Meta-analyses of Phase 3 randomised controlled trials of third generation aromatase inhibitors versus tamoxifen as first-line endocrine therapy in postmenopausal women with hormone receptor-positive advanced breast cancer

Background Four randomised controlled trials (RCTs) in postmenopausal women with advanced breast cancer (ABC) comparing aromatase inhibitors (AIs) versus the selective estrogen receptor modulator tamoxifen, each individually reported significantly longer progression free survival (PFS) but none showed a significant difference in overall survival (OS). In these trials between 6.8%–55% of tumours were hormone receptor (HR) status unknown or negative. This meta-analysis restricted the comparison to HR-positive (HR+) tumours. MethodsAnonymised individual patient data were obtained from three RCTs, EORTC (exemestane versus tamoxifen), Study 0027 and Study 0030 (both anastrozole versus tamoxifen). For the remaining RCT (Femara Study PO25; letrozole versus tamoxifen), odds ratio (OR) or hazard ratio (HzR), with confidence intervals were obtained from the clinical study report, for patients with HR+ tumours, in addition to published data. In total, data were obtained from 2296 patients; 1560 (68%) had HR+ ABC. FindingsThe OR for clinical benefit rate was 1·56, in favour of AIs (p[less than] 0·001). The duration of clinical benefit was not significantly increased by AIs (hazard ratio [HzR] 0·88; p=0·08). For PFS the HzR (0·82) was in favour of AIs (p=0·007). However, for OS the HzR (1·05) was not significantly different between AIs and tamoxifen (p=0·42).InterpretationAlthough third generation AIs put significantly more patients into ‘clinical benefit’, their tumours were not controlled for significantly longer. Overall, while this resulted in a significantly greater PFS in favour of the AIs, this did not translate into improvement in OS

Unconditional and conditional monetary incentives to increase response to mailed questionnaire : a randomised controlled study within a trial (SWAT)

Rationale, aims, and objectives: High response rates to research questionnaires can help to ensure results are more representative of the population studied and provide increased statistical power, on which the study may have been predicated. Improving speed and quality of response can reduce costs.Method: We conducted a randomised Study Within A Trial (SWAT) to assess questionnaire response rates, reminders sent and data completeness with unconditional compared to conditional monetary incentives. Eligible individuals were mailed a series of psychological questionnaires as a follow-up to a baseline host trial questionnaire. Half received a £5 gift voucher with questionnaires (unconditional) and half were promised the voucher after returning questionnaires (conditional).Results: Of 1079 individuals, response rates to the first follow-up questionnaire were 94.2% and91.7% in the unconditional and conditional monetary incentive groups respectively (OR 1.78, 95% CI0.85 to 3.72). There were significantly greater odds of returning repeat questionnaires in the unconditional group at six months (OR 2.97, 95% CI 1.01 to 8.71; p = 0.047) but not at 12 months(OR 1.12, 95% CI 0.44 to 2.85). Incentive condition had no impact at any time point on the proportion of sent questionnaires that needed reminders. Odds of incomplete questionnaires were significantly greater at three months in the unconditional compared to the conditional incentive group (OR 2.45, 95% CI 1.32 to 4.55; p = 0.004).Conclusions: Unconditional monetary incentives can produce a transitory greater likelihood of mailed questionnaire response in a clinical trial participant group, consistent with the direction of effect in other settings. However, this could have been a chance finding. The use of multiple strategies to promote response may have created a ceiling effect. This strategy has potential to reduce administrative and postage costs, weighed against the cost of incentives used, but could risk compromising the completeness of data

Improving primary care identification of familial breast cancer risk using proactive invitation and decision support

Family history of breast cancer is a key risk factor, accounting for up to 10% of cancers. We evaluated the proactive assessment of familial breast cancer (FBC) risk in primary care. Eligible women (30 to 60 years) were recruited from eight English general practices. Practices were trained on familial breast cancer risk assessment. In four randomly-assigned practices, women were invited to complete a validated, postal family history questionnaire, which practice staff inputted into decision support software to determine cancer risk. Those with increased risk were offered specialist referral. Usual care was observed in the other four practices. In intervention practices, 1127/7012 women (16.1%) returned family history questionnaires, comprising 1105 (98%) self-reported white ethnicity and 446 (39.6%) educated to University undergraduate or equivalent qualification, with 119 (10.6%) identified at increased breast cancer risk and offered referral. Sixty-seven (56%) women recommended referral were less than 50 years old. From 66 women attending specialists, 26 (39.4%) were confirmed to have high risk and recommended annual surveillance (40-60 years) and surgical prevention; while 30 (45.5%) were confirmed at moderate risk, with 19 offered annual surveillance (40–50 years). The remaining 10 (15.2%) managed in primary care. None were recommended chemoprevention. In usual care practices, only ten women consulted with concerns about breast cancer family history. This study demonstrated proactive risk assessment in primary care enables accurate identification of women, including many younger women, at increased risk of breast cancer. To improve generalisability across the population, more active methods of engagement need to be explored

