Annals of Oncology Advance Access published online on November 6, 2007
Annals of Oncology, doi:10.1093/annonc/mdm509
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© 2007 European Society for Medical Oncology
Expression of ER, PgR, HER1, HER2, and response: a study of preoperative chemotherapy
1 Unit of Research in Medical Senology, Division of Medical Oncology, Department of Medicine, European Institute of Oncology, Milan
2 Division of Pathology, European Institute of Oncology
3 School of Medicine, University of Milan, Milan, Italy
4 International Breast Cancer Study Group, Statistical Center, Dana-Farber Cancer Institute, and Frontier Science and Technology Research Foundation, Boston, MA, USA
5 Division of Senology, European Institute of Oncology, Milan
6 Department of Medicine, European Institute of Oncology, Milan, Italy
* Correspondence to: Dr M. Colleoni, Unit of Research in Medical Senology, Division of Medical Oncology, Department of Medicine, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy. Tel: +39-02-57489439; Fax: +39-02-57489212; E-mail: marco.colleoni{at}ieo.it
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Abstract |
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Purpose: To identify the role of estrogen (ER), progesterone (PgR), epidermal growth factor 1 (HER1), and HER2 receptors in predicting response to preoperative chemotherapy.
Materials and methods: We reviewed the pretreatment biopsies of 485 patients with locally advanced breast cancer (cT2-T4, N0-2, M0) treated with preoperative chemotherapy. The incidence of pathological complete remission (pCR) and outcome were assessed with respect to clinical and pathological findings including ER/PgR status (absent versus expressed), HER1 (absent versus expressed) and HER2 (overexpressed versus none) expression.
Results: Patients with ER/PgR-absent tumors were 12.0 times [95% confidence interval (CI) 4.93–29.28] more likely to achieve a pCR (P < 0.0001). Predictors of disease-free survival (DFS) at the univariate analysis included HER1 [hazards ratio (HR) 1.6, 95% CI 1.04–2.32, P = 0.03] and HER2 (HR 1.6, 95% CI 1.08–2.38, P = 0.02) expression. A statistically significant difference in DFS was confirmed at the multivariate analysis for patients with ER/PgR-absent disease (HR 2.1, 95% CI 1.41–2.99, P = 0.0002).
Conclusions: The pCR rate is higher and outcome worse for patients with ER/PgR-absent tumors. HER1 and HER2 expression may have a prognostic role in locally advanced breast cancer and warrant further studies.
breast cancer, predictive factors, prognostic factors, primary chemotherapy
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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Experimental data support the hypothesis that chemotherapy given before surgery for breast cancer may improve patients' outcome [1], yet the most effective timing and sequencing for systemic chemotherapy in operable breast cancer is still unclear.
A useful strategy to improve knowledge about treatment effects is the early identification of features, which are associated with response or resistance to primary therapy. Previously published studies indicated that pathological complete remission (pCR) rate was significantly higher following preoperative chemotherapy for patients whose tumors did not express estrogen receptor (ER) and progesterone receptor (PgR), compared with the receptor-positive cohort [2–4]. Despite the significantly higher incidence of pCR achieved by preoperative chemotherapy for patients with endocrine-nonresponsive disease, the disease-free survival (DFS) was significantly worse for this cohort compared with the positive expression cohort in several studies [2, 4].
Epidermal growth factor receptor 2 (HER2) gene overexpression may influence the sensitivity of breast carcinoma to chemotherapy as recently published [5, 6]. Epidermal growth factor receptor 1 (HER1) expression has predictive or prognostic value in a number of malignancies [7], but the predictive and prognostic significance of HER1 in patients with breast carcinoma was uncommonly studied, leading to insufficient data concerning its biologic significance in particular in patients treated with preoperative chemotherapy [8].
Emerging experimental data indicate that the ER and PgR expression and HER1/HER2 pathways are interactive [9]. Several recent clinical studies have found a higher expression of HER1 and HER2 in ER-positive/PgR-negative breast cancers if compared with the ER-positive/PgR-positive cohort [9, 10].
To seek information on the predictive and prognostic value of the expression of ER, PgR, HER1, and HER2 either as single factor or combined, we evaluated the course of disease in 485 patients with large operable primary breast cancer who had preoperative diagnosis and surgery carried out at the European Institute of Oncology (EIO), Milan, Italy.
