- Email: [email protected]
Epigenetic test for breast cancer
News
A multicentre, phase 2 trial has shown that selumetinib (an inhibitor of MEK1 and MEK2) provided significantly better progression-free survival and tumour response than did chemotherapy in patients with advanced uveal melanoma. “Mutations in G-proteins GNAQ and GNA11 are present in 90–95% of patients with metastatic uveal melanoma”, explained senior author Gary Schwartz (Columbia University School of Medicine, Herbert Irving Comprehensive Cancer Center, New York, NY, USA). “These mutations activate a majority of signalling pathways, including MAPK, AKT, and PKC. In laboratory studies, selumetinib completely blocked the MEK pathway, and inhibited growth of uveal melanoma cells in culture.” To study the efficacy of inhibiting MEK1/2 in uveal melanoma, 101 patients were randomly assigned
to receive oral selumetinib or standard chemotherapy. Progression-free survival was significantly longer with selumetinib (15·9 weeks [95% CI 8·4–21·1]) than with chemotherapy (7 weeks [4·3–8·4]; hazard ratio [HR] 0·46 [0·30–0·71], p<0·001); no significant difference in overall survival was seen (11·8 months [95% CI 9·8–15·7] vs 9·1 months [6·1–11·1], respectively; HR 0·66 [0·41–1·06], p=0·09). 49% of patients assigned to selumetinib had tumour regression, whereas no objective responses were reported in the chemotherapy group. 65 (97%) of 67 patients receiving selumetinib had treatment-related adverse events, and 25 (37%) needed dose reductions. “Targeted therapy is a promising way forward in uveal melanoma”, commented Patrick Ott (Dana-Farber Cancer Institute, Boston, MA, USA). “No systemic treatment was previously shown to work in this disease.”
Lead author Richard Carvajal (Memorial Sloan Kettering Cancer Center, New York, NY, USA) said that future studies include SUMIT (NCT01974752), a phase 3 trial of selumetinib in combination with dacarbazine versus chemotherapy alone, and (based on preclinical data showing that efficacy of MEK inhibition can be enhanced with the addition of AKT or PKC inhibition) a study of trametinib alone or in combination with GSK2141795 and a study of MEK162 and AEB071. Sapna Patel (MD Anderson Cancer Center, Houston, TX, USA) said, “For the first time in uveal melanoma, we can use targeted therapy to effect tumour response…Targeted therapy with a MEK inhibitor really can potentially be the backbone of new therapy for this tumour.”
ISM/Science Photo Library
MEK1/2 inhibition delays progression of uveal melanoma
Published Online June 27, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70298-0 For Cavajal and collegues’ study see JAMA 2014; 311: 2397–405
Judith A Gilbert
A new study has identified a bloodbased epigenetic signature associated with breast cancer risk and mortality. The findings show the potential for an epigenetic test that could eventually be used to predict the development of breast cancer. The researchers profiled DNA samples from 72 women who carried the BRCA1 mutation and 72 women without mutations in either BRCA1 or BRCA2. They were able to extract a DNA methylation signature, comprising 1829 CpG islands, from the white blood cells of women with the BRCA1 mutation. They tested this signature in 152 women drawn from the National Survey of Health and Development, 19 of whom developed breast cancer. For the blood-cell DNA, the receiver operating characteristics area under the curve (AUC) was 0·65 (95% CI 0·51–0·78; p=0·02). The signature was tissue-specific: it www.thelancet.com/oncology Vol 15 August 2014
was not predictive in the matched buccal cells. Testing the signature against blood samples from the United Kingdom Collaborative Trial of Ovarian Cancer Screening—119 postmenopausal women who developed breast cancer, and 122 similar women who remained free of the disease—resulted in an AUC of 0·57 (95% CI 0·5–0·64; p=0·03). The test also predicted breast cancer mortality (AUC 0·67, 95% CI 0·51–0·83; p=0·02). “This is the first example of a blood test that’s not purely genetic that predicts breast cancer in the future—that’s certainly of tremendous interest”, said Steven Narod (University of Toronto, Canada). But he noted that AUC is an imperfect metric—it does not offer any indication of the importance of the association—and that it remains unclear as to the kind of timescale over which the test is predictive.
Lead author Martin Widschwendter (University College London, UK) does not believe that the blood cells are the most appropriate final target for a test of breast cancer risk. The test developed by his study showed low specificity and sensitivity—an AUC of 0·57 is little better than a guess. “We used blood because it was available, but blood is not the cell of origin for [breast] cancer”, said Widschwendter. He points out that the epigenome of epithelial cells is likely to record the individual response to risk factors for breast cancer. “Epithelial cells carry hormone receptors (unlike the blood cells); we aim to study epigenetic misprogramming in hormone-sensitive epithelial cells in order to not only predict breast cancer, but all other women-specific cancers which are hormonally related”.
