- Email: [email protected]
Can NOAH guide us to improved survival in breast cancer?
Comment
maintenance or reintroduction on progression. MRC FOCUS 4, a molecularly stratified, multisite randomised trial of patients with colorectal cancer—which has already started accrual in the UK—might help to define the best strategy to use. Andrés Cervantes INCLIVA Biomedical Research Institute, University of Valencia, Hospital Clínico de Valencia, Av Blasco Ibáñez, 17, 46010 Valencia, Spain [email protected] I have received personal fees and non-financial support from Merck Serono and personal fees from Amgen.
4
5
6
7
8
© Cervantes. Open Access article distributed under the terms of CC-BY-NC-ND. 1
2
3
Schmoll HJ, van Cutsem E, Stein A, et al. ESMO Consensus Guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making. Ann Oncol 2012; 23: 2479–515. Adam R, De Gramont A, Figueras J, et al. The oncosurgery approach to managing liver metastases from colorectal cancer: a multidisciplinary international consensus. Oncologist 2012; 17: 1225–39. Douillard JY, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Eng J Med 2013; 369: 1023–34.
9
10
11
Stintzing S, Jung A, Rossius L, et al. Analysis of KRAS/NRAS and BRAF mutations in FIRE-3: a randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients. European Cancer Congress 2013; Amsterdam, Netherlands; Sept 27–Oct 1, 2013. Wasan H, Meade A, Adams R, et al. Intermittent chemotherapy plus either intermittent or continuous cetuximab for first-line treatment of patients with KRAS wild-type advanced colorectal cancer (COIN-B): a randomised phase 2 trial. Lancet Oncol 2014; published online April 3. http://dx.doi. org/10.1016/S1470-2045(14)70106-8. Adams RA, Meade AM, Seymour MT, et al. Intermittent versus continuous and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol 2011; 12: 642–53. Tian S, Simon I, Moreno V, et al. A combined oncogenic pathway signature of BRAF, KRAS and PI3KCA mutation improves colorectal cancer classification and cetuximab treatment prediction. Gut 2013; 62: 540–49. Roepman P, Schlicker A, Tabernero J, et al. Colorectal cancer intrinsic subtypes predict chemotherapy benefit, deficient mismatch repair and epithelial-tomesenchymal transition. Int J Cancer 2014; 134: 552–62. Sadanandam A, Lyssiotis CA, Homicsko K, et al. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med 2013; 19: 519–25. Diaz LA Jr, Williams RT, Wu J, et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancer. Nature 2012; 486: 537–40. Diaz LA Jr, Bardelli A. Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol 2014; 32: 579–86.
Life In View/Science Photo Library
Can NOAH guide us to improved survival in breast cancer?
Published Online March 20, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70116-0 See Articles page 640
550
Introduction of adjuvant therapy with the monoclonal antibody trastuzumab has been the most significant advance in the management of women with early stage HER2-positive breast cancer, with improvement of disease-free and overall survival in these patients with a biologically aggressive subtype of the disease.1–4 For patients with large operable or locally advanced breast cancer, induction (neoadjuvant) chemotherapy is a standard approach. The NOAH trial5 established for the first time that, in women with HER2-positive locally advanced or inflammatory breast cancer, addition of trastuzumab to neoadjuvant chemotherapy significantly increased the pathological complete response (pCR) compared with chemotherapy alone (35% vs 15%). In The Lancet Oncology, Luca Gianni and colleagues report the long-term results from NOAH.6 The updated results show that the benefit from addition of trastuzumab to chemotherapy in achievement of pathological complete response in the neoadjuvant setting translated into a significant effect on the primary endpoint of event-free survival, with an unadjusted hazard ratio for event-free survival between the two randomised HER2-positive treatment groups of 0·64 (95% CI 0·44–0·93, p=0·016). Furthermore, the investigators report an improvement
in overall survival.6 This study has helped to define the role of neoadjuvant trials as an appropriate setting for assessment of novel targeted therapies in subsets of early stage breast cancer. The key to the success of this trial was appropriate patient selection for assessment of the targeted therapy—namely those with HER2-positive disease. Despite the small study size and subsequent crossover after the approval of adjuvant trastuzumab in 2005 that potentially limited the ability of the NOAH trial to show a benefit on overall survival, a sensitivity analysis to account for the effect of crossover still showed a significant reduction in risk of death with the addition of trastuzumab to chemotherapy. Patients allocated to neoadjuvant trastuzumab in this trial continued the drug in the adjuvant setting for 1 year, such that improvements in event-free survival and overall survival could have been affected by trastuzumab given after surgery. However, the most relevant finding from this updated analysis is that for those patients who achieved pathological complete response after neoadjuvant therapy, the HR for eventfree survival by treatment group was 0·29 (p=0·0135), which favours patients given trastuzumab, thus showing the significant effect of neoadjuvant therapy with this www.thelancet.com/oncology Vol 15 May 2014
