Table 9.
Biomarker expression and ipsilateral recurrence risk following surgery for DCIS
| Biomarker | First author and reference | Year | No. of patients | Treatment groups | Median follow-up time, months | Endocrine therapy use | Marker expression associated with increased risk of local-regional recurrence | Comments |
|---|---|---|---|---|---|---|---|---|
| Steroid Receptors | ||||||||
| ER | ||||||||
| Ringberg 16 | 2001 | 187 | Lumpectomy with XRT—66; Lumpectomy without XRT—121 | 62 | No | Yes (when combined with other biological markers) | The investigators evaluated a cell biological index (CBI-7) that included ER and PR negativity, overexpression of HER2, low Bcl-2 expression, accumulation of p53, nondiploidy, and high Ki-67 expression. ER negativity combined with all those markers was a strong predictor of recurrence (RR: 1.3; 95% CI: 1.0-1.6; P=0.051). | |
| Provenzano 22 | 2003 | 95 (53 cases and 42 controls) | Lumpectomy without XRT—85; Lumpectomy with XRT—10 | 101 | Yes | Yes | Patients with local-regional recurrence were more likely than patients without recurrence to have ER-negative disease (62% vs. 35%; OR: 0.2; P=0.01). ER negativity was individually associated with recurrence. | |
| Roka 23 | 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 DCIS (12.2% vs. 3.7%; P<0.04). | |
| Cornfield 46 | 2004 | 151 | All patients were treated with lumpectomy without XRT | 65 | No | No | ER was not associated with disease recurrence in either univariate or multivariate analysis. | |
| Barnes 35 | 2005 | 129 | Lumpectomy—89; Mastectomy—40(8 patients received XRT) | Not provided | No | No | ER was not associated with disease recurrence in multivariate analysis. | |
| Kepple 59 | 2006 | 94 | Lumpectomy without XRT—17; Lumpectomy with XRT—20; Mastectomy—57 | 48 months | Yes | Unknown | Difficult to assess effect. Only 37 patients underwent lumpectomy, and there were only 4 recurrences in that group. Some of those 37 patients received radiotherapy and some did not. | |
| Barnes 54 | 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. | |
| Wilson 37 | 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. | |
| de Roos 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. | |
| Millar 31 | 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. | |
| Kulkarni 21 | 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. | |
| 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. | |
| Kerlikowske 24 | 2010 | 329(Controls with no recurrence, 186; cases with invasive recurrence, 72; cases with DCIS recurrence, 71) | All patients were treated with lumpectomy alone | 98 | No | Yes (when combined with other biomarkers) | In the univariate analysis, patients with DCIS recurrence were more likely than those without recurrence to have ER-negative disease (31% vs. 20%). ER negativity was individually associated with DCIS recurrence. In addition, ER negativity combined with either HER2 positivity or Ki-67 positivity was also associated with DCIS recurrence. In the multivariate analysis, the phenotype ER-HER2+Ki-67+ was a strong predictor of subsequent DCIS recurrence (HR: 5.8; 95% CI: 2.4-14). | |
| Zhou 25 | 2010 | 392 | Lumpectomy without XRT—158; Lumpectomy with XRT—140; Mastectomy —94 | 97.5 | No | No | The investigators looked at basal-like tumors (tumors negative for ER, PR, and HER2). In the univariate and multivariate analyses, basal-like DCIS was associated with a higher risk of invasive recurrence than non-basal-like DCIS. However, the difference was not statistically significant. | |
| Witkiewicz 61 | 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. | |
| Holmes 58 | 2011 | 141 | All patients underwent lumpectomy alone | 125 | No | No | In the univariate and multivariate analyses, ER was not a predictor of recurrence. | |
| PR | ||||||||
| Ringberg 16 | 2001 | 187 | Lumpectomy with XRT—66; Lumpectomy without XRT—121 | 62 | No | Yes (when combined with other biological markers) | The investigators evaluated a cell biological index (CBI-7) that included ER and PR negativity, overexpression of HER2, low Bcl-2 expression, accumulation of p53, nondiploidy, and high Ki-67 expression. PR negativity combined with all those markers was a strong predictor of recurrence (RR: 1.3; 95% CI: 1.0-1.6; P=0.051). | |
