Cristina Oliva

Lapatinib Combined With Letrozole Versus Letrozole and Placebo As First-Line Therapy for Postmenopausal Hormone Receptor-Positive Metastatic Breast Cancer

PURPOSE Cross-talk between human epidermal growth factor receptors and hormone receptor pathways may cause endocrine resistance in breast cancer. This trial evaluated the effect of adding lapatinib, a dual tyrosine kinase inhibitor blocking epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2), to the aromatase inhibitor letrozole as first-line treatment of hormone receptor (HR) -positive metastatic breast cancer (MBC). PATIENTS AND METHODS Postmenopausal women with HR-positive MBC were randomly assigned to daily letrozole (2.5 mg orally) plus lapatinib (1,500 mg orally) or letrozole and placebo. The primary end point was progression-free survival (PFS) in the HER2-positive population. Results In HR-positive, HER2-positive patients (n = 219), addition of lapatinib to letrozole significantly reduced the risk of disease progression versus letrozole-placebo (hazard ratio [HR] = 0.71; 95% CI, 0.53 to 0.96; P = .019); median PFS was 8.2 v 3.0 months, respectively. Clinical benefit (responsive or stable disease >or= 6 months) was significantly greater for lapatinib-letrozole versus letrozole-placebo (48% v 29%, respectively; odds ratio [OR] = 0.4; 95% CI, 0.2 to 0.8; P = .003). Patients with centrally confirmed HR-positive, HER2-negative tumors (n = 952) had no improvement in PFS. A preplanned Cox regression analysis identified prior antiestrogen therapy as a significant factor in the HER2-negative population; a nonsignificant trend toward prolonged PFS for lapatinib-letrozole was seen in patients who experienced relapse less than 6 months since prior tamoxifen discontinuation (HR = 0.78; 95% CI, 0.57 to 1.07; P = .117). Grade 3 or 4 adverse events were more common in the lapatinib-letrozole arm versus letrozole-placebo arm (diarrhea, 10% v 1%; rash, 1% v 0%, respectively), but they were manageable. CONCLUSION This trial demonstrated that a combined targeted strategy with letrozole and lapatinib significantly enhances PFS and clinical benefit rates in patients with MBC that coexpresses HR and HER2.

Multicenter Phase II Study of Lapatinib in Patients with Brain Metastases from HER2-Positive Breast Cancer

Purpose: Brain metastases develop in one third of patients with advanced HER2+ breast cancer. Effective therapy for patients with central nervous system (CNS) progression after cranial radiation is extremely limited and represents a major clinical challenge. Lapatinib, an epidermal growth factor receptor/HER2 inhibitor, was associated with regressions of CNS lesions in a small phase 2 trial. The current study was done to further evaluate the CNS activity of lapatinib. The study was later amended to allow patients who progressed on lapatinib the option of receiving lapatinib plus capecitabine. Experimental Design: Eligible patients had HER2+ breast cancer, progressive brain metastases, prior trastuzumab, and cranial radiotherapy. The primary end point was CNS objective response, defined as ≥50% volumetric reduction of CNS lesion(s) in the absence of increasing steroid use, progressive neurologic signs and symptoms, or progressive extra-CNS disease. Results: Two-hundred and forty-two patients entered the study. CNS objective responses to lapatinib were observed in 6% of patients. In an exploratory analysis, 21% of patients experienced a ≥20% volumetric reduction in their CNS lesions. An association was observed between volumetric reduction and improvement in progression-free survival and neurologic signs and symptoms. Of the 50 evaluable patients who entered the lapatinib plus capecitabine extension, 20% experienced a CNS objective response and 40% experienced a ≥20% volumetric reduction in their CNS lesions. Conclusions: This study confirms the modest CNS antitumor activity of lapatinib. Additional responses were observed with the combination of lapatinib and capecitabine. Further studies of lapatinib-based regimens for CNS metastases from HER2+ breast cancer are warranted.