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patients and methods |
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patients
Prospectively collected data from 485 consecutive patients with clinical (c) stage T2-T4d, N0-2, M0 treated with preoperative chemotherapy from 1994 to 2004 were analyzed. Eligibility criteria for preoperative chemotherapy included no previous chemotherapy/hormonotherapy, performance status zero to two (Eastern Cooperative Oncology Group scale), measurable lesions, age between 18 and 70 years, white blood cells >4000/mm3, platelets >100 000/mm3, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, gamma GT
2.5 x upper limit of normal and bilirubin level 3 mg/100 ml. Each patient gave a written informed consent.
treatment
Patients were treated with preoperative chemotherapy given in 3-week courses. Patients with partial remission (PR) or complete remission (CR) were candidates to receive a maximum of six courses. The regimens used during the conduct of the study included anthracycline-containing regimens, taxane-containing regimens, and navelbine-containing regimens as previously reported [4].
response criteria
Responses were evaluated according to both radiological (breast ultrasound plus Rx mammography) and clinical evaluation and graded according to standard World Health Organization criteria. pCRs were evaluated according to Kuerer et al. criteria [11]. In particular, the absence of invasive cancer on both the primary breast tumor and axillary lymph nodes qualified for pCR.
pathology and immunohistochemistry
All patients had pathological evaluation carried out at the EIO. The original receptor status determinations, carried out before the patient was included in the study were used.
Immunostaining experiments for the localization of ER and PgR, HER2 protein, and Ki-67 antigen were carried out on consecutive tissue sections of the tru-cut biopsies obtained before primary treatment, as previously reported [4]. The following primary antibodies were used: the mAb to ER (Dako, Glostrup, Denmark, at 1/100 dilution), the mAb to PgR (Dako, 1/800), the MIB-1 mAb to the Ki-67 antigen (Immunotech, Marseille, France, 1/1200), the polyclonal antiserum (Dako, 1/3200) to the HER2 protein, and the antibody 31G7 (Zymed Laboratories, San Francisco, CA; pronase, 1:20) to HER1.
The immunostained slides were evaluated independently by two of the authors. Only nuclear reactivity was taken into account for ER, PgR, and Ki-67 antigen, whereas only an intense and complete membrane staining >10% of the tumor cells was taken as evidence of HER2 overexpression (3+). For HER1 only distinct membranous staining was defined as positive. Both intensity and positivity percentage of the tumor cells were recorded. Any staining for HER1, regardless of intensity or percentage of positive cells, was considered as HER1 positive, as previously published [8]. HER1 expression was not determined in the population with ER- and PgR-positive breast cancer based on literature data indicating limited [9, 12, 13] or no expression [14] of HER1 in this patient cohort. Steroid hormone receptors status was classified as absent (ER and PgR 0% of the cells positive), low (ER and/or PgR 
1% and <10% of the cells), or positive (ER and PgR 10% of the cells).
statistical methods
The primary end points were achieving a pCR, DFS, and overall survival (OS). We used logistic regression to model the probability of achieving a pCR first in univariate analyses and then in multiple regression analyses to identify the baseline factors that predicted a pCR. Odds ratios (ORs), 95% confidence intervals (CIs), and P values were estimated. The Wald test was used to evaluate significance of individual coefficients and the likelihood ratio test was used to assess a factor with more than two levels (e.g. tumor size). In addition, we explored all the logistic regression models that included two baseline factors and the two-way interaction between those factors.
DFS was calculated from the date of first treatment until breast cancer recurrence or a new breast cancer primary or death without recurrence whichever occurred first. OS was defined as the length of time from the date of random assignment to death from any cause. Results are available at a median follow-up of 6.7 years. Survival curves were estimated using the Kaplan–Meier method. Assessment of DFS and OS according to ER/PgR, HER1, and HER2 status were summarized using the 5-year DFS and OS percent ± the standard error (SE) and hazards ratios (HRs), with the respective 95% CI, and P values were estimated using Cox multiple regression models. The same baseline factors included in the modeling of a pCR were included in the Cox proportional hazards regression models. P values 0.05 were considered to be statistically significant.