A good drug made better: the Fulvestrant Dose Response Story

Sequential use of endocrine therapies remains the cornerstone of treatment for hormone receptor-positive advanced breast cancer, prior to use of cytotoxic chemotherapy for unresponsive disease. Fulvestrant is an estrogen receptor (ER) antagonist approved for treatment of postmenopausal women with ER+ advanced breast cancer following failure of prior antiestrogen therapy. Initially approved at a monthly dose of 250 mg, the recommended fulvestrant dose was revised to 500 mg (500 mg/month plus 500 mg on Day 14 of Month 1) following demonstration of improved progression-free survival versus fulvestrant 250 mg. We have reviewed the dose-dependent effects of fulvestrant, both from a retrospective combined analysis of dose-dependent reduction of tumor biomarkers in the pre-surgical setting (three previously reported studies: Study 18, NEWEST [Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumors] and Trial 57), and from a review of clinical studies for advanced breast cancer in postmenopausal women. Analysis of pre-surgical data revealed a consistent dose-dependent effect for fulvestrant on tumor biomarkers, with increasing fulvestrant dose resulting in greater reductions in ER, progesterone receptor and Ki67 labeling index. The dose-dependent biological effect corresponds with the dose-dependent clinical efficacy observed in the treatment of advanced breast cancer following failure of prior antiestrogen therapy. Although it remains to be determined in a Phase III trial, cross-trial comparisons suggest a dose-dependent relationship for fulvestrant as first-line treatment for advanced breast cancer. Overall, biological and clinical data demonstrate a strong dose-dependent relationship for fulvestrant, supporting the efficacy benefit seen with fulvestrant 500 mg over the 250 mg dose

Biological effects of fulvestrant on estrogen receptor positive human breast cancer: Short, medium and long-term effects based on sequential biopsies.

We report the first study of the biological effect of fulvestrant on ER positive clinical breast cancer using sequential biopsies through to progression. Thirty-two locally/systemically advanced breast cancers treated with first-line fulvestrant (250 mg/month) were biopsied at therapy initiation, 6 weeks, 6 months and progression and immunohistochemically-analyzed for Ki67, ER, EGFR and HER2 expression/signaling activity. This series showed good fulvestrant responses (duration of response [DoR] = 25.8 months; clinical benefit = 81%). Ki67 fell (p < 0.001) in 79% of tumours by 6 months and lower Ki67 at all preprogression time-points predicted for longer DoR. ER and PR significantly decreased in all tumours by 6 months (p < 0.001), with some declines in ER (serine 118) phosphorylation and Bcl-2 (p = 0.007). There were modest HER2 increases (p = 0.034, 29% tumours) and loss of any detectable EGFR phosphorylation (p = 0.024, 50% tumours) and MAP kinase (ERK1/2) phosphorylation (p = 0.019, 65% tumours) by 6 months. While ER remained low, there was some recovery of Ki67, Bcl-2 and (weakly) EGFR/MAPK activity in 45–67% patients at progression. Fulvestrant's anti-proliferative impact is related to DoR, but while commonly downregulating ER and indicators of its signaling and depleting EGFR/MAPK signaling in some patients, additional elements must determine response duration. Residual ER at fulvestrant relapse explains reported sensitivity to further endocrine therapies. Occasional modest treatment-induced HER2 and weakly detectable EGFR/HER2/MAPK signaling at relapse suggests targeting of such activity might have value alongside fulvestrant in some patients. However, unknown pathways must drive relapse in most. Ki67 has biomarker potential to predict fulvestrant outcome and as a quantitative measure of response

Health-related quality of life from the FALCON phase III randomised trial of fulvestrant 500 mg versus anastrozole for hormone receptor-positive advanced breast cancer

