Comment
the peptide pool.7 However, it is obviously not sufficient to induce abscopal responses, as proven by clinical observation in patients receiving radiochemotherapy. The immunological balance has to be pushed towards anti-tumour immunity, and addition of immunotherapy is the solution.8 Flt3-L and GM-CSF are both strong stimulators of dendritic cells. The Sipuleucel-T vaccine study9 for prostate cancer shows commonalities with the study of Golden and colleagues.5 Since no control group consisting of only GM-CSF was included in the study of Kantoff and colleagues9 the observed increase of median survival with the vaccine might also be due to GM-CSF and not the antigenic peptide. The abscopal anti-tumour responses were accompanied by stable low concentrations of neutrophils. A challenge for future research is to determine whether these stable concentrations, together with increasing amounts of dendritic cells and CD8+ T cells, might be predictors for radio-immunotherapy-induced abscopal responses. Further, correlations with quality of life of responding patients should be assessed, since metastatic lesions are the specific targets of such immune responses. Whether bone and spinal metastases respond differently compared with visceral metastases also needs to be explored, since their accessibility by the immune system is reduced. In patients with a high metastatic tumour burden, the induction of abscopal anti-tumour reactions could be a welcome means to palliate the disease when the immune evasion of the tumour is at a maximum. The continuing rapid development of more precise and sophisticated accelerators for delivery of ionising irradiation should allow us to investigate the immunological consequences of classical fractionated versus hypofractionated or stereotactic high-dose delivery. Current preclinical data are not conclusive. For instance, the combination of anti-CTLA-4 immunotherapy with fractionated but not hypofractionated radiotherapy induced abscopal
anti-tumour responses in a mouse breast cancer model,10 whereas in a mouse model of melanoma, ablative radiotherapy was particularly immunogenic.11 The study by Golden and colleagues shows, for the first time, that abscopal anti-tumour responses can be induced in solid metastatic tumours by combining classical radiochemotherapy with simple immunotherapy. Nevertheless, randomised trials are needed for detailed assessment of the efficacy of radio-immunotherapy in inducing abscopal responses, in particular assessing the best combinations and chronology of treatments. Benjamin Frey, Udo S Gaipl Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitaetsstrasse 27, 91054 Erlangen, Germany [email protected] We declare no competing interests. 1 2
3 4
5
6
7
8
9 10
11
Nobler MP. The abscopal effect in malignant lymphoma and its relationship to lymphocyte circulation. Radiology 1969; 93: 410–12. Twyman-Saint Victor C, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 2015; 520: 373–77. Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med 2012; 366: 925–31. Frey B, Rubner Y, Kulzer L, et al. Antitumor immune responses induced by ionizing irradiation and further immune stimulation. Cancer Immunol Immunother 2014; 63: 29–36. Golden EB, Chhabra A, Chachoua A, et al. Local radiotherapy and granulocytemacrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of-principle trial. Lancet Oncol 2015; published June 19. http://dx.doi.org/10.1016/S1470-2045(15)00054-6. van der Sluis TC, van Duikeren S, Huppelschoten S, et al. Vaccine-induced tumor necrosis factor-producing T cells synergize with cisplatin to promote tumor cell death. Clin Cancer Res 2015; 21: 781–94. Hodge JW, Ardiani A, Farsaci B, Kwilas AR, Gameiro SR. The tipping point for combination therapy: cancer vaccines with radiation, chemotherapy, or targeted small molecule inhibitors. Semin Oncol 2012; 39: 323–39. Demaria S, Ng B, Devitt ML, et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys 2004; 58: 862–70. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363: 411–22. Dewan MZ, Galloway AE, Kawashima N, et al. Fractionated but not singledose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res 2009; 15: 5379–88. Lee Y, Auh SL, Wang Y, et al. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood 2009; 114: 589–95.