Comment
therapeutic on long-term outcome. By contrast, for patients with HER2-positive breast cancer receiving chemotherapy alone who still achieved a pathological complete response, this treatment had less impact on improving their long-term outcome. The NOAH trial clearly shows how data regarding clinical efficacy for a novel therapeutic agent can be obtained quickly in early stage disease, with a relatively small number of patients (n=235), compared with adjuvant studies where several thousand patients must be treated and followedup for many years to show any benefit. Moreover, when the correct targeted therapy for the appropriate breast cancer subtype is given before surgery it can have a large effect on eradication of cancer cells and induction of pathological complete response, which in the long-term means more patients survive the disease. Additionally, the NOAH trial has demonstrated that achieving pathological complete response could potentially be a surrogate endpoint for event-free survival and overall survival in patients with early breast cancer. The meta-analysis of Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) undertaken by the US Food and Drug Administration (FDA) confirmed that individual patients who achieve pathological complete response have significantly improved survival.7 Patient-level data from almost 12 000 women treated in 12 international randomised trials of neoadjuvant chemotherapy confirmed the clear association between pathological complete response and both eventfree and overall survival, which was driven by more aggressive breast cancer subtypes, such as HER2-positive hormone-receptor-negative disease. By contrast, a triallevel analysis showed a very weak association between pathological complete response and either event-free or overall survival with the exception of the NOAH trial. This low association was mainly because other trials treated heterogeneous subsets of primary breast cancer with different chemotherapy regimens, whereas the success of the NOAH trial relates to treatment of a homogenous group with an appropriate targeted therapy. Was the effect of pathological complete response gain on event-free and overall survival in the NOAH trial only seen because the control group lacked an effective targeted therapy for HER2-positive breast cancer— namely trastuzumab? If so, will subsequent neoadjuvant studies of HER2-positive disease now be unable to show a large enough gain in pathological complete response to www.thelancet.com/oncology Vol 15 May 2014
have an effect on event-free and overall survival because all patients will receive some form of HER2-directed targeted therapy? Although dual targeting of HER2 has become a more effective strategy for improvement of pathological complete response in several neoadjuvant studies, not all designs have yielded a statistical gain in pathological complete response.8 In the NeoSphere trial, addition of the monoclonal antibody pertuzumab, which targets the HER2 dimerisation domain to standard trastuzumab and docetaxel chemotherapy, showed a significant increase in pathological complete response in patients given pertuzumab plus docetaxel compared with those given trastuzumab plus docetaxel (45·8% vs 29·0%),9 which, in addition to supportive data from the metastatic setting, allowed the FDA to grant accelerated approval for this combination in the neoadjuvant setting in September, 2013.10 To what extent a further 16·8% gain in pathological complete response over trastuzumabbased therapy might affect survival is difficult to know, but gains of at least this order of magnitude are almost certainly what are needed to make ongoing progress. So how has the NOAH trial guided the ultimate quest of improving overall survival for women with early-stage breast cancer? The key lesson should be to always do an appropriately controlled neoadjuvant trial in a fairly homogenous subset of the disease with a validated targeted therapy. As molecular profiling unravels the complexity of breast cancer, several targeted therapeutics continue to be developed. The challenge will be whether the quantum gain in pathological complete response and patient survival noted with trastuzumab can be replicated in other subsets of breast cancer. Stephen R D Johnston The Breast Unit, The Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK [email protected] The Royal Marsden Hospital receives support from the National Institute for Health Research Biomedical Research Centre, and research funding from Roche and Genetech. I have received honoraria for advisory boards from Roche and Genetech. 1
2
3 4
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, 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, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353: 1673–84. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011; 365: 1273–83. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al. Adjuvant docetaxel or vinorelbine with or without tratsuzumab for breast cancer. N Engl J Med 2006; 354: 809–20.
