NFκB-Mediated Mechanisms Drive PEDF Expression and Function in Pre- and Post-Menopausal Oestrogen Levels in Breast Cancer.

Pigment epithelium-derived factor (PEDF) protein regulates normal bone, with anti-tumour roles in bone and breast cancer (BC). Pre- and post-menopausal oestrogen levels may regulate PEDF expression and function in BC, though the mechanisms behind this remain unknown. In this study, in vitro models simulating pre- and post-menopausal bone microenvironments were used to evaluate if PEDF regulates pro-metastatic biomarker expression and downstream functional effects on BC cells. PEDF treatment reduced phosphorylated-nuclear factor-κB p65 subunit (p-NFκB-p65), tumour necrosis factor-α (TNFα), C-X-C chemokine receptor type-4 (CXCR4), and urokinase plasminogen activator receptor (uPAR) in oestrogen receptor (ER)+/human epidermal growth factor receptor-2 (HER2)- BC cells under post-menopausal oestrogen conditions. In triple negative BC (TNBC) cells, PEDF treatment reduced pNFκB-p65 and uPAR expression under pre-menopausal oestrogen conditions. A potential reciprocal regulatory axis between p-NFκB-65 and PEDF in BC was identified, which was BC subtype-specific and differentially regulated by menopausal oestrogen conditions. The effects of PEDF treatment and NFκB inhibition on BC cell function under menopausal conditions were also compared. PEDF treatment exhibited superior anti-viability effects, while combined PEDF and NFκB-p65 inhibitor treatment was superior in reducing BC cell colony formation in a subtype-specific manner. Lastly, immunohistochemical evaluation of p-NFκB-p65 and PEDF expression in human BC and bone metastases specimens revealed an inverse correlation between nuclear PEDF and NFκB expression in bone metastases. We propose that menopausal status is associated with a PEDF/NFκB reciprocal regulatory axis, which drives PEDF expression and anti-metastatic function in a subtype-specific manner. Altogether, our findings identify pre-menopausal TNBC and post-menopausal ER+/HER2- BC patients as target populations for future PEDF research.

Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study.

BACKGROUND: Palbociclib added to endocrine therapy improves progression-free survival in hormone-receptor-positive, HER2-negative, metastatic breast cancer. The PALLAS trial aimed to investigate whether the addition of 2 years of palbociclib to adjuvant endocrine therapy improves invasive disease-free survival over endocrine therapy alone in patients with hormone-receptor-positive, HER2-negative, early-stage breast cancer. METHODS: PALLAS is an ongoing multicentre, open-label, randomised, phase 3 study that enrolled patients at 406 cancer centres in 21 countries worldwide with stage II-III histologically confirmed hormone-receptor-positive, HER2-negative breast cancer, within 12 months of initial diagnosis. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients were randomly assigned (1:1) in permuted blocks of random size (4 or 6), stratified by anatomic stage, previous chemotherapy, age, and geographical region, by use of central telephone-based and web-based interactive response technology, to receive either 2 years of palbociclib (125 mg orally once daily on days 1-21 of a 28-day cycle) with ongoing standard provider or patient-choice adjuvant endocrine therapy (tamoxifen or aromatase inhibitor, with or without concurrent luteinising hormone-releasing hormone agonist), or endocrine therapy alone, without masking. The primary endpoint of the study was invasive disease-free survival in the intention-to-treat population. Safety was assessed in all randomly assigned patients who started palbociclib or endocrine therapy. This report presents results from the second pre-planned interim analysis triggered on Jan 9, 2020, when 67% of the total number of expected invasive disease-free survival events had been observed. The trial is registered with ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30). FINDINGS: Between Sept 1, 2015, and Nov 30, 2018, 5760 patients were randomly assigned to receive palbociclib plus endocrine therapy (n=2883) or endocrine therapy alone (n=2877). At the time of the planned second interim analysis, at a median follow-up of 23·7 months (IQR 16·9-29·2), 170 of 2883 patients assigned to palbociclib plus endocrine therapy and 181 of 2877 assigned to endocrine therapy alone had invasive disease-free survival events. 3-year invasive disease-free survival was 88·2% (95% CI 85·2-90·6) for palbociclib plus endocrine therapy and 88·5% (85·8-90·7) for endocrine therapy alone (hazard ratio 0·93 [95% CI 0·76-1·15]; log-rank p=0·51). As the test statistic comparing invasive disease-free survival between groups crossed the prespecified futility boundary, the independent data monitoring committee recommended discontinuation of palbociclib in patients still receiving palbociclib and endocrine therapy. The most common grade 3-4 adverse events were neutropenia (1742 [61·3%] of 2840 patients on palbociclib and endocrine therapy vs 11 [0·3%] of 2903 on endocrine therapy alone), leucopenia (857 [30·2%] vs three [0·1%]), and fatigue (60 [2·1%] vs ten [0·3%]). Serious adverse events occurred in 351 (12·4%) of 2840 patients on palbociclib plus endocrine therapy versus 220 (7·6%) of 2903 patients on endocrine therapy alone. There were no treatment-related deaths. INTERPRETATION: At the planned second interim analysis, addition of 2 years of adjuvant palbociclib to adjuvant endocrine therapy did not improve invasive disease-free survival compared with adjuvant endocrine therapy alone. On the basis of these findings, this regimen cannot be recommended in the adjuvant setting. Long-term follow-up of the PALLAS population and correlative studies are ongoing. FUNDING: Pfizer.

