Adjuvant trastuzumab for breast cancer
http://www.100md.com
《英国医生杂志》
We need to ensure that equity exists for access to effective and expensive treatments
In an era when encouraging headlines for the treatment of cancer seem to come and go, the results of randomised trials of adjuvant trastuzumab for treating breast cancers that overexpress human epidermal growth factor receptor 2 (HER2) have been rightly viewed as "stunning."1 The implications are relevant not only to patients with respect to significantly reducing the risk of cancer recurrence and death but also to all involved in the delivery of health care. We need to ensure that the process for funding of these highly effective treatments remains equitable not only between patients with different types of cancer but also between patients in different countries.
HER2 normally helps in the regulation of cell proliferation. Amplification of the HER2/neu oncogene occurs in 25-30% of human primary breast cancers and portends a poorer prognosis.2 Trastuzumab is a recombinant humanised monoclonal antibody directed against HER2. The success of trastuzumab is an example of true bench to bedside research. Rapid translation of experimental models led to groundbreaking results, initially in HER2 positive metastatic breast cancer and now as an adjuvant for women with early disease.3 4
We now have the results of three large appropriately powered studies (and the interim results of a fourth) assessing the role of trastuzumab in addition to adjuvant chemotherapy for patients with HER2 positive tumours.5-7 The HERA (herceptin adjuvant) trial, with nearly 5100 patients, compared one and two years of trastuzumab treatment with a control intervention in patients who had already completed their adjuvant chemotherapy.5 Two other trials were combined for analysis (National Surgical Adjuvant Breast and Bowel Project, B-31 and North Central Cancer Treatment Group trial, N9831).6 These trials differ from HERA in that patients were randomised before the start of chemotherapy and had the chance of being randomised to trastuzumab concurrently or sequentially to chemotherapy. Finally, BCIRG006 evaluated the use of two different chemotherapy regimens with or without concurrent trastuzumab.7
The most impressive finding from these trials is the enormity of the hazard ratios. In the combined trial of B-31 and N9831, the hazard ratio for breast cancer recurrence in the group receiving trastuzumab with chemotherapy, compared with chemotherapy alone, was 0.48 (95% confidence interval 0.39 to 0.59; P < 0.0001). In the HERA trial, the unadjusted hazard ratio for recurrence of breast cancer in the trastuzumab group, compared with the control group, was 0.54 (0.43 to 0.67; P < 0.0001 by the log-rank test, crossing the interim analysis boundary). The results were significant for all women regardless of age, hormone receptor status, tumour size, or number of positive lymph nodes. A major concern was the risk of cardiac toxicity associated with trastuzumab. The three year cumulative incidence of class III or IV congestive heart failure or death from cardiac causes in the trastuzumab group was 0.5% in the HERA trial, 4.1% in the B-31 trial, and 2.9% in the N9831 trial.
On the basis of these results, the standard of care in North America has already seen a paradigm shift. But what are the implications for women with breast cancer worldwide? Trastuzumab is currently licensed in Britain for advanced breast cancer but has not been approved for early stage disease. One of the barriers to licensing is undoubtedly cost. In Canada the cost of the drug alone is almost $C50 000 (￡25 000, US$43 000, 36 000) for one year of treatment. Although rapidly adopted as standard of care in the United States, trastuzumab was not approved for funding in Ontario, Canada, until after a substantial media frenzy.
Trastuzumab is the first (though certainly not the last) monoclonal antibody to show a survival benefit as an adjuvant treatment. The implications of these novel treatments in oncology are important not only for patients but also for healthcare costs. The costs incurred are not just the price of the drug but also the resources related to giving the drug (such as nursing, pharmacy, physician time, serial cardiac multiple gated acquisition scans). Another barrier is the cost of testing for HER2 expression. Many centres offer HER2 testing to women with early disease, but this is by no means standard. A recent survey in England and Wales found that more than a quarter of women are never tested for HER2 overexpression, and only half are currently tested at the time of initial diagnosis.8
Novel targeted treatments for other cancer types are continually being tested and developed, and treatments have advanced rapidly advanced in other common malignancies besides breast cancer. If we are to ensure equity of access to such highly effective but expensive targeted treatments we need transparent, timely, and appropriately funded processes in place to prepare healthcare systems for these important advances. It is no longer appropriate for healthcare systems to be continuously "trying to drink water from the proverbial fire hose."
