Leaders in the field of lung cancer research at the first American Association for Cancer Research-International Association for the Study of Lung Cancer Joint Conference on Molecular Origins of Lung Cancer emphasized the importance of bringing together basic scientists and translational and clinical researchers.
Following the spirit of that effort, the program included studies on the basic mechanisms of disease and new clinical approaches to therapy. During a news conference, community leaders discussed several studies, including a blood test for lung cancer diagnosis, tests to identify treatment-resistant small-cell lung cancer, a study on smoking, genetic variation, and green tea, the potential benefit of re-treating patients with gefitinib after progression, and erlotinib dosing in smokers.
“It is a very dynamic time [in lung cancer research],” said AACR President Tyler Jacks, PhD, Director of the David H. Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology. “There have been a great number of very important discoveries, and it is critical to bring people together to share ideas to best take advantage of new findings and translate them as rapidly as possible for the benefit of cancer patients.”
Blood Test for Early Diagnosis
Screening tests that allow for early diagnosis of lung cancer have been an elusive goal for researchers. But a new blood test designed to detect lung cancer in patients with good accuracy may have moved the field a bit closer to the goal, according to a study led by Steven Dubinett, MD, Professor of Medicine and Pathology and Director of the Lung Cancer Research Program at the Jonsson Comprehensive Cancer Center at the David Geffen School of Medicine at the University of California, Los Angeles.
“This study really demonstrates the feasibility of using blood markers for the detection of and identification of early lung cancer,” said Matthew Meyerson, MD, PhD, Professor of Pathology at Dana-Farber Cancer Institute and the Broad Institute, who was not involved in the work but discussed it at the news conference. “It is not yet at the level of precision required for a clinical test, but I think we are all hopeful that further analysis of this study will lead to a useful clinical test.”
Dr. Dubinett and colleagues selected a panel of 40 serum proteins that had been previously implicated in lung cancer either in his own laboratory or in the literature. They then used an antibody-bead capture system to test the level of each of the proteins in 90 patients with Stages I-IV lung cancer and 56 controls, all of whom were former smokers (30 or more pack years) at high risk of the disease.
Twenty-one of the serum proteins were differentially expressed in the patients with Stage I disease compared with controls. The 21-protein panel was able to identify lung cancer patients with 92% accuracy.
When the team used just three of the serum proteins—IL2, IL3, and macrophage-derived chemokine—the blood test showed 93% accuracy, with 97% sensitivity and 77% specificity.
The team is now validating the approach using blood samples drawn before and after surgery from 1,072 patients who were undergoing resection for suspicious lung nodules as part of the ACOSOG Z4031 study. Serving as controls for the validation of the serum test were the 20% of the participants in that trial found to have benign lesions upon resection.
The sensitivity and specificity required for a test to be clinically useful depends on the population being screened, noted David P. Carbone, MD, PhD, the Harold L. Moses Chair in Cancer Research and Director of the Specialized Program of Research Excellence in Lung Cancer at Vanderbilt-Ingram Cancer Center.
“If you are screening well children in elementary school, the criteria are much different than if you are screening heavy smokers in a high-risk patient population. My feeling is that the sensitivities and specificities that they have reported—if they hold up in a test population—could be useful in guiding therapy for individuals at very high risk of lung cancer, who, for example, have a CT-detected pulmonary nodule.”
Dr. Carbone, who was a co-chair of the meeting and who was involved with the serum markers study but not an author, said that the 20% of benign nodules found in the ACOSOG study population is typical, even at the best equipped centers. A serum marker test like the one described by Dr. Dubinett and colleagues might lessen the likelihood these individuals would undergo unnecessary surgery.
MicroRNA Panel Identifies Treatment-Resistant SCLC
While Dr. Dubinett is trying to find a blood test that identifies patients with NSCLC early, Glen J. Weiss, MD, Director of Thoracic Oncology at the Virginia G. Piper Cancer Center at Scottsdale Healthcare and Co-Head of the Lung Cancer Unit at the Translational Genomics Research Institute, and colleagues have been looking for a way to identify patients with small cell lung cancer (SCLC) who are resistant to first-line chemotherapy. As many as 30% of SCLC patients are resistant to standard platinum-based chemotherapy and have no other options for first-line treatment.
“This is a patient population that hasn't had a lot of innovation in therapy, and as a medical oncologist I am trying to find new ways for treating patients that might be better than everyone being treated the same way,” Dr. Weiss said in an interview. “If we can identify the patients upfront who will be resistant to standard chemotherapy, then maybe we can stratify them for new clinical trials of upfront therapy that might work better in those patient groups.”
To identify a marker of de novo resistance, Dr. Weiss and colleagues performed microRNA (miRNA) profiling on tumor samples from 34 patients, all of whom had received standard chemotherapy. Of the 21 patients with CT images available for evaluation, two had had a complete response to therapy; 13, partial responses; two, stable disease; and four, progressive disease.
Of the more than 1,300 RNAs on a microarray platform, the team identified 16 that appeared to correlate with resistance. When they retested those 16 miRNAs using RT-PCR, three miRNAs—miR-92a-2, miR-147, and miR-574-5p—were significantly associated with primary chemoresistance. The team did not find any co-morbidities or demographic characteristics that predicted resistance.
Dr. Weiss group is now working to validate these markers in a larger population of SCLC patients and to attempt to understand the biological mechanism that underlies the correlation between miRNA expression and resistance.
Dr. Jacks, who discussed the study during the press conference, said that while the study reported was relatively small and thus would need to be validated in a larger cohort, the miRNAs did appear to correlate with de novo resistance.