Hepatocellular carcinoma surveillance with miRNAs Hepatocellular carcinoma is one of the most lethal cancers worldwide.1 Chronic liver disease is the main risk factor for its development and hepatocellular carcinoma is the most frequent cause of death in this population.2 The likelihood of long-term disease-free survival www.thelancet.com/oncology Vol 16 July 2015
increases when the cancer is diagnosed at an early, asymptomatic stage, when potential curative treatments are feasible.1 Early diagnosis before appearance of symptoms is only feasible in a surveillance programme and several observational and cost-effectiveness studies
Published Online June 16, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)00014-5 See Articles page 804
743
Comment
Steve Gschmeissner/Science Photo Library
and one randomised controlled trial have confirmed the effectiveness of this approach.1 Current scientific guidelines recommend surveillance for hepatocellular carcinoma1 using abdominal ultrasound every 6 months. Crucially, ultrasound is an acceptable screening tool and has a well-defined and prospectively validated recall strategy once a suspicious nodule is detected.3,4 Unfortunately, the diagnostic accuracy of ultrasound is not optimal, with a reported sensitivity of around 60% and specificity of less than 90%.5 These figures translate into screening failures6 and an unacceptable rate of false-positive diagnoses, with associated costs and harms.7 This scenario is dramatically aggravated if expertise is not in place. Serum tumour markers are an attractive alternative for surveillance because they allow a non-operator dependent, objective, and reproducible evaluation, overcoming the limitations of ultrasound. Several tumour markers have been evaluated in hepatocellular carcinoma, with α-fetoprotein (AFP) the most widely tested. Unfortunately, AFP has a suboptimum performance, with an excessive rate of false-positive and false-negative results, which prevents its use in surveillance.8 Other tumour markers deemed to be promising, such as des-gamma-carboxy prothrombin (DCP), the ratio of glycosylated AFP (L3 fraction) to total AFP, α-fucosidase, osteopontin, or glypican-3 have the same shortcomings.1,3,4 Recently, Dickkopf-1 (DKK1) has been proposed as an accurate tumour marker in patients infected with hepatitis B virus (HBV), but its performance has not been externally validated in western countries.9 In The Lancet Oncology, Xue-Jia Lin and colleagues10 assess the performance of circulating microRNAs (miRNAs) as biomarkers for early diagnosis of hepatocellular carcinoma. The authors analysed 1416 serum samples from five groups, including healthy controls, inactive HBsAg carriers, patients with chronic HBV infection, patients with HBV-related cirrhosis, and patients with hepatocellular carcinoma. In the training cohort, the authors built a serum miRNA classifier for detection of hepatocellular carcinoma of seven miRNAs (miR-29a, miR-29c, miR-133a, miR-143, miR-145, miR-192, and miR-505). This was then validated in two independent cohorts, which, when combined, contained almost 500 participants. Compared with AFP at a cutoff of 20 ng/mL and 400 ng/mL, the seven miRNA classifier had higher accuracy (assessed with area under the ROC curve) to identify individuals with 744
