Stephen Houston

Detection of bone metastases in breast cancer by 18FDG PET: differing metabolic activity in osteoblastic and osteolytic lesions.

PURPOSE 99mTechnetium methylene diphosphonate (99mTc MDP) bone scintigraphy is currently the method of choice for the detection of bone metastases, but 18F-fluoro-deoxy-D-glucose positron emission tomography (18FDG PET) offers superior spatial resolution and improved sensitivity. We have compared 18FDG PET with 99mTc MDP bone scintigraphy in patients with skeletal metastases from breast cancer and have analyzed the data in subgroups based on radiographic characteristics of lesions. PATIENTS AND METHODS Twenty-three women with breast cancer and confirmed bone metastases were studied with both 99mTC MDP bone scintigraphy and 18FDG PET, and the number of lesions detected and the quantitation of uptake (standardized uptake values [SUVs]) of 18FDG in osteolytic and osteoblastic metastases were compared. Survival was compared for both lytic and blastic bone metastases and for patients with high and low accumulation of 18FDG. RESULTS 18FDG PET detected more lesions than 99mTc MDP scintigraphy (mean, 14.1 and 7.8 lesions, respectively; P < .01). However, 18FDG detected fewer bone metastases compared with 99mTc MDP scintigraphy in a subgroup of patients with osteoblastic disease (P < .05). Higher SUVs were observed for osteolytic than osteoblastic disease (mean, 6.77 and 0.95, respectively; P < .01). Survival was lower in patients with osteolytic disease compared with the remainder (P=.01). A difference in survival was not found for those patients with high SUVs (> 3.6; P=.4). CONCLUSION 18FDG PET is superior to bone scintigraphy in the detection of osteolytic breast cancer metastases, which led to a poorer prognosis. In contrast, osteoblastic metastases show lower metabolic activity and are frequently undetectable by PET. The biologic explanation for this observation remains to be elucidated.

Breast-cancer adjuvant therapy with zoledronic acid

BACKGROUND Data suggest that the adjuvant use of bisphosphonates reduces rates of recurrence and death in patients with early-stage breast cancer. We conducted a study to determine whether treatment with zoledronic acid, in addition to standard adjuvant therapy, would improve disease outcomes in such patients. METHODS In this open-label phase 3 study, we randomly assigned 3360 patients to receive standard adjuvant systemic therapy either with or without zoledronic acid. The zoledronic acid was administered every 3 to 4 weeks for 6 doses and then every 3 to 6 months to complete 5 years of treatment. The primary end point of the study was disease-free survival. A second interim analysis revealed that a prespecified boundary for lack of benefit had been crossed. RESULTS At a median follow-up of 59 months, there was no significant between-group difference in the primary end point, with a rate of disease-free survival of 77% in each group (adjusted hazard ratio in the zoledronic acid group, 0.98; 95% confidence interval [CI], 0.85 to 1.13; P=0.79). Disease recurrence or death occurred in 377 patients in the zoledronic acid group and 375 of those in the control group. The numbers of deaths--243 in the zoledronic acid group and 276 in the control group--were also similar, resulting in rates of overall survival of 85.4% in the zoledronic acid group and 83.1% in the control group (adjusted hazard ratio, 0.85; 95% CI, 0.72 to 1.01; P=0.07). In the zoledronic acid group, there were 17 confirmed cases of osteonecrosis of the jaw (cumulative incidence, 1.1%; 95% CI, 0.6 to 1.7; P<0.001) and 9 suspected cases; there were no cases in the control group. Rates of other adverse effects were similar in the two study groups. CONCLUSIONS These findings do not support the routine use of zoledronic acid in the adjuvant management of breast cancer. (Funded by Novartis Pharmaceuticals and the National Cancer Research Network; AZURE Current Controlled Trials number, ISRCTN79831382.).