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Of the 485 patients with response data, 8.2% had a pCR, 62.5% had objective clinical remission (CR + PR), 28.0% had stable disease, and 1.2% had progressive disease. Patients within the ER/PgR-absent cohort were 12.0 times (95% CI 4.93–29.28) more likely to achieve a pCR than patients within the ER/PgR-positive or low cohort. The pCR percent for patients with grade 3 tumors was 13.2% compared with 4.6% with grades 1 and 2 [OR (grade 3/grades 1, 2): 3.1, 95% CI 1.43–6.94] (Table 1). Patients presenting with Ki-67
20% were 8.7 times (95% CI 2.06–36.61) more likely to achieve a pCR compared with patients presenting with Ki-67 <20%. None of the two-way interactions were statistically significant. The significant predictors in the univariate analysis of pCR retained their statistical significance after adjusting for the other baseline factors in a logistic regression model with the exception of Ki-67 (P = 0.30). Differences in pCR rate according to HER1 and HER2 expression were not statistically significant in either the univariate or multivariate analyses.
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There was a significant association between ER/PgR status and both HER1 and HER2 overexpression (P = 0.0008 and P = 0.0002, respectively; Table 2). Of 137 patients with ER/PgR-absent tumors and assessable for HER1 analysis, 40% were positive for HER1. Moreover, of 55 assessable patients with ER/PgR-absent tumors and HER2 not overexpressed (triple negative), 45% were positive for HER1. On 126 patients assessable for HER2 analysis with ER/PgR-absent tumors, 35% had overexpression of HER2.
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The factors that showed a significantly poorer DFS in the univariate analysis were absence of ER and PgR expression (Figure 1, Table 3) HER1 and HER2 expression, negative nodes, grade 3, Ki-67
20%, and large tumor size. In particular, a significant predictor of DFS and OS within the univariate analysis was HER1 expression [unadjusted HRs (HER1 expressed/HER1 not expressed): 1.6, 95% CI 1.04–2.32, P = 0.003 for DFS (Figure 2, Table 3); 1.8, 95% CI 1.08–2.85, P = 0.02 for OS]. Also, HER2 overexpression was a significant predictor of DFS within the univariate analysis and a marginally significant predictor of OS (unadjusted HRs [HER2 overexpressed/HER2 not overexpressed]: 1.6, 95% CI 1.08–2.38, P = 0.02 for DFS (Figure 3, Table 3); 1.6, 95% CI 0.97–2.66, P = 0.07 for OS). A test of ER status by HER2 expression interaction was statistically significant for DFS (P = 0.03) and OS (P = 0.05). In patients with endocrine-nonresponsive tumors a significantly worse DFS and a marginally significantly worse OS was observed if HER2 was overexpressed (unadjusted HRs: 1.8, 95% CI 1.11–2.91, P = 0.02 for DFS; 1.6, 95% CI 0.91–2.93, P = 0.10 for OS; Table 4). The interaction effect between ER status and HER1 expression was not statistically significant for either DFS (P = 0.67) or OS (P = 0.54) nor was the interaction between HER1 and HER2 expression for either DFS (P = 0.14) or OS (P = 0.09). ER/PgR status, nodal status, and tumor size were the only factors that predicted DFS and OS in a multivariate analysis that included all of the factors studied [HR(ER/PgR absent)/(ER/PgR low/positive): 2.1, 95% CI 1.41–2.99, P = 0.0002 for DFS; 3.1, 95% CI 1.93–5.09, P < 0.0001 for OS; HR(T4/T2): 3.0, 95% CI 2.15–4.26, HR(T3/T20) : 1.8, 95% CI 1.23–2.59, P < 0.0001 for DFS; HR(T4/T2): 4.5, 95% CI 2.83–7.01, HR(T3/T2): 2.4, 95% CI 1.52–3.93, P < 0.0001 for OS].
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Historically, preoperative chemotherapy has been given almost universally to patients with large tumors with few exceptions of small series of elderly women for whom an endocrine preoperative therapy seemed to be the only treatment which could be proposed [4]. A change in the algorithm for selection of neo-adjuvant systemic therapies for patients with early breast cancer was recently proposed at the International Expert Panel on the Use of Neo-adjuvant (Primary) Systemic Treatment of Operable Breast Cancer [15]. Expression of steroid hormone receptors and HER2 overexpression were considered to be pivotal factors in selecting a program of neo-adjuvant therapy.
