- Email: [email protected]
Common germline polymorphisms in COMT, CYP19A1, ESR1, PGR, SULT1E1 and STS and survival after a diagnosis of breast cancer
such as tumor grade or the presence of a spindle cell component or focal acantholytic pattern. In this study, it is unclear whether an increased proportion of high-grade tumors or other potentially aggressive histologic variants account for the shorter survival of patients with SCC of the breast. Most SCCs have a triple-negative phenotype, and triple-negative tumors are known to be an aggressive subtype of invasive breast cancer. Moreover, the patients with SCC tumors in this study presented at a relatively more advanced stage than patients with nonsquamous tumors. Although patients with invasive SCCs had shorter survival than those with nonsquamous tumors, it is unclear whether the patients with invasive SCCs had worse outcomes than
patients with triple-negative tumors who presented at a similar stage. Although the data so far on the outcomes of patients with SCC of the breast appear inconsistent, some data suggest that conventional chemotherapy is less effective for patients with SCC.5,6 If this claim proves to be true, accurate classification of these tumors will be important so that patients with invasive SCC may be treated with cisplatin-based chemotherapy or whatever proves to be most effective. M. Z. Gilcrease, MD, PhD
References 1. Wargotz ES, Norris HJ. Metaplastic carcinomas of the breast. IV.
Squamous cell carcinoma of ductal origin. Cancer. 1990;65:272-276. 2. Cardoso F, Leal C, Meira A, et al. Squamous cell carcinoma of the breast. Breast. 2000;9:315-319. 3. Toikkanen S. Primary squamous cell carcinoma of the breast. Cancer. 1981;48:1629-1632. 4. Eggers JW, Chesney TM. Squamous cell carcinoma of the breast: a clinicopathologic analysis of eight cases and review of the literature. Hum Pathol. 1984;15:526-531. 5. Hennessy BT, Krishnamurthy S, Giordano S, et al. Squamous cell carcinoma of the breast. J Clin Oncol. 2005;23:7827-7835. 6. Menes T, Schachter J, Morgenstern S, Fenig E, Lurie H, Gutman H. Primary squamous cell carcinoma (SqCC) of the breast. Am J Clin Oncol. 2003;26: 571-573.
PROGNOSTIC FACTORS Common germline polymorphisms in COMT, CYP19A1, ESR1, PGR, SULT1E1 and STS and survival after a diagnosis of breast cancer Udler MS, Azzato EM, Healey CS, et al (Univ of Cambridge, UK; et al) Int J Cancer 125:2687-2696, 2009
Although preliminary evidence suggests that germline variation in genes involved in steroid hormone metabolism may alter breast cancer prognosis, this has not been systematically evaluated. We examined associations between germline polymorphisms in 6 genes involved in the steroid hormone metabolism and signaling
pathway (COMT, CYP19A1, ESR1, PGR, SULT1E1, STS) and survival among women with breast cancer participating in SEARCH, a population-based case–control study. Blood samples from up to 4,470 women were genotyped for 4 possible functional SNPs in CYP19A1 and 106 SNPs tagging the common variation in the remainder of the genes. The genotypes of each polymorphism were tested for association with survival after breast cancer diagnosis using Cox regression analysis. Significant evidence of an association was observed for a COMT polymorphism (rs4818 p ¼ 0.016) under the codominant model. This SNP appeared to fit a dominant model better (HR ¼ 0.80 95% CI: 0.69–0.95,
p ¼ 0.009); however, the result was only marginally significant after permutation analysis adjustment for multiple hypothesis tests (p ¼ 0.047). To further evaluate this finding, somatic expression microarray data from 8 publicly available datasets were used to test the association between survival and tumor COMT gene expression; no statistically significant associations were observed. A correlated SNP in COMT, rs4860, has recently been associated with breast cancer prognosis in Chinese women in a dominant model. These results suggest that COMT rs4818, or a variant it tags, is associated with breast cancer prognosis. Further study of COMT and its putative association with breast cancer prognosis is warranted.
Breast Diseases: A Year BookÒ Quarterly Vol 21 No 2 2010
147
In this study, Udler and colleagues investigated the associations between singlenucleotide polymorphisms (SNPs) in 6 genes involved in estrogen and progesterone metabolism and survival in 4470 women with breast cancer from an ongoing population-based case-control study in England. They used a comprehensive SNP tagging approach to genotype 106 tagging SNPs for COMT, ESR1, PGR, SULT1E1, and STS and 4 functional SNPs in CYP19A1 based on previously published studies on this gene, including a tagging SNP analysis. The results showed that COMT polymorphism rs4818 was significantly associated with survival of breast cancer patients. The variant allele G had a protective effect. Udler and colleagues did not perform a combined variant alleles or
a haplotype analysis in a single gene based on all genotyped tagging SNPs, which may provide more evidence that genetic variations in the lowpenetrance susceptibility genes have a cumulative effect on clinical outcomes.1 This effect may also be modified by ethnicity.2,3 This is a large individual study; however, it still does not have enough statistical power to perform a stratification analysis, for example, by age, treatment regimens, stage, etc. Definitely, the key finding of this study is that genes involved in steroid hormone metabolism and signaling play a role in breast cancer prognosis. Overall, this study will dramatically contribute to the future meta-analysis of these genes.
