Review Outlines Successes, Limitations of Personalized Medicine in Oncology

The evolution of cancer treatment towards a precision-based approach has led to significant progress in cancer therapy. However, some challenges do arise when shifting from an organ-centric concept guiding treatment choices to a more personalized approach, according to a review published in Cancers.

When it comes to recent successes in the revolution of tumor treatment from tumor site to molecular alterations, researchers point out “attention has gradually turned to biomarkers rather than the anatomic site of origin of a given tumor.”

Due to this transition, groups of patients whose tumors have a particular molecular feature have been treated with a singular targeted drug. The first instance of this was recorded in treatment of luminal breast cancer via endocrine therapy. In addition, approval of imatinib for patients with chronic myeloid leukemia bearing the t (9,22) translocation was also instrumental in the transition to a new approach.

“The identification of druggable molecular alterations marked a new era in oncology,” authors said, with the most important advancements achieved in the treatment of breast and lung cancer, and melanoma.

Locating and treating specific molecular characteristics, somatic or germline mutations, or gene fusions could ultimately improve patient outcomes regardless of where a tumor is located. In order to determine which patient subgroups could benefit from this type of therapy, authors note it is necessary to identify specific biomarkers to predict patient response or resistance.

They point out, “in umbrella trials, patients diagnosed with the same type of solid tumors are treated according to their molecular features, while in basket trials, patients diagnosed with different types of solid tumors with a common driver molecular alteration are selected and treated with a specific inhibitor.”

However, genetic mutations may not always result in the predicted change of a corresponding protein. Additional factors like protein modifications, metabolism, and the microbiome contribute to tumor behavior.

Another area of progress for precision molecular oncology relies on understanding the role of new drivers with novel drugs. “Several potential targets for novel drugs have been identified using high-throughput technologies and several compounds have recently been approved or are under investigation,” authors said.

Investigations into PIK3CA mutations in solid tumors, inhibition of BRAF mutations, neurotrophic tyrosine receptor kinases (NTRK) fusions, and activation of fibroblast growth factor receptor (FGFR) pathways have all contributed to new developments.

Despite promising advancements made in molecular driven treatments, certain negative trial results have highlighted limitations of precision medicine. In one trial patients with any kind of solid tumor were randomized to receive either targeted therapy selected according to their molecular profile, or their physician’s preferred treatment. “No benefit in median progression-free survival (PFS) was observed in molecularly oriented patients versus conventional approach (Hazard-ratio [HR] 0.88, P = .41), suggesting that off-label use of molecularly targeted agents does not improve progression-free survival compared with standard treatment,” authors said.

Complexity of cancer cells enriched with concomitant molecular alterations can complicate identification of the driver, while tumor heterogeneity could be responsible for the lack of benefit when targeted agents are used, authors explain. They continue, “Several discordant results have been obtained using selected targets in solid tumors sharing the same molecular alterations.”

Limitations could also result from factors that impact precision treatment variability such as gender, weight, ethnicity, and renal and hepatic functions. Because of this, targeting multiple drivers or resistance pathways may be the optimal method of antitumor therapy.

Efficient and effective use of tools such as patient-derived organoids (PDOs), patient-derived xenografts, liquid biopsy, and molecular tumor boards may aid in addressing challenges accompanying personalized cancer treatments.

“The possibility to offer a molecular-based personalized approach for cancer patients represents an attractive possibility in oncology,” authors conclude. “To obtain a relevant and real change which could improve all clinical outcome, a better understanding of molecular biology is needed.”

Reference

Gambardella V, Tarazona N, Cejalvo JM, et al. Personalized medicine: Recent progress in cancer therapy. Cancers (Basel). 2020;12(4):1009. doi: 10.3390/cancers12041009.