Trastuzumab Resistance: Bringing Tailored Therapy to the Clinic

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[3] 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.

Target Identification

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.

Biomarker Generalizability

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[4] before consensus guidelines were agreed upon for HER2 testing criteria to guide clinical decision-making.[5] 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.[8]

Up to one-third of patients may exhibit discordance in HER2 status between primary and metastatic lesions,[9] 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.

Host Variability

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.[10] The relationship between cytochrome P450 enzyme polymorphisms and long-term outcome with tamoxifen therapy[11] 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.

Conclusions

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,[12] 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

References:

References

1. Cameron D, Casey M, Press M, et al: A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: Updated efficacy and biomarker analyses. Breast Cancer Res Treat Jan 11, 2008 (epub ahead of print).
2. Geyer CE, Forster J, Lindquist D, et al: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733-2743, 2006.
3. Von Minckwitz G, Zielinski C, Maarteense E, et al: Capecitabine vs capecitabine + trastuzumab in patients with HER2-positive metastatic breast cancer progressing during trastuzumab treatment: The TBP phase III study (GBG 26/BIG 3-05) (abstract 1025). J Clin Oncol 26(15S):47s, 2008.
4. Akiyama T, Kadooka T, Ogawara H, et al: Characterization of the epidermal growth factor receptor and the erbB oncogene product by site-specific antibodies. Arch Biochem Biophys 245:531-536, 1986.
5. Wolff AC, Hammond MEH, Schwartz JN, et al: American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25:118-145, 2007.
6. Paik S, Bryant J, Tan-Chiu E, et al: Real-world performance of HER2 testing-National Surgical Adjuvant Breast and Bowel Project experience. J Natl Cancer Inst 94:852-854, 2002.
7. Roche PC, Suman VJ, Jenkins RB, et al: Concordance between local and central laboratory HER2 testing in the breast intergroup trial N9831. J Natl Cancer Inst 94:855-857, 2002.
8. Paik S, Kim C, Wolmark N: HER2 status and benefit from adjuvant trastuzumab in breast cancer. N Engl J Med 358:1409-1411, 2008.
9. Lower EE, Glass E, Blau R, et al: HER-2/neu expression in primary and metastatic breast cancer. Breast Cancer Res Treat Feb 14, 2008 (epub ahead of print).
10. Musolino A, Naldi N, Bortesi B, et al: Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J Clin Oncol 26:1789-1796, 2008.
11. Goetz MP, Kamal A, Ames MM: Tamoxifen pharmacogenomics: The role of CYP2D6 as a predictor of drug response. Clin Pharmacol Ther 83:160-166, 2008.
12. Johnston SR, Martin LA, Leary A, et al: Clinical strategies for rationale combinations of aromatase inhibitors with novel therapies for breast cancer. J Steroid Biochem Mol Biol 106:180-186, 2007.