Give Precision Medicine a Chance

Maurie Markman, MD

The expression precision medicine has generated not only major interest in both the lay and medical press, but also considerable controversy. And, the intensity of the often-misguided rhetoric challenging this concept is perhaps most evident in the oncology sphere.

For example, the results of a single small randomized phase II trial that failed to reveal the superiority of molecularly selected therapy compared with physician’s choice has been cited by some as solid evidence questioning the entire concept of precision medicine in cancer.¹ This conclusion has been reached despite the fact that one can easily and quite appropriately argue what was “proven” in this particular study is either that the particular target itself or—what is far more likely— the drugs employed to attempt to favorably impact that target are not clinically relevant.

Thus, in contrast to the stated opinions of the paper’s authors and others, this study can be cited as evidence in support of the process of precision medicine in cancer, where the simple yet profound goal is to attempt to make antineoplastic therapy more precise by examining the molecular characteristics of the individual cancer and, hopefully in the near future, the patient’s own germline variants.

It is the purpose of this commentary to highlight several recent reports that demonstrate both the favorable impact of this revolutionary paradigm, as well as steady progress in this fundamental cancer drug development and management process, whereby investigators specifically examine the relevance of our rapidly expanding knowledge of the molecular basis of malignant disease and mechanisms of resistance for the purpose of discovering approaches that favorably alter the course of the malignancy for an individual patient with cancer.

There can be no more powerful statement regarding the potential clinical utility of the process of precision medicine in cancer than the spectacular transformation in the management and anticipated outcome of chronic myeloid leukemia (CML) resulting from the introduction of imatinib, the first therapeutic agent specifically targeted to the malignancy’s long-recognized characteristic molecular abnormality.²

Prior to this event, which occurred because of a very specific focus on this unique molecular characteristic, the only justification for labeling this illness a “chronic” leukemia was the fact that the anticipated survival (median approximately 3 years) was superior to the dismal survival outcome observed in this earlier era for patients diagnosed with “acute” leukemia. In addition, in a large percentage of patients, the so-called chronic phase would transform into a “blast crisis,” ultimately resulting in a terminal stage of the illness essentially identical to an untreatable acute leukemia.

In a report from Sweden, investigators analyzed the survival of 2662 patients diagnosed with CML from 1973 until 2013.² These population-based data provide rather profound documentation of the real-world impact of this therapeutic strategy specifically developed to favorably influence a relevant molecular target. The data reveal, for example, that for a 55-year-old Swedish male diagnosed with CML in 1980, his life expectancy would on average only be an additional 3.5 years. However, a man of the same age diagnosed with CML in 2010 would have on average 27.3 years of remaining life.²

Even the much older-aged population benefited from the introduction of this precision medicine—based therapeutic. For example, an 85-year-old male in Sweden diagnosed with CML in 1980 had a life expectancy on average of only 0.8 years, which increased to 4.1 years in 2010. Overall, these data revealed that for all patients with CML, regardless of age, life expectancy on average in 2010 was only 3 years less than that of the general population.

Turning to the clearly less dramatic but still unquestionably relevant experience with rarer molecular events in specific tumor types, recent reports in a high-impact medical journal have noted the major effect of precision medicine—based therapeutic strategies in both the very common tumor type of prostate cancer and the quite rare malignancy of hairy cell leukemia.^3,4

In prostate cancer, investigators reported that among 16 heavily pretreated patients with metastatic disease whose cancers contained one of several types of mutations in DNA-repair genes, 14 (88%) achieved a response to the targeted therapeutic olaparib.³ In the case of hairy cell leukemia, a malignancy relatively recently associated with a BRAF V600E mutation, the administration of the oral BRAF inhibitor vemurafenib achieved a 96% overall response rate in 26 evaluable patients with refractory disease.⁴

It is critical to acknowledge that nothing in this commentary is meant to suggest advances in our understanding of the molecular basis of cancer will be easily translated into new effective therapeutics.

Rather, what is meant to be highlighted here is the process whereby future therapeutic strategies will be developed, evaluated, and subsequently utilized in routine clinical practice. For example, provocative data suggest a high mutational burden found within a particular patient’s cancer may be a useful biomarker for the subsequent utility of the class of immunotherapeutics known as checkpoint inhibitors.⁵ The hypothesis is that finding cancers whose individual cells contain a large number of mutations may identify a setting where a sufficient level of theorized neoantigens are present to which the immune system can mount a clinically robust response.

Again, while not proven, it is the process of precision medicine that demands there be a constant search for such biomarkers that will help predict the clinical utility for individual patients with cancer of these clearly beneficial but potentially toxic and very expensive antineoplastic agents.

Maurie Markman, MD, editor-in-chief, is president of Medi- cine & Science at Cancer Treatment Centers of America, and clinical professor of Medicine, Drexel University College of Medicine. maurie.markman@ctca-hope.com.

References

1. Le Tourneau C, Delord JP Goncalves A, et al. Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomized, controlled phase 2 trial. Lancet Oncol. 2015;16(13):1324-1334. doi:10.1016/S1470-2045(15ö)00188-6.
2. Bower H, Björkholm M, Dickman PW, et al. Life expectancy of patients with chronic myeloid leukemia approaches the life expectancy of the general population. J Clin Oncol. 2016;34(24):2851-2857. doi:10.1200/JCO.2015.66.2866.
3. Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373(18):1697- 1708. doi:10.1056/NEJMoa1506859.
4. Tiacci E, Park JH, De Carolis L, et al. Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia. N Engl J Med. 2015;373(18):1733-1747. doi:10.1056/NEJMoa1506583.
5. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509-2520. doi:10.1056/NEJMoa1500596.