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Purpose: Despite promising activity in hematopoietic malignancies, efficacy of the B-cell lymphoma 2 (BCL2) inhibitor venetoclax in solid tumors is unknown. We report the prespecified VERONICA primary results, a randomized phase II clinical trial evaluating venetoclax and fulvestrant in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer, post–cyclin-dependent kinase (CDK) 4/6 inhibitor progression. Patients and Methods: Pre-/postmenopausal females ≥18 years were randomized 1:1 to venetoclax (800 mg orally daily) plus fulvestrant (500 mg intramuscular; cycle 1: days 1 and 15; subsequent 28-day cycles: day 1) or fulvestrant alone. The primary endpoint was clinical benefit rate (CBR); secondary endpoints were progression-free survival (PFS), overall survival, and safety. Exploratory biomarker analyses included BCL2 and BCL extra-large (BCLXL) tumor expression, and PIK3CA circulating tumor DNA mutational status. Results: At primary analysis (cutoff: August 5, 2020; n = 103), venetoclax did not significantly improve CBR [venetoclax plus fulvestrant: 11.8% (n = 6/51; 95% confidence interval (CI), 4.44–23.87); fulvestrant: 13.7% (7/51; 5.70–26.26); risk difference –1.96% (95% CI, –16.86 to 12.94)]. Median PFS was 2.69 months (95% CI, 1.94–3.71) with venetoclax plus fulvestrant versus 1.94 months (1.84–3.55) with fulvestrant (stratified HR, 0.94; 95% CI, 0.61–1.45; P = 0.7853). Overall survival data were not mature. A nonsignificant improvement of CBR and PFS was observed in patients whose tumors had strong BCL2 expression (IHC 3+), a BCL2/BCLXL Histoscore ratio ≥1, or PIK3CA-wild-type status. Conclusions: Our findings do not indicate clinical utility for venetoclax plus fulvestrant in endocrine therapy–resistant, CDK4/6 inhibitor–refractory metastatic breast tumors, but suggest possible increased dependence on BCLXL in this setting.

Supplementary Data from VERONICA: Randomized Phase II Study of Fulvestrant and Venetoclax in ER-Positive Metastatic Breast Cancer Post-CDK4/6 Inhibitors – Efficacy, Safety, and Biomarker Results

Purpose:Despite promising activity in hematopoietic malignancies, efficacy of the B-cell lymphoma 2 (BCL2) inhibitor venetoclax in solid tumors is unknown. We report the prespecified VERONICA primary results, a randomized phase II clinical trial evaluating venetoclax and fulvestrant in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer, post–cyclin-dependent kinase (CDK) 4/6 inhibitor progression.Patients and Methods:Pre-/postmenopausal females ≥18 years were randomized 1:1 to venetoclax (800 mg orally daily) plus fulvestrant (500 mg intramuscular; cycle 1: days 1 and 15; subsequent 28-day cycles: day 1) or fulvestrant alone. The primary endpoint was clinical benefit rate (CBR); secondary endpoints were progression-free survival (PFS), overall survival, and safety. Exploratory biomarker analyses included BCL2 and BCL extra-large (BCLXL) tumor expression, and PIK3CA circulating tumor DNA mutational status.Results:At primary analysis (cutoff: August 5, 2020; n = 103), venetoclax did not significantly improve CBR [venetoclax plus fulvestrant: 11.8% (n = 6/51; 95% confidence interval (CI), 4.44–23.87); fulvestrant: 13.7% (7/51; 5.70–26.26); risk difference –1.96% (95% CI, –16.86 to 12.94)]. Median PFS was 2.69 months (95% CI, 1.94–3.71) with venetoclax plus fulvestrant versus 1.94 months (1.84–3.55) with fulvestrant (stratified HR, 0.94; 95% CI, 0.61–1.45; P = 0.7853). Overall survival data were not mature. A nonsignificant improvement of CBR and PFS was observed in patients whose tumors had strong BCL2 expression (IHC 3+), a BCL2/BCLXL Histoscore ratio ≥1, or PIK3CA-wild-type status.Conclusions:Our findings do not indicate clinical utility for venetoclax plus fulvestrant in endocrine therapy–resistant, CDK4/6 inhibitor–refractory metastatic breast tumors, but suggest possible increased dependence on BCLXL in this setting.

Supplementary Table from VERONICA: Randomized Phase II Study of Fulvestrant and Venetoclax in ER-Positive Metastatic Breast Cancer Post-CDK4/6 Inhibitors – Efficacy, Safety, and Biomarker Results

ObjectiveTwo randomized phase III trials demonstrated the efficacy and safety of combining bevacizumab with front-line carboplatin/paclitaxel for advanced ovarian cancer. The OSCAR (NCT01863693) study assessed the impact of front-line bevacizumab-containing therapy on safety and oncologic outcomes in patients with advanced ovarian cancer in the UK.MethodsBetween May 2013 and April 2015, patients with high-risk stage IIIB–IV advanced ovarian cancer received bevacizumab (7.5 or 15 mg/kg every 3 weeks, typically for ≤12 months, per UK clinical practice) combined with front-line chemotherapy, with bevacizumab continued as maintenance therapy. Co-primary endpoints were progression-free survival and safety (NCI-CTCAE v4.0). Patients were evaluated per standard practice/physician’s discretion.ResultsA total of 299 patients received bevacizumab-containing therapy. The median age was 64 years (range 31–83); 80 patients (27%) were aged ≥70 years. Surgical interventions were primary debulking in 21%, interval debulking in 36%, and none in 43%. Most patients (93%) received bevacizumab 7.5 mg/kg with carboplatin/paclitaxel. Median duration of bevacizumab was 10.5 months(range ConclusionsMedian progression-free survival in this study was similar to that in the high-risk subgroup of the ICON7 phase III trial. Median progression-free survival was shortest in patients who did not undergo surgery.

Question Which is the optimal endocrine partner (fulvestrant vs letrozole) for cyclin-dependent kinase 4 and 6 inhibitor palbociclib in previously untreated, endocrine-sensitive, hormone receptor-positive, ERBB2-negative advanced breast cancer? Findings In this randomized, open-label, phase 2 trial, 486 patients were assigned in equal numbers to receive palbociclib plus fulvestrant or letrozole. Median investigator-assessed progression-free survival was 27.9 months for fulvestrant-palbociclib vs 32.8 months for letrozole-palbociclib, a difference that was not statistically significant. Meaning Fulvestrant-palbociclib demonstrated no improvement in progression-free survival over letrozole-palbociclib, confirming letrozole as the preferred palbociclib partner in this patient population. This randomized clinical trial investigates fulvestrant-palbociclib vs letrozole-palbociclib as initial therapy for endocrine-sensitive, hormone receptor-positive, ERBB2-negative breast cancer. IMPORTANCE The cyclin-dependent kinase 4 and 6 inhibitor palbociclib in combination with letrozole has become a standard first-line treatment for patients with endocrine-sensitive, hormone receptor-positive, ERBB2-negative advanced breast cancer. Meanwhile, the antiestrogen fulvestrant was shown to be superior to anastrozole in the absence of cyclin-dependent kinase 4 and 6 inhibition for this patient population. OBJECTIVE To assess whether fulvestrant is superior to letrozole when combined with palbociclib in the first-line scenario. DESIGN, SETTING, AND PARTICIPANTS In this international, randomized, open-label, phase 2 clinical study conducted from July 30, 2015, to January 8, 2018, patients with hormone receptor-positive, ERBB2-negative advanced breast cancer with no prior therapy in the metastatic setting and endocrine-sensitive criteria were recruited from 47 centers in 7 countries. Data were analyzed from February 11 to May 15, 2020. INTERVENTIONS Patients were randomly assigned (1:1 ratio) to receive palbociclib with either fulvestrant or letrozole. Stratification factors were type of disease presentation (de novo vs recurrent) and the presence of visceral involvement (yes vs no). MAIN OUTCOMES AND MEASURES The primary end point was investigator-assessed progression-free survival determined by Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS A total of 486 women (median age, 63 years [range, 25-90 years]; 3 Asian women [0.6%]; 4 Black women [0.8%]; 461 White women [94.9%]; 18 women of unknown race [3.7%]) were randomized (243 to fulvestrant-palbociclib and 243 to letrozole-palbociclib). Median investigator-assessed progression-free survival was 27.9 months (95% CI, 24.2-33.1 months) in the fulvestrant-palbociclib group vs 32.8 months (95% CI, 25.8-35.9 months) in the letrozole-palbociclib group (hazard ratio, 1.13; 95% CI, 0.89-1.45; P = .32). This result was consistent across the stratification factors. No significant differences were observed in objective response rate (46.5% vs 50.2%) and 3-year overall survival rate (79.4% vs 77.1%) for fulvestrant-palbociclib and letrozole-palbociclib, respectively. Grade 3-4 adverse events were comparable among treatment groups, and no new safety signals were identified. No treatment-related deaths were reported. CONCLUSIONS AND RELEVANCE Although fulvestrant-palbociclib demonstrated significant antitumor activity, this randomized clinical trial failed to identify an improvement in progression-free survival with this regimen over letrozole-palbociclib in patients with endocrine-sensitive, hormone receptor-positive, ERBB2-negative advanced breast cancer.

