Anne Hamilton

Prognostic and Clinicopathologic Associations of Oncogenic BRAF in Metastatic Melanoma

PURPOSEnTo assess the frequency and type of oncogenic BRAF mutations in metastatic melanoma and correlate BRAF status with clinicopathologic features and outcome.nnnPATIENTS AND METHODSnConsecutive BRAF-tested Australian patients with metastatic melanoma (n = 197) were observed prospectively. A comprehensive range of clinicopathologic variables were correlated with BRAF mutation status, and a survival analysis was conducted.nnnRESULTSnForty-eight percent of patients had a BRAF mutation; 70 patients (74%) had V600E, 19 (20%) had V600K, and six (6%) had other genotypes. Other than age at diagnosis of distant metastasis (median age, 56 v 63 years for BRAF-mutant v BRAF wild-type patients, respectively; P < .001), there was no significant difference in clinical features of patients with metastatic melanoma by mutation status. Features of the antecedent primary melanoma significantly associated with a BRAF mutation (P < .05) were histopathologic subtype, presence of mitoses, single or occult primary melanoma, truncal location, and age at diagnosis of primary tumor ≤ 50 years. The interval from diagnosis of first-ever melanoma to distant metastasis was not significantly different between BRAF-mutant and BRAF wild-type patients; however, the median survival of patients with newly diagnosed metastatic melanoma was 5.7 months for BRAF-mutant patients not treated with a BRAF inhibitor, 8.5 months for BRAF wild-type patients, and not reached for BRAF-mutant patients treated with a BRAF inhibitor.nnnCONCLUSIONnV600K mutations comprised 20% of BRAF mutations. Characteristics of the antecedent primary melanoma and age at diagnosis differed in BRAF-mutant and BRAF wild-type patients. The presence of mutant BRAF had no impact on the disease-free interval from diagnosis of first-ever melanoma to first distant metastasis; however, it may have impacted survival thereafter.

The contribution of molecular markers to the prediction of response in the treatment of breast cancer: A review of the literature on HER-2, p53 and BCL-2

BACKGROUNDnThe selection of therapies for breast cancer is today based on prognostic features (chemotherapy, radiotherapy), hormone receptor status (hormonal therapy) and HER-2 status (trastuzumab therapy). HER-2, p53 and BCL-2 are tumour-related proteins that have the potential to further improve individualisation of patient management, by predicting response to chemotherapy, hormonal therapy and radiotherapy.nnnMATERIALS AND METHODSnThis paper reviews the rationale for the use of these proteins as predictive factors, as well as the published literature addressing the use of each one to predict response to hormonal therapy, chemotherapy and radiotherapy.nnnRESULTSnHER-2, p53 and BCL-2 remain inadequately assessed as predictive factors in breast cancer. HER-2 evaluation is required for the selection of patients for trastuzumab (Herceptin) therapy, as trials of this therapy have been limited to HER-2 overexpressors. HER-2 overexpression may be predictive of resistance to hormonal therapy. Anthracyclines are effective therapy for breast cancer regardless of HER-2 status, but patients whose tumours overexpress HER-2 appear to receive the greatest relative benefit from this therapy. Studies of HER-2 as a predictor of response to CMF and to radiotherapy are inconclusive at this time. No data yet exist to support the use of p53 or BCL-2 as predictive factors in the therapy of breast cancer.nnnCONCLUSIONSnAt this point in time, there is inadequate evidence to support the use of HER-2, p53 or BCL-2 to guide the selection of hormonal therapy, chemotherapy or radiotherapy for breast cancer.

Dose-Escalating and Pharmacological Study of Oxaliplatin in Adult Cancer Patients With Impaired Renal Function: A National Cancer Institute Organ Dysfunction Working Group Study

