Mark Beresford

Phase III, Double-Blind, Randomized Trial That Compared Maintenance Lapatinib Versus Placebo After First-Line Chemotherapy in Patients With Human Epidermal Growth Factor Receptor 1/2–Positive Metastatic Bladder Cancer

Purpose To establish whether maintenance lapatinib after first-line chemotherapy is beneficial in human epidermal growth factor receptor (HER) 1/HER2-positive metastatic urothelial bladder cancer (UBC). Methods Patients with metastatic UBC were screened centrally for HER1/HER2 overexpression. Patients who screened positive for HER1/2 and who did not have progressive disease during chemotherapy (four to eight cycles) were randomly assigned one to one to lapatinib or placebo after completion of first-line/initial chemotherapy for metastatic disease. The primary end point was progression-free survival (PFS). Results Between 2007 and 2013, 446 patients with UBC were screened, and 232 with HER1- or HER2-positive disease were randomly assigned. The median PFS for lapatinib and placebo was 4.5 (95% CI, 2.8 to 5.4) and 5.1 (95% CI, 3.0 to 5.8) months, respectively (hazard ratio, 1.07; 95% CI, 0.81 to 1.43; P = .63). The overall survival for lapatinib and placebo was 12.6 (95% CI, 9.0 to 16.2) and 12.0 (95% CI, 10.5 to 14.9) months, respectively (hazard ratio, 0.96; 95% CI, 0.70 to 1.31; P = .80). Discontinuation due to adverse events were similar in both arms (6% lapatinib and 5% placebo). The rate of grade 3 to 4 adverse events for lapatinib and placebo was 8.6% versus 8.1% ( P = .82). Preplanned subset analysis of patients strongly positive for HER1/HER2 (3+ on immunohistochemistry; n = 111), patients positive for only HER1 (n = 102), and patients positive for only HER2 (n = 42) showed no significant benefit with lapatinib in terms of PFS and overall survival ( P > .05 for each). Conclusion This trial did not find significant improvements in outcome by the addition of maintenance lapatinib to standard of care.

Searching for prostate cancer stem cells: markers and methods

The cancer stem cell hypothesis postulates that a single stem-like cancer cell is able to produce all cancer cell types found in a tumor. These cells are also thought to be the causative agents of relapse following therapy. In order to confirm the importance of cancer stem cells in tumor formation and patient prognosis, their role in prostate cancer must be comprehensively studied. This review describes current methods and markers for isolating and characterizing prostate cancer stem cells, including assays for self-renewal, multipotency and resistance to therapy. In particular the advantages and limitations of these approaches are analyzed. The review will also examine novel methods for studying the lineage of cancer stem cells in vivo using transgenic mouse models. These lineage tracing approaches have significant advantages and, if a number of challenges can be addressed, offer great potential for understanding the significance of cancer stem cells in human prostate cancer.

Evaluation of FLT-PET-CT as an imaging biomarker of proliferation in primary breast cancer

Background:[18F]fluorothymidine (FLT) has been proposed as a positron emission tomography (PET)-imaging biomarker of proliferation for breast cancer. The aim of this prospective study was to assess the feasibility of FLT-PET-CT as a technique for predicting the response to neoadjuvant chemotherapy (NAC) in primary breast cancer and to compare baseline FLT with Ki-67.Methods:Twenty women with primary breast cancer had a baseline FLT-PET-CT scan that was repeated before the second cycle of chemotherapy. Expression of Ki-67 in the diagnostic biopsy was quantified. From the FLT-PET-CT scans lesion maximum and mean standardised uptake values (SUVmax, SUVmean) were calculated.Results:Mean baseline SUVmax was 7.3, and 4.62 post one cycle of NAC, representing a drop of 2.68 (36.3%). There was no significant association between baseline, post chemotherapy, or change in SUVmax and pathological response to NAC. There was a significant correlation between pre-chemotherapy Ki-67 and SUVmax of 0.604 (P=0.006).Conclusions:Baseline SUVmax measurements of FLT-PET-CT were significantly related to Ki-67 suggesting that it is a proliferation biomarker. However, in this series neither the baseline value nor the change in SUVmax after one cycle of NAC were able to predict response as most patients had a sizeable SUVmax reduction.