Objective Breast cancer treatment can negatively impact cardiac function in some breast cancer patients. Current methods (MUGA, echocardiography) used in clinical practice to detect abnormal cardiac changes as a result of treatment suffer from important limitations. Use of alternative techniques that would offer safe, inexpensive and non-invasive cardiac function assessment in this population would be highly advantageous. The aim of this study was to examine the agreement between impedance cardiography (ICG) and cardiac magnetic resonance imaging (CMR) in quantifying stroke volume (SV), cardiac output (CO) and end-diastolic volume (EDV) in this population. Approach Sixteen breast cancer patients underwent ICG and CMR assessments at three time-points (before treatment, immediately after chemotherapy, and four months after chemotherapy). Bland-Altman analysis was used to quantify the accuracy and precision of ICG (relative to CMR) in estimating absolute values of SV, CO and EDV. Four methods (concordance rate, polar concordance rate, clinical concordance rate and trend interchangeability rate) were also used to assess ICG performance in tracking changes in these variables. Main results Bland-Altman analysis showed that the accuracy of ICG relative to CMR was -3.1 ml (SV), 0.2 L·min-1 (CO) and -26.0 ml (EDV) and precision was 13.2 ml (SV), 1.1 L·min-1 (CO) and 20.1 ml (EDV), respectively. Trending ability assessment showed that 1) the concordance rate was 87% (SV), 73% (CO) and 73% (EDV), 2) the polar concordance rate was 67% (SV), 53% (CO) and 33% (EDV), 3) the clinical concordance rate was 33% (SV), 40% (CO) and 20% (EDV) and 4) the trend interchangeability rate was 29% (SV), 43% (CO) and 17% (EDV), respectively. Significance Our findings show that, although ICG showed good accuracy for absolute SV and CO measurements and for CO and EDV changes, precision was poor for all variables in terms of both absolute measurements and trend tracking performance. This suggests that ICG cannot be used interchangeably with CMR in breast cancer patients.

1004 Background: For patients (pts) with ER-positive, HER2-negative MBC, CDK4/6 inhibitors + endocrine therapy (ET) is standard first-line treatment, with single-agent ET considered for second-line. Nevertheless, most pts progress. A novel therapeutic target is the antiapoptotic protein BCL2, which is overexpressed in ̃85% of primary ER-positive breast cancers. VEN is a potent, selective BCL2 inhibitor that has shown promising clinical activity in pts with ER-positive and BCL2-positive MBC who have received prior ET. We report the prespecified primary and updated (for overall survival [OS]) analysis of VERONICA (NCT03584009), a phase II study of VEN + F vs F in ER-positive, HER2-negative LA/MBC. Methods: Pts were ≥18-year-old women with ER-positive, HER2-negative LA/MBC, who received ≤2 prior lines of ET and no prior chemotherapy in the LA/MBC setting and experienced disease recurrence/progression during/after CDK4/6 inhibitor therapy (received ≥8 weeks prior). Pts were randomized 1:1 to VEN (oral; 800 mg daily) + F (intramuscular; 500 mg day 1 and 15 of cycle 1; day 1 of subsequent 28-day cycles) or F, and were treated until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end. Pts were stratified by prior lines of therapy in the LA/MBC setting (1 vs 2) and BCL2 status (high vs low). Primary endpoint was clinical benefit rate (CBR; complete response, partial response, and stable disease ≥24 weeks). Secondary endpoints included progression-free survival (PFS) and OS; safety and exploratory subgroup analyses were also conducted. Results: At primary analysis (cutoff: Aug 5, 2020), 103 pts had been randomized (intention-to-treat [ITT] population). Median age was 58.0 and 59.5 years in the VEN + F and F arms, respectively. CBR was similar between arms (VEN + F: 11.8% [n = 6/51; 95% confidence interval (CI) 4.44–23.87]; F: 13.7% [7/51; 5.70–26.26]; risk difference: -1.96% [95% CI -16.86–12.94]). Median PFS was 2.69 months (95% CI 1.94–3.71) in the VEN + F vs 1.94 months (1.84–3.55) in the F arm (stratified hazard ratio: 0.94 [95% CI 0.61–1.45]). Results for CBR and PFS were similar in the BCL2-high and -low subgroups vs the ITT population. More grade 3–4 adverse events (AEs) were observed in the VEN + F vs F arm (n = 13/50 [26%] vs 6/51 [11.8%]). AEs observed with VEN + F were consistent with their individual safety profiles. At updated analysis (cutoff: Oct 22, 2020), OS data were not mature (35.0% event/pt ratio); median OS was 16.99 months in the VEN + F vs not reached in the F arm (stratified hazard ratio: 2.06 [1.04–4.09]). Conclusions: From the primary analysis, VERONICA did not show an improved CBR or PFS with VEN + F, vs F alone, in pts with endocrine- and CDK4/6 inhibitor-refractory LA/MBC. Biomarker analysis is ongoing. Clinical trial information: NCT03584009 .

Objectives This study represents the first reported outcomes for patients with advanced ovarian cancer (AOC) in South-West Wales undergoing treatment with primary debulking surgery or primary chemotherapy respectively. Methods This is a retrospective study of consecutive, unselected patients with advanced ovarian, fallopian tube or primary peritoneal cancer (FIGO III/IV) presenting to a regional cancer centre between October 2007 and October 2014. Patients were identified from Welsh Cancer Services records and relevant data was extracted from electronic National Health Service (NHS) databases. Main outcome measures were median overall survival (OS), progression free survival (PFS) and perioperative adverse events. Hazard ratio estimation was carried out with Cox Regression analysis and survival determined by Kaplan-Meier plots. Results Of 220 women with AOC, 32.3% underwent primary debulking surgery (PDS) and 67.7% primary chemotherapy and interval debulking (PCT-IDS). Patients were often elderly (median age 67 years) with a poor performance status (26.5% PS >1). Complete cytoreduction (0 cm residual) was achieved in 32.4% of patients in the PDS group and in 50.0% of patients undergoing IDS. Median OS for all patients was 21.9 months (PDS: 27.0 and PCT-IDS: 19.2 months; p > 0.05) and median PFS was 13.1 months (PDS: 14.3 months and PCT-IDS: 13.0 months; p > 0.05). Median overall and progression free survival for patients achieving complete cytoreduction were 48.0 and 23.2 months respectively in the PDS group and 35.4 months and 18.6 months in the IDS group (p > 0.05). Conclusion This retrospective study of an unselected, consecutive cohort of women with AOC in South West Wales shows comparable survival outcomes with recently published trials, despite the relatively advanced age and poor performance status of our patient cohort. Over the seven-year study period, our data also demonstrated a non-significant trend towards improved survival following primary surgery in patients who achieved maximal cytoreduction. Our future aim therefore is to examine and develop the role of extended surgery in these patients.

