Defining Precision Cancer Medicine the Right Way

Maurie Markman, MD

Today, there is perhaps no expression more polarizing in oncology than “precision cancer medicine.” Despite very strong supporting evidence, certain individuals continue to challenge the validity of this paradigm-changing concept that is favorably influencing both clinical research and routine cancer management.

One editorialist, widely known for his Twitter comments and relatively large social media following, contends that only a small number of patients with cancer currently benefit from precision medicine.¹ In another recent commentary on the topic, the authors opine that exceptional responders “still represent an elusive outcome” and that “much of the informed consent process requires assessing [patients’] potential expectations of cure and tempering them considerably.”²

The critical issue is the unfortunate but often seriously misguided nature of this rhetoric. The message of these and many other commentaries is that the success of precision cancer medicine is determined by a particular outcome, documented at a specific point in time, and that failure to attain the arguably quite arbitrary and increasingly dubious statistical “gold standard” of P <.05 will suggest that the word precision is not a fit.

Bluntly stated, this argument incorrectly defines precision cancer medicine as an event whose value is to be analyzed through the conduct, completion, and ultimate outcome of traditional evidence-based clinical trials. Further, some members of the academic community believe such evidence includes only phase III randomized placebo-controlled studies with overall survival as the sole valid endpoint.

Nothing could be further from the truth.

In fact, it is critical for all to understand that precision cancer medicine does not represent the completion of a particular event for which success or failure can be declared; rather, it is a fundamental discovery and treatment process whereby investigators and clinicians continuously search for approaches that are more precise in the management of an individual patient with cancer.

The concept is very simple. It is highly relevant to appreciate that precision cancer medicine (although it has not always been called this) is among the oldest of all effective anticancer therapies. The discovery that the performance of a bilateral oophorectomy or the administration of antiestrogen therapy would cause regression of metastatic breast cancer in women whose cancers possessed certain clinical features (eg, patient age) or whose tumors were found to contain specific biomarkers (eg, estrogen receptor—positive) provided physicians with greater power to discriminate. These are excellent examples of clinical management being appropriately directed, at least in part, as a result of acquired knowledge.

Similarly, the discovery of the relevance of HER2 overexpression in breast cancer as a marker for the clinical benefit of anti-HER2—directed anti-neoplastic therapy has improved clinical discretion. In the absence of HER2 overexpression, the necessary avoidance of this therapeutic approach is another example of the value of the precision medicine concept.

Recently added to the increasingly long list of breast cancer precision medicine success stories are data revealing that a proprietary 21-gene assay can effectively help determine whether more- or less-intensive therapy is appropriate for early-stage patients with breast cancer: adjuvant cytotoxic chemotherapy or adjuvant hormonal therapy, which results in fewer short- and long-term adverse effects.³

Again, this is precision cancer medicine. But the results of this specific trial do not define success or failure of this therapeutic concept; they signify only that in this particular setting, the search for a more precise approach resulted in a favorable outcome. If the study had not unearthed any benefit from this molecular testing platform, all that would have been demonstrated is the lack of clinical utility of this specific strategy. However, the search for other biomarkers of clinical relevance would have continued, just as it will continue today, building on these important trial results.

The goal is to be more precise in the selection of the most effective anticancer therapeutics. Concurrently, one should strive to minimize treatment-related adverse effects and optimize overall clinical value.

The success of precision cancer medicine continues to be revealed through innovative nontraditional—but still highly relevant—clinical trials. The recent regulatory agency approval of checkpoint inhibitor therapy that is tumor site-of-origin agnostic and based on the vulnerability of tumors with mismatch repair deficiency is a striking example of the value of novel approaches to treatment.⁴ The importance of therapeutic investigation becomes more striking as clinically relevant patient populations diminish in size based on evidence of unique molecularly defined features.

It is impossible in this brief commentary to adequately capture the magnitude of the ever-increasing number of such studies published as full peer-reviewed manuscripts or presented to date only as abstracts at national oncology meetings. However, the steady stream of provocative and sometimes remarkable clinically meaningful outcomes resulting from this focus on precision cancer medicine continues.

Consider, for example, the report of 17 pediatric patients whose advanced and metastatic cancers possessed the very rare tropomyosin receptor kinase (TRK) fusion abnormality. This phase I/II tumor-agnostic study examined the clinical activity of the small molecule TRK inhibitor larotrectinib.⁵ Fourteen of 15 patients (93%) with TRK fusion—positive cancers attained an objective response (by RECIST), with the final patient also experiencing a response but not satisfying RECIST criteria. At the time of this report, all but 1 patient remained on treatment or had undergone curative intent surgery (median 8.2 months).

The future role of larotrectinib and many other biomarker-directed/targeted therapeutics remains to be determined, but in enabling greater clinical discrimination for superior outcomes, these agents will define and be defined by the paradigm-changing concept of precision medicine.

References

1. Kaiser J. Is genome-guided cancer treatment hyped? Science 2018;360(6387):365. doi: 10.1126/science.360.6387.365.
2. Marchiano EJ, Birkeland AC, Swieciki PL, Spector-Bagdady K, Shuman AG. Revising expectations in the era of precision oncology. Oncologist. 2018;23(3):386-388. doi: 10.1634/theoncologist.2017-0269.
3. Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer [published online June 3, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1804710.
4. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair de ciency. N Engl J Med. 2015;372(26):2509-2520. doi: 10.1056/NEJMoa1500596.
5. Laetsch W, DuBois SG, Mascarenhas L, et al. Larotrectinib for paediatric solid tumors harbouring NTRK gene fusions: phase 1 results from a multi- center, open-label, phase 1/2 study. Lancet Oncol. 2018;19(5):705-714. doi: 10.1016/S1470-2045(18)30119-0.