Comparison of outcomes across low-intensity psychological interventions for depression and anxiety within a stepped-care setting: A naturalistic cohort study using propensity score modelling.

Low-intensity interventions for common mental disorders (CMD) address issues such as clinician shortages and barriers to accessing care. However, there is a lack of research into their comparative effectiveness in routine care. We aimed to compare treatment effects of three such interventions, utilizing four years' worth of routine clinical data. Users completing a course of guided self-help bibliotherapy (GSH), internet-delivered cognitive behavioural therapy (iCBT) or psychoeducational group therapy (PGT) from a stepped-care service within the NHS in England were included. Propensity score models (stratification and weighting) were used to control for allocation bias and determine average treatment effect (ATE) between the interventions. 21,215 users comprised the study sample (GSH = 12,896, iCBT = 6862, PGT = 1457). Adherence-to-treatment rates were higher in iCBT. All interventions showed significant improvements in depression (PHQ-9), anxiety (GAD-7) and functioning (WSAS) scores, with largest effect sizes for iCBT. Both propensity score models showed a significant ATE in favour of iCBT versus GSH and PGT, and in favour of GSH versus PGT. Discernible differences in effectiveness were seen for iCBT in comparison with GSH and PGT. Given variance in delivery mode and human resources between different low-intensity interventions, building on these findings would be valuable for future service provision and policy decision making.

The employment and mental health impact of integrated Improving Access to Psychological Therapies: Evidence on secondary health care utilization from a pragmatic trial in three English counties.

OBJECTIVE: Patients with a combination of long-term physical health problems can face barriers in obtaining appropriate treatment for co-existing mental health problems. This paper evaluates the impact of integrating the improving access to psychological therapies services (IAPT) model with services addressing physical health problems. We ask whether such services can reduce secondary health care utilization costs and improve the employment prospects of those so affected. METHODS: We used a stepped-wedge design of two cohorts of a total of 1,096 patients with depression and/or anxiety and comorbid long-term physical health conditions from three counties within the Thames Valley from March to August 2017. Panels were balanced. Difference-in-difference models were employed in an intention-to-treat analysis. RESULTS: The new Integrated-IAPT was associated with a decrease of 6.15 (95% CI: -6.84 to -5.45) [4.83 (95% CI: -5.47 to -4.19]) points in the Patient Health Questionnaire-9 [generalized anxiety disorder-7] and £360 (95% CI: -£559 to -£162) in terms of secondary health care utilization costs per person in the first three months of treatment. The Integrated-IAPT was also associated with an 8.44% (95% CI: 1.93% to 14.9%) increased probability that those who were unemployed transitioned to employment. CONCLUSIONS: Mental health treatment in care model with Integrated-IAPT seems to have significantly reduced secondary health care utilization costs among persons with long-term physical health conditions and increased their probability of employment.

Erratum: Author Correction: A pragmatic randomized waitlist-controlled effectiveness and cost-effectiveness trial of digital interventions for depression and anxiety.

[This corrects the article DOI: 10.1038/s41746-020-0293-8.].

A pragmatic randomized waitlist-controlled effectiveness and cost-effectiveness trial of digital interventions for depression and anxiety.

Utilization of internet-delivered cognitive behavioural therapy (iCBT) for treating depression and anxiety disorders in stepped-care models, such as the UK's Improving Access to Psychological Therapies (IAPT), is a potential solution for addressing the treatment gap in mental health. We investigated the effectiveness and cost-effectiveness of iCBT when fully integrated within IAPT stepped-care settings. We conducted an 8-week pragmatic randomized controlled trial with a 2:1 (iCBT intervention: waiting-list) allocation, for participants referred to an IAPT Step 2 service with depression and anxiety symptoms (Trial registration: ISRCTN91967124). The primary outcomes measures were PHQ-9 (depressive symptoms) and GAD-7 (anxiety symptoms) and WSAS (functional impairment) as a secondary outcome. The cost-effectiveness analysis was based on EQ-5D-5L (preference-based health status) to elicit the quality-adjust life year (QALY) and a modified-Client Service Receipt Inventory (care resource-use). Diagnostic interviews were administered at baseline and 3 months. Three-hundred and sixty-one participants were randomized (iCBT, 241; waiting-list, 120). Intention-to-treat analyses showed significant interaction effects for the PHQ-9 (b = -2.75, 95% CI -4.00, -1.50) and GAD-7 (b = -2.79, 95% CI -4.00, -1.58) in favour of iCBT at 8-week and further improvements observed up to 12-months. Over 8-weeks the probability of cost-effectiveness was 46.6% if decision makers are willing to pay £30,000 per QALY, increasing to 91.2% when the control-arm's outcomes and costs were extrapolated over 12-months. Results indicate that iCBT for depression and anxiety is effective and potentially cost-effective in the long-term within IAPT. Upscaling the use of iCBT as part of stepped care could help to enhance IAPT outcomes. The pragmatic trial design supports the ecological validity of the findings.

