• Matthew Hiznay

The Importance of Precision Medicine

The best way I can demonstrate the importance of precision medicine is to tell you my story. My name is Matt Hiznay, I am a Clinical Genomics Curator at GenomOncology, and I am an eight-year survivor of metastatic, ALK-positive lung cancer. If precision medicine did not exist, then it is very probable that I would be dead.

My story begins in summer 2011, when I was 24 years old. Throughout that summer, I developed a persistent, dry cough. I recall being exceptionally sore during a trip to Cedar Point and swimming with difficulty in Lake Erie, eventually confessing to myself that I was no longer a spring chicken. In August, I told my internist about my cough when I visited him for my annual physical. I also showed him a muscle knot in my lower neck. He informed me that it was a lymph node, not a muscle knot, in my neck. I was scheduled for surgical removal and biopsy of the lymph node. August 17, 2011, was a gloriously sunny day in my hometown of Poland, Ohio. Around 8:30 that morning, my life was forever changed upon hearing the surgeon say, “Matt, I’m sorry to have to tell you this. This is going to be some type of malignancy.”

The cancer was poorly differentiated, delaying a final diagnosis. In the meantime, I traveled to Cleveland Clinic. Although Dr. Rob Dean was a hematologist (I was first suspected to have lymphoma), he shepherded me to thoracic oncologist Dr. Nate Pennell, who revealed I had stage IV lung adenocarcinoma, a type of non-small cell lung cancer (NSCLC). It was August 26. Yes, a lifelong nonsmoker, like me, can be diagnosed with lung cancer. The cancer had likely formed in my lower left lung, then metastasized to my right lung, mediastinum, breastbone, lower neck, and a few lymph nodes between my stomach and liver. Dr. Pennell explained that my biopsy was to be tested for unique mutations in two genes, EGFR and ALK. If I were to test positive, then my treatment regimen would drastically change. This was my introduction to precision medicine.

For a cancer patient, precision medicine is a strategy in which a cancer’s genetics aids the oncologist’s treatment decisions. Although cancer arises from a patient’s cells, the cancer itself has a different genome, albeit “different” to the least degree—the genomes are nearly identical. This similarity allows the cancer to escape detection by a patient’s immune system. A few major changes drive carcinogenesis. Precision medicine enables an oncologist to use those few major genetic changes against the cancer by prescribing drugs called targeted therapies. A wonderful benefit of targeted therapies is a lessened severity of side effects. Most people know about the dreadful, long-lasting side effects that can accompany chemotherapy, radiation therapy, or surgery. Those side effects occur because those treatments indiscriminately attack all cells, whether cancerous or healthy. Targeted therapies, however, attack only cells that have a unique genetic target.

Dr. Pennell said that a result would take two weeks. I resolved to begin chemotherapy until the test had a result. I wanted to start hitting back. I searched the internet for the five-year survival rate of stage IV NSCLC. In 2011, that number was 1%. When I returned to Cleveland Clinic for chemotherapy on September 1, my health had critically worsened. Dr. Pennell deemed me too sick to begin chemotherapy, so I was admitted to the hospital. I fell asleep watching the Cleveland Browns’ final preseason game. In the early morning of September 2, I stopped breathing.

Intensivist Dr. Ren Ashton was arriving for his shift when the elevator doors opened and I was wheeled past him. He sprang into action. I was intubated, whereupon my blood pressure crashed. Dr. Ashton realized that cancer-filled mediastinal lymph nodes had caused a large amount of fluid to surround my heart. He called for a cardiothoracic surgery team to insert a catheter to drain the fluid. When Dr. Ashton was told the team would arrive in ten minutes, he resolved to insert the catheter himself. Never mind that he was not a cardiothoracic surgeon nor that one wrong move could puncture my heart and kill me—Dr. Ashton knew that I would be dead if he did nothing before the surgeons arrived. With a steady hand and a focused team, Dr. Ashton inserted the drain and withdrew the fluid from around my heart.

Once Dr. Ashton had performed his miraculous procedure and I had been stabilized, chest tubes were placed around both lungs to drain more fluid. Pulmonary embolisms had formed, so I began to take a blood thinner. Dr. Pennell had said that the new targeted therapies, should I be eligible for one, had been observed to act swiftly. Thus began the waiting game, though my clock was ticking. I, unlike most patients on a ventilator, was kept conscious to assess if any brain damage had occurred. Although intubated, I was given a pen and legal pad when my then girlfriend (and now wife) realized I had been tracing words in her hand. Fears were alleviated when, after writing questions asking where I was (the ICU) and what day it was (Saturday, September 3), I asked if the Browns won that preseason game (they lost). A few days later, I was stable enough to be taken off the ventilator. A feeling I will never forget is the removal of the breathing tube and using my own lungs and voice again.

