Pragmatic medicine in solid cancer: a translational alternative to precision medicine

Abstract

The precision medicine (PM) initiative is a response to the dismal outlook in solid cancer. Despite heterogeneity, common mechanistic denominators may exist across the spectrum of solid cancer. A shift from conventional research and development (R&D) toward PM will require conceptual and structural change. As individuals and as a society, we welcome innovation, but question change. We ask: In solid cancer, does PM identify and address the causes of prior failures, and, if so, are the proposed solutions feasible? And, when may we expect safer, more effective and affordable drugs in the clinic? Considerations that prompt a pragmatic rethink include a failure analysis of translational R&D in solid cancer suggesting that trials and regulations need to be aligned with the natural history of the disease. In successful therapeutic interventions in chronic, complex disease, surrogate markers and endpoints should be consistent with the Prentice’s criteria. In solid cancer, drug induced tumor shrinkage, is a drug effect and not a disease response; tumor shrinkage does not reflect nor predict interruption of the disease. Overall, we support a pragmatic, multidisciplinary, and collaborative R&D, and suggest that direction be set by clinical need and utility, and by questions, not answers. PM will prove worthwhile if it could improve clinical outcomes. The lag in therapeutics relative to diagnostics is a cause for confusion. Overdiagnosis adds to fear and harm, especially in the absence of effective interventions. A revised initiative that prioritizes metastasis research could replicate the successful HIV/AIDS model in solid cancer. A pragmatic approach may further translational efforts toward meaningfully effective, generally available, and affordable solutions.

Immune cells as tumor drug delivery vehicles

“…Compared to the ever-changing cancer cells themselves, more stable tumor properties can be found in the TME of both primary tumors and metastatic niches [20][21][22]. For example, rapid tumor growth requires an increased influx of nutrients and efflux of waste products.…”

Solid cancer: the new tumour spread endpoint opens novel opportunities

“…Drug-induced tumour shrinkage, which is easily measured, is rarely sustained and does not reflect a meaningful alteration in the natural history of solid cancer. 6 To date, the approval of drugs for solid cancer are primarily based on tumour shrinkage. Progression-free survival may appear as a meaningful endpoint; it is not.…”

“…10 In this context, RECIST is not fit for purpose. 6,11 Based on its ability to provide early detection of metastases, 68 Ga-PSMA-11 PET imaging is appropriate for pharmacologic and radiotherapeutic interventional trials in oligometastatic prostate cancer. 12,13 For the evaluation of candidate migrastatic agents we propose a trial in oligometastatic disease using advanced imaging technology and employing a common protocol.…”

Oligonucleotide Aptamer-Mediated Precision Therapy of Hematological Malignancies

“…Precision medicine targets specific abnormalities within the cancer cell genome, proteome, and immunome and markers involved in cancer initiation, development, and growth. 2 , 3 In contrast to conventional chemotherapy, precision medicine specifically targets the individual characteristics of each patient’s cancer phenotypic profile, resulting in significantly increased therapeutic efficacy and decreased non-specific toxicity. To date, precision medicine has been extensively applied in various cancers, especially hematological malignancies.…”