Effects of Radiotherapy in Early-Stage, Low-Recurrence Risk, Hormone-Sensitive Breast Cancer.

Background: Radiotherapy after breast conservation has become the standard of care. Prior meta-analyses on effects of radiotherapy predated availability of gene expression profiling (GEP) to assess recurrence risk and/or did not include all relevant outcomes. This analysis used GEP information with pooled individual-level data to evaluate the impact of omitting radiotherapy on recurrence and mortality. Methods: We considered trials that evaluated or administered radiotherapy after lumpectomy in women with low-risk breast cancer. Women included had undergone lumpectomy and were treated with hormonal therapy for stage I, ER+ and/or PR+, HER2- breast cancer with Oncotype scores no greater than 18. Recurrence-free interval (RFI), type of RFI (locoregional or distant), and breast cancer-specific and overall survival were compared between no radiotherapy and radiotherapy using adjusted Cox models. All statistical tests were two-sided. Results: The final sample included 1778 women from seven trials. Omission of radiotherapy was associated with an overall adjusted hazard ratio of 2.59 (95% confidence interval [CI] = 1.38 to 4.89, P = .003) for RFI. There was a statistically significant increase in any first locoregional recurrence (P = .001), but not distant recurrence events (P = .90), or breast cancer-specific (P = .85) or overall survival (P = .61). Five-year RFI rate was high (93.5% for no radiotherapy vs 97.9% for radiotherapy; absolute reduction = 4.4%, 95% CI = 0.7% to 8.1%, P = .03). The effects of radiotherapy varied across subgroups, with lower RFI rates for those with Oncotype scores of less than 11 (vs 11-18), older (vs younger), and ER+/PR+ status (vs other). Conclusions: Omission of radiotherapy in hormone-sensitive patients with low recurrence risk may lead to a modest increase in locoregional recurrence event rates, but does not appear to increase the rate of distant recurrence or death.

Simulation Modeling of Cancer Clinical Trials: Application to Omitting Radiotherapy in Low-risk Breast Cancer.

Background: We used two models to simulate a proposed noninferiority trial of radiotherapy (RT) omission in low-risk invasive breast cancer to illustrate how modeling could be used to predict the trial's outcomes, inform trial design, and contribute to practice debates. Methods: The proposed trial was a prospective randomized trial of no-RT vs RT in women age 40 to 74 years undergoing lumpectomy and endocrine therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative, stage I breast cancer with an Oncotype DX score of 18 or lower. The primary endpoint was recurrence-free interval (RFI), including locoregional recurrence, distant recurrence, and breast cancer death. Noninferiority required the two-sided 90% confidence interval of the RFI hazard ratio (HR) for no-RT vs RT to be entirely below 1.7. Model inputs included published data. The trial was simulated 1000 times, and results were summarized as percent concluding noninferiority and mean (standard deviation) of hazard ratios for Model GE and Model M, respectively. Results: Noninferiority was demonstrated in 18.0% and 3.7% for the two models. The respective means (SD) of the RFI hazard ratios were 1.8 (0.7) and 2.4 (0.9); most were locoregional recurrences. The mean five-year RFI rates for no-RT vs RT (SD) were 92.7% (2.9%) vs 95.5% (2.2%) and 88.4% (2.0%) vs 94.5% (1.6%). Both models showed little or no difference in breast cancer-specific or overall survival. Alternative definitions of low risk based on combinations of age and grade produced similar results. Conclusions: The proposed trial was unlikely to show noninferiority of omitting radiotherapy even using alternative definitions of low-risk, as the endpoint included local recurrence. Future trials regarding radiotherapy should address absolute reduction in recurrence and impact of type of recurrence on the patient.

Effects of Celecoxib and Low-dose Aspirin on Outcomes in Adjuvant Aromatase Inhibitor-Treated Patients: CCTG MA.27.