Safety and impact of dose reductions on efficacy in the randomised MONALEESA-2, -3 and -7 trials in hormone receptor-positive, HER2-negative advanced breast cancer.

BACKGROUND: This pooled analysis of MONALEESA trials evaluated the safety of ribociclib plus endocrine therapy (RIB + ET) with a focus on dose reductions in first-line patients. METHODS: In the dose reduction analysis, data were pooled from MONALEESA-2 (all patients), MONALEESA-3 (patients receiving treatment as first-line ET) and MONALEESA-7 (patients receiving combination therapy with an NSAI as initial ET). Efficacy was analysed by ribociclib relative dose intensity (DI). Safety was analysed in all patients in the trials (except those receiving tamoxifen in MONALEESA-7) and those with/without ≥1 ribociclib dose reduction. RESULTS: Of 818 women who received first-line RIB + ET, 41.8% required ≥1 dose reduction due to AEs (most commonly, neutropenia). Median RIB relative DI in patients without and with dose reductions was 99.3% and 65.6% in MONALEESA-2, 98.4% and 67.8% in MONALEESA-3 and 98·0% and 66·3% in MONALEESA-7. Median PFS was 24.8, 24.9 and 29.6 months for patients who received ≤71% (30th percentile), 72-96% (60th percentile) and 97-100% (90th percentile) RIB relative DI, respectively. No new safety signals emerged in the pooled safety analysis. CONCLUSIONS: This analysis provides reassuring data showing that the clinical benefit of RIB is preserved when dose modifications are undertaken to manage AEs. TRIAL REGISTRATION: MONALEESA-2 (NCT01958021) first posted October 8, 2013; MONALEESA-3 (NCT02422615) first posted April 21, 2015; MONALEESA-7 (NCT02278120) first posted October 29, 2014.

Pigment epithelium-derived factor regulation of neuronal and stem cell fate.

Pigment epithelium-derived factor (PEDF) is an endogenous human glycoprotein first identified as a neurotrophic factor in retinal pigmented epithelium cells. PEDF has since been shown to play a central role in mediating cellular protection against oxidative stress, by promoting cell survival, reducing inflammation, and inhibiting pathological angiogenesis in a range of cell types and tissues. PEDF is a well-established neurotrophic factor which supports neurogenesis and provides neuroprotection in response to cellular stress, with numerous studies demonstrating the ability of PEDF to promote neuronal survival and growth following injury. PEDF is an essential component of the stem cell microenvironment and bone extracellular matrix, where it regulates the differentiation of osteoblast precursor cells to promote normal bone development. Accumulating evidence indicates that PEDF maintains stem cell populations and promotes neuronal growth and bone formation by directing cell fate and regulating cell cycle progression. The ability of PEDF to promote neurogenesis, osteogenesis, and stemness indicates therapeutic potential in diseases characterised by tissue degeneration. In this review, we provide a current summary of the role of PEDF in regulating cellular survival and differentiation in bone, the central nervous system, and other stem cell niches, and highlight the emerging potential of PEDF as a regenerative therapeutic agent.

Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with hormone receptor-positive, HER2-positive advanced breast cancer (monarcHER): a randomised, open-label, phase 2 trial.