Clinical and patient-reported outcomes of SPARE - a randomised feasibility study of selective bladder preservation versus radical cystectomy

To test the feasibility of a randomised trial in muscle‐invasive bladder cancer (MIBC) and compare outcomes in patients who receive neoadjuvant chemotherapy followed by radical cystectomy (RC) or selective bladder preservation (SBP), where definitive treatment [RC or radiotherapy (RT)] is determined by response to chemotherapy.

Neoadjuvant Therapy in Early Breast Cancer: Treatment Considerations and Common Debates in Practice

Neoadjuvant treatment offers a number of benefits for patients with early breast cancer, and is an important option for consideration by multidisciplinary teams. Despite literature showing its efficacy, the use of neoadjuvant therapy varies widely. Here we discuss the clinical evidence supporting the use of neoadjuvant therapy in early stage breast cancer, including patient selection, monitoring response, surgery and radiotherapy considerations, with the aim of assisting multidisciplinary teams to determine patient suitability for neoadjuvant treatment.

A subset of high Gleason grade prostate carcinomas contain a large burden of prostate cancer syndecan-1 positive stromal cells

There is a pressing need to identify prognostic and predictive biomarkers for prostate cancer to aid treatment decisions in both early and advanced disease settings. Syndecan‐1, a heparan sulfate proteoglycan, has been previously identified as a potential prognostic biomarker by multiple studies at the tissue and serum level. However, other studies have questioned its utility.

Greater Anti-Angiogenic Effects with Docetaxel Compared with Anthracyclines in the Neoadjuvant Treatment of Breast Cancer.

Background: Dynamic contrast-enhanced MRI (DCE-MRI) allows for the functional assessment of tumour permeability and perfusion and has been previously shown to predict for clinical and pathologic response in women with breast cancer undergoing neoadjuvant anthracycline based chemotherapy 1 . Changes in DCE-MRI kinetic parameters after 2 cycles of neoadjuvant chemotherapy (NAC) predicts clinical and pathological benefit, with transfer constant K trans being the best predictive biomarker. This study examines (1) whether DCE-MRI can predict for final clinical response in women undergoing neoadjuvant docetaxel and (2) whether taxanes demonstrate greater anti-angiogenic activity over anthracyclines in the NAC setting. Methods : 30 patients with histologically proven primary breast cancer (T2-4, N0-1, M0) due to receive neoadjuvant docetaxel chemotherapy underwent DCE-MRI before and after 2 cycles of NAC as part of a prospective study. Whole tumour regions of interest were outlined and values for inflow transfer constant (K trans ), outflow rate constant (k ep ), leakage space (v e ), initial area under gadolinium-time curve (IAUGC 60 ), relative blood volume (rBV), Mean Transit Time (MTT) and relative blood flow (rBF) calculated. Both baseline and changes in DCE-MRI kinetic parameters were correlated with final clinical response using the Mann-Whitney U test. DCE-MRI results of the docetaxel NAC cohort were compared with a previously analysed cohort of 28 patients who received neoadjuvant FEC chemotherapy 1 . MRI data acquisition and pharmacokinetic modelling analysis for both cohorts were identical. Results: 25 docetaxel patients were assessable (median age 42, range 26-62; docetaxel 100mg/m 2 ; median number of cycles 4, range 2-6). 1 patient received 1 cycle of docetaxel only and 4 were not able to complete their imaging. There were 21 clinical responders (CR)(9 complete and 12 partial responders) and 4 non-responders (NR)(3 with SD, 1 with PD). There was no significant difference in pretreatment parameters between CR and NR. The median reduction in K trans in CR was -58.1% vs -8.9% in NR (95% CI -81.1 to -19.8, p=0.011) and in IAUGC 60 , -57.6% vs -3.7% (95% CI -79.9 to -14.7, p=0.011). ROC analysis revealed that both K trans and IAUGC 60 changes were good predictors of clinical response (K trans : sensitivity 81%, specificity 100%, area under ROC curve 0.89; IAUGC 60 : sensitivity 76%, specificity 100%, area under ROC curve 0.89). Comparison of docetaxel versus FEC cohorts showed greater reductions in kinetic parameters in clinical responders in the docetaxel group (K trans : -58.1% vs -29.5%, p=0.022; IAUGC 60 values: -57.5% vs -20.4%, p=0.006). Discussion: Early changes in DCE-MRI biomarkers depicting tumour vascularity can predict clinical benefit from docetaxel NAC in breast cancer, similar to a finding previously shown for anthracyclines. Significantly larger changes in DCE-MRI biomarkers related to tumour perfusion and permeability in responding patients suggest a greater anti-angiogenic effect with docetaxel. References: 1. Ah-See, M-L. W et al. Early Changes in Functional Dynamic Magnetic Resonance Imaging Predict for Pathologic Response to Neoadjuvant Chemotherapy in Primary Breast Cancer. Clinical Cancer Research 2008;14(20):6580-6589. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5013.