551
Comment
5
6
7
Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzuamb versus neoadjuvant chemotehrapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH tial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet 2010; 375: 377–84. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (the NOAH trial): follow-up. Lancet Oncol 2014; published online March 20. http://dx.doi.org/10.1016/S1470-2045(14)70080-4. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014; published online Feb 14. http://dx.doi.org/10.1016/S01406736(13)62422-8.
8 9
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Johnston SRD. Dual HER2 targeting for early breast cancer. Lancet Oncol 2013; 14: 1145–36. Gianni L, Pienkowski T, Im Y-H, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 2012; 13: 25–32. Jin J. FDA Advisory panel recommends approval of drug for pre-operative treatment of breast cancer. JAMA 2013; 310: 1434.
Dna Illustrations/Science Photo Library
Interleukin-1α neutralisation in patients with cancer
Published Online April 17, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70164-0 See Articles page 656
552
Inflammation contributes to the severity of most diseases, and cytokine-specific blocking treatments are well established for autoinflammatory and autoimmune diseases.1 However, cytokine-mediated inflammation also has a role in the pathogenesis of cancer; for example, in the immunosuppression of the disease.2 Cytokinemediated systemic inflammation is also a debilitating aspect of cancer. Many tumours produce inflammatory cytokines, which promote angiogenesis and tumour growth. Therefore, blocking a cytokine is a therapeutic option for treatment of cancer, particularly since anticytokine treatment lacks side-effects and tumours are unlikely to develop resistance to cytokine blockade. In The Lancet Oncology, David Hong and colleagues3 report the effects of neutralising interleukin-1α in patients with end-stage cancers of various origins. The study is a unique contribution because it opens entire new areas in cancer therapeutics. The study also provides a rationale for early use of anti-cytokine therapy in cancer and sets the stage for use of anti-cytokine treatment in combination with kinase inhibitors and antiimmunosuppressive treatments. Although blocking the interleukin-1 receptor with anakinra reduces the progression of smouldering myeloma into overt myeloma,4 patients with epithelial cancers are rarely treated with specific anti-cytokine drugs such as those that block interleukin-1.5 A prevailing, but misunderstood, notion is that blocking an immunostimulating cytokine such as interleukin-1 would reduce the ability of the immune system to kill cancer cells and would therefore be contraindicated. However, since reversal of immunosuppression rather than stimulation of immune responses in cancer has been validated by blocking cytotoxic T-lymphocyte antigen 4 (CTLA4) and programmed cell death 1 (PD-1), there is less reluctance
to neutralise an immunostimulatory cytokine such as interleukin-1α. Nevertheless, in what may be a landmark study, patients with various refractory end-stage cancers and who were losing weight received a course of MAPp1, a naturally occurring human neutralising interleukin-1α antibody.3 After treatment, a significant number of patients responded, with an increase in lean body mass (p=0·02), decreased constitutional symptoms (fatigue p=0·008, pain p=0·025, and appetite loss p=0·020), and extended survival compared with baseline. The study, albeit small, is the first to specifically neutralise interleukin-1α, a highly inflammatory member of the interleukin-1 family. It is a unique contribution to the literature for many reasons, particularly in end-stage cancer. Since blocking the interleukin-1 receptor with anakinra or neutralising interleukin-1β with canakinumab or rilonacept are without symptomatic adverse events,1 it is not surprising that there were no adverse events with MABp1. Importantly, findings from the study point to the need to investigate likely mechanisms of action of MABp1. First, the data show that treatment reduces systemic inflammation since a decrease in circulating interleukin-6 concentrations remains one of the most consistent findings of interleukin-1 blockade,1 although in this study, the reduction was only significant in patients who also gained lean body mass. The source of the inflammatory trigger is probably the tumour itself, because all cancer cells of epithelial cell origin contain interleukin-1α in its precursor form. Inflammation is also caused by invasion of the tumour microenvironment by stromal cells. As tumours outgrow their vascular supply, they become necrotic and the interleukin-1α precursor is readily released, which triggers local production of chemokines, facilitating an influx of neutrophils and monocytes.1 Unlike the precursor of interleukin-1β, the interleukin-1α www.thelancet.com/oncology Vol 15 May 2014
maintenance or reintroduction on progression. MRC FOCUS 4, a molecularly stratified, multisite randomised trial of patients with colorectal cancer—which has already started accrual in the UK—might help to define the best strategy to use. Andrés Cervantes INCLIVA Biomedical Research Institute, University of Valencia, Hospital Clínico de Valencia, Av Blasco Ibáñez, 17, 46010 Valencia, Spain [email protected] I have received personal fees and non-financial support from Merck Serono and personal fees from Amgen.
