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Biological Markers in DCIS and Risk of Breast Recurrence: A Systematic Review

By Sara A. Lari and Henry M. Kuerer

Abstract

Understanding of the biology and clinical behavior of ductal carcinoma in situ (DCIS) is currently inadequate. The aim of this comprehensive review was to identify important molecular biological markers associated with DCIS and candidate markers associated with increased risk of ipsilateral recurrence after diagnosis of DCIS. A comprehensive systematic review was performed to identify studies published in the past 10 years that investigated biological markers in DCIS. To be included in this review, studies that investigated the rate of biological expression of markers had to report on at least 30 patients; studies that analyzed the recurrence risk associated with biomarker expression had to report on at least 50 patients. There were 6,252 patients altogether in our review. Biological markers evaluated included steroid receptors, proliferation markers, cell cycle regulation and apoptotic markers, angiogenesis-related proteins, epidermal growth factor receptor family receptors, extracellular matrix-related proteins, and COX-2. Although the studies in this review provide valuable preliminary information regarding the expression and prognostic significance of biomarkers in DCIS, common limitations of published studies (case-series, cohort, and case-control studies) were that they were limited to small patient cohorts in which the extent of surgery and use of radiotherapy or endocrine therapy varied from patient to patient, and variable methods of determining biomarker expression. These constraints made it difficult to interpret the absolute effect of expression of various biomarkers on risk of local recurrence. No prospective validation studies were identified. As the study of biomarkers are in their relative infancy in DCIS compared with invasive breast cancer, key significant prognostic and predictive markers associated with invasive breast cancer have not been adequately studied in DCIS. There is a critical need for prospective analyses of novel and other known breast cancer molecular markers in large cohorts of patient with DCIS to differentiate indolent from aggressive DCIS and better tailor the need and extent of current therapies

Topics: Review
Publisher: Ivyspring International Publisher
OAI identifier: oai:pubmedcentral.nih.gov:3088863
Provided by: PubMed Central

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  2. [43] 2007 87 Lumpectomy—39; Mastectomy—48 (21 patients received XRT) 49.8 No No ER was not associated with disease recurrence in either univariate or multivariate analysis.
  3. [43] 2007 87 Lumpectomy—39; Mastectomy—48 (21 patients received XRT) 49.8 No No PR was not associated with disease recurrence in either univariate or multivariate analysis.
  4. [70] 2010 271 33.7 Results of immunohistochemical assays were evaluated using a proportion score and an intensity score. HER2 status was defined as positive for scores of 9-12.
  5. [70] 2010 271 52.7 Results of immunohistochemical assays were evaluated using a proportion score and an intensity score. Tumors that scored over 1 were scored as positive.
  6. [70] 2010 271 67.3 Results of immunohistochemical assays were evaluated using a proportion score and an intensity score. Tumors that scored over 1 were scored as positive.
  7. (2002). 100 40 HER2 gene amplification was analyzed by FISH. A ratio of greater than 2.0 was considered indicative of HER2 gene amplification.
  8. (2001). 103 27 Strong nuclear staining in more than 10% of tumor cells.
  9. (2002). 120 71.7 Moderate or strong nuclear staining in tumor cells.
  10. (2006). 129 50.4 The percentage of positively stained nuclei (at least 1.000 cells were counted for each case) was determined using a grid graticule and cell counter at X400 magnification. 50.4% of cases exhibited staining in at least 10% of tumor cells.
  11. (2006). 129 64.8 On a 3-point scale, a score of at least 2.
  12. (2005). 129 66.4 Nuclear staining in at least 5% of tumor cells.
  13. (2005). 129 Lumpectomy—89; Mastectomy—40 (8 patients received XRT) 5 years Unknown No The investigators concluded that the biological marker, HER2, is not an independent predictor of recurrence.
  14. (2005). 129 Lumpectomy—89; Mastectomy—40 (8 patients received XRT) Not provided No No ER was not associated with disease recurrence in multivariate analysis.
  15. (2006). 129 Patients underwent definitive surgery for DCIS, but no details were provided Not provided No No ER was not associated with disease recurrence in either univariate or multivariate analysis.