Rebecca Dent, medical oncology fellow
Division of Medical Oncology, Sunnybrook and Women's College Health Sciences Centre, 2075 Bayview Avenue, Toronto ON, Canada M4N 3M5
Mark Clemons, medical oncologist
(mark.clemons@sw.ca)
Division of Medical Oncology, Sunnybrook and Women's College Health Sciences Centre, 2075 Bayview Avenue, Toronto ON, Canada M4N 3M5
Competing interests: MC has had research support from Roche Pharmaceuticals, the manufacturer of herceptin, as well as being reimbursed for speaking at several conferences.
References
Hortobagyi GN. Trastuzumab in the treatment of breast cancer. N Engl J Med 2005;353: 1734-6.
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: 177-82.
Sato JD, Kawamoto T, Le AD, Mendelsohn J, Polikoff J, Sato GH. Biological effects in vitro of monoclonal antibodies to human epidermal growth factor receptors. Mol Biol Med 1983;1: 511-29.
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. N Engl J Med 2001;344: 783-92.
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353: 1659-72.
Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CG, Davidson NE, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353: 1673-84.
Breast Cancer International Research Group (BCIRG), Sanofi Aventis. Interim analysis of phase III study shows docetaxel-based chemotherapy regimens combined with trastuzumab significantly improved disease free survival in early stage HER2 positive breast cancer . www.bcirg.org/Internet/Press+Releases/default.htm (accessed 28 October 2005).
CancerBACUP. Cancer drug testing shortfall. BBC News, 5 Oct 2005. http://news.bbc.co.uk/1/hi/health/4312476.stm (accessed 25 Oct 2005).
In an era when encouraging headlines for the treatment of cancer seem to come and go, the results of randomised trials of adjuvant trastuzumab for treating breast cancers that overexpress human epidermal growth factor receptor 2 (HER2) have been rightly viewed as "stunning."1 The implications are relevant not only to patients with respect to significantly reducing the risk of cancer recurrence and death but also to all involved in the delivery of health care. We need to ensure that the process for funding of these highly effective treatments remains equitable not only between patients with different types of cancer but also between patients in different countries.
HER2 normally helps in the regulation of cell proliferation. Amplification of the HER2/neu oncogene occurs in 25-30% of human primary breast cancers and portends a poorer prognosis.2 Trastuzumab is a recombinant humanised monoclonal antibody directed against HER2. The success of trastuzumab is an example of true bench to bedside research. Rapid translation of experimental models led to groundbreaking results, initially in HER2 positive metastatic breast cancer and now as an adjuvant for women with early disease.3 4
We now have the results of three large appropriately powered studies (and the interim results of a fourth) assessing the role of trastuzumab in addition to adjuvant chemotherapy for patients with HER2 positive tumours.5-7 The HERA (herceptin adjuvant) trial, with nearly 5100 patients, compared one and two years of trastuzumab treatment with a control intervention in patients who had already completed their adjuvant chemotherapy.5 Two other trials were combined for analysis (National Surgical Adjuvant Breast and Bowel Project, B-31 and North Central Cancer Treatment Group trial, N9831).6 These trials differ from HERA in that patients were randomised before the start of chemotherapy and had the chance of being randomised to trastuzumab concurrently or sequentially to chemotherapy. Finally, BCIRG006 evaluated the use of two different chemotherapy regimens with or without concurrent trastuzumab.7
The most impressive finding from these trials is the enormity of the hazard ratios. In the combined trial of B-31 and N9831, the hazard ratio for breast cancer recurrence in the group receiving trastuzumab with chemotherapy, compared with chemotherapy alone, was 0.48 (95% confidence interval 0.39 to 0.59; P < 0.0001). In the HERA trial, the unadjusted hazard ratio for recurrence of breast cancer in the trastuzumab group, compared with the control group, was 0.54 (0.43 to 0.67; P < 0.0001 by the log-rank test, crossing the interim analysis boundary). The results were significant for all women regardless of age, hormone receptor status, tumour size, or number of positive lymph nodes. A major concern was the risk of cardiac toxicity associated with trastuzumab. The three year cumulative incidence of class III or IV congestive heart failure or death from cardiac causes in the trastuzumab group was 0.5% in the HERA trial, 4.1% in the B-31 trial, and 2.9% in the N9831 trial.
