Discrepancies in central review re-testing of patients with ER-positive and HER2-negative breast cancer in the OPTIMA prelim randomised clinical trial.

BACKGROUND: There is limited data on results of central re-testing of samples from patients with invasive breast cancer categorised in their local hospital laboratories as oestrogen receptor (ER) positive and human epidermal growth factor receptor homologue 2 (HER2) negative. METHODS: The Optimal Personalised Treatment of early breast cancer usIng Multiparameter Analysis preliminary study (OPTIMA prelim) was the feasibility phase of a randomised controlled trial to validate the use of multiparameter assay-directed chemotherapy decisions in the UK National Health Service (NHS). Eligibility criteria included ER positivity and HER2 negativity. Central re-testing of receptor status was mandatory. RESULTS: Of the 431 patients tested centrally, discrepant results between central and local laboratory results were identified in only 19 (4.4%; 95% confidence interval 2.5-6.3%) patients (with 21 tumours). On central review, seven patients had cancers that were ER-negative (1.6%) and 13 (3.0%) patients with 15 tumours had HER2-positive disease, including one tumour discrepant for both biomarkers. CONCLUSIONS: Central re-testing of receptor status of invasive breast cancers in the UK NHS setting shows a high level of reproducibility in categorising tumours as ER-positive and HER2-negative, and raises questions regarding the cost effectiveness and clinical value of central re-testing in this sub-group of breast cancers in this setting.

Adaptive designs for clinical trials assessing biomarker-guided treatment strategies.

BACKGROUND: The Biomarker Strategy Design has been proposed for trials assessing the value of a biomarker in guiding treatment in oncology. In such trials, patients are randomised to either receive the standard chemotherapy treatment or a biomarker-directed treatment arm, in which biomarker status is used to guide treatment. METHODS: Motivated by a current trial, we consider an adaptive design in which two biomarkers are assessed. The trial is conducted in two stages. In the first stage, patients in the biomarker-guided arm are assessed using a standard and an alternative cheaper biomarker, with the standard biomarker guiding treatment. An analysis comparing biomarker results is then used to choose the biomarker to use for the remainder of the trial. The new biomarker is used if the results for the two biomarkers are sufficiently similar. RESULTS: We show that in practical situations the first-stage results can be used to adapt the trial without type I error rate inflation. We also show that there can be considerable cost gains with only a small loss in power in the case where the alternative biomarker is highly concordant with the standard one. CONCLUSIONS: Adaptive designs have an important role in reducing the cost and increasing the clinical utility of trials evaluating biomarker-guided treatment strategies.

Strategies to Improve Recruitment to a De-escalation Trial: A Mixed-Methods Study of the OPTIMA Prelim Trial in Early Breast Cancer.

AIMS: De-escalation trials are challenging and sometimes may fail due to poor recruitment. The OPTIMA Prelim randomised controlled trial (ISRCTN42400492) randomised patients with early stage breast cancer to chemotherapy versus 'test-directed' chemotherapy, with a possible outcome of no chemotherapy, which could confer less treatment relative to routine practice. Despite encountering challenges, OPTIMA Prelim reached its recruitment target ahead of schedule. This study reports the root causes of recruitment challenges and the strategies used to successfully overcome them. MATERIALS AND METHODS: A mixed-methods recruitment intervention (QuinteT Recruitment Intervention) was used to investigate the recruitment difficulties and feedback findings to inform interventions and optimise ongoing recruitment. Quantitative site-level recruitment data, audio-recorded recruitment appointments (n = 46), qualitative interviews (n = 22) with trialists/recruiting staff (oncologists/nurses) and patient-facing documentation were analysed using descriptive, thematic and conversation analyses. Findings were triangulated to inform a 'plan of action' to optimise recruitment. RESULTS: Despite best intentions, oncologists' routine practices complicated recruitment. Discomfort about deviating from the usual practice of recommending chemotherapy according to tumour clinicopathological features meant that not all eligible patients were approached. Audio-recorded recruitment appointments revealed how routine practices undermined recruitment. A tendency to justify chemotherapy provision before presenting the randomised controlled trial and subtly indicating that chemotherapy would be more/less beneficial undermined equipoise and made it difficult for patients to engage with OPTIMA Prelim. To tackle these challenges, individual and group recruiter feedback focussed on communication issues and vignettes of eligible patients were discussed to address discomforts around approaching patients. 'Tips' documents concerning structuring discussions and conveying equipoise were disseminated across sites, together with revisions to the Patient Information Sheet. CONCLUSIONS: This is the first study illuminating the tension between oncologists' routine practices and recruitment to de-escalation trials. Although time and resources are required, these challenges can be addressed through specific feedback and training as the trial is underway.