This work was supported by Cancer Research UK (EHW, TJ: C42738/A24868); National Institute of Health Research Cambridge Biomedical Research Centre (HE); National Institute of Health Research UK Academic Clinical Fellowship (CMC); and National Institutes of Health USA Cancer Center support grant (TJ: 5P30CA045508-31). Important oncological management decisions rely on kidney function assessed by serum creatinine-based estimated glomerular filtration rate (eGFR). However, no large-scale multicentre comparison of methods to determine eGFR in patients with cancer are available. To compare the performance of formulas for eGFR based on routine clinical parameters and serum creatinine not calibrated with isotope dilution mass spectrometry (non-IDMS), we studied 3,620 patients with cancer and 166 without cancer who had their GFR measured with an exogenous nuclear tracer at one of seven clinical centres. The mean measured GFR was 86 ml/min. Accuracy of all models was centre-dependent, reflecting inter-centre variability of non-IDMS creatinine measurements. CamGFR was the most accurate model for eGFR (root-mean-squared-error (RMSE) 17.3 ml/min) followed by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) model (RMSE 18.2 ml/min).Important oncological management decisions rely on kidney function assessed by serum creatinine-based estimated glomerular filtration rate (eGFR). However, no large-scale multicentre comparison of methods to determine eGFR in patients with cancer are available. To compare the performance of formulas for eGFR based on routine clinical parameters and serum creatinine not calibrated with isotope dilution mass spectrometry (non-IDMS), we studied 3,620 patients with cancer and 166 without cancer who had their GFR measured with an exogenous nuclear tracer at one of seven clinical centres. The mean measured GFR was 86 ml/min. Accuracy of all models was centre-dependent, reflecting inter-centre variability of non-IDMS creatinine measurements. CamGFR was the most accurate model for eGFR (root-mean-squared-error (RMSE) 17.3 ml/min) followed by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) model (RMSE 18.2 ml/min).Important oncological management decisions rely on kidney function assessed by serum creatinine–based estimated glomerular filtration rate (eGFR). However, no large-scale multicenter comparisons of methods to determine eGFR in patients with cancer are available. To compare the performance of formulas for eGFR based on routine clinical parameters and serum creatinine not calibrated with isotope dilution mass spectrometry, we studied 3620 patients with cancer and 166 without cancer who had their glomerular filtration rate (GFR) measured with an exogenous nuclear tracer at one of seven clinical centers. The mean measured GFR was 86 mL/min. Accuracy of all models was center dependent, reflecting intercenter variability of isotope dilution mass spectrometry–creatinine measurements. CamGFR was the most accurate model for eGFR (root-mean-squared error 17.3 mL/min) followed by the Chronic Kidney Disease Epidemiology Collaboration model (root-mean-squared error 18.2 mL/min). Publisher PDF

Adjuvant bisphosphonates improve disease outcomes in postmenopausal early breast cancer (EBC) but the long-term effects are poorly described. The AZURE trial (ISRCTN79831382) was designed to determine whether adjuvant zoledronic acid (ZOL) improves disease outcomes in EBC. Previous analyses showed no effect on overall outcomes but identified benefits in postmenopausal women. Here we present the long-term risks and benefits of adjuvant ZOL with 10-years follow-up. Patients and methods: 3360 patients with stage II/III breast cancer were included in an academic, international, phase III, randomized, open label trial. Patients were followed up on a regular schedule until 10 years. Patients were randomized on a 1:1 basis to standard adjuvant systemic therapy +/− intravenous ZOL 4 mg every 3–4 weeks x6, and then at reduced frequency to complete 5 years treatment. The primary outcome was disease free survival (DFS). Secondary outcomes included invasive DFS (IDFS), overall survival (OS), sites of recurrence, skeletal morbidity and treatment outcomes according to primary tumor amplification of the transcription factor, MAF. Pre-planned subgroup analyses focused on interactions between menopausal status and treatment effects. Results: With a median follow up of 117 months [IQR 70.4–120.4), DFS and IDFS were similar in both arms (HRDFS = 0.94, 95%CI = 0.84–1.06, p = 0.340; HRIDFS = 0.91, 95%CI = 0.82–1.02, p = 0.116). However, outcomes remain improved with ZOL in postmenopausal women (HRDFS = 0.82, 95%CI = 0.67–1.00; HRIDFS = 0.78, 95%CI = 0.64–0.94). In the 79% of tested women with a MAF FISH negative tumor, ZOL improved IDFS (HRIDFS = 0.75, 95%CI = 0.58–0.97) and OS HROS = 0.69, 95%CI = 0.50–0.94), irrespective of menopause. ZOL did not improve disease outcomes in MAF FISH + tumors. Bone metastases as a first DFS recurrence (BDFS) were reduced with ZOL (HRB-DFS = 0.76, 95%CI = 0.63–0.92, p = 0.005). ZOL reduced skeletal morbidity with fewer fractures and skeletal events after disease recurrence. 30 cases of osteonecrosis of the jaw in the ZOL arm (1.8%) have occurred. Conclusions: Disease benefits with adjuvant ZOL in postmenopausal early breast cancer persist at 10 years of follow-up. The biomarker MAF identified a patient subgroup that derived benefit from ZOL irrespective of menopausal status.

Aim: This review aims to assist physicians and payers in assessing the efficacy and safety of bevacizumab in real-world clinical practice by identifying evidence on the comparative effectiveness and safety of bevacizumab in its most frequent indications. Materials & methods: In a systematic review of the published literature, electronic databases (Embase®, MEDLINE® and the Cochrane Library) were searched in May 2016 and updated in January 2017; 20 scientific congresses were searched in 2014–2017. Results: Of 61 included publications, 49, eight, four and 0 concerned metastatic colorectal cancer, metastatic breast cancer, advanced ovarian cancer and cervical cancer, respectively. Fifteen publications (metastatic colorectal cancer) reported on factors predictive of response to therapy. Conclusion: Effectiveness findings from real-world studies broadly supported results from registration studies.

PURPOSE: The 21-gene Recurrence Score assay (Oncotype DX) provides prognostic/predictive information in oestrogen receptor positive (ER+) early breast cancer, but access/reimbursement has been limited in most European countries in the absence of prospective outcome data. Recently, two large prospective studies and a real-life 5-year outcome study have been reported. We performed a pooled analysis of prospective European impact studies to generate robust data on impact of use in different clinical subgroups. METHODS: The analysis included four studies (French, German, Spanish, and British) in ER+ human epidermal growth factor receptor 2-negative breast cancer patients (n = 527). Node-positive patients were excluded. RESULTS: The analysis demonstrated that treatment recommendations changed in 32% of patients post-testing; chemotherapy recommendation rate decreased from 55% to 34%. Change rates in the individual studies ranged from 30% to 37%. The highest change rates were in patients originally recommended chemotherapy and in grade II tumours; there was no subgroup without a treatment recommendation change. Notably, 31% of patients with an intermediate Recurrence Score result had a treatment recommendation change suggesting that testing provides actionable information in this group. With the exception of the German study (where chemotherapy rates remained high [41%] post-testing), between-study variability in treatment recommendations decreased post-testing (chemotherapy: from 36-52% to 26-29%; hormonal therapy: from 48-64% to 71-74%). Physicians' confidence regarding treatment recommendations improved in all the studies after testing. CONCLUSION: Recurrence Score testing led to changes in adjuvant chemotherapy use in approximately a third of patients, to an overall reduced chemotherapy use, and to more homogeneous decision making. J.A. acknowledges FIS PI12/00680 RD12/0036/0051, 2014SGR740 intensification grant ISCIII, and A Ll./nPI12/01421 and RD12/0036/0070.