Ratio Between Positive Lymph Nodes and Total Excised Axillary Lymph Nodes as an Independent Prognostic Factor for Overall Survival in Patients with Nonmetastatic Lymph Node-Positive Breast Cancer
the total number of excised nodes has received less emphasis. Thus, several studies have focused on the utility of the axillary lymph node ratio (ALNR) as an independent prognostic indicator of OS. However, most studies suffered from shortcomings, such as including patients who received neoadjuvant therapy or failing to consider the use of adjuvant therapy and tumor receptor status in their analysis. Methods.—We conducted a singlecenter retrospective review of 669 patients with nonmetastatic lymph node-positive BC. Data collected included patient demographics; breast cancer risk factors; tumor size, histopathological, receptor, and lymph node status; and treatment modalities used. Patients were subdivided into four groups according to ALNR value (<.25, .25–.49, .50–.74, .75–1.00).
Hatoum HA, Jamali FR, El-Saghir NS, et al (American Univ of Beirut Med Ctr, Lebanon; et al) Ann Surg Oncol 16:3388-3395, 2009
Background.—The status of the axillary lymph nodes in nonmetastatic lymph node-positive breast cancer (BC) patients remains the single most important determinant of overall survival (OS). Although the absolute number of nodes involved with cancer is important for prognosis, the role of
148
References 1. Peterson NB, Trentham-Dietz A, Garcia-Closas M, et al. Association of COMT haplotypes and breast cancer risk in Caucasian women. Anticancer Res. 2010;30:217-220. 2. Ding H, Fu Y, Chen W, Wang Z. COMT Val158Met polymorphism and breast cancer risk: evidence from 26 case-control studies [published online ahead of print February 4, 2010]. Breast Cancer Res Treat. doi:10.1007/s10549-010-0759-5. 3. Long JR, Cai Q, Shu XO, Cai H, Gao YT, Zheng W. Genetic polymorphisms in estrogenmetabolizing genes and breast cancer survival. Pharmacogenet Genomics. 2007;17:331-338.
L.-E. Wang, MD
Breast Diseases: A Year BookÒ Quarterly Vol 21 No 2 2010
Study parameters were compared at the univariate and multivariate levels for their effect on OS. Results.—On univariate analysis, both the absolute number of positive lymph nodes and the ALNR were significant predictors of OS. On multivariate analysis, only the ALNR remained an independent predictor of OS, with a 2.5-fold increased risk of dying at an ALNR of $.25. Conclusions.—Our study demonstrates that ALNR is a stronger factor in predicting OS than the absolute number of positive axillary lymph nodes. While the incidence of BC has grown rapidly in developing countries and BC remains the most common cancer in women worldwide,1 information on BC management and
patients with triple-negative tumors who presented at a similar stage. Although the data so far on the outcomes of patients with SCC of the breast appear inconsistent, some data suggest that conventional chemotherapy is less effective for patients with SCC.5,6 If this claim proves to be true, accurate classification of these tumors will be important so that patients with invasive SCC may be treated with cisplatin-based chemotherapy or whatever proves to be most effective. M. Z. Gilcrease, MD, PhD
References 1. Wargotz ES, Norris HJ. Metaplastic carcinomas of the breast. IV.
Squamous cell carcinoma of ductal origin. Cancer. 1990;65:272-276. 2. Cardoso F, Leal C, Meira A, et al. Squamous cell carcinoma of the breast. Breast. 2000;9:315-319. 3. Toikkanen S. Primary squamous cell carcinoma of the breast. Cancer. 1981;48:1629-1632. 4. Eggers JW, Chesney TM. Squamous cell carcinoma of the breast: a clinicopathologic analysis of eight cases and review of the literature. Hum Pathol. 1984;15:526-531. 5. Hennessy BT, Krishnamurthy S, Giordano S, et al. Squamous cell carcinoma of the breast. J Clin Oncol. 2005;23:7827-7835. 6. Menes T, Schachter J, Morgenstern S, Fenig E, Lurie H, Gutman H. Primary squamous cell carcinoma (SqCC) of the breast. Am J Clin Oncol. 2003;26: 571-573.