hepatocellular carcinoma from controls in the validation cohorts. Interestingly, the authors subsequently did a nested case-control study to assess the capacity of this serum miRNA classifier to detect preclinical hepatocellular carcinoma in a surveillance programme of patients with HBV. The classifier detected eight (30%) cases of hepatocellular carcinoma at 12 months before diagnosis, whereas AFP20 detected only two (7%). This study opens the door to assess miRNAs as potential biomarkers for surveillance of hepatocellular carcinoma. However, much needs to be done before acceptance of this miRNA classifier as an acceptable screening method. Lin and colleagues10 show that this classifier is better than AFP, but as AFP has a very poor performance for early hepatocellular carcinoma diagnosis there is still room for improvement. Examining the diagnostic accuracies in the different sub-analyses reported by Lin and colleagues, the specificities of the classifier were around 85–90%, which are less than those reported with AFP. Furthermore, it is unclear whether increases of miRNA classifier levels are associated with or caused by the tumour itself, rather than the related clinical or biochemical profile of underlying causes such as cirrhosis. Patients with hepatocellular carcinoma might have a more advanced liver disease (with presence of portal hypertension or cirrhosis decompensation or both) than do the patients without hepatocellular carcinoma in the study (eg, inactive HBsAg carriers, patients with chronic HBV infection and patients with liver cirrhosis, etc). Other relevant variables such as platelets count, Child-Pugh/MELD, presence of decompensation, albumin, bilirubin or prothrombin time (as a marker of degree of liver dysfunction) are missing and thus potential bias cannot be completely disregarded. Finally, before acceptance of this miRNA classifier as a useful screening method, external, prospective validation studies are needed in patients with HBV-related hepatocellular carcinoma, in patients with hepatitis C-related hepatocellular carcinoma, and in patients with alcohol-related hepatocellular carcinoma. In summary, the miRNA classifier evaluated by Lin and colleagues10 offers promising diagnostic accuracy and constitutes the proof of concept that miRNA profiling could be an accepted strategy for early diagnosis. However, further study is required before its acceptance into surveillance programmes for hepatocellular carcinoma. www.thelancet.com/oncology Vol 16 July 2015
Comment
Alejandro Forner Barcelona Clinic Liver Cancer (BCLC) group, Liver Unit, Hospital Clinic Barcelona, University of Barcelona, Barcelona, E-08036, Spain; and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain [email protected]
5
6
7
I declare no competing interests. 1 2
3 4
Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet 2012; 379: 1245–55. Trinchet J-C, Bourcier V, Chaffaut C, et al. Complications and competing risks of death in compensated viral cirrhosis (ANRS CO12 CirVir prospective cohort). Hepatology 2015; published online Feb 11. DOI:10.1002/hep.27743. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology 2011; 53: 1020–22. EASL-EORTC. EASL-EORTC Clinical Practice Guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56: 908–43.
8 9
10
Singal A, Volk ML, Waljee A, et al. Meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis. Aliment Pharmacol Ther 2009; 30: 37–47. Singal AG, Nehra M, Adams-Huet B, et al. Detection of hepatocellular carcinoma at advanced stages among patients in the HALT-C trial: where did surveillance fail? Am J Gastroenterol 2013; 108: 425–32. Croswell JM, Ransohoff DF, Kramer BS. Principles of cancer screening: lessons from history and study design issues. Semin Oncol 2010; 37: 202–15. Sherman M. Alphafetoprotein: an obituary. J Hepatol 2001; 34: 603–05. Shen Q, Fan J, Yang XR, et al. Serum DKK1 as a protein biomarker for the diagnosis of hepatocellular carcinoma: a large-scale, multicentre study. Lancet Oncol 2012; 13: 817–26. Lin X-J, Chong Y, Guo Z-W, et al. A serum microRNA classifier for early detection of hepatocellular carcinoma: a multicentre, retrospective, longitudinal biomarker identification study with a nested case-control study. Lancet Oncol 2015; published online June 16. http://dx.doi. org/10.1016/S1470-2045(15)00048-0.