BACKGROUND: Patients with HER2-positive breast cancer who have received two or more previous therapies for advanced disease have few effective treatment options. The monarcHER trial aimed to compare the efficacy of abemaciclib plus trastuzumab with or without fulvestrant with standard-of-care chemotherapy of physician's choice plus trastuzumab in women with advanced breast cancer. METHODS: This phase 2, three-group, open-label trial was done across 75 hospitals, clinics, and medical centres in 14 countries. Eligible patients were women aged 18 years or older, who had hormone receptor-positive, HER2-positive advanced breast cancer with unresectable, locally advanced, recurrent or metastatic disease, Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received at least two HER2-targeted therapies for advanced disease. Patients were randomly assigned 1:1:1 to the abemaciclib, trastuzumab, and fulvestrant (group A), abemaciclib and trastuzumab (group B), or standard-of-care chemotherapy and trastuzumab (group C). Oral abemaciclib 150 mg 12 hourly was administered on days 1-21 of a 21-day cycle, intravenous trastuzumab 8 mg/kg on cycle 1 day 1, followed by 6 mg/kg on day 1 of each subsequent 21-day cycle, and intramuscular fulvestrant 500 mg on days 1, 15, and 29 and once every 4 weeks thereafter. Standard-of-care chemotherapy was administered as specified by the product label. Randomisation was by a computer-generated random sequence by means of an interactive web-response system and stratified by number of previous systemic therapies for advanced breast cancer and measurable versus non-measurable disease. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, first testing group A versus group C and, if this result was significant, then group B versus group C. Safety was assessed in all patients who had received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov (NCT02675231) and is ongoing for long-term survival follow-up. FINDINGS: Between May 31, 2016, and Feb 28, 2018, 325 patients were screened, of whom 237 eligible patients were enrolled and randomly assigned to groups A (n=79), B (n=79), and C (n=79). Median follow-up was 19·0 months (IQR 14·7-25·1). The study met its primary endpoint, showing a significant difference at the prespecified two-sided α of 0·2 in median progression-free survival between group A (8·3 months, 95% CI 5·9-12·6) and group C (5·7 months, 5·4-7·0; HR 0·67 [95% CI 0·45-1·00]; p=0·051). No difference was observed between median progression-free survival in group B (5·7 months, 95% CI 4·2-7·2) and group C (HR 0·94 [0·64-1·38]; p=0·77). The most common grade 3-4 treatment-emergent adverse event in groups A, B, and C was neutropenia (21 [27%] of 78 patients, 17 [22%] of 77, and 19 [26%] of 72). The most common serious adverse events were: in group A, pyrexia (three [4%]), diarrhoea (two [3%]), urinary tract infection (two [3%]), and acute kidney injury (two [3%]); in group B, diarrhoea (two [3%]) and pneumonitis (two [3%]); and in group C, neutropenia (four [6%]) and pleural effusion (two [3%]). Two deaths were attributed to treatment: one due to pulmonary fibrosis in group B and one due to febrile neutropenia in group C. INTERPRETATION: The combination of abemaciclib, fulvestrant, and trastuzumab significantly improved progression-free survival versus standard-of-care chemotherapy plus trastuzumab while showing a tolerable safety profile. Our results suggest that a chemotherapy-free regimen might potentially be an alternative treatment option for patients with hormone receptor-positive, HER2-positive advanced breast cancer. FUNDING: Eli Lilly and Company.

Adjuvant denosumab in early breast cancer (D-CARE): an international, multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: Denosumab is a fully human monoclonal antibody that binds to, and inhibits, the receptor activator of RANKL (TNFSF11) and might affect breast cancer biology, as shown by preclinical evidence. We aimed to assess whether denosumab combined with standard-of-care adjuvant or neoadjuvant systemic therapy and locoregional treatments would increase bone metastasis-free survival in women with breast cancer. METHOD: In this international, double-blind, randomised, placebo-controlled, phase 3 study (D-CARE), patients were recruited from 389 centres in 39 countries. We enrolled women (aged ≥ 18 years) with histologically confirmed stage II or III breast cancer and an Eastern Cooperative Oncology Group performance status of 0 or 1. On eligibility confirmation, investigators at each site telephoned an interactive voice response system to centrally randomly assign patients (1:1) based on a fixed stratified permuted block randomisation list (block size 4) to receive either denosumab (120 mg) or matching placebo subcutaneously every 3-4 weeks, starting with neoadjuvant or adjuvant chemotherapy, for about 6 months and then every 12 weeks for a total duration of 5 years. Stratification factors were breast cancer therapy, lymph node status, hormone receptor and HER2 status, age, and geographical region. The primary endpoint was the composite endpoint of bone metastasis-free survival. This trial is registered with ClinicalTrials.gov, NCT01077154. FINDINGS: Between June 2, 2010, and Aug 24, 2012, 4509 women were randomly assigned to receive denosumab (n=2256) or placebo (n=2253) and included in the intention-to-treat analysis. The primary analysis of the study was done when all patients had the opportunity to complete 5 years of follow-up with an analysis data cutoff date of Aug 31, 2017. The primary endpoint of bone metastasis-free survival was not significantly different between the groups (median not reached in either group; hazard ratio 0·97, 95% CI 0·82-1·14; p=0·70). The most common grade 3 or worse treatment-emergent adverse events, reported in patients who had at least one dose of the investigational product (2241 patients with denosumab vs 2218 patients with placebo), were neutropenia (340 [15%] vs 328 [15%]), febrile neutropenia (112 [5%] vs 142 [6%]), and leucopenia (62 [3%] vs 61 [3%]). Positively adjudicated osteonecrosis of the jaw occurred in 122 (5%) of 2241 patients treated with denosumab versus four (<1%) of 2218 patients treated with placebo; treatment-emergent hypocalcaemia occurred in 152 (7%) versus 82 (4%). Two treatment-related deaths occurred in the placebo group due to acute myeloid leukaemia and depressed level of consciousness. INTERPRETATION: Despite preclinical evidence suggesting RANKL inhibition might delay bone metastasis or disease recurrence in patients with early-stage breast cancer, in this study, denosumab did not improve disease-related outcomes for women with high-risk early breast cancer. FUNDING: Amgen.

