In the PALOMA-3 study, palbociclib plus fulvestrant demonstrated improved progression-free survival compared with fulvestrant plus placebo in HR+/HER2- endocrine-resistant metastatic breast cancer (MBC). This analysis compared patient reported outcomes (PROs) between the two treatment groups.
Patients were randomized 2:1 to receive palbociclib 125 mg/day orally for 3 weeks followed by 1 week off (n=347) plus fulvestrant (500 mg intramuscularly per standard of care) or placebo plus fulvestrant (n=174). PROs were assessed on Day 1 of Cycles 1-4 and of every other subsequent cycle starting with Cycle 6 using the EORTC QLQ-C30 and its breast cancer module, QLQ-BR23. High scores (range 0-100) could indicate better functioning/quality of life (QoL) or worse symptom severity. Repeated measures mixed-effects analyses were performed to compare on-treatment overall scores and changes from baseline between treatment groups while controlling for baseline. Between-group comparisons of time to deterioration in global QoL and pain were made using an unstratified log-rank test and Cox proportional hazards model.
Questionnaire completion rates were high at baseline and during treatment (from baseline to Cycle 14, ≥95.8% in each group completed ≥1 question on the EORTC QLQ-C30). On treatment, estimated overall global QoL scores significantly favored the palbociclib plus fulvestrant group (66.1, 95% confidence interval [CI]: 64.5, 67.7 vs 63.0, 95% CI: 60.6, 65.3; P=0.0313). Significantly greater improvement from baseline in pain was also observed in this group (-3.3, 95% CI: -5.1,-1.5 vs 2.0, 95% CI:-0.6, 4.6; P=0.0011). No significant differences were observed for other QLQ-BR 23 functioning domains, breast, or arm symptoms. Treatment with palbociclib plus fulvestrant significantly delayed deterioration in global QoL (P<0.025) and pain (P <0.001) compared with fulvestrant alone.
Palbociclib plus fulvestrant allowed patients to maintain good QoL in the endocrine resistance setting while experiencing substantially delayed disease progression.
ClinicalTrials.gov identifier NCT01942135.
© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

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Glucose-regulated protein (GRP) 78 is overexpressed in multiple myeloma (MM) and both, its surface expression as well as its biological significance as key sensor of the unfolded protein response make GRP78 an ideal candidate for immunotherapeutic intervention. The monoclonal antibody PAT-SM6 targets surface (s) GRP78 and leads to disease stabilization when used as single-agent in a clinical trial. In this paper, we evaluated expression of GRP78 in relapsed-refractory disease and explored PAT-SM6 therapy in combination regimens.
GRP78 expression was immunohistochemically analyzed during disease progression and development of drug resistance throughout different stages of MM. Activity of PAT-SM6 was evaluated in combination with anti-MM agents lenalidomide, bortezomib and dexamethasone in vitro. Finally, we report on a MM patient with relapsed and refractory disease treated with PAT-SM6 in combination with bortezomib and lenalidomide.
Although sGRP78 expression was present at all stages, it increased with disease progression and was even stronger elevated in patients with drug-resistant and extramedullary disease. Pre-treatment with dexamethasone as well as dual combination of PAT-SM6/lenalidomide further increased sGRP78 expression and consecutively showed synergistic anti-MM effects with PAT-SM6 in proliferation assays. As proof of concept, a 62-year-old male with triple resistant MM treated with PAT-SM6, bortezomib and lenalidomide experienced partial remission of both intra- and extramedullary lesions.
PAT-SM6 therapy in combination regimens showed efficacy in relapsed refractory MM.
Copyright ©2016, American Association for Cancer Research (AACR) (Free AACR Whitepaper).

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Neuroendocrine tumors (NETs) are malignant solid tumors arising in hormone-secreting tissue. They have historically been very difficult to treat, and advanced NETs are considered incurable. Surgery is the only potentially curative treatment option, though research is ongoing, investigating the efficacy of targeted therapies combined with more traditional chemotherapies. Frequent bowel movements and episodes of flushing are the most common symptoms.
The present study reports data from an anonymous patient survey of 663 eligible NET patients, identified with the assistance of patient advocacy groups. This study investigated the impact of treatment (surgery alone; surgery plus somatostatin analogue; other treatments) on quality of life (QOL). Finally, we investigate whether recurrent disease results in poorer QOL compared to disease treated curatively with surgery and remaining in remission.
Results suggest that increased frequency of bowel movements and presence of any flushing symptoms are correlated with decreased quality of life. Treatment groups differed on most Patient Reported Outcomes Measurement Information System (PROMIS) global health and PROMIS-29 scores, including physical function, fatigue, pain, social function, and general physical and mental health, with the surgery group reporting significantly better scores than the other groups (effect size of differences ranged from 0.28 to 0.54). This may be possibly due to effective symptom control reached for these patients through surgery alone. After adjustment for carcinoid syndrome, the association with the treatment group disappeared for all domains except physical functioning. In terms of disease status, patients with recurrent disease reported poorer physical, social, and mental functions. Depression scores were similar between groups; however, patients with recurrent disease reported significantly higher anxiety compared to those with no current NET. Physical functioning was even more markedly different between groups, with recurrent NET patients reporting significantly impaired overall physical function, impaired sleep, and significant fatigue compared to those with no current NET. To our knowledge, this is the first study to comprehensively examine the effect of treatment group, disease status, and symptom burden on the quality of life in NET patients in a large sample. Limitations and future research directions are discussed.

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The cullin-RING ubiquitin E3 ligase (CRL) family comprises over 200 members in humans. The COP9 signalosome complex (CSN) regulates CRLs by removing their ubiquitin-like activator NEDD8. The CUL4A-RBX1-DDB1-DDB2 complex (CRL4A(DDB2)) monitors the genome for ultraviolet-light-induced DNA damage. CRL4A(DBB2) is inactive in the absence of damaged DNA and requires CSN to regulate the repair process. The structural basis of CSN binding to CRL4A(DDB2) and the principles of CSN activation are poorly understood. Here we present cryo-electron microscopy structures for CSN in complex with neddylated CRL4A ligases to 6.4 Å resolution. The CSN conformers defined by cryo-electron microscopy and a novel apo-CSN crystal structure indicate an induced-fit mechanism that drives CSN activation by neddylated CRLs. We find that CSN and a substrate cannot bind simultaneously to CRL4A, favouring a deneddylated, inactive state for substrate-free CRL4 complexes. These architectural and regulatory principles appear conserved across CRL families, allowing global regulation by CSN.

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5-Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway. The MTAP gene is frequently deleted in human cancers because of its chromosomal proximity to the tumor suppressor gene CDKN2A. By interrogating data from a large-scale short hairpin RNA-mediated screen across 390 cancer cell line models, we found that the viability of MTAP-deficient cancer cells is impaired by depletion of the protein arginine methyltransferase PRMT5. MTAP-deleted cells accumulate the metabolite methylthioadenosine (MTA), which we found to inhibit PRMT5 methyltransferase activity. Deletion of MTAP in MTAP-proficient cells rendered them sensitive to PRMT5 depletion. Conversely, reconstitution of MTAP in an MTAP-deficient cell line rescued PRMT5 dependence. Thus, MTA accumulation in MTAP-deleted cancers creates a hypomorphic PRMT5 state that is selectively sensitized toward further PRMT5 inhibition. Inhibitors of PRMT5 that leverage this dysregulated metabolic state merit further investigation as a potential therapy for MTAP/CDKN2A-deleted tumors.
Copyright © 2016, American Association for the Advancement of Science.

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