| Provenzano 22 | 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 PR-negative disease (63% vs. 34%; OR: 0.2; P=0.04). PR negativity was individually associated with recurrence. | |
| Roka 23 | 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. | |
| Cornfield 46 | 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. | |
| Kepple 59 | 2006 | 94 | Lumpectomy without XRT—17; Lumpectomy with XRT—20; Mastectomy—57 | 48 months | Yes | Unknown | Difficult to assess effect. Only 37 patients underwent lumpectomy, and there were only 4 recurrences in that group. Some of those 37 patients received radiotherapy and some did not. | |
| de Roos 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. | |
| Millar 31 | 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. | |
| Kulkarni 21 | 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. | |
| 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. | |
| Zhou 25 | 2010 | 392 | Lumpectomy without XRT—158; Lumpectomy with XRT—140; Mastectomy —94 | 97.5 | No | No | The investigators looked at basal-like tumors (tumors negative for ER, PR, and HER2). In the univariate and multivariate analyses, basal-like DCIS was associated with a higher risk of local recurrence (HR: 1.7) than non-basal-like DCIS (HR: 1.8). However, the difference was not statistically significant. | |
| Kerlikowske 24 | 2010 | 329(Controls with no recurrence, 186; cases with invasive recurrence, 72; cases with DCIS recurrence, 71) | All patients were treated with lumpectomy alone | 98 | No | No | PR was not associated with invasive or DCIS recurrence in either univariate or multivariate analysis. | |
| Witkiewicz 61 | 2010 | 97 | All patients underwent lumpectomy (no information was available about XRT) | 110.8 | No | No | The investigators did not find PR to be an independent predictor of recurrence. | |
| Holmes 58 | 2011 | 141 | All patients underwent lumpectomy alone | 125 | No | No | PR was not associated with disease recurrence in either univariate or multivariate analysis. | |
| AR | ||||||||
| Provenzano 22 | 2003 | 95 | Lumpectomy without XRT—85; Lumpectomy with XRT—10 | 101 | Yes | No | The investigators did not find AR to be associated with disease recurrence. | |
| Proliferation marker Ki-67 | ||||||||
| Ringberg 16 | 2001 | 187 | Lumpectomy with XRT—66; Lumpectomy without XRT—121 | 62 | No | Yes (when combined with other biological markers) | The investigators evaluated a cell biological index (CBI-7) that included ER and PR negativity, overexpression of HER2, low Bcl-2 expression, accumulation of p53, nondiploidy, and high Ki-67 expression. High Ki-67 expression combined with all those markers was a strong predictor of recurrence (RR: 1.3; 95% CI: 1.0-1.6; P=0.051). | |
| Chasle 38 | 2003 | 50 | All patients underwent lumpectomy followed by XRT | Unknown | No | Yes (when combined with cyclin A) | A global proliferation factor (GPF) was calculated that was a sum of Ki-67 and cyclin A. In both univariate and multivariate analyses, GPF was an independent predictor of recurrence. | |
| Cornfield 46 | 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. | |
| Barnes 35 | 2005 | 129 | Lumpectomy—89; Mastectomy—40(8 patients received XRT) | Not provided | No | Yes | Patients with recurrence were more likely than patients without recurrence to have high proliferative activity (15.5% vs. 10.9%; P=0.005). In the multivariate analysis, Ki-67 was an independent predictor of recurrence (OR: 1.03, 95% CI: 1.00-1.06; P=0.038) | |
| Wilson 37 | 2006 | 129 | Patients underwent definitive surgery for DCIS, but no details were provided | Not provided | No | No | In the univariate analysis, patients with recurrence were more likely than patients without recurrence to have high proliferative activity compared to patients without a recurrence (71.4 vs. 42.2%, P=0.006). However, in the multivariate analysis, Ki-67 was not an independent predictor of recurrence. | |
| Barnes 54 | 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: 1.00-1.06; P=0.006). | |
