Susana Banerjee

Basal-like breast carcinomas: clinical outcome and response to chemotherapy

Background: Grade-III invasive ductal carcinomas of no special type (IDCs-NST) constitute a heterogeneous group of tumours with different clinical behaviour and response to chemotherapy. As many as 25% of all grade-III IDCs-NST are known to harbour a basal-like phenotype, as defined by gene expression profiling or immunohistochemistry for basal cytokeratins. Patients with basal-like breast carcinomas (BLBC) are reported to have a shorter disease-free and overall survival. Material and methods: A retrospective analysis of 49 patients with BLBC (as defined by basal cytokeratin expression) and 49 controls matched for age, nodal status and grade was carried out. Histological features, immunohistochemical findings for oestrogen receptor (ER), progesterone receptor (PgR) and HER2, and clinical outcome and survival after adjuvant chemotherapy were compared between the two groups. Results: It was more likely for patients with BLBCs to be found negative for ER (p<0.0001), PgR (p<0.0001) and HER2 (p<0.01) than controls. Patients with BLBCs were found to have a significantly higher recurrence rate (p<0.05) and were associated with significantly shorter disease-free and overall survival (both p<0.05). In the group of patients who received anthracycline-based adjuvant chemotherapy (BLBC group, n = 47; controls, n = 49), both disease-free and overall survival were found to be significantly shorter in the BLBC group (p<0.05). Conclusions: BLBCs are a distinct clinical and pathological entity, characterised by high nuclear grade, lack of hormone receptors and HER2 expression and a more aggressive clinical course. Standard adjuvant chemotherapy seems to be less effective in these tumours and new therapeutic approaches are indicated.

New Strategies in the Treatment of Ovarian Cancer: Current Clinical Perspectives and Future Potential

The treatment of ovarian cancer is set to undergo rapid changes, as strategies incorporating molecular targeted therapies begin to take shape. These are based on a better appreciation of approaches targeting the tumor microenvironment as well as specific subtypes of the disease, with distinct molecular aberrations. Targeting the VEGF pathway through bevacizumab is clearly effective, with positive randomized trials at all disease stages; targeting defective homologous recombination repair pathways with PARP inhibitors is also proving successful in a substantial proportion of patients with high-grade serous ovarian cancer. In this article, we will review progress in these two leading areas and also discuss the potential for targeting other pathways and receptors that may be activated in ovarian cancer, including the RAS/RAF/MEK and PI3K/AKT/mToR pathways, the ErbB and IGF family of receptors, mitotic check points, and also the folate receptor. Here, single-agent therapy may play a role in selected cases but essential components of future strategies should include combination treatments aimed at dealing with the key problem of drug resistance, together with rational approaches to patient selection. Clin Cancer Res; 19(5); 961–8. ©2013 AACR.

Mechanisms of disease: angiogenesis and the management of breast cancer.

Demonstration of the clinically significant activity of bevacizumab in breast cancer has attracted a great deal of interest. Numerous other antiangiogenic treatments are in clinical development and some established therapies including tamoxifen and trastuzumab might function, in part, by suppressing angiogenesis. In this Review, we discuss the potential of various components of the angiogenic pathway as prognostic and predictive factors in breast cancer. In addition, we describe existing clinical trials of antiangiogenic agents and the challenges facing the clinical development and optimum use of these agents for the treatment of breast cancer.

Making the best of PARP inhibitors in ovarian cancer

Drugs that inhibit the enzyme poly(ADP-ribose)polymerase (PARP) are showing considerable promise for the treatment of cancers that have mutations in the BRCA1 or BRCA2 tumor suppressors. This therapeutic approach exploits a synthetic lethal strategy to target the specific DNA repair pathway in these tumors. High-grade ovarian cancers have a generally poor prognosis, and accumulating evidence suggests that mutations in BRCA1 or BRCA2, or silencing of BRCA1 by promoter methylation, may be common in this disease. Here, we consider how the potential benefit of PARP inhibitors might be maximized in ovarian cancer. We suggest that it will be crucial to explore novel therapeutic trial strategies and drug combinations, and incorporate robust biomarkers predictive of response if these drugs are to reach their full potential.

ERBB2 influences the subcellular localization of the estrogen receptor in tamoxifen-resistant MCF-7 cells leading to the activation of AKT and RPS6KA2.

