Search

Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca.

BACKGROUND Although the combination of doxorubicin (DOX) and trastuzumab (TRZ) reduces the progression and recurrence of breast cancer, these anticancer drugs are associated with significant cardiotoxic side effects. OBJECTIVE We investigated whether prophylactic administration of flaxseed (FLX) and its bioactive components, α-linolenic acid (ALA) and secoisolariciresinol diglucoside (SDG), would be cardioprotective against DOX + TRZ-mediated cardiotoxicity in a chronic in vivo female murine model. METHODS Wild-type C57BL/6 female mice (10-12 wk old) received daily prophylactic treatment with one of the following diets: 1) regular control (RC) semi-purified diet; 2) 10% FLX diet; 3) 4.4% ALA diet; or 4) 0.44% SDG diet for a total of 6 wks. Within each arm, mice received 3 weekly injections of 0.9% saline or a combination of DOX [8 mg/(kg.wk)] and TRZ [3 mg/(kg.wk)] starting at the end of week 3. The main outcome was to evaluate the effects of FLX, ALA, and SDG on cardiovascular remodeling and markers of apoptosis, inflammation, and mitochondrial dysfunction. Significance between measurements was determined using a 4 (diet) × 2 (chemotherapy) × 2 (time) mixed factorial design with repeated measures. RESULTS In the RC + DOX + TRZ-treated mice at week 6 of the study, the left ventricular ejection fraction (LVEF) decreased by 50% compared with the baseline LVEF (P

The product monograph for reference bevacizumab (Avastin) and biosimilar bevacizumab (Mvasi) recommend to infuse the first dose of bevacizumab over 90 min, second dose over 60 min and third and subsequent doses over 30 min. Despite the product monograph recommendations, many institutions adopted an accelerated bevacizumab (Avastin) 0.5 mg/kg/min infusion time. Our province adopted the accelerated infusion time at time of biosimilar bevacizumab (Mvasi) adoption. Our experience with the accelerated infusion time was well tolerated in the first five months of biosimilar bevacizumab adoption across different tumor types.

Background Aromatase inhibitors (AIs) used in breast cancer induce loss in bone mineral density (BMD) and are reported to increase fracture risk. Materials and Methods Using a population-based BMD registry, we identified women aged at least 40 years initiating AIs for breast cancer with at least 12 months of AI exposure (n = 1,775), women with breast cancer not receiving AIs (n = 1,016), and women from the general population (n = 34,205). Fracture outcomes were assessed to March 31, 2017 (mean, 6.2 years for AI users). Results At baseline, AI users had higher body mass index (BMI), higher BMD, lower osteoporosis prevalence, and fewer prior fractures than women from the general population or women with breast cancer without AI use (all p < .001). After adjusting for all covariates, AI users were not at significantly greater risk for major osteoporotic fractures (hazard ratio [HR], 1.15; 95% confidence interval [CI], 0.93–1.42), hip fracture (HR, 0.90; 95% CI, 0.56–1.43), or any fracture (HR, 1.06; 95% CI, 0.88–1.28) compared with the general population. Conclusion Higher baseline BMI, BMD, and lower prevalence of prior fracture at baseline may offset the adverse effects of AI exposure. Although confirmatory data from large cohort studies are required, our findings challenge the view that all women with breast cancer initiating AI therapy should be considered at high risk for fractures. Implications for Practice In a population-based observational registry that included 1,775 patients initiating long-term aromatase inhibitor therapy, risk for major osteoporotic fracture, hip fracture, or any fracture was similar to the general population. Higher baseline body mass index, bone mineral density, and lower prevalence of prior fracture at baseline may offset the adverse effects of aromatase inhibitor exposure.

A universal health care system has been a source of both identity and pride for Canadians for the last 6 decades. Currently, Canada actively negotiates the prices of cancer drugs but is not immune to their overwhelming financial toxicities. Prices of cancer drugs are set to ensure maximal profit based on what the market will bear rather than by the value they offer or solely because of the cost of research and development, as often is claimed by the manufacturers. The pan-Canadian Oncology Drug Review (pCODR) is mandated to provide funding recommendations to Canada's provinces and territories. For the most part, the pCODR has been crucial in assessing the cost-effectiveness and feasibility of new drugs in the Canadian context but it could assist more in safeguarding payers against extreme drug costs. Herein, the author suggests a few strategies by which national efforts such as the pCODR and its partners can help Canada to become a leader in facilitating value-based sustainable cancer care.

Three Cyclin Dependent Kinase 4/6 (CDK) inhibitors have been approved by the United Stated Food and Drug Administration for front line treatment of advanced hormone receptor positive breast cancer based on improvements in progression free survival against endocrine monotherapy. Two clinical trials have so far reported results on overall survival but both are negative. CDK inhibitors are usually tolerated well but they do add to inconvenience and cost - for example, grade III-IV neutropenia occur at a frequency of over 60% requiring frequent blood work at least during the initial months of treatment. These drugs cost over $ 13,500 for a 4-week cycle in the United States, and are responsible for billions of dollars annually in drug cost alone. Importantly, many women with metastatic breast cancer do well for a long time with endocrine therapy alone and CDK inhibitors do not have a predictive marker. Selective use of these agents in later lines may improve substantially the convenience and cost without compromise in overall outcome. However, with results demonstrating impressive improvements in PFS published in major medical journals coupled with patients' natural desire for “best available” options, the trend among oncologists is to prescribe these drugs as the default front-line treatment. In this commentary I caution readers against over interpretation of results from the CDK inhibitor trials, describe adverse consequences of routine front-line use, and explain why selective use in later line may yield a higher value.

Background The US Food and Drug Administration (FDA) introduced an Accelerated Approval (AA) pathway to expedite patient access to new drugs. AA accepts less rigorous trial designs, including single-arm studies (SAS), owing to perceived lack of feasibility of timely randomized controlled trials (RCTs). Methods We designed hypothetical RCTs with endpoints of overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) for FDA approvals based on SAS for solid tumors during 2010-2019. Existing standards of care served as controls. RCTs were designed to detect a difference with power of 0.80, α-error of 5% (2-sided), and 1:1 randomization. Accrual duration was estimated based on participation by less than 5% of eligible patients derived from cancer-specific incidence and mortality rates in the United States. Results Of 172 (18.0%) approvals during the study period, 31 (18.0%) were based on SAS. Median sample size was 104 (range = 23-411), and 77.4% were AA. All studies reported ORR, 55% reported duration of response, 19.4% reported PFS, and 22.5% reported OS. Median sample sizes needed to conduct RCTs with endpoints of ORR, PFS, and OS were 206, 130, and 396, respectively. It would have been theoretically possible to conduct RCTs within duration comparable with that required by SAS for 84.6%, 94.1%, and 80.0% of approvals with endpoints of ORR, PFS, and OS, respectively. Conclusion An overwhelming majority of FDA approvals based on SAS should be feasible as RCTs within a reasonable time frame. Given the collateral harms to patients and to scientific rigor, drug approval based on SAS should only be permitted under exceptional circumstances.

One year of trastuzumab, chosen empirically, improves survival of women with early-stage, HER2-positive breast cancer but also adds substantially to cost, toxicity, and inconvenience. Longer treatment does not improve outcomes, but potentiates toxicities.Medline, Embase, and major conference proceedings were searched systematically in June 2017 to identify Randomized Controlled Trials (RCTs) comparing one year versus shorter durations of trastuzumab in adjuvant treatment of breast cancer. Reported Hazard-Ratios (HR) for Overall Survival (OS) and Disease-Free Survival (DFS), and Odds-Ratio for cardiac events, with respective 95% Confidence Intervals (CI) from each study was weighted using generic inverse-variance, and pooled in a meta-analysis. Inter-study heterogeneity and sub-group difference (based on hormone-receptors and node-positivity) were assessed using IFour studies (n=7614) satisfied inclusion criteria. Individual RCTs had diverse pre-specified upper-limits of 95% CI for declaring non-inferiority (range:1.15 to1.53). Pooled results demonstrated significant improvements in OS (HR 1.28, p=0.04), and DFS (HR 1.24, p=0.005) with 1year of trastuzumab compared to shorter durations. Absence of multiplicity argument allowed for declaring superiority of 1year of trastuzumab based on our results despite non-inferiority designs of individual trials. No influence on overall effect by duration of trastuzumab in experimental arm (9weeks versus 6months) was noted. No statistical interaction by hormone-receptor status and node-positivity on overall results was noticed [p(sub-group difference) 0.73, and 0.52, respectively]. Odds-Ratio for cardiac events was 2.65 (p0.001) favoring shorter duration.One year of trastuzumab prolongs overall, and disease-free survivals in women with early-stage HER2 positive breast cancer compared to shorter durations and this should remain as the standard of care. Cardiotoxicity increased significantly with the 1-year treatment.