  16. (2005). 148 28 Strong membrane staining in more than 10% of tumor cells (equivalent to a score of 3+ with the DakoCytomation HercepTest).
  17. (2005). 148 77 Nuclear staining in at least 10% of tumor cells.
  18. (2004). 151 All patients were treated with lumpectomy alone 65 No No HER2 was not associated with disease recurrence in either univariate or multivariate analysis.
  19. (2004). 151 All patients were treated with lumpectomy alone 65 No No Ki-67 was not associated with disease recurrence in either univariate or multivariate analysis.
  20. (2004). 151 All patients were treated with lumpectomy alone 65 No No p21 was not associated with disease recurrence in either univariate or multivariate analysis.
  21. (2004). 151 All patients were treated with lumpectomy alone 65 No No PR was not associated with disease recurrence in either univariate or multivariate analysis.
  22. (2004). 151 All patients were treated with lumpectomy without 65 No No ER was not associated with disease recurrence in either univariate or multivariate analysis.
  23. (2006). 161 63.6 Nuclear staining in at least 5% of tumor cells.
  24. (2006). 161 Lumpectomy—103; Mastectomy—47; Information unavailable for 11 patients. No information available on XRT Not provided Unknown No ER was not associated with disease recurrence in multivariate analysis.
  25. (2006). 161 Lumpectomy—103; Mastectomy—47; Information unavailable for 11 patients. No information available on XRT Not provided Unknown No HER2 was not associated with disease recurrence in multivariate analysis.
  26. (2006). 161 Lumpectomy—103; Mastectomy—47; Information unavailable for 11 patients. No information available on XRT Not provided Unknown Yes In the multivariate analysis, Ki-67 was an independent predictor of recurrence (OR: 1.03, 95% CI:
  27. (2008). 163 26 Nuclear staining in more than 25% of tumor cells.
  28. (2008). 163 37 Strong nuclear staining in more than 10% of tumor cells.
  29. (2008). 163 39 Strong membranous staining in more than 10% of tumor cells.
  30. (2008). 163 64 Weak cytoplasmic staining in more than 10% of tumor cells.
  31. (2003). 177 Lumpectomy without XRT—64; Lumpectomy with XRT—113 63 No No The investigators concluded that the biological marker, cyclin E, is not an independent risk factor for recurrence.
  32. (2003). 177 Lumpectomy without XRT—64; Lumpectomy with XRT—113 63 No No The investigators concluded that the biological marker, p27, is not an independent risk factor for recurrence.
  33. (2001). 187 26 Nuclear staining in more than 10% of tumor cells.
  34. (2001). 187 43 Nuclear staining in more than 10% of tumor cells.
  35. (2004). 187 49.2 The percentage of positively stained nuclei (at least 1,000 cells were counted for each case) was determined using a grid graticule and cell counter at X400 magnification. 50.8% of cases exhibited staining in at least 10% of tumor cells.
  36. (2001). 187 54 Membrane staining in more than 10% of tumor cells.
  37. (2004). 187 54.5 On a 3-point scale, a score of at least 2.
  38. (2004). 187 59.7 Nuclear staining in at least 5% of tumor cells.
  39. (2001). 187 60 Nuclear staining in more than 10% of tumor cells.
  40. (2004). 187 67 On a 3-point scale, a score of at least 2. Expression was based on the extent and intensity of epithelial cell staining.
  41. (2004). 190 41 Nuclear staining in at least 10% of tumor cells.
  42. (2004). 190 41.3 Nuclear staining in more than 30% of tumor cells.
  43. (2004). 190 57.2 Nuclear staining in at least 10% of tumor cells.
  44. (2004). 190 57.9 Nuclear staining in at least 10% of tumor cells.
  45. (2004). 190 Lumpectomy without XRT—33; Lumpectomy with XRT—99; Mastectomy and XRT—58 61.6 Yes No The investigators did not find p53 to be an independent predictor of disease recurrence.
  46. (2004). 190 Lumpectomy without XRT—33; Lumpectomy with XRT—99; Mastectomy with XRT—58 61.6 Yes No PR-negative DCIS was associated with a higher rate of recurrence than PR-positive DCIS (9.1% vs. 3.6%), but this difference did not reach statistical significance.