Psychosocial consequences in offspring of women with breast cancer.

OBJECTIVE: Breast cancer (BC) accounts for 24% of female cancers, with approximately one quarter of women likely to have offspring aged less than 25 years. Recent publications demonstrate negative psychosocial well-being in these offspring. We prospectively assessed for psychological distress and unmet needs in offspring of BC patients. METHODS: Eligible offspring aged 14 to 24 years were consented and completed the Kessler-10 Questionnaire and Offspring Cancer Needs Instrument. Demographic and BC details were obtained. RESULTS: Over a 7-month period, 120 offspring from 74 BC patients were included. Fifty-nine mothers had nonmetastatic BC (nMBC), and 27 had metastatic BC (MBC) with median time from diagnosis of 27.6 and 36.1 months, respectively. The prevalence of high/very high distress was 31%, with significantly higher scores reported by female offspring (P = .017). Unmet needs were reported by more than 50% of offspring with the majority of needs relating to information about their mother's cancer. Greater unmet needs were seen in female offspring and offspring with none or one sibling for several domains (practical assistance, time-out, dealing with feelings, and support from friends; P < .05). Greater unmet needs were seen in regard to feelings for MBC patients' offspring compared with nMBC but were similar for other unmet needs. CONCLUSIONS: Our study confirms high levels of psychological distress in offspring of BC patients, with female offspring reporting significantly higher emotional distress and unmet needs. More than 50% of respondents reported unmet needs in areas that can potentially be supported, including greater information provision, improving practical issues, and enabling sufficient recreational time.

PIK3CA alterations and benefit with neratinib: analysis from the randomized, double-blind, placebo-controlled, phase III ExteNET trial.

BACKGROUND: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor that inhibits PI3K/Akt and MAPK signaling pathways after HER2 receptor activation. The ExteNET study showed that neratinib significantly improved 5-year invasive disease-free survival (iDFS) in women who completed trastuzumab-based adjuvant therapy for early breast cancer (EBC). We assessed the prognostic and predictive significance of PIK3CA alterations in patients in ExteNET. METHODS: Participants were women aged ≥ 18 years (≥ 20 years in Japan) with stage 1-3c (modified to stage 2-3c in February 2010) operable breast cancer, who had completed (neo)adjuvant chemotherapy plus trastuzumab ≤ 2 years before randomization, with no evidence of disease recurrence or metastatic disease at study entry. Patients were randomized to oral neratinib 240 mg/day or placebo for 1 year. Formalin-fixed, paraffin-embedded primary tumor specimens underwent polymerase chain reaction (PCR) PIK3CA testing for two hotspot mutations in exon 9, one hot-spot mutation in exon 20, and fluorescence in situ hybridization (FISH) analysis for PIK3CA amplification. The primary endpoint (iDFS) was tested with log-rank test and hazard ratios (HRs) estimated using Cox proportional-hazards models. RESULTS: Among the intent-to-treat population (n = 2840), tumor specimens were available for PCR testing (991 patients) and PIK3CA FISH (702 patients). Overall, 262 samples were PIK3CA altered: 201 were mutated (77%), 52 (20%) were amplified, and 9 (3%) were mutated and amplified. iDFS was non-significantly worse in placebo-treated patients with altered vs wild-type PIK3CA (HR 1.34; 95% CI 0.72-2.50; P = 0.357). Neratinib's effect over placebo was significant in patients with PIK3CA-altered tumors (HR 0.41; 95% CI 0.17-0.90, P = 0.028) but not PIK3CA wild-type tumors (HR 0.72; 95% CI 0.36-1.41; P = 0.34). The interaction test was non-significant (P = 0.309). CONCLUSIONS: Although there was a greater absolute risk reduction associated with neratinib treatment of patients with PIK3CA-altered tumors in ExteNET, current data do not support PIK3CA alteration as a predictive biomarker of response to neratinib in HER2-positive EBC. TRIAL REGISTRATION: ClinicalTrials.gov , NCT00878709 . Trial registered April 9, 2009.

Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer.

BACKGROUND: The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) and negative for human epidermal growth factor receptor 2 (HER2). METHODS: In this randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in 668 postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease. We randomly assigned the patients to receive either ribociclib (600 mg per day on a 3-weeks-on, 1-week-off schedule) plus letrozole (2.5 mg per day) or placebo plus letrozole. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. A preplanned interim analysis was performed on January 29, 2016, after 243 patients had disease progression or died. Prespecified criteria for superiority required a hazard ratio of 0.56 or less with P<1.29×10-5. RESULTS: The duration of progression-free survival was significantly longer in the ribociclib group than in the placebo group (hazard ratio, 0.56; 95% CI, 0.43 to 0.72; P=3.29×10-6 for superiority). The median duration of follow-up was 15.3 months. After 18 months, the progression-free survival rate was 63.0% (95% confidence interval [CI], 54.6 to 70.3) in the ribociclib group and 42.2% (95% CI, 34.8 to 49.5) in the placebo group. In patients with measurable disease at baseline, the overall response rate was 52.7% and 37.1%, respectively (P<0.001). Common grade 3 or 4 adverse events that were reported in more than 10% of the patients in either group were neutropenia (59.3% in the ribociclib group vs. 0.9% in the placebo group) and leukopenia (21.0% vs. 0.6%); the rates of discontinuation because of adverse events were 7.5% and 2.1%, respectively. CONCLUSIONS: Among patients receiving initial systemic treatment for HR-positive, HER2-negative advanced breast cancer, the duration of progression-free survival was significantly longer among those receiving ribociclib plus letrozole than among those receiving placebo plus letrozole, with a higher rate of myelosuppression in the ribociclib group. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT01958021 .).

Neratinib after trastuzumab-based adjuvant therapy in patients from Asia with early stage HER2-positive breast cancer.

Aim: To evaluate the efficacy and safety of neratinib as extended adjuvant therapy in patients from Asia based on exploratory analyses of the Phase III ExteNET trial. Patients & methods: A total of 2840 women with early stage HER2-positive breast cancer were randomly assigned to neratinib 240 mg/day or placebo for 1 year after trastuzumab-based adjuvant therapy. Results: A total of 341 patients were from Asia (neratinib, n = 165; placebo, n = 176). 2-year invasive disease-free survival rates were 92.8 and 90.8% with neratinib and placebo, respectively (HR: 0.70; 95% CI: 0.31-1.55), and 5-year rates were 91.9 and 87.2%, respectively (HR: 0.57; 95% CI: 0.27-1.13). Diarrhea was the most common adverse event with neratinib. Conclusion: Extended adjuvant therapy with neratinib reduces disease recurrences in Asian women with HER2-positive breast cancer. Trial registration: Clinicaltrials.gov NCT00878709.

Decentralizing the delivery of HIV pre-exposure prophylaxis (PrEP) through family physicians and sexual health clinic nurses: a dissemination and implementation study protocol.

BACKGROUND: Gay, bisexual and other men who have sex with men (gbMSM) in Canada continue to experience high rates of incident HIV. Pre-exposure prophylaxis (PrEP, the regular use of anti-HIV medication) reduces HIV acquisition and could reduce incidence. However, there are too few physicians with expertise in HIV care to meet the projected demand for PrEP. To meet demand and achieve greater public health impact, PrEP delivery could be 'decentralized' by incorporating it into front-line prevention services provided by family physicians (FPs) and sexual health clinic nurses. METHODS: This PrEP decentralization project will use two strategies. The first is an innovative knowledge dissemination approach called 'Patient-Initiated CME' (PICME), which aims to empower individuals to connect their family doctors with online, evidence-based, continuing medical education (CME) on PrEP. After learning about the project through community agencies or social/sexual networking applications, gbMSM interested in PrEP will use a uniquely coded card to access an online information module that includes coaching on how to discuss their HIV risk with their FP. They can provide their physician a link to the accredited CME module using the same card. The second strategy involves a pilot implementation program, in which gbMSM who do not have a FP may bring the card to designated sexual health clinics where trained nurses can deliver PrEP under a medical directive. These approaches will be evaluated through quantitative and qualitative methods, including: questionnaires administered to patients and physicians at baseline and at six months; focus groups with patients, FPs, and sexual health clinic staff; and review of sexual health clinic charts. The primary objective is to quantify the uptake of PrEP achieved using each decentralization strategy. Secondary objectives include a) characterizing barriers and facilitators to PrEP uptake for each strategy, b) assessing fidelity to core components of PrEP delivery within each strategy, c) measuring patient-reported outcomes including satisfaction with clinician-patient relationships, and d) conducting a preliminary costing analysis. DISCUSSION: This study will assess the feasibility of a novel strategy for disseminating knowledge about evidence-based clinical interventions, and inform future strategies for scale-up of an underutilized HIV prevention tool.

Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [<1%] grade 4 with neratinib vs 23 [2%] grade 3 with placebo), vomiting (grade 3: 47 [3%] vs five [<1%]), and nausea (grade 3: 26 [2%] vs two [<1%]). Treatment-emergent serious adverse events occurred in 103 (7%) women in the neratinib group and 85 (6%) women in the placebo group. No evidence of increased risk of long-term toxicity or long-term adverse consequences of neratinib-associated diarrhoea were identified with neratinib compared with placebo. INTERPRETATION: At the 5-year follow-up, 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significantly reduced the proportion of clinically relevant breast cancer relapses-ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast-without increasing the risk of long-term toxicity. An analysis of overall survival is planned after 248 events. FUNDING: Wyeth, Pfizer, and Puma Biotechnology.

Randomized phase II placebo-controlled study to evaluate the efficacy of topical pure emu oil for joint pain related to adjuvant aromatase inhibitor use in postmenopausal women with early breast cancer: JUST (Joints Under Study).

PURPOSE: Aromatase inhibitors are standard of care in women with hormone receptor-positive early breast cancer. Published evidence demonstrates that adverse effects may have an impact on drug compliance, with arthralgias being one of the most commonly reported adverse effects. METHODS: Eligible patients were postmenopausal women who had experienced arthralgia following initiation of an aromatase inhibitor. Patients who experienced arthralgias following a minimum of a 3-month treatment on the aromatase inhibitor were randomized to emu oil or placebo oil. The primary endpoint was to assess for a reduction in pain as measured by a visual analogue score after 8 weeks of treatment. RESULTS: Seventy-three patients comprised the intent-to-treat population, and there was no statistically significant benefit with use of EO. However, there was a statistically significant improvement in pain (visual analogue score was -1.28; p < 0.001) and Brief Pain Inventory severity score -0.88 (p < 0.001), as well as functional interference (Brief Pain Inventory interference -1.10 (p < 0.001) for the entire population following an 8-week administration of EO or placebo oil. CONCLUSIONS: Arthralgias, as a result of aromatase inhibitor use, may be ameliorated by the use of topical oil massaged onto the joint. Further research into interventions for this common side effect is needed.

Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Neratinib, an irreversible tyrosine-kinase inhibitor of HER1, HER2, and HER4, has clinical activity in patients with HER2-positive metastatic breast cancer. We aimed to investigate the efficacy and safety of 12 months of neratinib after trastuzumab-based adjuvant therapy in patients with early-stage HER2-positive breast cancer. METHODS: We did this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 495 centres in Europe, Asia, Australia, New Zealand, and North and South America. Eligible women (aged ≥18 years, or ≥20 years in Japan) had stage 1-3 HER2-positive breast cancer and had completed neoadjuvant and adjuvant trastuzumab therapy up to 2 years before randomisation. Inclusion criteria were amended on Feb 25, 2010, to include patients with stage 2-3 HER2-positive breast cancer who had completed trastuzumab therapy up to 1 year previously. Patients were randomly assigned (1:1) to receive oral neratinib 240 mg per day or matching placebo. The randomisation sequence was generated with permuted blocks stratified by hormone receptor status (hormone receptor-positive [oestrogen or progesterone receptor-positive or both] vs hormone receptor-negative [oestrogen and progesterone receptor-negative]), nodal status (0, 1-3, or ≥4), and trastuzumab adjuvant regimen (sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system. Patients, investigators, and trial sponsors were masked to treatment allocation. The primary outcome was invasive disease-free survival, as defined in the original protocol, at 2 years after randomisation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00878709. FINDINGS: Between July 9, 2009, and Oct 24, 2011, we randomly assigned 2840 women to receive neratinib (n=1420) or placebo (n=1420). Median follow-up time was 24 months (IQR 20-25) in the neratinib group and 24 months (22-25) in the placebo group. At 2 year follow-up, 70 invasive disease-free survival events had occurred in patients in the neratinib group versus 109 events in those in the placebo group (stratified hazard ratio 0·67, 95% CI 0·50-0·91; p=0·0091). The 2-year invasive disease-free survival rate was 93·9% (95% CI 92·4-95·2) in the neratinib group and 91·6% (90·0-93·0) in the placebo group. The most common grade 3-4 adverse events in patients in the neratinib group were diarrhoea (grade 3, n=561 [40%] and grade 4, n=1 [<1%] vs grade 3, n=23 [2%] in the placebo group), vomiting (grade 3, n=47 [3%] vs n=5 [<1%]), and nausea (grade 3, n=26 [2%] vs n=2 [<1%]). QT prolongation occurred in 49 (3%) patients given neratinib and 93 (7%) patients given placebo, and decreases in left ventricular ejection fraction (≥grade 2) in 19 (1%) and 15 (1%) patients, respectively. We recorded serious adverse events in 103 (7%) patients in the neratinib group and 85 (6%) patients in the placebo group. Seven (<1%) deaths (four patients in the neratinib group and three patients in the placebo group) unrelated to disease progression occurred after study drug discontinuation. The causes of death in the neratinib group were unknown (n=2), a second primary brain tumour (n=1), and acute myeloid leukaemia (n=1), and in the placebo group were a brain haemorrhage (n=1), myocardial infarction (n=1), and gastric cancer (n=1). None of the deaths were attributed to study treatment in either group. INTERPRETATION: Neratinib for 12 months significantly improved 2-year invasive disease-free survival when given after chemotherapy and trastuzumab-based adjuvant therapy to women with HER2-positive breast cancer. Longer follow-up is needed to ensure that the improvement in breast cancer outcome is maintained. FUNDING: Wyeth, Pfizer, Puma Biotechnology.

