Feasibility of Randomized Controlled Trials for Cancer Drugs Approved by the Food and Drug Administration Based on Single-Arm Studies.

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.

Incidence, Characteristics, and Outcomes of Interval Breast Cancers Compared With Screening-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 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 < .001; and OR, 2.88; 95% CI, 2.01-4.13; P < .001, respectively). After a median follow-up of 7 years, breast cancer-specific mortality was significantly higher for IBC compared with SBC cancers (hazard ratio [HR] 3.55; 95% CI, 2.01-6.28; P < .001), for a sojorn time of 2 years. Non-breast cancer mortality was similar between IBC and SBC (HR, 1.33; 95% CI, 0.43-4.15). Conclusions and Relevance: In this cohort study, interval cancers were highly prevalent in women participating in population screening, represented a worse biology, and had a hazard for breast cancer death more than 3-fold that for SBC. Strategies beyond current mammographic screening practices are needed to reduce incidence, improve detection, and reduce deaths from these potentially lethal breast cancers.

Association of Mindfulness-Based Interventions With Anxiety Severity in Adults With Cancer: A Systematic Review and Meta-analysis.

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.

Off-label infusion of biosimilar bevacizumab: A provincial experience.

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.

The Cardioprotective Role of Flaxseed in the Prevention of Doxorubicin- and Trastuzumab-Mediated Cardiotoxicity in C57BL/6 Mice.

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 < 0.05). However, the prophylactic administration of the FLX, ALA, or SDG diet was partially cardioprotective, with mice in these treatment groups showing an ∼68% increase in LVEF compared with the RC + DOX + TRZ-treated group at week 6 (P < 0.05). Although markers of inflammation (nuclear transcription factor κB), apoptosis [poly (ADP-ribose) polymerase-1 and the ratio of BCL2-associated X protein to B-cell lymphoma-extra large], and mitochondrial dysfunction (BCL2-interacting protein 3) were significantly elevated by approximately 2-fold following treatment with RC + DOX + TRZ compared with treatment with RC + saline at week 6, prophylactic administration of FLX, ALA, or SDG partially downregulated these signaling pathways. CONCLUSION: In a chronic in vivo female C57BL/6 mouse model of DOX + TRZ-mediated cardiotoxicity, FLX, ALA, and SDG were partially cardioprotective.

Fracture Risk in Women with Breast Cancer Initiating Aromatase Inhibitor Therapy: A Registry-Based Cohort Study.

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.

Strategizing health technology assessment for containment of cancer drug costs in a universal health care system: Case of the pan-Canadian Oncology Drug Review.

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.

Performance of FRAX in Women with Breast Cancer Initiating Aromatase Inhibitor Therapy: A Registry-Based Cohort Study.

FRAX was developed to predict 10-year probability of major osteoporotic fracture (MOF) and hip fracture in the general population. Aromatase inhibitors (AI) used in breast cancer induce loss in bone mineral density (BMD) and are reported to increase fracture risk. AI exposure is not a direct input to FRAX but is captured under "secondary osteoporosis". To inform use of FRAX in women treated with AI, we used a population-based registry for the Province of Manitoba, Canada, to identify women aged ≥40 years initiating AI for breast cancer with at least 12 months' AI exposure (n = 1775), women with breast cancer not receiving AI (n = 1016), and women from the general population (n = 34,205). Among AI users, fracture probability estimated without BMD (AI use coded as secondary osteoporosis) significantly overestimated risk (10-year observed/predicted ratio 0.56, 95% confidence interval [CI] 0.45-0.68; 10-year hip fracture observed/predicted ratio 0.33, 95% CI 0.18-0.49). However, when BMD was included in the fracture probability, there was no significant difference between observed and predicted fracture risk. In Cox proportional hazards models, FRAX stratified risk of MOF, hip, and any fracture equally well in all subgroups (p-interaction >0.1). When adjusted for FRAX score without BMD, with AI use coded as secondary osteoporosis, AI users were at significantly lower risk for MOF (hazard ratio [HR] = 0.78, 95% CI 0.64-0.95), hip fracture (HR = 0.46, 95% CI 0.29-0.73) and any fracture (HR = 0.75, 95% CI 0.63-0.89). AI use was no longer significantly associated with fractures when AI use was not entered as secondary osteoporosis in FRAX without BMD or when BMD was included in the FRAX calculation. In conclusion, FRAX scores stratify fracture risk equally well in women receiving AI therapy as in non-users, but including secondary osteoporosis as a risk factor for AI users overestimates fracture risk. Our results call this practice into question. © 2019 American Society for Bone and Mineral Research.