The BOLERO-1 study,1 reported in The Lancet Oncology, is the second attempt to establish the role of an mTOR inhibitor in patients with HER2-positive metastatic breast cancer. The study was based on findings that mTOR inhibition sensitises PTEN-deficient tumours to trastuzumab.2,3 Therefore, simultaneous treatment with the mTOR inhibitor everolimus and trastuzumab could increase the population of p atients benefiting from trastuzumab as treatment for their newly diagnosed metastatic disease. Researchers noted that although there was no benefit from adding everolimus to trastuzumab for the overall population, a clinically (although not statistically) significant benefit was noted for women with hormone receptor (HR)-negative disease. These results raise three main questions: is the reported difference in benefit for patients with HR-negative tumours compared with HR-positive tumours real? Can we improve on the benefit noted in HR-negative tumours? And what are the alternative strategies for patients with HR-positive tumours? First, the sponsor and the study steering committee should be congratulated for the proactive handling of the trial in view of emerging data.4 Because accrual to the trial was already closed by the time evidence of a possible differential effect of everolimus by HR status was available, the researchers were unable to increase the sample size to augment the statistical power to study this. Hurvitz and colleagues1 were optimistic because the assumed hazard ratio for progression-free survival with the addition of everolimus (0·737) was higher than that noted in BOLERO-3 for the HR-negative subgroup (0·65).4 www.thelancet.com/oncology Vol 16 July 2015
However, the investigators could not know that their statistical power would be reduced by the progressionfree survival recorded in the control group being more than twice the assumed duration, probably contributing to the final lack of significance. Nevertheless, the threshold for significance was only marginally exceeded, and although the BOLERO-1 study was not powered for this comparison, a significant interaction between treatment and HR status was shown. Taken together, both BOLERO-1 and BOLERO-3 strongly support the hypothesis that mTOR inhibition has different effects in HR-negative and HR-positive HER2-positive breast cancer. Even if the BOLERO-1 results cannot be used to obtain regulatory approval for everolimus in patients with HER2-positive or HR-negative metastatic breast cancer, they provide great insight into the disease. At the annual meeting of the American Society of Clinical Oncology 2015, a biomarker analysis combining patients from the BOLERO-1 and BOLERO-3 studies was presented.5 Although the analysis showed that everolimus was only effective in tumours with an activated PI3K pathway (defined as either low PTEN or known PIK3CA or AKT1 Glu17Lys mutations), the low number of patients with tumour material available did not provide acceptable power to investigate an interaction with HR status. However, these findings support further investigation of PI3K inhibitors in a more predefined setting of PI3K pathway-activated or HER2-positive or HR-negative disease. A phase 1 study4 exploring the use of the PI3K inhibitor pilaralisib in combination with paclitaxel and trastuzumab recently reported a promising median
Steve Gschmeissner/Science Photo Library
A step towards a HER2-positive breast cancer super family
Published Online June 17, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)00037-6 See Articles page 816
745
the peptide pool.7 However, it is obviously not sufficient to induce abscopal responses, as proven by clinical observation in patients receiving radiochemotherapy. The immunological balance has to be pushed towards anti-tumour immunity, and addition of immunotherapy is the solution.8 Flt3-L and GM-CSF are both strong stimulators of dendritic cells. The Sipuleucel-T vaccine study9 for prostate cancer shows commonalities with the study of Golden and colleagues.5 Since no control group consisting of only GM-CSF was included in the study of Kantoff and colleagues9 the observed increase of median survival with the vaccine might also be due to GM-CSF and not the antigenic peptide. The abscopal anti-tumour responses were accompanied by stable low concentrations of neutrophils. A challenge for future research is to determine whether these stable concentrations, together with increasing amounts of dendritic cells and CD8+ T cells, might be predictors for radio-immunotherapy-induced abscopal responses. Further, correlations with quality of life of responding patients should be assessed, since metastatic lesions are the specific targets of such immune responses. Whether bone and spinal metastases respond differently compared with visceral metastases also