Challenges to effective cancer control in China, India, and Russia.

Cancer is one of the major non-communicable diseases posing a threat to world health. Unfortunately, improvements in socioeconomic conditions are usually associated with increased cancer incidence. In this Commission, we focus on China, India, and Russia, which share rapidly rising cancer incidence and have cancer mortality rates that are nearly twice as high as in the UK or the USA, vast geographies, growing economies, ageing populations, increasingly westernised lifestyles, relatively disenfranchised subpopulations, serious contamination of the environment, and uncontrolled cancer-causing communicable infections. We describe the overall state of health and cancer control in each country and additional specific issues for consideration: for China, access to care, contamination of the environment, and cancer fatalism and traditional medicine; for India, affordability of care, provision of adequate health personnel, and sociocultural barriers to cancer control; and for Russia, monitoring of the burden of cancer, societal attitudes towards cancer prevention, effects of inequitable treatment and access to medicine, and a need for improved international engagement.

Adjuvant trastuzumab in HER2-positive breast cancer.

BACKGROUND: Trastuzumab improves survival in the adjuvant treatment of HER-positive breast cancer, although combined therapy with anthracycline-based regimens has been associated with cardiac toxicity. We wanted to evaluate the efficacy and safety of a new nonanthracycline regimen with trastuzumab. METHODS: We randomly assigned 3222 women with HER2-positive early-stage breast cancer to receive doxorubicin and cyclophosphamide followed by docetaxel every 3 weeks (AC-T), the same regimen plus 52 weeks of trastuzumab (AC-T plus trastuzumab), or docetaxel and carboplatin plus 52 weeks of trastuzumab (TCH). The primary study end point was disease-free survival. Secondary end points were overall survival and safety. RESULTS: At a median follow-up of 65 months, 656 events triggered this protocol-specified analysis. The estimated disease-free survival rates at 5 years were 75% among patients receiving AC-T, 84% among those receiving AC-T plus trastuzumab, and 81% among those receiving TCH. Estimated rates of overall survival were 87%, 92%, and 91%, respectively. No significant differences in efficacy (disease-free or overall survival) were found between the two trastuzumab regimens, whereas both were superior to AC-T. The rates of congestive heart failure and cardiac dysfunction were significantly higher in the group receiving AC-T plus trastuzumab than in the TCH group (P<0.001). Eight cases of acute leukemia were reported: seven in the groups receiving the anthracycline-based regimens and one in the TCH group subsequent to receiving an anthracycline outside the study. CONCLUSIONS: The addition of 1 year of adjuvant trastuzumab significantly improved disease-free and overall survival among women with HER2-positive breast cancer. The risk-benefit ratio favored the nonanthracycline TCH regimen over AC-T plus trastuzumab, given its similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia. (Funded by Sanofi-Aventis and Genentech; BCIRG-006 ClinicalTrials.gov number, NCT00021255.).

Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial.