Why upfront use of CDK inhibitors for the treatment of advanced breast cancer may be wasteful, and how we can increase their value.

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.

Optimal duration of adjuvant trastuzumab in treatment of early breast cancer: a meta-analysis of randomized controlled trials.

BACKGROUND: One year of adjuvant trastuzumab, chosen empirically, improves survival of women with early-stage, Human Epidermal Growth Factor Receptor 2 (HER2) positive breast cancer. Two years of trastuzumab does not improve efficacy but increases cost, inconvenience, and adverse effects. We aimed to evaluate if less than 1 year of adjuvant trastuzumab retained efficacy while reducing toxicities and cost. METHODS: We performed a pooled analyses of efficacy and toxicity from Randomized Controlled Trials (RCTs) comparing 1 year of trastuzumab to shorter durations in adjuvant treatment of HER2-positive breast cancer. Hazard Ratios (HR) for Overall Survival (OS) and Disease-Free Survival (DFS), and Odds Ratios (OR) for cardiac events with respective 95% Confidence Intervals (CI) were weighted using generic inverse variance approach and pooled in meta-analyses using random effects models with RevMan 5.3 software. Sub-group analyses of outcomes based on Estrogen Receptor (ER) and nodal status were performed. RESULTS: Five RCTs involving approximately 12,000 patients qualified-three assessing 6 months and two assessing 9 weeks of trastuzumab compared to 1 year. All RCTs were designed to test non-inferiority of the shorter treatment. One year of trastuzumab resulted into better OS (pooled HR 1.23, 95% CI 1.07-1.42) and DFS (pooled HR 1.21, 95% CI 1.09-1.36) in overall population, but the benefit of longer treatment was statistically insignificant in node negative (HR 1. 20, p = 0.11), and ER positive disease (HR 1.15, p = 0.09). Odds ratio for cardiac events was significantly higher with the longer duration (OR 2.48, p < 0.001). CONCLUSION: One year of trastuzumab for adjuvant treatment of breast cancer improves outcomes compared to shorter treatments in overall population. Cardiotoxicity is increased with the longer treatment.

New Cancer Drug Approvals From the Perspective of a Universal Healthcare System: Analyses of the Pan-Canadian Oncology Drug Review Recommendations.

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<.01). Conclusions: A substantial number of cancer drugs that are FDA approved for public use do not meet Canadian standards for efficacy. Cost of cancer drugs increases by a third annually in Canada, but the benefits-measured mostly with surrogates that did not correlate with survival-are stable. With finite resources to share among multiple societal priorities, such as education and preventive health, cancer drug cost may be unsustainable despite price regulation.

Cancer treatment in the last 6 months of life: when inaction can outperform action.

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.

Duration of suppression of bone turnover following treatment with zoledronic acid in men with metastatic castration-resistant prostate cancer.

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.

Duration of adjuvant trastuzumab in HER2 positive breast cancer: Overall and disease free survival results from meta-analyses of randomized controlled trials.

BACKGROUND: 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. METHODS: 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 I2, and chi2 statistics, respectively. RESULTS: Four studies (n=7614) satisfied inclusion criteria. Individual RCTs had diverse pre-specified upper-limits of 95% CI for declaring non-inferiority (range: <1.15 to <1.53). 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 (p<0.001) favoring shorter duration. CONCLUSION: 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.

Relevance of randomised controlled trials in oncology.

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.

Mechanism of drug resistance in relation to site of metastasis: Meta-analyses of randomized controlled trials in advanced breast cancer according to anticancer strategy.

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 (6701pts.) 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.

The Cardioprotective Role of N-Acetyl Cysteine Amide in the Prevention of Doxorubicin and Trastuzumab-Mediated Cardiac Dysfunction.

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.

Screening mammography: sparing the emperor's blushes.

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.