Acquired resistance to endocrine therapies remains a major clinical obstacle in hormone-sensitive breast tumors. We used an MCF-7 breast tumor cell line (Tam(R)-1) resistant to tamoxifen to investigate this mechanism. We demonstrate that Tam(R)-1 express elevated levels of phosphorylated AKT and MAPK3/1-activated RPS6KA2 compared with the parental MCF-7 cell line (MCF-7). There was no change in the level of total ESR between the two cell lines; however, the Tam(R)-1 cells had increased phosphorylation of ESR1 ser(167). SiRNA blockade of AKT or MAPK3/1 had little effect on ESR1 ser(167) phosphorylation, but a combination of the two siRNAs abrogated this. Co-localization studies revealed an association between ERBB2 and ESR1 in the Tam(R)-1 but not MCF-7 cells. ESR1 was redistributed to extranuclear sites in Tam(R)-1 and was less transcriptionally competent compared with MCF-7 suggesting that nuclear ESR1 activity was suppressed in Tam(R)-1. Tamoxifen resistance in the Tam(R)-1 cells could be partially overcome by the ERBB2 inhibitor AG825 in combination with tamoxifen, and this was associated with re-localization of ESR1 to the nucleus. These data demonstrate that tamoxifen-resistant cells have the ability to switch between ERBB2 or ESR1 pathways promoting cell growth and that pharmacological inhibition of ERBB2 may be a therapeutic strategy for overcoming tamoxifen resistance.

Efficacy of Chemotherapy in BRCA1/2 Mutation Carrier Ovarian Cancer in the Setting of PARP Inhibitor Resistance: A Multi-Institutional Study

Purpose: Preclinical data suggest that exposure to PARP inhibitors (PARPi) may compromise benefit to subsequent chemotherapy, particularly platinum-based regimens, in patients with BRCA1/2 mutation carrier ovarian cancer (PBMCOC), possibly through the acquisition of secondary BRCA1/2 mutations. The efficacy of chemotherapy in the PARPi-resistant setting was therefore investigated. Experimental Design: We conducted a retrospective review of PBMCOC who received chemotherapy following disease progression on olaparib, administered at ≥200 mg twice daily for one month or more. Tumor samples were obtained in the post-olaparib setting where feasible and analyzed by massively parallel sequencing. Results: Data were collected from 89 patients who received a median of 3 (range 1–11) lines of pre-olaparib chemotherapy. The overall objective response rate (ORR) to post-olaparib chemotherapy was 36% (24 of 67 patients) by Response Evaluation Criteria in Solid Tumors (RECIST) and 45% (35 of 78) by RECIST and/or Gynecologic Cancer InterGroup (GCIG) CA125 criteria with median progression-free survival (PFS) and overall survival (OS) of 17 weeks [95% confidence interval (CI), 13–21] and 34 weeks (95% CI, 26–42), respectively. For patients receiving platinum-based chemotherapy, ORRs were 40% (19 of 48) and 49% (26/53), respectively, with a median PFS of 22 weeks (95% CI, 15–29) and OS of 45 weeks (95% CI, 15–75). An increased platinum-to-platinum interval was associated with an increased OS and likelihood of response following post-olaparib platinum. No evidence of secondary BRCA1/2 mutation was detected in tumor samples of six PARPi-resistant patients [estimated frequency of such mutations adjusted for sample size: 0.125 (95%-CI: 0–0.375)]. Conclusions: Heavily pretreated PBMCOC who are PARPi-resistant retain the potential to respond to subsequent chemotherapy, including platinum-based agents. These data support the further development of PARPi in PBMCOC. Clin Cancer Res; 19(19); 5485–93. ©2013 AACR.

Trabectedin in advanced uterine leiomyosarcomas: A retrospective case series analysis from two reference centers

BACKGROUND Treatment options for patients with metastatic uterine leiomyosarcoma are limited. Over the last few years, trabectedin has emerged as an effective agent for patients with advanced soft tissue sarcomas resistant to anthracyclines and ifosfamide. The aim of this retrospective analysis was to look at the efficacy of trabectedin in the subgroup of uterine leiomyosarcoma. PATIENTS AND METHODS A retrospective analysis was carried out on patients with uterine leiomyosarcoma treated with trabectedin at two reference sarcoma centers between 2000 and 2010. Radiological response, progression-free and overall survival, as well as serious and unexpected adverse events, were assessed. RESULTS Sixty-six patients with metastatic uterine leiomyosarcoma were identified. The median number of previous chemotherapy regimens was 3 (range 1-5). Eleven patients (16%) achieved a partial response and 23 (35%) had a stable disease. The progression-free survival of the entire cohort was 3.3 months (CI 95% 2-5), and the progression-free rate at 3 and 6 months was 53% and 33%, respectively. CONCLUSIONS Trabectedin is a therapeutic option in the palliative approach to the metastatic uterine leiomyosarcoma patient.