needs to be explored, since their accessibility by the immune system is reduced. In patients with a high metastatic tumour burden, the induction of abscopal anti-tumour reactions could be a welcome means to palliate the disease when the immune evasion of the tumour is at a maximum. The continuing rapid development of more precise and sophisticated accelerators for delivery of ionising irradiation should allow us to investigate the immunological consequences of classical fractionated versus hypofractionated or stereotactic high-dose delivery. Current preclinical data are not conclusive. For instance, the combination of anti-CTLA-4 immunotherapy with fractionated but not hypofractionated radiotherapy induced abscopal
anti-tumour responses in a mouse breast cancer model,10 whereas in a mouse model of melanoma, ablative radiotherapy was particularly immunogenic.11 The study by Golden and colleagues shows, for the first time, that abscopal anti-tumour responses can be induced in solid metastatic tumours by combining classical radiochemotherapy with simple immunotherapy. Nevertheless, randomised trials are needed for detailed assessment of the efficacy of radio-immunotherapy in inducing abscopal responses, in particular assessing the best combinations and chronology of treatments. Benjamin Frey, Udo S Gaipl Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitaetsstrasse 27, 91054 Erlangen, Germany [email protected] We declare no competing interests. 1 2
3 4
5
6
7
8
9 10
11
Nobler MP. The abscopal effect in malignant lymphoma and its relationship to lymphocyte circulation. Radiology 1969; 93: 410–12. Twyman-Saint Victor C, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 2015; 520: 373–77. Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med 2012; 366: 925–31. Frey B, Rubner Y, Kulzer L, et al. Antitumor immune responses induced by ionizing irradiation and further immune stimulation. Cancer Immunol Immunother 2014; 63: 29–36. Golden EB, Chhabra A, Chachoua A, et al. Local radiotherapy and granulocytemacrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of-principle trial. Lancet Oncol 2015; published June 19. http://dx.doi.org/10.1016/S1470-2045(15)00054-6. van der Sluis TC, van Duikeren S, Huppelschoten S, et al. Vaccine-induced tumor necrosis factor-producing T cells synergize with cisplatin to promote tumor cell death. Clin Cancer Res 2015; 21: 781–94. Hodge JW, Ardiani A, Farsaci B, Kwilas AR, Gameiro SR. The tipping point for combination therapy: cancer vaccines with radiation, chemotherapy, or targeted small molecule inhibitors. Semin Oncol 2012; 39: 323–39. Demaria S, Ng B, Devitt ML, et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys 2004; 58: 862–70. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363: 411–22. Dewan MZ, Galloway AE, Kawashima N, et al. Fractionated but not singledose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res 2009; 15: 5379–88. Lee Y, Auh SL, Wang Y, et al. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood 2009; 114: 589–95.
Hepatocellular carcinoma surveillance with miRNAs Hepatocellular carcinoma is one of the most lethal cancers worldwide.1 Chronic liver disease is the main risk factor for its development and hepatocellular carcinoma is the most frequent cause of death in this population.2 The likelihood of long-term disease-free survival www.thelancet.com/oncology Vol 16 July 2015
increases when the cancer is diagnosed at an early, asymptomatic stage, when potential curative treatments are feasible.1 Early diagnosis before appearance of symptoms is only feasible in a surveillance programme and several observational and cost-effectiveness studies
Published Online June 16, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)00014-5 See Articles page 804
743
Comment
Steve Gschmeissner/Science Photo Library
and one randomised controlled trial have confirmed the effectiveness of this approach.1 Current scientific guidelines recommend surveillance for hepatocellular carcinoma1 using abdominal ultrasound every 6 months. Crucially, ultrasound is an acceptable screening tool and has a well-defined and prospectively validated recall strategy once a suspicious nodule is detected.3,4 Unfortunately, the diagnostic accuracy of ultrasound is not optimal, with a reported sensitivity of around 60% and specificity of less than 90%.5 These figures translate into screening failures6 and an unacceptable rate of false-positive diagnoses, with associated costs and harms.7 This scenario is dramatically aggravated if expertise is not in place. Serum tumour markers are an attractive alternative for surveillance because they allow a non-operator dependent, objective, and reproducible evaluation, overcoming the limitations of ultrasound. Several tumour markers have been evaluated in hepatocellular