Advancing Healthcare Through Personalized Medicine

Priya Hays

• Publisher: CRC Press
• Year: 2017
• ISBN:
  9781315350288
• Edition: 1
• Topic: Negocios y empresa
• Subtopic: Sector de servicios

This innovative book provides a unique perspective on the biomedical and societal implications of personalized medicine and how it will help mitigate the healthcare crisis and rein in ever-growing expenditure. It introduces the reader to underlying concepts at the heart of personalized medicine - pharmacogenomics, targeted therapies and individualized diagnosis and treatment - and shows how, with the advent of genomic technologies, clinicians will have the capability to predict and diagnose disease more efficiently. Advocating a patient-centred approach at the heart of care, this introduction to personalized medicine, the science behind it, its economic effects, its effects upon patients and its overall implications for society will be invaluable to clinicians, to healthcare providers and to patients.

Chapter 1

Introduction: Biomedical innovation and policy in the twenty-first century

The question is not whether personalized medicine is here to stay; it is how fast is it going to be implemented.

Raju Kucherlapati, PhD

Professor of Medicine and Paul C. Cabot Professor of Genetics

Harvard Medical School

The development of Xalkori, also known as crizotinib, a small molecular inhibitor encoded by the ALK gene targeted to treat non-small-cell lung cancer (NSCLC), began several years ago. Analysis of a cDNA library Japanese patient with lung adenocarcinoma identified a novel fusion between the EML4 and ALK genes with the ability to transform 3T3 fibroblasts. Analysis of a series of biopsies from NSCLC patients revealed that ∼5% of patients carry this fusion protein (Ranade et al., 2014). After this initial finding in 2007, crizotinib was discovered to be an effective targeted therapy for patients whose NSCLC tumors harbored the ALK gene. According to Ranade et al., it caused tumors to shrink or stabilize in 90% of 82 patients carrying the ALK fusion gene, and tumors shrank at least 30% in 57% of people treated. These promising clinical results led to phase II and a phase III trials, which selectively enrolled NSCLC patients with ALK fusion genes. Astonishingly, within four years of the initial publication by Soda et al. (2007), the Food and Drug Administration (FDA) approved crizotinib for the treatment of certain late-stage (locally advanced or metastatic) NSCLC patients whose tumors had ALK fusion genes, as identified by a companion diagnostic that was approved simultaneously with the drug, as Ranade et al., noted.

When the FDA approved the cancer drug known as Gleevec in 2001 for treatment against chronic myeloid leukemia (CML), the agency did so after one of the shortest drug review processes on record. Novartis, the maker of Gleevec, also known as imatinib mesylate, had sponsored the clinical trials behind the drug. The FDA approved the drug within 10 weeks of reviewing three separate studies on 1000 patients. On May 10, 2001, at the press conference announcing the FDA approval of Gleevec, Health and Human Services (HHS) secretary Tommy Thompson declared:

Today I have the privilege of announcing a medical breakthrough. Like most scientific breakthroughs, this one is not sudden, nor does it stand alone. Rather, like most scientific advancement, it is a culmination of years of work and years of investment, by many people in many different institutions, and even in different fields of medicine. We are here to announce one dramatic product of all those efforts. But we believe many more products will follow, based on years of scientific groundwork. So this is the right time to acknowledge those efforts, to recognize that our investments in research are paying off, and to praise the teamwork that has brought us here. It’s also the right time to talk about what this can mean for our future—a future that promises a new level of precision and power in many of our pharmaceutical products. Today the Food and Drug Administration has approved a new drug, Gleevec, for treatment of chronic myeloid leukemia—or CML. Let me just say that it appears to change the odds dramatically for patients. And it does so with relatively low occurrence of serious side effects.

With the details of the effectiveness of Gleevec and its implications, Thompson’s announcement quickly gained the news media’s attention. CNN cycled the story every half hour throughout the day of the press conference. The Associated Press wrote and updated the story several times, and the news made the front page of newspapers nationwide. In the weeks following the announcement, extraordinary coverage was given to Gleevec and its effects on cancer, including a cover story in TIME magazine (May 28, 2001) and reports in the New York Times, USA Today, and Newsweek.