  47. (2004). 190 Lumpectomy without XRT—33; Lumpectomy with XRT—99; Mastectomy with XRT—58 61.6 Yes No The investigators did not find HER2 to be an independent predictor of disease recurrence.
  48. (2004). 190 Lumpectomy without XRT—33; Lumpectomy with XRT—99; Mastectomy with XRT—58 61.6 Yes Yes The recurrence rate was higher for ER-negative DCIS than for ER-positive
  49. (2001). 194 19 19% of cases exhibited staining in at least 10% of the tumor cells.
  50. (2001). 194 43 Nuclear staining in at least 10% of tumor cells.
  51. (2001). 194 48 Nuclear staining in at least 10% of tumor cells.
  52. (2001). 194 55 Moderate or strong membrane staining in at least 30% of tumor cells or complete membrane staining in more than 60% of tumor cells regardless of the intensity of the staining.
  53. (2001). 194 68 Nuclear staining in at least 10% of tumor cells.
  54. (2001). 200 0.99–2.59 Ki-67 labeling index was determined by computerized image analysis.
  55. (2005). 2011 141 27.7 On a 3-point scale, a score of 3.
  56. (2001). 2011 141 All patients underwent lumpectomy alone 125 No No In the univariate and multivariate analyses, ER was not a predictor of recurrence.
  57. (2002). 219 28 On a 4-point scale, any score other than 0.
  58. (2002). 219 62 Nuclear staining in more than 10% of tumor cells.
  59. (2007). 245 31 Nuclear or nuclear and cytoplasmic staining in more than 10% of tumor cells.
  60. (2008). 272 27.2 Moderate or strong membrane staining (2+ of higher on a 3-point scale) in at least 10% of tumor cells.
  61. (2008). 272 59.9 Nuclear staining in more than 10% of tumor cells.
  62. (2008). 272 74 Nuclear staining in more than 10% of tumor cells.
  63. (2003). 45 25 Moderate or strong nuclear staining in more than 40% of tumor cells.
  64. (2003). 45 42.2 Nuclear staining in more than 10% of tumor cells.
  65. (2003). 45 45.5 45.5% of cases exhibited staining in more than 10% of the tumor cells.
  66. (2003). 45 46.7 On a 3-point scale, a score of greater than 2. Scoring was based on the positive staining of the cell membrane.
  67. (2003). 45 48.8 Nuclear staining in more than 10% of tumor cells.
  68. (2003). 45 50 Nuclear staining in at least 10% of tumor cells.
  69. (2003). 45 55 Nuclear staining in at least 10% of tumor cells.
  70. (2005). 49 26.5 Nuclear staining in more than 10% of tumor cells.
  71. (2001). 49 30.6 Nuclear staining in more than 5% of tumor cells.
  72. (2005). 49 65.3 Nuclear staining in more than 10% of tumor cells.
  73. (2001). 49 65.3 Nuclear staining in more than 5% of tumor cells.
  74. (2005). 49 66.7 Complete membrane staining in more than 10% of tumor cells.
  75. (2005). 49 75.5 Nuclear staining in more than 10% of tumor cells.
  76. (2005). 49 87.8 On a 12-point scale for immunoreactivity, an immunohistochemistry score of 9-12 was considered strong, 5-8 was considered moderate, 1-4 was considered weak, and 0 was considered negative.
  77. (2005). 49 93.8 Staining (defined as appropriate brown staining in the tumor cell cytoplasm) in more than 10% of tumor cells.
  78. (2003). 50 37 The percentage of marked nuclei was determined for 300-400 nuclei in the most positive foci. The mean for cyclin D1 was reported to be 37%.
  79. (2003). 50 76 The percentage of marked nuclei was determined for 300-400 nuclei in the most positive foci.
  80. (2003). 50 88 The percentage of marked nuclei was determined for 300-400 nuclei in the most positive foci.
  81. (2003). 50 All patients underwent lumpectomy followed by XRT Unknown No No According to univariate and multivariate analyses, p21 was not observed to be an independent predictor of recurrence.
  82. (2003). 50 All patients underwent lumpectomy followed by XRT Unknown No No Cyclin D1 was not a predictor of recurrence in either univariate or multivariate analysis.