Phase II Study of the Efficacy and Tolerability of Two Dosing Regimens of the Farnesyl Transferase Inhibitor, R115777, in Advanced Breast Cancer

PURPOSE R115777 is an orally active farnesyl transferase inhibitor that specifically blocks farnesylation of proteins involved in growth-factor-dependent cell-signal-transduction pathways. We conducted a phase II study in 76 patients with advanced breast cancer. PATIENTS AND METHODS Two cohorts of patients were recruited sequentially. The first cohort (n = 41) received a continuous dosing [CD] regimen of R115777 400 or 300 mg bid. The second cohort (n = 35) received 300 mg bid in a cyclical regimen of 21 days of treatment followed by 7 days of rest (intermittent dosing [ID]). RESULTS In the CD cohort, four patients (10%) had a partial response (PR) and six patients (15%) had stable disease at > or = 24 weeks (SD). In the ID cohort, five patients (14%) had a PR and three patients (9%) had prolonged SD. The first six patients in the CD cohort treated at 400 mg bid all developed grade 3 to 4 neutropenia, so the subsequent 35 patients were treated at 300 mg bid. The incidence of hematologic toxicity was significantly lower in the ID than in the CD (300-mg bid) cohort: grade 3 to 4 neutropenia (14% v 43%; P =.016) and grade 3 to 4 thrombocytopenia (3% v 26%; P =.013). One patient in the ID cohort developed grade 2 to 3 neurotoxicity compared with 15 patients in the CD cohort (3% v 37%; P =.0004). CONCLUSION The farnesyl transferase inhibitor R115777 has demonstrated clinical activity in patients with metastatic breast cancer, and the ID regimen has a significantly improved therapeutic index compared with the CD regimen.

Effects of the addition of gemcitabine, and paclitaxel-first sequencing, in neoadjuvant sequential epirubicin, cyclophosphamide, and paclitaxel for women with high-risk early breast cancer (Neo-tAnGo): an open-label, 2×2 factorial randomised phase 3 trial

BACKGROUND Anthracyclines and taxanes have been the standard neoadjuvant chemotherapies for breast cancer in the past decade. We aimed to assess safety and efficacy of the addition of gemcitabine to accelerated paclitaxel with epirubicin and cyclophosphamide, and also the effect of sequencing the blocks of epirubicin and cyclophosphamide and paclitaxel (with or without gemcitabine). METHODS In our randomised, open-label, 2×2 factorial phase 3 trial (Neo-tAnGo), we enrolled women (aged >18 years) with newly diagnosed breast cancer (tumour size >20 mm) at 57 centres in the UK. Patients were randomly assigned via a central randomisation procedure to epirubicin and cyclophosphamide then paclitaxel (with or without gemcitabine) or paclitaxel (with or without gemcitabine) then epirubicin and cyclophosphamide. Four cycles of each component were given. The primary endpoint was pathological complete response (pCR), defined as absence of invasive cancer in the breast and axillary lymph nodes. This study is registered with EudraCT (2004-002356-34), ISRCTN (78234870), and ClinicalTrials.gov (NCT00070278). FINDINGS Between Jan 18, 2005, and Sept 28, 2007, we randomly allocated 831 participants; 207 received epirubicin and cyclophosphamide then paclitaxel; 208 were given paclitaxel then epirubicin and cyclophosphamide; 208 had epirubicin and cyclophosphamide followed by paclitaxel and gemcitabine; and 208 received paclitaxel and gemcitabine then epirubicin and cyclophosphamide. 828 patients were eligible for analysis. Median follow-up was 47 months (IQR 37-51). 207 (25%) patients had inflammatory or locally advanced disease, 169 (20%) patients had tumours larger than 50 mm, 413 (50%) patients had clinical involvement of axillary nodes, 276 (33%) patients had oestrogen receptor (ER)-negative disease, and 191 (27%) patients had HER2-positive disease. Addition of gemcitabine did not increase pCR: 70 (17%, 95% CI 14-21) of 404 patients in the epirubicin and cyclophosphamide then paclitaxel group achieved pCR compared with 71 (17%, 14-21) of 408 patients who received additional gemcitabine (p=0·98). Receipt of a taxane before anthracycline was associated with improved pCR: 82 (20%, 95% CI 16-24) of 406 patients who received paclitaxel with or without gemcitabine followed by epirubicin and cyclophosphamide achieved pCR compared with 59 (15%, 11-18) of 406 patients who received epirubicin and cyclophosphamide first (p=0·03). Grade 3 toxicities were reported at expected levels: 173 (21%) of 812 patients who received treatment and had full treatment details had grade 3 neutropenia, 66 (8%) had infection, 41 (5%) had fatigue, 41 (5%) had muscle and joint pains, 37 (5%) had nausea, 36 (4%) had vomiting, 34 (4%) had neuropathy, 23 (3%) had transaminitis, 16 (2%) had acute hypersensitivity, and 20 (2%) had a rash. 86 (11%) patients had grade 4 neutropenia and 3 (<1%) had grade 4 infection. INTERPRETATION Although addition of gemcitabine to paclitaxel and epirubicin and cyclophosphamide chemotherapy does not improve pCR, sequencing chemotherapy so that taxanes are received before anthracyclines could improve pCR in standard neoadjuvant chemotherapy for breast cancer. FUNDING Cancer Research UK, Eli Lilly, Bristol-Myers Squibb.