Bevacizumab has become a 'community standard' at many UK centres as part of first-line treatment of patients with ovarian cancer at high risk of progression [International Federation of Gynecology and Obstetrics (FIGO) stage IV, or suboptimally debulked stage III] based on the results of phase III trials such as ICON-7. Its impact in patients treated outside clinical trials is, however, still unknown. In this study, we investigated patient characteristics, treatment patterns, adverse events and progression-free survival in 'real-world' patients in South West Wales. A total of 60 patients, treated between 2012 and 2015, were included in the study. Patient characteristics were less favourable compared to the bevacizumab-treated high-risk group in the ICON-7 trial (median age: 66 vs. 60 years; stage IV: 58% vs. 42%; performance status 0: 18% vs. 41%); 75% had received neoadjuvant chemotherapy before starting bevacizumab. After a median treatment duration of 8 months (range=0-34 months), 45 patients (75%) had experienced disease progression and 34 (56.7%) had died. Median progression-free survival was 16 months (95% confidence interval=14.4-17.6 months). The most common toxicities consisted of proteinuria (66.7%, all grade 1) and grade 1-2 hypertension (15%). Cardiovascular incidents, two of which were fatal, occurred in 6.7% of patients. In conclusion, our study provides encouraging evidence that the routine use of bevacizumab as part of first-line treatment of patients with ovarian cancer at high risk of progression may be associated with outcomes comparable with those obtained in clinical trials.

Purpose The role of temporary ovarian suppression with gonadotropin-releasing hormone agonists (GnRHa) during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal women remains controversial. This systematic review and meta-analysis using individual patient–level data was conducted to better assess the efficacy and safety of this strategy in patients with early breast cancer. Methods The trials in which premenopausal women with early breast cancer were randomly assigned to receive (neo)adjuvant chemotherapy alone or with concurrent GnRHa were eligible for inclusion. Primary end points were premature ovarian insufficiency (POI) rate and post-treatment pregnancy rate. Disease-free survival and overall survival were secondary end points. Because each study represents a cluster, statistical analyses were performed using a random effects model. Results A total of 873 patients from five trials were included. POI rate was 14.1% in the GnRHa group and 30.9% in the control group (adjusted odds ratio, 0.38; 95% CI, 0.26 to 0.57; P < .001). A total of 37 (10.3%) patients had at least one post-treatment pregnancy in the GnRHa group and 20 (5.5%) in the control group (incidence rate ratio, 1.83; 95% CI, 1.06 to 3.15; P = .030). No significant differences in disease-free survival (adjusted hazard ratio, 1.01; 95% CI, 0.72 to 1.42; P = .999) and overall survival (adjusted hazard ratio, 0.67; 95% CI, 0.42 to 1.06; P = .083) were observed between groups. Conclusion Our findings provide evidence for the efficacy and safety of temporary ovarian suppression with GnRHa during chemotherapy as an available option to reduce the likelihood of chemotherapy-induced POI and potentially improve future fertility in premenopausal patients with early breast cancer.

Background Chemotherapy-induced premature ovarian insufficiency (POI) impacts fertility and other aspects of women's health. The OPTION trial tested whether administration of a gonadotropin-releasing hormone agonist during chemotherapy for early breast cancer reduced the risk of POI. Patients and methods This was a prospective, randomized, parallel group study of the gonadotropin-releasing hormone agonist goserelin administered before and during chemotherapy for breast cancer with stage I–IIIB disease. The primary outcome was amenorrhoea between 12 and 24 months after randomization, supported by elevated follicle stimulating hormone concentrations to give an additional analysis as rate of POI. Results A total of 227 patients were randomized and the primary analysis was conducted on 202 patients. Goserelin reduced the prevalence of amenorrhoea between 12 and 24 months to 22% versus 38% in the control group (P = 0.015) and the prevalence of POI to 18.5% versus 34.8% in the control group (P = 0.048). Follicle stimulating hormone concentrations were also lower in all women treated with goserelin at both 12 and 24 months (P = 0.027, P = 0.001, respectively). The effect of goserelin was not statistically significant in women >40 years. Assessment of the ovarian reserve using anti-Mullerian hormone showed a marked fall in both groups during treatment to median values of 5% of pretreatment levels in the control group and 7% in the goserelin group, which were not significantly different between groups. Conclusion This study shows that goserelin reduced the risk of POI in women treated with chemotherapy for early breast cancer, with particular efficacy in women aged ≤40 years old. The degree of ovarian protection also seems limited and the clinical significance for fertility and longer term prevention of estrogen deficiency-related outcomes needs to be determined.

Purpose The Intergroup Exemestane Study, an investigator-led study of 4,724 postmenopausal patients with early breast cancer (clinical trial information: ISRCTN11883920), has previously demonstrated that a switch from adjuvant endocrine therapy after 2 to 3 years of tamoxifen to exemestane was associated with clinically relevant improvements in efficacy. Here, we report the final efficacy analyses of this cohort. Patients and Methods Patients who remained disease free after 2 to 3 years of adjuvant tamoxifen were randomly assigned to continue tamoxifen or switch to exemestane to complete a total of 5 years of adjuvant endocrine therapy. Given the large number of non–breast cancer–related deaths now reported, breast cancer–free survival (BCFS), with censorship of intercurrent deaths, was the primary survival end point of interest. Analyses focus on patients with estrogen receptor-positive or unknown tumors (n = 4,599). Results At the time of the data snapshot, median follow-up was 120 months. In the population that was estrogen receptor positive or had unknown estrogen receptor status, 1,111 BCFS events were observed with 508 (22.1%) of 2,294 patients in the exemestane group and 603 (26.2%) of 2,305 patients in the tamoxifen group. The data corresponded to an absolute difference (between exemestane and tamoxifen) at 10 years of 4.0% (95% CI, 1.2% to 6.7%), and the hazard ratio (HR) of 0.81 (95% CI, 0.72 to 0.92) favored exemestane. This difference remained in multivariable analysis that was adjusted for nodal status, prior use of hormone replacement therapy, and prior chemotherapy (HR, 0.80; 95% CI, 0.71 to 0.90; P < .001). A modest improvement in overall survival was seen with exemestane; the absolute difference (between exemestane and tamoxifen) at 10 years in the population that was estrogen receptor positive or had unknown estrogen receptor status was 2.1% (95% CI, −0.5% to 4.6%), and the HR was 0.89 (95% CI, 0.78 to 1.01; P = .08). For the intention-to-treat population, the absolute difference was 1.6% (95% CI, −0.9% to 4.1%); the HR was 0.91 (95% CI, 0.80 to 1.03, P = .15). No statistically significant difference was observed in the proportion of patients who reported a fracture event in the post-treatment period. Conclusion The Intergroup Exemestane Study and contemporaneous studies have established that a strategy of switching to an aromatase inhibitor after 2 to 3 years of tamoxifen can lead to sustained benefits in terms of reduction of disease recurrence and breast cancer mortality.