  83. (2003). 50 All patients underwent lumpectomy followed by XRT Unknown No No p53 was not an independent predictor of recurrence in either univariate or multivariate analysis.
  84. (2008). 52 17.3 On a 3-point scale, a score of 3 (strong staining).
  85. (2008). 52 17.9 The percentage of cancer cells with positively stained nuclei was determined.
  86. (2008). 52 69.2 Nuclear staining in more than 10% of tumor cells.
  87. (2008). 52 70.6 Nuclear staining in more than 10% of tumor cells.
  88. (2008). 52 71.2 Nuclear staining in more than 10% of tumor cells.
  89. (2008). 52 73.1 Nuclear staining in more than 10% of tumor cells.
  90. (2008). 52 76.5 Nuclear staining in more than 10% of tumor cells.
  91. (2009). 58 55 Nuclear staining in at least 1% of tumor cells.
  92. (2009). 58 60 Nuclear staining in at least 1% of tumor cells.
  93. (2009). 58 9 On a 3-point scale, a score of 3 or positive for HER2 gene amplification when HER2/CEP17 greater than 2.2. Altintas [15] 2009 159 40 Score of at least 2.
  94. (2007). 60 55 Nuclear staining in more than 50% of tumor cells.
  95. (2007). 60 58 Nuclear staining in more than 5% of tumor cells.
  96. (2007). 60 58.3 Nuclear staining in more than 10% of tumor cells.
  97. (2007). 60 Lumpectomy with or without XRT—56 (51 received XRT); Mastectomy without XRT—4 98 No No In the univariate analysis conducted with clinicopathological parameters, cyclin A was not associated with disease recurrence.
  98. (2007). 60 Lumpectomy with or without XRT—56 (51 received XRT); Mastectomy without XRT—4 98 No No In the univariate analysis conducted with clinicopathological parameters, cyclin D1 was not associated with disease recurrence.
  99. (2007). 60 Lumpectomy with or without XRT—56 (51 received XRT); Mastectomy without XRT—4 98 No No In the univariate analysis conducted with clinicopathological parameters, ER was not associated with disease recurrence.
  100. (2007). 60 Lumpectomy with or without XRT—56 (51 received XRT); Mastectomy without XRT—4 98 No No In the univariate analysis conducted with clinicopathological parameters, PR was not associated with disease recurrence.
  101. (2006). 66 22 Any cytoplasmic and/or membranous staining of tumor cells.
  102. (2006). 66 40 Nuclear staining in at least 10% of tumor cells. All cases were high-nuclear-grade DCIS.
  103. (2006). 66 56 Nuclear staining in at least 10% of tumor cells. All cases were high-nuclear-grade DCIS.
  104. (2008). 69 29.6 Nuclear staining in at least 10% of tumor cells.
  105. (2010). 69 35 On a 3-point scale, a 3+ score was considered to be positive by IHC or positive for HER2 gene amplification when HER2/CEP17 ratio greater than 2.0 by FISH.
  106. (2010). 69 44.29 ± 3.42 No cut-off value was mentioned in the paper. The mean (± standard deviation) percentage of cells with
  107. (2008). 69 45.8 Cytoplasmic granular staining in more than 10% of tumor cells.
  108. (2008). 69 60.4 On a 3-point scale, 3+ staining in more than 10% of tumor cells.
  109. (2008). 69 61.5 Nuclear staining in at least 10% of tumor cells.
  110. (2008). 69 67.9 Nuclear staining in at least 10% of tumor cells.
  111. (2008). 69 75.9 Nuclear staining in more than 10% of tumor cells.
  112. (2008). 69 77.8 Nuclear staining in at least 10% of tumor cells.
  113. (2008). 69 Lumpectomy without XRT—26; Lumpectomy with XRT—43 Mean time to recurrence: 38.5 Yes No The investigators concluded that the biological marker, cyclin D1, is not an independent predictor of recurrence.
  114. (2008). 69 Lumpectomy without XRT—26; Lumpectomy with XRT—43 Mean time to recurrence: 38.5 Yes No The investigators concluded that the biological marker, ER, is not an independent predictor of recurrence.
