Simona Giovannelli

Comparison of HER-2 and hormone receptor expression in primary breast cancers and asynchronous paired metastases: impact on patient management.

INTRODUCTION The assessment of hormone receptors (HRs) and human epidermal growth factor receptor (HER)-2 is necessary to select patients who are candidates for hormonal and anti-HER-2 therapy. The evaluation of these parameters is generally carried out in primary tumors and it is not clear if reassessment in metastatic lesions might have an impact on patient management. The primary aim of this analysis was to compare HER-2 and HR status in primary tumors versus metastatic sites in breast cancer patients. PATIENTS AND METHODS Seventy-five patients with available samples from primary tumors and paired metastases were included. HER-2 status was evaluated by immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH); HR status was assessed by IHC. RESULTS Nineteen percent of primary tumors were HER-2 positive; 77% were HR positive. Sites of biopsied or resected metastases were: locoregional soft tissues (n = 30), liver (n = 20), central nervous system (n = 5), bone (n = 5), pleura (n = 4), distant soft tissues (n = 3), abdomen (stomach, colon, peritoneum) (n = 3), bronchus (n = 3), and bone marrow (n = 2). For paired metastases, the HER-2 status was unchanged in 84% of cases; two patients changed from positive to negative, while 10 patients converted from negative to positive (agreement, 84%; kappa = 0.5681). A change in HR status was observed in 16 cases (21%): nine cases from positive to negative and seven cases from negative to positive (agreement, 78.7%; kappa = 0.4158). CONCLUSIONS Further studies are necessary to better define the level of discordance in HER-2 or HR status between primary tumors and paired metastases. However, a biopsy of metastatic disease can be recommended, if feasible with minimal invasiveness, because treatment options might change for a significant proportion of patients.

A prognostic model based on nodal status and Ki-67 predicts the risk of recurrence and death in breast cancer patients with residual disease after preoperative chemotherapy

BACKGROUND Preoperative chemotherapy (PCT) allows for in vivo testing of treatment effects on tumor and its microenvironment. Aim of this analysis was to evaluate the effect of PCT on tumor biomarker expression and to evaluate the prognostic role of treatment-induced variation of these biomarkers (molecular response). METHODS Two hundred and twenty-one stage II-III breast cancer patients were included. The following parameters were evaluated at baseline and on surgical specimens after PCT: estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), Ki-67, p53, human epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor 2 (VEGFR2), and apoptosis. RESULTS A pathological complete response was observed in 8.8% of the patients. PCT induced a significant reduction in the expression of ER, PgR, Ki-67, and apoptosis. As by multivariable model, Ki-67 > or = 15% and nodal positivity after preoperative chemotherapy (PCT) were significant predictors of worse disease-free survival [hazard ratio (HR) 3.79, P < 0.0001 and HR 2.31, P = 0.037, respectively]. Ki-67 > or = 15% after PCT was also a significant predictor of overall survival (HR 3.75, P = 0.013). On the basis of these two parameters, patients were classified into three groups: (i) low risk (negative nodes and Ki-67 <15%), (ii) intermediate risk (nodal positivity or Ki-67 > or = 15%), and (iii) high risk (nodal positivity and Ki-67 > or = 15%). As compared with the low-risk group, the HRs for recurrence were 3.1 and 9.3 for the intermediate- and high-risk group, respectively (P = 0.0001); the HRs for death were 2.4 and 6.5 for the intermediate- and high-risk group, respectively (P = 0.042). CONCLUSIONS Ki-67 and nodal status have been used to generate a simple and easily reproducible prognostic model, able to discriminate patients with worse prognosis among the heterogeneous group of women with residual disease after PCT.

Letrozole versus letrozole plus lapatinib (GW572016) in hormone-sensitive, HER2-negative operable breast cancer: A double-blind, randomized, phase II study with biomarker evaluation (EGF109077-LAP107692/LETLOB)

Many hormone receptor-positive tumors show primary or acquired resistance, possibly because of a crosstalk with other growth factor-related transduction pathways (mainly epidermal growth factor receptor family related). The LETLOB study is a European multicenter, placebo-controlled, randomized phase II trial in postmenopausal patients with hormone-sensitive, HER2-negative, stage II-IIIA (T > 2 cm, N0-1, M0) breast cancer, in which letrozole or the combination of letrozole plus lapatinib will be administered for 6 months before surgery. Clinical endpoints (primary [ultrasonographic objective response], secondary [rate of pathologic complete response and of conservative surgery, safety, and time to treatment failure], and biologic [inhibition of intermediate and final biomarkers of the proliferative and apoptosis pathways and gene profile correlation with response]) will be evaluated.