On September 9, exactly two weeks after my biopsy had been sent for molecular testing, Dr. Ashton walked into my ICU room, shook my hand, and said, “Congratulations, Matt, you’re a mutant!” My biopsy had tested positive for a fusion gene called EML4-ALK. ALK is an active gene in embryos and newborns, when rapid cell division is crucial, but ALK expression decreases to select tissues in adulthood. ALK is reactivated after fusing with EML4, again causing rapid cell division, a key step in carcinogenesis. I now qualified for a targeted therapy called crizotinib. Crizotinib, unlike chemotherapy, attacks only cancerous cells with the EML4-ALK fusion gene. Thanks to the tireless efforts of Cleveland Clinic, Pfizer, and my very determined mother, crizotinib was in my hands the next day. Fun fact: the FDA approved crizotinib on August 26, 2011—the same day I was diagnosed with lung cancer.

Dr. Pennell was correct; my health rapidly improved. Soon, my chest tubes and pericardial drain were removed. I stood up for the first time in two weeks. Finally on September 21, three weeks after I was admitted to Cleveland Clinic and thirty pounds lighter, I walked out the front doors unaided and without any supplemental oxygen. Dr. Ashton maintains that I am the sickest person he has ever known to leave the ICU alive. Dr. Pennell told me that I had experienced every lung cancer–related complication known, except I had done so over days instead of months. Two months later, I returned to Cleveland Clinic for my first scans. Unbelievably and astonishingly, I had a complete response to the crizotinib—the cancer could not be seen on the scans!

I wish this was the end of my story, but this would not be the last time my cancer reared its ugly head. Seven months later, another lymph node swelled in my lower neck. A biopsy later confirmed that my cancer had returned. Crizotinib was the sole targeted therapy for ALK-positive patients in 2012. Now that my cancer had developed resistance to crizotinib, traditional chemotherapy, which I wanted to avoid for as long as possible, was next. Instead, I was enrolled on a phase II clinical trial that was studying the second-generation ALK inhibitor LDK378 (it was approved by the FDA as ceritinib in 2014). Six months after my enrollment, I began chemotherapy when the cancer developed resistance to LDK378. I received carboplatin, pemetrexed, and bevacizumab. This regimen led to my second complete response and bought me a year and a half. Less than two months before my wedding in June 2014, the cancer decided to crash the party early. I began cisplatin and radiation therapy, which destroyed the cancer and bought me another year. They also became a likely source of enduring side effects, like the partial paralysis of my left arm and some hearing loss. My most recent recurrence occurred in March 2015. Again faced with limited options, I was enrolled on another clinical trial. This time, it was a phase I (first in humans) study of the third-generation ALK-inhibitor PF-06463922. I experienced another complete response by the final months of 2015. I remained on this trial until the FDA approved lorlatinib (formerly PF-06463922) in 2018. I still take lorlatinib every day at lunchtime, and I intend to do so for the remainder of my life.

Personalized medicine saved my life. Cancer research saved my life. Clinical trials saved my life. Without groundbreaking clinical trials, the development of new treatments would cease. Without brave patients altruistically enrolling on clinical trials, cancer research would cease. Personalized medicine, though still in its relative infancy, grew exponentially throughout the past decade. In precision medicine, it is even possible to teach an old dog new tricks: as scientists learn more about the genetics of cancer, once disregarded drugs have been adopted as new targeted therapies.

From a patient’s perspective, cancer treatment buys time. My early years as a survivor were about buying time until the best treatment for me arrived. I envision a future where all newly diagnosed cancer patients have their biopsies molecularly tested. Molecular testing is still the exception, not the rule. I recognize that my story is exceptional. I am fortunate to have had both health insurance and access to the best oncologists. We have learned much, but there is still far more to know.

GenomOncology, in partnership with our clients, combats cancer with a team of dedicated employees and a bevy of software options. We provide next generation answers for battling cancer. I thank all clinical trial participants for furthering my cancer care. As a GenomOncology employee, I look forward to helping you further your cancer care.

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