Background: Celecoxib and low-dose aspirin might decrease risk of breast cancer recurrence. Methods: In the Canadian Cancer Trials Group MA.27, postmenopausal hormone receptor-positive breast cancer patients were randomly assigned (2 × 2) to adjuvant exemestane or anastrozole, and celecoxib or placebo. Low-dose aspirin of 81 mg or less was a stratification factor. Due to concerns about cardiac toxicity, celecoxib use was stopped in December 2004, while stratification by aspirin use was removed through protocol amendment. We examined the effects of celecoxib and low-dose aspirin on event-free survival (EFS), defined as time from random assignment to time of locoregional or distant disease recurrence, new primary breast cancer, or death from any cause; distant disease-free survival (DDFS); and overall survival (OS). All statistical tests were two-sided. Results: Random assignment to celecoxib (n = 811, 50.0%) or placebo (n = 811, 50.0%) was discontinued after 18 months (n = 1622). At a median of 4.1 years' follow-up, among 1622 patients, 186 (11.5%) patients had an EFS event: 80 (4.9%) had distant relapse, and 125 (7.7%) died from any cause. Celecoxib did not statistically significantly impact EFS, DDFS, or OS in univariate analysis (respectively, P = .92, P = .55, and P = .56) or multivariable analysis (respectively, P = .74, P = .60, and P = .76). Low-dose aspirin use (aspirin users n = 476, 21.5%; non-aspirin users n = 1733, 78.5%) was associated in univariate analyses with worse EFS (hazard ratio [HR] = 1.48, 95% confidence interval [CI] = 1.12 to 1.96, P = 0.006) and worse OS (HR = 1.87, 95% CI = 1.35 to 2.61, P < .001). After adjusting for baseline characteristics and treatment arm, aspirin use showed no statistical association with EFS (P = .08) and DDFS (P = .82), but was associated with statistically worse OS (HR = 1.67, 95% CI = 1.13 to 2.49, P = .01). Conclusion: Random assignment to short-term (≤18 months) celecoxib as well as use of low-dose aspirin showed no effect on DDFS and EFS in multivariable analysis. Low-dose aspirin increased "all-cause" mortality, presumably because of higher preexisting cardiovascular risks.

Patient-reported predictors of early treatment discontinuation: treatment-related symptoms and health-related quality of life among postmenopausal women with primary breast cancer randomized to anastrozole or exemestane on NCIC Clinical Trials Group (CCTG) MA.27 (E1Z03).

PURPOSE: Aromatase inhibitors are the most commonly prescribed adjuvant endocrine therapy for hormone-dependent early breast cancer in postmenopausal women. Among Canadian Cancer Trials Group MA.27 participants, anastrozole and exemestane had comparable 5-year event-free survival. This companion study examined differences in patient-reported treatment-related symptoms (TRS) and health-related quality of life (HRQL) among postmenopausal women randomized to anastrozole or exemestane. METHODS: MA.27 participants (N = 686, of 7576) randomized to 5 years of anastrozole (1 mg/day, n = 371, Arm A) or exemestane (25 mg/day, n = 315, Arm E) completed the 56-item Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES) questionnaire to assess TRS and HRQL. The FACT-ES was completed at baseline, 3, 6, 12, and 24 months. RESULTS: No significant differences in FACT-ES median scores measuring TRS and HRQL were observed between treatment arms at any time point. Change in TRS from baseline was statistically significant at 3, 6, 12, and 24 months. HRQL was stable over time in both arms. Greater TRS burden was associated with poorer HRQL (coefficient = 0.57, p < 0.001). Twenty percent of patients discontinued AI therapy by month 24 and 32% discontinued AIs at 4 years. In both arms, patients reporting more side effect bother prior to initiating study treatment had a higher risk of discontinuing treatment before completing protocol therapy (hazard ratio [HR] 1.29, 95% CI 1.08-1.55, p = 0.01). CONCLUSIONS: TRS and HRQL were comparable between anastrozole and exemestane. TRS negatively affect HRQL. Women who report being bothered by treatment side effects prior to initiating an AI are at increased risk for early treatment discontinuation.

Impact of serum HER2, TIMP-1, and CAIX on outcome for HER2+ metastatic breast cancer patients: CCTG MA.31 (lapatinib vs. trastuzumab).

BACKGROUND: The lapatinib-taxane combination led to shorter PFS than trastuzumab-taxane in HER2+ metastatic breast cancer. We investigated the prognostic and predictive effects of pretreatment serum HER2, CAIX, and TIMP-1. METHODS: MA.31 accrued 652 patients; 537 (82%) were centrally confirmed HER2+. Biomarkers were categorized for univariate and multivariable predictive investigations with a median cut-point, ULN cut-points (15 ng/ml for HER2; 506 pg/ml for CAIX; 454 pg/ml for TIMP-1), and custom cut-points (30 and 100 ng/ml for HER2). Stratified step-wise forward Cox multivariable analysis examined continuous and categorical effects of biomarkers on PFS in the ITT and central HER2+ populations; central HER2+ biomarker results are shown. RESULTS: Serum was banked for 472 (72%) of 652 patients. Higher serum HER2 (>median; >15; >30; or >100 ng/ml; p = 0.05-0.002); higher CAIX (>median; >506 pg/ml; p = 0.02; p = 0.001); and higher TIMP-1 (> median; > 454 pg/ml; p = 0.001; p = 0.02) had shorter univariate PFS. In multivariable analysis, higher continuous TIMP-1 was associated with significantly shorter PFS: HR = 1.001 (95% CI = 1.00-01.002; p = 0.004). Continuous serum HER2 and CAIX were not significantly associated with PFS. HER2 of 15 ng/ml or higher had shorter PFS (p = 0.02); higher categorical CAIX had shorter PFS (p = 0.01-0.08). Interaction terms of HER2, CAIX, and TIMP-1 with treatment were not significant; the predictive test power was low. CONCLUSIONS: Higher levels of serum TIMP-1, CAIX, and HER2 were significant prognostic biomarkers of shorter PFS. We found no significant interaction between serum biomarkers and response to lapatinib versus trastuzumab. Evaluation of TIMP-1 and CAIX-targeted therapy in addition to HER2-targeted therapy appears warranted in patients with elevated serum levels of these biomarkers.