Power and Syred/Science Photo Library
Epigenetic test for breast cancer
Published Online July 4, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70315-8 For the provisional study see Genome Med 2014; 6: 47
Talha Khan Burki e366
A multicentre, phase 2 trial has shown that selumetinib (an inhibitor of MEK1 and MEK2) provided significantly better progression-free survival and tumour response than did chemotherapy in patients with advanced uveal melanoma. “Mutations in G-proteins GNAQ and GNA11 are present in 90–95% of patients with metastatic uveal melanoma”, explained senior author Gary Schwartz (Columbia University School of Medicine, Herbert Irving Comprehensive Cancer Center, New York, NY, USA). “These mutations activate a majority of signalling pathways, including MAPK, AKT, and PKC. In laboratory studies, selumetinib completely blocked the MEK pathway, and inhibited growth of uveal melanoma cells in culture.” To study the efficacy of inhibiting MEK1/2 in uveal melanoma, 101 patients were randomly assigned
to receive oral selumetinib or standard chemotherapy. Progression-free survival was significantly longer with selumetinib (15·9 weeks [95% CI 8·4–21·1]) than with chemotherapy (7 weeks [4·3–8·4]; hazard ratio [HR] 0·46 [0·30–0·71], p<0·001); no significant difference in overall survival was seen (11·8 months [95% CI 9·8–15·7] vs 9·1 months [6·1–11·1], respectively; HR 0·66 [0·41–1·06], p=0·09). 49% of patients assigned to selumetinib had tumour regression, whereas no objective responses were reported in the chemotherapy group. 65 (97%) of 67 patients receiving selumetinib had treatment-related adverse events, and 25 (37%) needed dose reductions. “Targeted therapy is a promising way forward in uveal melanoma”, commented Patrick Ott (Dana-Farber Cancer Institute, Boston, MA, USA). “No systemic treatment was previously shown to work in this disease.”
Lead author Richard Carvajal (Memorial Sloan Kettering Cancer Center, New York, NY, USA) said that future studies include SUMIT (NCT01974752), a phase 3 trial of selumetinib in combination with dacarbazine versus chemotherapy alone, and (based on preclinical data showing that efficacy of MEK inhibition can be enhanced with the addition of AKT or PKC inhibition) a study of trametinib alone or in combination with GSK2141795 and a study of MEK162 and AEB071. Sapna Patel (MD Anderson Cancer Center, Houston, TX, USA) said, “For the first time in uveal melanoma, we can use targeted therapy to effect tumour response…Targeted therapy with a MEK inhibitor really can potentially be the backbone of new therapy for this tumour.”
ISM/Science Photo Library
MEK1/2 inhibition delays progression of uveal melanoma
Published Online June 27, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70298-0 For Cavajal and collegues’ study see JAMA 2014; 311: 2397–405
Judith A Gilbert
A new study has identified a bloodbased epigenetic signature associated with breast cancer risk and mortality. The findings show the potential for an epigenetic test that could eventually be used to predict the development of breast cancer. The researchers profiled DNA samples from 72 women who carried the BRCA1 mutation and 72 women without mutations in either BRCA1 or BRCA2. They were able to extract a DNA methylation signature, comprising 1829 CpG islands, from the white blood cells of women with the BRCA1 mutation. They tested this signature in 152 women drawn from the National Survey of Health and Development, 19 of whom developed breast cancer. For the blood-cell DNA, the receiver operating characteristics area under the curve (AUC) was 0·65 (95% CI 0·51–0·78; p=0·02). The signature was tissue-specific: it www.thelancet.com/oncology Vol 15 August 2014
was not predictive in the matched buccal cells. Testing the signature against blood samples from the United Kingdom Collaborative Trial of Ovarian Cancer Screening—119 postmenopausal women who developed breast cancer, and 122 similar women who remained free of the disease—resulted in an AUC of 0·57 (95% CI 0·5–0·64; p=0·03). The test also predicted breast cancer mortality (AUC 0·67, 95% CI 0·51–0·83; p=0·02). “This is the first example of a blood test that’s not purely genetic that predicts breast cancer in the future—that’s certainly of tremendous interest”, said Steven Narod (University of Toronto, Canada). But he noted that AUC is an imperfect metric—it does not offer any indication of the importance of the association—and that it remains unclear as to the kind of timescale over which the test is predictive.
Lead author Martin Widschwendter (University College London, UK) does not believe that the blood cells are the most appropriate final target for a test of breast cancer risk. The test developed by his study showed low specificity and sensitivity—an AUC of 0·57 is little better than a guess. “We used blood because it was available, but blood is not the cell of origin for [breast] cancer”, said Widschwendter. He points out that the epigenome of epithelial cells is likely to record the individual response to risk factors for breast cancer. “Epithelial cells carry hormone receptors (unlike the blood cells); we aim to study epigenetic misprogramming in hormone-sensitive epithelial cells in order to not only predict breast cancer, but all other women-specific cancers which are hormonally related”.
Power and Syred/Science Photo Library
Epigenetic test for breast cancer
Published Online July 4, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70315-8 For the provisional study see Genome Med 2014; 6: 47
Talha Khan Burki e366