The best magazine
Evaluating New Treatments in the Age of Biomarkers
Recognition of unique types of EOC is already having an impact on clinical trials. Failure to consider accurate diagnosis could dilute any type-specific treatment benefits or imply benefit within a disease type where it does not exist while exposing all subjects to potential toxicities. More selective trials will also more accurately characterize baseline type-specific clinical metrics.
There is a compelling need to identify valid clinically relevant biomarkers. Most biomarkers are prognostic, such as the extent of residual disease after cytoreductive surgery, and are associated with outcomes that are independent of any specific treatment. Factors associated with a reduced risk of recurrence, such as KRAS or BRAF mutation in LGSC, could also be used to minimize postsurgical interventions.
Predictive biomarkers define the potential for response to a specific treatment intervention. Often these represent genetic aberrations, for example, HER2 amplification predicts clinical benefit from anti-HER2 therapy in breast cancer. In non–small cell lung cancer, biomarkers related to ALK kinase rearrangements predict susceptibility to a class of ALK inhibitors, with similar data in melanoma for selected mutations in BRAF. Predictive markers in EOC have been more difficult to define. This is perhaps best illustrated by the dramatic response to VEGF inhibition observed in a minority of patients, which cannot be predicted on the basis of any validated molecular biomarker. Indeed, clinical biomarkers, such as the presence of ascites and pleural effusions, have been used to help select patients for anti-VEGF therapy in the setting of recurrent disease.
In EOC, germline BRCA1/2 mutations have demonstrated diagnostic, prognostic, and predictive significance. It is now appreciated that deleterious germline BRCA1/2 mutations are present in at least 15% of women with HGSC, and these tumors have a better prognosis compared with sporadic HGSC, regardless of treatment. Although a diagnosis of HGSC, in and of itself, predicts for response to polyADP-ribose polymerase inhibition, there is greater predictive value when correlated with BRCA1/2 mutation status. In addition, tumors with BRCA1/2 mutations are also more likely to respond to nontargeted cytotoxic agents, such as doxorubicin. Based on these findings, there is agreement that HGSC, with or without BRCA1/2 mutations, should be studied independently from other EOC types. In addition, a number of strategies to better identify tumors with more broadly defined defects in double-strand break repair are under development.
Validated biomarkers can be used for subject selection and stratification to enhance pharmacodynamic and outcome analysis. There is enthusiasm to stratify within a trial where a putative biomarker is being evaluated. Caution is needed, as was observed in LGSC, where the MEK inhibitor selumetinib appeared less active in subjects with KRAS or BRAF mutations, which had initially been proposed to predict for increased activity. This emphasizes the importance of validating sensitivity, specificity, and predictive value of molecular markers before limiting therapy to a marker-positive population. Parallel molecular networks, feedback loops, and secondary mutations can also influence response over time.
Large-scale collaborative mining of molecular data has revealed unanticipated complexity within the HGSC family, with the emergence of four subtypes based on mRNA expression profiles. Although more study is needed to validate key pathways and potential targets within each subset, these data suggest that more consideration might be given to the selective use of immune modulators, angiogenesis- and stromal-targeted agents, and polyADP-ribose polymerase inhibition with chemotherapy, reflecting current areas of research.
Ovarian CCC has been shown to depend upon the IL6/JAK2/STAT3 pathway, and sunitinib, an agent that shows activity against renal CCC, has also shown activity against ovarian CCC xenografts. Trials open to CCC could corroborate this molecular signature while also determining whether CCC histology, irrespective of primary tumor site, reliably identifies patients for whom pathway-targeted therapy may have greater therapeutic relevance. In addition, efficient nontraditional strategies are needed to evaluate potential targets and therapies in rare tumor subsets, such as the overexpression of HER2 in a proportion of mucinous tumors, which is being studied through a consortium of investigators (http://www.smartcancerproject/com).
Appreciation of the different types of EOC, including subtypes of HGSC, as well as the targeting profiles of available agents, must inform clinical trial development. Clearly, collection of tumor and validation of potential surrogates (such as ascites, circulating tumor cells or microsomal fragments, or free DNA), is crucial within the context of clinical trials, ideally with pre- and post-treatment samples to investigate targeting and evolution of resistance. Guided needle biopsy techniques have become safer, and high-quality molecular data can be obtained from small samples. However, the issue of intratumoral heterogeneity and the need for multiple specimens must be considered, as well as the substantial nonreimbursed costs of these minimally invasive procedures. Integration of specimen acquisition with routine treatment would be ideal and facilitated by strategies such as neoadjuvant chemotherapy with interval cytoreductive surgery.
Source: ...