Efficacy of neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide, for women with HER2-negative early breast cancer (ARTemis): an open-label, randomised, phase 3 trial

BACKGROUND The ARTemis trial was developed to assess the efficacy and safety of adding bevacizumab to standard neoadjuvant chemotherapy in HER2-negative early breast cancer. METHODS In this randomised, open-label, phase 3 trial, we enrolled women (≥18 years) with newly diagnosed HER2-negative early invasive breast cancer (radiological tumour size >20 mm, with or without axillary involvement), at 66 centres in the UK. Patients were randomly assigned via a central computerised minimisation procedure to three cycles of docetaxel (100 mg/m(2) once every 21 days) followed by three cycles of fluorouracil (500 mg/m(2)), epirubicin (100 mg/m(2)), and cyclophosphamide (500 mg/m(2)) once every 21 days (D-FEC), without or with four cycles of bevacizumab (15 mg/kg) (Bev+D-FEC). The primary endpoint was pathological complete response, defined as the absence of invasive disease in the breast and axillary lymph nodes, analysed by intention to treat. The trial has completed and follow-up is ongoing. This trial is registered with EudraCT (2008-002322-11), ISRCTN (68502941), and ClinicalTrials.gov (NCT01093235). FINDINGS Between May 7, 2009, and Jan 9, 2013, we randomly allocated 800 participants to D-FEC (n=401) and Bev+D-FEC (n=399). 781 patients were available for the primary endpoint analysis. Significantly more patients in the bevacizumab group achieved a pathological complete response compared with those treated with chemotherapy alone: 87 (22%, 95% CI 18-27) of 388 patients in the Bev+D-FEC group compared with 66 (17%, 13-21) of 393 patients in the D-FEC group (p=0·03). Grade 3 and 4 toxicities were reported at expected levels in both groups, although more patients had grade 4 neutropenia in the Bev+D-FEC group than in the D-FEC group (85 [22%] vs 68 [17%]). INTERPRETATION Addition of four cycles of bevacizumab to D-FEC in HER2-negative early breast cancer significantly improved pathological complete response. However, whether the improvement in pathological complete response will lead to improved disease-free and overall survival outcomes is unknown and will be reported after longer follow-up. Meta-analysis of available neoadjuvant trials is likely to be the only way to define subgroups of early breast cancer that would have clinically significant long-term benefit from bevacizumab treatment. FUNDING Cancer Research UK, Roche, Sanofi-Aventis.