Background In the breast cancer setting, anticancer therapies including doxorubicin (DOX) and trastuzumab (TRZ) are associated with a significantly increased risk of cardiotoxicity. Despite the increasing support for the role of oxidative stress (OS) in its pathophysiology, we still do not have an optimal antioxidant for the prevention of DOX + TRZ–mediated cardiac dysfunction. The objective of this study was to investigate whether the novel antioxidant N-acetylcysteine amide (NACA) can attenuate DOX + TRZ–induced heart failure in a murine model. Methods A total of 100 C57Bl/6 female mice received 1 of the following drug regimens: (1) saline, (2) NACA, (3) DOX, (4) TRZ, (5) DOX + TRZ, (6) NACA + DOX, (7) NACA + TRZ, and (8) NACA + DOX + TRZ. Serial echocardiography was performed over a 10-day study period, after which the mice were killed for histologic and biochemical analyses. Results In mice receiving DOX, the left ventricular ejection fraction (LVEF) decreased from 73% ± 4% to 43% ± 2% on day 10. In mice receiving DOX + TRZ, the LVEF decreased from 72% ± 3% to 32% ± 2% on day 10. Prophylactic administration of NACA to mice receiving DOX or DOX + TRZ was cardioprotective, with an LVEF of 62% ± 3% and 55% ± 3% on day 10, respectively. Histologic and biochemical analyses demonstrated a loss of cellular integrity, increased OS, and increased cardiac apoptosis in mice treated with DOX + TRZ, which was attenuated by the prophylactic administration of NACA. Conclusions NACA attenuated the cardiotoxic side effects of DOX + TRZ in a murine model of chemotherapy-induced cardiac dysfunction by decreasing OS and apoptosis.

Summary Well-designed randomised controlled trials (RCTs) can prevent bias in the comparison of treatments and provide a sound basis for changes in clinical practice. However, the design and reporting of many RCTs can render their results of little relevance to clinical practice. In this Personal View, we discuss the limitations of RCT data and suggest some ways to improve the clinical relevance of RCTs in the everyday management of patients with cancer. RCTs should ask questions of clinical rather than commercial interest, avoid non-validated surrogate endpoints in registration trials, and have entry criteria that allow inclusion of all patients who are fit to receive treatment. Furthermore, RCTs should be reported with complete accounting of frequency and management of toxicities, and with strict guidelines to ensure freedom from bias. Premature reporting of results should be avoided. The bar for clinical benefit should be raised for drug registration, which should require publication and review of mature data from RCTs, post-marketing health outcome studies, and value-based pricing.

Background Data on the comparative efficacy of fulvestrant and other endocrine treatments are inconsistent. Clinical markers predictive of greater benefit from fulvestrant compared to the alternate endocrine agents have not been identified. Methods We searched the literature from inception to May 2015, using MEDLINE, EMBASE, and major conference proceedings. We included randomized controlled trials (RCTs) that compared fulvestrant containing arm to either tamoxifen or an aromatase inhibitors (AI) and presented results for subgroup analyses as Hazard Ratios (HR) for Time to Progression (TTP) or Progression Free Survival (PFS). Subgroup analyses reported in at least two RCTs were included. Data were then weighted using generic inverse variance approach and pooled in meta-analysis using RevMan 5.3 software. Difference between sub-groups was tested with chi 2 statistics. Results Analysis included 4 RCTs comparing fulvestrant-based therapy to AI alone and comprising 2382 patients (1190 on fulvestrant and 1192 on control arms). TTP/PFS was the primary endpoint in all included studies. Four sub-groups fulfilled our criteria. Fulvestrant was associated with greater benefit in patients with visceral metastasis (HR 0.85 vs 1.02 for no visceral disease, p for difference = 0.05) and in those patients with a time to recurrence >5 years (HR 0.80 vs 1.09 for recurrence ⩽5 years, p for difference = 0.02). There was no apparent difference in benefit based on age >65 years (HR 0.86 vs 0.96, p for difference = 0.32) or HER2/neu status (HR 0.36 vs 0.92, p for difference = 0.09). Conclusion Patients with advanced breast cancer with visceral involvement and longer time from diagnosis to recurrence had significantly better TTP/PFS with the use of fulvestrant. These results may have implications for selection of patients in the design of future clinical trials and to inform treatment decisions in clinical practice.

Background: While fulvestrant is approved by the United Stated Food and Drug Administration as an alternate endocrine therapy for treatment of advanced breast cancer, data on its efficacy compared to other endocrine treatments are inconsistent. Clinical markers predictive of greater benefit from fulvestrant compared to the alternate endocrine agents have not been identified. Methods: We searched the literature from inception to May, 2015 from MEDLINE, EMBASE, and major conference proceedings. We included randomized controlled trials that evaluated Fulvestrant compared to either tamoxifen or an AI. We collected the efficacy data reported as Time to Progression (TTP) or Progression Free Survival (PFS) on 7 distinct subgroup of patients from the RCTs defined by: age, time to cancer reoccurrence from primary diagnosis, presence of visceral metastasis, previous chemotherapy exposure, presence of measurable disease, hormone receptor status and, HER-2 status. Data on rates of occurrences of 9 most frequently reported adverse events were also collected from both arms of the studies. Data on both efficacy and toxicity were then weighted using generic inverse variance approach and pooled in a meta-analysis using RevMan 5.3 software. Results: We identified 8 RCTs that fulfilled our criteria and involved 4,024 patients (2,032 on fulvestrant and 1,992 on control arms). TTP/PFS was the primary endpoint in 7 out of 8 RCTs and secondary endpoint in one. Compared to an AI or tamoxifen, there was a statistically significant improvement in TTP favoring fulvestrant in patients who had visceral metastasis [Hazards Ratio (HR) 0.86; 95% Confidence Interval (CI) 0.77 to 0.96, p Conclusion: Patients with advanced breast cancer that have visceral disease, measurable disease, or HER-2 driven disease are likely to derive higher benefits from treatment with fulvestrant compared to tamoxifen or an AI. These results may have implications for selection of patients in the design of future clinical trials and to inform treatment decisions in clinical practice. Citation Format: Niraula S, Pitz M, Gordon V, Grenier D, Amir E, Brandes L. Clinical predictors of benefit from fulvestrant in advanced breast cancer: A meta-analysis of randomized controlled trials. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-14-02.