Osteoporosis therapy and outcomes for postmenopausal patients with hormone receptor-positive breast cancer: NCIC CTG MA.27.

BACKGROUND: Breast cancer patients in the MA.27 trial had similar outcomes with steroidal aromatase inhibitor (AI) exemestane and nonsteroidal anastrozole. AIs increase the risk of osteoporosis. This study examined the effects of self-reported osteoporosis and osteoporosis therapy (OPT) on outcomes. METHODS: The MA.27 phase 3 adjuvant trial enrolled 7576 postmenopausal women. The primary outcome was event-free survival (EFS), and the secondary outcome was distant disease-free survival (DDFS). Patients were permitted bisphosphonates to prevent or treat osteopenia/osteoporosis. In a multivariate, stratified Cox regression, factors were significant with a 2-sided Wald test P value ≤ .05. RESULTS: Osteoporosis was reported at the baseline by 654 of the 7576 women (8.6%) and in total by 1294 patients. Oral OPT was received at the baseline by 815 of the 7576 women (10.8%) and in total by 2711 patients (36%). With a median follow-up of 4.1 years, 693 EFS events (9.15%) and 321 DDFS events (4.2%) occurred. Osteoporosis was not associated with EFS or DDFS. Few EFS events occurred before the initiation of OPT, with no substantive evidence of a time-differing effect on outcomes (nonproportional hazards). OPT (yes vs no) was significantly associated with improved EFS (hazard ratio [HR] for yes vs no, 0.67; 95% confidence interval [CI], 0.57-0.80; P < .001) and DDFS (HR, 0.57; 95% CI, 0.44-0.73; P <. 001). Time-differing (time-dependent) OPT was not (EFS; P = .45). OPT did not alter the incidence of visceral-only metastasis (P = .31). CONCLUSIONS: Oral OPT, administered to postmenopausal breast cancer patients receiving adjuvant AI therapy, was associated with improved EFS and DDFS; the time of OPT initiation (a time-dependent effect) did not affect the outcome. OPT did not alter the risk of visceral metastasis. Cancer 2017;123:2444-51. © 2017 American Cancer Society.

Competing Risks of Mortality by PAM50 Intrinsic Subtype of British Columbia Tamoxifen-Treated Cohort of Postmenopausal Patients With Breast Cancer.

BACKGROUND: PAM50 intrinsic subtypes have been shown to affect breast cancer prognosis. METHODS: A British Columbia cohort of 718 postmenopausal women treated with tamoxifen, without chemotherapy, had tumors intrinsically subtyped (luminal A, luminal B, basal, HER2) and centrally reviewed by immunohistochemistry (IHC) for estrogen and progesterone receptor (ER and PgR). We tested whether intrinsic subtype and other patient and tumor characteristics were associated with type of death. RESULTS: At median 11.7 years of follow-up, 429 (60%) of 718 women died: 30% of deaths were breast cancer-specific; 30% were other type. In 425 women <70 years, 32% died of breast cancer and 19% of other type. In 293 women ≥ 70, 27% died of breast cancer and 45% of other type. Intrinsic subtype was associated with breast cancer (P = .001); and older age, with other type (P < .001). Additionally, stepwise cause-specific models indicated larger tumor size (P < .001), more positive lymph nodes (P < .001), and less PgR stain (P = .03) were associated with worse breast cancer survival; more positive lymph nodes (P = .002) and lymphovascular invasion (P = .02) were associated with worse other type. Adjusted breast cancer and other type survival is provided by factors at 5, 10, and 15 years. CONCLUSIONS: Intrinsic subtype was associated with breast cancer death, whereas age was associated with other type; most deaths in women ≥ 70 were from other type.