Adjuvant bevacizumab in patients with melanoma at high risk of recurrence (AVAST-M): Preplanned interim results from a multicentre, open-label, randomised controlled phase 3 study

BACKGROUND Bevacizumab, a monoclonal antibody that targets VEGF, has shown restricted activity in patients with advanced melanoma. We aimed to assess the role of bevacizumab as adjuvant treatment for patients with resected melanoma at high risk of recurrence. We report results from the preplanned interim analysis. METHODS We did a multicentre, open-label, randomised controlled phase 3 trial at 48 centres in the UK between July 18, 2007, and March 29, 2012. Patients aged 16 years or older with American Joint Committee on Cancer stage (AJCC) stage IIB, IIC, and III cutaneous melanoma were randomly allocated (1:1), via a central, computer-based minimisation procedure, to receive intravenous bevacizumab 7.5 mg/kg, every 3 weeks for 1 year, or to observation. Randomisation was stratified by Breslow thickness of the primary tumour, N stage according to AJCC staging criteria, ulceration of the primary tumour, and patient sex. The primary endpoint was overall survival; secondary endpoints included disease-free interval, distant-metastases interval and quality of life. Analysis was by intention-to-treat. This trial is registered as an International Standardised Randomised Controlled Trial, number ISRCTN81261306. FINDINGS 1343 patients were randomised to either the bevacizumab group (n=671) or the observation group (n=672). Median follow-up was 25 months (IQR 16-37) in the bevacizumab group and 25 months (17-37) in the observation group. At the time of interim analysis, 286 (21%) of 1343 enrolled patients had died: 140 (21%) of 671 patients in the bevacizumab group, and 146 (22%) of 672 patients in the observation group. 134 (96%) of patients in the bevacizumab group died because of melanoma versus 139 (95%) in the observation group. We noted no significant difference in overall survival between treatment groups (hazard ratio [HR] 0.97, 95% CI 0.78-1.22; p=0.76); this finding persisted after adjustment for stratification variables (HR 1.03; 95% CI 0.81-1.29; p=0.83). Median duration of treatment with bevacizumab was 51 weeks (IQR 21-52) and dose intensity was 86% (41-96), showing good tolerability. 180 grade 3 or 4 adverse events were recorded in 101 (15%) of 671 patients in the bevacizumab group, and 36 (5%) of 672 patients in the observation group. Bevacizumab resulted in a higher incidence of grade 3 hypertension than did observation (41 [6%] vs one [<1%]). There was an improvement in disease-free interval for patients in the bevacizumab group compared with those in the observation group (HR 0.83, 95% CI 0.70-0.98, p=0.03), but no significant difference between groups for distant-metastasis-free interval (HR 0.88, 95% CI 0.73-1.06, p=0.18). No significant differences were noted between treatment groups in the standardised area under the curve for any of the quality-of-life scales over 36 months. Three adverse drug reactions were regarded as both serious and unexpected: one patient had optic neuritis after the first bevacizumab infusion, a second patient had persistent erectile dysfunction, and a third patient died of a haemopericardium after receiving two bevacizumab infusions and was later identified to have had significant predisposing cardiovascular risk factors. INTERPRETATION Bevacizumab has promising tolerability. Longer follow-up is needed to identify an effect on the primary endpoint of overall survival at 5 years.

Abstract S4-5: Adjuvant Treatment with Zoledronic Acid in Stage II/III Breast Cancer. The AZURE Trial (BIG 01/04)

