Trastuzumab: a Picky Partner? □□ Commentary on Francia Et Al., P

Published OnlineFirst October 14, 2009; DOI: 10.1158/1078-0432.CCR-09-1917

CCR Translations

Trastuzumab: A Picky Partner? □□ Commentary on Francia et al., p. 6358

Heather L. McArthur and Clifford A. Hudis

Preclinical and clinical models of HER2-positive breast cancer show that human epidermal growth factor receptor 2 (HER2)-targeted therapy with trastuzumab adds significant benefits and modest risks to conventional cytotoxic therapies. Building on this advance will likely depend on elucidation of relevant signaling pathways and mechanisms of action for effective HER2-targeted therapies. (Clin Cancer Res 2009;15(20):6311–3)

In this issue of Clinical Cancer Research, Francia and colleagues with trastuzumab and why tumors that initially exhibit sensitivity explore pulsatile, maximally tolerated doses of cyclophospha- ultimately acquire apparent clinical resistance. On the other mide chemotherapy or the same drug using a daily low-dose hand, it is difficult to explain why trastuzumab in combina- schedule combined with the human epidermal growth factor tion with chemotherapy is active even after progression on receptor 2 (HER2)-targeted antibody trastuzumab in a preclin- trastuzumab (7). It is perhaps easier to explain activity in this ical model of HER2-positive breast cancer (1). One of the most treatment-refractory setting for a drug with a different mecha- notable developments in breast cancer translational research nism of anti-HER2 activity, such as lapatinib, a HER1- and has been the identification of the HER2-positive subset of hu- HER2-directed tyrosine kinase inhibitor (TKI), (the only other man breast cancers and the subsequent successful development HER2-targeted agent approved by the United States Food and of HER2-targeted therapies. HER2 is a member of the epidermal Drug Administration). This TKI was approved on the basis of a growth factor receptor (EGFR) family of transmembrane glyco- significant progression-free survival benefit in combination protein receptor tyrosine kinases, which mediate cell growth, with capecitabine compared with capecitabine alone in women differentiation, and survival through complex, interconnected, with HER2-positive, trastuzumab-refractory metastatic breast and incompletely understood, signal transduction pathways cancer (8). In contrast to the first-line trastuzumab study, in (2). Amplification of HER2 or overexpression of its protein the pivotal lapatinib study the improvement in progression-free product is observed in approximately 20% of human breast survival did not translate into a significant survival benefit. cancers and has historically been associated with a poor prog- The reasons for variable outcome improvements with differ- nosis (3). However, the negative prognostic impact of HER2 ent anti-HER2 agents and in different populations may include gene amplification and/or protein overexpression has largely study design limitations and early closure (underpowering), in- been ameliorated by the development of HER2-targeted thera- accurate patient selection (testing), or suboptimal administra- py. The first such agent was trastuzumab, a humanized, HER2- tion strategies (dose, schedule, and concurrent therapies). It is targeted monoclonal antibody, and it provides significant effi- the last possibility that Francia and colleagues address in this cacy benefits in both the metastatic (4) and adjuvant settings issue of Clinical Cancer Research (1). Specifically, they explored (5, 6). However, a significant proportion of women with HER2-positive early stage breast cancer still experience a chemotherapy drug (cyclophosphamide) and schedule (low distant relapses despite adjuvant trastuzumab therapy and the dose weekly) thought to act through inhibition of the enhanced majority of patients with metastatic disease experience time- angiogenic signal (vascular endothelial growth factor, VEGF) limited benefits (4–6).Furthermore,themajorityofHER2- generated in response to HER2 signaling (2). In a preclinical positive metastatic breast cancers are resistant to trastuzumab model they combined trastuzumab with traditional, pulsatile, when used as a single agent (2). It is as yet poorly understood maximally tolerated doses of cyclophosphamide or the same why more than 50% of HER2-positive metastatic breast cancers drug using a daily low-dose (so-called metronomic) presump- exhibit this intrinsic resistance to HER2-targeted monotherapy tively anti-angiogenic schedule in HER2-positive breast cancer. Conventional chemotherapeutics typically exert their cytotoxic effects by damaging DNA or interfering with microtubules to inhibit or kill rapidly dividing cells (Fig. 1). Authors' Affiliation: Breast Cancer Medicine Service, Department of Historically, cytotoxics have been administered at the highest Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York Received 8/7/09; accepted 8/14/09; published OnlineFirst 10/13/09. possible, or maximum tolerated dose (MTD). However, be- Note: C. A. Hudis is a consultant for Genentech. cause of the associated deleterious effects on rapidly dividing Requests for reprints: Clifford A. Hudis, Breast Cancer Medicine Service, healthy tissues, most notably the infection-fighting white Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 blood cell lines, successive cytotoxic administration requires York Avenue, New York, NY 10065. Phone: 646-888-4551; Fax: 646-888- scheduling that permits adequate recovery between cycles. 4555; E-mail: [email protected]. F 2009 American Association for Cancer Research. This consideration has been overcome, in part, in the adjuvant doi:10.1158/1078-0432.CCR-09-1917 breast cancer setting with the concomitant administration of