PURPOSEnThis study was undertaken to determine the toxicities, pharmacokinetics, and maximum tolerated doses of oxaliplatin in patients with renal impairment and to develop formal guidelines for oxaliplatin dosing in this patient population.nnnPATIENTS AND METHODSnThirty-seven adult cancer patients with variable renal function received intravenous oxaliplatin at 60 to 130 mg/m2 every 3 weeks. Patients were stratified by 24-hour creatinine clearance (CrCL) into four cohorts: group A (controls, CrCL > or =60 mL/min), group B (mild dysfunction, CrCL 40 to 59 mL/min), group C (moderate dysfunction, CrCL 20 to 39 mL/min), and group D (severe dysfunction, CrCL <20 mL/min). Doses were escalated in cohorts of three patients, and urine and plasma ultrafiltrates were assayed for platinum concentrations.nnnRESULTSnNo dose-limiting toxicities were observed in any patient group during the first cycle of therapy. Escalation of oxaliplatin to the maximum dose of 130 mg/m2 was well tolerated in all patient groups with a CrCL > or =20 mL/min (groups A, B, and C). Pharmacokinetic analysis showed that patients with decreased CrCL had a corresponding decrease in the clearance of plasma ultrafiltrable platinum (r2 = 0.765). However, oxaliplatin-induced side effects were not more common or severe in patients with mild to moderate renal dysfunction, despite the decrease in ultrafiltrable platinum clearance.nnnCONCLUSIONnOxaliplatin at 130 mg/m2 every 3 weeks is well tolerated by patients with mild to moderate degrees of renal dysfunction. These data strongly support the recommendation that dose reductions of single-agent oxaliplatin are not necessary in patients with a CrCL greater than 20 mL/min.

Chemotherapy: What Progress in the Last 5 Years?

It is 1999, during the American Society of Clinical Oncology (ASCO) Annual Meeting, and the plenary session is dedicated to the randomized studies that have failed to demonstrate a meaningful benefit from high-dose therapy in breast cancer. The aromatase inhibitors are showing real promise, though. They have already become the agents of choice in postmenopausal women with estrogen receptor (ER) –positive metastatic disease after tamoxifen failure, and are challenging tamoxifen as the gold standard in metastatic disease. Trastuzumab is US Food and Drug Administration (FDA) –approved as a single agent in HER-2 overexpressed metastatic disease, and an indication for combination therapy is imminent. Pamidronate has just been registered for bone metastases. Docetaxel is now the reference cytotoxic in metastatic disease, but paclitaxel and capecitabine also have US FDA indications in this setting. Although lacking a US FDA indication in breast cancer, vinorelbine (registered for non–smallcell lung cancer), gemcitabine (registered for pancreatic cancer and non–small-cell lung cancer), pegylated liposomal doxorubicin (registered for Kaposi’s sarcoma and submitted for ovarian cancer), and mitoxantrone (registered for hormone-refractory prostate cancer and acute nonlymphocytic leukemia) are also in use in third-, fourth-, and fifth-line therapy. In the adjuvant setting, doxorubicin and cyclophosphamide are the mainstay of current adjuvant regimens, paclitaxel has just received an accelerated approval for use after standard doxorubicin-containing therapy and, after years of use in the rest of the world, epirubicin has finally hit the US market. Since 1999, though, fulvestrant and zoledronic acid are the only new agents to be US FDA–approved for breast cancer therapy (http://www.fda.gov). The relative lack of new drug registrations does not reflect a lack of progress, however. The turn of the century marked the start of a profound shift in attitude regarding management of metastatic disease. Improvements in both efficacy and tolerability of systemic therapy have been achieved by modifying drug formulation and/or dose schedule; liposomal encapsulation can modify both the pharmacokinetics and tissue distribution of active agents, oral formulations permit continuous exposure of the tumor to the cytotoxic, tumor-specific enzymes can be harnessed to selectively activate prodrugs in order to spare normal tissues from toxicity, and the traditional 3-weekly dosing schedule is now the exception rather than the rule.

Correlation of BRAF and NRAS mutation status with outcome, site of distant metastasis and response to chemotherapy in metastatic melanoma

Background:The prognostic significance of BRAF and NRAS mutations in metastatic melanoma patients remains uncertain, with several studies reporting conflicting results, often biased by the inclusion of patients treated with BRAF and MEK (MAPK) inhibitors. We therefore interrogated a historical cohort of patients free of the confounding influence of MAPK inhibitor therapy.Methods:Patients with available archival tissue first diagnosed with metastatic melanoma between 2002 and 2006 were analysed. Mutational analysis was performed using the OncoCarta Panel. Patient characteristics, treatment outcome and survival were correlated with BRAF/NRAS mutation status.Results:In 193 patients, 92 (48%) melanomas were BRAF-mutant, 39 (20%) were NRAS-mutant and 62 (32%) were wild-type for BRAF/NRAS mutations (wt). There was no difference in response to chemotherapy based on mutation status (35–37%). The distant disease-free interval (DDFI) was significantly shorter in patients with wt melanoma (27.9 months vs 35.1 for BRAF and 49.1 for NRAS) although this was not significant in multivariate analysis. Survival from stage IV melanoma diagnosis was not significantly different based on mutation status. The DDFI was significantly shorter in patients with BRAFV600K/R versus BRAFV600E melanoma in univariate and multivariate analyses.Conclusions:BRAF and NRAS mutation status does not influence survival in metastatic melanoma.