4
5
6
7
8
© Cervantes. Open Access article distributed under the terms of CC-BY-NC-ND. 1
2
3
Schmoll HJ, van Cutsem E, Stein A, et al. ESMO Consensus Guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making. Ann Oncol 2012; 23: 2479–515. Adam R, De Gramont A, Figueras J, et al. The oncosurgery approach to managing liver metastases from colorectal cancer: a multidisciplinary international consensus. Oncologist 2012; 17: 1225–39. Douillard JY, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Eng J Med 2013; 369: 1023–34.
9
10
11
Stintzing S, Jung A, Rossius L, et al. Analysis of KRAS/NRAS and BRAF mutations in FIRE-3: a randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients. European Cancer Congress 2013; Amsterdam, Netherlands; Sept 27–Oct 1, 2013. Wasan H, Meade A, Adams R, et al. Intermittent chemotherapy plus either intermittent or continuous cetuximab for first-line treatment of patients with KRAS wild-type advanced colorectal cancer (COIN-B): a randomised phase 2 trial. Lancet Oncol 2014; published online April 3. http://dx.doi. org/10.1016/S1470-2045(14)70106-8. Adams RA, Meade AM, Seymour MT, et al. Intermittent versus continuous and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol 2011; 12: 642–53. Tian S, Simon I, Moreno V, et al. A combined oncogenic pathway signature of BRAF, KRAS and PI3KCA mutation improves colorectal cancer classification and cetuximab treatment prediction. Gut 2013; 62: 540–49. Roepman P, Schlicker A, Tabernero J, et al. Colorectal cancer intrinsic subtypes predict chemotherapy benefit, deficient mismatch repair and epithelial-tomesenchymal transition. Int J Cancer 2014; 134: 552–62. Sadanandam A, Lyssiotis CA, Homicsko K, et al. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med 2013; 19: 519–25. Diaz LA Jr, Williams RT, Wu J, et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancer. Nature 2012; 486: 537–40. Diaz LA Jr, Bardelli A. Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol 2014; 32: 579–86.
Life In View/Science Photo Library
Can NOAH guide us to improved survival in breast cancer?
Published Online March 20, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70116-0 See Articles page 640
550
Introduction of adjuvant therapy with the monoclonal antibody trastuzumab has been the most significant advance in the management of women with early stage HER2-positive breast cancer, with improvement of disease-free and overall survival in these patients with a biologically aggressive subtype of the disease.1–4 For patients with large operable or locally advanced breast cancer, induction (neoadjuvant) chemotherapy is a standard approach. The NOAH trial5 established for the first time that, in women with HER2-positive locally advanced or inflammatory breast cancer, addition of trastuzumab to neoadjuvant chemotherapy significantly increased the pathological complete response (pCR) compared with chemotherapy alone (35% vs 15%). In The Lancet Oncology, Luca Gianni and colleagues report the long-term results from NOAH.6 The updated results show that the benefit from addition of trastuzumab to chemotherapy in achievement of pathological complete response in the neoadjuvant setting translated into a significant effect on the primary endpoint of event-free survival, with an unadjusted hazard ratio for event-free survival between the two randomised HER2-positive treatment groups of 0·64 (95% CI 0·44–0·93, p=0·016). Furthermore, the investigators report an improvement
in overall survival.6 This study has helped to define the role of neoadjuvant trials as an appropriate setting for assessment of novel targeted therapies in subsets of early stage breast cancer. The key to the success of this trial was appropriate patient selection for assessment of the targeted therapy—namely those with HER2-positive disease. Despite the small study size and subsequent crossover after the approval of adjuvant trastuzumab in 2005 that potentially limited the ability of the NOAH trial to show a benefit on overall survival, a sensitivity analysis to account for the effect of crossover still showed a significant reduction in risk of death with the addition of trastuzumab to chemotherapy. Patients allocated to neoadjuvant trastuzumab in this trial continued the drug in the adjuvant setting for 1 year, such that improvements in event-free survival and overall survival could have been affected by trastuzumab given after surgery. However, the most relevant finding from this updated analysis is that for those patients who achieved pathological complete response after neoadjuvant therapy, the HR for eventfree survival by treatment group was 0·29 (p=0·0135), which favours patients given trastuzumab, thus showing the significant effect of neoadjuvant therapy with this www.thelancet.com/oncology Vol 15 May 2014
Comment
