Molecular Profiling in Routine Practice for Advanced Cancers

Limited clinical benefit achieved in the ProfiLER study

ProfiLER, prospective multicentric study explores the identification of genomic profiles combined to the use of matched molecular targeted agents to steer decision-making in advanced cancer patients in routine clinical practice. Only 0.9% of the whole cohort, ie. 13% of patients receiving a matched molecular targeted agent, experienced an objective response. Jean-Yves Blay and ProfiLER investigators published their findings in the Annals of Oncology and concluded that molecular screening should not be used at present to guide decision-making in routine clinical practice outside of clinical trials.

Many targeted agents have been developed and approved in the last 15 years and they are nowadays prescribed in routine clinical practice with encouraging antitumour activity.

The large genomic profiling programme ProfiLER aims to describe distribution of genomic alterations in a routine population of cancer patients in curative treatment failure, as well as feasibility, efficacy and therapeutic impact of molecular profiling in routine setting.

In the Annals of Oncology, theProfiLER investigators reported the activating and actionable alterations identified in solid and haematological tumours from adults and paediatric patients, assessed their respective frequencies, and considered their use for guiding molecular targeted agent recommendations, as well as described the responses to molecular-based recommended therapy in the first 2579 enrolled patients.

Each molecular profile was established on tumour, relapse or biopsies, and reviewed by a molecular tumour board to identify molecular-based recommended therapies. The main outcome was to assess the incidence rate of genomic mutations in routine setting, across specific histological types. Secondary objectives included a description of patients with actionable alterations and for whom molecular-based recommended therapy was initiated, and overall response rate.

Four centers included 2579 patients from February 2013 to February 2017, and the molecular tumour board reviewed the molecular profiles achieved for 1980 (76.8%) patients. The most frequently altered genes were CDKN2A (n=181, 7%), KRAS (n=177, 7%), PIK3CA (n=185, 7%), and CCND1 (n=104, 4%).

Molecular-based recommended therapy was recommended for 699/2579 patients (27%), and only 163/2579 patients (6%) received at least one of such treatments. Out of the 182 lines of molecular-based recommended therapies initiated, 23 (13%) partial responses were observed. However, only 0.9% of the whole cohort experienced an objective response.

The authors noted when they started the ProfiLER study, the promising insights of probing the molecular landscape of solid tumours via a liquid biopsy were not addressed yet.

The low rate of molecular-based recommended therapies initiation may be partially explained by long timeframes of genomic analysis processing (86 days), hardly compatible with rapid disease progression in a population rarely meeting therapeutic clinical trials requirements, and by molecular targeted agent scarcity. Off-label use of molecular-based recommended therapy was rare with 28% of such treatments prescribed off-label.

The authors recognised that such genomic approaches require significant human and financial resource deployment and could not be implemented in the standard medical practice without extensive institutional support, and a full cost-effectiveness analysis should be conducted.

Investigators were given the opportunity to select the more appropriate treatment option for their patient based on their medical history, clinical prognostic factors, clinical trial availabilities, and most importantly patient’s inclination.

However, the clinical benefit achieved with this genomic screening programme using single tumour biopsy assessment was very limited.

Two ongoing clinical studies are exploring this question using a broader panel (NCT03163732) and whole exome sequencing (NCT01774409).

The study was supported by Institut National du Cancer (INCa), LYRICAN, LYric, Bpifrance Financement abounded by European Community, the European Commission, Agence Nationale de la Recherche-LabEx DEvweCAN and received funding form InterSARC, Association DAM’s, Ensemble contre Le GIST, la Fondation ARC, Infosarcome, Ligue de l’Ain contre le Cancer, and Centre Léon Bérard.

 

Reference

Trédan O, Wang D, Pissaloux P, et al. Molecular screening program to select molecular-based recommended therapies for metastatic cancer patients: analysis from the ProfiLER trial. Ann Oncol2019; 30(5):757-765. doi: 10.1093/annonc/mdz080.