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A targeted approach to maintenance of tumour response. Clinical and translational studies in metastatic colorectal cancer.

Hagman, Helga LU (2017)
Abstract (Swedish)
In metastatic colorectal cancer (mCRC) chemotherapy +/- targeted therapy with palliative intent aims at prolonging survival with sustained quality of life. Maintenance of tumour response by a period of less intense treatment may
delay progression and accumulation of unacceptable toxicity. We studied the combination of targeted treatment with the angiogenesis inhibiting antibody bevacizumab (bev) and the epidermal growth factor tyrosine kinase inhibitor
erlotinib (erlo) as maintenance treatment in two clinical trials.
The Nordic ACT trial (paper I) included 249 mCRC patients. Following first line induction doublet chemotherapy plus bev, responding patients were randomised to maintenance treatment with bev or bev+erlo. We found... (More)
In metastatic colorectal cancer (mCRC) chemotherapy +/- targeted therapy with palliative intent aims at prolonging survival with sustained quality of life. Maintenance of tumour response by a period of less intense treatment may
delay progression and accumulation of unacceptable toxicity. We studied the combination of targeted treatment with the angiogenesis inhibiting antibody bevacizumab (bev) and the epidermal growth factor tyrosine kinase inhibitor
erlotinib (erlo) as maintenance treatment in two clinical trials.
The Nordic ACT trial (paper I) included 249 mCRC patients. Following first line induction doublet chemotherapy plus bev, responding patients were randomised to maintenance treatment with bev or bev+erlo. We found no significant difference in survival outcomes between the arms. We then hypothesized that KRAS mutation of the tumour would have a negative impact on the erlo effect.
In the Nordic ACT2 trial (paper II, N=233), the KRAS wildtype (wt) patients were randomised in the same manner as in Nordic ACT. The KRAS mutated (mut) patients recieved bev alone or metronomic low dose capecitabine and arms were compared without significant difference in effect or safety. The KRASwt patient cohorts from the both Nordic ACT trials were pooled in an analysis of survival outcomes (N=126) with no statistically significant gain from the addition of erlo to bev as maintenance.
There are no validated biomarkers of anti-angiogenic therapy. Treatment induced hypertension has been associated with better response to angiogenesis inhibition. The vasoactive peptides (VPs) atrial natriuretic peptide, adrenomedullin, and copeptin are linked to regulation of blood pressure and angiogenesis. In paper III, the stable
pro-peptides of each VP were analysed in plasma from ACT2 study patients with documented progressive disease (N=97). IncreasingVP levels during the first six weeks of induction chemotherapy + bev were significantly associated with better clinical outcome. In paper IV, we collected serum samples at start of induction, start of maintenance and at progression from ACT2 patients (N=22). Analyses of 55 circulating, angiogenesis-related proteins were performed at each time point by
antibody array membrane technology. Levels of some, mostly pro-angiogenic, proteins decreased significantly during response and/or increased at progression.
In summary, these studies demonstrate that mCRC patients may not benefit from bev+erlo as maintenance therapy in terms of efficacy, and that the clinical benefit can be further questioned due to tocixity concerns. KRAS status is not likely a predictive biomarker for erlo in mCRC. Microarray methodology for simultaneous detection of multiple proteins in serum is convenient for exploration of signalling patterns related to the response and resistance to angiogenesis inhibition. Our translational results support the evidence of an interaction between host-related vascular effects and response to chemotherapy plus bev. Both VPs and other counterbalancing pro-angiogenic factors are promising biomarkers that warrant further studies in this setting. (Less)
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author
supervisor
opponent
  • MD Folprecht, Gunnar, University Hospital Carl Gustav Carus, University Cancer Center, Dresden, Germany
organization
publishing date
type
Thesis
publication status
published
subject
keywords
kolorektal cancer, underhållsbehandling, biomarkörer, angiogeneshämning
pages
127 pages
publisher
Lund University, Faculty of Medicine
defense location
Lecture Hall of the Radiotherapy Building, 3rd floor, Department of Oncology, Skåne University, Lund
defense date
2017-04-07 09:00
ISBN
978-91-7619-427-0
language
English
LU publication?
yes
id
65444014-592c-426f-9c4d-984196dac66f
date added to LUP
2017-04-12 16:07:37
date last changed
2017-06-21 10:24:13
@phdthesis{65444014-592c-426f-9c4d-984196dac66f,
  abstract     = {In metastatic colorectal cancer (mCRC) chemotherapy +/- targeted therapy with palliative intent aims at prolonging survival with sustained quality of life. Maintenance of tumour response by a period of less intense treatment may<br/>delay progression and accumulation of unacceptable toxicity. We studied the combination of targeted treatment with the angiogenesis inhibiting antibody bevacizumab (bev) and the epidermal growth factor tyrosine kinase inhibitor<br/>erlotinib (erlo) as maintenance treatment in two clinical trials.<br/>The Nordic ACT trial (paper I) included 249 mCRC patients. Following first line induction doublet chemotherapy plus bev, responding patients were randomised to maintenance treatment with bev or bev+erlo. We found no significant difference in survival outcomes between the arms. We then hypothesized that KRAS mutation of the tumour would have a negative impact on the erlo effect.<br/>In the Nordic ACT2 trial (paper II, N=233), the KRAS wildtype (wt) patients were randomised in the same manner as in Nordic ACT. The KRAS mutated (mut) patients recieved bev alone or metronomic low dose capecitabine and arms were compared without significant difference in effect or safety. The KRASwt patient cohorts from the both Nordic ACT trials were pooled in an analysis of survival outcomes (N=126) with no statistically significant gain from the addition of erlo to bev as maintenance.<br/>There are no validated biomarkers of anti-angiogenic therapy. Treatment induced hypertension has been associated with better response to angiogenesis inhibition. The vasoactive peptides (VPs) atrial natriuretic peptide, adrenomedullin, and copeptin are linked to regulation of blood pressure and angiogenesis. In paper III, the stable<br/>pro-peptides of each VP were analysed in plasma from ACT2 study patients with documented progressive disease (N=97). IncreasingVP levels during the first six weeks of induction chemotherapy + bev were significantly associated with better clinical outcome. In paper IV, we collected serum samples at start of induction, start of maintenance and at progression from ACT2 patients (N=22). Analyses of 55 circulating, angiogenesis-related proteins were performed at each time point by<br/>antibody array membrane technology. Levels of some, mostly pro-angiogenic, proteins decreased significantly during response and/or increased at progression.<br/>In summary, these studies demonstrate that mCRC patients may not benefit from bev+erlo as maintenance therapy in terms of efficacy, and that the clinical benefit can be further questioned due to tocixity concerns. KRAS status is not likely a predictive biomarker for erlo in mCRC. Microarray methodology for simultaneous detection of multiple proteins in serum is convenient for exploration of signalling patterns related to the response and resistance to angiogenesis inhibition. Our translational results support the evidence of an interaction between host-related vascular effects and response to chemotherapy plus bev. Both VPs and other counterbalancing pro-angiogenic factors are promising biomarkers that warrant further studies in this setting.},
  author       = {Hagman, Helga},
  isbn         = {978-91-7619-427-0},
  keyword      = {kolorektal cancer, underhållsbehandling, biomarkörer, angiogeneshämning},
  language     = {eng},
  pages        = {127},
  publisher    = {Lund University, Faculty of Medicine},
  school       = {Lund University},
  title        = {A targeted approach to maintenance of tumour response. Clinical and translational studies in metastatic colorectal cancer.},
  year         = {2017},
}