Phase III, Double-Blind, Randomized Study Comparing Lapatinib Plus Paclitaxel With Placebo Plus Paclitaxel As First-Line Treatment for Metastatic Breast Cancer

PURPOSE Lapatinib, a dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR/ErbB1) and human epidermal growth factor receptor 2 (HER-2/ErbB2), is effective against HER-2-positive locally advanced or metastatic breast cancer (MBC). This phase III trial evaluated the efficacy of lapatinib in HER-2-negative and HER-2-uncharacterized MBC. PATIENTS AND METHODS Women with MBC were randomly assigned to first-line therapy with paclitaxel 175 mg/m(2) every 3 weeks plus lapatinib 1,500 mg/d or placebo. A preplanned retrospective evaluation of HER-2 status was performed using fluorescence in situ hybridization and immunohistochemistry. The primary end point was time to progression (TTP); secondary end points were objective response rate (ORR), clinical benefit rate (CBR), event-free survival (EFS), and overall survival (OS). RESULTS In the intent-to-treat population (n = 579), there were no significant differences in TTP, EFS, or OS between treatment arms, although differences in ORR and CBR were noted. In 86 HER-2-positive patients (15%), treatment with paclitaxel-lapatinib resulted in statistically significant improvements in TTP, EFS, ORR, and CBR compared with paclitaxel-placebo. No differences between treatment groups were observed for any end point in HER-2-negative patients. The most common adverse events were alopecia, rash, and diarrhea. The incidence of diarrhea and rash was significantly higher in the paclitaxel-lapatinib arm. The rate of cardiac events was low, and no difference was observed between treatment arms. CONCLUSION Patients with HER-2-negative or HER-2-untested MBC did not benefit from the addition of lapatinib to paclitaxel. However, first-line therapy with paclitaxel-lapatinib significantly improved clinical outcomes in HER-2-positive patients. Prospective evaluation of the efficacy and safety of this combination is ongoing in early and metastatic HER-2-positive breast cancer patients.

Lapatinib Plus Capecitabine in Women with HER-2–Positive Advanced Breast Cancer: Final Survival Analysis of a Phase III Randomized Trial

The article presents final analyses of overall survival from a phase III trial of lapatinib and capecitabine in patients with human epidermal growth factor receptor 2–positive locally advanced or metastatic breast cancer that progressed following prior therapy including trastuzumab.

HER-2 Gene Amplification, HER-2 and Epidermal Growth Factor Receptor mRNA and Protein Expression, and Lapatinib Efficacy in Women with Metastatic Breast Cancer

Purpose: Biomarkers from two randomized phase III trials were analyzed to optimize selection of patients for lapatinib therapy. Experimental Design: In available breast cancer tissue from EGF30001 (paclitaxel ± lapatinib in HER-2-negative/unknown metastatic breast cancer, n = 579) and EGF100151 (capecitabine ± lapatinib in HER-2-positive metastatic breast cancer, n = 399), HER-2 gene amplification by fluorescence in situ hybridization (FISH), HER-2 mRNA by reverse transcription-PCR (RT-PCR), HER-2 protein expression by HercepTest immunohistochemistry (IHC), epidermal growth factor receptor (EGFR) mRNA level by RT-PCR, and EGFR protein by IHC were analyzed and compared with clinical outcome. HER-2 was determined by FISH in an academic reference/research laboratory and in a large, high-volume commercial reference laboratory. Results: The HER-2 gene was amplified in 47% (344 of 733) and IHC was 3+ in 35% (279 of 798), with significant correlation (P < 0.01) between FISH and IHC. Positive EGFR immunostaining (IHC 1+, 2+, or 3+) in 28% (213 of 761) correlated with EGFR mRNA levels by RT-PCR (r = 0.59; P < 0.01). HER-2 gene amplification/overexpression was associated with improved clinical outcomes (progression-free survival; P < 0.001) in both trials. A significant improvement in outcome was seen in FISH-positive and IHC 0, 1+, or 2+ patients. HER-2 mRNA expression correlated with HER-2 FISH (r = 0.83) and IHC status (r = 0.72; n = 138). No correlation was found between EGFR expression (IHC or mRNA) and responsiveness to lapatinib regardless of HER-2 status. Although a significant correlation with lapatinib responsiveness was observed among “HER-2-negative” breast cancer patients in the large, high-volume commercial reference laboratory, this was not confirmed in the academic reference/research laboratory. Conclusions: Women with HER-2-positive metastatic breast cancer benefit from lapatinib, whereas women with HER-2-negative metastatic breast cancer derive no incremental benefit from lapatinib.