Dose-related endocrine effects and pharmacokinetics of oral and intramuscular 4-hydroxyandrostenedione in postmenopausal breast cancer patients.

4-Hydroxyandrostenedione (CGP32349; 4-OHA) is a clinically effective treatment for advanced postmenopausal breast cancer by both the parenteral and p.o. routes, as a result of its inhibition of aromatase and consequent suppression of plasma estrogen levels. Thirty patients were randomized to treatment with 250 mg 4-OHA orally once, twice, and 4 times daily for 2 weeks and 29 of these plus a further 11 patients were then randomized to treatment with 250 or 500 mg i.m. every 2 weeks to determine the optimal dose for each route according to the suppression of serum estradiol levels. There was no significant difference between the 3 oral doses in their suppression of estradiol levels indicating that the maximum required p.o. dose of 4-OHA is probably 250 mg daily. Suppression by the parenteral dose of 250 mg every 2 weeks was marginally suboptimal but clinical considerations of response and tolerability indicate this as the optimal dose for i.m. injection. 4-OHA had no effect on serum levels of androstenedione, testosterone, or 5 alpha-dihydrotestosterone when given by either route but p.o. treatment with 4 doses of 250 mg daily reduced sex hormone-binding globulin levels by a mean of 34%. Serum levels of estrone as measured by gas chromatography-mass spectrometry were suppressed to approximately 40% of baseline by parenteral treatment. The half-life of 4-OHA p.o. was approximately 3 h, whereas the apparent half-life of injected drug was between 5 and 10 days after a more rapid clearance during the first 4 days after injection.

Preliminary study of the treatment of advanced breast cancer in postmenopausal women with the aromatase inhibitor CGS 16949A.

Thirty-one postmenopausal women with advanced breast cancer have been treated with the nonsteroidal competitive aromatase inhibitor CGS 16949A at p.o. doses of 0.3, 1, and 2 mg twice a day. All patients were assessed for response. Five patients, all treated with 1 mg twice daily, had objective evidence of response (two complete responses and three partial responses); disease stabilized in 17 patients. Minor side effects were reported by ten patients. Two further patients treated with 2 mg twice a day experienced persistent nausea which improved after dose reduction, and one patient, treated with 0.3 mg twice daily, developed a vasculitic rash requiring discontinuation of CGS 16949A. Estradiol levels measured in 24 patients were significantly suppressed 2 wk after starting CGS 16949A treatment at all doses used. Treatment with 2 mg twice a day lowered estradiol levels to a mean of 29% of pretreatment values which was significantly lower than the corresponding figure of 57% for patients treated with 0.3 mg twice daily. Aldosterone levels were significantly lowered below pretreatment values by the 1- and 2-mg twice daily doses. No clinically apparent cases of adrenocortical insufficiency occurred, although small changes in serum electrolyte levels were noted. The results indicate that CGS 16949A is an effective aromatase inhibitor, requiring further evaluation in the treatment of advanced breast cancer. The optimal dose is likely to be 1 mg twice a day.

Viewpoint: Availability of oestrogen receptor and HER2 status for the breast multidisciplinary meeting discussion; time to get it right.