therapeutic on long-term outcome. By contrast, for patients with HER2-positive breast cancer receiving chemotherapy alone who still achieved a pathological complete response, this treatment had less impact on improving their long-term outcome. The NOAH trial clearly shows how data regarding clinical efficacy for a novel therapeutic agent can be obtained quickly in early stage disease, with a relatively small number of patients (n=235), compared with adjuvant studies where several thousand patients must be treated and followedup for many years to show any benefit. Moreover, when the correct targeted therapy for the appropriate breast cancer subtype is given before surgery it can have a large effect on eradication of cancer cells and induction of pathological complete response, which in the long-term means more patients survive the disease. Additionally, the NOAH trial has demonstrated that achieving pathological complete response could potentially be a surrogate endpoint for event-free survival and overall survival in patients with early breast cancer. The meta-analysis of Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) undertaken by the US Food and Drug Administration (FDA) confirmed that individual patients who achieve pathological complete response have significantly improved survival.7 Patient-level data from almost 12 000 women treated in 12 international randomised trials of neoadjuvant chemotherapy confirmed the clear association between pathological complete response and both eventfree and overall survival, which was driven by more aggressive breast cancer subtypes, such as HER2-positive hormone-receptor-negative disease. By contrast, a triallevel analysis showed a very weak association between pathological complete response and either event-free or overall survival with the exception of the NOAH trial. This low association was mainly because other trials treated heterogeneous subsets of primary breast cancer with different chemotherapy regimens, whereas the success of the NOAH trial relates to treatment of a homogenous group with an appropriate targeted therapy. Was the effect of pathological complete response gain on event-free and overall survival in the NOAH trial only seen because the control group lacked an effective targeted therapy for HER2-positive breast cancer— namely trastuzumab? If so, will subsequent neoadjuvant studies of HER2-positive disease now be unable to show a large enough gain in pathological complete response to www.thelancet.com/oncology Vol 15 May 2014
have an effect on event-free and overall survival because all patients will receive some form of HER2-directed targeted therapy? Although dual targeting of HER2 has become a more effective strategy for improvement of pathological complete response in several neoadjuvant studies, not all designs have yielded a statistical gain in pathological complete response.8 In the NeoSphere trial, addition of the monoclonal antibody pertuzumab, which targets the HER2 dimerisation domain to standard trastuzumab and docetaxel chemotherapy, showed a significant increase in pathological complete response in patients given pertuzumab plus docetaxel compared with those given trastuzumab plus docetaxel (45·8% vs 29·0%),9 which, in addition to supportive data from the metastatic setting, allowed the FDA to grant accelerated approval for this combination in the neoadjuvant setting in September, 2013.10 To what extent a further 16·8% gain in pathological complete response over trastuzumabbased therapy might affect survival is difficult to know, but gains of at least this order of magnitude are almost certainly what are needed to make ongoing progress. So how has the NOAH trial guided the ultimate quest of improving overall survival for women with early-stage breast cancer? The key lesson should be to always do an appropriately controlled neoadjuvant trial in a fairly homogenous subset of the disease with a validated targeted therapy. As molecular profiling unravels the complexity of breast cancer, several targeted therapeutics continue to be developed. The challenge will be whether the quantum gain in pathological complete response and patient survival noted with trastuzumab can be replicated in other subsets of breast cancer. Stephen R D Johnston The Breast Unit, The Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK [email protected] The Royal Marsden Hospital receives support from the National Institute for Health Research Biomedical Research Centre, and research funding from Roche and Genetech. I have received honoraria for advisory boards from Roche and Genetech. 1
2
3 4
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, 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, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353: 1673–84. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011; 365: 1273–83. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al. Adjuvant docetaxel or vinorelbine with or without tratsuzumab for breast cancer. N Engl J Med 2006; 354: 809–20.