Background The phase III randomised FALCON trial (NCT01602380) demonstrated improved progression-free survival with fulvestrant 500 mg versus anastrozole 1 mg in endocrine therapy-naïve postmenopausal women with hormone receptor-positive (HR+) locally advanced or metastatic breast cancer (LA/MBC). Furthermore, overall health-related quality of life (HRQoL) was maintained and comparable for fulvestrant and anastrozole. Here, we present additional analyses of patient-reported HRQoL outcomes from FALCON. Methods Women with endocrine therapy-naïve HR+ LA/MBC were randomised 1:1 to fulvestrant (days 0, 14, 28, then every 28 d) or anastrozole (daily) until disease progression or discontinuation. HRQoL was assessed by FACT-B questionnaire (TOI and FACT-B total score) at randomisation and every 12 weeks during treatment. HRQoL data post-treatment (with or without progression) were also collected. Results In total, 462 patients were randomised (fulvestrant, n = 230; anastrozole, n = 232). Compliance to FACT-B overall ranged from 60.0 to 97.4%. Mean change from baseline in TOI and FACT-B total score remained broadly stable (approximately ± 3 points to week 132) and was similar between arms during treatment. HRQoL was also maintained in FACT-B subscales. Approximately one-third of patients had improved TOI (≥+6 points) and FACT-B (≥+8 points) total scores from baseline up to week 120 and 132, respectively, of treatment with fulvestrant (ranges 26.4–45.0% and 22.4–35.8%, respectively) and anastrozole (ranges 18.6–32.9%, and 22.7–37.9%, respectively). Conclusions Mean change from baseline in TOI and FACT-B total score was maintained for fulvestrant and anastrozole; similar proportions of patients in both arms had improved TOI and FACT-B total scores

Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial

Background Aromatase inhibitors are a standard of care for hormone receptor-positive locally advanced or metastatic breast cancer. We investigated whether the selective oestrogen receptor degrader fulvestrant could improve progression-free survival compared with anastrozole in postmenopausal patients who had not received previous endocrine therapy. Methods In this phase 3, randomised, double-blind trial, we recruited eligible patients with histologically confirmed oestrogen receptor-positive or progesterone receptor-positive, or both, locally advanced or metastatic breast cancer from 113 academic hospitals and community centres in 20 countries. Eligible patients were endocrine therapy-naive, with WHO performance status 0–2, and at least one measurable or non-measurable lesion. Patients were randomly assigned (1:1) to fulvestrant (500 mg intramuscular injection; on days 0, 14, 28, then every 28 days thereafter) or anastrozole (1 mg orally daily) using a computer-generated randomisation scheme. The primary endpoint was progression-free survival, determined by Response Evaluation Criteria in Solid Tumors version 1·1, intervention by surgery or radiotherapy because of disease deterioration, or death from any cause, assessed in the intention-to-treat population. Safety outcomes were assessed in all patients who received at least one dose of randomised treatment (including placebo). This trial is registered with ClinicalTrials.gov, number NCT01602380. Findings Between Oct 17, 2012, and July 11, 2014, 524 patients were enrolled to this study. Of these, 462 patients were randomised (230 to receive fulvestrant and 232 to receive anastrozole). Progression-free survival was significantly longer in the fulvestrant group than in the anastrozole group (hazard ratio [HR] 0·797, 95% CI 0·637–0·999, p=0·0486). Median progression-free survival was 16·6 months (95% CI 13·83–20·99) in the fulvestrant group versus 13·8 months (11·99–16·59) in the anastrozole group. The most common adverse events were arthralgia (38 [17%] in the fulvestrant group vs 24 [10%] in the anastrozole group) and hot flushes (26 [11%] in the fulvestrant group vs 24 [10%] in the anastrozole group). 16 (7%) of 228 patients in in the fulvestrant group and 11 (5%) of 232 patients in the anastrozole group discontinued because of adverse events. Interpretation Fulvestrant has superior efficacy and is a preferred treatment option for patients with hormone receptor-positive locally advanced or metastatic breast cancer who have not received previous endocrine therapy compared with a third-generation aromatase inhibitor, a standard of care for first-line treatment of these patients

Psychological impact of lung cancer screening using a novel antibody blood test followed by imaging: the ECLS randomised controlled trial

