- Email: [email protected]
Blood gene expression profiling of breast cancer survivors experiencing fibrosis
women treated at smaller rural facilities, as their outcomes may not be the same as those of women treated at Tata Memorial Hospital. Overall, this trial is interesting in the sense that it attempted to elucidate the relationship between body image and treatment-related QOL for women
in developing countries. There is reason to believe that these women benefit from BCS in much the same way that women in the Western world do, even though BCS is more time consuming and expensive. Further QOL research comparing long-term outcomes for women with early-stage
breast cancer treated with BCS or mastectomy (with or without postmastectomy RT) should be undertaken.
Blood gene expression profiling of breast cancer survivors experiencing fibrosis
observed, and 87 differentially expressed genes were identified through linear analysis. Transforming growth factor-b1 signaling was identified as the most significant gene set, showing a down-regulation of most of the core genes, together with up-regulation of a transcriptional activator of the inhibitor of fibrinolysis, Plasminogen activator inhibitor 1 in the BC survivors with fibrosis. Conclusion.dTransforming growth factor-b1 signaling was found downregulated during the maintenance phase of fibrosis as opposed to the upregulation reported during the early, initiating phase of fibrosis. Hence, once the fibrotic tissue has developed, the maintenance phase might rather involve a deregulation of fibrinolysis and altered degradation of extracellular matrix components.
was to use whole transcriptome expression analysis following irradiation and to identify the genes whose expression displayed substantial differences between patients who developed fibrotic changes and those who did not exhibit this form of normal tissue toxicity. An important aspect of this study was that the authors performed the expression analysis using blood samples obtained from patients with BC several years following completion of radiotherapy rather than within hours following irradiation, as has been done in previous work.1 Therefore, the focus of this study was on the identification of genes associated with the maintenance of the fibrotic process. The investigators performed a genewise analysis that identified genes that were differentially expressed between women who developed fibrotic changes and those who did not. However, the more interesting aspect of this study was when the analysis was performed in the context of gene sets in which the genes were grouped by function. The gene sets that exhibited the strongest association with development of fibrosis were those associated with the transforming growth factor-b1 (TGF-b1) signaling pathway. Most striking was that all but 2 of the core genes in this signaling pathway were actually downregulated during this maintenance phase of RIF. This is in contrast to the acute upregulation
Landmark-Høyvik H, Dumeaux V, Reinertsen KV, et al (Oslo Univ Hosp Radiumhospitalet, Norway; Univ of Tromsø, Norway; Univ of Oslo, Norway) Int J Radiat Oncol Biol Phys 79:875-883, 2011
Purpose.dTo extend knowledge on the mechanisms and pathways involved in maintenance of radiationinduced fibrosis (RIF) by performing gene expression profiling of whole blood from breast cancer (BC) survivors with and without fibrosis 3e7 years after end of radiotherapy treatment. Methods and Materials.dGene expression profiles from blood were obtained for 254 BC survivors derived from a cohort of survivors, treated with adjuvant radiotherapy for breast cancer 3e7 years earlier. Analyses of transcriptional differences in blood gene expression between BC survivors with fibrosis (n ¼ 31) and BC survivors without fibrosis (n ¼ 223) were performed using R version 2.8.0 and tools from the Bioconductor project. Gene sets extracted through a literature search on fibrosis and breast cancer were subsequently used in gene set enrichment analysis. Results.dSubstantial differences in blood gene expression between BC survivors with and without fibrosis were
314
The development of fibrotic changes within the breast following radiotherapy for BC represents a significant adverse event for many BC survivors, as it may lead to pain and a poor cosmetic outcome. Therefore, an understanding of the genes and molecular pathways associated with RIF is critical since this knowledge may facilitate the development of drugs capable of either preventing or mitigating this form of injury. The approach used by LandmarkHøyvik and colleagues in this article
Breast Diseases: A Year BookÒ Quarterly Vol 22 No 3 2011
K. U. Hunter, MD J. A. Hayman, MD
of TGF-b1 that has been reported following irradiation.2 Furthermore, an upregulation of TGF-b1 during the hours following irradiation has been correlated with a greater risk of fibrotic reactions. The results of this study demonstrate that it is important to gain a full picture of gene expression patterns not only within hours to days after radiotherapy but also years later. To explain their finding, the authors note that expression of TFE3 was upregulated in the BC survivors who had fibrosis. This gene encodes a transcriptional activator that induces the transcription of PAI-1, whose product inhibits fibrinolysis by inhibiting the enzymes that convert plasminogen to plasmin.3 In addition, plasmin plays a central role in the degradation of extracellular matrix components, including collagen. Thus, the women who had fibrosis may have had a limited ability to undergo
fibrinolysis and a diminished capacity to degrade components of the extracellular matrix during the maintenance phase of fibrosis. One important limitation to this study that should be noted is that a validation cohort was not screened. The inclusion of an additional population in all studies involving array analysis is particularly important since the screening of large numbers of genes often leads to false-positives. It will clearly be essential for the results of this study to be validated in one replication cohort, if not several replication cohorts, before further study is warranted to elucidate the mechanisms through which RIF is maintained in patients with BC following radiotherapy.