Key Points Question What are the differences and similarities in characteristics and outcomes of breast cancers detected by mammographic screening vs those detected between screening mammograms (interval cancers) in women participating in a population-based screening program? Findings In this cohort study of 69 025 women, interval breast cancers accounted for one-fourth of breast cancers in routinely screened women, were 6 times more likely to be grade III, and had 3.5 times increased hazards of breast cancer death compared with screen-detected cancers. Meaning Heterogeneity in breast cancer defies assumptions necessary for screening mammography in its current form to be maximally effective; strategies beyond routine screening mammography are needed to prevent, detect, and avert deaths from the more lethal interval breast cancers., This population-based cohort study examines breast cancer–specific mortality rates associated with interval breast cancer compared with those of screen-detected breast cancers., Importance Breast cancer comprises a highly heterogeneous group of diseases. Many breast cancers, particularly the more lethal ones, may not satisfy the assumptions about biology and natural history of breast cancer necessary for screening mammography to be effective. Objectives To compare tumor characteristics of breast cancers diagnosed within 2 years of a normal screening mammogram (interval breast cancer [IBC]) with those of screen-detected breast cancers (SBC) and to compare breast cancer–specific mortality of IBC with SBC. Design, Setting, and Participants In this registry-based cohort study, we collected data about relevant tumor- and patient-related variables on women diagnosed with breast cancer between January 2004 and June 2010 who participated in the population-based screening program in Manitoba, Canada, and those diagnosed with breast cancer outside the screening program in the province. We performed multinomial logistic regression analysis to assess tumor and patient characteristics associated with a diagnosis of IBC compared with SBC. Competing risk analysis was performed to examine risk of death by cancer detection method. Exposures Breast cancer diagnosis. Main Outcomes and Measures Differences in tumor characteristics and breast cancer–specific mortality. Results A total of 69 025 women aged 50 to 64 years had 212 579 screening mammograms during the study period. There were 1687 breast cancer diagnoses (705 SBC, 206 IBC, 275 were noncompliant, and 501 were detected outside the screening program), and 225 deaths (170 breast cancer–specific deaths). Interval cancers were more likely than SBC to be of high grade and estrogen receptor negative (odds ratio [OR], 6.33; 95% CI, 3.73-10.75; P

Importance Mindfulness-based interventions (MBIs), grounded in mindfulness, focus on purposely paying attention to experiences occurring at the present moment without judgment. MBIs are increasingly used by patients with cancer for the reduction of anxiety, but it remains unclear if MBIs reduce anxiety in patients with cancer. Objective To evaluate the association of MBIs with reductions in the severity of anxiety in patients with cancer. Data Sources Systematic searches of MEDLINE, Embase, Cochrane Central Register of Controlled Trials, CINAHL, PsycINFO, and SCOPUS were conducted from database inception to May 2019 to identify relevant citations. Study Selection Randomized clinical trials (RCTs) that compared MBI with usual care, waitlist controls, or no intervention for the management of anxiety in cancer patients were included. Two reviewers conducted a blinded screening. Of 101 initially identified studies, 28 met the inclusion criteria. Data Extraction and Synthesis Two reviewers independently extracted the data. The Cochrane Collaboration risk-of-bias tool was used to assess the quality of RCTs, and the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline was followed. Summary effect measures were reported as standardized mean differences (SMDs) and calculated using a random-effects model. Main Outcomes and Measures Our primary outcome was the measure of severity of short-term anxiety (up to 1-month postintervention); secondary outcomes were the severity of medium-term (1 to ≤6 months postintervention) and long-term (>6 to 12 months postintervention) anxiety, depression, and health-related quality of life of patients and caregivers. Results This meta-analysis included 28 RCTs enrolling 3053 adults with cancer. None of the trials were conducted in children. Mindfulness was associated with significant reductions in the severity of short-term anxiety (23 trials; 2339 participants; SMD, −0.51; 95% CI, −0.70 to −0.33;I2 = 76%). The association of mindfulness with short-term anxiety did not vary by evaluated patient, intervention, or study characteristics. Mindfulness was also associated with the reduction of medium-term anxiety (9 trials; 965 participants; SMD, −0.43; 95% CI, −0.68 to −0.18;I2 = 66%). No reduction in long-term anxiety was observed (2 trials; 403 participants; SMD, −0.02; 95% CI, −0.38 to 0.34;I2 = 68%). MBIs were associated with a reduction in the severity of depression in the short term (19 trials; 1874 participants; SMD, −0.73; 95% CI; −1.00 to −0.46;I2 = 86%) and the medium term (8 trials; 891 participants; SMD, −0.85; 95% CI, −1.35 to −0.35;I2 = 91%) and improved health-related quality of life in patients in the short term (9 trials; 1108 participants; SMD, 0.51; 95% CI, 0.20 to 0.82;I2 = 82%) and the medium term (5 trials; 771 participants; SMD, 0.29; 95% CI, 0.06 to 0.52;I2 = 57%). Conclusions and Relevance In this study, MBIs were associated with reductions in anxiety and depression up to 6 months postintervention in adults with cancer. Future trials should explore the long-term association of mindfulness with anxiety and depression in adults with cancer and determine its efficacy in more diverse cancer populations using active controls.

e19115 Background: US FDA introduced an Accelerated Approval (AA) pathway in 1992 to expedite access to promising new drugs, based on the assumption that RCTs would delay introduction or prove unfeasible. One resulting trade-off is an “interim” compromise in acceptable level of evidence: such approvals have increasingly relied on Overall Response Rates (ORR) from Single Arm Studies (SAS). FDA requires confirmation of benefits for such drugs in future RCTs, but that requirement may take years and often never met. Methods: We pooled drugs approved by FDA over 5 years based on ORR observed in SASs for solid tumors. We calculated the differences in ORR between the newly approved drugs and existing standard of care for each cancer sub-type, and designed hypothetical RCTs necessary to detect that difference. RCTs were designed based on power of 0.80, α-error of 5% (two-sided), and 1:1 randomization, using PS software (Vanderbilt University). We estimated accrual time for the RCTs using disease incidence and annual death rates for each cancer subtype in USA using Surveillance, Epidemiology & End Results records. Results: 28 of 129 (22%) FDA approved drugs for solid tumors, from 2015-2019, were based on SAS. Median sample size of 107 patients per approval (range 26-550). Drugs were approved based on median ORR of 38.9% (range 13-78%), compared to median ORR of 24.4% (range 5-62%) for existing standard of care [median difference in ORR 14.9% (range 6-45%)]. Using established statistical standards, median sample size required to conduct RCTs was 206 patients (range 44-1724); based on a conservative accrual rate of 5% of all eligible US patients, for 22 of 24 approvals RCTs with ORR as primary endpoint could have been completed within a timeframe equal to or less than the time used for undertaking the SAS. Drugs for 4 indications of 28 had a lower ORR compared to existing standard of care, while lacking evidence of superiority in any other survival outcome, raising important concerns about the approval process. Conclusions: Feasibility of conducting RCTs with an ORR endpoint within an acceptable time-frame does not appear to be a practical constraint for an overwhelming majority of drugs approved by FDA based on SAS alone. This finding questions the necessity of accepting a lower bar for efficacy and toxicity while approving drugs using the AA pathway, especially when supported by clinical equipoise with existing standards of care. ORR was lower than existing standard of care for 4 indications, putting rationale for these approvals into question.

Background: FDA approvals do not consider cost, but they set the tone for regulatory approvals worldwide, including in countries with universal healthcare where cost-effectiveness, utility, and adoption feasibility are considered rigorously. Methods: Data from the pan-Canadian Oncology Drug Review (pCODR), a national drug review system that makes evidence-based funding recommendations to Canada's provinces and territories, were collected. Our objectives were to assess (1) temporal trends in cost and efficacy of drugs reviewed, (2) correlations among magnitude of benefits, cost, and pCODR decisions, and (3) predictors of approvals. Results: A total of 60 drugs for 91 indications were reviewed by pCODR from January 2012 to January 2018. Of the 91 reviews (approved previously by FDA), 18 received negative recommendations on the grounds of inadequate clinical benefits; 87% (64/73) of those approved were conditional on improvement in cost. Surrogate outcomes were used to support approvals in 83% of the reviews, which were not correlated with overall survival (rSpearman = +0.16; P=.24). Median cost/quality-adjusted life years (QALY) increased by 36% per annum (quantile regression, P=.0029), although benefits in overall and progression-free survival were stable (P=.21 and .65, respectively). Median-based incremental cost-effectiveness ratio (ICER) of new drugs was $186,403 CAD (range, $7,200 to $2.1 million). Higher ICER was a strong predictor of a negative pCODR recommendation (P

When an investigational anticancer drug is being tested, demonstration of improvement in overall survival (OS) will generally lead to regulatory approval. However, the value that improvement in OS adds to patients' lives is guided largely by the context of the improvement and accompanying trade-offs. For example, when a patient's life expectancy is less than 6 months, many oncologists will not embark on any active cancer treatments. However, multiple new anticancer drugs have been approved recently after being tested in end-stage cancer patients and demonstrating median OS in the experimental arm close to 6 months. Such practice, particularly when the treatment is also accompanied by serious toxicities and cost, can undermine a peaceful life-death transition. In this commentary, we review regulatory approvals in the last 5 years and the ethical considerations involved in testing active cancer treatment in terminal cancer patients.