Background: The Early CDT®-Lung antibody blood test plus serial CT-scans for test-positives reduces late-stage lung cancer presentation. This study assessed psychological outcomes of this approach.Methods: Randomised controlled trial (n=12,208) comparing psychological outcomes 1-12 months post-recruitment in a subsample (n=1032) of test-positive (TPG), test-negative (TNG) and control groups (CG).Results: Compared to TNG, TPG had lower positive affect (Difference between means (DBM), 3-months (3m):-1.49 (-2.65, - 0.33)), greater impact of worries (DBM 1m:0.26 (0.05, 0.47); 3m:0.28 (0.07, 0.50)), screening distress (DBM 1m:3.59 (2.28, 4.90); 3m:2.29 (0.97, 3.61); 6m:1.94 (0.61, 3.27)) worry about tests (OR 1m:5.79 (2.66, 12.63) and more frequent lung cancer worry (Odds ratio (OR) 1m:2.52 (1.31, 4.83); 3m:2.43 (1.26, 4.68); 6m:2.87 (1.48, 5.60)). Compared to CG, TPG had greater worry about tests (OR 1m:3.40 (1.69, 6.84)). TNG had lower negative affect (log-transformed DBM 3m:-0.08 (-0.13, -0.02)), higher positive affect (DBM 1m:1.52 (0.43, 2.61); 3m:1.43 (0.33, 2.53); 6m:1.27 (0.17, 2.37)), less impact of worries (DBM 3m:-0.27 (-0.48, -0.07)) and less frequent lung cancer worry (OR 3m:0.49 (0.26, 0.92)). Conclusions: Negative psychological effects in TPG and positive effects in TNG were short-lived and most differences were small

Lung cancer CT screening: psychological responses in the presence and absence of pulmonary nodules

Objectives: To determine the psychological response (thoughts, perceptions and affect) to a diagnosis of pulmonary nodules following a novel antibody blood test and computed tomography (CT) scans within a UK population. Materials and methods: This study was nested within a randomised controlled trial of a blood test (Early CDT®-Lung test), followed by a chest x-ray and serial CT-scanning of those with a positive blood test for early detection of lung cancer (ECLS Study). Trial participants with a positive Early CDT®-Lung test were invited to participate (n=338) and those agreeing completed questionnaires assessing psychological outcomes at 1, 3 and 6 months following trial recruitment. Responses of individuals with pulmonary nodules on their first CT scan were compared to those without (classified as normal CT) at 3 and 6 months follow-up using random effects regression models to account for multiple observations per participant, with loge transformation of data where modelling assumptions were not met. Results: There were no statistically significant differences between the nodule and normal CT groups in affect, lung cancer worry, health anxiety, illness perceptions, lung cancer risk perception or intrusive thoughts at 3 or 6 months post-recruitment. The nodule group had statistically significantly fewer avoidance symptoms compared to the normal CT group at 3 months (impact of events scale avoidance (IES-A) difference between means -1.99, 95%CI -4.18, 0.21) than at 6 months (IES-A difference between means 0.88, 95%CI -1.32, 3.08; p-value for change over time =0.003) with similar findings using loge transformed data. Conclusion: A diagnosis of pulmonary nodules following an Early CDT®-Lung test and CT scan did not appear to result in adverse psychological responses compared to those with a normal CT scan

Lung cancer screening: does pulmonary nodule detection affect a range of smoking behaviours?

Background Lung cancer screening can reduce lung cancer mortality by 20%. Screen-detected abnormalities may provide teachable moments for smoking cessation. This study assesses impact of pulmonary nodule detection on smoking behaviours within the first UK trial of a novel auto-antibody test, followed by chest x-ray and serial CT scanning for early detection of lung cancer (Early Cancer Detection Test-Lung Cancer Scotland Study). Methods Test-positive participants completed questionnaires on smoking behaviours at baseline, 1, 3 and 6 months. Logistic regression compared outcomes between nodule (n=95) and normal CT groups (n=174) at 3 and 6 months follow-up. Results No significant differences were found between the nodule and normal CT groups for any smoking behaviours and odds ratios comparing the nodule and normal CT groups did not vary significantly between 3 and 6 months. There was some evidence the nodule group were more likely to report significant others wanted them to stop smoking than the normal CT group (OR across 3 and 6 month time points: 3.04, 95%CI 0.95, 9.73; p=0.06). Conclusion Pulmonary nodule detection during lung cancer screening has little impact on smoking behaviours. Further work should explore whether lung cancer screening can impact on perceived social pressure and promote smoking cessation