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Genetic polymorphisms in DNA repair and damage response genes and late normal tissue complications of radiotherapy for breast cancer
Genetic polymorphisms in DNA repair and damage response genes and late normal tissue complications of radiotherapy for breast cancer Chang-Claude J, Ambrosone CB, Lilla C, et al (German Cancer Res Ctr, Heidelberg; Roswell Park Cancer Inst, Buffalo, NY; et al) Br J Cancer 100:1680-1686, 2009
Breast-conserving surgery followed by radiotherapy is effective in reducing recurrence; however, telangiectasia and fibrosis can occur as late skin side effects. As radiotherapy acts through producing DNA damage, we investigated whether genetic variation in DNA repair and damage response confers increased susceptibility to develop late normal skin complications. Breast cancer patients who received radiotherapy after breastconserving surgery were examined for late complications of radiotherapy after a median follow-up time of 51 months. Polymorphisms in genes involved in DNA repair (APEX1, XRCC1, XRCC2, XRCC3, XPD) and damage response (TP53, P21) were determined. Associations between telangiectasia and genotypes were assessed among 409 patients, using multivariate logistic regression. A total of 131 patients presented with telangiectasia and 28 patients with fibrosis. Patients with variant TP53 genotypes either for the Arg72Pro or the PIN3 polymorphism were at increased risk of telangiectasia. The odds ratios (OR) were 1.66 (95% confidence interval (CI): 1.02–2.72) for 72Pro carriers and 1.95 (95% CI: 1.13–3.35) for PIN3 A2 allele carriers compared with non-carriers. The TP53 haplotype containing both variant alleles was associated with almost a two-fold increase in risk (OR 1.97, 95% CI: 1.11–3.52) for
172
telangiectasia. Variants in the TP53 gene may therefore modify the risk of late skin toxicity after radiotherapy. Evidence suggests that inherited genetic factors influence patients’ susceptibility to the development of normal tissue toxicities resulting from radiotherapy for breast cancer.1 Therefore, identifying these genetic markers would enable the creation of an assay to predict which breast cancer patients were at greatest risk for the development of adverse effects resulting from a standard course of radiotherapy. Using this information, radiation oncologists could optimize each patient’s treatment plan, which may include the use of a partial-breast protocol to spare much of the breast from irradiation. Alternatively, a standard whole-breast regimen may be appropriate, but with the use of a lower treatment dose since the cancer cells may also prove radiosensitive. In an effort to identify the genetic factors that could serve as the basis of a predictive assay, many investigators have performed retrospective casecontrol studies in which singlenucleotide polymorphisms (SNPs) in specific candidate genes were screened from patients who developed radiation-induced injuries and similarly treated patients who did not develop these complications. SNPs represent a major source of genetic variation between individuals. These studies have resulted in the publication of approximately 50 articles reporting associations between SNPs in a series of genes and a variety of normal tissue toxicities.1,2 Many of these studies were performed with breast cancer patients. An excellent example of a wellconducted study is presented in this article by Chang-Claude and colleagues. For this study, the authors genotyped SNPs in several candidate
Breast Diseases: A Year BookÒ Quarterly Vol 21 No 2 2010
genes selected because of the role their encoded products play in DNA damage response and repair. The genotyping was performed using DNA samples obtained from breast cancer patients following breast-conserving surgery and radiotherapy. The results showed that SNPs in TP53 were associated with the development of telangiectasia. Although this represents a well-conducted study, it will be critical for these or other investigators to perform a validation study in which additional breast cancer radiotherapy patients who developed telangiectasia will be screened for these SNPs. Without validation in 1 or preferably several other patient cohorts, these results must be considered