Abstract SY45-02: Evaluation of targeted therapies in advanced breast cancer
Authors: Piccart Martine J. 
Published: May 2015

Abstract
Martine Piccart, Fabrice André, David Cameron, Peter Campbell, Lisa Carey, Stephen Friend, Charles Perou, Kamal Saini, Daniel Hayes.
Among the most recent important developments in oncology is the advance in high-throughput technologies. These “omics” technologies are becoming increasingly robust, cheap, and widespread (1) and they have generated three sets of data that should change the way clinical trials are being designed and conducted.
First, genomic characterization of breast cancer (BC) has shown that it includes a large number of rare genomic entities, driven by different molecular aberrations (2,3). Some BC subpopulations (such as HER2 mutated BC) are maybe rare enough to qualify as orphan diseases. As the categorization of molecular features continues to evolve, such fragmentation is increasing.
Second, the genomic characterization of metastatic BC has shown that metastatic process and resistance to therapy follows a branched evolution, with the genomic landscapes of primary and metastatic BC being different (4,5). As illustration, it has been shown that metastatic BC is enriched for ESR1 mutations, with this aberration detected after resistance to endocrine therapy has occurred (6).
Finally, these new technologies have opened new frontiers in the field of personalized medicine since it is now possible to sequence hundreds of genes for less than US$ 2000 with short turnaround times and these figures are expected to continue to decrease, while accuracy and reproducibility of sequencing techniques continue to improve.
These three major advances are changing the way clinical trials are being designed and performed. One challenge is to prospectively test drugs against this large list of molecular aberrations in a cost- and time-effective manner. Considering the rarity of these genomic segments, the conventional strategy of large phase III “all comer” BC trials is unsuitable for testing drugs that are predicted to be efficacious only among a small fraction of BC patients. Therefore, innovative clinical trial designs are needed.
There are three basic questions that need to be addressed: a. how to optimally screen patients for genomic alterations? b. how to design strategies that will improve outcome? c. how to translate findings generated in metastatic BC in the early-stage disease?
Testing for single genetic alterations at progression is inefficient and likely to result in screen-failure of the majority of patients. There is thus a need for molecular screening using multiplex technologies in order to maximize the likelihood of a patient to be a candidate for a molecularly targeted therapy. Moreover, there is a need to scale-up the number of patients screened in order to identify enough patients with a rare genomic alteration to constitute a cohort for a therapeutic trial. Thanks to funding from different sources, including the Breast Cancer Research Foundation, the Breast International Group has embarked on an ambitious program called AURORA (Aiming to Understand the Molecular Aberrations in Metastatic Breast Cancer), involving molecular characterization of host DNA, primary and metastatic tumor samples. AURORA will provide the structure for a large international network capable of running biology-driven trials for rare subpopulations of BC. AURORA has an innovative design, being a longitudinal cohort study with downstream nested biology-driven clinical trials. A similar initiative is planned to roll out in the United States. Such programs could make recruitment into biology-driven trials logistically and financially feasible.
Although performed at large scale, AURORA will not be linked with large phase III registration trials, so that a further scale-up will be needed to screen enough patients to run them in rare genomic populations. One possibility could be to use blood-based assays, and no longer biopsies, in large cohorts of patients treated in community hospitals, and to refer the ones presenting “rare” genomic alterations to comprehensive cancer centers. However, the implementation of such an approach requires proof that the mutational landscape of metastatic BC is accurately reflected in the blood (7).
There is an ever-increasing list of targeted compounds under clinical development targeting rare molecular alterations (8). A new approach could be to test an algorithm for drug prediction and not the drugs themselves. SAFIR02 is an illustration of such a trial, where patients are randomized between standard of care and a panel of targeted therapies matched with the genomic alterations found. In this “multidrug arm” trial, the hypothesis is that the use of the technology + the algorithm + the targeted compound will improve outcome. It is unclear whether regulatory agencies will accept this “package” approach.
