Risk of Subsequent Breast Cancer in Human EGFR 2-Positive DCIS
Risk of Subsequent Breast Cancer in Human EGFR 2-Positive DCIS
From January 1996 to December 2008, a total of 1667 patients with DCIS grade 1–3 were referred to the interdisciplinary evaluation. Among this population, we identified a total of 560 cases with HER2 overexpression (3+). Table 1 lists clinical, pathological characteristics, biological features of disease and local and systemic treatments of the population analyzed at the time of surgery (n = 1667), categorized according to HER2 status [positive (560) versus negative (1107)]. Nearly 50% (n = 277) of HER2-positive DCIS were ER and PgR negative, almost 90% (n = 501) had Ki-67 ≥14% and 60% (n = 336) were G3. The median follow-up was 7.6 years (interquartile range 5.9–9.5).
We observed 422 first events among the 1667 patients: 141 (8.5%) in situ recurrences, 201 (12.1%) invasive recurrence and 80 other events (64 s primaries and 16 deaths). We included in isBCR, IBCR and BCR events also controlateral tumors (both in situ and infiltrating). BCR includes isBCR and IBCR (Table 2).
A significant difference was observed in isBCR when comparing HER2-positive and -negative groups. The 10-year isBCR proportions were 11.8% (n = 61 of 560) (95% CI 9.0% to 15.4%) in the HER2-positive group and 8.8% (n = 80 of 1107) (95% CI 6.9% to 11.0%) in the HER2-negative group (Gray test, P = 0.010). At multivariable analyses, the adjusted risk of isBCR was higher in the HER2-positive group than in the HER2-negative group [HR HER2 positive versus negative: 1.59 (95% CI 1.06–2.39) as shown in Figure 1]. We carried out a multivariate analysis stratifying the association between events of interest and size, margins and age, and we did not found a statistically significant association in BCR or IBCR. The 10-year BCR proportions were 23.8% (n = 120) (95% CI 19.7% to 28.7%) in the HER2-positive group and 24.6% (n = 222) (95% CI 21.5% to 28.1%) in the HER2-negative group, (Gray test, P = 0.44). The 10-year IBCR proportions were 12% (n = 59) (95% CI 9.0% to 16.1%) in the HER2-positive group and 15.8% (n = 142) (95% CI 13.3% to 18.8%) in the HER2-negative group (Gray test, P = 0.18).
(Enlarge Image)
Figure 1.
Cumulative incidence of any breast cancer recurrence (BCR), in situ breast cancer recurrence (isBCR) and INvasive breast cancer recurrence (IBCR), by HER2 status. Hazard ratio adjusted for: ER/PgR, hormone therapy, type of surgery, radiotherapy, menopausal status, and grade.
The adjusted risk of BCR or IBCR did not show a significant difference according to HER2 expression [HR HER2 positive versus negative: 1.18 (95% CI 0.90–1.54) and HR HER2 positive versus negative: 0.94 (95% CI 0.66–1.35), respectively] (Figure 1).
We stratified survival data according to ER/PgR and endocrine therapy. The subgroup analysis showed a borderline significant difference in isBCR for patients with ER- or PgR-positive DCIS receiving hormone therapy [adjusted HR HER2 positive versus negative: 1.89 (95% CI 0.99–3.61)], and not for patients with ER- or PgR-positive DCIS who did not receive endocrine therapy [adjusted HR HER2 positive versus negative: 1.14 (95% CI 0.61–2.14)], or in patients with ER- and PgR-negative DCIS [adjusted HR HER2 positive versus negative: 3.12 (95% CI 0.94–10.3)]. No significant difference was observed in BCR or isBCR in all subgroups (supplementary Figure S2, available at Annals of Oncology online http://annonc.oxfordjournals.org/content/26/4/682/suppl/DC1).
The subgroup analysis by local treatment (surgery and radiotherapy) showed a significant difference in BCR and isBCR for patients treated by quadrantectomy without radiotherapy (n = 54) versus patients treated with radiotherapy (n = 48) [adjusted HR HER2 positive versus negative: 1.53 (95% CI 1.07–2.18) and adjusted HR HER2 positive versus negative: 2.18 (95% CI 2.18–3.69), respectively] whereas no significant difference was observed in IBCR [adjusted HR HER2 positive versus negative: 1.14 (95% CI 0.69–1.88)] (supplementary Figure S3, available at Annals of Oncology online http://annonc.oxfordjournals.org/content/26/4/682/suppl/DC1). No significant difference was observed in BCR, isBCR and IBCR in patients that underwent quadrantectomy and received radiotherapy or in patients that underwent mastectomy (supplementary Figure S3, available at Annals of Oncology online http://annonc.oxfordjournals.org/content/26/4/682/suppl/DC1). The subgroup analysis by menopausal status showed a significant difference in BCR and isBCR in postmenopausal patients [adjusted HR HER2 positive versus negative: 1.42 (95% CI 0.99–2.04) and adjusted HR HER2 positive versus negative: 1.86 (95% CI 1.07–3.26), respectively], while no significant difference was observed in isBCR [adjusted HR HER2 positive versus negative: 1.19 (95% CI 0.74–1.92)]. No significant difference was observed in BCR, isBCR and IBCR in premenopausal patients (supplementary Figure S4, available at Annals of Oncology online http://annonc.oxfordjournals.org/content/26/4/682/suppl/DC1). Supplementary Figure S5, available at Annals of Oncology online http://annonc.oxfordjournals.org/content/26/4/682/suppl/DC1, summarized as a flow chart of all the cohort of patients included in the analysis and events described.