carcinoma, with α-fetoprotein (AFP) the most widely tested. Unfortunately, AFP has a suboptimum performance, with an excessive rate of false-positive and false-negative results, which prevents its use in surveillance.8 Other tumour markers deemed to be promising, such as des-gamma-carboxy prothrombin (DCP), the ratio of glycosylated AFP (L3 fraction) to total AFP, α-fucosidase, osteopontin, or glypican-3 have the same shortcomings.1,3,4 Recently, Dickkopf-1 (DKK1) has been proposed as an accurate tumour marker in patients infected with hepatitis B virus (HBV), but its performance has not been externally validated in western countries.9 In The Lancet Oncology, Xue-Jia Lin and colleagues10 assess the performance of circulating microRNAs (miRNAs) as biomarkers for early diagnosis of hepatocellular carcinoma. The authors analysed 1416 serum samples from five groups, including healthy controls, inactive HBsAg carriers, patients with chronic HBV infection, patients with HBV-related cirrhosis, and patients with hepatocellular carcinoma. In the training cohort, the authors built a serum miRNA classifier for detection of hepatocellular carcinoma of seven miRNAs (miR-29a, miR-29c, miR-133a, miR-143, miR-145, miR-192, and miR-505). This was then validated in two independent cohorts, which, when combined, contained almost 500 participants. Compared with AFP at a cutoff of 20 ng/mL and 400 ng/mL, the seven miRNA classifier had higher accuracy (assessed with area under the ROC curve) to identify individuals with 744
hepatocellular carcinoma from controls in the validation cohorts. Interestingly, the authors subsequently did a nested case-control study to assess the capacity of this serum miRNA classifier to detect preclinical hepatocellular carcinoma in a surveillance programme of patients with HBV. The classifier detected eight (30%) cases of hepatocellular carcinoma at 12 months before diagnosis, whereas AFP20 detected only two (7%). This study opens the door to assess miRNAs as potential biomarkers for surveillance of hepatocellular carcinoma. However, much needs to be done before acceptance of this miRNA classifier as an acceptable screening method. Lin and colleagues10 show that this classifier is better than AFP, but as AFP has a very poor performance for early hepatocellular carcinoma diagnosis there is still room for improvement. Examining the diagnostic accuracies in the different sub-analyses reported by Lin and colleagues, the specificities of the classifier were around 85–90%, which are less than those reported with AFP. Furthermore, it is unclear whether increases of miRNA classifier levels are associated with or caused by the tumour itself, rather than the related clinical or biochemical profile of underlying causes such as cirrhosis. Patients with hepatocellular carcinoma might have a more advanced liver disease (with presence of portal hypertension or cirrhosis decompensation or both) than do the patients without hepatocellular carcinoma in the study (eg, inactive HBsAg carriers, patients with chronic HBV infection and patients with liver cirrhosis, etc). Other relevant variables such as platelets count, Child-Pugh/MELD, presence of decompensation, albumin, bilirubin or prothrombin time (as a marker of degree of liver dysfunction) are missing and thus potential bias cannot be completely disregarded. Finally, before acceptance of this miRNA classifier as a useful screening method, external, prospective validation studies are needed in patients with HBV-related hepatocellular carcinoma, in patients with hepatitis C-related hepatocellular carcinoma, and in patients with alcohol-related hepatocellular carcinoma. In summary, the miRNA classifier evaluated by Lin and colleagues10 offers promising diagnostic accuracy and constitutes the proof of concept that miRNA profiling could be an accepted strategy for early diagnosis. However, further study is required before its acceptance into surveillance programmes for hepatocellular carcinoma. www.thelancet.com/oncology Vol 16 July 2015
Comment
Alejandro Forner Barcelona Clinic Liver Cancer (BCLC) group, Liver Unit, Hospital Clinic Barcelona, University of Barcelona, Barcelona, E-08036, Spain; and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain [email protected]
5
6
7
I declare no competing interests. 1 2
3 4
Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet 2012; 379: 1245–55. Trinchet J-C, Bourcier V, Chaffaut C, et al. Complications and competing risks of death in compensated viral cirrhosis (ANRS CO12 CirVir prospective cohort). Hepatology 2015; published online Feb 11. DOI:10.1002/hep.27743. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology 2011; 53: 1020–22. EASL-EORTC. EASL-EORTC Clinical Practice Guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56: 908–43.