The efficacy and pivotal role of the multidisciplinary meeting (MDM) in informed decision making is well established. It aims to provide a forum in which clinical evidence combines with individual patient data to create a personalized treatment plan. It does not fulfil this role adequately when undertaken without the full results of the patient's investigations being available. Neither doctor nor patient can make an informed decision about treatment options without knowledge of the tumour receptor status. Both targeted therapies and the aim to treat a majority of patients within clinical trials must now drive MDM decision making to be based on accuracy and best available treatment choices. A fully informed decision on treatment delayed by 1-2 weeks is clearly preferable to rushed time target-driven decisions made without the patient being offered a fully informed choice as ratified by a multidisciplinary team. Whilst the early anxiety of waiting for all relevant information to be available may be stressful for patients, not being sure that they have been offered fully informed treatment choices is also stressful and could cause longer lasting anxiety both during and after treatment. MDMs need to develop (along with targeted therapies) to retain their role as a forum whereby patients receive a correct, but specifically a full diagnosis and allow a fully informed discussion of all treatment options, including pre-operative clinical trials.

Solution structure of the C-terminal SH2 domain of the p85 alpha regulatory subunit of phosphoinositide 3-kinase.

Heterodimeric class IA phosphoinositide 3-kinase (PI 3-kinase) plays a crucial role in a variety of cellular signalling events downstream of a number of cell-surface receptor tyrosine kinases. Activation of the enzyme is effected in part by the binding of two Src homology-2 domains (SH2) of the 85 kDa regulatory subunit to specific phosphotyrosine-containing peptide motifs within activated cytoplasmic receptor domains. The solution structure of the uncomplexed C-terminal SH2 (C-SH2) domain of the p85 alpha subunit of PI 3-kinase has been determined by means of multinuclear, double and triple-resonance NMR experiments and restrained molecular-dynamics simulated-annealing calculations. The solution structure clearly indicates that the uncomplexed C-SH2 domain conforms to the consensus polypeptide fold exhibited by other SH2 domains, with an additional short helical element at the N terminus. In particular, the C-SH2 structure is very similar to both the p85 alpha N-terminal SH2 domain (N-SH2) and the Src SH2 domain with a root mean square difference (rmsd) for 44 C alpha atoms of 1.09 and 0.89 A, respectively. The canonical BC, EF and BG loops are less well-defined by the experimental restraints and show greater variability in the ensemble of C-SH2 conformers. The lower level of definition in these regions may reflect the presence of conformational disorder, an interpretation supported by the absence or broadening of backbone and side-chain NMR resonances for some of these residues. NMR experiments were performed, where C-SH2 was titrated with phosphotyrosine-containing peptides corresponding to p85 alpha recognition sites in the cytoplasmic domain of the platelet-derived growth-factor receptor. The ligand-induced chemical-shift perturbations indicate the amino-acid residues in C-SH2 involved in peptide recognition follow the pattern predicted from homologous complexes. A series of C-SH2 mutants was generated and tested for phosphotyrosine peptide binding by surface plasmon resonance. Mutation of the invariant Arg36 (beta B5) to Met completely abolishes phosphopeptide binding. Mutation of each of Ser38, Ser39 or Lys40 in the BC loop to Ala reduces the affinity of C-SH2 for a cognate phosphopeptide, as does mutation of His93 (BG5) to Asn. These effects are consistent with the involvement of the BC loop and BG loops regions in ligation of phosphopeptide ligands. Mutation of Cys57 (beta D5) in C-SH2 to Ile, the corresponding residue type in the p85 alpha N-SH2 domain, results in a change in peptide binding selectivity of C-SH2 towards that demonstrated by p85 alpha N-SH2. This pattern of p85 alpha phosphopeptide binding specificity is interpreted in terms of a model of the p85 alpha/PDGF-receptor interaction.

Prospects for phosphoinositide 3-kinase inhibition as a cancer treatment.

The phosphoinositide 3-kinases (PI3-kinases) are a family of lipid kinases that have a key role in the regulation of many cellular processes including proliferation, survival, carbohydrate metabolism, and motility. There is now strong evidence that some members of the PI3-kinase family have an important role in cancer. Emerging evidence for functional specialisation of PI3-kinase isoforms suggests that isoform selective inhibitors, in contrast to the existing non-selective inhibitors wortmannin and LY294002, may prove to be useful anticancer drugs.