PROGNOSTIC FACTORS Common germline polymorphisms in COMT, CYP19A1, ESR1, PGR, SULT1E1 and STS and survival after a diagnosis of breast cancer Udler MS, Azzato EM, Healey CS, et al (Univ of Cambridge, UK; et al) Int J Cancer 125:2687-2696, 2009
Although preliminary evidence suggests that germline variation in genes involved in steroid hormone metabolism may alter breast cancer prognosis, this has not been systematically evaluated. We examined associations between germline polymorphisms in 6 genes involved in the steroid hormone metabolism and signaling
pathway (COMT, CYP19A1, ESR1, PGR, SULT1E1, STS) and survival among women with breast cancer participating in SEARCH, a population-based case–control study. Blood samples from up to 4,470 women were genotyped for 4 possible functional SNPs in CYP19A1 and 106 SNPs tagging the common variation in the remainder of the genes. The genotypes of each polymorphism were tested for association with survival after breast cancer diagnosis using Cox regression analysis. Significant evidence of an association was observed for a COMT polymorphism (rs4818 p ¼ 0.016) under the codominant model. This SNP appeared to fit a dominant model better (HR ¼ 0.80 95% CI: 0.69–0.95,
p ¼ 0.009); however, the result was only marginally significant after permutation analysis adjustment for multiple hypothesis tests (p ¼ 0.047). To further evaluate this finding, somatic expression microarray data from 8 publicly available datasets were used to test the association between survival and tumor COMT gene expression; no statistically significant associations were observed. A correlated SNP in COMT, rs4860, has recently been associated with breast cancer prognosis in Chinese women in a dominant model. These results suggest that COMT rs4818, or a variant it tags, is associated with breast cancer prognosis. Further study of COMT and its putative association with breast cancer prognosis is warranted.
Breast Diseases: A Year BookÒ Quarterly Vol 21 No 2 2010
147
In this study, Udler and colleagues investigated the associations between singlenucleotide polymorphisms (SNPs) in 6 genes involved in estrogen and progesterone metabolism and survival in 4470 women with breast cancer from an ongoing population-based case-control study in England. They used a comprehensive SNP tagging approach to genotype 106 tagging SNPs for COMT, ESR1, PGR, SULT1E1, and STS and 4 functional SNPs in CYP19A1 based on previously published studies on this gene, including a tagging SNP analysis. The results showed that COMT polymorphism rs4818 was significantly associated with survival of breast cancer patients. The variant allele G had a protective effect. Udler and colleagues did not perform a combined variant alleles or
a haplotype analysis in a single gene based on all genotyped tagging SNPs, which may provide more evidence that genetic variations in the lowpenetrance susceptibility genes have a cumulative effect on clinical outcomes.1 This effect may also be modified by ethnicity.2,3 This is a large individual study; however, it still does not have enough statistical power to perform a stratification analysis, for example, by age, treatment regimens, stage, etc. Definitely, the key finding of this study is that genes involved in steroid hormone metabolism and signaling play a role in breast cancer prognosis. Overall, this study will dramatically contribute to the future meta-analysis of these genes.
Ratio Between Positive Lymph Nodes and Total Excised Axillary Lymph Nodes as an Independent Prognostic Factor for Overall Survival in Patients with Nonmetastatic Lymph Node-Positive Breast Cancer
the total number of excised nodes has received less emphasis. Thus, several studies have focused on the utility of the axillary lymph node ratio (ALNR) as an independent prognostic indicator of OS. However, most studies suffered from shortcomings, such as including patients who received neoadjuvant therapy or failing to consider the use of adjuvant therapy and tumor receptor status in their analysis. Methods.—We conducted a singlecenter retrospective review of 669 patients with nonmetastatic lymph node-positive BC. Data collected included patient demographics; breast cancer risk factors; tumor size, histopathological, receptor, and lymph node status; and treatment modalities used. Patients were subdivided into four groups according to ALNR value (<.25, .25–.49, .50–.74, .75–1.00).
Hatoum HA, Jamali FR, El-Saghir NS, et al (American Univ of Beirut Med Ctr, Lebanon; et al) Ann Surg Oncol 16:3388-3395, 2009
Background.—The status of the axillary lymph nodes in nonmetastatic lymph node-positive breast cancer (BC) patients remains the single most important determinant of overall survival (OS). Although the absolute number of nodes involved with cancer is important for prognosis, the role of
148
References 1. Peterson NB, Trentham-Dietz A, Garcia-Closas M, et al. Association of COMT haplotypes and breast cancer risk in Caucasian women. Anticancer Res. 2010;30:217-220. 2. Ding H, Fu Y, Chen W, Wang Z. COMT Val158Met polymorphism and breast cancer risk: evidence from 26 case-control studies [published online ahead of print February 4, 2010]. Breast Cancer Res Treat. doi:10.1007/s10549-010-0759-5. 3. Long JR, Cai Q, Shu XO, Cai H, Gao YT, Zheng W. Genetic polymorphisms in estrogenmetabolizing genes and breast cancer survival. Pharmacogenet Genomics. 2007;17:331-338.
L.-E. Wang, MD
Breast Diseases: A Year BookÒ Quarterly Vol 21 No 2 2010
Study parameters were compared at the univariate and multivariate levels for their effect on OS. Results.—On univariate analysis, both the absolute number of positive lymph nodes and the ALNR were significant predictors of OS. On multivariate analysis, only the ALNR remained an independent predictor of OS, with a 2.5-fold increased risk of dying at an ALNR of $.25. Conclusions.—Our study demonstrates that ALNR is a stronger factor in predicting OS than the absolute number of positive axillary lymph nodes. While the incidence of BC has grown rapidly in developing countries and BC remains the most common cancer in women worldwide,1 information on BC management and