| Gauthier 45 | 2007 | 70 | Patients underwent definitive surgery for DCIS, but no details were provided | Not provided | Unknown | Yes (as an independent factor and combined with p16 expression and COX-2 expression) | High Ki-67 expression was an independent predictor of recurrence (HR: 2.7, 95% CI: 1.2-5.9). In addition, patients with recurrence were more likely than patients without recurrence to have the combination of high Ki-67, high p16, and high COX-2 expression. | |
| Altintas 15 | 2009 | 159 | Lumpectomy—112; mastectomy—45Information 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. | |
| Kerlikowske 24 | 2010 | 329(Controls with no recurrence, 186; cases with invasive recurrence, 72; cases with DCIS recurrence, 71) | All patients were treated with lumpectomy alone | 98 | No | Yes | In the univariate analysis, patients with invasive recurrence were more likely than those without recurrence to exhibit the phenotype p16+COX-2+Ki-67+ or p16+Ki-67+. Ki-67 was individually associated with DCIS recurrence. In addition, patients with DCIS recurrence were more likely to have ER-Ki-67+ or p16+COX-2-Ki-67+ disease than were patients without recurrence. In the multivariate analysis, the phenotype p16+COX-2+Ki-67+ was a strong predictor of invasive recurrence (HR: 2.2; 95% CI: 1.1-4.5). Phenotypes p16+COX-2+Ki-67+ (HR: 3.7; 95% CI: 1.7-7.9) and ER- HER2+Ki-67+ (HR: 5.8, 95% CI: 2.4-14) were strong predictors of DCIS recurrence. | |
| Cell Cycle Regulation and Apoptotic Markers | ||||||||
| cyclin D1 | ||||||||
| Jirström 42 | 2003 | 177 | Lumpectomy without XRT—64; Lumpectomy with XRT—113 | 63 | No | Yes | The investigators reported cyclin D1 expression to be strongly and inversely related with risk of ipsilateral local recurrence. | |
| Chasle 38 | 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. | |
| de Roos 43 | 2007 | 87 | Lumpectomy—39; Mastectomy—48(21 patients received XRT) | 49.8 | No | No | Cyclin D1 was not associated with disease recurrence in either univariate or multivariate analysis. | |
| Millar 31 | 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. | |
| Kulkarni 21 | 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. | |
| cyclin A | ||||||||
| Chasle 38 | 2003 | 50 | All patients underwent lumpectomy followed by XRT | Unknown | No | Yes (when combined with Ki-67) | A global proliferation factor (GPF) was calculated that was a sum of Ki-67 and cyclin A. In the univariate and multivariate analyses, GPF was an independent predictor of recurrence. | |
| Millar 31 | 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. | |
| cyclin E | ||||||||
| Jirström 42 | 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. | |
| p16 | ||||||||
| Jirström 42 | 2003 | 177 | Lumpectomy without XRT—64; Lumpectomy with XRT—113 | 63 | No | No | The investigators concluded that the biological marker, p16, is not an independent risk factor for recurrence. | |
| Gauthier 45 | 2007 | 70 | Patients underwent definitive surgery for DCIS, but no details were provided | Not provided | Unknown | Yes (when combined with high COX-2 expression and high Ki-67 expression) | Patients with recurrence were more likely than patients without recurrence to have the combination of high Ki-67, high p16, and high COX-2 expression. | |
| Kerlikowske 24 | 2010 | 329(Controls with no recurrence, 186; cases with invasive recurrence, 72; cases with DCIS recurrence, 71)329 patients | All patients were treated with lumpectomy alone | 98 | No | Yes | In the univariate analysis, patients with invasive recurrence were more likely than those without recurrence to have p16-positive disease (57% vs. 30%). p16 positivity combined with Ki-67 positivity and COX-2 positivity was also associated with invasive recurrence. p16 was individually associated with invasive recurrence. In addition, p16 positivity combined with Ki-67 positivity and COX-2 negativity was associated with DCIS recurrence. In the multivariate analysis, the phenotype p16+COX-2+Ki-67+ was a strong predictor of invasive recurrence (HR: 2.2; 95% CI: 1.1-4.5). Also, the phenotype p16+COX-2-Ki-67+ was a strong predictor of DCIS recurrence (HR: 3.7; 95% CI: 2.4-14). | |
| p21 | ||||||||
| Provenzano 22 | 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 p21-positive disease (54% vs. 15%; OR: 6.0; P=0.01). p21 positivity was individually associated with recurrence. According to the multiple conditional logistic regression analysis, p21 expression was an independent predictor of recurrence (OR range: 4.31-6.54). | |
