Precision Medicine Unfolds in Oncology, Bearing Substantial Implications for the Future

Maurie Markman, MD

One of the largest roles for precision cancer medicine could be in the longitudinal monitoring of the disease, scanning the blood not only for signs of progression at the earliest onset but for identifiable and actionable markers that could signal both a need for a change in treatment and accurately predict its efficacy, according to Maurie Markman, MD.

“We certainly have to be concerned about cost, but assuming we can deal with these issues, the idea of monitoring the status of an illness in a cost-effective way, and modifying therapy to allow a patient to continue with an excellent quality of life, as defined by the patient, through this type of a strategy, is a very reasonable hope for the future,” Markman, editor-in-chief of OncologyLive^®, said.

In this special with OncLive, Markman, who is president of medicine & science at City of Hope Atlanta, Chicago, and Phoenix, discussed the past and present waves of precision medicine in oncology and explained how these advances could translate to future patient management.

The Past of Precision Cancer Medicine

Markman: Precision cancer medicine didn’t just start recently. You can go back and say it was the original form of anti-cancer treatment. And what I mean by that is that it was noted that in the premenopausal state, [surgical] removal of the ovaries, which even in some circumstances might be done today, was an anti-cancer therapy. There was short-term regression of the metastatic or locally advanced breast cancer. That happened many decades ago, even longer than that. Removal of the testicles, we didn’t even know that was called testosterone at the time, was a form of treatment for metastatic prostate cancer. So again, precision cancer medicine is not a new concept. What happened is we began to understand [more]. We understood estrogen receptors, progesterone receptors, androgen receptors, and that became an incredibly important form of therapy. Those therapies were widely used, but that was pretty much it. We did not understand the gene or genes, nor the concept of genetic abnormalities, whether they were somatic or germline.

The revolution began and is continuing today, with the understanding of the molecular biology of the cancers. We learned not much more than 20 years ago about the importance of targeting HER2 overexpression as a treatment, first in metastatic breast cancer, and then as an adjuvant treatment. The world of chronic myeloid leukemia [CML] treatment was revolutionized with the understanding of targeting what is called oncogene addiction, with imatinib [Gleevec] for the treatment of BCR:ABL CML-related disease; [this] has revolutionized the treatment of that illness. We have a number of other examples going back that length of time where the standard of care [SOC] completely changed the management of these diseases.

We had a number of false starts, [including] the assumption that all we need to do is find overexpression of a particular receptor. EGFR is a classic example. We just find all the tumors, and there are many, if not most, where EGFR is overexpressed, and we simply target overexpression. That didn’t work, and billions of dollars were spent by the pharmaceutical industry and academic institutions simply looking at overexpression of EGFR until we learned it was a particular mutation, or mutations that one needed to target and drug for those abnormalities that changed those illnesses. So much has happened over this period leading up to what I would say is the present.

The Present of Precision Cancer Medicine

The present is a massive expansion of the role of precision cancer medicine, with our understanding of somatic mutations, germline mutations, and, critically, the molecular platforms that allow us to now not spend several billion dollars to look at a single gene. Now we’re at a point, and this took years to do, where we can look at the patterns in individual patients’ genes, [regardless of whether they’re germline or somatic] in the sort of thousand-dollar range, and at timelines that are measured in weeks or less. We have standard-of-care [treatments] in multiple tumor types [for] very specific abnormalities that are identified. Lung cancer is a wonderful example where one would hopefully not think about giving therapy in metastatic non–small cell lung cancer without finding out whether there was an EGFR mutation or an ALK mutation, for example, [because] that is SOC. In breast cancer, we have now been looking for HER2 overexpression. In ovarian cancer, the question of using PARP inhibitor maintenance therapy based on germline or somatic mutations is now SOC. So SOC with the use of these precision cancer approaches is evolving. Drugs are evolving. Settings are involving. It’s a very exciting time.

However, we are still largely focused on, with some important exceptions, the tissue in the solid tumor space, and in specific abnormalities that might be determined with liquid tumor biopsies. This is evolving, but SOC today clearly includes, without any question, in multiple tumor types, obtaining the molecular profile of a tumor and using that to define the standard treatment, both in the frontline and perhaps in the second-line setting, in an increasing number of tumor types. This is a very exciting area era. It’s very important to emphasize how rapidly it’s moving.

I’ll end this section by mentioning the increasing number of FDA approvals for drugs based on the presence of a molecular abnormality that are not related to the site of origin or the tissue of origin. The term that has been used is tumor agnostic. So, finding these abnormalities should lead to the use of a particular drug, independent of the site of origin. Questions remain, as well. When do you use it? Should it be [given in the] first line, second line, or third line? Much needs to be answered. The important point is it’s been recognized that the presence of these molecular abnormalities in certain settings should be an indication for using the drugs, because they’re effective in that setting, in the presence of a particular molecular abnormality. There’s no question that we’re going to see more and more of these indications as we move along in our increasing understanding of the molecular biology of cancer.

The Future of Precision Cancer Medicine

The future in this area is in evolution. It doesn’t suddenly start. We’re beginning to see some of what I’m going to describe over the next few minutes, but one of the important developments as relates to the future will be the idea of routine, SOC, molecular monitoring of cancer and that implies in the blood. We look at tissue, we can even look at a liquid tumor biopsy for cancers at the beginning to define therapy, but the idea that we could potentially monthly, take a tube of blood and routinely monitor the course of the disease in terms of progression, but more important than that in terms of therapy, find an abnormality in that assay that can predict whether a future drug will be effective. We’re beginning to do this in lung cancer, where we find mutations that are present that indicate that now this EGFR mutation, which we’ve originally seen, is mutated in terms of a large percentage of the tumor to a different mutation, so we have another drug that might be effective. [With] the idea that we can routinely monitor [is the implication that we’re] able to do it at a cost that is in the hundreds of dollars if we’re talking about monthly or every-other-month monitoring. We are not there yet, but hopefully we will be there in the future of many tumor types.

It’s one thing to say we are going to monitor progression of the disease, and one can argue very appropriately that if the therapy isn’t working, you shouldn’t be giving the drug, both because of adverse effects and costs. But from a patient’s perspective and from the doctor’s perspective, what you want to be able to find is not just that the disease is progressing, and the drug isn’t working, but what might might be employed now. It’s this documenting quickly, or as quickly as possible before the disease progresses in a major way, with large masses, symptoms, etc., that the biology of the cancer has changed. We won’t necessarily know how it’s going to change, but we’ll find it, and we will hopefully have a platform of drugs. I’m now talking about the future, [where we may have] 4, 5, 6, 7, 10 different drugs based upon the molecular abnormalities that we’ve seen as these tumors change, document that, and switch the therapies. Cancer is increasingly in advanced stages, becoming more chronic in nature. I’m talking about a situation where we have to be concerned about toxicity.

When will that occur? It’s going to evolve over a period, and one would anticipate that certain disease types will evolve quicker than others. On the other hand, we may see a number of drugs that may be relevant across the tumor-agnostic platforms, so we might be able to see with a particular abnormality whether this is a relevant drug for multiple tumor types whether we see this pattern again. All that is to be determined through research over the coming years. This is a very exciting, very provocative, very complex time, but from the perspective of potentially helping our patients live lives of excellent quality, this is a very reasonable hope and plan for the future.