George Sledge, MD, FASCO

ALTHOUGH PRECISION medicine may be a recent discovery in some fields, it is an old story in the field of breast cancer, and one that has been exceptionally important in terms of managing the disease, according to George Sledge, MD, FASCO, Professor of Medicine and Medical Oncologist at the Stanford Cancer Center in Stanford, California. 

“Precision medicine is real and has been a major driver of success in the field of oncology in recent decades. It’s a phenomenon that has hugely and positively impacted the lives of most breast cancer patients,” he said at the 2017 European School of Oncology (ESO)/European Society for Medical Oncology (ESMO) International Consensus Conference for Advanced Breast Cancer (ABC4) in Lisbon, Portugal.¹ “The technology is moving at a very rapid pace, and our ability to measure mutations will get ever cheaper over the next few years.” 

Slicing the Pie 

ACCORDING TO Dr. Sledge, the genomic revolution has changed the field of precision medicine. When this field of research was brand new, genome sequencing cost billions of dollars. Currently, the price of conducting human whole-exome sequencing is somewhere around $1,000, he noted. 

“The likelihood is low that a random drug being pulled off the shelf and applied to a random mutation will provide a huge benefit.”

— George Sledge, MD, FASCO

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“In oncology, what precision medicine has involved, by and large, has been ever finer slicing of the pie,” shared Dr. Sledge. “Whereas in the past we might have viewed breast cancer as a single disease, slicing it up first by luminal, basal, etc., what we’re hearing about today is the further slicing of this pie, allowing us to identify specific lesions, measure them in a clinic—and based upon these measurements—target therapy. This approach has carried us a long way in breast cancer and overall oncology.” 

When it comes to the genomic revolution, the cost is as important as the science, he argued. “The high cost of cancer drugs is well known, but what we’re seeing in genomic terms is more akin to what goes on in the computer world; there’s a race to the bottom in terms of cost,” he said. “Whereas in the past the barrier to genomic testing was significantly financial, it is very reasonable to assume, based upon existing trends, that in 5 years or so the cost of doing whole-exome sequencing on a human tumor might be a couple hundred dollars.” 

This continued race to the bottom may make it possible to carry out whole-exome sequencing on a population basis. The price of testing for mutations in circulating tumor DNA will also likely collapse in the next few years, making this an inexpensive and likely ubiquitous test. 

Hope of Precision Medicine 

DR. SLEDGE suggested the hope of precision medicine is fairly straightforward: “omic testing” (ie, genomics, proteomics, etc.) will result in identifiable, actionable alterations, and identifying these alterations will result in clinical benefit for patients. “But it seems to me the problem comes about when we talk about the word ‘actionable,’ because it means very different things to different people,” he noted.

To a researcher, “actionable” frequently means that mutation X is associated with “badness” in some form. There is a drug for mutation X; therefore, mutation X is “actionable.” 

But what the word means to a patient is quite different, he argued. “Actionable” typically refers to identifying a drug that will prolong life and reduce suffering. “I would argue the patients’ view on actionable is indeed a much more appropriate use of the word than what we use clinically,” Dr. Sledge said. 

In the future, the hope is a patient will be able to hand over his or her gene sequence to a physician and be “fitted” for a drug. 

Profiling Patients in Clinical Trials 

CURRENTLY, NUMEROUS trials are using these technologies to profile patients with therapeutic intent. The largest of these trials is the NCI MATCH (National Cancer Institute Molecular Analysis for Therapy Choice) trial, which has already screened several thousands of patients. The trial profiles patients with next-generation sequencing to identify tumors with mutations/amplifications in pathways targetable by existing agents, assigns them to receive one of the agents/regimens defined to work on one of the identified mutations/amplifications in a phase II setting, and assesses response and progression-free survival. 

A trial investigating the novel tropomyosin receptor kinase (TRK) inhibitor larotrectinib (LOXO-101) showed consistent and durable antitumor activity in advanced cancers with TRK fusions, with responses seen in the majority of patients and across all tumor types.² According to Dr. Sledge, this is an exceptional result and demonstrates the hope of precision medicine. But unfortunately, the reality is better illustrated by the response to another targeted agent, neratinib (Nerlynx), across tumor types. In some tumors, responses are relatively common, but in many cancers with exactly the same somatic mutation, 0% response rates are seen. 

“Precision medicine is not a panacea; it’s a tool. And like all tools, it needs to be used appropriately.”

— George Sledge, MD, FASCO

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“So the idea that we will be able to base a drug upon a mutation— independent of the organ from which the cancer came—and see a response will not be the case for most mutations,” he explained. 

‘Most New Drugs Don’t Work Very Well’ 

“I THINK there’s an even larger problem,” continued Dr. Sledge. “One of the dirty little secrets of oncology is that most new drugs don’t work very well.” 

From 2009 to 2013, the European Medicines Agency approved the use of 48 cancer drugs for 68 indications. A total of 26 of the 68 drugs (38%) were associated with a survival benefit, with a median survival benefit of only 2.7 months.³ 

“I say this not to depress you, but rather to ask you a question: If we measured an oncogene in someone’s metastatic breast tumor and took an off-the-shelf drug that was  used for soft-tissue sarcoma and applied it to the patient with that mutation, do we really think it would do better than what has been seen in randomized phase III trials with drugs that have been through a rigorous process of development and testing? My advice would be no.” 

Perhaps more important, significant quality-of-life improvements were reported in just 10% of those 68 indications. “If our ultimate goal is for patients to live longer with better quality of life, I’d have to say the likelihood is low that a random drug being pulled off the shelf and applied to a random mutation will provide a huge benefit,” he added. 

Actionable Mutations Associated With Therapeutic Failure 

ACTIONABLE MUTATIONS may be associated with therapeutic failure for a number of reasons. Cancers frequently have more than one driver mutation, context matters, and organ specificity and tumor heterogeneity are real. 

Cases of compensatory resistance are also frequently seen. For example, in triple-negative breast cancer with upregulation of MEK, inhibiting MEK will frequently result in loss of ERK. Loss of ERK leads to c-Myc degradation, and c-Myc degradation results in the activation of multiple other receptor tyrosine kinases. The end result of the addition of one oncogenic driver may be the compensatory activation of multiple growth factor pathways. Although not particularly well studied, this compensatory resistance is a potential challenge to the idea of matching drugs to tumors of different origins. 

Sometimes the wrong tumor is being measured, with a focus on the primary tumor rather than the metastasis. “Evolution can have its way in terms of producing more variants that are capable of resistance,” he said. Finally, the financial toxicity of these agents limits their applicability on a population basis. 

“At the end of the day, biology is still messy and science is still hard,” Dr. Sledge continued. “Precision medicine is not a panacea; it’s a tool. And like all tools, it needs to be used appropriately. If not, it will not work.” ■

DISCLOSURE: Dr. Sledge reported no conflicts of interest. 

REFERENCES 

1. Sledge G: Precision/personalized medicine. 2017 ABC4 International Consensus Conference. Abstract IN22. Presented November 3, 2017. 

2. Dramatic responses seen with TRK inhibitor. Cancer Discov 7:787, 2017. 

3. Davis C, Naci H, Gurpinar E, et al: Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: Retrospective cohort study of drug approvals 2009-13. BMJ 359:j4530, 2017.