accompanying editorial re early trial results of adding everolimus to herceptin once

[Rich66]

active link:

http://jco.ascopubs.org/content/earl...1.36.4091.long

Some excerpts:

The PI3K/Akt/mTOR cascade has key regulatory functions in normal and oncogenic cellular growth, survival, proliferation, migration, and metabolism.4 Mutational activation of this pathway is observed in the majority of breast cancers and occurs through
amplification of the HER2 receptor, activation of mutations in PIK3CA (PI3K), or loss of the phosphatase and tensin homolog (PTEN) phosphatase. In laboratory models of HER2-positive breast cancer, the PI3K/Akt/mTOR pathway has been shown to have essential roles in tumor maintenance, and it is not surprising that a key mechanism for the antitumor action of trastuzumab is downregulation of this pathway. Several studies have implicated second mutational hits in the pathway in mediating resistance to HER2-targeted therapies and suggested that adding a direct inhibitor of PI3K/Akt/mTOR signaling may overcome trastuzumab resistance.5-7 In their combined studies of the mTOR inhibitor with trastuzumab, Morrow et al3 find an objective response rate of 15% and clinical benefit rate of 34% for the combination in a population of patients who were refractory to trastuzumab. The reported results are at once both meaningful and modest, as they provide some important insights but also leave open the question of the true utility of targeting the PI3K/Akt/mTOR pathway in HER2-positive breast cancer.

To their credit, the authors of the everolimus plus trastuzumab study3 were keenly aware of the need to develop biomarkers to guide therapy and incorporated a detailed analysis of the prevalence of PIK3CA mutation, PTEN expression, and other surrogates for activation of the pathway (p-Akt, p-S6k, p-Src) from patient tumor samples.
However, none of the individual biomarkers of pathway activation correlated with response or improved progression-free survival,

At present, there are at least fourHER2targeting agents in clinical development that have apparently similar or superior efficacy for trastuzumab-refractory HER2-positive breast cancer, including trastuzumab emtansine, neratinib, pertuzumab, and tanespimycin (Table 1). Although all of these have rather unique mechanisms of drug action, their efficacy is impressively similar, and, like everolimus, they cause relatively little toxicity. In addition to these inhibitors that differentially target HER2, there are a number of agents targeting PI3K, Akt, or mTOR that are currently in phase I and II evaluation. Is there a meaningful way to discern which of these agents, all of which may have similar response rates, should be advanced clinically? And how should we choose which therapies should be integrated into combinations for both metastatic and adjuvant disease? For these reasons, a more comprehensive analysis of in vivo mechanisms of resistance and the unique susceptibilities of such tumors is needed. With such a plethora of pharmacologic options in clinical development, perhaps no oncologic disease is more poised to benefit from personalized medicine than HER2-positive breast cancer.

The early understanding of the key role of HER2 in HER2-positive breast cancer has made this disease into a paradigm for advances in translational oncology. Once the community has moved past the excitement of novel target identification and initial therapy,the labor shifts to integrating competing therapies rationally and efficiently.
This article3 presents a challenge and a model. Certainly the efficacy that was reported does push everolimus onto the list of promising therapies for HER2-positive breast cancer and highlights mTOR
as a relevant target, but all the more, it focuses a spotlight on our need for robust biomarkers to rationalize an otherwise uninterpretable menu of options. A successful effort at making headway in this regard will require the sort of collaborative spirit that was modeled by this group of investigators to share their data and resources in a way that accelerates knowledge while minimizing excessive use of scarce resources.
Going forward, such efforts will be bound to include the acquisition (and sharing) of fresh tumor biopsies to allow a molecular interrogation of human tumors, not simply as a snapshot of a fixed and final state, but as the dynamic entities we so often observe them to be.