BACKGROUND Androgen deprivation therapy (ADT) with luteinizing hormone releasing hormone (LHRH) agonists is an effective initial therapy for men with advanced prostate cancer. LHRH agonists are usually administered indefinitely at a fixed interval. METHODS We recruited men with advanced prostate cancer who had been on fixed-schedule injections of an LHRH agonist for ≥1 year and had castrate serum testosterone [1 year. In univariable analysis, lower baseline testosterone [≤1 vs. >1 nmol/l (approx. 30 ng/dl)] and longer time on ADT (>5 vs. ≤5 years) predicted for prolonged time to testosterone recovery, but only lower baseline testosterone remained significant in multivariable analysis (Hazard Ratio = 5.2, P = 0.03). Overall EPIC scores remained stable but improvement from baseline was observed in the hormonal domain (P = 0.002). Median per-patient saving in cost was approximately USD 3,100 (1,050–6,200). CONCLUSIONS Testosterone-guided ADT reduces exposure to LHRH agonists, with reduction in cost and improvement in some symptoms from ADT. Testosterone-guided ADT should be considered an alternative to fixed schedule treatment by physicians and policy makers. Prostate. © 2015 Wiley Periodicals, Inc.

Differing interpretations about evidence on benefits and harms of screening mammography has led to conflicting recommendations among different jurisdictions that range from intensive screening starting at age 40 to no screening at all. Despite broad attention of scientific and nonscientific media, evidence suggests substantial discrepancy between real and perceived benefits of screening mammography among women. In this commentary, underlying concept of mammographic screening, limitations in primary evidence, results from secondary evidence, and existing misunderstandings are underscored with a critical gaze at available information.

Purpose There are increasing reports of rare but serious toxicities caused by new anticancer drugs, and there are costs associated with their management. Methods We identified anticancer drugs approved by the US Food and Drug Administration from 2000 to 2011 and pivotal trials supporting their registration. Twelve frequent grade 3 to 4 adverse event (AEs) were weighted and pooled in a meta-analysis. Estimates of incremental drug prices and incremental costs for management of AEs were calculated according to type of new agent based on target specificity. Results We identified 41 studies comprising 27,539 patients and evaluating 19 experimental drugs. Agents directed against a specific molecular target on cancer cells had a lower incidence of grade 3 to 4 toxicities compared with controls (median risk ratio [RR], 0.67; P = .22), whereas less-specific targeted agents, including angiogenesis inhibitors (median RR, 3.39; P < .001) and chemotherapeutic agents (median RR, 1.73; P < .001), were more toxic. Risk was increased regardless of whether the control arm contained active treatment (RR, 2.11; P < .001) or not (RR, 3.02; P < .001). Median incremental drug price for experimental agents was $6,000 per patient per month. Median cost of managing toxicity was low compared with drug costs but higher than controls for treatment with less-specific targeted agents and chemotherapies. Conclusion Newly approved anticancer drugs are associated with increased toxicity, except for agents with a specific molecular target on cancer cells. Management of toxicity leads to a small increase in overall cost of treatment. Frequency of toxicity and associated costs are likely higher in less-selected patients treated in general oncologic practice. Development of biomarker-driven agents should be encouraged.

6595 Background: The province of Manitoba, Canada has an organized population based biennial mammographic screening program. Here we report outcomes of women diagnosed with Interval Cancers (IC), defined as cancer diagnosed within 24 months of a normal screening mammogram and before the next screening mammogram, compared to Screen Detected (SD) cancers. Methods: The Manitoba Cancer Registry was used to obtain data about tumor and host characteristics and cause-specific mortality for women 52 to 64 years of age diagnosed with invasive breast cancer from January 2004 to December 2010. Lead time bias in SD cancers was adjusted based on Duffy's correction factor. Competing risk analysis was used to examine the risk of death by cancer detection method. To examine the relationship between breast cancer detection type and personal and tumour characteristics, we performed multinomial logistic regression analysis with age, area-level income quintile, tumour grade, hormone receptor, and HER2 receptor as independent variables. Results: There were 5,884 women diagnosed with invasive breast cancer during the study period of which 1,338 were SD, 362 were IC, and the remainder were diagnosed outside the screening program or were non-compliant to screening. IC were more likely than SD cancers to be high grade [Odds Ratio (OR) 3.8, 95% Confidence Interval (CI): 2.1-6.8], and ER negative [OR 1.7, 95% CI: 1.02-3.12]. At data cut-off date of June 30, 2012, risk of death from breast cancer was significantly higher for IC compared to SD cancers [Hazard Ratio (HR) 4.18, 95% CI: 1.97-8.87)], for sojorn time (period when tumour is asymptomatic but screen detectable) of 2 years adjusting for area-level average income quintile and age. Sensitivity analyses with sojourn times of 1, 3, and 4 years showed similar results. Risk of non-breast cancer death was not increased with IC compared to SD cancers (HR 1.33, 95% CI: 0.43-4.15). Conclusions: Among women who participated in a systematic population-based screening program, IC occurred frequently; breast cancer-related death for IC was 4-times that of SD cancers. These results highlight the discordance between the principles underpinning population based breast cancer screening and natural history of these more lethal breast cancers.

There has been a substantial surge of 'targeted agents' in contemporary anticancer drug armamentarium and some of these agents have revolutionized the outcome of cancer patients. However, on contrary to the nomenclature, not all new targeted agents are selected based on presence of target molecules on the cancer cells. Drugs are typically approved based on demonstration of benefit in randomized controlled trials with regards to efficacy outcomes although both the 'benefits' and 'outcomes' are defined inconsistently. Surrogates that are not validated properly are often used as endpoints. Furthermore, new anticancer drugs are frequently associated with increased inconvenience to the patients and/or to the society due to added toxicity and cost. In this perspective article, emphasis is given to the above problems focusing on room for improvement in anticancer drug development. An illustration of a recently approved drug to treat advanced breast cancer, everolimus and a previously revoked drug bevacizumab is given.

Background Breast cancer is heterogeneous at different levels: biologic subtypes, intratumoral areas, and sites of metastases. Randomized controlled trials (RCTs) classify metastatic sites as visceral or non-visceral, but this has little influence in treatment decisions, particularly in the absence of clinical urgency. Indeed, it is unclear if response to treatments differs among sites of metastases. Patients and methods RCTs investigating 3 different anticancer strategies in metastatic breast cancer were identified: (1) new hormonal therapy, (2) new targeted therapies in hormone receptor positive tumours (everolimus or palbociclib), and (3) new anti-HER2 therapies. RCTs reporting hazard ratios (HR) for Progression Free Survival (PFS) and Overall Survival (OS) for sub-groups based on sites of metastases were weighted using generic inverse variance approach, and pooled in meta-analyses using Revman 5.3. Subgroup difference was tested with Chi2 statistics. Results Eleven RCTs (6701 pts.) qualified. There was a significant difference in PFS between women with visceral versus non-visceral metastases when two endocrine strategies were compared, with benefits limited to women with visceral metastases [Pooled HR 0.85; 95% CI, 0.77–0.95 versus 1.02 (0.88–1.18) for non-visceral; p(difference) = 0.05]. However, combination of an endocrine therapy and a targeted therapy was associated with better PFS compared to endocrine therapy alone for both groups [HR 0.51 (0.43–0.60) versus 0.45 (0.36–0.56) for non-visceral; p(difference) = 0. 36]. Novel HER-2 targeted therapies were associated with significantly better PFS and OS only in visceral metastases [HR 0.59 (0.52–0.66) versus 0.71(0.44–1.13) for non-visceral, p(difference) = 0.45, for PFS; and 0.64 (0.56–0.73) versus 0.82 (0.57 = 1.19) for non-visceral, p(difference) = 0.20, for OS]. Conclusion Combination of targeted agents and endocrine therapy results in concordant, superior PFS suggesting targetable endocrine resistance across metastatic sites. Discordant responses with endocrine strategy alone support use of targeted therapy, rather than change in endocrine agent at disease progression. HER2 targeted therapies may be less effective in areas of poor vascularization.

