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
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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.
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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
Comment
progression-free survival of 21·1 weeks in patients with trastuzumab-refractory HER2-positive breast cancer. However, the promising activity of everolimus or the new more specific PI3K inhibitors have to take into account the toxic effects that were noted. Everolimus at the 10 mg per day dose studied in BOLERO-1 is associated with clinically relevant severe stomatitis and diarrhoea, which lead not only to a dose intensity as low as 0·54, but also, especially in the hands of less experienced investigators, to a significant risk of treatment-related deaths.1 PI3K inhibitors in combination with trastuzumab with or without chemotherapy show high rates of diarrhoea, fatigue, and rash, and also seem to have specific toxic effects such as depression, chronic colitis with a specific lymphocytic or neutrophilic infiltrate, increased liver enzyme concentrations and, similar to mTOR inhibitors, hyperglycaemia.6 Therefore, a more feasible option might be to replace paclitaxel and trastuzumab with the better tolerated trastuzumab emtansine. Because the combination of trastuzumab emtansine and pertuzumab did not improve progression-free survival compared with trastuzumab emtansine alone,7 combination of trastuzumab emtansine with an mTOR or PI3K inhibitor might be a reasonable pairing to investigate, especially in patients with HER2-positive or HR-negative tumours. By contrast, for patients with HER2-positive and HR-positive disease, both pathways could be blocked by adding an PI3K/mTOR inhibitor to endocrine and HER2-targeted therapy; the results of continuing studies (NCT01791478 and NCT02152943) will show if efficacy and tolerability support subsequent registrational studies.
In summary, despite the formally negative outcome of BOLERO-1, the trial’s results support the idea that HER2positive disease is a super family of disease, composed of various subgroups that can be discriminated at least by HR status and possibly also by PI3K mutation status,8 providing further insights into the development of further subgroup-specific treatment approaches. Gunter von Minckwitz GBG Forschungs GmbH, 63263 Neu-Isenburg, Germany [email protected] GvM’s institution has received grants from Novartis and Roche. 1
2
3
4
5
6
7
8
Hurvitz SA, Andre F, Jiang Z, et al. Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double-blind, multicentre trial. Lancet Oncol 2015. Published online June 17. http://dx.doi. org/10.1016/S1470-2045(15)00051-0 Dave B, Migliaccio I, Gutierrez MC, et al. Loss of phosphatase and tensin homolog or phosphoinositol-3 kinase activation and response to trastuzumab or lapatinib in human epidermal growth factor receptor 2– overexpressing locally advanced breast cancers. J Clin Oncol 2011; 29: 166–73. Lu C-H, Wyszomierski SL, Tseng LM, et al. Preclinical testing of clinically applicable strategies for overcoming herceptin resistance caused by PTEN deficiency. Clin Cancer Res 2007; 13: 5883–88. André F, O’Regan R, Ozguroglu M, et al. Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 2014; 15: 580–91. Slamon D, Hurvitz SA, Chan D et al. Predictive biomarkers of everolimus efficacy in HER2+ advanced breast cancer: combined exploratory analysis from BOLERO-1 and BOLERO-3. Proc Am Soc Clin Oncol 2015; 33 (suppl): abstr 512. Tolaney S, Burris H, Gartner E, et al. Phase I/II study of pilaralisib (SAR245408) in combination with trastuzumab or trastuzumab plus paclitaxel in trastuzumab-refractory HER2-positive metastatic breast cancer. Breast Cancer Res Treat 2015; 149: 151–61. Ellis PA, Barrios CH, Eiermann W, et al. Phase III, randomized study of trastuzumab emtansine (T-DM1) ± pertuzumab (P) vs trastuzumab + taxane (HT) for first-line treatment of HER2-positive MBC: primary results from the MARIANNE study. Proc Am Soc Clin Oncol 2015; 33 (suppl): abstr 507. Loibl S, Majewski I, Guarneri V, et al. Correlation of PIK3CA mutation with pathological complete response in primary HER2-positive breast cancer: Combined analysis of 967 patients from three prospective clinical trials. Proc Am Soc Clin Oncol 2015; 33 (suppl): abstr 511.