The role of targeted therapy in ovarian cancer

Ovarian cancer is the second most common gynaecological malignancy and the leading cause of death from gynaecological cancer. Although in some cases treatment is initially effective, there is a considerable risk of disease recurrence and resistance to therapy. Therapies targeting molecular alterations in tumours offer the promise of significantly improved treatment. So far, the most promising targeted agents are angiogenesis inhibitors and PARP inhibitors. Here, we review the various targeted therapeutic approaches under clinical investigation in phase I and II trials of ovarian cancer and the challenges facing their future success in the clinic.

The Future of Targeted Therapies in Ovarian Cancer

Ovarian cancer is the second most common gynecological malignancy and the leading cause of death from gynecological cancer. Most women present with advanced disease with little prospect for cure. There have been some advances in surgical and chemotherapeutic strategies, but these approaches have led to only minor improvements in outcome. There remains a significant risk for recurrence and resistance to therapy, and hence there is a need to improve upon the current treatment options. Molecularly directed therapy aims to target tumor cells and the tumor microenvironment by blocking specific molecular changes in the cancer. The most promising agents so far are the antiangiogenic agents and polyadenosine diphosphate-ribose polymerase inhibitors. This article reviews the various targeted therapeutic approaches under clinical investigation in ovarian cancer and the challenges facing their future success in the clinic.

Cediranib combined with carboplatin and paclitaxel in patients with metastatic or recurrent cervical cancer (CIRCCa): a randomised, double-blind, placebo-controlled phase 2 trial

Summary Background Patients treated with standard chemotherapy for metastatic or relapsed cervical cancer respond poorly to conventional chemotherapy (response achieved in 20–30% of patients) with an overall survival of less than 1 year. High tumour angiogenesis and high concentrations of intratumoural VEGF are adverse prognostic features. Cediranib is a potent tyrosine kinase inhibitor of VEGFR1, 2, and 3. In this trial, we aimed to assess the effect of the addition of cediranib to carboplatin and paclitaxel chemotherapy in patients with metastatic or recurrent cervical cancer. Methods In this randomised, double-blind, placebo-controlled phase 2 trial, which was done in 17 UK cancer treatment centres, patients aged 18 years or older initially diagnosed with metastatic carcinoma or who subsequently developed metastatic disease or local pelvic recurrence after radical treatment that was not amenable to exenterative surgery were recruited. Eligible patients received carboplatin AUC of 5 plus paclitaxel 175 mg/m2 by infusion every 3 weeks for a maximum of six cycles and were randomised centrally (1:1) through a minimisation approach to receive cediranib 20 mg or placebo orally once daily until disease progression. The stratification factors were disease site, disease-free survival after primary therapy or primary stage IVb disease, number of lines of previous treatment, Eastern Cooperative Oncology Group performance status, and investigational site. All patients, investigators, and trial personnel were masked to study drug allocation. The primary endpoint was progression-free survival. Efficacy analysis was by intention to treat, and the safety analysis included all patients who received at least one dose of study drug. This trial is registered with the ISCRTN registry, number ISRCTN23516549, and has been completed. Findings Between Aug 19, 2010, and July 27, 2012, 69 patients were enrolled and randomly assigned to cediranib (n=34) or placebo (n=35). After a median follow-up of 24·2 months (IQR 21·9–29·5), progression-free survival was longer in the cediranib group (median 8·1 months [80% CI 7·4–8·8]) than in the placebo group (6·7 months [6·2–7·2]), with a hazard ratio (HR) of 0·58 (80% CI 0·40–0·85; one-sided p=0·032). Grade 3 or worse adverse events that occurred in the concurrent chemotherapy and trial drug period in more than 10% of patients were diarrhoea (five [16%] of 32 patients in the cediranib group vs one [3%] of 35 patients in the placebo group), fatigue (four [13%] vs two [6%]), leucopenia (five [16%] vs three [9%]), neutropenia (10 [31%] vs four [11%]), and febrile neutropenia (five [16%] vs none). The incidence of grade 2–3 hypertension was higher in the cediranib group than in the control group (11 [34%] vs four [11%]). Serious adverse events occurred in 18 patients in the placebo group and 19 patients in the cediranib group. Interpretation Cediranib has significant efficacy when added to carboplatin and paclitaxel in the treatment of metastatic or recurrent cervical cancer. This finding was accompanied by an increase in toxic effects (mainly diarrhoea, hypertension, and febrile neutropenia). Funding Cancer Research UK and AstraZeneca.