On the basis of these results, the standard of care in North America has already seen a paradigm shift. But what are the implications for women with breast cancer worldwide? Trastuzumab is currently licensed in Britain for advanced breast cancer but has not been approved for early stage disease. One of the barriers to licensing is undoubtedly cost. In Canada the cost of the drug alone is almost $C50 000 (￡25 000, US$43 000, 36 000) for one year of treatment. Although rapidly adopted as standard of care in the United States, trastuzumab was not approved for funding in Ontario, Canada, until after a substantial media frenzy.
Trastuzumab is the first (though certainly not the last) monoclonal antibody to show a survival benefit as an adjuvant treatment. The implications of these novel treatments in oncology are important not only for patients but also for healthcare costs. The costs incurred are not just the price of the drug but also the resources related to giving the drug (such as nursing, pharmacy, physician time, serial cardiac multiple gated acquisition scans). Another barrier is the cost of testing for HER2 expression. Many centres offer HER2 testing to women with early disease, but this is by no means standard. A recent survey in England and Wales found that more than a quarter of women are never tested for HER2 overexpression, and only half are currently tested at the time of initial diagnosis.8
Novel targeted treatments for other cancer types are continually being tested and developed, and treatments have advanced rapidly advanced in other common malignancies besides breast cancer. If we are to ensure equity of access to such highly effective but expensive targeted treatments we need transparent, timely, and appropriately funded processes in place to prepare healthcare systems for these important advances. It is no longer appropriate for healthcare systems to be continuously "trying to drink water from the proverbial fire hose."
Rebecca Dent, medical oncology fellow
Division of Medical Oncology, Sunnybrook and Women's College Health Sciences Centre, 2075 Bayview Avenue, Toronto ON, Canada M4N 3M5
Mark Clemons, medical oncologist
(mark.clemons@sw.ca)
Division of Medical Oncology, Sunnybrook and Women's College Health Sciences Centre, 2075 Bayview Avenue, Toronto ON, Canada M4N 3M5
Competing interests: MC has had research support from Roche Pharmaceuticals, the manufacturer of herceptin, as well as being reimbursed for speaking at several conferences.
References
Hortobagyi GN. Trastuzumab in the treatment of breast cancer. N Engl J Med 2005;353: 1734-6.
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: 177-82.
Sato JD, Kawamoto T, Le AD, Mendelsohn J, Polikoff J, Sato GH. Biological effects in vitro of monoclonal antibodies to human epidermal growth factor receptors. Mol Biol Med 1983;1: 511-29.
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. N Engl J Med 2001;344: 783-92.
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353: 1659-72.
Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CG, Davidson NE, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353: 1673-84.
Breast Cancer International Research Group (BCIRG), Sanofi Aventis. Interim analysis of phase III study shows docetaxel-based chemotherapy regimens combined with trastuzumab significantly improved disease free survival in early stage HER2 positive breast cancer . www.bcirg.org/Internet/Press+Releases/default.htm (accessed 28 October 2005).
CancerBACUP. Cancer drug testing shortfall. BBC News, 5 Oct 2005. http://news.bbc.co.uk/1/hi/health/4312476.stm (accessed 25 Oct 2005).