Risk of Subsequent Breast Cancer in Human EGFR 2-Positive DCIS
Risk of Subsequent Breast Cancer in Human EGFR 2-Positive DCIS
We assessed the prognostic value of HER2 overexpression in women with DCIS to quantify the risk of subsequent DCIS or invasive cancer. Our findings corroborate previous results of population-based cohort studies of individuals with DCIS treated by breast-conserving surgery. In our study, HER2 overexpression in primary DCIS was associated with a higher risk of in situ recurrence. Notably, no association with a higher risk of IBCR was noted. We described the prognostic significance of Ki-67 status as predictive marker in DCIS. In this analysis, Ki-67 appeared to be a useful prognostic and predictive biomarker in DCIS patients for better selection of adjuvant treatment. The role of HER2 in DCIS is unclear. It has been proposed that HER2 overexpression in DCIS is of major importance for tumor progression toward invasive cancer. The findings from our present study cannot confirm such an influence regarding progression to invasive tumor. Recently, Agosto-Arroyo et al have shown that some HER2-positive DCIS are associated with high risk of developing invasive breast cancer, when compared with more indolent DCIS. They carried out gene expression profiles in high nuclear grade DCIS. Approximately 30 genes were identified to be expressed differently in the HER2 subtype when compared with the two other groups (ER/PR+ and triple negative). Uncovering gene expression signatures of HER2-positive DCIS can enhance our understanding of the mechanisms of breast cancer progression and become the basis for developing new predictive biomarkers and/or therapeutic targets. The subgroup analysis by local treatment (surgery and radiotherapy) showed significant differences both in BCR and isBCR for patients treated by quadrantectomy without radiotherapy [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]. Our data have shown a clear benefit from radiotherapy in HER2-positive DCIS. In this study, 117 HER2-positive DCIS patients (20.9%) received no radiotherapy following quadrantectomy. In our institution, the indication for radiotherapy after breast cancer surgery for DCIS is the presence of necrosis and/or high tumor grade (G3), large tumor size, margins and younger age of the patient. A total of 136 (24.3%) patients with HER2-positive DCIS received hormone therapy (mainly 5 mg low-dose tamoxifen). A borderline significant difference was observed 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)]. In the adjuvant treatment of invasive breast cancer, HER-2 overexpression may predict resistance to tamoxifen. 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]. In premenopausal patients, we observed no difference in BCR, isBCR and IBCR. Postmenopausal women with HER2-positive DCIS were more frequently ER/PgR negative, thus taking no tamoxifen.
A number of studies aimed at identifying factors that predict the risk of invasive recurrence following a diagnosis of DCIS, but few have included HER2 in their analyses. Our series is, to our knowledge, the largest ever published with HER2 assessed. HER2 status is not routinely assessed in clinical practice and there is no indication to anti-HER2 blockade in the preventive setting. Preclinical reports associated HER2 signaling with tumor cell migration, expression of proangiogenic factors and cyclooxygenase-2, suggesting a potentially significant role in inducing invasion or the elaboration of a stroma that supports tumor growth. The close association between HER2-overexpressing phenotypes and increased risk of isBCR should have clinical implications. First, indication to radiotherapy should be mandatory to ER/PgR-negative, HER2-positive DCIS in addition to the presence of necrosis and/or high tumor grade. Secondly, patients with HER2-positive DCIS could benefit from magnetic resonance imaging (MRI) surveillance program. In a prospective observational study comparing MRI to mammography, MRI was more sensitive and specific in diagnosing high-grade DCIS; in this report, 48% of DCIS were missed by mammography, but diagnosed by MRI alone. Third, the fundamental question now, having documented a major risk of local recurrence, is what to do next in terms of systemic therapy. A trial with trastuzumab in HER2-positive DCIS was conducted. In that study, a single loading dose of 8 mg/kg of trastuzumab was administered to test the biological effects of the agent on DCIS 3–4 weeks before surgical resection. Twelve patients received study drug and 12 patients served as controls with no treatment. Pre- and post-treatment tissues with DCIS were studied for proliferation and apoptosis in patients treated with trastuzumab. The conclusion was that a single-dose monotherapy with trastuzumab for patients with HER2-positive DCIS does not result in significant clinically, histologic, proliferative or apoptotic changes but results in an antibody-dependent cell-mediated cytotoxicity response through NK cells and may also induce humoral immunity in a T-cell-dependent