Predictive and prognostic role of p53 according to tumor phenotype in breast cancer patients treated with preoperative chemotherapy: a single-institution analysis

Introduction and aims The p53 protein is a mediator of the cellular response to DNA damage. The aim of this study was to evaluate the predictive and/or prognostic value of p53 expression in relation to the molecular subtypes of breast cancer in patients treated with preoperative chemotherapy. Patients and methods Patients with stage II-III breast cancer were included in the study. The expression of p53 was evaluated by immunohistochemistry on the diagnostic core biopsy specimen. Patients received 4–6 courses of preoperative chemotherapy. Pathological complete response (pCR) was defined as complete disappearance of invasive tumor in the breast and axillary lymph nodes. Results 154 patients were included in the study and the molecular subtypes of their tumors were classified as follows: triple negative 18.2%, hormone receptor positive 60.4%, and HER2 positive 21.4%. p53 was expressed in 43.5% of the patients. A significant association between p53 expression and breast cancer molecular subtypes, tumor differentiation, and proliferation was observed. pCR was achieved in 8 patients (5.2%). p53 expression, molecular subtype, and nuclear grading were significant predictors of pCR (odds ratio for pCR in patients with p53-expressing tumors 10.03, p=0.0077). In univariate analysis, the expression of p53 as well as high proliferation and lymph node involvement after preoperative chemotherapy were predictors of a worse disease-free survival. Patients with p53 positivity also had a worse overall survival. In multivariate analysis, both p53 expression and nodal status after preoperative chemotherapy were significantly associated with disease-free and overall survival: the hazard ratios for relapse and death in patients with p53-expressing versus non-p53-expressing tumors were 2.29 (p=0.015) and 7.74 (p=0.002), respectively. The hazard ratios for relapse and death in node-positive versus node-negative patients were 3.63 (p=0.003) and 3.64 (p=0.041), respectively. Conclusions In this series of patients, p53 expression was significantly associated with markers of aggressive tumor biology, and with a higher likelihood of attaining pCR. p53 expression was a negative prognostic parameter for disease-free and overall survival in univariate and multivariate analysis.

A prognostic model based on nodal status and Ki 67 predicts the risk of recurrence and death in breast cancer patients with residual disease after preoperative chemotherapy.

Abstract #1066 Introduction and Aims: The achievement of a pathologic complete response (pCR) after preoperative chemotherapy (PCT) is a validated surrogate end point for long term outcome. On the other side, patients with residual disease in the breast and/or axilla are an heterogeneous group with very different prognosis, including both patients with truly chemo-resistant disease as well as patients with an important tumor downstaging even if not in pCR. Aim of this analysis is to identify, in patients with residual disease, potential markers able to discriminate patients at higher risk of relapse.
 Patients and Methods:. The following parameters were evaluated on the surgical specimen in patients with less than pCR following PCT: residual breast disease, number of involved nodes, proliferation (Ki 67), hormone receptor, HER2, p53, EGFR, VEGFR2. Survival curves were estimated with the Kaplan-Meier method and the log rank test was used to test for differences between groups. Hazard Ratios and their confidence intervals were estimated by using Cox model.
 Results: 195 breast cancer patients were included. Median age 51 yrs (range: 27-73); 71% of the patients had ER+ tumors at diagnosis, 20% were HER2+. After PCT, 55% of the patients received mastectomy, 45% underwent conservative surgery. 57% of the patients had residual breast disease 10 nodes; 50% of the patients had Ki 67 >/= 15%. Among the examined parameters, nodal positivity and Ki 67>/=15% were significantly related with a higher risk of relapse (HR 2.5 , p=0.014 and HR 3.4, p /=15% was also predictive of a higher risk of death (HR 4.1, p=0.007). On the basis of these two parameters, patients were classified in three groups: 1) low risk (negative nodes and Ki 67 /= 15%): 54.4% of the patients; 3) high risk (nodal positivity and Ki 67>/= 15%): 31.2% of the patients. Five-year DFS rates were 90%, 72%, and 43% respectively (log rank test p Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1066.

