As Calabrich and colleagues illustrate in their comprehensive review in this issue of ONCOLOGY, there is a seemingly endless array of mechanisms by which the HER2-positive breast cancer cell can escape the control of trastuzumab (Herceptin). The recent clinical successes with lapatinib (Tykerb)[1,2] or trastuzumab in combination with capecitabine (Xeloda) provide proof of principle that the HER2-signaling axis remains an important therapeutic target following progression on trastuzumab therapy. Capitalizing on this new found understanding of the mechanisms of trastuzumab to further improve the outcome of women diagnosed with HER2-positive breast cancer, however, is a daunting task.
A sound preclinical rationale supports the notion that steric hindrance, cleavage of the extracellular domain, and activation of downstream kinases by alternative growth factor pathways, such as insulin-like growth factor–1 receptor (IGF-1R) and epidermal growth factor receptor (EGFR), can mitigate the antitumor effects of trastuzumab against the HER2 receptor in breast cancer cell lines and animal models. However, there is precious little supportive evidence from human breast cancers exposed to trastuzumab to validate their clinical importance.
The history of oncology is rife with examples of promising preclinical targets that have not held up to further clinical scrutiny. Advances in molecular biology, bioinformatics, and nanotechnology will make piecemeal efforts to validate select candidate markers in clinical specimens obsolete. In order to harness the power of these technologies to characterize multidimensional predictors of outcome combining information from the DNA, RNA, and protein levels of the cancer cell, there must be improved collaboration between clinicians, pathologists, and basic scientists that transcends traditional institutional and national divides.
Ensuring the reliability and reproducibility of biomarkers indicative of specific mechanisms of resistance is essential. More than 20 years elapsed after the initial discovery of the HER2 receptor before consensus guidelines were agreed upon for HER2 testing criteria to guide clinical decision-making. In spite of these efforts, there remain important unanswered questions about interlaboratory variability in HER2 testing[6,7] and the possibility that a subset of patients with early disease characterized as HER2-negative may benefit from adjuvant trastuzumab.
Up to one-third of patients may exhibit discordance in HER2 status between primary and metastatic lesions, further emphasizing the importance of repeat biopsy for HER2 analysis at metastatic relapse whenever it is feasible to do so. If specific subpopulations of patients with HER2-positive disease who develop resistance to trastuzumab are identified, standardized biomarker assays must be developed in tandem with clinical testing, so that the findings of trials with novel agents can be applied to the broader clinical setting.
Variations in the host genotype introduce an additional level of complexity that must be accounted for. Immune response activation through antibody-dependent cellular cytoxicity is thought to be an important means by which trastuzumab exerts its antitumor effects. A recent study suggests that inherited polymorphisms in the IgG fragment C receptor expressed by immune effector cells may influence the antitumor activity of trastuzumab. The relationship between cytochrome P450 enzyme polymorphisms and long-term outcome with tamoxifen therapy further illustrates the evolving role of pharmacogenetics in the assessment of therapeutic effectiveness. Prospective collection and storage of whole-blood samples for germline DNA evaluation is a critical element of modern clinical trial design that must be considered to maximize the insight that can be gained from large-scale clinical trials.
The authors provide a valuable summary of the promising results that many novel agents designed to overcome trastuzumab resistance have produced in early-phase clinical trials. However, as illustrated by the recent disappointments with combinations of targeted therapy and endocrine agents in the setting of endocrine-resistant disease, sound preclinical rationales along with early signs of clinical activity do not necessarily translate into clinical success in larger phase III trials.
The challenges for future clinical researchers are to dissect the relevant pathways of trastuzumab resistance for individual patients, identify relevant subpopulations of HER2-positive disease, and design innovative clinical trials that can appropriately interrogate novel biologic therapies. Such forward-thinking clinical research will require strong new partnerships among scientists, clinicians, patients, industrial sponsors, and regulators with a shared commitment to upfront translational research.
The review by Calabrich and colleagues serves as a timely reminder that HER2-positive breast cancer is a fascinating disease. Trastuzumab represents merely the first chapter in an evolving story, with the goal of individualized therapy for HER2-positive breast cancer looming on the horizon.
—Philippe L. Bedard, MD
—Martine J. Piccart-Gebhart, MD, PhD
This commentary refers to the following article: Trastuzumab: Mechanisms of Resistance and Therapeutic Opportunities
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