| Chasle 38 | 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. | |
| Cornfield 46 | 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. | |
| Kulkarni 21 | 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. | |
| p27 | ||||||||
| Millar 31 | 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, p27 was not associated with disease recurrence. | |
| Jirström 42 | 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. | |
| p53 | ||||||||
| Hieken 48 | 2001 | 103 | Lumpectomy without XRT—34; Lumpectomy with XRT—41; Mastectomy—28 | 58 (mean follow-up time) | Yes | Yes | p53 was expressed in 63% of patients with recurrence and 24% of patients without recurrence (P=0.03). The investigators concluded that strong p53 expression is associated with ipsilateral tumor recurrence. | |
| Ringberg 16 | 2001 | 187 | Lumpectomy with XRT—66; Lumpectomy without XRT—121 | 62 | No | Yes (when combined with other biological markers) | The investigators evaluated a cell biological index (CBI-7) that included ER and PR negativity, overexpression of HER2, low Bcl-2 expression, accumulation of p53, nondiploidy, and high Ki-67 expression. High p53 expression combined with all those markers was a strong predictor of recurrence (RR: 1.3; 95% CI: 1.0-1.6; P=0.051). | |
| Provenzano 22 | 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. | |
| Chasle 38 | 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. | |
| Cornfield 46 | 2004 | 151 | All patients were treated with lumpectomy without XRT | 65 | No | No | p53 was not associated with disease recurrence in either univariate or multivariate analysis. | |
| Roka 23 | 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. | |
| Kepple 59 | 2006 | 94 | Lumpectomy without XRT—17; Lumpectomy with XRT—20; Mastectomy—57 | 48 months | Yes | Unknown | Difficult to assess effect. Only 37 patients underwent lumpectomy, and there were only 4 recurrences in that group. Some of those 37 patients received radiotherapy and some did not. | |
| de Roos 43 | 2007 | 87 | Lumpectomy—39; Mastectomy—48(21 patients received XRT) | 49.8 | No | Yes | p53 was an independent predictor of disease recurrence in multivariate (HR: 3.0, 95% CI: 1.1-8.2, P=0.036) and univariate (HR: 3.5, 95% CI: 1.3-9.3, P=0.014) analyses. | |
| Kulkarni 21 | 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. | |
| Kerlikowske 24 | 2010 | 329(Controls with no recurrence, 186; cases with invasive recurrence, 72; cases with DCIS recurrence, 71) | All patients were treated with lumpectomy alone | 98 | No | No | p53 was not associated with invasive or DCIS recurrence either individually or when combined with other phenotypes. | |
| Bcl-2 | ||||||||
| Ringberg 16 | 2001 | 187 | Lumpectomy with XRT—66; Lumpectomy without XRT—121 | 62 | No | Yes (when combined with other biological markers) | The investigators evaluated a cell biological index (CBI-7) that included ER and PR negativity, overexpression of HER2, low Bcl-2 expression, accumulation of p53, nondiploidy, and high Ki-67 expression. Low Bcl-2 expression combined with all those markers was a strong predictor of recurrence (RR: 1.3; 95% CI: 1.0-1.6; P=0.051). | |
| Provenzano 22 | 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: 0.18). | |
| Cornfield 46 | 2004 | 151 | All patients were treated with lumpectomy alone | 65 | No | No | Bcl-2 was not associated with disease recurrence in either univariate or multivariate analysis. | |
| Survivin | ||||||||
| Barnes 54 | 2006 | 161 | Lumpectomy—103; Mastectomy—47; Information unavailable for 11 patients. No information available on XRT | Not provided | Unknown | Yes (not as an independent factor, but when combined with COX-2 expression) | Patients with recurrence were more likely than those without recurrence to have co-expression of COX-2 and cytoplasmic survivin (70% vs. 41%; P=0.013). | |
| c-myc | ||||||||
| Altintas 15 | 2009 | 159 | Lumpectomy—112; Mastectomy—45Information unavailable for 2 patients. No information available on XRT | 54 | No | No | The investigators concluded that the biological marker, c-myc, is not an independent predictor of recurrence. | |
| Angiogenesis-related proteins | ||||||||
| VEGF | ||||||||