Phase III data on Caelyx in ovarian cancer.

Impressive responses to pegylated liposomal doxorubicin (Doxil/Caelyx) in pretreated ovarian cancer patients during phase I studies led to a phase II study in platinum and taxane failures. A 26% objective response rate was obtained in this trial and this was confirmed by further phase II studies. The stage was set for a phase III trial in comparison with topotecan, the drug that had become standard in the salvage treatment of patients who were platinum-refractory or -resistant. The completed trial indicates equivalence of results in terms of response rates, time to treatment failure and survival. Differences exist in the toxicity spectrum and in subset analysis according to platinum resistance. On this basis, Caelyx is being positioned as part of chemotherapeutic regimens in first-line phase III trials.

Dose-Escalating and Pharmacological Study of Bortezomib in Adult Cancer Patients With Impaired Renal Function: A National Cancer Institute Organ Dysfunction Working Group Study

PurposeTo determine the toxicities, pharmacokinetics, pharmacodynamics, and maximum tolerated dose of bortezomib in patients with renal impairment and to develop dosing guidelines for such a patient population.Patients and MethodsSixty-two adult cancer patients received intravenous bortezomib at 0.7–1.5xa0mg/m2 on days 1, 4, 8, and 11 every 3xa0weeks. Patients were stratified by 24-h creatinine clearance (CrCl) normalized to body surface area (BSA) 1.73xa0m2 into five cohorts: normal renal function (≥60xa0ml/min/1.73xa0m2); mild dysfunction (40–59xa0ml/min/1.73xa0m2); moderate dysfunction (20–39xa0ml/min/1.73xa0m2); severe dysfunction (<20xa0ml/min/1.73xa0m2); and dialysis. Dose escalation was planned for the four cohorts with renal dysfunction. Plasma bortezomib concentrations and blood 20S proteasome inhibition were assayed.ResultsBortezomib escalation to the standard 1.3xa0mg/m2 dose was well tolerated in all patients with CrCl ≥20xa0ml/min/1.73xa0m2; 0.7xa0mg/m2 was tolerated in three patients with severe renal dysfunction (<20xa0ml/min/1.73xa0m2). Bortezomib dose escalation was well tolerated in nine dialysis patients, including to 1.3xa0mg/m2 in four patients. Decreased CrCl did not affect bortezomib pharmacokinetics or pharmacodynamics. Bortezomib-related side-effects were neither more common nor severe in patients with renal dysfunction versus those with normal renal function.ConclusionBortezomib 1.3xa0mg/m2 is well tolerated, and dose reductions are not necessary in patients with renal dysfunction. Extrapolation from clinical and pharmacologic data suggests patients with severe renal dysfunction, including dialysis patients, can receive bortezomib at the full dose established to be clinically effective in the general patient population.

Phase I Study of Combined Pegylated Liposomal Doxorubicin with Protracted Daily Topotecan for Ovarian Cancer

Purpose: To determine the maximum tolerated dose and dose-limiting toxicity of Doxil with low-dose continuous infusion topotecan and subsequently with low-dose oral topotecan. Other specific aims were preliminary assessment of activity in advanced ovarian and tubal malignancies, pharmacokinetics of oral topotecan, and correlation of response with topoisomerase I and II expression in tumors. Methods: Eligible patients had histopathologically documented advanced cancers beyond standard therapy, performance status <2, and adequate organ functions. Doxil (30-40 mg/m2 i.v.) was given on day 1, with topotecan either oral topotecan 0.4 mg/m2 bid for 14 days or continuous infusion topotecan (0.3-0.4 mg/m2/d) for 14 to 21 days, in 28-day cycles. Fifty-seven patients, 23 with epithelial ovarian or tubal cancers were enrolled. Plasma levels of lactone form of topotecan were determined on patients receiving oral topotecan. Results: Grade 4 neutropenia and thrombocytopenia and grade 3 diarrhea were dose-limiting toxicities at the highest dose levels explored. Doxil (40 mg/m2/day 1) and continuous infusion topotecan at 0.4 mg/m2/days 1 to 14 could be safely given and is the recommended phase II dose. Oral topotecan was limited by low and erratic plasma topotecan levels and frequent gastrointestinal toxicity. Particularly long partial responses and stable disease were observed in patients with epithelial ovarian or tubal cancers. Clinical benefit (objective responses and stable diseases) correlated with elevated expression of both topoisomerases by immunohistochemistry in four of six epithelial ovarian or tubal cancer tumor samples. Conclusion: Doxil with 14-day topotecan infusion is a well-tolerated regimen and suitable for study in platinum-resistant or refractory ovarian or tubal cancers. Frequent gastrointestinal toxicity and/or erratic absorption complicate treatment with a longer topotecan infusion or with oral topotecan, respectively, and these combinations are not recommended.