Genetic Polymorphisms in the Long Noncoding RNA MIR2052HG Offer a Pharmacogenomic Basis for the Response of Breast Cancer Patients to Aromatase Inhibitor Therapy.

Genetic risks in breast cancer remain only partly understood. Here, we report the results of a genome-wide association study of germline DNA from 4,658 women, including 252 women experiencing a breast cancer recurrence, who were entered on the MA.27 adjuvant trial comparing the aromatase inhibitors (AI) anastrozole and exemestane. Single-nucleotide polymorphisms (SNP) of top significance were identified in the gene encoding MIR2052HG, a long noncoding RNA of unknown function. Heterozygous or homozygous individuals for variant alleles exhibited a ∼40% or ∼63% decrease, respectively, in the hazard of breast cancer recurrence relative to homozygous wild-type individuals. Functional genomic studies in lymphoblastoid cell lines and ERα-positive breast cancer cell lines showed that expression from MIR2052HG and the ESR1 gene encoding estrogen receptor-α (ERα) was induced by estrogen and AI in a SNP-dependent manner. Variant SNP genotypes exhibited increased ERα binding to estrogen response elements, relative to wild-type genotypes, a pattern that was reversed by AI treatment. Further, variant SNPs were associated with lower expression of MIR2052HG and ERα. RNAi-mediated silencing of MIR2052HG in breast cancer cell lines decreased ERα expression, cell proliferation, and anchorage-independent colony formation. Mechanistic investigations revealed that MIR2052HG sustained ERα levels both by promoting AKT/FOXO3-mediated ESR1 transcription and by limiting ubiquitin-mediated, proteasome-dependent degradation of ERα. Taken together, our results define MIR2052HS as a functionally polymorphic gene that affects risks of breast cancer recurrence in women treated with AI. More broadly, our results offer a pharmacogenomic basis to understand differences in the response of breast cancer patients to AI therapy. Cancer Res; 76(23); 7012-23. ©2016 AACR.

Relapse-free survival of statistically standardized continuous RT-PCR estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2): NCIC CTG MA.14.

Recent ASCO/CAP guidelines focus on decision making associated with the presence/absence of continuous breast biomarkers. Statistical standardization (SS) is demonstrated as a method to evaluate the effects of continuous RT-PCR biomarker expression levels on breast cancer outcomes. MA.14 allocated 667 postmenopausal patients to tamoxifen based on locally determined ER/PR. Of 299 available patient tumor samples, 292 passed internal quality control. All tumors were centrally assessed by RT-PCR ER/PR/HER2 with each biomarker's z-scores categorized: ≥1.0 standard deviation (SD) below mean; <1.0 SD below mean; ≤1.0 SD above mean; >1.0 SD above mean. Log-rank statistics tested univariate differences in breast cancer relapse-free survival (RFS). Continuous SS-ER/PR/HER2 were assessed in multivariate Cox step-wise forward regression, adding a factor if p ≤ 0.05. Sensitivity analyses examined an external HER2+ cut-point of 1.32. Patients whose tumors were tested were representative of the MA.14 population (p values = 0.18-0.90). At 9.8 years median follow-up, SS-ER did not univariately impact RFS (p = 0.31). SS-PR values above the mean (z ≥ 0.0) had the best univariate RFS (p = 0.03). SS-HER2 also univariately impacted RFS (p = 0.004) with lowest (z-scores ≤ -1.0) and highest (z-scores > 1.0) having shortest RFS. Multivariate stratified/unstratified Cox models indicated patients with T1 tumors (p = 0.02/p = 0.0002) and higher SS-PR (p = 0.02/p = 0.01) had longer RFS; node-negative patients had better RFS (in unstratified analysis, p < 0.0001). Local ER/PR status did not impact RFS (p > 0.05). Patients with SS HER2+ ≥ 1.32 had worse RFS (univariate, p = 0.05; multivariate, p = 0.06). We demonstrated that higher SS-PR, and SS HER2 levels, measured by RT-PCR impacted breast cancer RFS outcomes. Evaluation in other trials may provide support for this methodology.

Competing risks of death in women treated with adjuvant aromatase inhibitors for early breast cancer on NCIC CTG MA.27.