manner. A second study was conducted in our institution. It was a randomized, placebo-controlled trial of lapatinib (1500 mg/day) administered orally for 3 weeks between biopsy and surgery in 60 women with HER-2-positive breast cancer to assess lapatinib biomarker (including the primary end point, Ki-67) and clinical activity in invasive breast cancer, adjacent ductal intraepithelial neoplasia (which comprises DCIS and atypical ductal hyperplasia), and distant ductal hyperplasia (DH) without atypia. In our study, short-term lapatinib significantly decreased cell proliferation in DIN, DH and invasive HER-2-positive (especially ER-negative) breast cancer. In a third study, patients with HER2-positive DCIS received 1500 mg daily of lapatinib for 4 consecutive weeks before surgical resection. MRI was used to determine changes in tumor volume. The molecular effects of lapatinib on HER2 signaling (PI3K/AKT and RAS/MAPK pathways), cell proliferation (Ki-67 and p27) and apoptosis (TUNEL) were determined in pre- and post-lapatinib treatment samples. A total of 20 patients were included. Lapatinib was well tolerated with only minor and transient side-effects. The agent effectively modulated HER2 signaling decreasing significantly pHER2 and pERK1 expression, together with a decrease in tumor size evaluated by MRI. There was no evidence of changes in Ki-67. To determine the clinical effect of anti-HER2 blockade, the National Surgical Adjuvant Breast Project (NSABP) B-43 phase III randomized trial is currently ongoing to test the efficacy of adding trastuzumab to conventional surgical and radiation therapy treatment of patients with HER2-overexpressing DCIS.
Our study does not support the premise that HER2 overexpression in primary DCIS is of any major importance for tumor progression toward invasive cancer which has been proposed. However, more studies are needed to evaluate the impact of other biomarkers that differentiate individuals at risk of in situ recurrence from those at risk of developing invasive one. The evaluation of joint expression of HER2/neu, Ki-67 and of other combinations of biomarkers on the risks of local and invasive recurrence could help clinicians in the addressing of a more personalized local (radiation therapy) and systemic treatment.
Discussion
We assessed the prognostic value of HER2 overexpression in women with DCIS to quantify the risk of subsequent DCIS or invasive cancer. Our findings corroborate previous results of population-based cohort studies of individuals with DCIS treated by breast-conserving surgery. In our study, HER2 overexpression in primary DCIS was associated with a higher risk of in situ recurrence. Notably, no association with a higher risk of IBCR was noted. We described the prognostic significance of Ki-67 status as predictive marker in DCIS. In this analysis, Ki-67 appeared to be a useful prognostic and predictive biomarker in DCIS patients for better selection of adjuvant treatment. The role of HER2 in DCIS is unclear. It has been proposed that HER2 overexpression in DCIS is of major importance for tumor progression toward invasive cancer. The findings from our present study cannot confirm such an influence regarding progression to invasive tumor. Recently, Agosto-Arroyo et al have shown that some HER2-positive DCIS are associated with high risk of developing invasive breast cancer, when compared with more indolent DCIS. They carried out gene expression profiles in high nuclear grade DCIS. Approximately 30 genes were identified to be expressed differently in the HER2 subtype when compared with the two other groups (ER/PR+ and triple negative). Uncovering gene expression signatures of HER2-positive DCIS can enhance our understanding of the mechanisms of breast cancer progression and become the basis for developing new predictive biomarkers and/or therapeutic targets. The subgroup analysis by local treatment (surgery and radiotherapy) showed significant differences both in BCR and isBCR for patients treated by quadrantectomy without radiotherapy [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]. Our data have shown a clear benefit from radiotherapy in HER2-positive DCIS. In this study, 117 HER2-positive DCIS patients (20.9%) received no radiotherapy following quadrantectomy. In our institution, the indication for radiotherapy after breast cancer surgery for DCIS is the presence of necrosis and/or high tumor grade (G3), large tumor size, margins and younger age of the patient. A total of 136 (24.3%) patients with HER2-positive DCIS received hormone therapy (mainly 5 mg low-dose tamoxifen). A borderline significant difference was observed 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)]. In the adjuvant treatment of invasive breast cancer, HER-2 overexpression may predict resistance to tamoxifen. 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]. In premenopausal patients, we observed no difference in BCR, isBCR and IBCR. Postmenopausal women with HER2-positive DCIS were more frequently ER/PgR negative, thus taking no tamoxifen.
