Risk of Subsequent Breast Cancer in Human EGFR 2-Positive DCIS
We carried out a retrospective analysis through the institutional clinical database on all consecutive women with de novo DCIS who underwent surgery at the European Institute of Oncology, Milan, Italy, between January 1996 and December 2008. Data on patients' medical history, concurrent diseases, type of surgery, pathological assessment of morphological and biological features were combined. DCIS were classified according to ductal intraepithelial neoplasia (DIN) classification as follows: DIN 1c: DCIS grade 1 (low grade); DIN2: DCIS grade 2 (intermediate grade); DIN3: DCIS grade 3 (high grade). Estrogen receptor (ER), progesterone receptor (PgR) status and Ki-67 labeling index were determined as previously reported. HER2 immunohistochemical (IHC) expression was evaluated using the A0485 polyclonal antiserum and, since 2007, the HercepTest (both from Dako, Glostrup, Denmark). HER2 IHC expression was scored as follows: 0 (any staining in <10% of the neoplastic cells), 1+ (faint incomplete membrane staining in >10% of tumor cells), 2+ (weak-to-moderate complete membrane staining in >10% of tumor cells) and 3+ (intense complete membrane staining in >10% of tumor cells). Biomarker assessment was retrospectively collected. ER and PgR were scored positive if finding of ≥1% of tumor cell nuclei immunoreactive. Ki-67 cutoff was defined ad ≥14% of stained cells.
Clinical and pathological data were entered by surgeons into a 'user-friendly' database®. Data were available regarding age, menopausal status, date of surgery, tumor characteristics (tumor size, grade, Ki-67, ER/PgR and HER2 expression, necrosis, microcalcifications and multifocality) and treatment modality (type of surgery, adjuvant radiotherapy and/or endocrine therapy).
We identified female patients with a de novo DCIS with the following characteristics: M0, pN0, pTis and HER2/neu protein overexpression (study group). The data collection was approved by the Institutional Review Board.
Differences in the distribution of subject characteristics between groups were evaluated by the χ test. The end points evaluated were cumulative incidence of In-Situ Breast cancer Recurrence (isBCR), INvasive Breast Cancer Recurrence (IBCR) and any Breast Cancer recurrence (BCR). isBCR, IBCR and BCR were defined as the time from surgery to the breast cancer recurrence as first event (in situ, invasive or both, respectively) or to last visit in case of no events. Other first events such as other primary tumors and deaths were considered as competing events.
The isBCR, IBCR and BCR functions were estimated according to methods described by Kalbfleisch and Prentice, taking into account the competing causes of recurrence. The Gray's test was used to assess cumulative incidence differences between groups. The hazard ratios (HRs) comparing patients with HER2-positive tumor versus patients with HER2-negative tumor were estimated with a Cox proportional hazards multivariable model, controlled for ER/PgR expression, hormone therapy, type of surgery, radiotherapy, menopausal status and tumor grade. All analyses were carried out with the SAS software (SAS Institute, Cary, NC) and the R software (http://cran.r-project.org/) with the cmprsk package developed by Gray (http://biowww.dfci.harvard.edu/~gray/). All reported P values are two-sided.
Patients and Methods
Study Population
We carried out a retrospective analysis through the institutional clinical database on all consecutive women with de novo DCIS who underwent surgery at the European Institute of Oncology, Milan, Italy, between January 1996 and December 2008. Data on patients' medical history, concurrent diseases, type of surgery, pathological assessment of morphological and biological features were combined. DCIS were classified according to ductal intraepithelial neoplasia (DIN) classification as follows: DIN 1c: DCIS grade 1 (low grade); DIN2: DCIS grade 2 (intermediate grade); DIN3: DCIS grade 3 (high grade). Estrogen receptor (ER), progesterone receptor (PgR) status and Ki-67 labeling index were determined as previously reported. HER2 immunohistochemical (IHC) expression was evaluated using the A0485 polyclonal antiserum and, since 2007, the HercepTest (both from Dako, Glostrup, Denmark). HER2 IHC expression was scored as follows: 0 (any staining in <10% of the neoplastic cells), 1+ (faint incomplete membrane staining in >10% of tumor cells), 2+ (weak-to-moderate complete membrane staining in >10% of tumor cells) and 3+ (intense complete membrane staining in >10% of tumor cells). Biomarker assessment was retrospectively collected. ER and PgR were scored positive if finding of ≥1% of tumor cell nuclei immunoreactive. Ki-67 cutoff was defined ad ≥14% of stained cells.
Clinical and pathological data were entered by surgeons into a 'user-friendly' database®. Data were available regarding age, menopausal status, date of surgery, tumor characteristics (tumor size, grade, Ki-67, ER/PgR and HER2 expression, necrosis, microcalcifications and multifocality) and treatment modality (type of surgery, adjuvant radiotherapy and/or endocrine therapy).
We identified female patients with a de novo DCIS with the following characteristics: M0, pN0, pTis and HER2/neu protein overexpression (study group). The data collection was approved by the Institutional Review Board.
Statistical Methods
Differences in the distribution of subject characteristics between groups were evaluated by the χ test. The end points evaluated were cumulative incidence of In-Situ Breast cancer Recurrence (isBCR), INvasive Breast Cancer Recurrence (IBCR) and any Breast Cancer recurrence (BCR). isBCR, IBCR and BCR were defined as the time from surgery to the breast cancer recurrence as first event (in situ, invasive or both, respectively) or to last visit in case of no events. Other first events such as other primary tumors and deaths were considered as competing events.
The isBCR, IBCR and BCR functions were estimated according to methods described by Kalbfleisch and Prentice, taking into account the competing causes of recurrence. The Gray's test was used to assess cumulative incidence differences between groups. The hazard ratios (HRs) comparing patients with HER2-positive tumor versus patients with HER2-negative tumor were estimated with a Cox proportional hazards multivariable model, controlled for ER/PgR expression, hormone therapy, type of surgery, radiotherapy, menopausal status and tumor grade. All analyses were carried out with the SAS software (SAS Institute, Cary, NC) and the R software (http://cran.r-project.org/) with the cmprsk package developed by Gray (http://biowww.dfci.harvard.edu/~gray/). All reported P values are two-sided.