Background: Numerous clinical studies have reported that diabetic patients receiving metformin exhibit decreased cancer incidence and cancer related mortality. Metformin's mechanism of anti-tumor action has been attributed to both direct effects on cancer cells and systemic changes in insulin metabolism. Indeed, metformin reduces circulating insulin levels, which may be integral to its effectiveness in the breast cancer (BC) setting where hyperinsulinemia is associated with both recurrence and death. While the impact of metformin on blood glucose and insulin is well documented, its effects on other systemic physiologic and inflammatory factors are unknown. We completed a neoadjuvant "window of opportunity" study of metformin in non-diabetic women with BC and a series of analyses were performed on plasma samples to assess the impact of metformin on circulating inflammatory markers, growth factors, and tumor associated antigens. Methods: Non-diabetic women with early stage, untreated BC were given metformin 500 mg tid for ≥2 weeks post diagnostic core biopsy until surgery. Fasting blood was collected at diagnosis and surgery to assess circulating markers pre- and post-metformin administration. Plasma was isolated from blood samples and evaluated for CRP, TNF-alpha, IL-6, IL-8, VEGF, EGF, PlGF (placenta growth factor), CA15-3, and SHBG (sex hormone binding globulin). Change scores (post-metformin minus pre-) were calculated and the degree of change characterized by the median change and the rank-biserial correlation. The Wilcoxon signed-rank test was used to test the null hypothesis that the change scores were symmetrically distributed around zero versus more positive or negative change. Results: A total of 39 patients (mean age 51 years) completed the study and received metformin for a median of 18 days (range 13-40). Metformin was associated with changes in the levels of growth factors, with increases seen in EGF (median increase 1.1 pg/mL, r=0.42, p=0.027) and VEGF (1.7 pg/mL, r=0.31, p=0.09). A reduction in PlGF levels (-0.18 pg/mL, r=-0.6, p=0.0028) was also observed. The tumor associated antigen CA15-3 was significantly reduced after metformin treatment (-0.4 pg/mL, r=-0.56, p=0.0024) and a marker of sex hormone bioavailability (SHBG) was increased (2 nM, r=0.30, p=0.1). For circulating inflammatory markers, a significant increase in the levels of IL-8 (0.8 pg/mL, r=0.36, p=0.048) was observed, but changes in TNF-alpha and IL-6 were minimal (TNF-alpha 0.2 pg/mL, r=0.20, p=0.29; IL-6 0.1 pg/mL, r=0.14, p=0.46) and no change was seen in CRP (0 mg/L, r=-0.05, p=0.93). Conclusions: Short-term metformin administration was associated with alterations in systemic physiologic and inflammatory factors. Such increases in circulating cytokines and growth factors indicate possible alterations in the inflammatory state of the host and/or tumor. Of note, the reduction seen in the tumor antigen CA15-3 may reflect a disease-modifying effect of metformin in BC. The authors wish to acknowledge the generous support of the Hold'Em For Life Charity Challenge and the Breast Cancer Research Foundation. Citation Format: Dowling RJ, Niraula S, Chang MC, Ennis M, Stambolic V, Goodwin PJ. Circulating inflammatory markers, growth factors, and tumor associated antigens in women with early stage breast cancer receiving neoadjuvant metformin [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-02-03.

Aromatase inhibitors are associated with consistent improvements in disease-free survival but not in overall survival. We conducted a literature-based meta-analysis of randomized trials to examine whether the relative toxicity of aromatase inhibitors compared with tamoxifen may explain this finding.We conducted a systematic review to identify randomized controlled trials that compared aromatase inhibitors and tamoxifen as primary adjuvant endocrine therapy in postmenopausal women by searching MEDLINE, EMBASE, and databases of the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium. Odds ratios (ORs), 95% confidence intervals (CIs), absolute risks, and the number needed to harm associated with one adverse event were computed for prespecified serious adverse events including cardiovascular disease, cerebrovascular disease, bone fractures, thromboembolic events, endometrial carcinoma and other second cancers not including new breast cancer. All statistical tests were two-sided.Seven trials enrolling 30,023 patients met the inclusion criteria. Longer duration of aromatase inhibitor use was associated with increased odds of developing cardiovascular disease (OR = 1.26, 95% CI = 1.10 to 1.43, P.001; number needed to harm = 132) and bone fractures (OR = 1.47, 95% CI = 1.34 to 1.61, P.001; number needed to harm = 46), but a decreased odds of venous thrombosis (OR = 0.55, 95% CI = 0.46 to 0.64, P.001; number needed to harm = 79) and endometrial carcinoma (OR = 0.34, 95% CI = 0.22 to 0.53, P.001; number needed to harm = 258). Five years of aromatase inhibitors was associated with a non-statistically significant increased odds of death without recurrence compared with 5 years of tamoxifen alone or tamoxifen for 2-3 years followed by an aromatase inhibitor for 2-3 years (OR = 1.11, 95% CI = 0.98 to 1.26, P = .09).The cumulative toxicity of aromatase inhibitors when used as up-front treatment may explain the lack of overall survival benefit despite improvements in disease-free survival. Switching from tamoxifen to aromatase inhibitors reduces this toxicity and is likely the best balance between efficacy and toxicity.

Purpose: To determine differences in serious adverse events (AEs) associated with aromatase inhibitors (AIs) compared with tamoxifen, and to explore whether these AEs might be ameliorated by switching to AIs after 2-3 years of tamoxifen. Materials and Methods: Published data from trials contributing to the Aromatase Inhibitor Overview Group were included in a meta-analysis. Odds ratios (OR), 95% confidence intervals (CI) and absolute risks (number needed to treat [NNT] associated with one AE) were computed for serious AEs Results: Any duration of AIs was associated with a higher probability of developing cardiovascular disease (OR 1.20, p=0.01; NNT 143) and bone fractures (OR 1.48, P Conclusion: Treatment with AIs is associated with a statistically significant increase in cardiovascular risk, which is of similar magnitude to the risk of venous thrombosis and endometrial cancer with 5-years of tamoxifen. While switching to AIs does not appear to reduce the risk for the development of serious AEs when compared to upfront use of AIs, fewer deaths unrelated to breast cancer occur with switching than with upfront strategies. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S2-7.