preliminary. Also, these findings must be viewed as hypothesis-generating since a P-value correction for testing multiple hypotheses using an appropriate statistical methodology, such as the Bonferroni correction or false discovery rate, was not performed, although 13 SNPs were screened. Similar to those published by Chang-Claude and colleagues, other results obtained in this field of research, termed ‘‘radiogenomics,’’ have suggested that possession of the minor allele of SNPs in other candidate genes is associated with the development of radiation-induced adverse effects.1 However, it should be noted that conflicting results have been obtained for the genes that have been genotyped in several cohorts. In addition, many investigators have not been able to publish the negative results of studies, which did not confirm previous SNP associations. Thus, in recognition of the urgent need for collaboration, most of the investigators performing work in radiogenomics, including ChangClaude, met in Manchester, UK, in November 2009 to create a Radiogenomics Consortium.3 The purpose
of this consortium is to perform analyses on pooled data from both published and unpublished studies with a goal of determining whether specific SNPs have been identified that could be included in a predictive assay. In addition, much of the thrust of current research in radiogenomics is the performance of genome-wide association studies, in which patients are being screened for upward of 1 million SNPs. A significant limitation of these studies is the testing of multiple hypotheses, thereby requiring large sample sizes to obtain statistically significant results. The Radiogenomics Consortium will therefore play a key role in addressing
this issue by facilitating the pooling of data from multiple genome-wide association studies. It is anticipated that over the next few years, particularly through the international cooperation that has developed through the creation of the Radiogenomics Consortium, it will be possible to identify the SNPs that will form the basis of a predictive assay to identify patients at greatest risk for the development of normal tissue toxicities following a standard course of radiotherapy for breast cancer.
Chest wall radiotherapy: middle ground for treatment of patients with one to three positive lymph nodes after mastectomy
overall survival were analyzed according to the delivery of radiotherapy and multiple prognostic factors. Results.—LRR and DFS were significantly improved by postmastectomy radiotherapy (PMRT), with a 5- and 10-year LRR rate without PMRT of 6% and 11%, respectively and, with PMRT, of 0% at both 5 and 10 years (p ¼ .02). The 5- and 10-year DFS rate without PMRT was 85% and 75%, respectively, and, with PMRT, was 93% at both 5 and 10 years (p ¼ .03). A similar benefit was found for patients treated with RT to the CW alone. The LRR, DFS, and overall survival rate for patients treated to the CW only was 0%, 96%, and 95% at 10 years, respectively. Conclusion.—Our data suggest that adjuvant PMRT to the CW alone provides excellent disease control for patients with breast cancer <5 cm with one to three positive lymph nodes.
MacDonald SM, Abi-Raad RF, Alm El-Din MA, et al (Massachusetts General Hosp, Boston) Int J Radiat Oncol Biol Phys 75:1297-1303, 2009
Purpose.—To evaluate the outcomes for patients with Stage II breast cancer and one to three positive lymph nodes after mastectomy who were treated with observation or adjuvant radiotherapy to the chest wall (CW) with or without the regional lymphatics. Methods and Materials.—We retrospectively analyzed 238 patients with Stage II breast cancer (one to three positive lymph nodes) treated with mastectomy at the Massachusetts General Hospital between 1990 and 2004. The estimates of locoregional recurrence (LRR), disease-free survival (DFS), and
References 1. Barnett GC, West CM, Dunning AM, et al. Normal tissue reactions to radiotherapy: towards tailoring treatment dose by genotype. Nat Rev Cancer. 2009;9:134-142. 2. Andreassen CN, Alsner J. Genetic variants and normal tissue toxicity after radiotherapy: a systematic review. Radiother Oncol. 2009;92: 299-309. 3. West C, Rosenstein BS. Establishment of a radiogenomics consortium. Radiother Oncol. 2010; 94:117-118.
