Serum Tumor Markers Used to Monitor Therapeutic Outcomes in NSCLC

D. Ross Camidge, MD, PhD

Four tumor serum markers commonly used in other solid tumors could be used in monitoring therapeutic outcomes in patients with stage IV lung adenocarcinoma, according to a single-center retrospective analysis. The markers studied were carcinoembryonic antigen (CEA), CA125, CA19.9, and CA27.29. These markers are traditionally associated with colorectal, ovarian, pancreatic, and breast cancers, respectively, and have not previously been investigated in detail with non—small cell lung cancer (NSCLC).

“If you ask some oncologists, they might say that there is no point checking these markers in lung cancer because it doesn’t express them,” said lead author D. Ross Camidge, MD, PhD, the Joyce Zeff Chair in Lung Cancer Research at the University of Colorado Cancer Center and director of thoracic oncology at the University of Colorado School of Medicine.

However, when Camidge and colleagues examined levels of these markers that are classically associated with other cancers, they found that if all 4 markers were checked, at least 1 of them was elevated in 95% of advanced NSCLCs. Some cases expressed only 1 marker, whereas others expressed multiple markers.

In recent years, dramatic anticancer responses have become possible for some patients with advanced NSCLC, with targeted therapies used against specific mutations. By focusing on some of the most prominent examples of oncogene-addicted NSCLC— notably, cases of advanced EGFR, ALK, or ROS1- positive NSCLC treated with the appropriate EGFR, ALK, or ROS1 targeted therapy—the Colorado group was able to study the potential for these blood tumor markers to reflect both initial therapeutic outcomes and the later development of treatment resistance.

In the study, 142 patients were analyzed for the gene rearrangements, EGFR (50), ALK (60), ROS1 (4), and KRAS (28). They reported no signficant difference and frequency of elevation between the 4 markers (Figure). Only CA27.29 differed significantly by oncogene (less common in KRAS) (P = .016). Camidge and colleagues reported that the median time to nadir for patients on tyrosine kinase inhibitor (TKI) therapy in EGFR and ALK cases was 16.4 and 20 weeks, respectively.

Interestingly, 24 of 41 (59%) of patients with EGFR, ALK, or ROS1 demonstrated an initial increase in tumor marker levels within the first 4 weeks of TKI therapy, which subsequently fell below baseline in 58% of these patients. Later, marker elevation ≥10% from nadir occurred in 53% of systemic and 22% of central nervous system-only progression.

“These data mean that you shouldn’t worry about marker elevations in the first few weeks of targeted therapy in the absence of other evidence, such as worsening symptoms, as most of the time, things settle down,” said Camidge. Further, “if you’re going to use these marker levels to try to give you an early read out to determine if your treatment is working or not, the first 4 weeks are just noise. That’s a useful observation.”

The Art of Medicine Although the tumor markers may not be very useful for predicting initial success or failure, once a patient is benefiting from a targeted treatment, increases in tumor markers from their lowest point may provide useful information about the development of resistance. When a patient’s cancer was progressing in the body, a ≥10% rise in the blood tumor markers occurred in 53% of patients.

In cases of progression in the brain, however, the investigators observed that tumor markers only went up in 22% of cases. “The marker doesn’t tend to go up if the disease is only progressing in the brain, which is a problem with lung cancer, as brain metastases are common,” said Camidge. “And it doesn’t go up in everyone who is progressing in the body. We are still trying to figure out what degree of change should be called ‘marker progression.’ We used a 10% change, but that was just our first analysis. Checking these markers are not a substitute for a scan, particularly not a brain scan. But when you do use them, it’s an adjunctive piece of information that in experienced hands could give you a lead time to prompt you to do a scan sooner or a more detailed scan if the marker is going up but the first scan suggests that everything looks normal. This is where the art of medicine may have to be appreciated. If the markers are rising, but a CT scan says everything is still fine, maybe these data should nudge the clinician to do a more detailed scan—such as a PET/CT scan.”

Despite patients in this retrospective study having undergone multiple scans and blood draws, the data still show that rises in tumor markers on therapy could occur well in advance of radiographic changes of progression (up to 84 days). Although Camidge says a prospective randomized trial is needed to fully validate the potential of these markers to act as an early warning system, the real question may turn out to be whether finding progression several months earlier matters.

Oligoprogressive Disease Since 2012, researchers have known that lung cancer can be described as an oligoprogressive disease, in which a highly effective targeted therapy could suppress the cancer and only allow for a single clone of the disease to progress. In this state, “clinicians can be much more aggressive about using a local therapy, like radiation treatment, to destroy the clone, yet allowing the patient to continue on the targeted therapy,” Camidge said.

Finding the disease earlier could affect a clinician’s decision on treatment modality, he added. “If adapting your treatment plan earlier versus later in progression doesn’t impact outcomes, an early warning system could just give everyone more time to stress about things.” However, particularly for oncogeneaddicted lung cancer, in which national guidelines now support using strategies such as targeted radiation to control small pockets of treatment-resistant disease, Camidge is optimistic that an early warning system for progression could be very useful.

“An oligoprogressive state gives us therapeutic options that we wouldn’t have if the progression was more widespread,” he says. “Developing methods to catch this earlier stage of progression in more people should definitely be explored further.”

Next Steps Camidge sees the next steps in the research using a formalized clinical trial to determine the true potential of tumor markers and their potential to introduce a lead time advantage. “It could translate to a higher proportion of oligoprogressive disease, and I think I’d also like to see them explored as a potential marker of minimum residual disease post—radical treatment or as a marker in recurrent post–radical treatment.”

These markers have been around for many years, but “they have not been explored fully in lung cancer,” said Camidge. “And they are freely available to most practicing oncologists through their biochemistry laboratories. It’s an opportunity to start collecting data.”

Reference:

Noonan SA, Patil T, Gao D, et al. Brief Report: Baseline and on treatment characteristics of serum tumor markers in stage IV oncogene-addicted adenocarcinoma of the lung [printed online August 23, 2017]. J Thorac Oncol. pii: S1556-0864(17)30680-9. doi: 10.1016/j.jtho.2017.08.005.