551
Comment
5
6
7
Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzuamb versus neoadjuvant chemotehrapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH tial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet 2010; 375: 377–84. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (the NOAH trial): follow-up. Lancet Oncol 2014; published online March 20. http://dx.doi.org/10.1016/S1470-2045(14)70080-4. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014; published online Feb 14. http://dx.doi.org/10.1016/S01406736(13)62422-8.
8 9
10
Johnston SRD. Dual HER2 targeting for early breast cancer. Lancet Oncol 2013; 14: 1145–36. Gianni L, Pienkowski T, Im Y-H, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 2012; 13: 25–32. Jin J. FDA Advisory panel recommends approval of drug for pre-operative treatment of breast cancer. JAMA 2013; 310: 1434.
Dna Illustrations/Science Photo Library
Interleukin-1α neutralisation in patients with cancer
Published Online April 17, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70164-0 See Articles page 656
552
Inflammation contributes to the severity of most diseases, and cytokine-specific blocking treatments are well established for autoinflammatory and autoimmune diseases.1 However, cytokine-mediated inflammation also has a role in the pathogenesis of cancer; for example, in the immunosuppression of the disease.2 Cytokinemediated systemic inflammation is also a debilitating aspect of cancer. Many tumours produce inflammatory cytokines, which promote angiogenesis and tumour growth. Therefore, blocking a cytokine is a therapeutic option for treatment of cancer, particularly since anticytokine treatment lacks side-effects and tumours are unlikely to develop resistance to cytokine blockade. In The Lancet Oncology, David Hong and colleagues3 report the effects of neutralising interleukin-1α in patients with end-stage cancers of various origins. The study is a unique contribution because it opens entire new areas in cancer therapeutics. The study also provides a rationale for early use of anti-cytokine therapy in cancer and sets the stage for use of anti-cytokine treatment in combination with kinase inhibitors and antiimmunosuppressive treatments. Although blocking the interleukin-1 receptor with anakinra reduces the progression of smouldering myeloma into overt myeloma,4 patients with epithelial cancers are rarely treated with specific anti-cytokine drugs such as those that block interleukin-1.5 A prevailing, but misunderstood, notion is that blocking an immunostimulating cytokine such as interleukin-1 would reduce the ability of the immune system to kill cancer cells and would therefore be contraindicated. However, since reversal of immunosuppression rather than stimulation of immune responses in cancer has been validated by blocking cytotoxic T-lymphocyte antigen 4 (CTLA4) and programmed cell death 1 (PD-1), there is less reluctance
to neutralise an immunostimulatory cytokine such as interleukin-1α. Nevertheless, in what may be a landmark study, patients with various refractory end-stage cancers and who were losing weight received a course of MAPp1, a naturally occurring human neutralising interleukin-1α antibody.3 After treatment, a significant number of patients responded, with an increase in lean body mass (p=0·02), decreased constitutional symptoms (fatigue p=0·008, pain p=0·025, and appetite loss p=0·020), and extended survival compared with baseline. The study, albeit small, is the first to specifically neutralise interleukin-1α, a highly inflammatory member of the interleukin-1 family. It is a unique contribution to the literature for many reasons, particularly in end-stage cancer. Since blocking the interleukin-1 receptor with anakinra or neutralising interleukin-1β with canakinumab or rilonacept are without symptomatic adverse events,1 it is not surprising that there were no adverse events with MABp1. Importantly, findings from the study point to the need to investigate likely mechanisms of action of MABp1. First, the data show that treatment reduces systemic inflammation since a decrease in circulating interleukin-6 concentrations remains one of the most consistent findings of interleukin-1 blockade,1 although in this study, the reduction was only significant in patients who also gained lean body mass. The source of the inflammatory trigger is probably the tumour itself, because all cancer cells of epithelial cell origin contain interleukin-1α in its precursor form. Inflammation is also caused by invasion of the tumour microenvironment by stromal cells. As tumours outgrow their vascular supply, they become necrotic and the interleukin-1α precursor is readily released, which triggers local production of chemokines, facilitating an influx of neutrophils and monocytes.1 Unlike the precursor of interleukin-1β, the interleukin-1α www.thelancet.com/oncology Vol 15 May 2014