B. S. Rosenstein, PhD
In the era of effective adjuvant systemic therapy, PMRT is now widely
acknowledged to improve overall survival and locoregional control. Controversy continues, however, as to whether or not all stage II and III patients are appropriately treated with PMRT. In particular, the debate has centered on patients with 1-3 positive nodes (it is generally agreed that those with 4 or more nodes involved should receive RT). The question of appropriate treatment volumes has received less attention but is also quite controversial, particularly with regard to internal mammary nodal RT. If PMRT is to be given, should one treat the entire locoregional area at risk, ie, the CW, internal mammary nodes (IMNs), and supraclavicular nodes (SCs), or some part thereof, eg, the CW alone or the CW in combination with some varying nodal target volume? (It is generally agreed that following full axillary dissection, axillary RT may be omitted.) The current interesting report by MacDonald and colleagues at the
Breast Diseases: A Year BookÒ Quarterly Vol 21 No 2 2010
173
Breast-conserving surgery followed by radiotherapy is effective in reducing recurrence; however, telangiectasia and fibrosis can occur as late skin side effects. As radiotherapy acts through producing DNA damage, we investigated whether genetic variation in DNA repair and damage response confers increased susceptibility to develop late normal skin complications. Breast cancer patients who received radiotherapy after breastconserving surgery were examined for late complications of radiotherapy after a median follow-up time of 51 months. Polymorphisms in genes involved in DNA repair (APEX1, XRCC1, XRCC2, XRCC3, XPD) and damage response (TP53, P21) were determined. Associations between telangiectasia and genotypes were assessed among 409 patients, using multivariate logistic regression. A total of 131 patients presented with telangiectasia and 28 patients with fibrosis. Patients with variant TP53 genotypes either for the Arg72Pro or the PIN3 polymorphism were at increased risk of telangiectasia. The odds ratios (OR) were 1.66 (95% confidence interval (CI): 1.02–2.72) for 72Pro carriers and 1.95 (95% CI: 1.13–3.35) for PIN3 A2 allele carriers compared with non-carriers. The TP53 haplotype containing both variant alleles was associated with almost a two-fold increase in risk (OR 1.97, 95% CI: 1.11–3.52) for
172
telangiectasia. Variants in the TP53 gene may therefore modify the risk of late skin toxicity after radiotherapy. Evidence suggests that inherited genetic factors influence patients’ susceptibility to the development of normal tissue toxicities resulting from radiotherapy for breast cancer.1 Therefore, identifying these genetic markers would enable the creation of an assay to predict which breast cancer patients were at greatest risk for the development of adverse effects resulting from a standard course of radiotherapy. Using this information, radiation oncologists could optimize each patient’s treatment plan, which may include the use of a partial-breast protocol to spare much of the breast from irradiation. Alternatively, a standard whole-breast regimen may be appropriate, but with the use of a lower treatment dose since the cancer cells may also prove radiosensitive. In an effort to identify the genetic factors that could serve as the basis of a predictive assay, many investigators have performed retrospective casecontrol studies in which singlenucleotide polymorphisms (SNPs) in specific candidate genes were screened from patients who developed radiation-induced injuries and similarly treated patients who did not develop these complications. SNPs represent a major source of genetic variation between individuals. These studies have resulted in the publication of approximately 50 articles reporting associations between SNPs in a series of genes and a variety of normal tissue toxicities.1,2 Many of these studies were performed with breast cancer patients. An excellent example of a wellconducted study is presented in this article by Chang-Claude and colleagues. For this study, the authors genotyped SNPs in several candidate
Breast Diseases: A Year BookÒ Quarterly Vol 21 No 2 2010
genes selected because of the role their encoded products play in DNA damage response and repair. The genotyping was performed using DNA samples obtained from breast cancer patients following breast-conserving surgery and radiotherapy. The results showed that SNPs in TP53 were associated with the development of telangiectasia. Although this represents a well-conducted study, it will be critical for these or other investigators to perform a validation study in which additional breast cancer radiotherapy patients who developed telangiectasia will be screened for these SNPs. Without validation in 1 or preferably several other patient cohorts, these results must be considered preliminary. Also, these findings must be viewed as hypothesis-generating since a P-value correction for testing multiple hypotheses using an appropriate statistical methodology, such as the Bonferroni correction or false discovery rate, was not performed, although 13 SNPs were screened. Similar to those published by Chang-Claude and colleagues, other results obtained in this field of research, termed ‘‘radiogenomics,’’ have suggested that possession of the minor allele of SNPs in other candidate genes is associated with the development of radiation-induced adverse effects.1 However, it should be noted that conflicting results have been obtained for the genes that have been genotyped in several cohorts. In addition, many investigators have not been able to publish the negative results of studies, which did not confirm previous SNP associations. Thus, in recognition of the urgent need for collaboration, most of the investigators performing work in radiogenomics, including ChangClaude, met in Manchester, UK, in November 2009 to create a Radiogenomics Consortium.3 The purpose
of this consortium is to perform analyses on pooled data from both published and unpublished studies with a goal of determining whether specific SNPs have been identified that could be included in a predictive assay. In addition, much of the thrust of current research in radiogenomics is the performance of genome-wide association studies, in which patients are being screened for upward of 1 million SNPs. A significant limitation of these studies is the testing of multiple hypotheses, thereby requiring large sample sizes to obtain statistically significant results. The Radiogenomics Consortium will therefore play a key role in addressing
this issue by facilitating the pooling of data from multiple genome-wide association studies. It is anticipated that over the next few years, particularly through the international cooperation that has developed through the creation of the Radiogenomics Consortium, it will be possible to identify the SNPs that will form the basis of a predictive assay to identify patients at greatest risk for the development of normal tissue toxicities following a standard course of radiotherapy for breast cancer.
