Increasingly, breast cancer is being thought of as at least three or four diseases with somewhat distinctive clinical behaviours and requiring different treatment approaches. Such 'tailoring' of treatments is a work in progress, but particularly spectacular gains have been made for the subtype of breast cancer that used to be most feared: HER2-positive breast cancer.
HER2 is a protein that traverses the cell surface and transmits growth signals. In HER2-positive breast cancer cells, this protein is present in the millions instead of the normal thousands, making these cells divide and spread more readily than other normal or cancer cells. About 15% to 20% of breast cancers are HER2-positive (determined by routine tests done on a tumour biopsy) and women with these cancers have historically had a poorer prognosis than those with HER2-negative disease.
However, the important role of HER2 in promoting abnormal cell growth also makes it a potential target for treatment, and drugs that can block the activity of HER2 have been developed. The first of these to be tested in clinical trials was trastuzumab, and there are now sufficient numbers of mature trials to be able to conduct a systematic review of the effects of treatment for women with metastatic (advanced) breast cancer.
In their new Cochrane Review, Lorenzo Moja and colleagues have pooled results from seven trials involving almost 1500 women. Their analysis confirms the potent effect of trastuzumab, with cancer progression reduced by more than a third (hazard ratio (HR) 0.61; confidence interval (CI) 0.54 to 0.70, P < 0.00001). This is highly consistent with a companion Cochrane review of trastuzumab in early (curable) HER2-positive breast cancer by the same authors (9935 participants; HR 0.60; 95% CI 0.50 to 0.71, P < 0.00001).
Overall survival was also improved (HR 0.82; 95%CI 0.71 to 0.94, P = 0.004), but additional commentary is appropriate here. In cancer trials the apparent effect on overall survival (obviously a critical consideration) is often attenuated so that, at first glance, the effect is not as pronounced as expected. However, when an effective treatment is being tested, patients who start to develop resistance to that treatment are usually (and completely appropriately) then given further treatment. This is good for the patient (she lives longer) but bad for science (the true effect of the tested treatment is diluted). So we welcome the apparent beneficial effect of trastuzumab on survival, but we suspect that it is better than quoted.
Next, the cost. Trastuzumab is an expensive drug, and individual societies with their various health systems need to make their own decisions about this. From a toxicity point of view, as shown in this Cochrane Review, trastuzumab is relatively non-toxic (especially compared with chemotherapy), but there is a concern about effects on heart function. While the overall risk is small, those receiving trastuzumab were approximately three times more likely to develop either overt heart failure or a reduction in measured heart function than those not on trastuzumab. The good news is that most of these effects are reversible. However, the Cochrane Review does underline the importance of careful clinical appraisal before using trastuzumab.
Overall, this review confirms the impression of clinicians who treat breast cancer that trastuzumab is a very effective treatment for women with metastatic HER2-positive breast cancer, but one needs to be careful about heart function. Future updated reviews may have the opportunity to review non-randomised studies, specifically to examine and perhaps more accurately quantify any toxic effects of trastuzumab. Meanwhile, other drugs targeting HER2 are being tested in clinical trials and will be the subject of further systematic reviews.
Director of Medical Oncology and Associate Professor of Medicine, Westmead Hospital, University of Sydney, Australia; and Co-ordinating Editor, Cochrane Breast Cancer Group email@example.com
How to cite: Wilcken N. Treating metastatic breast cancer: the evidence for targeted therapy [editorial]. Cochrane Database of Systematic Reviews 2014;(6):ED000083.
1. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235(4785):177-182. dx.doi.org/10.1126/science.3798106
2. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. New England Journal of Medicine 2001;344(11):783-792. dx.doi.org/10.1056/NEJM200103153441101
3. Balduzzi S, Mantarro S, Guarneri V, Tagliabue L, Pistotti V, Moja L, et al. Trastuzumab-containing regimens for metastatic breast cancer. Cochrane Database of Systematic Reviews 2014;(6):CD006242. onlinelibrary.wiley.com/doi/10.1002/14651858.CD006242.pub2/abstract
4. Moja L, Tagliabue L, Balduzzi S, Parmelli E, Pistotti V, Guarneri V, et al. Trastuzumab containing regimens for early breast cancer. Cochrane Database of Systematic Reviews 2012;(4):CD006243. dx.doi.org/10.1002/14651858.CD006243.pub2
5. Suter TM, Procter M, van Veldhuisen DJ, Muscholl M, Bergh J, Carlomagno C, et al. Trastuzumab-associated cardiac adverse effects in the Herceptin adjuvant trial. Journal of Clinical Oncology 2007;25(25):3859-3865. dx.doi.org/10.1200/JCO.2006.09.1611
Competing interests: The author has completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available upon request) and declares that he has received honoraria for advisory board work for Roche, which markets trastuzumab in Australia.
Image credit: Alfred Pasieka/Science Photo Library
Feedback: Please contact David Tovey, Cochrane Library Editor in Chief, with feedback on this editorial and proposals for future editorials.