EGFR mutations and EGFR tyrosine kinase inhibitors Published Online June 5, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)00028-5 This publication has been corrected. The corrected version first appeared at thelancet.com on June 29, 2015 See Articles page 830
746
In 2004, three groups independently noted that the presence of activating mutations in patients with advanced non-small-cell lung cancer made tumours sensitive to EGFR tyrosine kinase inhibitors.1 Since then, nine randomised trials including almost 1800 patients have been done, which have compared chemotherapy with tyrosine kinase inhibitors for first-line treatment of a subpopulation of patients with advanced non-small-cell lung cancer tumours that contained these mutations.2 In most studies, patients were only eligible for inclusion if they had a deletion in exon 19 or the
Leu858Arg mutation in exon 21 of EGFR—ie, the most common EGFR mutations in this subset of patients. Retrospective data suggest that rare mutations, with the exception of Gly719Xaa and Leu861Gln, are more strongly associated with smoking habits, worse prognosis, and decreased responsiveness to EGFR inhibitors than are common mutations.3–6 Because preclinical data suggest that afatinib can irreversibly inhibit all ERBB family receptor tyrosine kinases, it was thought that the drug could be effective for patients with rare mutations, especially for patients www.thelancet.com/oncology Vol 16 July 2015
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
Comment
progression-free survival of 21·1 weeks in patients with trastuzumab-refractory HER2-positive breast cancer. However, the promising activity of everolimus or the new more specific PI3K inhibitors have to take into account the toxic effects that were noted. Everolimus at the 10 mg per day dose studied in BOLERO-1 is associated with clinically relevant severe stomatitis and diarrhoea, which lead not only to a dose intensity as low as 0·54, but also, especially in the hands of less experienced investigators, to a significant risk of treatment-related deaths.1 PI3K inhibitors in combination with trastuzumab with or without chemotherapy show high rates of diarrhoea, fatigue, and rash, and also seem to have specific toxic effects such as depression, chronic colitis with a specific lymphocytic or neutrophilic infiltrate, increased liver enzyme concentrations and, similar to mTOR inhibitors, hyperglycaemia.6 Therefore, a more feasible option might be to replace paclitaxel and trastuzumab with the better tolerated trastuzumab emtansine. Because the combination of trastuzumab emtansine and pertuzumab did not improve progression-free survival compared with trastuzumab emtansine alone,7 combination of trastuzumab emtansine with an mTOR or PI3K inhibitor might be a reasonable pairing to investigate, especially in patients with HER2-positive or HR-negative tumours. By contrast, for patients with HER2-positive and HR-positive disease, both pathways could be blocked by adding an PI3K/mTOR inhibitor to endocrine and HER2-targeted therapy; the results of continuing studies (NCT01791478 and NCT02152943) will show if efficacy and tolerability support subsequent registrational studies.
In summary, despite the formally negative outcome of BOLERO-1, the trial’s results support the idea that HER2positive disease is a super family of disease, composed of various subgroups that can be discriminated at least by HR status and possibly also by PI3K mutation status,8 providing further insights into the development of further subgroup-specific treatment approaches. Gunter von Minckwitz GBG Forschungs GmbH, 63263 Neu-Isenburg, Germany [email protected] GvM’s institution has received grants from Novartis and Roche. 1
2
3
4
5
6
7
8
Hurvitz SA, Andre F, Jiang Z, et al. Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double-blind, multicentre trial. Lancet Oncol 2015. Published online June 17. http://dx.doi. org/10.1016/S1470-2045(15)00051-0 Dave B, Migliaccio I, Gutierrez MC, et al. Loss of phosphatase and tensin homolog or phosphoinositol-3 kinase activation and response to trastuzumab or lapatinib in human epidermal growth factor receptor 2– overexpressing locally advanced breast cancers. J Clin Oncol 2011; 29: 166–73. Lu C-H, Wyszomierski SL, Tseng LM, et al. Preclinical testing of clinically applicable strategies for overcoming herceptin resistance caused by PTEN deficiency. Clin Cancer Res 2007; 13: 5883–88. André F, O’Regan R, Ozguroglu M, et al. Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 2014; 15: 580–91. Slamon D, Hurvitz SA, Chan D et al. Predictive biomarkers of everolimus efficacy in HER2+ advanced breast cancer: combined exploratory analysis from BOLERO-1 and BOLERO-3. Proc Am Soc Clin Oncol 2015; 33 (suppl): abstr 512. Tolaney S, Burris H, Gartner E, et al. Phase I/II study of pilaralisib (SAR245408) in combination with trastuzumab or trastuzumab plus paclitaxel in trastuzumab-refractory HER2-positive metastatic breast cancer. Breast Cancer Res Treat 2015; 149: 151–61. Ellis PA, Barrios CH, Eiermann W, et al. Phase III, randomized study of trastuzumab emtansine (T-DM1) ± pertuzumab (P) vs trastuzumab + taxane (HT) for first-line treatment of HER2-positive MBC: primary results from the MARIANNE study. Proc Am Soc Clin Oncol 2015; 33 (suppl): abstr 507. Loibl S, Majewski I, Guarneri V, et al. Correlation of PIK3CA mutation with pathological complete response in primary HER2-positive breast cancer: Combined analysis of 967 patients from three prospective clinical trials. Proc Am Soc Clin Oncol 2015; 33 (suppl): abstr 511.
EGFR mutations and EGFR tyrosine kinase inhibitors Published Online June 5, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)00028-5 This publication has been corrected. The corrected version first appeared at thelancet.com on June 29, 2015 See Articles page 830
746
In 2004, three groups independently noted that the presence of activating mutations in patients with advanced non-small-cell lung cancer made tumours sensitive to EGFR tyrosine kinase inhibitors.1 Since then, nine randomised trials including almost 1800 patients have been done, which have compared chemotherapy with tyrosine kinase inhibitors for first-line treatment of a subpopulation of patients with advanced non-small-cell lung cancer tumours that contained these mutations.2 In most studies, patients were only eligible for inclusion if they had a deletion in exon 19 or the
Leu858Arg mutation in exon 21 of EGFR—ie, the most common EGFR mutations in this subset of patients. Retrospective data suggest that rare mutations, with the exception of Gly719Xaa and Leu861Gln, are more strongly associated with smoking habits, worse prognosis, and decreased responsiveness to EGFR inhibitors than are common mutations.3–6 Because preclinical data suggest that afatinib can irreversibly inhibit all ERBB family receptor tyrosine kinases, it was thought that the drug could be effective for patients with rare mutations, especially for patients www.thelancet.com/oncology Vol 16 July 2015