Gleevec was proven to be effective not just against CML, but also against another cancer, gastrointestinal stromal tumor (GIST). Three days after Thompson’s press conference, during the annual meeting of the American Society of Clinical Oncology in San Francisco, Dr Charles Blanke announced that the so-called “leukemia pill” had stunning results against GIST (https://liferaftgroup.org/wp-content/uploads/2012/09/May2001newsletter.pdf).

According to a website for a GIST patient advocacy group a dozen years after its approval, Gleevec is a relatively unknown pill. Why all the attention focused on one orange pill against two relatively rare cancers (CML affects 4500 patients annually, while GIST is even rarer)? Although primarily addressing CML rather than GIST, Thompson broadly answered the question at the HHS press conference: Gleevec is targeted therapy—it kills leukemia cells while sparing normal white blood cells. Unlike other more strenuous chemotherapy regimens, Gleevec has relatively few side effects. Gleevec targets the signal in the cell that causes cancer, acting as a molecular switch. Gleevec is now the prototype of cancer drugs, and cancer research laboratories around the world are trying to mimic the effects of Gleevec on other types of cancers.

As reported by the National Cancer Institute, most of the 4500 Americans diagnosed with CML each year are middle-aged or older, although some are children. In the first stages of CML, most people do not have any symptoms of cancer, as disease progresses slowly. Bone marrow transplantation in the initial chronic phase of the disease is the only known cure for CML. However, many patients are not young or healthy enough to tolerate transplantation; of those expected to tolerate transplantation, many cannot find a suitable donor, and the procedure can cause serious side effects or death. For these patients, treatment with the drug interferon alfa, introduced about 20 years prior to Gleevec, may produce remission, restoring a normal blood count in up to 70% of patients with chronic-phase CML. If interferon alfa is ineffective or patients stop responding to the drug, the prognosis is generally bleak.

Gleevec has produced higher remission rates in three short-duration, early-phase clinical trials. In the results of one clinical trial, reported in April 2001 in the New England Journal of Medicine, Gleevec restored normal blood counts in 53 out of 54 interferon-resistant CML patients, a response rate rarely seen in cancer with a single agent. Fifty-one of these patients were still doing well after a year on the medicine, and most reported few minor side effects. Imatinib mesylate was invented in the late 1990s by scientists at Ciba-Geigy (which merged with Sandoz in 1996 to become Novartis), in a team led by biochemist Nicholas Lydon, and its use to treat CML was driven by oncologist Brian Druker of Oregon Health & Science University. Druker led the clinical trials confirming its efficacy in CML (Gambacorti-Passerini, 2008). The scientific story of Gleevec, which became known as targeted therapy, a medical breakthrough that was a result of years of research, heralds back to the discovery of the BCR-ABL mutation in chromosomes 9 and 22 by Janet Rowland at the University of Chicago, and the pioneering work of researchers at Johns Hopkins University who discovered that cancer cells harbor this mutation. Gleevec is targeted therapy, designed to attack cells with this BCR-ABL mutation (also known as translocation, when pieces of chromosomes detach from one or more chromosomes and move to another chromosome). This BCR-ABL mutation affects a growth pathway in the cell known as the tyrosine kinase pathway, which leads to a cancerous state.

For the first time, cancer researchers now have the necessary tools to probe the molecular anatomy of tumor cells in search of cancer-causing proteins,” said Richard Klausner of the National Cancer Institute. “Gleevec offers proof that molecular targeting works in treating cancer, provided that the target is correctly chosen. The challenge now is to find these targets (http://www.cccbiotechnology.com/WN/SU/gleevecnews.php).