In fact, the determination of steroid hormone receptor expression in the primary tumor is a factor that predicts both the response to chemotherapy and patients outcome as recently reported in retrospective analyses [2, 15]. In the trials described above, however, analyses were commonly carried out on the basis of a so-called ‘receptor-negative grouping’, which combines receptor-absent disease with that expressing low receptor levels. In the present study, which represents one of the largest available analysis conducted by the same team of pathologists on pretreatment biopsies, we demonstrated a statistically significant different pattern of response and outcome to chemotherapy for steroid hormone receptor-absent tumors. Some clinical studies [16] and gene expression profiling [17] already provide empirical data that receptor-absent breast cancer is a distinct entity from that with even low levels of receptor expression. The responsiveness of tumors expressing some receptors to adjuvant endocrine therapies (e.g. ovarian function suppression, tamoxifen, aromatase inhibitors) might partially explain the different outcome observed. In fact, following surgery, patients with endocrine unresponsive disease generally did not receive further systemic therapy while those with endocrine-responsive disease received additional endocrine treatment postoperatively. The poor outcome observed in the present study for patients with steroid hormone receptor-absent tumors provides substantial additional evidence to support the hypothesis that these patients might require further treatment after surgery.
Besides the confirmation of different patterns of relapse for endocrine-nonresponsive tumors, the results of the present study offer an opportunity to explore the identification of patient's subgroups that might require a tailored approach in future studies.
Limited data are available on the relationship between HER2 expression and response to chemotherapy in the preoperative setting. This might be explained by the small sample sizes, heterogeneity of examinations and methods, and especially cut-offs used in the various studies. In the majority of studies no correlation between HER2 status and response to chemotherapy was observed [18]. A recently published trial on a large number of patients showed a statistically significant positive correlation between HER2 positivity (defined as 3+ with immunohistochemistry), hormone receptor (HR) negativity, and pCR rate [19]. Also, results on HER2 expression and patient outcome after preoperative chemotherapy are conflicting. DFS was reported to be significantly worse for the population that overexpressed HER2 if compared with HER2-negative tumors in two large studies [19, 20]. In particular, in a retrospective analysis including 1731 patients, progression-free survival rates were significantly worse for HER2-positive disease in the cohort of patients HR positive and HR negative [19]. In the present study we observed at the univariate analysis a worse DFS and OS for patients with HER2-positive tumors, supporting tailored therapies for this patient cohort in future studies, as recently developed in both the adjuvant [21] and neo-adjuvant setting [22].
Data on HER1 expression and response to primary chemotherapy are very few and cannot be used currently to determine treatment options. A recently reported study on HER1 expression indicates a possible prognostic significance in patients with locally advanced breast carcinoma who are treated with anthracycline chemotherapy warranting further studies [8]. In the present study we found at the univariate analysis that DFS and OS were shorter in patients with locally advanced, HER1-positive breast carcinoma than in patients with HER1-negative breast carcinoma, supporting further studies focusing on the use of recently developed targeted agents against HER1.
ER/PgR-absent disease was a stronger predictor of DFS and OS than HER1 or HER2 in the multivariate analysis. As showed in Table 2, a significant proportion of the patients with overexpression of HER1 had ER/PgR-absent disease compared with patients with no expression of HER1. Similar results can be seen for HER2 (Table 2). These results may explain why these closely associated factors are not all significantly and independently predicting DFS or OS when taken together in the full regression models. Furthermore, 282 (58%) and 194 (40%) of patients were missing data for HER1 and HER2 expression, respectively, while 99% of the patients had ER/PgR status known.
Genomic expression profiling studies on breast tumors have identified distinct subtypes of breast carcinomas that are associated with different responses to chemotherapy and to different clinical outcomes [23]. In order to further explore the question on the prognostic role of HER1/2 and ER and PgR, we therefore present our results both overall and specifically focused on patient subgroups.
In particular, endocrine-nonresponsive tumors represent a heterogeneous group of diseases where the identification of distinct clinical entities is the key achievement for future trials. Triple-negative breast cancer is a recent term and refers to cancers that do not express ER, PgR, and HER2 receptors [24]. Tissue microarray studies have shown a high rate of HER1 overexpression in triple-negative disease [9, 25]. In the present study we confirmed a high probability of HER1 expression in endocrine-nonresponsive disease (40%) as well as in triple-negative breast cancer (45%). These data warrant further studies aimed at correlating HER1 expression and outcome in patients with endocrine-nonresponsive locally advanced carcinoma.
