YORK CITY—Leading medical experts gathered here earlier this month to jump start Lung Cancer Awareness Month with an open public forum discussing significant clinical discoveries and key areas for further investigation in lung cancer research.
Held by the Lung Cancer Research Foundation, the panel coincides with the organization's 5th Annual Lung Cancer Awareness Luncheon, a fundraising event to help support research projects.
Julia Rowland, PhD, Director of the Office of Cancer Survivorship at the National Cancer Institute, was one of three speakers at the symposium, titled Key Pieces in the Lung Cancer Puzzle.
“When I was asked to be a speaker, I thought, ‘What a wonderful opportunity to talk to this audience about survivorship and pair that with lung cancer,’ because I think many in this country don't put those two words together and yet this is an area where we need more focused attention.
“We have almost 371,00 individuals in this country who are survivors of lung cancer and we may think that that's an impressive figure until we realize that over 222,000 people will be diagnosed with lung cancer this year alone; then we realize 371,000 isn't enough.”
‘Tissue is the Issue’
In order to improve survivorship at an acceptable safety level, diagnostic methodologies must improve, said Mark Socinski, MD, Director of the Multidisciplinary Thoracic Oncology Program at UNC Lineberger Comprehensive Cancer Center.
“In this country, historically, we have provided our pathologists with small tissue samples. One of the messages that has to go out initially is that tissue is the issue. It starts at the time of initial diagnosis with getting enough tissue to allow the pathologist to tell you more definitely whether the cancer is squamous or non-squamous, and then in those patients who you want to interrogate for certain molecular abnormalities, you need to have the tissue to do that.”
While investigators are increasingly looking at blood and sputum for tumor analysis, Marc Ladanyi, MD, Director of the Laboratory of Diagnostic Molecular Pathology at Memorial Sloan-Kettering Cancer Center, said it's important to emphasize that these techniques are just in the research stage and not available for routine use.
“At the moment we have to focus on obtaining sufficient tumor tissue at the time of diagnosis so that there is sufficient material for us to examine the genetic changes in the tumor cells.”
A lot of thought is being given as to how to scale up mutation screening of tissue samples in lung cancer, Dr. Ladanyi added, noting the screening efforts currently in place for colon cancer and melanoma. “This idea that we have to determine the genetic changes in the tumor cells of each patient is being rolled out pretty much across all cancers and this is the tip of the iceberg.
“We are all trying to figure out how we are going to extract all of this information from relatively small biopsies and how we're going to perform all this testing in a timely manner.”
Survivorship and the Teachable Moment
Emphasizing the dependency of therapies on accurate tumor staging, Dr. Socinski said that while diagnostic methods, and furthermore treatment, have improved, an enormous survival benefit has not yet been documented.
“The major change that has happened in that setting is the adoption, based on multiple clinical trials, of chemotherapy following an operation which improves the survival or the ultimate cure rate of this disease.
“When you look back at the initial trials in breast cancer using what is now considered old-fashioned chemotherapy, the impact that those trials had is really identical to what we see in lung cancer. The role of adjuvant therapy is very important and we were not necessarily doing that five or six years ago.
“We may argue about the best drugs to use in certain patients, but this is certainly now the standard of care.”
Nonetheless, the increase in patient survival, although it may be modest, has presented a new area of focus on survivorship and the long-term effects of cancer diagnosis and treatment.
“One of the reasons our office was created is because more and more people were living months, years, decades after cancer diagnosis and the medical community was poorly equipped to determine the follow up for these individuals,” Dr. Rowland said.
Literature documenting survivors' experiences has shown that patients are remarkably resilient in their ability to tolerate aggressive regimens. That said, being told that you are cancer free, does not mean that you are free of the disease, she added.
“Some of these symptoms are acute and go away—for nausea, vomiting, hair loss, and anemia—and when treatment stops those things resolve fairly quickly, but there are a number of insidious or persistent effects like chronic fatigue, memory problems, depression, and sexual dysfunction that go on for months or years after treatment exposure, and those are the ones that we are trying to address.”
Currently, children, with a cure rate of 80%–90%, are the most documented survivors, allowing for several years of follow up after diagnosis. Researchers are now trying to take what they've learned from those patients and translate it to adult survivors.
A movement is under way at many centers to provide treatment summaries for patients detailing all of their exposures, what therapies they received, and treatment doses, along with a survivorship care plan identifying what follow-up tests need to be done and on what basis and who will be responsible for providing care (OT 8/10/10, 3/10/09, 9/10/07, 7/10/07 issues).
“An additional piece that we're beginning to add is taking advantage of what we call the teachable moment—making lifestyle changes that can improve the patient's overall well-being,” Dr. Rowland said.
Mutations and their Relationship to Smoking
The most obvious teachable moment in lung cancer is smoking cessation, Dr. Rowland added, citing details of a study of 383 dyads of survivors and caregivers.
“We found that 19% of lung cancer survivors were still smoking and 25% of their caregivers were still smoking. We have a lot of work to do. This is not acceptable and we need to do these studies much more often.”
Studies have shown an association of variations in constitutional DNA at the regions controlling the nicotine receptor where people with a certain variant at that location are more likely to develop lung cancer, Dr. Ladanyi said. However it has been debated whether the variant is indirectly associated with a propensity to nicotine addiction or whether there is a direct effect on lung cancer in those patients, he added.
On the flip side, mutations that were originally identified in never smokers, specifically patients with the epidermal growth factor receptor gene (EGFR), have also been found to occur in a lower rate in smokers.
“In our experience, almost any patient, even one who doesn't have a history of smoking, should have their tumor tested for EGFR mutations because what this suggests to us is that there are actually smokers who develop lung cancer which may be unrelated to smoking.
“Furthermore, we know from previous studies that tobacco smoke causes a particular type of mutation in DNA, and we can look for those mutations in those genes and distinguish the mutations that are likely to occur due to tobacco smoke and the ones that are less likely to occur.”
Mutations in the EGFR gene account for about 20% of lung adenocarcinomas, with mutations in the KRAS gene causing 25%; EML4-ALK mutations account for another 5% of these cancers.
“All of these mutations are mutually exclusive, so what's happening is we're trying to fill out the rest of the pie chart in terms of what drives these subgroups of lung cancer,” Dr. Ladanyi said.
Critical Study Populations
Despite killing more women than breast cancer an all gynecologic cancers, lung cancer remains much less understood in women than other malignancies, Dr. Socinski said.
“Breast cancer death rates have been pretty stable at 40,000 deaths per year and we have 80,000 women dying of lung cancer each year. That has paralleled tobacco consumption to a certain extent, but there is a sense that this is a population in which the epidemiology is very poorly understood.”
EGFR mutations are more likely to occur in women, although the cause of this finding is unknown. Furthermore, almost without exception, women do better than men in terms of surviving lung cancer regardless of disease stage or the impact of chemotherapy with a hazard ratio of 0.75-0.78, which translates into a 25% improvement in survivorship benefit for just being female, Dr. Socinski added.
“There is a lot more research to be done from an epidemiological point of view as well as a biologic point of view to explain this issue. We've done a great job with many things, but we haven't done a great job with that.”
Another challenge in lung cancer is that the vast majority of people diagnosed with lung cancer are age 65 and older, while most of the work is being done in individuals who are pediatric cancer survivors or in their middle years, not in the prevalent population of survivors.
“This is something that we need to be addressing,” Dr. Rowland said. “There is an aging stigma and there is a smoking stigma all attached to this disease and that makes it a challenge for us to make a public human cry about the epidemic that we are facing.”