A number of studies aimed at identifying factors that predict the risk of invasive recurrence following a diagnosis of DCIS, but few have included HER2 in their analyses. Our series is, to our knowledge, the largest ever published with HER2 assessed. HER2 status is not routinely assessed in clinical practice and there is no indication to anti-HER2 blockade in the preventive setting. Preclinical reports associated HER2 signaling with tumor cell migration, expression of proangiogenic factors and cyclooxygenase-2, suggesting a potentially significant role in inducing invasion or the elaboration of a stroma that supports tumor growth. The close association between HER2-overexpressing phenotypes and increased risk of isBCR should have clinical implications. First, indication to radiotherapy should be mandatory to ER/PgR-negative, HER2-positive DCIS in addition to the presence of necrosis and/or high tumor grade. Secondly, patients with HER2-positive DCIS could benefit from magnetic resonance imaging (MRI) surveillance program. In a prospective observational study comparing MRI to mammography, MRI was more sensitive and specific in diagnosing high-grade DCIS; in this report, 48% of DCIS were missed by mammography, but diagnosed by MRI alone. Third, the fundamental question now, having documented a major risk of local recurrence, is what to do next in terms of systemic therapy. A trial with trastuzumab in HER2-positive DCIS was conducted. In that study, a single loading dose of 8 mg/kg of trastuzumab was administered to test the biological effects of the agent on DCIS 3–4 weeks before surgical resection. Twelve patients received study drug and 12 patients served as controls with no treatment. Pre- and post-treatment tissues with DCIS were studied for proliferation and apoptosis in patients treated with trastuzumab. The conclusion was that a single-dose monotherapy with trastuzumab for patients with HER2-positive DCIS does not result in significant clinically, histologic, proliferative or apoptotic changes but results in an antibody-dependent cell-mediated cytotoxicity response through NK cells and may also induce humoral immunity in a T-cell-dependent manner. A second study was conducted in our institution. It was a randomized, placebo-controlled trial of lapatinib (1500 mg/day) administered orally for 3 weeks between biopsy and surgery in 60 women with HER-2-positive breast cancer to assess lapatinib biomarker (including the primary end point, Ki-67) and clinical activity in invasive breast cancer, adjacent ductal intraepithelial neoplasia (which comprises DCIS and atypical ductal hyperplasia), and distant ductal hyperplasia (DH) without atypia. In our study, short-term lapatinib significantly decreased cell proliferation in DIN, DH and invasive HER-2-positive (especially ER-negative) breast cancer. In a third study, patients with HER2-positive DCIS received 1500 mg daily of lapatinib for 4 consecutive weeks before surgical resection. MRI was used to determine changes in tumor volume. The molecular effects of lapatinib on HER2 signaling (PI3K/AKT and RAS/MAPK pathways), cell proliferation (Ki-67 and p27) and apoptosis (TUNEL) were determined in pre- and post-lapatinib treatment samples. A total of 20 patients were included. Lapatinib was well tolerated with only minor and transient side-effects. The agent effectively modulated HER2 signaling decreasing significantly pHER2 and pERK1 expression, together with a decrease in tumor size evaluated by MRI. There was no evidence of changes in Ki-67. To determine the clinical effect of anti-HER2 blockade, the National Surgical Adjuvant Breast Project (NSABP) B-43 phase III randomized trial is currently ongoing to test the efficacy of adding trastuzumab to conventional surgical and radiation therapy treatment of patients with HER2-overexpressing DCIS.
Our study does not support the premise that HER2 overexpression in primary DCIS is of any major importance for tumor progression toward invasive cancer which has been proposed. However, more studies are needed to evaluate the impact of other biomarkers that differentiate individuals at risk of in situ recurrence from those at risk of developing invasive one. The evaluation of joint expression of HER2/neu, Ki-67 and of other combinations of biomarkers on the risks of local and invasive recurrence could help clinicians in the addressing of a more personalized local (radiation therapy) and systemic treatment.
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