Aim To assess the safety and tolerability of adjuvant subcutaneous trastuzumab (Herceptin ® SC, H SC), delivered from an H SC Vial via hand-held syringe (Cohort A) or single-use injection device (Cohort B), with or without chemotherapy, for human epidermal growth factor receptor 2 (HER2)-positive stage I to IIIC early breast cancer (EBC) in the phase III SafeHer study (NCT01566721). Methods Patients received 600 mg fixed-dose H SC every 3 weeks for 18 cycles. The chemotherapy partner was at the investigators' discretion (H SC monotherapy was limited to ≤10% of the population). Data from the first H SC dose until 28 days (plus a 5-day window) after the last dose are presented. Results are descriptive. Results In the overall population, 2282/2573 patients (88.7%) experienced adverse events (AEs). Of the above, 128 (5.0%) patients experienced AEs leading to study drug discontinuation; 596 (23.2%) experienced grade ≥ 3 AEs and 326 (12.7%) experienced serious AEs. Grade ≥ 3 cardiac disorders were reported in 24 patients (0.9%), including congestive heart failure in eight (0.3%). As expected, the AE rates varied according to the timing of chemotherapy in both cohorts, with higher rates in concurrent versus sequential chemotherapy subgroups. In the concurrent chemotherapy subgroup, AEs were more common during the actual period of concurrent chemotherapy compared with the period when patients did not receive concurrent chemotherapy. Conclusion SafeHer confirms the safety and tolerability of the H SC 600 mg fixed dose for 1 year (every 3 weeks for 18 cycles) as adjuvant therapy with concurrent or sequential chemotherapy for HER2-positive EBC. These primary analysis results are consistent with the known safety profile for intravenous H and H SC.

Background: Tumour gene expression analysis is useful in predicting adjuvant chemotherapy benefit in early breast cancer patients. This study aims to examine the implications of routine Oncotype DX testing in the UK. Methods: Women with oestrogen receptor positive (ER+), pNO or pN1mi breast cancer were assessed for adjuvant chemotherapy and subsequently offered Oncotype DX testing, with changes in chemotherapy decisions recorded. A subset of patients completed questionnaires about their uncertainties regarding chemotherapy decisions pre- and post-testing. All patients were asked to complete a diary of medical interactions over the next 6 months, from which economic data were extracted to model the cost-effectiveness of testing. Results: Oncotype DX testing resulted in changes in chemotherapy decisions in 38 of 142 (26.8%) women, with 26 of 57 (45.6%) spared chemotherapy and 12 of 85 (14.1%) requiring chemotherapy when not initially recommended (9.9% reduction overall). Decision conflict analysis showed that Oncotype DX testing increased patients' confidence in treatment decision making. Economic analysis showed that routine Oncotype DX testing costs £6232 per quality-adjusted life year gained. Conclusion: Oncotype DX decreased chemotherapy use and increased confidence in treatment decision making in patients with ER+ early-stage breast cancer. Based on these findings, Oncotype DX is cost-effective in the UK setting.

Summary Background Long-term hormone therapy alone is standard care for metastatic or high-risk, non-metastatic prostate cancer. STAMPEDE—an international, open-label, randomised controlled trial—uses a novel multiarm, multistage design to assess whether the early additional use of one or two drugs (docetaxel, zoledronic acid, celecoxib, zoledronic acid and docetaxel, or zoledronic acid and celecoxib) improves survival in men starting first-line, long-term hormone therapy. Here, we report the preplanned, second intermediate analysis comparing hormone therapy plus celecoxib (arm D) with hormone therapy alone (control arm A). Methods Eligible patients were men with newly diagnosed or rapidly relapsing prostate cancer who were starting long-term hormone therapy for the first time. Hormone therapy was given as standard care in all trial arms, with local radiotherapy encouraged for newly diagnosed patients without distant metastasis. Randomisation was done using minimisation with a random element across seven stratification factors. Patients randomly allocated to arm D received celecoxib 400 mg twice daily, given orally, until 1 year or disease progression (including prostate-specific antigen [PSA] failure). The intermediate outcome was failure-free survival (FFS) in three activity stages; the primary outcome was overall survival in a subsequent efficacy stage. Research arms were compared pairwise against the control arm on an intention-to-treat basis. Accrual of further patients was discontinued in any research arm showing safety concerns or insufficient evidence of activity (lack of benefit) compared with the control arm. The minimum targeted activity at the second intermediate activity stage was a hazard ratio (HR) of 0·92. This trial is registered with ClinicalTrials.gov, number NCT00268476, and with Current Controlled Trials, number ISRCTN78818544. Findings 2043 patients were enrolled in the trial from Oct 17, 2005, to Jan 31, 2011, of whom 584 were randomly allocated to receive hormone therapy alone (control group; arm A) and 291 to receive hormone therapy plus celecoxib (arm D). At the preplanned analysis of the second intermediate activity stage, with 305 FFS events (209 in arm A, 96 in arm D), there was no evidence of an advantage for hormone therapy plus celecoxib over hormone therapy alone: HR 0·94 (95% CI 0·74–1·20). 2-year FFS was 51% (95% CI 46–56) in arm A and 51% (95% CI 43–58) in arm D. There was no evidence of differences in the incidence of adverse events between groups (events of grade 3 or higher were noted at any time in 123 [23%, 95% CI 20–27] patients in arm A and 64 [25%, 19–30] in arm D). The most common grade 3–5 events adverse effects in both groups were endocrine disorders (55 [11%] of patients in arm A vs 19 [7%] in arm D) and musculoskeletal disorders (30 [6%] of patients in arm A vs 15 [6%] in arm D). The independent data monitoring committee recommended stopping accrual to both celecoxib-containing arms on grounds of lack of benefit and discontinuing celecoxib for patients currently on treatment, which was endorsed by the trial steering committee. Interpretation Celecoxib 400 mg twice daily for up to 1 year is insufficiently active in patients starting hormone therapy for high-risk prostate cancer, and we do not recommend its use in this setting. Accrual continues seamlessly to the other research arms and follow-up of all arms will continue to assess effects on overall survival. Funding Cancer Research UK, Pfizer, Novartis, Sanofi-Aventis, Medical Research Council (London, UK).

Although there have been major improvements in the management of breast cancer, with a rapidly falling death rate despite an increasing incidence of the disease, metastatic breast cancer remains common and the cause of death in nearly 12 000 women annually in the UK. Numerous treatment options are available that either target the tumour or reduce the complications of the disease. Clinical decision making depends on knowledge of the extent and biology of the disease and available drug options, an understanding of the functional status, and also the wishes and expectations of the individual patient. In addition, the organisation of services and support of the patient are essential components of high-quality care. The National Institute for Health and Clinical Excellence (NICE) has produced guidelines for the treatment of advanced breast cancer, which in some areas have perhaps failed to appreciate the complexity of patient management. This guidance document aims to provide succinct practical advice on the treatment of metastatic breast cancer, highlight some limitations of the NICE guidelines, and provide suggestions for management where available data are limited.

Objectives: International guidelines support the use of the Oncotype DX derived Recurrence Score (RS) to provide additional prognostic and predictive information in early breast cancer but experience in the UK is limited. In our prospective study we evaluate this test for the NHS and its impact on costs (subject of a separate abstract) and treatment recommendations by UK oncologists. Methods: 150 tests were made available to consecutive patients with ER+, pN0, pN1itc or pN1mic early breast cancer who had no contraindication to adjuvant chemotherapy (CT) and who would accept CT + hormone therapy (HT) if recommended. CT recommendations of oncologists based on Adjuvant! Online figures were recorded at an initial consultation. Eligible patients were consented to Oncotype DX testing and review arranged once the result was available. After a second consultation a final decision on adjuvant therapy was recorded. Results: Analysis is based on 142 patients. (150 tests performed, 3 failed to give a result, 3 repeated tests giving a result on the second block, one bilateral and one test stopped because the patient withdrew from the study). Initial treatment recommendations changed in 38 (26.8%) cases. Of the patients initially recommended CT + HT (total 57 patients), 26 (45.6%) patients were spared chemotherapy after review with the RS. Of the 85 patients initially recommended HT only 12 (14.1%) were changed to HT + CT. Further analysis shows that Grade, estrogen receptor status by immunohistochemistry (ER by IHC) and progesterone receptor by immunohistochemistry (PR by IHC) are correlated to RS but in our cohort age, size and node status were not. (Spearman rank correlation for grade is 0.05, 95%, Cl 0.36 to 0.61; for ER by IHC is −0.36, Cl −0.49 to −0.20; and for PR by IHC is −0.49, 95%, Cl −0.60 to −0.35). Apart from HER2 positive patients who are already recognized to return a high RS, further analysis of our series shows no clear combination of currently available prognostic factors that would predict RS and therefore reliably avoid testing of any subset of patients. Conclusion: The results of our study suggest that Oncotype DX is applicable and feasible to perform in UK patients with a reduction in the use of adjuvant chemotherapy consistent with findings of reported studies. RS added prognostic information beyond information provided by Adjuvant! Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-14-26.

