Cancer Therapy Directed by Comprehensive Genomic Profiling: A Single Center Study

Abstract

Innovative molecular diagnostics deployed in the clinic enable new ways to stratify patients into appropriate treatment regimens. These approaches may resolve a major challenge for early-phase clinical trials, which is to recruit patients who, while having failed previous treatments, may nevertheless respond to molecularly targeted drugs. We report the findings of a prospective, single-center study conducted in patients with diverse refractory cancers who underwent comprehensive genomic profiling (CGP; next-generation sequencing, 236 genes). Of the 500 patients enrolled, 188 (37.6%) received either matched (N ¼ 122/188, 65%) or unmatched therapy (N ¼ 66/188, 35%). The most common reasons that patients were not evaluable for treatment included insufficient tissue, death, or hospice transfer. The median number of molecular alterations per patient was five (range, 1-14); median number of prior therapies, four. The most common diagnoses were ovarian cancer (18%), breast cancer (16%), sarcoma (13%), and renal cancer (7%). Of the 339 successfully profiled patients, 317 (93.5%) had at least one potentially actionable alteration. By calculating matching scores, based on the number of drug matches and genomic aberrations per patient, we found that high scores were independently associated with a greater frequency of stable disease !6 months/partial/complete remission [22% (high scores) vs. 9% (low scores), P ¼ 0.024], longer time-to-treatment failure [hazard ratio (HR) ¼ 0.52; 95% confidence interval (CI) ¼ 0.36-0.74; P ¼ 0.0003], and survival (HR ¼ 0.65; 95% CI ¼ 0.43-1.0; P ¼ 0.05). Collectively, this study offers a clinical proof of concept for the utility of CGP in assigning therapy to patients with refractory malignancies, especially in those patients with multiple genomic aberrations for whom combination therapies could be implemented.Cancer Res; 76(13); 3690-701. Ó2016 AACR.

Initiative for Molecular Profiling and Advanced Cancer Therapy (IMPACT): An MD Anderson precision medicine study.

“…13,17,18 Indeed, in some reports, approximately 95% of patients from whom adequate tissue is obtained are found to have molecular alterations. 13,[16][17][18][19][20] The complexity of using precision medicine is explained, in part, by the coexistence of multiple molecular alterations, as seen in our population, the lack of efficient targeted agents for all alterations, and the fact that some alterations are more difficult to target than others. 19 This observation is consistent with previously published results that have demonstrated that a matching score-number of matches divided by number of alterations-correlates well with all outcome parameters.…”

“…In a group 1 analysis, we used the traditional definition of matched therapy, as previously published 6,7,13 (Appendix and Table 1 footnote). Overall, 390 patients (27% of 1,436 total patients; or 61.2% of 637 patients) received matched therapy and 247 (17.2%) received nonmatched therapy.…”

Clinical factors of response in patients with advanced ovarian cancer participating in early phase clinical trials

“…There is increasing interest in routine molecular testing of all patients considering Phase I trials, so that germline and somatic mutation data can be incorporated into trial selection [34]. This molecular matching of target and agent has been reported to significantly improve both progression-free survival (3.9 vs 2.2 months), and median survival (11.4 vs 8.6 months) compared to unmatched therapy [35].…”

New Perspectives in Medical Oncology : Molecular Medicine and its Perspectives

“…Dans cette étude, une forte concordance était observée entre les anomalies observées dans la tumeur primaire et les métastases (seulement 2 cas sur les 64 testés qui présentaient des discordances (21). La présence de mutations de gènes codant pour des protéines actionnables est corrélée à l'obtention d'une réponse et un bénéfice pour le patient (22,23), notamment lorsque des combinaisons de thérapies ciblées sont envisagées. Plus de 50 programmes de screening moléculaire des cancers sont ouverts à travers le monde.…”