There are hundreds of known mutations for cystic fibrosis (CF), an inherited disease that affects the lung leading to complications such as pneumothorax. In 2012, the FDA approved a new therapy for CF called Kalydeco (known generically as ivacaftor), which was approved for patients with a specific genetic mutation—referred to as the G551D mutation—in a gene that is important for regulating the transport of salt and water in the body. The G551D mutation is responsible for only 4% of cases in the United States (approximately 1200 people). In these patients, Kalydeco works by helping restore the function of the protein that is made by the mutated gene. It allows a proper flow of salt and water on the surface of the lungs and helps prevent the buildup of sticky mucus that occurs in patients with CF and can lead to life-threatening lung infections and digestive problems.

The FDA’s profile of personalized medicine chronicles the development of Herceptin (Simoncelli, 2013):

The story of trastuzumab (Herceptin, made by Genentech, Inc.) began with the identification by Robert Weinberg in 1979 of “HER-2,” a gene involved in multiple cancer pathways. Over the next two decades, UCLA researcher Dennis Slamon worked to understand the link between HER2 and specific types of cancer. Slamon observed that changes in the HER2 gene caused breast cancer cells to produce the normal HER2 protein, but in abnormally high amounts.

Overexpression of the HER2 protein appeared to occur in approximately 20%–25% of breast cancer cases, and seemed to result in an especially aggressive form of the disease. These observations made it clear that HER2 protein overexpression could potentially serve as both a marker of aggressive disease as well as a target for treatment. In May 1998, before an audience of 18,000 attendees of the annual meeting of the American Society for Clinical Oncology (ASCO), Slamon presented evidence that Herceptin, a novel antibody therapy he had developed in collaboration with researchers at Genentech, was highly effective in treating patients with this extraordinarily aggressive and intractable form of breast cancer. What was so revolutionary about Herceptin was that it was the first molecularly targeted cancer therapy designed to “shut off” the HER2 gene, making the cancerous cells grow more slowly and without damaging normal tissue. This precision also meant that patients taking the new treatment generally suffered fewer severe side effects as compared with other cancer treatments available at that time.

In September 1998, FDA approved Herceptin for the treatment of HER2 positive metastatic breast cancers. On that same day, the Agency granted approval to DAKO Corp for HercepTest, an in vitro assay to detect HER2 protein overexpression in breast cancer cells.

Four stories, four drugs. Each of these highlights certain aspects of personalized medicine and positive lessons learned: the discovery of driver mutations that drugs could target, rapidly facilitated clinical trials that lessen FDA approval time for breakthrough drugs, and codevelopment of drug and companion diagnostics that lead to effective predictive treatment for patients. Raju Kucherlapati’s statement is telling of the coming revolution in biomedicine ahead of us.

One of the most remarkable changes has occurred in the landscape of clinical trials in the wake of personalized (physician approaches) and precision (pharma approaches) medicine. By identifying driver mutations in heterogenous tumors that could serve as targets for therapy, drug companies could save time and money in drug development by “designing small but highly effective trials targeted to those patients more likely to benefit from the therapy” (Ranade et al., 2014). In a study led by researchers at Weill Cornell Medical College in 2015, results identified 684, or 8%, of ­eligible trials as precision cancer medical trials that were significantly more likely to be phase II and multicenter; involved breast, colorectal, and skin cancers; and required 38 unique genome alterations for enrollment. The proportion of precision cancer medicine trials compared with the total number of trials increased from 3% in 2006 to 16% in 2013 (Roper et al., 2015).

In July 2015, oncologists will start enrolling patients in a clinical trial with 20 or more arms, each testing different agents against different molecular targets and each including patients with different cancers. In design, the trial itself couldn’t be more different from the classic clinical trial.

Instead of focusing on one cancer, as trials have for decades, the National Cancer Institute’s NCI-MATCH (Molecular Analysis for Therapy Choice) trial will include patients with any solid tumor or lymphoma who have one of many genomic abnormalities known to drive cancer. Patients will be matched with a targeted agent that has shown promise against their abnormality, regardless of what cancer they have. Known as a basket trial...