Previous studies [26], including one from our group [27], found a correlation between the degree of expression of ER and PgR and HER2 overexpression, clearly indicating the higher prevalence of endocrine-nonresponsive disease in the group of patients selected by HER2 overexpression. These results are confirmed in the present study where a 35% HER2 overexpression was found in patients with endocrine-nonresponsive disease. As shown in Table 4, in patients with ER- and PgR-absent tumors the 5-year DFS was worse if HER2 overexpressed, indicating that this cohort of patients might be candidated to targeted treatment in future studies.
A correlation was also found for HER1 positivity and the expression of ER and PgR. In particular, literature data support a limited role and expression of HER1 in ER- and PgR-positive breast cancer. Only 2%–8% of HER1 positivity, evaluated through heterogeneous examinations, methods, and cut-offs was reported in the literature in this patient cohort at surgery [9, 12, 13]. Moreover, using the same cut-offs and methodology of the present study, we found no expression (0%) of HER1 in patients with ER- and PgR-positive tumors at tru-cut biopsies obtained before primary treatment [14]. The low HER1 expression in the double receptor-positive cohort might be explained by results of previous studies in breast cancer cell lines that have implicated HER1 signaling in lowering the expression of PgR [28] and/or ER [29, 30]. On the basis of these considerations, in the present study HER1 expression was not determined in the population with ER- and PgR-positive breast cancer. On the other hand, in the subgroup of patients with ER-positive and PgR-absent disease, hyperactive cross-talk between ER- and growth factor-signaling pathways, leading to a more aggressive course of the disease, was recently reported [9, 10, 29, 30]. The low probability of expression of HER1 and HER2 observed within the ER-positive/PgR-negative cohort in the present study (Table 2), indicates, however, that other mechanisms might be involved in the disease progression.
In conclusion, the present study confirms the importance of ER and PgR expression on response and outcome of patients with locally advanced breast cancer treated with preoperative chemotherapy. Moreover, a possible prognostic role for HER1 and HER2 was observed in particular within the population with ER- and PgR-absent tumors. Further studies using database analyses or prospective trials are required to confirm the value and limitations of these factors in patients treated with primary chemotherapy. If confirmed, future preoperative treatment should explore in selected subgroups of patients selective HER1 and HER2 blockade in addition to conventional treatments in an attempt to improve results in the preoperative setting.
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United States National Cancer Institute (CA-75362).
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We thank the patients and physicians at the EIO. We also thank the International Breast Cancer Study Group Statistical Center for their invaluable contribution to this research.
Received for publication July 13, 2007. Revision received October 1, 2007. Accepted for publication October 2, 2007.
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1. Fisher B, Gunduz N, Saffer EA. Influence of the interval between primary tumor removal and chemotherapy on kinetics and growth of metastasis. Cancer Res (1983) 43:1488–1492.
2. Ring AE, Smith IE, Ashley S, et al. Oestrogen receptor status, pathological complete response and prognosis in patients receiving neoadjuvant chemotherapy for early breast cancer. Br J Cancer (2004) 91:2012–2017.[CrossRef][Web of Science][Medline]
3. Kaufmann M, von Minckwitz G, Smith R, et al. International expert panel on the use of primary (preoperative) systemic treatment of operable breast cancer: review and recommendations. J Clin Oncol (2003) 21:2600–2608.
4. Colleoni M, Viale G, Zahrieh D, et al. Chemotherapy is more effective in patients with breast cancer not expressing steroid hormone receptors: a study of preoperative treatment. Clin Cancer Res (2004) 10:6622–6628.
5. Petit T, Borel C, Ghnassia J, et al. Chemotherapy response of breast cancer depends on HER-2 status and anthracycline dose intensity in the neoadjuvant setting. Clin Cancer Res (2001) 7:1577–1581.
6. Hayes DF, Thor AD, Dressler LG, et al. HER2 and response to paclitaxel in node-positive breast cancer. N Engl J Med (2007) 357:1496–1506.
7. Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol (2003) 21:2787–2799.
8. Bucholz TA, Xyaiou TU, Kiang Ang K, et al. Epidermal growth factor receptor expression correlates with poor survival in patients who have breast carcinoma treated with doxorubicin-based neoadjuvant chemotherapy. Cancer (2005) 104:676–681.[CrossRef][Web of Science][Medline]
9. Arpino G, Weiss H, Lee A, et al. Estrogen receptor positive, progesterone receptor-negative breast cancer: correlation with growth factor receptor expression and tamoxifen resistance. J Natl Cancer Inst (2005) 97:1254–1261.