Background: Numerous epidemiological and pre-clinical studies have associated potential antineoplastic activity with the antidiabetic drug metformin in various tumor types including breast cancer (BC). We are conducting a neoadjuvant “window of opportunity” study to examine biologic and clinical effects of metformin in early stage BC. Data from a planned interim analysis are presented here. Materials and methods: 15 of planned 40 non-diabetic women < 75 yo with newly diagnosed untreated BC were given metformin 500 mg tid for ≥2 weeks post diagnostic core biopsy until definitive surgery. Fasting blood and tumor tissue were obtained, anthropometric measurements performed and the EORTC QLQ C-30 administered pre-metformin and on the day of surgery. Clinical (weight, symptoms, EORTC QLQ C-30) and biologic characteristics were compared pre-metformin and at the end of metformin treatment as were Ki67 (our primary end-point), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), cleaved caspase 3, physiologic markers (insulin, HOMA,TNF-alpha) and molecular markers [phosphorylated 4E-BP1, phosphorylated protein kinase B (P-PKB/Akt), phosphorylated AMPK (P-AMPK), insulin receptor(IR), Insulin-like growth factor 1 receptor(IGF-1R)]. Analysis of Ki67, cleaved Caspase 3 and TUNNEL were performed on a blinded fashion. Ki-67 was scored by manual count selected by and expressed as percentage of cells with positive nuclear staining. Results: Mean age was 51.7 years. 73.3% (11/15) and 26.7% (4/15) had T1 and T2 BC respectively; 40% (6/15) were node positive, 86.7% (13/15) were ER and PR positive and 26.6% (4/15) were HER-2 +. Metformin was administered for a median of 21 days (range 14 - 40). Gastrointestinal (GI) side effects were most frequent and usually self-limiting — mild diarrhoea 60% (9/15), anorexia 53% (8/15) and nausea 46% (7/15). EORTC30 QLQ scores were stable. Weight decreased (mean change -0.81 kg; Mann-Whitney U p-value 0.057). HOMA (a marker of insulin sensitivity) and C-reactive protein improved, mean change -0.32 and -0.21mg/L respectively. Ki67 decreased significantly after metformin treatment (from 27.6 to 22.7, Wilcoxon signed-rank test p-value = 0.043); TUNEL staining increased significantly (from 0.43 to 1.48, p=0.03) and cleaved Caspase 3 increased non-significantly (from 1.01 to 3.96, p=0.31). Conclusion: Preoperative metformin was well tolerated with mild GI toxicities, but no significant QOL effects; it was associated with improved insulin resistance. A short term administration of metformin significantly reduced breast cancer cell proliferation (as measured by change in Ki67 index) and induced apoptosis (reflected by TUNEL). Metformin administration elicited potential physiologic and cellular effects in breast cancer that are in keeping with beneficial anti-cancer effects. Updated results and the impact of metformin on IR/IGF1R/PI3K and AMPK/mTOR signaling pathways within the cancers will be reported. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD03-06.

6516Background: United States Food and Drug Administration (FDA) primarily takes into account the therapeutic index before approval of a new cancer drug whereas in countries with public funding of ...

Aim: Zoledronate is approved for use every 3 weeks in men with bone metastases from castrate-resistant prostate cancer (CRPC) but the basis for such frequency is unclear. Methods: In men with bone metastasis from CRPC we measured the markers of bone turnover - urine and serum telopeptides before the first injection of zoledronate and at four 3-weekly intervals thereafter. Men received further zoledronate treatment after 12 weeks, or earlier if the telopeptides did not meet predefined adequate suppression. The primary end point was the proportion of evaluable subjects with suppressed telopeptides at 12 weeks. Exploratory analyses evaluated predictors of bone turnover suppression and quality-of-life. Results: 31 patients were enrolled. Median age was 70 (range: 53–86) years. 65%, (95% CI: 46–81%) had suppressed telopeptides at 12 weeks. Prior skeletal-related events, chemotherapy, bone surgery and higher baseline levels of telopeptides were associated with shorter duration of telopeptides. Conclusion: 12-weekly zoledronate suppresses bone turnover in the majority of men with bone metastasis from CRPC., Lay abstract Zoledronic acid (ZA) is a bone strengthening drug used for treatment of men with advanced prostate cancer in their bones. Based on initial clinical trials, ZA is approved for use every 3 weeks. However, recent clinical trials suggest similar outcomes when ZA is used every 12 weeks. In this clinical trial, we reaffirm that majority of men with prostate cancer only require every 12 weeks of ZA to achieve a reasonable biochemical response. Less frequent treatments may spare patients of the side effects, inconvenience and cost.

Androgen deprivation therapy (ADT) with luteinizing hormone releasing hormone (LHRH) agonists is an effective initial therapy for men with advanced prostate cancer. LHRH agonists are usually administered indefinitely at a fixed interval.We recruited men with advanced prostate cancer who had been on fixed-schedule injections of an LHRH agonist for ≥1 year and had castrate serum testosterone [1.75 nmol/l (approx. 50 ng/ml)]. Testosterone levels were measured at 6-week intervals and ADT was withheld until testosterone levels were no longer in the castrate range and then reinstituted. Time to reinstitution of ADT was the primary outcome and was analyzed by the Kaplan-Meier method; Cox regression was used to identify factors predicting delay in reinstitution of treatment. Influence on quality-of-life (QoL) was evaluated by the Expanded Prostate Index Composite (EPIC).Forty-six evaluable men who had received LHRH agonist injections every 12 weeks were recruited. Median time to testosterone recovery (defined as testosterone outside the defined castrate level) after previous injection was1 year. In univariable analysis, lower baseline testosterone [≤1 vs.1 nmol/l (approx. 30 ng/dl)] and longer time on ADT (5 vs. ≤5 years) predicted for prolonged time to testosterone recovery, but only lower baseline testosterone remained significant in multivariable analysis (Hazard Ratio = 5.2, P = 0.03). Overall EPIC scores remained stable but improvement from baseline was observed in the hormonal domain (P = 0.002). Median per-patient saving in cost was approximately USD 3,100 (1,050-6,200).Testosterone-guided ADT reduces exposure to LHRH agonists, with reduction in cost and improvement in some symptoms from ADT. Testosterone-guided ADT should be considered an alternative to fixed schedule treatment by physicians and policy makers.

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al., [Background]: Companion diagnostics aim to identify patients that will respond to targeted therapies, therefore increasing the clinical efficacy of such drugs. Less is known about their influence on safety and tolerability of targeted anti-cancer agents. [Methods and findings]: Randomized trials evaluating targeted agents for solid tumors approved by the US Food and Drug Administration since year 2000 were assessed. Odds ratios (OR) and and 95% confidence intervals (CI) were computed for treatment-related death, treatment-discontinuation related to toxicity and occurrence of any grade 3/4 adverse events (AEs). The 12 most commonly reported individual AEs were also explored. ORs were pooled in a meta-analysis. Analysis comprised 41 trials evaluating 28 targeted agents. Seventeen trials (41%) utilized companion diagnostics. Compared to control groups, targeted drugs in experimental arms were associated with increased odds of treatment discontinuation, grade 3/4 AEs, and toxic death irrespective of whether they utilized companion diagnostics or not. Compared to drugs without available companion diagnostics, agents with companion diagnostics had a lower magnitude of increased odds of treatment discontinuation (OR = 1.12 versus 1.65, p < 0.001) and grade 3/4 AEs (OR = 1.09 versus 2.10, p < 0.001), but no difference in risk of toxic death (OR = 1.40 versus 1.27, p = 0.69). Differences between agents with and without companion diagnostics were greatest for diarrhea (OR = 1.29 vs. 2.43, p < 0.001), vomiting (OR = 0.86 vs. 1.44, p = 0.005), cutaneous toxicity (OR = 1.82 vs. 3.88, p < 0.001) and neuropathy (OR = 0.64 vs. 1.60, p < 0.001). [Conclusions]: Targeted drugs with companion diagnostics are associated with improved safety, and tolerability. Differences were most marked for gastrointestinal, cutaneous and neurological toxicity., Ministry of Economy and Competitiveness of Spain (BFU2012-39151 and RD12/0036/0003 to AP), and the AECC (to AP). Fondo de Investigación Sanitaria (PI13/01444) and CRIS Cancer Foundation and ACEPAIN (to AO).