BACKGROUND: The addition of bevacizumab to chemotherapy improves progression-free survival in metastatic breast cancer and pathological complete response rates in the neoadjuvant setting. Micrometastases are dependent on angiogenesis, suggesting that patients might benefit from anti-angiogenic strategies in the adjuvant setting. We therefore assessed the addition of bevacizumab to chemotherapy in the adjuvant setting for women with triple-negative breast cancer. METHODS: For this open-label, randomised phase 3 trial we recruited patients with centrally confirmed triple-negative operable primary invasive breast cancer from 360 sites in 37 countries. We randomly allocated patients aged 18 years or older (1:1 with block randomisation; stratified by nodal status, chemotherapy [with an anthracycline, taxane, or both], hormone receptor status [negative vs low], and type of surgery) to receive a minimum of four cycles of chemotherapy either alone or with bevacizumab (equivalent of 5 mg/kg every week for 1 year). The primary endpoint was invasive disease-free survival (IDFS). Efficacy analyses were based on the intention-to-treat population, safety analyses were done on all patients who received at least one dose of study drug, and plasma biomarker analyses were done on all treated patients consenting to biomarker analyses and providing a measurable baseline plasma sample. This trial is registered with ClinicalTrials.gov, number NCT00528567. FINDINGS: Between Dec 3, 2007, and March 8, 2010, we randomly assigned 1290 patients to receive chemotherapy alone and 1301 to receive bevacizumab plus chemotherapy. Most patients received anthracycline-containing therapy; 1638 (63%) of the 2591 patients had node-negative disease. At the time of analysis of IDFS, median follow-up was 31·5 months (IQR 25·6-36·8) in the chemotherapy-alone group and 32·0 months (27·5-36·9) in the bevacizumab group. At the time of the primary analysis, IDFS events had been reported in 205 patients (16%) in the chemotherapy-alone group and in 188 patients (14%) in the bevacizumab group (hazard ratio [HR] in stratified log-rank analysis 0·87, 95% CI 0·72-1·07; p=0·18). 3-year IDFS was 82·7% (95% CI 80·5-85·0) with chemotherapy alone and 83·7% (81·4-86·0) with bevacizumab and chemotherapy. After 200 deaths, no difference in overall survival was noted between the groups (HR 0·84, 95% CI 0·64-1·12; p=0·23). Exploratory biomarker assessment suggests that patients with high pre-treatment plasma VEGFR-2 might benefit from the addition of bevacizumab (Cox interaction test p=0·029). Use of bevacizumab versus chemotherapy alone was associated with increased incidences of grade 3 or worse hypertension (154 patients [12%] vs eight patients [1%]), severe cardiac events occurring at any point during the 18-month safety reporting period (19 [1%] vs two [<0·5%]), and treatment discontinuation (bevacizumab, chemotherapy, or both; 256 [20%] vs 30 [2%]); we recorded no increase in fatal adverse events with bevacizumab (four [<0·5%] vs three [<0·5%]). INTERPRETATION: Bevacizumab cannot be recommended as adjuvant treatment in unselected patients with triple-negative breast cancer. Further follow-up is needed to assess the potential effect of bevacizumab on overall survival.

Phase I trial of the oral PARP inhibitor olaparib in combination with paclitaxel for first- or second-line treatment of patients with metastatic triple-negative breast cancer.

INTRODUCTION: This Phase I study evaluated the safety, tolerability and efficacy of olaparib, a potent oral poly(ADPribose) polymerase (PARP) inhibitor, in combination with paclitaxel in patients with metastatic triple-negative breast cancer (mTNBC). METHODS: Eligible patients who had received ≤1 prior cytotoxic regimen for mTNBC were treated with olaparib 200 mg bid continuously plus weekly paclitaxel 90 mg/m2 for three weeks per four-week cycle. Dose modifications in a large proportion of patients due to neutropenia resulted in enrollment of a second cohort of patients who, if they experienced grade ≥2 neutropenia in cycle 1, received granulocyte-colony stimulating factor, which was continued prophylactically in subsequent cycles. All patients had measurable disease; tumor responses were evaluated according to RECIST (version 1.0). RESULTS: Nineteen patients (cohort 1, n = 9; cohort 2, n = 10) received treatment; 15 had received prior taxane chemotherapy. The most frequent adverse events were diarrhea (n = 12, 63%), nausea (n = 11, 58%) and neutropenia (n = 11, 58%). Seven neutropenia events were reported in cohort 1 (four grade ≥3) and four in cohort 2 (two grade ≥3, including one event of febrile neutropenia). The median (range) dose intensity of paclitaxel was 57% (26 to 100%) in cohort 1 and 73% (29 to 100%) in cohort 2. Seven patients (37%) had a confirmed partial response; one patient remains on olaparib monotherapy without progression. CONCLUSIONS: The combination of olaparib and weekly paclitaxel was complicated by a significant clinical interaction, with higher-than-expected rates of neutropenia despite secondary prophylaxis. Given the encouraging response rate, alternative scheduling and dosing strategies should be considered (funded by AstraZeneca; ClinicalTrials.gov, NCT00707707).