Baseline patient and tumor characteristics differentially affected type of death in the MA.17 placebo-controlled letrozole trial where cardiovascular death was not separately identified. The MA.27 trial allowed competing risks analysis of breast cancer (BC), cardiovascular, and other type (OT) of death. MA.27 was a phase III adjuvant breast cancer trial of exemestane versus anastrozole. Effects of baseline patient and tumor characteristics were tested for whether factors were associated with (1) all cause mortality and (2) cause-specific mortality. We also fit step-wise forward cause-specific-adjusted models. 7576 women (median age 64 years; 5417 (72 %) < 70 years and 2159 (28 %) ≥ 70 years) were enrolled and followed for median 4.1 years. The 432 deaths comprised 187 (43 %) BC, 66 (15 %) cardiovascular, and 179 (41 %) OT. Five baseline factors were differentially associated with type of death. Older patients had greater BC (p = 0.03), cardiovascular (p < 0.001), and other types (p < 0.001) of mortality. Patients with pre-existing cardiovascular history had worse cardiovascular mortality (p < 0.001); those with worse ECOG performance status had worse OT mortality (p < 0.001). Patients with T1 tumors (p < 0.001) and progesterone receptor positive had less BC mortality (p < 0.001). Fewer BC deaths occurred with node-negative disease (p < 0.001), estrogen receptor-positive tumors (p = 0.001), and without adjuvant chemotherapy (p = 0.005); worse cardiovascular mortality (p = 0.01), with trastuzumab; worse OT mortality, for non-whites (p = 0.03) and without adjuvant radiotherapy (p = 0.003). Overall, 57 % of deaths in MA.27 AI-treated patients were non-breast cancer related. Baseline patient and tumor characteristics differentially affected type of death with women 70 or older experiencing more non-breast cancer death.

A phase I/II trial of epirubicin and docetaxel in locally advanced breast cancer (LABC) on 2-weekly or 3-weekly schedules: NCIC CTG MA.22.

This phase I/II neoadjuvant trial (ClinicalTrials.gov identifier NCT00066443) determined maximally-tolerated doses (MTD), dose-limiting toxicities, response-to-therapy, and explored the role of novel response biomarkers. MA.22 accrued T3N0, any N2 or N3, and T4 breast cancer patients. Treatment was 6 cycles of 3-weekly (Schedule A; N = 47) or 8 cycles of 2-weekly (Schedule B; N = 46) epirubicin/docetaxel chemotherapy in sequential phase I/II studies, with growth factor support. In phase I of each schedule, MTDs were based on DLT. In phase II, clinical responses (CR/PR) and pathologic complete responses (pCR) were assessed. Tumor biopsy cores were obtained pre-, mid-, and post-treatment: 3 for pathologic assessment; 3 for microarray studies. DLT for Schedule A was febrile neutropenia at 105 mg/m(2) epirubicin and 75 mg/m(2) docetaxel; for schedule B, it was fatigue at 75 mg/m(2) for both agents. Phase II doses were 90 mg/m(2) epirubicin/75 mg/m(2) docetaxel for Schedule A and 60 mg/m(2) (both agents) for Schedule B. Schedule A CR/PR and pCR rates were 90 and 10 %, with large reductions in tumor RNA content and integrity following treatment; Schedule B results were 93 and 0 %, with smaller reductions in RNA quality. Pre-treatment expression of several genes was associated with clinical response, including those within a likely amplicon at 17q12 (ERBB2, TCAP, GSDMB, and PNMT). The combination regimens had acceptable toxicity, good clinical response, induction of changes in tumor RNA content and integrity. Pre-treatment expression of particular genes was associated with clinical responses, including several near 17q12, which with ERBB2, may better identify chemoresponsiveness.

Octreotide LAR and tamoxifen versus tamoxifen in phase III randomize early breast cancer trials: NCIC CTG MA.14 and NSABP B-29.

NCIC CTG MA.14 and NSABP B-29 trials examined the addition of Octreotide LAR (OCT) to 5 years of tamoxifen (TAM). Gallbladder toxicity led to B-29 discontinuation of OCT, and MA.14 OCT administration shortened to 2 years. Median follow-up was 9.8 years for 667 MA.14 patients and 6.8 years for 893 B-29 patients. The primary endpoint was disease-free survival (DFS), defined as time from randomization to time of breast cancer recurrence; second primary cancer other than squamous or basal cell skin carcinoma, cervical carcinoma in situ, or lobular breast carcinoma in situ; or death. The primary statistical test was a univariable pooled stratified log-rank test; multivariable assessment was with Cox regression. For MA.14, 97% of patients were ≥50 years; for B-29, 62%. MA.14 patients were 53% lymph node negative (LN-) while B-29 were 100% LN-; 33% of MA.14 patients received adjuvant chemotherapy, 2% concurrently, while B-29 had 53% concurrent chemotherapy. MA.14 patients were 90% hormone receptor positive; B-29, 100%. MA.14 patients experienced 5-year DFS of 80% with TAM, 76% with TAM + OCT; B-29 patients had 5-year DFS of 88% for both arms. Pooled univariable TAM + OCT to TAM hazard ratio (HR) was 0.99 (95% CI 0.81-1.20; p = 0.69): for MA.14, HR = 0.94 (0.73-1.20; p = 0.50); for B-29, HR = 1.09 (0.80-1.50; p = 0.59). Multivariable pooled HR = 0.98 (0.81-1.20; p = 0.84). Older patients (p < 0.001), with higher T stage (p < 0.001), and LN + (p < 0.001) had shorter DFS. Addition of OCT to TAM did not significantly improve DFS; gallbladder toxicity shortened the additional administration of OCT. This does not negate targeting the insulin-IGF-I receptor family with less toxic therapeutics.