  115. (2008). 69 Lumpectomy without XRT—26; Lumpectomy with XRT—43 Mean time to recurrence: 38.5 Yes No The investigators concluded that the biological marker, HER2, is not an independent predictor of recurrence.
  116. (2008). 69 Lumpectomy without XRT—26; Lumpectomy with XRT—43 Mean time to recurrence: 38.5 Yes No The investigators concluded that the biological marker, p21, is not an independent predictor of recurrence.
  117. (2008). 69 Lumpectomy without XRT—26; Lumpectomy with XRT—43 Mean time to recurrence: 38.5 Yes No The investigators concluded that the biological marker, p53, is not an independent predictor of recurrence.
  118. (2008). 69 Lumpectomy without XRT—26; Lumpectomy with XRT—43 Mean time to recurrence: 38.5 Yes No The investigators concluded that the biological marker, PR, is not an independent predictor of recurrence.
  119. (2008). 69 Lumpectomy without XRT—26; Lumpectomy with XRT—43 Mean time to recurrence: 38.5 Yes Yes In the multivariate analysis, COX-2 expression was significantly associated with increased risk of recurrence (OR: 7.89; 95%
  120. (2007). 70 37.1 37.1% of cases exhibited staining in more than 10% of the tumor cells.
  121. (2009). 84 28.6 Membranous staining of 3+ in any tumor cell or membranous staining of 2+ in more than 10% of tumor cells with fluorescence in situ hybridization evidence of HER2 gene amplification.
  122. (2010). 84 44 Moderate or strong membrane staining (2+ or higher on a 3-point scale) in more than 10% of tumor cells.
  123. (2007). 87 Lumpectomy—39; Mastectomy—48 (21 patients received XRT) 49.8 No Yes p53 was an independent predictor of disease recurrence
  124. (2008). 90 23 (high-grade DCIS); 81 (non-high-gr ade DCIS) Nuclear staining in at least 10% of tumor cells.
  125. (2008). 90 30 (high-grade DCIS); 96 (non-high-gr ade DCIS) Nuclear staining in at least 10% of tumor cells.
  126. (2010). 90 32 On a 3-point scale, a score of greater than 2. All cases were ER-positive DCIS.
  127. (2010). 90 58 A minimum of 500 cells was investigated across randomly selected areas of DCIS at a magnification of x 400 using a grid graticule and cell counter for each of the two sections. All cases were ER-positive DCIS.
  128. (2010). 90 72 Nuclear staining in more than 5% of tumor cells. All cases were ER-positive DCIS.
  129. (2008). 90 89 (non-high-gr ade DCIS); 93 (high-grade DCIS) Nuclear staining in at least 10% of tumor cells.
  130. (2008). 90 9 (non-high-grade DCIS); 55 (high-grade DCIS) Membrane staining of 3+.
  131. (2002). 91 34.1 On an 8-point scale, an IHC score of at least 5. In addition, a HER2/CEP17 ratio of at least 2 was considered positive for HER2/neu gene amplification.
  132. (2003). 92 25 A mean value was used as a cut-off to divide expression of cyclin E.
  133. (2003). 92 68.5 Nuclear and cytoplasmic staining intensity were evaluated using a 3-point semiquantitative scoring scale (0=none, 1=weak,
  134. (2006). 94 56 No cut-off value was mentioned in the paper.
  135. (2006). 94 74 No cut-off value was mentioned in the paper Wilson [37] 2006 129 65.1 Nuclear staining in at least 5% of tumor cells.
  136. (2003). 95 (53 cases and 42 controls) Lumpectomy without XRT—85; Lumpectomy with XRT—10 101 Yes No The investigators did not find p53 to be associated with disease recurrence.
  137. (2003). 95 32 Strong staining (equivalent to a score of 3+ with the DakoCytomation HercepTest).
  138. (2003). 95 34 On a 6-point scale, a score of 4-6 (moderate or strong stain-Journal of Cancer
  139. (2003). 95 48 Nuclear staining in at least 10% of tumor cells.
  140. (2003). 95 49 Nuclear staining in at least 10% of tumor cells.
  141. (2003). 95 50 On a 6-point scale, a score of 4-6 (moderate or strong staining).