Introduction: TACT2, a multicentre phase III trial with E-CMF as control (NEAT Poole NEJM 2006), tests 2 hypotheses in a 2x2 factorial design: A) accelerating chemotherapy (CT) offers superior benefits (CALGB9741 Citron JCO 2003); B) the oral 5FU prodrug capecitabine (X) gives similar efficacy but preferential side-effect profile to CMF. Here, focus is on hypothesis A with results for compliance, QL and acute toxicities (physician & patient (pt) reported) during E vs aE. Materials & Methods: Dec 2005-08 4391 pts (4371 women, 20 men) with node +ve or high risk node -ve invasive EBC were recruited. Pts were randomised to receive either E (100mg/m2 x 4) q3wk or q2wk aE (100mg/m2 x 4 plus pegfilgrastim, 6mg d2) followed by classical CMF q4wk x 4 or X (2500mg/m2/day x 14) q3wk x 4. Detailed CTCAE toxicity was to be assessed in subset (38 centres, 2137 pts). Of these, 2127 pts received ≥1 cycle CT. 1279 of these pts completed pt-reported outcomes (EORTC QLQ-C30 and pre-defined pt-reported TACT2 toxicities) with 910 completing baseline on time and having end cycle 4 data. P Results: 33/4391 pts did not start CT. 4259 (97%) completed the initial 4 cycles (E 2143 (96%), aE 2116 (98%) with RDI >85% for E 2058 (93%) and aE 1983 (91%). During cycles 1-4 higher rates of hand-foot syndrome & anaemia were seen with aE vs E (P Conclusion: In TACT2, the largest adjuvant trial reporting acute toxicities for standard vs accelerated E in EBC, serious CTCAE toxicity was less common with aE compared with E, however pts report poorer global QL, fatigue & role function which does not appear to be explained by impact on daily activities due to individual side-effects. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-10-06.

Non-randomised data suggest a protective benefit on ovarian function for using GnRH analogues to suppress menses during chemotherapy. However there have been no published randomised clinical trials to date that confirm this protection indicated by recovery of menstrual function. Observational data suggest that patient age and cumulative dose of alkylating agent or selection and intensity of dose other agents such as anthracyclines or taxanes are also important variables that determine the risk of chemotherapy-induced premature ovarian failure (POF). This trial in premenopausal women has tested the effect of goserelin (G) given randomly before and during adjuvant chemotherapy in premenopausal women with breast cancer. Any standard regimen was allowed but women were randomised in 2 strata, under 40 yrs and over 40 yrs at diagnosis. 227 patients were recruited by end December 2009, and 173 met the criteria for 1 year follow-up for this analysis; 140 patients of these 173 patients had provided adequate data on menstrual bleeding; 87 patients were aged under 40 and 53 patients were aged over 40 at the time of chemotherapy. Cessation of menstruation during chemotherapy was defined as at least two consecutive cycles with no menstrual bleeding since the previous cycle. Additionally, prior to the final cycle of chemotherapy, there had to be no return of menstrual bleeding. Of those patients who had ceased periods during chemotherapy, those with no further menstrual bleeding at 12 months follow up were deemed to have reached menopause. Patients were randomised to receive G or no G at start of chemotherapy. Primary endpoint was recovery of menses at 12 months from start of chemotherapy. Secondary endpoints included quality of life, oestrogen/LH/FSH levels at start and completion and at 12 months along with anti-mullerian hormone (AMH, as an indicator of impending ovarian failure). Endocrine data over time showed a close correlation with menses in that both measures indicated no protective effect in the treatment group. There was no significant difference with respect to POF when all patients were considered. However there was a trend to poorer recovery of menstrual function at 12 months in the under-40 yrs group who had G with 34.7% having POF in the G treated group and 15.8% in the chemotherapy only treated group (P ≥0.05). This is mirrored by the oestrogen data which show an incomplete recovery at 12 months of oestrogen in the G group compared with controls although a complete recovery at 24 months. LH and FSH levels showed appropriate suppression by G and thereafter similar levels to controls. Early follow up data on the hormone levels shows no difference between the treatment groups. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-13-07.

Inhibition of the aromatase enzyme in postmenopausal women reduces levels of estrogens, which is of therapeutic value in hormone-sensitive breast cancer. Exemestane is a third-generation steroidal irreversible inactivator of the aromatase enzyme used in early and advanced breast cancer for the treatment of postmenopausal women with estrogen-receptor-positive disease.The scientific literature on exemestane, including published articles and abstracts, was searched from 1988 to the present, and the most significant results are included in the review.The review outlines the pharmacological characteristics of exemestane and the evidence supporting its use in the treatment of postmenopausal women with early or advanced estrogen-receptor-positive breast cancer.Exemestane is an effective and well-tolerated aromatase inhibitor with a defined role in early-stage breast cancer following 2 - 3 years of adjuvant treatment with tamoxifen. Exemestane also has a role in the sequence of hormonal agents employed to control advanced hormone-sensitive breast cancer, in which clinicians may exploit its partial lack of cross-resistance with nonsteroidal aromatase inhibitors.

2565Background: Estimation of glomerular filtration rate (GFR) is essential for carboplatin chemotherapy dosing. However, the most accurate method to estimate GFR in patients with cancer is unknown...

Background: The antiestrogen tamoxifen may have partial estrogen-like effects on the postmenopausal uterus. Aromatase inhibitors (AIs) are increasingly used after initial tamoxifen in the adjuvant treatment of postmenopausal early breast cancer due to their mechanism of action: a potential benefit being a reduction of uterine abnormalities caused by tamoxifen. Patients and methods: Sonographic uterine effects of the steroidal AI exemestane were studied in 219 women participating in the Intergroup Exemestane Study: a large trial in postmenopausal women with estrogen receptor-positive (or unknown) early breast cancer, disease free after 2–3 years of tamoxifen, randomly assigned to continue tamoxifen or switch to exemestane to complete 5 years adjuvant treatment. The primary end point was the proportion of patients with abnormal (≥5 mm) endometrial thickness (ET) on transvaginal ultrasound 24 months after randomisation. Results: The analysis included 183 patients. Two years after randomisation, the proportion of patients with abnormal ET was significantly lower in the exemestane compared with tamoxifen arm (36% versus 62%, respectively; P = 0.004). This difference emerged within 6 months of switching treatment (43.5% versus 65.2%, respectively; P = 0.01) and disappeared within 12 months of treatment completion (30.8% versus 34.7%, respectively; P = 0.67). Conclusion: Switching from tamoxifen to exemestane significantly reverses endometrial thickening associated with continued tamoxifen.