Lapatinib or Trastuzumab Plus Taxane Therapy for Human Epidermal Growth Factor Receptor 2-Positive Advanced Breast Cancer: Final Results of NCIC CTG MA.31.

PURPOSE: The efficacy of lapatinib versus trastuzumab combined with taxanes in the first-line setting of human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (BC) is unknown. PATIENTS AND METHODS: The MA.31 trial compared a combination of first-line anti-HER2 therapy (lapatinib or trastuzumab) and taxane therapy for 24 weeks, followed by the same anti-HER2 monotherapy until progression. Stratification was by prior (neo)adjuvant anti-HER2 therapy, prior (neo)adjuvant taxane, planned taxane, and liver metastases. The primary end point was intention-to-treat (ITT) progression-free survival (PFS), defined as time from random assignment to progression by RECIST (version 1.0) criteria, or death for patients with locally assessed HER2-positive tumors. The primary test statistic was a stratified log-rank test for noninferiority. PFS was also assessed for patients with centrally confirmed HER2-positive tumors. RESULTS: From July 17, 2008, to December 1, 2011, 652 patients were accrued from 21 countries, resulting in 537 patients with centrally confirmed HER2-positive tumors. Median follow-up was 21.5 months. Median ITT PFS was 9.0 months with lapatinib and 11.3 months with trastuzumab. By ITT analysis, PFS was inferior for lapatinib compared with trastuzumab, with a stratified hazard ratio (HR) of 1.37 (95% CI, 1.13 to 1.65; P = .001). In patients with centrally confirmed HER2-positive tumors, median PFS was 9.1 months with lapatinib and 13.6 months with trastuzumab (HR, 1.48; 95% CI, 1.20 to 1.83; P < .001). More grade 3 or 4 diarrhea and rash were observed with lapatinib (P < .001). PFS results were supported by the secondary end point of overall survival, with an ITT HR of 1.28 (95% CI, 0.95 to 1.72; P = .11); in patients with centrally confirmed HER2-positive tumors, the HR was 1.47 (95% CI, 1.03 to 2.09; P = .03). CONCLUSION: As first-line therapy for HER2-positive metastatic BC, lapatinib combined with taxane was associated with shorter PFS and more toxicity compared with trastuzumab combined with taxane.

IAPT and Long Term Medical Conditions: What Can We Offer?

BACKGROUND: The proposal of a 4-year plan to integrate treatment of people with long term medical conditions (LTCs) into the IAPT service (Department of Health, 2011) seeks for research to understand the effectiveness of IAPT interventions for this patient group. AIM: The aim of this service development pilot work was to develop an intervention that is effective for people with Type 2 Diabetes Mellitus (T2DM). It was hypothesized that the standard IAPT intervention would not be effective, but that it can be adapted so that it is effective both in terms of mood and self-management of T2DM. METHOD: Clients (n = 95) who experienced mild to moderate depression and/or anxiety and had a diagnosis of T2DM opted to attend. The intervention was adapted over a series of cohorts from a standard Step 2 intervention. A team of Psychological Wellbeing Practitioners (PWPs), a Clinical Health Psychologist and a General Practitioner worked in collaboration, using outcomes measures and feedback from service users and facilitators. RESULTS: The standard IAPT Step 2 intervention met with challenges when specifically targeting this client group. Using paired t-tests, the modified Step 2 intervention demonstrated significant improvements from pre- to postintervention measures both in terms of psychological (n = 17) and physical (n = 9) outcomes. CONCLUSION: It is concluded that it may be possible to modify a generic Step 2 IAPT intervention to demonstrate improvements both in terms of psychological wellbeing and self-management of T2DM. The main adaptations were related to more targeted recruitment and linking of diabetes specifically into the CBT model.

Treatment-associated musculoskeletal and vasomotor symptoms and relapse-free survival in the NCIC CTG MA.27 adjuvant breast cancer aromatase inhibitor trial.