A phase I and pharmacokinetic study of docetaxel combined with Doxil (pegylated liposomal doxorubicin) without and with granulocyte colony stimulating factor.

The purpose of this study was (i) to determine the maximum tolerated dose (MTD) of docetaxel that can be administered in combination with Doxil, given without and with granulocyte colony stimulating factor (G-CSF), (ii) to define the pharmacokinetics (PK) of docetaxel when used in combination with Doxil, and (iii) to make preliminary observations on the anti-tumor activity of this combination in patients with metastatic solid tumors. Thirty-seven patients with metastatic cancer were enrolled. Courses were repeated every 3 weeks. Patients received a fixed dose of Doxil 30u2009mg/m2 in combination with escalating doses of docetaxel ranging from 40 to 100u2009mg/m2. After encountering dose-limiting febrile neutropenia, subsequent escalation was accomplished with G-CSF support. Selected patients at the recommended phase II dose underwent PK evaluation. The most common toxicity observed was neutropenia. Dose-limiting toxicity (30u2009mg/m2 Doxil+80u2009mg/m2 docetaxel) was febrile neutropenia in three of six patients treated without G-CSF. Major non-hematological toxicities included alopecia, mucositis and hand–foot syndrome, and were observed after cumulative doses of chemotherapy. Objective responses (complete/partial) were documented in eight of 37 patients (four with breast cancer) and stable disease was seen in 17 patients. PK studies showed an increased tissue retention (decreased clearance) of docetaxel when given with Doxil. The recommended phase II dose of Doxil/docetaxel is 30/60u2009mg/m2, q3 weeks, without G-CSF. Further dose escalation to 30/80u2009mg/m2 is safe with G-CSF support. Anti-tumor activity, particularly against breast cancer, was observed at various dose levels. Our observations should provide evidence for phase II studies of this combination in patients with breast cancer and other anthracycline/taxane-sensitive cancers.

An EORTC-IDBBC phase I study of gemcitabine and continuous infusion 5-fluorouracil in patients with metastatic breast cancer resistant to anthracyclines or pre-treated with both anthracyclines and taxanes.

The aim of this study was to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and potential activity of combined gemcitabine and continuous infusion 5-fluorouracil (5-FU) in metastatic breast cancer (MBC) patients that are resistant to anthracyclines or have been pretreated with both anthracyclines and taxanes. 15 patients with MBC were studied at three European Organization for Research and Treatment of Cancer centres. 13 patients had received both anthracylines and taxanes. Gemcitabine was given intravenously (i.v.) on days 1 and 8, and 5-FU as a continuous i.v. infusion on days 1 through to 14, both drugs given in a 21-day schedule at four different dose levels. Both were given at doses commonly used for the single agents for the last dose level (dose level 4). One of 6 patients at level 4 (gemcitabine 1200 mg/m2 and 5-FU 250 mg/m2/day) had a DLT, a grade 3 stomatitis and skin toxicity. One DLT, a grade 3 transaminase rise and thrombosis, occurred in a patient at level 2 (gemcitabine 1000 mg/m2 and 5-FU 200 mg/m2/day). Thus, the MTD was not reached. One partial response and four disease stabilisations were observed. Only 1 patient withdrew from the treatment due to toxicity. The MTD was not reached in the phase I study. The combination of gemcitabine and 5-FU is well tolerated at doses up to 1200 mg/m2 given on days 1 and 8 and 250 mg/m2/day given on days 1 through to 14, respectively, every 21 days. The clinical benefit rate (responses plus no change of at least 6 months) was 33% with one partial response, suggesting that MBC patients with prior anthracycline and taxane therapy may derive significant benefit from this combination with minimal toxicity.