Background The role of temporary ovarian suppression with gonadotropin-releasing hormone analogs (GnRHa) during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal early breast cancer patients remains highly controversial. This option is considered experimental by the ASCO and ESMO guidelines on fertility preservation in cancer patients. The present pooled analysis aimed at elucidating the efficacy and safety of temporary ovarian suppression with GnRHa during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal early breast cancer patients. Patients and methods This study included individual patient data from 5 trials (PROMISE-GIM6, POEMS/SWOG S0230, Anglo Celtic Group OPTION, GBG-37 ZORO, Moffitt-led trial) in which premenopausal women with early breast cancer were randomized to receive (neo)adjuvant chemotherapy alone or with concurrent administration of GnRHa. Efficacy endpoints were premature ovarian insufficiency (POI, according to the definition used as primary endpoint in the included trials), 1- and 2-year amenorrhea rates and post-treatment pregnancy rate. Safety endpoints were disease-free survival (DFS) and overall survival (OS). Odds ratio (OR), incidence rate ratio (IRR) and hazard ratio (HR) with 95% confidence intervals (CI) were calculated for the effect of adding GnRHa to chemotherapy alone. As each study represents a cluster, statistical analysis has been performed using a random effects model. The study is registered with the PROSPERO registration number CRD42014015638. Results A total of 873 patients from 5 randomized trials were included. Median age was 38 years (interquartile range: 34-42 years). POI rate was 14.1% in the GnRHa group and 30.9% in the control group (adjusted OR 0.38; 95% CI 0.26-0.57; p < 0.001). The incidence of 1-year amenorrhea was 36.8% in the GnRHa group and 40.4% in the control group (adjusted OR 0.92; 95% CI 0.66-1.28; p = 0.623). The incidence of 2-year amenorrhea was 18.2% in the GnRHa group and 30.0% in the control group (adjusted OR 0.51; 95% CI 0.31-0.85; p = 0.009). A total of 37 patients had at least one post-treatment pregnancy in the GnRHa group and 20 in the control group (IRR 1.83; 95% CI 1.06-3.15; p = 0.030). There were no significant differences in DFS (adjusted HR 1.01; 95% CI 0.72-1.42; p = 0.999) or OS (adjusted HR 0.67; 95% CI 0.42-1.06; p = 0.083) between the GnRHa and control groups. Subgroup analyses of both efficacy and safety endpoints according to age of the patients, hormone receptor status, type and duration of chemotherapy will be presented at the conference. Conclusions This study provides level 1A of evidence for the efficacy and safety of temporary ovarian suppression with GnRHa during chemotherapy in premenopausal early breast cancer patients. Given the findings of this pooled analysis, temporary ovarian suppression with GnRHa during chemotherapy should be considered as a new standard option to reduce the likelihood of chemotherapy-induced POF and possibly improve future fertility in premenopausal early breast cancer patients. Citation Format: Lambertini M, Moore HCF, Leonard RCF, Loibl S, Munster P, Bruzzone M, Boni L, Unger JM, Anderson RA, Mehta K, Minton S, Poggio F, Albain KS, Adamson DJA, Gerber B, Cripps A, Bertelli G, Seiler S, Ceppi M, Partridge AH, Del Mastro L. Pooled analysis of five randomized trials investigating temporary ovarian suppression with gonadotropin-releasing hormone analogs during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal early breast cancer patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS4-01.

Surveys carried out in Mediterranean countries demonstrated very low rates of awareness of both diagnosis and prognosis among cancer patients. In our institution, a long-term training program aimed at improving communication skills among all physicians interacting with cancer patients was conducted. We report here the results of an extensive assessment of patients' awareness conducted after the first training period.In a 2-year period, after every first visit of patients with a histological diagnosis of cancer, oncologists elicited perception of the patients and completed a structured questionnaire focusing on the understanding of the diagnosis and prognosis. Our data are thus a photograph of the results of the informative process conducted during the diagnostic phase.Among the enrolled 649 patients, 79.3% were aware of their diagnosis; factors significantly associated with higher levels of awareness were age younger than 70 and referral from surgery (versus internal medicine). Knowledge about the palliative or curative aims of future treatments (a surrogate sign of prognostic consciousness) was evident in 55.2%.Compared with historical data, our results show a high level of comprehension of the diagnosis of malignancy, probably due to the extensive training effort together with the method chosen for assessment.

A reduction of gynaecological adverse events has been reported in trials comparing aromatase inhibitors with tamoxifen as adjuvant treatment in postmenopausal women with early breast cancer, but there is a paucity of randomised studies specifically investigating their effects on the uterus. We report here the results of a prospective phase III trial comparing the effects of tamoxifen and exemestane by transvaginal ultrasound (TVUS).Postmenopausal patients with ER+ early breast cancer were randomised to receive tamoxifen 20 mg once daily or exemestane 25 mg once daily as adjuvant hormone therapy. TVUS was performed at baseline and at 6 and 12 months to measure endometrial thickness (ET) and uterine volume (UV).A total of 123 women were randomised to tamoxifen (n = 61) or exemestane (n = 62). A significantly higher proportion of patients in the tamoxifen group had increased ET at 6 and 12 months from randomisation compared with the exemestane group (66.1% and 64.3% versus 12.1% and 6.8%, respectively; P0.0001). Mean ET and UV also significantly increased with tamoxifen compared to exemestane at both time points (P0.01 for all comparisons).Tamoxifen is associated with endometrial thickening and increased uterine volume in a significant proportion of postmenopausal women with early breast cancer. Our study confirms the lack of endometrial effects of exemestane, which may be of interest to patients and clinicians when choosing among adjuvant endocrine options for breast cancer.

Increasingly, in castration-resistant prostate cancer, patients are often treated with docetaxel and the bisphosphonate zoledronic acid concurrently, yet there is still a paucity in the literature regarding the molecular basis of how this drug combination works. The study was performed on the hormone-resistant cell line PC-3. Cells were treated with clinically relevant concentrations of docetaxel and zoledronic acid either as single agents or in sequence and combination. Cell viability and apoptosis were assessed along with the prenylation status of the GTPases Ras and RhoA. Following 1-mM zoledronic acid treatment, inhibition of the prenylation of H-Ras and Rho A was observed along with an increase in the unprenylated form in the cytoplasm. Docetaxel 1 nM and zoledronic acid 1 mM also showed an increase in the unprenylated form of both small GTP-binding proteins in the cytoplasm and a reduction of protein in the membrane fraction. Overall, zoledronic acid followed by docetaxel was the best regimen producing the greatest reduction in cell viability and increase in apoptosis. At the highest concentrations of zoledronic acid and docetaxel, zoledronic acid followed by docetaxel was also the most effective at reducing the prenylation of both H-Ras and RhoA at the membrane. We have demonstrated that clinically achievable concentrations of zoledronic acid and docetaxel cause a reduction in the prenylation of both H-Ras and Rho A and a reduction of protein movement into the membrane. The most effective regimen overall was high-dose zoledronic acid followed by docetaxel, suggesting that this regimen may be of benefit in clinical practice.

Objectives: To investigate the safety and efficacy of docetaxel and zoledronic acid in patients with hormone-refractory prostate cancer (HRPC), based on preclinical evidence of synergism between taxanes and bisphosphonates. Methods: Twenty-five patients with advanced HRPC received weekly docetaxel 30 mg/m2: in 18 patients with symptomatic bone metastases and normal renal function, docetaxel was combined with zoledronic acid, 4 mg i.v. every 4 weeks. Premedication consisted of intravenous dexamethasone before docetaxel. No oral steroids were given. Results: Overall, 12 patients (48%) had a PSA response (reduction of 50% or more compared to baseline). A PSA response was achieved in 8/18 patients (44%) receiving concomitant docetaxel and zoledronic acid, and in 7/12 patients (58%) receiving docetaxel and zoledronic acid as first-line therapy. The weekly schedule of docetaxel resulted in a mean received dose intensity of 26 mg/m2/week, or 87% of the planned dose intensity. Toxicity was mild and as expected for docetaxel. The median time to progression was 7 months, and the median overall survival was 16 months. Conclusions: Concomitant treatment with docetaxel and zoledronic acid is safe and has encouraging activity in HRPC. The combination should be evaluated in randomised clinical trials.