PURPOSE: Treatment-emergent symptoms with adjuvant tamoxifen and aromatase inhibitors (AIs) have been associated with superior recurrence-free survival (RFS). We hypothesized that MA.27 anastrozole- or exemestane-treated patients with new or worsening vasomotor and/or joint symptoms would have improved RFS. PATIENTS AND METHODS: MA.27 randomly assigned 7,576 postmenopausal women with breast cancer to 5 years of anastrozole or exemestane. Patient-reported symptoms were collected using the Common Terminology Criteria for Adverse Events version 3.0 at protocol-specified baseline and 6- and 12-month clinical visits. Symptoms were considered present with either vasomotor and/or joint complaints. Associations between symptoms and baseline patient characteristics were examined with χ(2) and Fisher's exact tests. Subsequent effects of new or worsening symptoms on RFS were examined with landmark analyses and stratified univariable and multivariable Cox models. We examined the effects of 3-month symptoms arising from unplanned clinic visits as a result of severe toxicity. RESULTS: Patients were assessable if eligible for the MA.27 trial, received some trial therapy, and had no disease recurrence at the end of a symptom assessment period; 96% of patients (n = 7,306 patients) were included at 6 months, and 96% (n = 7,246) were included at 12 months. Thirty-four percent of patients had baseline symptoms. For patients without baseline symptoms, 25% and 52% had new symptoms by 6 and 12 months, respectively. Neither treatment-emergent nor baseline symptoms significantly impacted RFS (P > .10) in patients with or without baseline symptoms. CONCLUSION: In MA.27, anastrozole or exemestane treatment-emergent symptoms were not associated with improved RFS. Women should be supported through treatment and encouraged to remain on their AI regardless of their symptoms.

Effects of adjuvant exemestane versus anastrozole on bone mineral density for women with early breast cancer (MA.27B): a companion analysis of a randomised controlled trial.

BACKGROUND: Treatment of breast cancer with aromatase inhibitors is associated with damage to bones. NCIC CTG MA.27 was an open-label, phase 3, randomised controlled trial in which women with breast cancer were assigned to one of two adjuvant oral aromatase inhibitors-exemestane or anastrozole. We postulated that exemestane-a mildly androgenic steroid-might have a less detrimental effect on bone than non-steroidal anastrozole. In this companion study to MA.27, we compared changes in bone mineral density (BMD) in the lumbar spine and total hip between patients treated with exemestane and patients treated with anastrozole. METHODS: In MA.27, postmenopausal women with early stage hormone (oestrogen) receptor-positive invasive breast cancer were randomly assigned to exemestane 25 mg versus anastrozole 1 mg, daily. MA.27B recruited two groups of women from MA.27: those with BMD T-scores of -2·0 or more (up to 2 SDs below sex-matched, young adult mean) and those with at least one T-score (hip or spine) less than -2·0. Both groups received vitamin D and calcium; those with baseline T-scores of less than -2·0 also received bisphosphonates. The primary endpoints were percent change of BMD at 2 years in lumbar spine and total hip for both groups. We analysed patients according to which aromatase inhibitor and T-score groups they were allocated to but BMD assessments ceased if patients deviated from protocol. This study is registered with ClinicalTrials.gov, NCT00354302. FINDINGS: Between April 24, 2006, and May 30, 2008, 300 patients with baseline T-scores of -2·0 or more were accrued (147 allocated exemestane, 153 anastrozole); and 197 patients with baseline T-scores of less than -2·0 (101 exemestane, 96 anastrozole). For patients with T-scores greater than -2·0 at baseline, mean change of bone mineral density in the spine at 2 years did not differ significantly between patients taking exemestane and patients taking anastrozole (-0·92%, 95% CI -2·35 to 0·50 vs -2·39%, 95% CI -3·77 to -1·01; p=0·08). Respective mean loss in the hip was -1·93% (95% CI -2·93 to -0·93) versus -2·71% (95% CI -4·32 to -1·11; p=0·10). Likewise for those who started with T-scores of less than -2·0, mean change of spine bone mineral density at 2 years did not differ significantly between the exemestane and anastrozole treatment groups (2·11%, 95% CI -0·84 to 5·06 vs 3·72%, 95% CI 1·54 to 5·89; p=0·26), nor did hip bone mineral density (2·09%, 95% CI -1·45 to 5·63 vs 0·0%, 95% CI -3·67 to 3·66; p=0·28). Patients with baseline T-score of -2·0 or more taking exemestane had two fragility fractures and two other fractures, those taking anastrozole had three fragility fractures and five other fractures. For patients who had baseline T-scores of less than -2·0 taking exemestane, one had a fragility fracture and four had other fractures, whereas those taking anastrozole had five fragility fractures and one other fracture. INTERPRETATION: Our results demonstrate that adjuvant treatment with aromatase inhibitors can be considered for breast cancer patients who have T-scores less than -2·0. FUNDING: Canadian Cancer Society Research Institute, Pfizer, Canadian Institutes of Health Research.