8 9
10
Singal A, Volk ML, Waljee A, et al. Meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis. Aliment Pharmacol Ther 2009; 30: 37–47. Singal AG, Nehra M, Adams-Huet B, et al. Detection of hepatocellular carcinoma at advanced stages among patients in the HALT-C trial: where did surveillance fail? Am J Gastroenterol 2013; 108: 425–32. Croswell JM, Ransohoff DF, Kramer BS. Principles of cancer screening: lessons from history and study design issues. Semin Oncol 2010; 37: 202–15. Sherman M. Alphafetoprotein: an obituary. J Hepatol 2001; 34: 603–05. Shen Q, Fan J, Yang XR, et al. Serum DKK1 as a protein biomarker for the diagnosis of hepatocellular carcinoma: a large-scale, multicentre study. Lancet Oncol 2012; 13: 817–26. Lin X-J, Chong Y, Guo Z-W, et al. A serum microRNA classifier for early detection of hepatocellular carcinoma: a multicentre, retrospective, longitudinal biomarker identification study with a nested case-control study. Lancet Oncol 2015; published online June 16. http://dx.doi. org/10.1016/S1470-2045(15)00048-0.
The BOLERO-1 study,1 reported in The Lancet Oncology, is the second attempt to establish the role of an mTOR inhibitor in patients with HER2-positive metastatic breast cancer. The study was based on findings that mTOR inhibition sensitises PTEN-deficient tumours to trastuzumab.2,3 Therefore, simultaneous treatment with the mTOR inhibitor everolimus and trastuzumab could increase the population of p atients benefiting from trastuzumab as treatment for their newly diagnosed metastatic disease. Researchers noted that although there was no benefit from adding everolimus to trastuzumab for the overall population, a clinically (although not statistically) significant benefit was noted for women with hormone receptor (HR)-negative disease. These results raise three main questions: is the reported difference in benefit for patients with HR-negative tumours compared with HR-positive tumours real? Can we improve on the benefit noted in HR-negative tumours? And what are the alternative strategies for patients with HR-positive tumours? First, the sponsor and the study steering committee should be congratulated for the proactive handling of the trial in view of emerging data.4 Because accrual to the trial was already closed by the time evidence of a possible differential effect of everolimus by HR status was available, the researchers were unable to increase the sample size to augment the statistical power to study this. Hurvitz and colleagues1 were optimistic because the assumed hazard ratio for progression-free survival with the addition of everolimus (0·737) was higher than that noted in BOLERO-3 for the HR-negative subgroup (0·65).4 www.thelancet.com/oncology Vol 16 July 2015
However, the investigators could not know that their statistical power would be reduced by the progressionfree survival recorded in the control group being more than twice the assumed duration, probably contributing to the final lack of significance. Nevertheless, the threshold for significance was only marginally exceeded, and although the BOLERO-1 study was not powered for this comparison, a significant interaction between treatment and HR status was shown. Taken together, both BOLERO-1 and BOLERO-3 strongly support the hypothesis that mTOR inhibition has different effects in HR-negative and HR-positive HER2-positive breast cancer. Even if the BOLERO-1 results cannot be used to obtain regulatory approval for everolimus in patients with HER2-positive or HR-negative metastatic breast cancer, they provide great insight into the disease. At the annual meeting of the American Society of Clinical Oncology 2015, a biomarker analysis combining patients from the BOLERO-1 and BOLERO-3 studies was presented.5 Although the analysis showed that everolimus was only effective in tumours with an activated PI3K pathway (defined as either low PTEN or known PIK3CA or AKT1 Glu17Lys mutations), the low number of patients with tumour material available did not provide acceptable power to investigate an interaction with HR status. However, these findings support further investigation of PI3K inhibitors in a more predefined setting of PI3K pathway-activated or HER2-positive or HR-negative disease. A phase 1 study4 exploring the use of the PI3K inhibitor pilaralisib in combination with paclitaxel and trastuzumab recently reported a promising median
Steve Gschmeissner/Science Photo Library
A step towards a HER2-positive breast cancer super family
Published Online June 17, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)00037-6 See Articles page 816
745
