Molecular medicine – can we afford it?

Since the time I was a medical student, we were taught that for many of us, particularly those interested in pathology and laboratory medicine, that our jobs would be replaced by small computer chips and software applications that could predict clinical behavior of tumors and guide more personalized therapies with minimal cytotoxicity. For nearly 100 years, grading and staging of tumors have largely relied upon tried in tested methods and histology, immunohistochemistry, electron microscopy and more recently molecular medicine and advanced imaging techniques.

Shortly thereafter, as a resident, the National Institutes of Health put up their overarching mandate that medicine would become personal, predictive and preemptive.

Now, 20 years later, sadly, that is not entirely the case and those of us who did pathology residencies have not yet been replaced by computer chips and software.

There have been of course a significant number of medical discoveries that to provide hope for patient’s, particularly in the areas of childhood leukemias, breast cancer and gastrointestinal stromal tumors with highly effective, less cytotoxic chemotherapies with positive outcomes.

More recently, recent advances in the understanding of the molecular biology of lung cancer have led to practice-changing developments in molecularly targeted therapy. Over the past decade, activating mutations of the epidermal growth factor receptor (EGFR) tyrosine kinase domain have been identified as the major predictor of benefit with EGFR tyrosine kinase inhibitors (TKIs), and EGFR TKI therapy is the initial treatment of choice in patients with advanced EGFR mutation-positive non-small cell lung carcinoma.

Crizotinib is a TKI with known activity against EML-4ALK, MET and ROS1 genes.  The drug has dramatically increased response rates in progression-free survival in patients with advanced non–small cell lung carcinoma (NSCLC) with ALK rearrangements compared with secondary slide chemotherapy. The frequency of ALK translocations can advanced NSCLC has been estimated at between tube and 7%. The current US FDA label for the drug use it for monotherapy and advanced ALK-positive NSCLC, without restriction and prior therapies. It is expected that the ongoing trials and first-line advanced ALK-positive NSCLC will demonstrate superiority with crizotinib. There are several methods for detecting ALK-fusion gene rearrangements in tumor tissue. Fluorescent in situ hybridization (FISH) has emerged as a gold standard within FDA approved platform currently available (Abott Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular, Des Plaines, IL).

A recent study in the Journal of Clinical Oncology looked at the costal effectiveness of EML4-ALK fusion testing and first-line crizotinib treatment for patients with advanced ALK-positive non-small cell lung cancer.

The results suggest that molecular testing with first-line targeted crizotinib treatment in the population with advanced non-squamous NSCLC resulted in a gain of 0.011 quality-adjusted life-years (QALYs) compared with standard care. The study was performed in Canada and showed an incremental cost of $2,725 (CAN) per patient and the incremental cost-effectiveness ratio (ICER) was $255,970 per QALY gained. Among patients with known EML4-ALK-positive advanced NSCLC , first-line crizotinib therapy provided 0.379 additional QALYs at an additional cost of $95,043 compared with standard care, and provided and ICER of $250,632 per QALY gained.  The major driver of cost-effectiveness was drug price.

The authors concluded that EML4-ALK fusion testing and advanced stage (Stage IV) non-squamous NSCLC with crizotinib treatment for ALK-positive patients is not cost-effectiv in the setting of high drug costs and a low biomarker frequency and the population.

Disappointingly, lung cancer remains leading cause of death resulting from cancer in North America and worldwide. NSCLC account for 85% of all lung cancers, predominantly of non-squamous subtype, including adenocarcinoma. Most patients have advanced disease at the time of diagnosis. Although cytotoxic chemotherapy is the mainstay of treatment in advanced NSCLC, its effectiveness has reached a plateau, and therapeutic outcomes are poor.

So, we are left with effective, clinically validated and approved laboratory tests, targeted therapies with less cytotoxic effects to normal surrounding cells and with accumulated experience with the test and drug questions about whether healthcare systems can bear the costs while the mainstay treatments remain less effective, albeit, less expensive.

There is not an easy answer to the problem.  It is a moral dilemma currently.  This discussion has come up in 2 tumor boards in the past month.  We have morphology, molecular and management – the three M’s of cancer care and now clinicians are being forced to answer the question – is it worth it? Are those dollars available in the system being used in a cost-effective manner that could be used towards other diseases, screening programs, outreach activities or other needs of the healthcare system?

How will this discussion go when oncologists sit down with patients and tell them they either have a low likelihood of having the biomarker and if they do, the cost of therapy may be prohibitive.

Hopefully, lower drug cost, more targeted molecular testing and improved effectiveness will make the strategy is more economically feasible.  Future head-to-head clinical trials will provide insight into the optimal treatment for lung cancer, other cancer types and in other diseases which will benefit from a combination of morphology, molecular and cost-effective management and then we can afford it.