Complete Response of Brain Metastases from Breast Cancer Overexpressing HER-2/neu to Radiation and Concurrent Lapatinib and Capecitabine
brain metastases from breast cancer overexpressing HER-2 who achieved a complete radiologic response after treatment by radiation and concurrent Lapatinib and Capecitabine.
Abboud M, Saghir NSE, Salame J, et al (The American Univ of Beirut Med Ctr, Lebanon)
In this case report, Abboud and colleagues describe a patient with multiple HER-2/neu-positive brain metastases from a primary breast cancer who had a complete radiologic response following treatment with lapatinib with capecitabine and whole-brain irradiation. The literature continues to demonstrate the benefit of continued blockade of HER-2/neu overexpression during metastatic breast cancer progression.1 From prospective studies, the complete radiologic response rate is expected to be about 1% in women with multiple HER-2/neu-overexpressing
Breast J 16:644-646, 2010
Breast cancers that overexpress the human epidermal growth factor receptor 2 (HER-2) have a predilection to metastasize to the brain. Therapeutic options for brain metastases with systemic therapy remain a challenge in those patients since targeted and chemotherapeutic agents have limited penetration through the blood-brain barrier. Here we report the case of a patient with
References 1. Rødningen OK, Børresen-Dale AL, Alsner J, Hastie T, Overgaard J. Radiation-induced gene expression in human subcutaneous fibroblasts is predictive of radiation-induced fibrosis. Radiother Oncol. 2008;86: 314-320. 2. Anscher MS. Targeting the TGF-b1 pathway to prevent normal tissue injury after cancer therapy. Oncologist. 2010;15:350-359. 3. Hua X, Liu X, Ansari DO, Lodish HF. Synergistic cooperation of TFE3 and smad proteins in TGF-beta-induced transcription of the plasminogen activator inhibitor-1 gene. Genes Dev. 1998;12:3084-3095.
B. S. Rosenstein, PhD
brain metastases from a primary breast cancer who receive lapatinib with capecitabine but no radiation therapy. More commonly, a partial response is expected 35% of the time.2,3 The addition of radiation to the systemic approaches remains important because of the blood-brain barrier, and our clinical results demonstrate higher response rates with radiation in addition to systemic approaches. Less clear is the irradiation technique that would best serve these patients. Retrospective studies of patients with metastatic breast cancer have attempted to outline indications and outcomes for stereotactic radiosurgery (SRS) versus whole-brain radiation therapy. Ongoing phase I clinical trials are examining lapatinib plus alternative chemotherapy partners in addition to multiple radiation therapy
Breast Diseases: A Year BookÒ Quarterly Vol 22 No 3 2011
315
in developing countries. There is reason to believe that these women benefit from BCS in much the same way that women in the Western world do, even though BCS is more time consuming and expensive. Further QOL research comparing long-term outcomes for women with early-stage
breast cancer treated with BCS or mastectomy (with or without postmastectomy RT) should be undertaken.
Blood gene expression profiling of breast cancer survivors experiencing fibrosis
observed, and 87 differentially expressed genes were identified through linear analysis. Transforming growth factor-b1 signaling was identified as the most significant gene set, showing a down-regulation of most of the core genes, together with up-regulation of a transcriptional activator of the inhibitor of fibrinolysis, Plasminogen activator inhibitor 1 in the BC survivors with fibrosis. Conclusion.dTransforming growth factor-b1 signaling was found downregulated during the maintenance phase of fibrosis as opposed to the upregulation reported during the early, initiating phase of fibrosis. Hence, once the fibrotic tissue has developed, the maintenance phase might rather involve a deregulation of fibrinolysis and altered degradation of extracellular matrix components.