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CCR Translations

Fig. 1. HER2-targeting agents interfere with signaling pathways that mediate cell proliferation, mobility, invasiveness, survival, and potentially VEGF-mediated tumor neovascularization. Chemotherapy induces apoptosis by inducing DNA damage and/or inhibiting microtubules in cancer cells and blood vessel endothelial cells. Certain low dose chemotherapy schedules may enhance the anti-angiogenic effect.

hematopoietic growth factor support. However, because breast cancer studies (11), wherein cytotoxic agents adminis- chemotherapeutics target not only cancer cells but also endo- tered on a frequent schedule and at a low dose are associated thelial cells in newly formed blood vessels (along with other with greater tolerability and in some cases more activity than stromal cells), and because cancer cells are dependent on neo- the same drug(s) administered at higher doses on a less fre- vascularization for growth (with VEGF production a specific quent schedule. The lack of a clear efficacy benefit for the consequence of HER2 signaling), it is postulated that there more frequent dosing is consistent with the clinical observa- may be more (and less) anti-angiogenic effects when chemo- tion that trastuzumab may level the playing field, such that therapy agents are given using different schedules. Previous although an apoptotic signal is needed, how it is provided work has shown that in contrast to conventionally derived is not as critical as in settings in which this antibody is inef- MTD dosing using regularly intermittent dosing, low and min- fective. For example, it is notable that consistent benefits were imally toxic doses of chemotherapy given more frequently can observed across the pivotal adjuvant trastuzumab trials, re- damage blood vessel endothelial cells thereby inhibiting tu- gardless of the chemotherapy foundation (5, 6, 12). Further- mor neovascularization and ultimately mediating tumor cell more, in the metastatic setting, no difference was observed for death (9). This strategy may be particularly relevant in HER2- weekly versus every 3-weekly paclitaxel chemotherapy when positive breast cancers that generate VEGF via HER2-mediated trastuzumab was administered in the HER2-positive subset signaling. If such tumors are treated with HER-family inhibitors (11). A critical and inadequately addressed issue is whether but do not achieve full or adequate reductions in VEGF produc- the anti-angiogenic activity of the more frequent dosing is a tion, they could be particularly sensitive to the co-administration meaningful contribution to its activity because if not, that of anti-VEGF or anti-VEGF agents, and also to anti-angiogenic would explain the lack of a differential effect. optimization of concurrently administered chemotherapy (2). In summary, the study by Francia and colleagues highlights Consistent with results observed in human studies, minimal several critical issues about HER2-targeted therapy. First, it re- activity was observed in the study by Francia and colleagues minds us of the importance of HER2-targeted therapy as an ad- with trastuzumab monotherapy in the metastatic model, but junct to conventional cytotoxic strategies. Second, it suggests anti-tumor activity was more robust when chemotherapy that further gains in the optimization of HER2-based treatment was added. With regard to the schedule of administration of recommendations will likely depend on deeper and clearer elu- the chemotherapy, the benefits were similar for mice treated cidation of HER2-signaling pathways and the mechanism(s) of with trastuzumab and metronomic versus MTD cyclophospha- action of effective HER2-targeted agents such as trastuzumab. mide, although greater toxicity was reported with the latter Third, it suggests that general chemotherapy principles may regimen. Again, these results are consistent with numerous ad- not apply evenly in all situations. In that regard, it is important equately powered, randomized, adjuvant (10) and metastatic to note that although the activity of conventional cytotoxics has

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Trastuzumab: A Picky Partner? been augmented by HER2-targeted therapies across preclinical deliver the promise of trastuzumab and perhaps other targeted and clinical (adjuvant and metastatic) models, there has been therapies. no study to date in which HER2-targeted therapy has supplanted conventional cytotoxic strategies. Consequently, Disclosure of Potential Conflicts of Interest investigations such as this one by Francia and colleagues H. McArthur has received honoraria funded through Genentech- remain important as they offer the opportunity to more fully sponsored educational grants; C. Hudis, consultant, Genentech.

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Trastuzumab: A Picky Partner?

Heather L. McArthur and Clifford A. Hudis

Clin Cancer Res 2009;15:6311-6313. Published OnlineFirst October 14, 2009.

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