Chest wall radiotherapy: middle ground for treatment of patients with one to three positive lymph nodes after mastectomy
overall survival were analyzed according to the delivery of radiotherapy and multiple prognostic factors. Results.—LRR and DFS were significantly improved by postmastectomy radiotherapy (PMRT), with a 5- and 10-year LRR rate without PMRT of 6% and 11%, respectively and, with PMRT, of 0% at both 5 and 10 years (p ¼ .02). The 5- and 10-year DFS rate without PMRT was 85% and 75%, respectively, and, with PMRT, was 93% at both 5 and 10 years (p ¼ .03). A similar benefit was found for patients treated with RT to the CW alone. The LRR, DFS, and overall survival rate for patients treated to the CW only was 0%, 96%, and 95% at 10 years, respectively. Conclusion.—Our data suggest that adjuvant PMRT to the CW alone provides excellent disease control for patients with breast cancer <5 cm with one to three positive lymph nodes.
MacDonald SM, Abi-Raad RF, Alm El-Din MA, et al (Massachusetts General Hosp, Boston) Int J Radiat Oncol Biol Phys 75:1297-1303, 2009
Purpose.—To evaluate the outcomes for patients with Stage II breast cancer and one to three positive lymph nodes after mastectomy who were treated with observation or adjuvant radiotherapy to the chest wall (CW) with or without the regional lymphatics. Methods and Materials.—We retrospectively analyzed 238 patients with Stage II breast cancer (one to three positive lymph nodes) treated with mastectomy at the Massachusetts General Hospital between 1990 and 2004. The estimates of locoregional recurrence (LRR), disease-free survival (DFS), and
References 1. Barnett GC, West CM, Dunning AM, et al. Normal tissue reactions to radiotherapy: towards tailoring treatment dose by genotype. Nat Rev Cancer. 2009;9:134-142. 2. Andreassen CN, Alsner J. Genetic variants and normal tissue toxicity after radiotherapy: a systematic review. Radiother Oncol. 2009;92: 299-309. 3. West C, Rosenstein BS. Establishment of a radiogenomics consortium. Radiother Oncol. 2010; 94:117-118.
B. S. Rosenstein, PhD
In the era of effective adjuvant systemic therapy, PMRT is now widely
acknowledged to improve overall survival and locoregional control. Controversy continues, however, as to whether or not all stage II and III patients are appropriately treated with PMRT. In particular, the debate has centered on patients with 1-3 positive nodes (it is generally agreed that those with 4 or more nodes involved should receive RT). The question of appropriate treatment volumes has received less attention but is also quite controversial, particularly with regard to internal mammary nodal RT. If PMRT is to be given, should one treat the entire locoregional area at risk, ie, the CW, internal mammary nodes (IMNs), and supraclavicular nodes (SCs), or some part thereof, eg, the CW alone or the CW in combination with some varying nodal target volume? (It is generally agreed that following full axillary dissection, axillary RT may be omitted.) The current interesting report by MacDonald and colleagues at the
Breast Diseases: A Year BookÒ Quarterly Vol 21 No 2 2010
173