Management of metastatic prostate cancer in the elderly: identifying fitness for chemotherapy in the post-STAMPEDE world

The relative proportion of men aged >75 years is expected to double over the next 25 years, and older men are more likely to be diagnosed with advanced disease. Meta-analysis of the eagerly awaited ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED), Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE), and GETUG 15 trials have shown that men with newly diagnosed hormone-sensitive metastatic prostate cancer who were treated with docetaxel in addition to androgen-deprivation therapy (ADT), showed a 9% absolute overall survival benefit at 4 years [1]. As such, European Association of Urology (EAU) guidelines recommend that newly diagnosed metastatic prostate cancer should be treated with castration plus docetaxel chemotherapy ‘provided the patient is fit enough’. However, this assessment of ‘fitness’ for chemotherapy remains a clinical stumbling block.

Neoadjuvant chemotherapy and trastuzumab versus neoadjuvant chemotherapy followed by post-operative trastuzumab for patients with HER2-positive breast cancer

Neoadjuvant chemotherapy plus trastuzumab (NCT) increases the rate of pathological complete response (pCR) and event-free survival (EFS) compared to neoadjuvant chemotherapy (NC) alone in women with HER2 positive breast cancer (BC). pCR in this setting is associated with improved EFS. Whether NCT preferentially improves EFS in comparison to NC followed by adjuvant trastuzumab initiated postoperatively (NCAT) has not been addressed. Using clinical data from women with HER2 positive BC treated at 7 European institutions between 2007 and 2010 we sought to investigate the impact on breast cancer outcomes of concomitant (NCT) versus sequential (NCAT) treatment in HER2 positive early BC. The unadjusted hazard ratio (HR) for event free survival with NCT compared with NCAT was 0.63 (95% CI 0.37–1.08; p = 0.091). Multivariable analysis revealed that treatment group, tumour size and ER status were significantly associated with EFS from diagnosis. In the whole group NCT was associated with a reduced risk of an event relative to NCAT, an effect that was confined to ER negative (HR: 0.25; 95% CI, 0.10–0.62; p = 0.003) as opposed to ER positive tumours (HR: 1.07; 95% CI, 0.46–2.52; p = 0.869). HER2 positive/ER negative BC treated with NC gain greatest survival benefit when trastuzumab is administered in both the neoadjuvant and adjuvant period rather than in the adjuvant period alone. These data support the early introduction of targeted combination therapy in HER2 positive/ER negative BC.

Improving the surgical treatment of high-risk localised or locally advanced prostate cancer

Radiologists, oncologists, urologists and clinical nurse specialists met to evaluate how patients with high‐risk localised or locally advanced prostate cancer might be better diagnosed and managed. In the first article in this series, the authors reviewed diagnosis and hormonal and radiotherapy.1 In this second paper, they evaluate findings from the meeting relating to the surgical management of the disease and how this might be optimised.