Adaptive trial designs represent another innovative approach to accelerate successful clinical development of targeted agents. In this scenario, patients’ allocation to different treatment arms follows initial rules, with subsequent modifications taking place on the basis of continuous data generation during the study. In the setting of BC, this approach can be exemplified by the I-SPY 2 neoadjuvant clinical trial (9).
The ultimate goal will be to test whether the use of genomics and targeted therapies could cure early-stage BC patients. To this end, several neoadjuvant or ‘window’ preoperative trials are being designed that will evaluate whether targeted therapies will eradicate not only “driver” events, but also “lethal minority clones”. These trials will require genomic testing for early-stage BC patients. Interest in trials performed in the neoadjuvant setting was recently boosted, after FDA suggested possible drug approvals based on pathological complete response (pCR) as a surrogate endpoint (10). In the adjuvant setting one major challenge is the intratumoural heterogeneity of BC, since residual micrometastatic BC may have different molecular characteristics than the primary or the metastatic disease that we can currently interrogate (11).
Since most of the targeted therapies could lead to the induction of compensatory upregulation of alternative oncogenic signaling pathways, there is a need to design trials that aim to understand such resistance mechanisms (12). Obtaining tissues after relapse under targeted therapy shall thus be vital to design the further combination strategies. To address the lack of safety data for different combination strategies, “virtual phase I trials” based on models or simulations could be developed to inform us about the expected toxicities of combinations and the recommended doses for subsequent phase II “efficacy” trials.
Because of the real diversity that will be uncovered in patient’s tumors when we use these NextGen omics approaches, we also will need to learn to more quickly share the findings that we generate in the trials being run internationally. If we wait to share the data and the insights till after the findings are published, we will not move quickly enough towards improved patient care. To enable sharing we must develop ways to provide credit and incentives that move beyond calculations based on H factors and who is first or last author. The platforms being built by Sage Bionetworks such as “SYNAPSE” are examples of how to provide the provenance to track who contributed what and when (http://sagebase.org/synapse-overview/).
To conclude, while there have been genuine advances in basic and translational oncology, as well as elucidation of multiple candidate targeted therapies, the full potential of these advances has not been realized, partly as a result of outdated trial methodologies. Innovative approaches are needed to quickly test these molecules in smartly designed clinical trials.
References
1. Meyerson, M.et al. Advances in understanding cancer genomes through second-generation sequencing. Nat. Rev. Genet. 11, 685-696 (2010).
2. Stephens, P. J. et al. The landscape of cancer genes and mutational processes in breast cancer. Nature (2012). doi:10.1038/nature11017
3. Koboldt, D. C. et al. Comprehensive molecular portraits of human breast tumours. Nature 490, 61-70 (2012).
4. Ding, L. et al. Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature 464, 999-1005 (2010).
5. Navin, N. et al. Tumour evolution inferred by single-cell sequencing. Nature 472, 90-94 (2011).
6. Robinson, D. R. et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat. Genet. 45, 1446-1451 (2013).
7. Crowley, E.et al. Liquid biopsy: monitoring cancer-genetics in the blood. Nat. Rev. Clin. Oncol. 10, 472-484 (2013).
8. Zardavas, D.et al. Emerging targeted agents in metastatic breast cancer. Nat. Rev. Clin. Oncol. 10, 191-210 (2013).
9. Barker, A. D. et al. I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Clin. Pharmacol. Ther. 86, 97-100 (2009).
10.http://www.fda.gov/download/Drug/GuidanceComplianceRegulatoryInformation/Guidances/UCM305501.pdf.
11. Polzer, B. et al. Metastasis Awakening: The challenges of targeting minimal residual cancer. Nat. Med. 19, 274-275 (2013).
12. Duncan, J. S. et al. Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer. Cell 149, 307-321 (2012).
Citation Format: Martine J. Piccart. Evaluation of targeted therapies in advanced breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY45-02. doi:10.1158/1538-7445.AM2014-SY45-02