Unique Molecular Landscapes in Cancer: Implications for Individualized, Curated Drug Combinations

Abstract

With increasing lysophisticated technologies in molecular biology and ‘omic’ platforms to analyze patients’ tumors, more molecular diversity and complexity in cancer are being observed. Recently, we noted unique genomic profiles in a group of patients with metastatic breast cancer based on an analysis with next generation sequencing (NGS); amongst 57 consecutive patients, no two had the same molecular portfolio (1). Applied genomics therefore appears to represent a disruptive innovation in that it unveils a heterogeneity to metastatic cancer that may be ill suited to canonical clinical trials and practice paradigms. Upon recognizing that patients have unique tumor landscapes, it is possible that there may be a ‘mismatch’ between our traditional clinical trials system that selects patients based on common characteristics in order to evaluate a drug (drug-centric approach), and optimal treatment based on curated, individualized drug combinations for each patient (patient-centric approach).

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

“…As a major reason for failure to be treated was death or deterioration due to progressive cancer, increasing the proportion of treated patients will likely require moving CGP assessment to an earlier line of therapy. Importantly, as multi-gene panels have become available, it is apparent that most patients have numerous alterations (median ¼ five alterations/patient in our study), indicating that customized combination therapy may be necessary (8,50). For this reason, we developed an exploratory Matching Score that divided the number of matches by the number of molecular anomalies in each participant's malignancy (Materials and Methods).…”

“…Examining only "matched versus unmatched" as a variable revealed an independent/significant association between matching patients to cognate therapy and TTF, and a trend for higher rates of SD !6 months/PR/CR, but not OS. Therefore, understanding and optimizing the impact of matching strategies may require taking into account the need for and influence of matched combination treatments (50), as well as the effect of genomic complexity (8,52).…”

“…It is now well known that advanced tumors have multiple aberrations and that combination therapy is likely to be better than monotherapy (8). Therefore, an exploratory scoring system ("Matching Score") was developed that divided the number of matched drugs by the number of aberrations.…”

“…Outcome variables included rate of stable disease (SD) !6 months/partial/complete remission (SD !6 months/PR/ CR), time-to-treatment failure (TTF), overall survival (OS), as well as TTF on trial compared (TTF2) with the TTF of the immediately prior therapy (TTF1) uninformed by genomics (TTF2 vs. TTF1). In addition, because patients often have multiple genomic alterations and receive combination drug regimens (8), all of which could influence outcome, we also investigated a novel, exploratory Matching Score that incorporated the number of matched agents given to a patient and the number of gene alterations present in the tumor of that individual.…”

The Urgent Need for Clinical Research Reform to Permit Faster, Less Expensive Access to New Therapies for Lethal Diseases

“…Conversely, requiring large phase III trials that are restricted to small, defined subpopulations is enormously expensive and time consuing due to challenges in identifying eligible patients (28). In the era of precision medicine, we are discovering that individual cancers often have complex, unique genomic profiles, with no two identical, suggesting individualized therapy, rather than finding commonalities between patients, as the model for future cancer research (32,33), and as discussed by Siu and colleagues elsewhere in this CCR Focus, next-generation sequencing of tumor genetic material will play a key role in this effort (9).…”