| Hieken 48 | 2001 | 103 | Lumpectomy without XRT—34; Lumpectomy with XRT—41; Mastectomy—28 | 58 (mean follow-up time) | Yes | No | The investigators did not find VEGF to be an independent predictor of disease recurrence. | |
| 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. | |
| Altintas 15 | 2009 | 159 | Lumpectomy—112; mastectomy—45Information unavailable for 2 patients. No information on XRT | 54 | No | No | The investigators concluded that the biological marker, HER1, is not an independent predictor of recurrence. | |
| HER2 | ||||||||
| Ringberg 16 | 2001 | 187 | Lumpectomy with XRT—66; Lumpectomy without XRT—121 | 62 | No | Yes (when combined with other biological markers) | The investigators evaluated a cell biological index (CBI-7) that included ER and PR negativity, overexpression of HER2, low Bcl-2 expression, accumulation of p53, nondiploidy, and high Ki-67 expression. HER2 positivity combined with all those markers was a strong predictor of recurrence (RR: 1.3; 95% CI: 1.0-1.6; P=0.051). | |
| Provenzano 22 | 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: 5.0; P=0.008). | |
| Roka 23 | 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. | |
| Cornfield 46 | 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. | |
| Barnes 35 | 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. | |
| Barnes 54 | 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. | |
| Kepple 59 | 2006 | 94 | Lumpectomy without XRT—17; Lumpectomy with XRT—20; Mastectomy—57 | 48 months | Yes | Unknown | Difficult to assess effect. Only 37 patients underwent lumpectomy, and there were only 4 recurrences in that group. Some of those 37 patients received radiotherapy and some did not. | |
| de Roos 43 | 2007 | 87 | Lumpectomy—39; Mastectomy—48(21 patients received XRT) | 49.8 | No | No | HER2 overexpression was associated with recurrence in univariate analysis (HR: 3.1, 95% CI: 1.1-8.7; P=0.032). However, multivariate analysis did not show HER2 overexpression to be an independent predictor of recurrence. | |
| Kulkarni 21 | 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. | |
| Altintas 15 | 2009 | 159 | Lumpectomy—112; mastectomy—45Information unavailable for 2 patients. No information available on XRT | 54 | No | No | The investigators concluded that the biological marker, HER2, is not an independent predictor of recurrence. | |
| Stackievicz 74 | 2010 | 84 | Lumpectomy—80 (43 patients received XRT); Mastectomy—4 | 94.8 | Yes | No | The investigators concluded that the biological marker, HER2, is not an independent risk factor for recurrence. | |
| Kerlikowske 24 | 2010 | 329(Controls with no recurrence, 186; cases with invasive recurrence, 72; cases with DCIS recurrence, 71) | All patients were treated with lumpectomy alone | 98 | No | Yes | In the univariate analysis, patients with DCIS recurrence were more likely than patients without recurrence to have HER2-positive disease (30% vs. 13%). HER2 was individually associated with DCIS recurrence. Also, patients with DCIS recurrence were more likely than patients without recurrence to exhibit the ER-HER2+ phenotype (19% vs. 6.4%). In addition, a multivariate analysis showed that the phenotype ER-HER2+Ki-67+ was a strong predictor of subsequent DCIS recurrence (OR: 5.8; 95% CI: 2.4-14). | |
| Zhou 25 | 2010 | 392 | Lumpectomy without XRT—158; Lumpectomy with XRT—140; Mastectomy —94 | 97.5 | No | No | The investigators looked at basal-like tumors (tumors negative for ER, PR, and HER2). In the univariate and multivariate analyses, basal-like DCIS was associated with a higher risk of local recurrence (HR: 1.7) than non-basal-like DCIS (HR: 1.8). However, the difference was not statistically significant. (Note: The authors do not state in the paper how many patients with basal-like DCIS developed a recurrence—they only report HRs in the tables.) | |
| Witkiewicz 61 | 2010 | 97 | All patients underwent lumpectomy (no information was available about XRT) | 110.8 | No | No | The investigators did not find HER2 to be an independent predictor of recurrence. | |
| Holmes 58 | 2011 | 141 | All patients underwent lumpectomy alone | 125 | No | Yes | Univariate analysis with respect to time to recurrence found HER2 overexpression to be associated with local recurrence (P=0.028). In the multivariate analysis, HER2 overexpression was an independent predictor of disease recurrence (HR: 1.82, 95% CI: 1.03-3.22, P=0.041). | |