Clinical oncology: case presentations from oncology centres. 1. Ewing's sarcoma. The London Bone Tumour Service.

The management of a case of Ewing's sarcoma of the left proximal humerus in a 15-year-old girl is presented, and the radiological and pathological findings are described. The chemotherapeutic, radiotherapeutic and surgical management of Ewing's sarcoma are discussed with reference to the case.

A randomised prospective trial of surgical against medical tetracycline pleurodesis in the management of malignant pleural effusions secondary to breast cancer.

Malignant pleural effusion is a frequent complication of metastatic breast cancer leading to a significant degree of morbidity. Drainage of the effusion by thoracocentesis and pleurodesis with tetracycline as the sclerosing agent is an established means of symptomatic relief in these patients. To determine whether the efficacy of tetracycline pleurodesis is improved by surgical rather than medical drainage and instillation of sclerosant, 34 patients were prospectively randomised to a trial comparing the two treatment modalities, of whom 29 were evaluable for response. The total failure rate of primary pleurodesis was 13.4%, the rate of recurrence of effusion within the first month was 24%, and only 1 patient (3.4%) required repeat aspiration in that time period. There was no significant difference in the rate of recurrence or reaspiration of effusion between the two treatment groups. Although the overall survival time from treatment of effusion is significantly longer in the surgical treatment group than in the medical treatment group (P = 0.03), this is likely to be due to factors other than the method of treating the effusion. We conclude that surgical tetracycline pleurodesis has no advantage over medical tetracycline pleurodesis.

Mitozantrone and methotrexate chemotherapy with and without mitomycin C in the treatment of advanced breast cancer: a randomised clinical trial.

Patients with advanced breast cancer were randomised to 3M (mitozantrone 6.5 mg/m2q 21 days, methotrexate 30 mg/m2q 21 days, mitomycin C 6.5 mg/m2q 42 days) or 2M (as 3M but without mitomycin C). The objective response rates of 30% in 51 evaluable patients receiving 3M and 26% of 54 patients receiving 2M were not significantly different. 4/16 patients not responding to 2M responded to 3M on crossover. Both regimes were well tolerated but there was significantly less haematological toxicity and fewer dose reductions and delays with 2M. We conclude that patients should initially be treated with 2M and that non-responding patients should be crossed to 3M.

An endocrine and pharmacokinetic study of four oral doses of formestane in postmenopausal breast cancer patients.

43 postmenopausal breast cancer patients were treated orally with the aromatase inhibitor formestane (4-hydroxyandrostenedione) at daily doses of 62.5, 125, 250 or 500 mg for 4 weeks followed by 250 mg daily for a further 4 weeks. For some patients, 62.5 mg did not suppress serum oestradiol levels maximally. The doses of 250 and 500 mg did not differ in their effectiveness. Oestrone levels were suppressed by all doses of formestane but no consistent changes of aldosterone, cortisol or 17-hydroxyprogesterone occurred. Serum levels of sex hormone binding globulin fell by about 15% during treatment with 250 mg formestane reflecting its minor androgenic activity. The maximum concentration and area under the curve of serum formestane levels after the first dose varied in an approximately linear manner with dose. It is concluded that formestane is an effective, specific suppressant of oestradiol levels via the oral route requiring no more than 250 mg to be given daily.

Iodine-131-MIBG therapy of a patient with carcinoid liver metastases.

UNLABELLED: Iodine-13I-metaiodobenzylguanidine (MIBG) is highly concentrated by >60% of carcinoid metastases and thus provides a therapeutic opportunity. METHODS: A symptomatic patient with carcinoid liver metastases, unresponsive to chemotherapy combined with interferon-alpha, was subsequently treated with 131I-MIBG. RESULTS: Radionuclide therapy, which was without significant side effects, resulted in symptomatic improvement and reduced urinary 5-hydroxyindoleacetic acid levels. No new metastases were observed for 15 mo after 131I-MIBG therapy. Gross cystic change occurred in existing liver metastases, presumably as a result of ischemic necrosis. Surgical deroofing and aspiration of cysts led to regeneration of normal liver tissue. CONCLUSION: Iodine-131-MIBG therapy can provide prolonged symptomatic relief and improved quality of life in patients with metastatic carcinoid disease unresponsive to other therapies. The antitumor effect of 131I-MIBG was accompanied by few side effects, suggesting that this therapy should be considered in symptomatic patients with an early stage of disease.

