Cancer Patients, Genetic Testing and Clinical Outcomes

Two years ago in this blog, I described a young man with an aggressive non-small cell lung cancer. Following his diagnosis he was screened for EGFR mutation (the target of Erlotinib [Tarceva]) and ALK gene rearrangement (the target of Crizotinib [Xalkori]). Found negative for both, his options were limited to chemotherapy.

When I met the patient, a PleurX catheter had already been inserted to remove fluid that was rapidly re-accumulating in his right chest. This provided access to cancer-laden fluid and offered an excellent opportunity for EVA-PCD® laboratory analysis.

The results showed the expected resistance to Erlotinib (for which no mutation was found) but very high activity for Crizotinib. When he returned for follow-up we repeated a second analysis. The results were identical. One possibility was that the patient carried a second mutation sensitive to this class of drugs, like ROS-1 or MET, both targets of Crizotinib. However, at the time, MET and ROS-1 gene testing was not readily available. I referred the patient to a colleague who was conducting Crizotinib trials. Fluid was re-aspirated and submitted to a different reference lab for genomic analysis. The finding: The original laboratory test had been erroneous. The patient was indeed, ALK gene rearranged.

After a course of chemotherapy, he qualified for and responded beautifully to single-agent Crizotinib. In my blog, I examined how our functional profile more closely approximated the patient’s biology (phenotype) over the genomic profile (genotype). However appealing these genomic tests may be, they can only identify potential targets for therapy that may or may not be relevant to a patient’s ultimate clinical response.

A year later, a female patient with a mucinous adenocarcinoma presented with brain metastases. An EVA-PCD analysis revealed relative chemotherapy resistance and no activity for Erlotinib (Tarceva). She was found EGFR non-mutated. Unfortunately, there was insufficient tissue for the EVA-PCD to test Crizotinib.

During subsequent Cyber-Knife treatment for her brain metastases, a specimen of tumor showed the ALK gene rearrangement and the patient started Crizotinib. She responded promptly.

At the one-year point, signs of progression appeared in the opposite lung, but while she continued to experience good response in the original sites, a repeat biopsy was performed. This time the EVA-PCD functional profile revealed no activity for Crizotinib, but identified activity for the combination of Platinum and Vinorelbine. We combined these two drugs with the Crizotinib and she remained in remission for an additional year. Low blood counts forced us to withhold chemotherapy and her disease progressed. She was referred to a clinical trial with a second-generation ALK inhibitor. By the second month, her disease had progressed rapidly.

Cancerous cells from a bronchoscopic biopsy were submitted for analysis. The finding: No ALK gene mutation. Instead her tumor carried a MET mutation. The patient now rapidly progressing will require immediate therapy, but what?  Fortunately, a small sample of fluid aspirated from the lung provided adequate cells for analysis. The results are striking since they confirm persistent activity for Crizotinib. The patient has now been re-challenged with Crizotinib and we await clinical follow-up.

Taken together, these cases offer interesting insights. The first reflects the medical community’s preternatural faith in genomics. We, as a society, have so completely accepted the accuracy and predictive validity of genetic tests, that no one seems willing to scrutinize the data for its ultimate accuracy. This may not be serving our patients well, as both these cases exemplify. An error that missed the ALK gene re-arrangement in the first patient almost cost this young man his life, despite our protestations. Then, an error in this woman’s analysis serendipitously led to her response to the right drug for the wrong reason, her gene results notwithstanding

We forget at our peril, that all tests are fallible. Clinicians must recognize that highly sophisticated analyses using the most advanced technologies still function within the infinitely complex confines of human biology. The crosstalk, redundancy and promiscuity of human cellular circuitry remain demonstrably more complex than our best artificial neural networks. Genomic analyses and companion diagnostics now dictate who can and who cannot receive drugs, but as can be seen here, these wonders of modern science are not perfect predictors. They have the potential to deprive patients of life-saving treatment while subjecting others to drugs with little chance of benefit. Physicians must remember to be artful as we apply the science of our trade.

A Tale of Two Lung Cancers

I was recently asked to speak at a community outreach mixer to describe our work in lung cancer. I invited two patients to join me:

  1. A woman in her early 50s who presented to medical attention with metastatic adenocarcinoma of the lung with brain involvement.
  2. A woman in her early 60s, also with metastatic adenocarcinoma with brain involvement.

Under the microscope their tumors appeared almost identical. But, in the laboratory, the profiles were distinctly different. Patient no. 1 revealed a highly sensitive profile to the EGFR-TKI erlotinib (Tarceva) that was demonstrably enhanced by VEGF inhibition (e.g. Bevacizumab, Avastin). The second patient was resistant to erlotinib and VEGF inhibition, but was highly sensitive to the doublet of platinum plus gemcitabine.

Both patients attended the mixer and spoke to the crowd. They both looked the picture of health, sporting their own hair with no significant toxicities from therapy. Both had completed Cyberknife brain radiation and had gone on to exactly the right treatment for them. Despite their similarities in presentation and histology, their treatments were extremely different. Yet, both have had excellent and durable responses.

Every lung cancer patient has the capacity to do well. It is our job to find out which drugs and combinations are most likely to achieve that end. Functional profiling provided both of these patients exactly the right treatment for them. With the Rational Therapeutics EVA-PCD platform, every patient is treated as an individual.