  142. (2003). 95 60 On a 6-point scale, a score of 4-6 (moderate or strong staining).
  143. (2003). 95 Lumpectomy without XRT—85; Lumpectomy with XRT—10 101 Yes Yes Patients with local-regional recurrence were more likely than those without recurrence to have Bcl-2-negative disease (66% vs. 26%; P=0.003; OR:
  144. (2003). 95 Lumpectomy without XRT—85; Lumpectomy with XRT—10 101 Yes Yes Patients with local-regional recurrence were more likely than those without recurrence to have HER2-positive disease (41% vs. 12%; OR:
  145. (2010). 97 18.8 On a 3-point scale, a score of 2 (defined as strong staining of at least 30% of stromal cells).
  146. (2010). 97 33.3 Status obtained from pathology reports.
  147. (2010). 97 83.3 Status obtained from pathology reports.
  148. (2010). 97 96.6 Status obtained from the pathology reports.
  149. (2010). 97 All patients underwent lumpectomy (no information was 110.8 No No The investigators did not find PR to be an independent predictor of recurrence.
  150. (2010). 97 All patients underwent lumpectomy; no information was available about XRT 110.8 No No The investigators did not find ER to be an independent predictor of recurrence.
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  154. Altintas [15] 2009 159 37 Score of at least 2.
  155. (2005). Altintas [15] 2009 159 62 Score of at least 2. HER4
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  157. Altintas [15] 2009 159 72 Nuclear staining in at least10% of tumor cells.
  158. (2010). Altintas [15] 2009 159 Lumpectomy—112; mastectomy—45 Information unavailable for 2 patients. No information available on 54 No No The investigators concluded that the biological marker, HER2, is not an independent predictor of recurrence.
  159. Altintas [15] 2009 159 Lumpectomy—112; Mastectomy—45 Information unavailable for 2 patients. No information available on XRT 54 No No The investigators concluded that the biological marker, ER, is not an independent predictor of recurrence.
  160. Altintas [15] 2009 159 Lumpectomy—112; mastectomy—45 Information unavailable for 2 patients. No information available on XRT 54 No No The investigators concluded that the biological marker, Ki67, is not an independent predictor of recurrence.
  161. Altintas [15] 2009 159 Lumpectomy—112; mastectomy—45 Information unavailable for 2 patients. No information available on XRT 54 No No The investigators concluded that the biological marker, PR, is not an independent predictor of recurrence.
  162. Altintas [15] 2009 159 Lumpectomy—112; mastectomy—45 Information unavailable for 2 patients. No information on XRT 54 No No The investigators concluded that the biological marker, HER3, is not an independent predictor of recurrence.
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  165. Cytoplasm staining in more than 10% of tumor cells.
  166. Epidermal Growth Factor Receptor Family HER1 Barnes [35] 2005 129 Lumpectomy—89; Mastectomy—40 (8 patients received XRT) 5 years Unknown No The investigators concluded that the biological marker, HER1, is not an independent predictor of recurrence.
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  174. (1998). Kerlikowske [24] 2010 329 11.3 Nuclear staining in at least 10% of tumor cells.
  175. Kerlikowske [24] 2010 329 18.2 Moderate or strong membrane staining (2+ or higher)in at least 10% of tumor cells.
  176. (2001). Kerlikowske [24] 2010 329 39.3 On a 3-point scale, a score of at least 2. p21
  177. Kerlikowske [24] 2010 329 44.4 On a 3-point scale, a score of at least 2.
  178. Kerlikowske [24] 2010 329 74.5 Nuclear staining in at least 10% of tumor cells.
  179. Kerlikowske [24] 2010 329 77.9 Nuclear staining in at least 10% of tumor cells.
  180. (2007). of cases exhibited staining in more than 10% of the tumor cells.
  181. On a 4-point scale, any score other than 0.
  182. (2001). On an 8-point scale, a score of at least 5.
  183. (2009). Rational individualised selection of adjuvant therapy for ductal carcinoma in situ.
  184. (2010). Stromal CD10 and SPARC expression in ductal carcinoma in situ (DCIS) patients predicts disease recurrence. Cancer Biol Ther
  185. Torre [64] 2010 52 53 On a 3-point scale, a score of at least 2.