Background: The ABCSG XII trial demonstrated a 32% risk reduction in disease-free survival (DFS) events with Zoledronic acid (ZOL) use in a cohort of premenopausal women treated with endocrine therapy at 62 months median follow-up .[1,2] This strategy is increasingly being adopted in the wider breast cancer population. The AZURE trial is an academic study designed to determine whether treatment with ZOL added to standard adjuvant therapy improves DFS and bone metastasis-free survival (BMFS) in a broader range of patients with stage II/III breast cancer. Materials and methods: 3360 patients from 174 centres were randomized to receive (neo) adjuvant chemotherapy (CT) and/or endocrine therapy (ET) +/− ZOL 4mg iv every 3-4 weeks for 6 doses, then 3 monthly x 8 and 6 monthly x 5 to complete 5 years treatment. The primary DFS endpoint was to be determined after 940 DFS events, providing 80% power to detect a 17% reduction in hazard rates (HR) for DFS events. The rate of events on study has been slower than expected, resulting in an estimated final analysis in 2012. In light of the clinical interest in the results of AZURE, the DMEC has agreed to a second interim analysis after 705 events with boundaries set by an independent statistician, unaware of results at the first interim analysis, for both efficacy (HR ∼0.82, alpha spend 1%) and lack of clinical benefit (HR ∼0.935 with a 5% risk of declaring a false negative result). Contingent on DMEC advice, efficacy results that breach either boundary will be presented. A DMEC recommendation not to release the results at the second interim analysis may indicate that the point HR estimate lies between these boundaries. Results: Patient characteristics including stage, number of positive axillary nodes, CT type, ER status, menopausal status and statin use were well balanced. 3208 patients (96%) received (neo) adjuvant CT (93% anthracyclines, 23% taxanes). 152 patients received ET alone. As of June 9th 2010, with a median follow up of 49 (IQR 42-56) months, there have been 695 DFS events. The safety population comprised 3340 patients (ZOL 1665; control 1675). The addition of ZOL to standard treatment did not significantly impact on chemotherapy delivery. Serious adverse events (SAE) were similar in both treatment arms. To date 13 confirmed (0.83%; 95% CI 0.38%, 1.28%) and 12 possible (1.12%; 95% CI 0.39%, 1.85%) cases of osteonecrosis of the jaw (ONJ) in the ZOL arm have occurred. Discussion: AZURE is one of the largest phase III studies of adjuvant bisphosphonates, and the results from this study will help define the role of adjuvant ZOL in the management of early breast cancer. [1] Gnant M et al. NEJM 2009; 360(7):679-691 [2] Gnant M et al. ASCO 2010 Proceedings; abs #533. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S4-5.

Use of BIBW 2992, a Novel Irreversible EGFR/HER1 and HER2 Tyrosine Kinase Inhibitor To Treat Patients with HER2-Positive Metastatic Breast Cancer after Failure of Treatment with Trastuzumab.

Background: BIBW 2992 (Tovok™*) is a novel, oral, irreversible inhibitor of the epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor (HER)1 and HER2 inhibitor, with preclinical activity in trastuzumab-resistant cell lines overexpressing HER2 and Phase I clinical activity. A Phase II study of BIBW 2992 in patients with HER2-positive breast cancer who have progressed following treatment with trastuzumab was conducted in the US and the UK.Methods: A multi-institutional, open-label, single-arm Phase II study was conducted. Eligible patients had stage IIIB or IV HER2-positive metastatic breast cancer, with progression following trastuzumab treatment or intolerance of trastuzumab, received no prior EGFR-targeted therapy, had measurable disease, Eastern Cooperative Oncology Group performance status of 0–2 and adequate organ function. Patients received 50 mg BIBW 2992 once-daily until disease progression. Tumor assessments were performed every two treatment courses (one course is 28 days). The primary endpoint was objective response rate (Response Evaluation Criteria In Solid Tumors). Safety data were also collected.Results: A total of 41 patients started treatment on the trial. Patients had received a median of three lines of prior therapy (range, 0–15). Thirty-four patients are evaluable for response. Of these, four patients had a partial response (PR) and eight patients had stable disease maintained for at least four cycles. One patient with confirmed PR remained on treatment until progression at 63 weeks. The most frequently observed side-effects to date are rash (Common Terminology Criteria for Adverse Events [CTCAE] Grade 3 in four patients [9.8%]) and diarrhea (CTCAE Grade 3) in nine patients. There have been 21 dose reductions in 18 patients.Conclusion: BIBW 2992 was safe and induced promising early clinical responses in HER2-positive breast cancer patients who have progressed following treatment with trastuzumab. Manageable cutaneous adverse events and diarrhea were the main side-effects.*Trade name not FDA approved. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5060.

Adjuvant bevacizumab as treatment for melanoma patients at high risk of recurrence: Preplanned interim results for the AVAST-M trial.