Aromatization inhibition alone or in combination with GnRH agonists for the treatment of premenopausal breast cancer patients.

Aromatase inhibition in postmenopausal women causes a marked fall in the plasma levels of oestrogens and is an effective treatment for breast cancer, however, trials with aminoglutethimide found that this aromatase inhibitor was ineffective in suppressing plasma oestrogen levels in premenopausal breast cancer patients. We found that the more potent inhibitor, 4-hydroxyandrostenedione (4-OHA), which can suppress oestrogen synthesis in rodents and non-human primates with intact ovarian function, was also unsuccessful as an oestrogen suppressant in premenopausal women at its maximum tolerated dose (500 mg/week i.m.). GnRH agonists are effective suppressants of ovarian oestrogen synthesis but oestrogen production from peripheral sites is unaffected. Our studies of a combination of the GnRH agonist goserelin and 4-OHA demonstrated that the combination caused greater oestrogen suppression than goserelin alone and led to objective clinical response in 4/6 breast cancer patients after their relapse from treatment with goserelin as a single agent. The combination of a GnRH agonist and an aromatase inhibitor should be subjected to clinical trials.

Treatment of advanced breast cancer in postmenopausal women with 4-hydroxyandrostenedione.

4-Hydroxyandrostenedione (4-OHA), a new specific aromatase inhibitor, was used to treat 57 postmenopausal women with advanced breast cancer at a dose of 250 mg by i.m. injection every 2 weeks; 55 women were assessable for response. In all, 18 patients (33%) had objective evidence of a response to treatment, with a median duration of 12 months; the disease stabilised in 8 (14%) patients. Serum oestradiol levels, which were measured weekly in nine of the patients, were found to be suppressed to a mean of between 36% and 51% of pretreatment levels during the first 6 weeks of treatment. Three patients were withdrawn from treatment because of toxicity (pain at injection site, sterile abscess and rash). One patient had an isolated episode of anaphylaxis after 6 months of treatment. In comparison with our previous reports of 4-OHA treatment, a dose of 250 mg given i.m. fortnightly appears to be the optimal dose regimen. The efficacy of the drug seems to be similar to that of tamoxifen and aminoglutethimide.

A preliminary clinical study of gossypol in advanced human cancer.

A total of 34 patients with advanced cancer were given weekly or daily escalating doses of oral gossypol, a cottonseed-oil constituent showing evidence of antineoplastic activity in pre-clinical studies. No major adverse events occurred and there was no evidence of haematological or biochemical disturbance. As determined by dose escalation in 17 patients, the dose-limiting toxicity was emesis in 16 patients. There was no evidence of tumour regression in any of the 20 patients assessed for response. We conclude that gossypol is safe but unlikely to be clinically useful in patients with advanced cancer.

HER2 testing for breast carcinoma: recommendations for rapid diagnostic pathways in clinical practice.

Human epidermal growth factor receptor 2 (HER2) testing is required for newly diagnosed breast cancer and advised for recurrent and metastatic breast cancer, to determine treatment planning using HER2-directed therapy in the neoadjuvant, adjuvant and advanced disease settings. Wide variation, nationally, in the turnaround time for HER2 testing may hinder equity of access for patients to both clinical trials and the timely implementation of HER2-directed therapy particularly in the neo-adjuvant setting. Process mapping from three recognised laboratories in the UK was applied to the logistics of HER2 testing in different geographic hub and spoke models. Consequently, recommendations for HER2 testing likely to facilitate access to clinical trials and timely patient care are presented.