According to the American Cancer Society, lung cancer is the leading cause of cancer death in the United States, with approximately 155,870 deaths from the disease in 2016. Add to that an estimated 222,500 new diagnoses of lung cancer and it’s clear that a big challenge lies ahead for researchers. Still, recent advances in diagnosis and treatment have transformed lung-cancer care. That progress includes better lung-cancer diagnoses, personalized medicine and immunotherapy. In this post, we’d like to take a look at some of the major trends in lung-cancer research at Einstein and Montefiore and consider what they’ll mean for patient treatment and care.
The major diagnostic advances are low-dose CT screening and advanced bronchoscopic techniques.
- Low-dose CT screening. Virtually every major medical and radiologic society has now approved low-dose CT for the screening of smokers and others at high risk for lung cancer. At Montefiore, for example, the radiology department’s thoracic-imaging team runs a comprehensive program that screens people ages 55–74 who have smoked for more than 30 pack-years (an average of a pack a day for 30 years), and quit smoking less than 15 years ago.
- Advanced bronchoscopic techniques. The pulmonary division uses sophisticated bronchoscopic techniques, including endobronchial ultrasound (EBUS, linear and radial) and MRI/CT-directed navigational bronchoscopy, to assess all detected nodules and cancers.
In addition, Einstein researchers are examining the use of biomarkers.
Biomarkers to predict response to treatment, assess risk and select candidates for screening
- Immune biomarkers, such as PD-L1 testing, have been incorporated into the daily routine in the management of patients with lung cancer to identify those best served by treatment with immunotherapy rather than chemotherapy.
- Molecular biomarkers—including EGFR and ALK, somatic mutations that in the past had to be detected from tumor tissue obtained through risky biopsies—now can be assessed through innovative “liquid biopsy” technology, such as by detecting circulating tumor DNA in blood, urine and other bodily fluids.
- Exhaled breath. Einstein researchers are examining the possible use of exhaled genetic elements (microRNAs) as biomarkers to assess lung-cancer risk and select candidates for screening.
Personalized Medicine for Lung Cancer
Studies over the last decade have shown that non–small cell lung cancer—the most common type, associated with smoking—actually consists of many genetically definable subsets. This finding has opened up the possibility of treating patients with drugs that target their specific subtypes of lung cancer. These subtypes are often driven by oncogenes, including EGFR, MET and ALK.
Our researchers recently discovered a novel MET mutation that often occurs in the most aggressive form of lung cancer, called sarcomatoid carcinoma. Such molecular abnormalities are now routinely the subject of tests. Drugs capable of treating these lung-cancer subsets include erlotinib, gefitinib and afatinib (for EGFR) and crizotinib (for ALK-mutated non–small cell lung cancers). When used against the right subsets, these well-tolerated drugs surpass chemotherapy and often lead to the doubling of response rates and of progression-free survival.
Unfortunately, most cancers eventually develop resistance to these personalized therapies. Clinical studies by Einstein scientists have revealed a range of resistance mechanisms that can be specifically and effectively targeted. A good example: secondary mutations of EGFR (most commonly, a pivotal mutation called T790M). In addition, resistance to the first-generation ALK inhibitor crizotinib can be overcome by using second- and third-generation inhibitors developed to target resistance mutations.
Ongoing studies here (including the Alchemist and EVENT studies) are designed to assess personalized cancer therapies when used earlier in the course of lung cancer. And researchers are also investigating novel agents for treating molecularly defined subsets of patients, such as patients with MET and K-ras mutations.
Significant efforts continue to be made to detect and overcome acquired resistance to such targeted agents as well, both in the clinic and in the laboratory. And Einstein researchers actively collaborate on unique studies in which a patient’s tumor tissue is grown in mice as an “avatar,” where effective treatment can be established and then potentially offered to the patient.
Revolutionizing Lung-Cancer Treatment with Immunotherapy
Until recently, lung cancer has proven notoriously resistant to treatment efforts. But over the last several years, drugs known as immunotherapies have revolutionized lung-cancer treatment by “liberating” the immune system to attack and destroy tumors.
Tumors are able to evade the body’s immune response by expressing cell-surface proteins called “checkpoint” proteins. By engaging certain partner checkpoint receptors on T cells, these proteins put the brakes on T-cell activity—which allows tumors to avoid immune attack. Anticancer immunotherapy drugs are monoclonal antibodies that foil tumors’ evasion strategy by either preventing a checkpoint protein called PD-L1 from muzzling T-cell function or targeting the T-cell receptor PD-1 so that the PD-L1 protein can’t activate it.
In randomized trials, immunotherapies that target either PD-1 or PD-L1 have proven effective in treating advanced non–small cell lung cancers and now show activity in small-cell lung cancers as well. These therapies are superior to second-line docetaxel chemotherapy in producing significant and durable responses and allowing longer survival. Three such immunotherapy drugs—Opdivo, Keytruda and Tecentriq—have by now received FDA approval for treating advanced non–small cell lung cancers. Over the past year, we have further learned to tailor such treatments more optimally; in patients where the PD-L1 checkpoint protein is very strongly present, upfront Keytruda outperforms our best frontline chemotherapy regimens as well, and now about one third of patients with advanced non–small cell lung cancers receive such treatments, which are well tolerated overall, as opposed to aggressive, toxic chemotherapy combinations calling for the routine use of PD-L1 testing.
The introduction of targeted and immunotherapy agents has transformed the management of lung cancer. Yet more-effective treatments are still needed, and researchers in our thoracic oncology group are working to develop them. For example, they are assessing the safety and efficacy of a novel inhaled drug for treating lung cancer called deoxy-5-azacytidine.
“Silenced” genes have been implicated in many types of cancer, including lung cancer. Gene silencing is an “epigenetic” phenomenon, meaning gene expression is altered not because of gene mutation but typically because of methyl groups that bind to the gene. Gene silencing is a normal and important process for regulating gene expression. But cancer can occur when aberrant gene silencing occurs—that is, when tumor-suppressor genes are silenced. Deoxy-5-azacytidine shows promise for restoring gene function by stripping away methyl groups that have silenced the genes.
When it comes to lung-cancer research, treatment and care, science has come a long way, but we’re looking forward to greater advances in the years ahead—and potentially, to saving more lives.