10. Dowsett M, Harper-Wynne C, Boeddinghaus I, et al. HER-2 amplification impedes the antiproliferative effects of hormone therapy in estrogen receptor-positive primary breast cancer. Cancer Res (2001) 61:8452–8458.
11. Kuerer HM, Newman LA, Smith TM, et al. Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol (1999) 17:460–469.
12. Knoop AS, Bentzen SM, Nielsen MM, et al. Value of epidermal growth factor receptor, HER2, p53, and steroid receptors in predicting the efficacy of tamoxifen in high-risk postmenopausal breast cancer patients. J Clin Oncol (2001) 19:3376–3384.
13. Dowsett M, Houghton J, Iden C. Benefit from adjuvant tamoxifen therapy in primary breast cancer patients according oestrogen receptor, progesterone receptor, EGF receptor and HER2 status. Ann Oncol (2006) 17:818–826.
14. Torrisi R, Bagnardi V, Pruneri G, et al. Antitumour and biological effects of letrozole and GnRH analogue as primary therapy in premenopausal women with ER and PgR positive locally advanced operable breast cancer. Br J Cancer (2007) 97:802–808.[CrossRef][Web of Science][Medline]
15. Kaufmann M, von Minckwitz G, Bear HD, et al. Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: new perspectives 2006. Ann Oncol (2007) In press.
16. Colleoni M, Gelber S, Coates AS, et al. Influence of endocrine-related factors on response to perioperative chemotherapy for patients with node-negative breast cancer. J Clin Oncol (2001) 19:4141–4149.
17. Gruvberger S, Ringner M, Chen Y, et al. Estrogen receptor status in breast cancer is associated with remarkably distinct gene expression patterns. Cancer Res (2001) 61:5979–5984.
18. Barrett-Lee PJ. Growth factor signalling in clinical breast cancer and its impact on response to conventional therapies: a review of chemotherapy. Endocr Relat Cancer (2005) 12:125–133.[CrossRef]
19. Guarneri V, Broglio K, Kau SW, et al. Prognostic value of pathologic complete response after primary chemotherapy in relation to hormone receptor status and other factors. J Clin Oncol (2006) 24:1037–1044.
20. Gregory RK, Powles TJ, Salter J, et al. Prognostic relevance of cerbB2 expression following neoadjuvant chemotherapy in patients in a randomised trial of neoadjuvant versus adjuvant chemoendocrine therapy. Breast Cancer Res Treat (2000) 59:171–175.[CrossRef][Web of Science][Medline]
21. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med (2005) 353:1659–1672.
22. Buzdar AU, Valero V, Ibrahim NK, et al. Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: an update of the initial randomized study population and data of additional patients treated with the same regimen. Clin Cancer Res (2007) 13:228–233.
23. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A (2001) 98:10869–10874.
24. Cleator S, Heller W, Coombes RC. Triple-negative breast cancer: therapeutic options. Lancet Oncol (2007) 8:235–244.[CrossRef][Web of Science][Medline]
25. Nielsen TO, Hsu FD, Jensen K, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res (2004) 10:5367–5374.
26. Konecny G, Pauletti G, Pegram M, et al. Quantitative association between HER2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. J Natl Cancer Inst (2004) 95:142–153.[Web of Science]
27. Colleoni M, Rotmensz N, Martinelli G, et al. Lesson learned from high-dose chemotherapy for high-risk breast cancer (What you see is what you mean). Ann Oncol (2004) 15:355–356.
28. Cormier EM, Wolf MF, Jordan VC. Decrease in estradiol-stimulated progesterone receptor production in MCF-7 cells by epidermal growth factor and possible clinical implication for paracrine-regulated breast cancer growth. Cancer Res (1989) 49:576–580.
29. Kim HJ, Cui X, Hilsenbeck SG, et al. Progesterone receptor loss correlates with human epidermal growth factor receptor 2 overexpression in estrogen receptor positive breast cancer. Clin Cancer Res (2006) 12:1013–1018.[CrossRef]
30. Gee JM, Robertson JF, Gutteridge E, et al. Epidermal growth factor receptor/HER2/insulin-like growth factor receptor signalling and oestrogen receptor activity in clinical breast cancer. Endocr Relat Cancer (2005) 12:99–111.[Medline]
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