Interleukin 6, a Nuclear Factor-κB Target, Predicts Resistance to Docetaxel in Hormone-Independent Prostate Cancer and Nuclear Factor-κB Inhibition by PS-1145 Enhances Docetaxel Antitumor Activity

Purpose: To investigate whether nuclear factor κB (NF-κB)/interleukin 6 (IL-6) was linked to docetaxel response in human prostate cancer cell lines, and whether inhibition of NF-κB sensitized tumor cells to docetaxel. We also aimed to correlate IL-6 (as a surrogate marker of NF-κB) and docetaxel response in hormone-independent prostate cancer (HIPC) patients. Experimental Design: Hormone-dependent (LNCaP) and hormone-independent (PC-3 and DU-145) prostate cancer cell lines were exposed to docetaxel alone or combined with the NF-κB inhibitor PS-1145 (an inhibitor of IκB kinase-2). Effects of dose, exposure time, and schedule dependence were assessed. Activation of NF-κB was assayed by electrophoresis mobility shift assay and luciferase reporter assay, IL-6 levels by ELISA, and cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell cycle and apoptosis were assessed by fluorescence-activated cell sorting analysis. Apoptosis was also measured by detection of cleavage of poly(ADP-ribose) polymerase. In patients with metastatic HIPC receiving docetaxel-based chemotherapy, IL-6 serum levels were assayed before chemotherapy and every 3 to 4 weeks thereafter. Results: PC-3 and DU-145 cells had higher NF-κB activity, secreted more IL-6, and were more resistant to docetaxel than LNCaP cells. NF-κB activity was induced by docetaxel. Cotreatment with docetaxel and PS-1145 prevented docetaxel-induced NF-κB activation, reduced IL-6 production, and increased docetaxel effects on cell viability in PC-3 and DU-145 cells but not in LNCaP. Synergism with docetaxel and PS-1145, as assayed by median-effect principle, was observed in DU-145 and PC-3. In HIPC patients, pretreatment IL-6 serum levels correlated to prostate-specific antigen (PSA) response: median IL-6 level was 10.8 ± 9.5 pg/mL in PSA responders versus 36.7 ± 20.8 pg/mL (P = 0.006) in nonresponders. A PSA response was also linked to a decline in IL-6 levels during treatment. Median overall survival was 6.8 months in patients with high IL-6 versus 16.6 months in those with low IL-6 (P = 0.0007). On multivariate analysis, pretreatment IL-6 (P = 0.05) was an independent prognostic factor for time to disease progression and survival. Conclusions: Inhibition of NF-κB emerges as an attractive strategy to enhance docetaxel response in prostate cancer. The interest of this view is further supported by a significant association between high IL-6 in sera of HIPC patients and decreased response to docetaxel.

Mitogen-Activated Protein Kinase Phosphatase-1 in Human Breast Cancer Independently Predicts Prognosis and Is Repressed by Doxorubicin