Objectives: Maintenance hormone therapy after first-line chemotherapy is routinely used by many clinicians in advanced breast cancer patients with potentially hormone-sensitive tumors, although there are insufficient evidences in the literature to support this practice. We investigated the effects of the third-generation aromatase inhibitor letrozole as a maintenance therapy in postmenopausal patients who had responded or had stable disease with first-line chemotherapy. Methods: Fifty-eight patients (median age 62 years, range 31–80) were recruited and received letrozole, 2.5 mg/day starting within 8 weeks since the last cycle of chemotherapy. Estrogen and/or progesterone receptor status was positive in 81% of the patients, unknown in 19%; 57% of the patients had visceral disease. First-line chemotherapy included anthracyclines and/or taxanes in 74% of cases. Results: The median time to progression (TTP) from starting letrozole was 18.5 months. A shorter TTP was found in patients with abnormal CA 15-3 levels at the start of maintenance letrozole (median TTP, 9.9 months: p = 0.01), or with levels increasing >25% from baseline during the first 6 months of letrozole therapy (median TTP, 8.2 months: p < 0.0001). Response status improved during letrozole in 15.5% of patients who had obtained less than a complete response to chemotherapy. Maintenance treatment was well tolerated and had no significant impact on quality of life scores. Conclusions: This study provides evidence in support of the common clinical practice of maintenance hormone therapy after chemotherapy in suitably selected patients with advanced breast cancer.

Recent data indicates that the sentinel lymph node biopsy (SLNB) is a possible alternative to axillary lymph node dissection (ALND) in early breast cancer patients, with minimal risk of complications. From the medical oncologist's point of view, the impact of SLNB on the management of patients should consider if SLNB is useful to choose adjuvant treatment, if it is adequate to provide local control, and what is the significance of lymph node micrometastases on treatment and staging. Lymph node involvement has always been recognised as the most important prognostic factor in early-stage breast cancer, even if many other parameters have been evaluated in recent years. However, the lack of knowledge of nodal status in patients with false-negative SLNB seems to result in an undertreatment in a very low percentage of patients. Adjuvant chemotherapy and hormonal therapy with tamoxifen are associated with an absolute reduction of the risk of recurrence and death both in node-positive and in node-negative patients, then if patients are treated with modern adjuvant systemic therapy, any effect associated with false negative SLN should be minimised. The impact of axillary treatment on survival is still controversial, but in recent times axillary lymph node positivity is considered as an indicator for high risk of systemic diffusion of the disease rather than a possible origin of systemic metastases. The significance of occult sentinel lymph node metastases detected by immunohistochemistry (IHC) or molecular biology on prognosis is still uncertain. The new version of the staging system of breast cancer has recognised the need for a standard diagnostic approach and of a nomenclature system which also takes SLNB into account.

e17051 Background:Carboplatin based chemotherapy is widely used to treat women with Ovarian cancer (OC) in the adjuvant, neoadjuvant and palliative settings. Carboplatin is normally dosed by the Calvert formula: [GRF+25] x AUC, with a target AUC (area under the plasma concentration curve) of 5-6 mg/ml/min. GFR (glomerular filtration rate) can be precisely measured with radionuclide based ligands such as 51Cr-ethylenediamine tetraacetic acid (51Cr-EDTA), but in clinical practice is often estimated using formulae incorporating serum creatinine, weight and age, such as the Cockcroft–Gault (CG) or Wright (WR) formulae. It is unknown, however, if these formulae allow a sufficiently accurate dosing of carboplatin in OC patients. Methods:We retrospectively compared measured (EDTA-based) and estimated (CG and WR formulae) GFR and the resulting carboplatin doses, in women with stage 1c to IV OC treated with carboplatin AUC 6 at our centre between 2015 and 2016. All patients (pts) had concurrent 51Cr-EDTA GFR and serum creatinine measurement before starting carboplatin. Accuracy and bias of The WR and CG formulae were analysed using mean absolute percentage error (MAPE) and mean percentage error (MPE). Results:92 pts were included in the study (median age = 69 years (r. 25 -89), median serum creatinine 63.5 umol/L (r. 38 – 168)). MPE was -37.3 and -26.0 and MAPE was 38.0 and 32.2 for the WR and CG formulae, respectively. If the WR or CG formulae had been used instead of EDTA to calculate the dose of carboplatin, the discrepancy would have been at least 10% in 77.1% and 69.8% of pts, respectively; a discrepancy of 50% or more would have occurred in 10% and 13% of pts. Conclusions:Neither the WR nor CG formulae precisely predict renal function in ovarian cancer pts. They often overestimate GFR, meaning that if these formulae are used instead of isotope-based measurement of GFR, most pts will receive a higher dose of carboplatin. Our findings are relevant for clinical practice and for the design and interpretation of clinical trials, where the choice between EDTA- or formulae- based calculations of carboplatin dose are often left to investigators’ preference.

A 45-year-old man presented with a large para-aortic retroperitoneal tumour, a smaller second mediastinal tumour and elevated lactate dehydrogenase (LDH). Biopsy established a diagnosis of extragonadal seminoma. Treatment with cisplatin and etoposide resulted in complete resolution of the mediastinal mass, reduction of the size of the retroperitoneal mass and normalisation of LDH. Postchemotherapy positron emission tomography (PET) scan showed a small residual focus of uptake in the retroperitoneal mass and an unexpected focus in the left side of the neck. This was initially thought to represent residual active disease, but an ultrasound (US) scan and US-guided core biopsy of a cervical lymph node demonstrated metastatic papillary thyroid cancer rather than seminoma. A small (1 cm) primary papillary tumour in the thyroid was identified subsequently. The patient received consolidation radiotherapy to the retroperitoneum and underwent total thyroidectomy and neck dissection followed by radio-iodine treatment. He is currently in complete remission from both cancers.

Progress in biomarkers research has resulted in increasing awareness of the heterogeneity of breast cancer. The identification of subtypes with different clinical behavior and the possibility of using targeted therapy in specific subgroup of patients (eg, those with tumors overexpressing HER2) raise expectations for increasing personalization of treatment. However, there is a widening gap between scientific discoveries and practical application in everyday practice: too many patients are still being managed based only on traditional clinical and pathologic parameters, because of lack of access to up to date technology-such as gene profiling, or cell proliferation assays-in many cancer centers in the United Kingdom. In this article, we provide some examples of this contrast, drawn from the literature and from our own clinical experience in South West Wales, and discuss possible solutions.

The need for endometrial surveillance in breast cancer patients undergoing adjuvant treatment with tamoxifen is still controversial. In this study, 164 asymptomatic breast cancer patients (110 on treatment with tamoxifen, 20 mg/day, and 54 controls) were examined with pelvic ultrasound and endometrial biopsy. No differences in ultrasound and biopsy findings were observed in the pre- and perimenopausal group between patients treated with tamoxifen and controls. Postmenopausal patients on tamoxifen had a significantly thicker endometrium (mean+/-SD, 7.2+/-8.5 vs. 1.5+/-4.3 mm, p=0.00002) and significantly larger uterine volume (mean+/-SD, 63.2+/-39.9 vs. 43.7+/-38.8 cm3, p=0.0001) than controls. Fifty-four percent of patients on tamoxifen had an endometrial thickness > or = 5 mm, often with multiple irregular sonolucencies suggesting the presence of cysts. Ultrasound findings, however, did not correlate with the presence of endometrial abnormalities on biopsy, and no endometrial cancer or atypical hyperplasia were found. This lack of correlation makes questionable the use of routine sonography in asymptomatic breast cancer patients on tamoxifen. Obtaining routine endometrial samples, on the other hand, may be difficult in some patients because of cervical stenosis or refusal. Until the benefits of endometrial surveillance will be proved, asymptomatic patients should not be submitted routinely to ultrasound examination or biopsy, but encouraged to report promptly any abnormal vaginal bleeding.