Background: The anti-diabetic drug metformin, commonly used to treat type 2 diabetes due to its ability to reduce circulating glucose and insulin, has emerged as a potential anti-cancer agent. Observational studies have reported decreased cancer incidence and mortality in diabetics receiving metformin. Metformin's ability to reduce insulin may be particularly important for breast cancer (BC) because hyperinsulinemia is an adverse prognostic factor and most cells express the insulin receptor (IR). The anti-cancer effects of metformin are associated with both direct (insulin-independent) and indirect (insulin-dependent) actions. Direct effects are linked to activation of AMPK and an inhibition of mTOR signalling, while indirect effects are mediated by reductions in circulating insulin levels, leading to reduced IR-activated PI3K signalling. We conducted a neoadjuvant, single arm, “window of opportunity” trial examining the clinical and biological effects of metformin on thirty-nine locoregional BC patients awaiting definitive surgery. Methods: Non-diabetic women with newly diagnosed, untreated BC were given metformin 500 mg tid for ≥2 weeks post diagnostic core biopsy until surgery. Fasting blood and tumour samples were collected at diagnosis and surgery. Blood glucose and insulin were assayed to assess the physiologic effects of metformin, while IHC analysis of tumours was used to characterize cellular markers before and after metformin. Specifically, IR levels and the phosphorylation status of proteins involved in AMPK and PI3K/AKT/mTOR signalling, including AMPK (T172) and AKT (S473), were examined. Results: 39 patients with a mean age of 51 years received metformin for a median of 18 days (range 13–40) with minor GI toxicities. The clinical effects (previously reported) included significant (p < 0.05) decreases in body mass index (−0.5 kg/m2), weight (−1.2 kg), glucose (−0.14 mM) and HOMA (an estimate of insulin resistance, −0.21), and a decrease in insulin (−4.7 pmol/L) that approached significance (p = 0.0686). Ki67 staining in tumour tissue decreased significantly and TUNEL increased significantly. Levels of IR expression decreased significantly (from 4.39 to 3.82, p = 0.0375) as did the phosphorylation status of AKT (S473) and AMPK (T172) (from 9.82 to 7.08, p = Conclusions: Metformin impact was consistent with beneficial anti-cancer effects. Reduced AKT phosphorylation, coupled with decreased insulin and IR levels, suggest insulin-dependent effects are important in the clinical setting. Assessment of additional factors in BC cells, including OCT1 expression (required for metformin uptake), and the phosphorylation of ACC (a marker of AMPK activation), is underway and will be reported. Integrated analysis of these factors combined with the physiological and molecular data described above will further enhance understanding of metformin action in the clinical setting. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD03-05.

Purpose Uncertainty exists regarding benefits of intermittent androgen deprivation (IAD) compared with continuous androgen deprivation (CAD) for treatment of prostate cancer. On the basis of a systematic review of evidence, our aim was to formulate a recommendation for either IAD or CAD to treat relapsing, locally advanced, or metastatic prostate cancer. Methods We searched literature published up to September 2012 from MEDLINE, EMBASE, the Cochrane Library, and major conference proceedings. We included randomized controlled trials comparing IAD and CAD if they reported overall survival (OS) or biochemical/radiologic time to disease progression. Results Nine studies with 5,508 patients met our criteria. There were no significant differences in time-to-event outcomes between the groups in any studies. The pooled hazard ratio (HR) for OS was 1.02 (95% CI, 0.94 to 1.11) for IAD compared with CAD, and the HR for progression-free survival was 0.96 (95% CI, 0.76 to 1.20). More prostate cancer–related deaths with IAD tended to be balanced by more deaths not related to prostate cancer with CAD. Superiority of IAD for sexual function, physical activity, and general well-being was observed in some trials. Median cost savings with IAD was estimated to be 48%. Conclusion There is fair evidence to recommend use of IAD instead of CAD for the treatment of men with relapsing, locally advanced, or metastatic prostate cancer who achieve a good initial response to androgen deprivation. This recommendation is based on evidence against superiority of either strategy for time-to-event outcomes and substantial decrease with IAD in exposure to androgen deprivation, resulting in less cost, inconvenience, and potential toxicity.

Metformin may exert anti-cancer effects through indirect (insulin-mediated) or direct (insulin-independent) mechanisms. We report results of a neoadjuvant “window of opportunity” study of metformin in women with operable breast cancer. Newly diagnosed, untreated, non-diabetic breast cancer patients received metformin 500 mg tid after diagnostic core biopsy until definitive surgery. Clinical (weight, symptoms, and quality of life) and blood [fasting serum insulin, glucose, homeostasis model assessment (HOMA), C-reactive protein (CRP), and leptin] attributes were compared pre- and post-metformin as were terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and Ki67 scores (our primary endpoint) in tumor tissue. Thirty-nine patients completed the study. Mean age was 51 years, and metformin was administered for a median of 18 days (range 13–40) up to the evening prior to surgery. 51 % had T1 cancers, 38 % had positive nodes, 85 % had ER and/or PgR positive tumors, and 13 % had HER2 overexpressing or amplified tumors. Mild, self-limiting nausea, diarrhea, anorexia, and abdominal bloating were present in 50, 50, 41, and 32 % of patients, respectively, but no significant decreases were seen on the EORTC30-QLQ function scales. Body mass index (BMI) (−0.5 kg/m2, p

The anti-diabetic drug metformin is rapidly emerging as a potential anti-cancer agent. Metformin, effective in treating type 2 diabetes and the insulin resistance syndromes, improves insulin resistance by reducing hepatic gluconeogenesis and by enhancing glucose uptake by skeletal muscle. Epidemiological studies have consistently associated metformin use with decreased cancer incidence and cancer-related mortality. Furthermore, numerous preclinical and clinical studies have demonstrated anti-cancer effects of metformin, leading to an explosion of interest in evaluating this agent in human cancer. The effects of metformin on circulating insulin levels indicate a potential efficacy towards cancers associated with hyperinsulinaemia; however, metformin may also directly inhibit tumour growth. In this review, we describe the mechanism of action of metformin and summarise the epidemiological, clinical and preclinical evidence supporting a role for metformin in the treatment of cancer. In addition, the challenges associated with translating preclinical results into therapeutic benefit in the clinical setting will be discussed.

Obesity is associated with poor survival after breast cancer diagnosis in individual studies and meta-analyses. Evidence regarding associations of obesity with breast cancer-specific survival (BCSS) and overall survival (OS) in relation to hormone receptor status, or BCSS in relation to menopausal status has not been evaluated in a previous meta-analysis. In this study, we conducted a meta-analysis of the association of obesity with OS and BCSS in relation to hormone receptor status and menopausal status. MEDLINE, EMBASE, and COCHRANE databases from the first record to December 2011 and presentations made at major international meetings in the last 5 years were searched. We included observational or interventional studies reporting hazard ratios (HRs) of obesity with OS and/or BCSS in relation to hormone receptor and/or menopausal status. Twenty-one studies qualified, meeting the above criteria. The pooled HR for OS in heavier versus lighter women was 1.31 (95 % CI 1.17-1.46) for estrogen receptor/progesterone receptor (ER/PgR) positive cancers; 1.18 (95 % CI 1.06-1.31) for ER/PgR negative cancers; and the difference between the two groups was not significant (p = 0.31). The pooled HR for OS in heavier versus lighter women was 1.23 (95 % CI 1.07-1.42) for premenopausal women and 1.15 (95 % CI 1.06-1.26) for post-menopausal women, and the difference between the two groups was not significant (p = 0.57). Comparable pooled HRs for BCSS were 1.36 (95 % CI 1.20-1.54) for ER/PgR positive cancers and 1.46 (95 % CI 0.98-2.19) for ER/PgR negative cancers; and 1.18 (95 % CI 0.82-1.70) for pre-menopausal women and 1.38 (95 % CI 1.11-1.71) for post-menopausal women, also without significant group differences. Results were similar after adjustment for BMI measurement technique, years of follow-up, or study design. These findings led us to conclude that there is no evidence showing that the association of obesity with breast cancer outcome differs by hormone receptor or menopausal status. This has implications for studies of weight loss interventions in the adjuvant BC setting.