LBA9000 Background: Bevacizumab (Bev) is a recombinant humanized monoclonal antibody to vascular endothelial growth factor (VEGF) shown to improve survival in several advanced solid tumors. Multiple adjuvant trials are underway, but trials that have reported in colon and triple-negative breast cancer did not meet their primary end points. Since VEGF is a relevant target in melanoma, AVAST-M aimed to evaluate the role of Bev in patients (pts) with resected melanoma at high risk of recurrence. METHODS AVAST-M is a randomized phase III trial evaluating single agent Bev (7.5mg/kg IV 3 weekly for 1 year) as adjuvant therapy following resection of AJCC stage IIB, IIC, and III cutaneous melanoma compared to standard observation (Obs). 1,320 pts were required to detect 8% differences in 5-year overall survival (OS) rate from 40% to 48%; 85% power, 5% alpha level. Primary endpoint is OS; secondary endpoints are disease free interval (DFI), distant-metastasis free interval (DMFI), safety, and quality of life (QoL). An associated translational study is ongoing. Results of the first pre-planned interim analysis (agreed by the IDSMC) are reported here. RESULTS Between July 2007 and March 2012, 1,343 pts were recruited. 56% were male; median age 56 years (range 18-88 years), 16% were stage IIB, 11% IIC, 15% IIIA, 36% IIIB, 20% IIIC, and 2% unknown stage. Ulceration status of the primary melanoma was: 38% present, 45% absent, 17% unknown. At the time of the interim analysis, 286 (21%) patients had died. Median follow-up for survival was 25 months. Median duration of Bev treatment in 671 treated pts was 51 weeks (dose intensity 86%). Main outcomes are shown in the table. Grade 3/4 adverse events were experienced in 101 (15%) Bev pts and 36 (5%) Obs pts. CONCLUSIONS Interim analysis of this large, multicenter trial of melanoma patients at high risk of recurrence has shown that adjuvant Bev monotherapy is well tolerated and improved DFI. Longer follow-up is required to determine an impact on the primary endpoint of 5-year OS. CLINICAL TRIAL INFORMATION 81261306. [Table: see text].

Central pathology review with two-stage quality assurance for pathological response after neoadjuvant chemotherapy in the ARTemis Trial

The ARTemis Trial tested standard neoadjuvant chemotherapy±bevacizumab in the treatment of HER2-negative early breast cancer. We compare data from central pathology review with report review and also the reporting behavior of the two central pathologists. Eight hundred women with HER2-negative early invasive breast cancer were recruited. Response to chemotherapy was assessed from local pathology reports for pathological complete response in breast and axillary lymph nodes. Sections from the original core biopsy and surgical excision were centrally reviewed by one of two trial pathologists blinded to the local pathology reports. Pathologists recorded response to chemotherapy descriptively and also calculated residual cancer burden. 10% of cases were double-reported to compare the central pathologists’ reporting behavior. Full sample retrieval was obtained for 681 of the 781 patients (87%) who underwent surgery within the trial and were evaluable for pathological complete response. Four hundred and eighty-three (71%) were assessed by JSJT, and 198 (29%) were assessed by EP. Residual cancer burden calculations were possible in 587/681 (86%) of the centrally reviewed patients, as 94/681 (14%) had positive sentinel nodes removed before neoadjuvant chemotherapy invalidating residual cancer burden scoring. Good concordance was found between the two pathologists for residual cancer burden classes within the 65-patient quality assurance exercise (kappa 0.63 (95% CI: 0.57–0.69)). Similar results were obtained for the between-treatment arm comparison both from the report review and the central pathology review. For pathological complete response, report review was as good as central pathology review but for minimal residual disease, report review overestimated the extent of residual disease. In the ARTemis Trial central pathology review added little in the determination of pathological complete response but had a role in evaluating low levels of residual disease. Calculation of residual cancer burden was a simple and reproducible method of quantifying response to neoadjuvant chemotherapy as demonstrated by performance comparison of the two pathologists.