| HER3 | ||||||||
| Barnes 35 | 2005 | 129 | Lumpectomy—89; Mastectomy—40(8 patients received XRT) | 5 years | Unknown | No | The investigators concluded that the biological marker, HER3, is not an independent predictor of recurrence. | |
| Altintas 15 | 2009 | 159 | Lumpectomy—112; mastectomy—45Information 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. | |
| HER4 | ||||||||
| Barnes 35 | 2005 | 129 | Lumpectomy—89; Mastectomy—40(8 patients received XRT) | 5 years | Unknown | Yes | The investigators concluded that HER4 expression is an independent predictor of a reduced risk of recurrence (OR: 0.69, 95% CI: 0.48-0.98, P=0.038). | |
| Altintas 15 | 2009 | 159 | Lumpectomy—112; mastectomy—45Information unavailable for 2 patients. No information on XRT | 54 | No | No | The investigators concluded that the biological marker, HER4, is not an independent predictor of recurrence. | |
| Extracellular matrix-related proteins | ||||||||
| CD10 | ||||||||
| Toussaint 60 | 2010 | 154 | Surgical information was reported according to VNPI. 58% of patients with low VNPI were treated with lumpectomy alone; 41% of those with intermediate VNPI received XRT following lumpectomy; 81% of patients with high VNPI underwent mastectomy | 6 years | Yes | Yes | According to the multivariate analysis, CD10 was an independent predictor of recurrence. Patients with low CD10 expression were more likely than those with high CD10 expression to develop recurrence (HR: 2.39, 95% CI: 1.52-3.76, P=0.001). | |
| Witkiewicz 61 | 2010 | 97 | All patients underwent lumpectomy (no information was available about XRT) | 110.8 | No | Yes | In the multivariate analysis, CD10 was an independent predictor of recurrence. Patients with recurrence were more likely than those without recurrence to exhibit strong stromal CD10 expression (OR: 10.2, 95% CI: 2.7, 37.7). | |
| SPARC | ||||||||
| Witkiewicz 61 | 2010 | 97 | All patients underwent lumpectomy (no information was available about XRT) | 110.8 | No | Yes | In the multivariate analysis, SPARC was an independent predictor of recurrence. Patients with recurrence were more likely than those without recurrence to exhibit strong stromal SPARC expression (OR: 3.9, 95% CI: 1.1, 14.3). | |
| COX-2 | ||||||||
| Barnes 54 | 2006 | 161 | Lumpectomy—103; Mastectomy—47; Information unavailable for 11 patients. No information available on XRT | Not provided | Unknown | Yes (as an independent factor and in combination with survivin) | In the multivariate analysis, COX-2 was an independent predictor of recurrence. In addition, patients with recurrence were more likely than those without recurrence to have co-expression of COX-2 and cytoplasmic survivin compared to patients without recurrences co-expressing both proteins (70% vs. 41%; P=0.013). | |
| Gauthier 45 | 2007 | 70 | Patients underwent definitive surgery for DCIS, but no details were provided | Not provided | Unknown | Yes (when combined with high p16 expression and high Ki-67 expression) | COX-2 was not an independent predictor of recurrence. However, patients with recurrence were more likely than those without recurrence to express the combination of high Ki-67, high p16, and high COX-2 expression. | |
| Kulkarni 21 | 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% CI 1.7-36.2). | |
| Kerlikowske 24 | 2010 | 329(Controls with no recurrence, 186; cases with invasive recurrence, 72; cases with DCIS recurrence, 71) | All patients were treated with lumpectomy alone | 98 | No | Yes (in combination with other markers) | In the univariate analysis, patients with invasive recurrence were more likely than those without recurrence to exhibit the phenotype p16+COX-2+Ki-67+ (23% vs. 8.5%). Patients with DCIS recurrence were more likely than those without a recurrence to exhibit the phenotype p16+COX-2-Ki-67+ (19% vs. 2.6%). COX-2 was not individually associated with recurrence. In the multivariate analysis the phenotype p16+COX-2+Ki-67+ was a strong predictor of invasive recurrence (HR: 2.2; 95% CI: 1.1-4.5). Another phenotype, p16+COX-2-Ki-67+, was a strong predictor of DCIS recurrence (HR: 3.7; 95% CI: 1.7-7.9). | |
XRT, radiotherapy; VNPI, Van Nuys Prognostic Index.