It is now almost 70 years since Charles Huggins described the relationship between testosterone and the prostate gland. Arguably defining one of the first targeted therapies, the reduction of testosterone to castrate levels remains unaltered as the standard of care for men with metastatic prostate cancer. The failure of castration to permanently control the growth of prostate cancer leads to a state called castration-resistant prostate cancer (CRPC). Whilst numerous mechanisms have been suggested for the emergence of castration resistance [Scher and Sawyers (J Clin Oncol 23(32):8253-8261, 2005); Chen et al. (Curr Opin Pharmacol 8(4):440-448, 2008), Pienta and Bradley (Clin Cancer Res 12(6):1665-1671, 2006); Feldman and Feldman (Nat Rev Cancer 1(1):34-45, 2001); Mostaghel and Nelson (Best Pract Res Clin Endocrinol Metab 22(2):243-258, 2008)], a greater understanding of prostate cancer biology suggests that many such cancers retain a dependency on androgens and endeavour to increase bioavailable androgens through mechanisms such as AR amplification and intracrine androgen synthesis [Mohler et al. (Clin Cancer Res 10(2):440-448, 2004); Attard et al. (Clin Cancer Res 17(7):1649-1657, 2011); Hu et al. (Expert Rev Endocrinol Metab 5(5):753-764, 2010)]. With the recent approval of abiraterone acetate (Zytiga) and the pending approval of MDV3100, this article previews the future directions in clinical development and issues that will arise with the next generation of androgen-targeted agents.

HORMONAL THERAPY: Testosterone suppression achieved either medically or surgically is the standard initial treatment for men with advanced prostate cancer. Most men respond but the disease progresses after a median of 1-2 years. Clinical trials suggest that intermittent androgen deprivation therapy (ADT) provides equal or longer time to castration-independence than continuous ADT, and is preferred, especially since there are subtle long-term toxicities associated with ADT. Further hormonal manipulations (including addition and withdrawal of peripheral antiandrogens, steroid synthesis inhibitors such as ketoconazole, and estrogens) can be transiently effective in selected patients with castration-resistant prostate cancer (CRPC). Androgen-dependent signalling pathways remain active in most men with CRPC and are associated with mutation, changes in expression or modulation of the androgen receptor (AR); abiraterone acetate and MDV3100 are promising drugs being evaluated in clinical trials that may lead to further hormonal response.Eventually men who progress rapidly, are symptomatic, and/or develop metastasis to visceral organs require chemotherapy. Three-weekly docetaxel with prednisone has been shown to improve survival and relieve symptoms but eventually men develop progressive disease or become intolerant to docetaxel. Multiple trials are evaluating new drugs (mainly molecular targeted agents) either given first line with docetaxel chemotherapy, or to men who have progressive disease after receiving docetaxel. Cabazitaxel was shown recently to improve survival as compared to mitoxantrone when used second line and has been approved by the United States Food and Drug Administration (FDA).Despite major advances, treatment of men with advanced CRPC remains a challenge both for the seeker and giver of care.

Obesity is a major threat to health worldwide and if the current trend continues, more than 50% of the world’s population is projected to be obese by the year 2030 [1]. As reviewed by Irwin et al. in another chapter [2], obesity has been linked to both cancer risk and cancer outcome. Although obesity, insulin resistance and hyperinsulinemia are interrelated [3], until recently the primary focus of epidemiologic and clinical cancer research has been on obesity. Eugenia Calle et al. [4] provided an elegant demonstration of the association between body size and mortality from cancer in the prospective Cancer Prevention Study II, conducted by the American Cancer Society. Studying over 900,000 American adults, they found that individuals with a body mass index (BMI = weight(kg)/height(m)2) of at least 40 had death rates from cancer that were 52% higher (for men) and 62% higher (for women) than the rates seen in normal weight individuals. Higher BMI was significantly associated with increased death rates from a number of common cancers, including colon and rectum, breast, uterus and prostate as well as from less common cancers such as liver, gallbladder, pancreas, kidney, stomach, cervix, non-Hodgkin’s lymphoma and multiple myeloma. The only cancer demonstrating an inverse association between BMI and future cancer mortality was lung cancer. The results of this study (which combine the effect of obesity on cancer risk and cancer progression) suggest that obesity may contribute to 14% of all deaths from cancer in men and 20% of all deaths from cancer in women, evidence of an important contribution of obesity to cancer death. Similar results were obtained in a recent study by Whitlock et al. [5] in an analysis involving approximately 90,000 subjects that ­obesity was associated with significantly increased mortality from several causes, including cancer; with every 5 kg/m2 increase in BMI, risk of cancer-specific ­mortality increased by 10%. Furthermore, a recent meta-analysis by Renehan et al. [6] that focused on cancer incidence rather than mortality, reported that increased BMI was associated with increased risk of several different cancers including esophageal, thyroid, colon, rectal, renal, endometrial, gallbladder, breast (postmenopausal) and pancreatic, as well as melanoma, leukaemia, multiple myeloma, and non-Hodgkin lymphoma.

5039 Background: ADT with LHRH agonists that reduce testosterone production is effective initial therapy for treatment of men with advanced prostate cancer. LHRH agonists are usually administered i...

e17556 Background: Frequency of rare but serious adverse events (AEs) caused by new anticancer drugs, and costs associated with their management, are poorly documented. The type of anticancer drug ...

We thank Zhu and Zheng for their interest and comments on our study. As indicated in our publication, we included heterogeneous stages of prostate cancer among and within studies. However, results of these trials were comparable with regard to time to development of castration-resistant disease, time off treatment in the intermittent strategy, quality of life, and survival. Furthermore, we believe that presence of metastasis versus rising PSA reflects more a difference between overt and occult metastasis (extent of disease), thereby allowing us to fit one recommendation to all. As indicated by Zhu and Zheng, most trials showed increased nonprostate cancer–related deaths with continuous androgen deprivation therapy (CAD) and increased prostate cancer–related deaths with intermittent androgen deprivation therapy (IAD). Although we agree that pre-existing comorbidity can influence toxicity of an intervention, none of the studies were powered to evaluate subgroups, and the randomized nature of the included studies should have distributed any comorbidity between the groups. Also, the baseline level of PSA in the study by Salonen et al, although numerically different between the groups, has a wide standard deviation around the mean, warranting cautious interpretation (116.0 173.4 ng/mL in the IAD group and 186.3 454.4 ng/mL in the CAD group). We do not agree that we should interpret the results of the two large trials by Crook et al and Hussein et al as having a trend to favor one strategy versus the other: the hazard ratio for overall survival with IAD compared with CAD was 1.03 for the first study and 1.10 for the second, with 95% CIs encompassing unity. Nine randomized controlled trials, three of them of good quality and four of fair quality according to standard prespecified criteria, have shown no consistent survival advantage of one strategy versus the other, with IAD being more favorable in terms of some quality of life scores, cost and convenience. We disagree that further resources should be spent to address the same question in further randomized controlled trials.

Objectives: The TAX 327 trial was pivotal in establishing docetaxel in castration refractory metastatic prostate cancer. Various commonly prescribed and over-the-counter co-administered medications are thought to exhibit anti-neoplastic properties and/or could potentially have pharmacokinectic interactions with docetaxel lessening the effectiveness of chemotherapy.Methods: To examine the effect of on prostate cancer outcomes within this trial, we examined overall survival, prostate-specific antigen (PSA) response, percent PSA reduction, pain response and QOL responses for 14 families of medications including metformin, digoxin, verapamil, proton pump inhibitors, nitrates, statins, cox-2 inhibitors, warfarin, heparins, ascorbic acid, selenium, tocopherol,antidepressants and erythropoietin.Results: Our findings did not reveal any medication that had asignificant additive or synergistic effect with docetaxel. We did note, however, that patients on digoxin or verapamil had pooreroverall survival, possibly due to a trend of fewer cycles of administered chemotherapy being administered to the verapamil group,consistent with a pharmacokinectic interaction.Conclusions: These data are only hypothesis-generating given the statistical limitations, but may form a basis for similar future analysis in other malignancies. The data suggest the need to be aware of pharmacokinectic interactions with medications that may interactwith docetaxel.