Smoking, Genetic Polymorphisms, & Green Tea
Data from epidemiological and laboratory studies suggest that green tea may reduce an individual's risk of developing certain types of cancer. To get a better idea of whether green tea might have an impact on lung cancer risk, I-Hsin Lin, MS, a student at the Chung Shan Medical University in Taiwan, and colleagues examined green tea consumption in 170 NSCLC patients and 340 controls. The team also examined the participants’ genetic polymorphisms in insulin-like growth factor genes (IGF1, IGF2, and IGFBP3), the expression of which is altered by polyphenols in green tea.
Study participants filled out questionnaires on dietary habits, including green tea consumption, smoking history, cooking practices, and family history. Based on these data, Ms. Lin and colleagues found that individuals who did not drink green tea had a 5.16-fold higher risk of lung cancer compared with those participants who drank one or more cups of green tea per day, after adjusting for other risk factors.
The effect of not drinking green tea grew to 12.71-fold increased risk when the team limited their analysis to just those participants who were current or former smokers.
Interestingly, when the team examined individuals’ IGF1 and IGF2 genotypes, they found that carriers of some gene polymorphisms benefited from green tea consumption more than others. No effect was found with variants of the IGFBP3 gene.
Based on their data, the researchers hypothesize that green tea may reduce the risk of lung cancer, particularly smoking-induced cancer, and that genetic variants could further modulate those effects.
Repeat Therapy with Gefitinib Shows Benefit
In a small single-institution study, Korean researchers found that re-treating NSCLC patients with gefitinib after chemotherapy may be beneficial.
The team, led by In-Jae Oh, MD, PhD, Assistant Professor of Chonnam University Hwasun Hospital in the Republic of Korea, enrolled 18 patients with advanced or metastatic NSCLC who initially responded to gefitinib but then had disease progression on the agent and were subsequently treated with cytotoxic chemotherapy. Patients were then re-treated with 250 mg gefitinib daily.
Of the 15 patients available for evaluation, four had a partial response, six had stable disease, and two showed disease progression. When the investigators divided their population into patients who had had a partial response to their first gefitinib treatment and those with stable disease, those who initially had a partial response were found to be likely to respond to a second round of therapy.
Specifically, among six patients with initial partial responses, two had a partial response on re-treatment and three had stable disease. Of the nine patients who had stable disease as their best response during their initial treatment, two had a partial response and three had stable disease.
“The main reason for progression after an extended response is the development of secondary mutations—most commonly another mutation in the [epidermal growth factor receptor] gene, called T790-M,” said IASLC Executive Director Paul A. Bunn, Jr., MD, Professor of Medicine and the James Dudley Chair in Cancer Research at the University of Colorado.
“That mutation makes it more difficult for gefitinib or erlotinib to bind to the receptor. When that mutation occurs, it is in the minority of tumor cells. The majority of tumor cells still have the original activating mutation. So there are two approaches [to treatment]. One that is not so sexy, but is realistic, is to give a standard chemotherapy, and often those resistant cells are still sensitive to standard chemotherapy. When you finish with the chemotherapy, you can put the people back on gefitinib or erlotinib. That is currently my standard of practice.”
He noted that the Korean data are consistent with a previously reported study from Memorial Sloan-Kettering Cancer Center in New York that suggested that re-treatment with gefitinib after a month-long hiatus induced tumor shrinkage in the majority of patients.
“So I think this actually has clinical implications,” Dr. Bunn said, referring to the newly reported Korean data.
Increasing Erlotinib Dosing in Smokers
British researchers reported last year that smokers may require a higher dose of erlotinib than non-smokers. Smoking increases expression of cytochrome enzymes, which alters the pharmacokinetics of erlotinib metabolism. In their study, the investigators found that plasma levels and rash in smokers dosed at 300 mg were similar to plasma levels and rash in non-smokers dosed at 150 mg, which is the current standard dose.
Following on those data, Lynsay L. Waller, MD, a fellow at Wake Forest University Comprehensive Cancer Center in Winston-Salem, NC, reported at the meeting that dosing patients based on smoking status and increasing their doses over time is possible.
The team has enrolled 25 patients in a Phase II study, with a target enrollment of 50. Current smokers receive 300 mg erlotinib daily as a starting dose while former and never smokers receive an initial dose of 150 mg daily. The investigators then increase the dose by 75 mg every two weeks until patients develop Grade 2 non-hematologic toxicity. The dose is then held at that level; if a patient develops Grade 3 or 4 toxicity, the dose is decreased.
Thus far, the median maximum tolerated dose (MTD) achieved for smokers is 300 mg compared with 225 mg for non-smokers. The dose range for smokers is 300 to 525 mg and 150 to 225 mg for non-smokers. The toxicities preventing further dose increases included Grade 2 rash (23.5%), Grade 2 diarrhea (23.5%), Grade 3 rash (18%), Grade 3 diarrhea (18%), Grade 3 dehydration (6%) and disease progression (12%).
Because enrollment is continuing, the investigators did not analyze the data in terms of patient responses, which is the primary endpoint of their trial. However, Dr. Waller says that it is possible that the higher doses will improve responses in smokers: “In the original studies off of which erlotinib was approved, they found that active smokers did not respond as well as non-smokers,” she said.
That could be due to the fact that smokers are less likely to have activating mutations in the EGFR gene, which confers extreme sensitivity to the drug. “But it also could be partly due to the fact that smokers aren't being dosed at what their MTD is.”© 2010 Lippincott Williams & Wilkins, Inc.
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