Purpose: Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) dephosphorylates mitogen-activated protein kinase [extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38], mediates breast cancer chemoresistance, and is repressible by doxorubicin in breast cancer cells. We aimed to characterize doxorubicin effects on MKP-1 and phospho-MAPKs in human breast cancers and to further study the clinical relevance of MKP-1 expression in this disease. Experimental Design: Doxorubicin effects on MKP-1, phospho-ERK1/2 (p-ERK1/2), phospho-JNK (p-JNK), and phospho-p38 were assayed in a panel of human breast cancer cells by Western blot and in human breast cancer were assayed ex vivo by immunohistochemistry (n = 50). MKP-1 expression was also assayed in a range of normal to malignant breast lesions (n = 30) and in a series of patients (n = 96) with breast cancer and clinical follow-up. Results: MKP-1 was expressed at low levels in normal breast and in usual ductal hyperplasia and at high levels in in situ carcinoma. MKP-1 was overexpressed in ∼50% of infiltrating breast carcinomas. Similar to what was observed in breast cancer cell lines, ex vivo exposure of breast tumors to doxorubicin down-regulated MKP-1, and up-regulated p-ERK1/2 and p-JNK, in the majority of cases. However, in a proportion of tumors overexpressing MKP-1, doxorubicin did not significantly affect MKP-1 or phospho-MAPKs. With regard to patient outcome, MKP-1 overexpression was an adverse prognostic factor for relapse both by univariate (P < 0.001) and multivariate analysis (P = 0.002). Conclusions: MKP-1 is overexpressed during the malignant transformation of the breast and independently predicts poor prognosis. Furthermore, MKP-1 is repressed by doxorubicin in many human breast cancers.

The impact of received dose intensity on the outcome of advanced ovarian cancer

It has been demonstrated that the prognosis of ovarian cancer is influenced by the dose intensity of cytotoxic treatment. The impact of received dose intensity of platinum-based combination chemotherapy on disease outcome was analysed in 226 stage III-IV ovarian cancer patients entered into two prospective randomised trials. All patients received either cisplatin or carboplatin and cyclophosphamide with or without doxorubicin for six courses after primary surgery. The impact of the received dose intensity of each drug (RDI), the average received dose intensity of the treatment regimen (ARDI) and the relative total drug dose (RTD) on progression-free survival (PFS) and survival were analysed. In the 198 patients receiving the full six courses of treatment, RDI of cisplatin or carboplatin, ARDI and RTD were > 0.76 in 74.2, 61.1 and 65.1% of cases, respectively. Although the differences were not significant, pathological complete response was more frequently observed in the group of patients with ARDI < 0.75, whereas the partial response rate was higher in the ARDI > or = 0.76 group. Median survival and PFS were 19 and 13 months; 22 and 10 months; 23 and 13 months for the groups of patients receiving chemotherapy at a ARDI of < 0.75, > or = 0.76-0.99 and > 1.00, respectively (P = not significant). It appears that modest dose modifications and brief treatment delays during first-line platinum-based chemotherapy do not affect response rate, survival and PFS in advanced ovarian cancer patients.

Long-term prognosis following macroscopic complete response at second-look laparotomy in advanced ovarian cancer patients treated with platinum-based chemotherapy

Abstract Survival (S) and progression-free survival (PFS) were evaluated in 129 advanced ovarian cancer patients, who achieved a macroscopic complete response (112 pathological complete response and 17 microscopic disease) at second-look after platinum-based combination chemotherapy with or without doxorubicin (DX). The impact on S and PFS of age, performance status (PS), stage, histology, grade (G), residual disease after first surgery (RD), chemotherapy regimen, disease status at second-look and consolidation therapy were evaluated by univariate and multivariate analysis. In the 118 months observation period, median S and PFS were 81 and 34 months, respectively. Stage, G, RD, PS and disease status at second-look had significant impact on both S and PFS in univariate analysis, whereas consolidation therapy did not influence outcome. Coxs regression analysis showed that G, RD and PS had an independent impact on PFS. Test for interaction demonstrated no statistically significant relationship between RD, chemotherapy regimen and outcome. In conclusion, advanced ovarian cancer patients with macroscopically complete remission at second-look have a substantial risk of relapse after aggressive treatment. The risk of recurrence was estimated to be maximal in the first 3 years after restaging, and was correlated with poor PS, RD > 2 cm after first surgery and undifferentiated tumour.

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.