Results
From January 1996 to December 2008, a total of 1667 patients with DCIS grade 1–3 were referred to the interdisciplinary evaluation. Among this population, we identified a total of 560 cases with HER2 overexpression (3+). Table 1 lists clinical, pathological characteristics, biological features of disease and local and systemic treatments of the population analyzed at the time of surgery (n = 1667), categorized according to HER2 status [positive (560) versus negative (1107)]. Nearly 50% (n = 277) of HER2-positive DCIS were ER and PgR negative, almost 90% (n = 501) had Ki-67 ≥14% and 60% (n = 336) were G3. The median follow-up was 7.6 years (interquartile range 5.9–9.5).
We observed 422 first events among the 1667 patients: 141 (8.5%) in situ recurrences, 201 (12.1%) invasive recurrence and 80 other events (64 s primaries and 16 deaths). We included in isBCR, IBCR and BCR events also controlateral tumors (both in situ and infiltrating). BCR includes isBCR and IBCR (Table 2).
A significant difference was observed in isBCR when comparing HER2-positive and -negative groups. The 10-year isBCR proportions were 11.8% (n = 61 of 560) (95% CI 9.0% to 15.4%) in the HER2-positive group and 8.8% (n = 80 of 1107) (95% CI 6.9% to 11.0%) in the HER2-negative group (Gray test, P = 0.010). At multivariable analyses, the adjusted risk of isBCR was higher in the HER2-positive group than in the HER2-negative group [HR HER2 positive versus negative: 1.59 (95% CI 1.06–2.39) as shown in Figure 1]. We carried out a multivariate analysis stratifying the association between events of interest and size, margins and age, and we did not found a statistically significant association in BCR or IBCR. The 10-year BCR proportions were 23.8% (n = 120) (95% CI 19.7% to 28.7%) in the HER2-positive group and 24.6% (n = 222) (95% CI 21.5% to 28.1%) in the HER2-negative group, (Gray test, P = 0.44). The 10-year IBCR proportions were 12% (n = 59) (95% CI 9.0% to 16.1%) in the HER2-positive group and 15.8% (n = 142) (95% CI 13.3% to 18.8%) in the HER2-negative group (Gray test, P = 0.18).
(Enlarge Image)
Figure 1.
Cumulative incidence of any breast cancer recurrence (BCR), in situ breast cancer recurrence (isBCR) and INvasive breast cancer recurrence (IBCR), by HER2 status. Hazard ratio adjusted for: ER/PgR, hormone therapy, type of surgery, radiotherapy, menopausal status, and grade.
The adjusted risk of BCR or IBCR did not show a significant difference according to HER2 expression [HR HER2 positive versus negative: 1.18 (95% CI 0.90–1.54) and HR HER2 positive versus negative: 0.94 (95% CI 0.66–1.35), respectively] (Figure 1).
We stratified survival data according to ER/PgR and endocrine therapy. The subgroup analysis showed a borderline significant difference in isBCR for patients with ER- or PgR-positive DCIS receiving hormone therapy [adjusted HR HER2 positive versus negative: 1.89 (95% CI 0.99–3.61)], and not for patients with ER- or PgR-positive DCIS who did not receive endocrine therapy [adjusted HR HER2 positive versus negative: 1.14 (95% CI 0.61–2.14)], or in patients with ER- and PgR-negative DCIS [adjusted HR HER2 positive versus negative: 3.12 (95% CI 0.94–10.3)]. No significant difference was observed in BCR or isBCR in all subgroups (supplementary Figure S2, available at Annals of Oncology online http://annonc.oxfordjournals.org/content/26/4/682/suppl/DC1).
The subgroup analysis by local treatment (surgery and radiotherapy) showed a significant difference in BCR and isBCR for patients treated by quadrantectomy without radiotherapy (n = 54) versus patients treated with radiotherapy (n = 48) [adjusted HR HER2 positive versus negative: 1.53 (95% CI 1.07–2.18) and adjusted HR HER2 positive versus negative: 2.18 (95% CI 2.18–3.69), respectively] whereas no significant difference was observed in IBCR [adjusted HR HER2 positive versus negative: 1.14 (95% CI 0.69–1.88)] (supplementary Figure S3, available at Annals of Oncology online http://annonc.oxfordjournals.org/content/26/4/682/suppl/DC1). No significant difference was observed in BCR, isBCR and IBCR in patients that underwent quadrantectomy and received radiotherapy or in patients that underwent mastectomy (supplementary Figure S3, available at Annals of Oncology online http://annonc.oxfordjournals.org/content/26/4/682/suppl/DC1). The subgroup analysis by menopausal status showed a significant difference in BCR and isBCR in postmenopausal patients [adjusted HR HER2 positive versus negative: 1.42 (95% CI 0.99–2.04) and adjusted HR HER2 positive versus negative: 1.86 (95% CI 1.07–3.26), respectively], while no significant difference was observed in isBCR [adjusted HR HER2 positive versus negative: 1.19 (95% CI 0.74–1.92)]. No significant difference was observed in BCR, isBCR and IBCR in premenopausal patients (supplementary Figure S4, available at Annals of Oncology online http://annonc.oxfordjournals.org/content/26/4/682/suppl/DC1). Supplementary Figure S5, available at Annals of Oncology online http://annonc.oxfordjournals.org/content/26/4/682/suppl/DC1, summarized as a flow chart of all the cohort of patients included in the analysis and events described.
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