Future role of bevacizumab in breast cancer

In the past years, anti-angiogenic therapies have rapidly developed for many solid tumors, including breast cancer. The first phase III trial of bevacizumab in combination with capecitabine versus capecitabine alone was conducted in 462 patients with MBC previously treated with antracycline or taxane: although the addition of bevacizumab did not improve PFS, there was an absolute increase of approximately 11% in ORR (20 vs 9%; P = 0.001) [1]. In the E2100 trial the addition of bevacizumab to first-line weekly paclitaxel resulted in doubling of both the objective RR (36.9 vs 21.2%; P < 0.0001) and median PFS (11.8 vs 5.9 months; P < 0.0001), compared with paclitaxel alone in more than 700 HER2-negative MBC patients, although there was no impact on OS [2]. These findings were corroborated by more complete analyses for regulatory purpose and confirmed by IRF. The AVADO phase III trial compared bevacizumab with placebo in combination with docetaxel as first-line chemotherapy for patients with HER2-negative locally recurrent breast cancer or MBC, showing a significant improvement in PFS (8.8 months for bevacizumab 15 mg/kg vs 8 months for docetaxel; P < 0.0001) [3]. These results have led to the development of multiple phase III trials of bevacizumab in combination with chemotherapy agents in first-line MBC, along with trials investigating the addition of bevacizumab to other anticancer therapies such as trastuzumab and endocrine agents. To date no predictive biomarkers for benefit from bevacizumab have been identified; several ongoing trials incorporate molecular studies with the aim of targeting the correct subset of patients (such as triple-negative patients) for bevacizumab therapy. Clinical trials are underway to evaluate the use of bevacizumab in the adjuvant and neoadjuvant setting. The BEATRICE phase III trial will assess the benefit of adding bevacizumab to standard adjuvant chemotherapy (anthracycline ± taxane or taxane only) in triple-negative early breast cancer. The addition of bevacizumab to adjuvant chemotherapy (docetaxel/carboplatin or docetaxel–FEC) and trastuzumab will be studied in a further phase III trial (BETH) in patients with HER2-positive breast cancer. Other phase III adjuvant trials are evaluating the addition of bevacizumab to standard chemotherapy in HER2-negative and in node-positive or high-risk breast cancer. The NSABP B-40 ongoing phase III trial will evaluate the addition of bevacizumab to either neoadjuvant docetaxel, docetaxel plus capecita-bine or docetaxel plus gemcitabine followed by doxorubicin plus cyclophosphamide in patients with operable breast cancer. The phase III GeparQuinto trial will evaluate the integration of bevacizumab, everolimus and lapatinib into current neoadjuvant regimens [4]. Bevacizumab will probably have an established role in the treatment of some subgroups of MBC and as adjuvant therapy in early breast cancer; we need to identify which subgroups of patients may specifically benefit from bevacizumab therapy.

Oral vinorelbine in metastatic breast cancer

A new oral formulation of vinorelbine has been introduced in clinical studies since 1994, following increasing interest in the development of oral chemotherapy, driven by pharmacoeconomic issues, patient convenience and the potential for improved quality of life. A dose-finding study [1] established that 100 mg/m2 was the MTD dose, limiting toxicities being neutropenia, nausea and vomiting, and neuroconstipation; the recommended dose was then defined at 80 mg/m2 per week. The first phase II studies conducted in chemotherapy-naive NSCLC and as first-line chemotherapy in advanced breast cancer (ABC) showed an excessive rate of complicated neutropenia. This led to the formulation of a new schedule in which a lower dose of 60 mg/m2 per week was administered for the first three courses with escalation to 80 mg/m2, with a safety profile qualitatively comparable to that of intravenous vinorelbine at standard doses [2]. Equivalent blood concentrations were demonstrated between 80 mg/m2 oral and 30 mg/m2 intravenous, and between 60 mg/m2 oral and 25 mg/m2 intravenous [3].