was to use whole transcriptome expression analysis following irradiation and to identify the genes whose expression displayed substantial differences between patients who developed fibrotic changes and those who did not exhibit this form of normal tissue toxicity. An important aspect of this study was that the authors performed the expression analysis using blood samples obtained from patients with BC several years following completion of radiotherapy rather than within hours following irradiation, as has been done in previous work.1 Therefore, the focus of this study was on the identification of genes associated with the maintenance of the fibrotic process. The investigators performed a genewise analysis that identified genes that were differentially expressed between women who developed fibrotic changes and those who did not. However, the more interesting aspect of this study was when the analysis was performed in the context of gene sets in which the genes were grouped by function. The gene sets that exhibited the strongest association with development of fibrosis were those associated with the transforming growth factor-b1 (TGF-b1) signaling pathway. Most striking was that all but 2 of the core genes in this signaling pathway were actually downregulated during this maintenance phase of RIF. This is in contrast to the acute upregulation
Landmark-Høyvik H, Dumeaux V, Reinertsen KV, et al (Oslo Univ Hosp Radiumhospitalet, Norway; Univ of Tromsø, Norway; Univ of Oslo, Norway) Int J Radiat Oncol Biol Phys 79:875-883, 2011
Purpose.dTo extend knowledge on the mechanisms and pathways involved in maintenance of radiationinduced fibrosis (RIF) by performing gene expression profiling of whole blood from breast cancer (BC) survivors with and without fibrosis 3e7 years after end of radiotherapy treatment. Methods and Materials.dGene expression profiles from blood were obtained for 254 BC survivors derived from a cohort of survivors, treated with adjuvant radiotherapy for breast cancer 3e7 years earlier. Analyses of transcriptional differences in blood gene expression between BC survivors with fibrosis (n ¼ 31) and BC survivors without fibrosis (n ¼ 223) were performed using R version 2.8.0 and tools from the Bioconductor project. Gene sets extracted through a literature search on fibrosis and breast cancer were subsequently used in gene set enrichment analysis. Results.dSubstantial differences in blood gene expression between BC survivors with and without fibrosis were
314
The development of fibrotic changes within the breast following radiotherapy for BC represents a significant adverse event for many BC survivors, as it may lead to pain and a poor cosmetic outcome. Therefore, an understanding of the genes and molecular pathways associated with RIF is critical since this knowledge may facilitate the development of drugs capable of either preventing or mitigating this form of injury. The approach used by LandmarkHøyvik and colleagues in this article
Breast Diseases: A Year BookÒ Quarterly Vol 22 No 3 2011
K. U. Hunter, MD J. A. Hayman, MD
of TGF-b1 that has been reported following irradiation.2 Furthermore, an upregulation of TGF-b1 during the hours following irradiation has been correlated with a greater risk of fibrotic reactions. The results of this study demonstrate that it is important to gain a full picture of gene expression patterns not only within hours to days after radiotherapy but also years later. To explain their finding, the authors note that expression of TFE3 was upregulated in the BC survivors who had fibrosis. This gene encodes a transcriptional activator that induces the transcription of PAI-1, whose product inhibits fibrinolysis by inhibiting the enzymes that convert plasminogen to plasmin.3 In addition, plasmin plays a central role in the degradation of extracellular matrix components, including collagen. Thus, the women who had fibrosis may have had a limited ability to undergo
fibrinolysis and a diminished capacity to degrade components of the extracellular matrix during the maintenance phase of fibrosis. One important limitation to this study that should be noted is that a validation cohort was not screened. The inclusion of an additional population in all studies involving array analysis is particularly important since the screening of large numbers of genes often leads to false-positives. It will clearly be essential for the results of this study to be validated in one replication cohort, if not several replication cohorts, before further study is warranted to elucidate the mechanisms through which RIF is maintained in patients with BC following radiotherapy.
Complete Response of Brain Metastases from Breast Cancer Overexpressing HER-2/neu to Radiation and Concurrent Lapatinib and Capecitabine
brain metastases from breast cancer overexpressing HER-2 who achieved a complete radiologic response after treatment by radiation and concurrent Lapatinib and Capecitabine.
Abboud M, Saghir NSE, Salame J, et al (The American Univ of Beirut Med Ctr, Lebanon)
In this case report, Abboud and colleagues describe a patient with multiple HER-2/neu-positive brain metastases from a primary breast cancer who had a complete radiologic response following treatment with lapatinib with capecitabine and whole-brain irradiation. The literature continues to demonstrate the benefit of continued blockade of HER-2/neu overexpression during metastatic breast cancer progression.1 From prospective studies, the complete radiologic response rate is expected to be about 1% in women with multiple HER-2/neu-overexpressing
Breast J 16:644-646, 2010
Breast cancers that overexpress the human epidermal growth factor receptor 2 (HER-2) have a predilection to metastasize to the brain. Therapeutic options for brain metastases with systemic therapy remain a challenge in those patients since targeted and chemotherapeutic agents have limited penetration through the blood-brain barrier. Here we report the case of a patient with
References 1. Rødningen OK, Børresen-Dale AL, Alsner J, Hastie T, Overgaard J. Radiation-induced gene expression in human subcutaneous fibroblasts is predictive of radiation-induced fibrosis. Radiother Oncol. 2008;86: 314-320. 2. Anscher MS. Targeting the TGF-b1 pathway to prevent normal tissue injury after cancer therapy. Oncologist. 2010;15:350-359. 3. Hua X, Liu X, Ansari DO, Lodish HF. Synergistic cooperation of TFE3 and smad proteins in TGF-beta-induced transcription of the plasminogen activator inhibitor-1 gene. Genes Dev. 1998;12:3084-3095.
B. S. Rosenstein, PhD
brain metastases from a primary breast cancer who receive lapatinib with capecitabine but no radiation therapy. More commonly, a partial response is expected 35% of the time.2,3 The addition of radiation to the systemic approaches remains important because of the blood-brain barrier, and our clinical results demonstrate higher response rates with radiation in addition to systemic approaches. Less clear is the irradiation technique that would best serve these patients. Retrospective studies of patients with metastatic breast cancer have attempted to outline indications and outcomes for stereotactic radiosurgery (SRS) versus whole-brain radiation therapy. Ongoing phase I clinical trials are examining lapatinib plus alternative chemotherapy partners in addition to multiple radiation therapy
Breast Diseases: A Year BookÒ Quarterly Vol 22 No 3 2011
315