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ObjectiveTo evaluate correlations between rucaparib exposure and selected efficacy and safety endpoints in patients with recurrent ovarian carcinoma using pooled data from Study 10 and ARIEL2.MethodsEfficacy analyses were limited to patients with carcinomas harboring a deleterious BRCA1 or BRCA2 mutation who had received ≥2 prior lines of chemotherapy. Safety was evaluated in all patients who received ≥1 rucaparib dose. Steady-state daily area under the concentration-time curve (AUCss) and maximum concentration (Cmax,ss) for rucaparib were calculated for each patient and averaged by actual dose received over time (AUCavg,ss and Cmax,avg,ss) using a previously developed population pharmacokinetic model.ResultsRucaparib exposure was dose-proportional and not associated with baseline patient weight. In the exposure-efficacy analyses (n=121), AUCavg,ss was positively associated with independent radiology review-assessed RECIST response in the subgroup of patients with platinum-sensitive recurrent disease (n=75, p=0.017). In the exposure-safety analyses (n=393, 40mg once daily to 840mg twice daily [BID] starting doses), most patients received a 600mg BID rucaparib starting dose, with 27% and 21% receiving 1 or≥2 dose reductions, respectively. Cmax,ss was significantly correlated with grade≥2 serum creatinine increase, grade≥3 alanine transaminase/aspartate transaminase increase, platelet decrease, fatigue/asthenia, and maximal hemoglobin decrease (p&nbsp

Highlights • Bone health should be prioritised when men with prostate cancer start long-term ADT. • Assessment by FRAX (±bone mineral density) identifies those at highest risk of fracture. • Treatment can minimise skeletal complications and reduce morbidity and mortality., Context and objective Incidence of prostate cancer (PC) is increasing, but androgen deprivation therapy (ADT) and other therapies are substantially improving survival. In this context, careful consideration of skeletal health is required to reduce the risk of treatment-related fragility fractures and their associated morbidity and mortality. This risk is currently not well-managed. ADT causes significant loss of bone mineral density (BMD). In the metastatic setting, systemic treatments (e.g. chemotherapy, abiraterone, enzalutamide) are used alongside ADT and may require concomitant glucocorticoids. Both ADT and glucocorticoids pose significant challenges to skeletal health in a population of patients already likely to have ongoing age-related bone loss and/or comorbid conditions. Current PC guidelines lack specific recommendations for optimising bone health. This guidance presents evidence for assessment and management of bone health in this population, with specific recommendations for clinical practitioners in day-to-day PC management. Methods Structured meetings of key opinion leaders were integrated with a systematic literature review. Input and endorsement was sought from patients, nursing representatives and specialist societies. Summary of guidance All men starting or continuing long-term ADT should receive lifestyle advice regarding bone health. Calcium/vitamin D supplementation should be offered if required. Fracture risk should be calculated (using the FRAX® tool), with BMD assessment included where feasible. BMD should always be assessed where fracture risk calculated using FRAX® alone is close to the intervention threshold. Intervention should be provided if indicated by local or national guidelines e.g. UK National Osteoporosis Guideline Group (NOGG) thresholds. Men requiring bone protection therapy should be further assessed (e.g. renal function), with referral to specialist centres if available and offered appropriate treatment to reduce fracture risk. Those near to, but below an intervention threshold, and patients going on to additional systemic therapies (particularly those requiring glucocorticoids), should have FRAX® (including BMD) repeated after 12–18 months. Patient summary Modern treatments for prostate cancer have led to significant improvements in survival and quality of life. However, some of these treatments may lead to weakening of patient’s bones with risk of fracture and it is therefore important to monitor patients’ bone health and provide bone protection where needed. This paper provides specific guidance to clinical teams, based on the most recent research evidence, to ensure optimal bone health in their patients.

Highlights • PI3K/AKT pathway alterations are frequently seen in ovarian cancer, providing rationale for targeted AKT inhibition. • AKT inhibitor MK-2206 in platinum resistant high grade serous ovarian cancer was notable for dermatologic toxicity. • Best response of stable disease was seen, with one patient experiencing a prolonged SD of 19 weeks., Platinum-resistant, recurrent, high grade epithelial ovarian carcinoma remains challenging to treat. Chemotherapy produces limited responses with modest survival benefits in the treatment of recurrent disease. In this context, targeted therapies may improve upon conventional therapies. PI3K/AKT pathway alterations are frequently found in several cancer types, including ovarian cancer, and thus AKT inhibition is a rational targeted therapy. Here we report the results of an abbreviated trial of AKT inhibitor MK-2206 in platinum resistant high grade serous ovarian, fallopian tube, and primary peritoneal cancer with PTEN loss.

Ovarian cancer remains the deadliest gynecologic cancer. Although there are many subtypes of ovarian cancer, high-grade serous ovarian cancer accounts for more than 70% of ovarian cancer deaths, and overall survival has not changed significantly for several decades. An improved understanding of the precursor sites has allowed for new prevention strategies. Moreover, rapidly growing knowledge regarding the molecular and cellular features of ovarian cancer has resulted in new and effective therapeutic approaches.

Pain is a major symptom of bone metastases from advanced cancer and represents a clinical challenge to treat effectively. Basic neurobiology in preclinical animal models implicates enhanced sensory processing in the central nervous system, acting through N-methyl-D-aspartate (NMDA) glutamate receptors, as an important mechanism underpinning persistent pain. The non-receptor tyrosine kinase Src is thought to act as a hub for regulating NMDA receptor activity and the orally available Src inhibitor saracatinib has shown promise as a potential analgesic in recent animal studies. Here we tested the efficacy of saracatinib as a novel analgesic in an exploratory phase II randomized controlled trial on cancer patients with painful bone metastases. Twelve patients completed the study, with 6 receiving saracatinib 125 mg/day for 28 days and 6 receiving placebo. Pharmacokinetic measurements confirmed appropriate plasma levels of drug in the saracatinib-treated group and Src inhibition was achieved clinically by a significant reduction in the bone resorption biomarker serum cross-linked C-terminal telopeptide of type I collagen. Differences between the saracatinib and placebo groups self-reported pain scores, measured using the short form of the Brief Pain Inventory, were not clinically significant after 4 weeks of treatment. There was also no change in consumption of maintenance analgesia in the saracatinib-treated group and no improvement in Quality-of-Life scores. The data were insufficient to demonstrate saracatinib has efficacy as analgesic, although it may have a role as an anti-bone resorptive agent. Keywords: Cancer pain, Src inhibitor, Metastasis, Clinical trial, Saracatinib

Highlights • Bone metastases negatively impact on patients’ quality of life (QoL). • Skeletal related events have a detrimental effect on both QoL and survival. • Both local and systemic treatments are often required to manage bone metastases. • Bone turnover modulators reduce the risk of skeletal complications and improve pain. • Novel agents may deserve further investigation for the management of bone metastases., Bone metastases (BM) are a common complication of cancer, whose management often requires a multidisciplinary approach. Despite the recent therapeutic advances, patients with BM may still experience skeletal-related events and symptomatic skeletal events, with detrimental impact on quality of life and survival. A deeper knowledge of the mechanisms underlying the onset of lytic and sclerotic BM has been acquired in the last decades, leading to the development of bone-targeting agents (BTA), mainly represented by anti-resorptive drugs and bone-seeking radiopharmaceuticals. Recent pre-clinical and clinical studies have showed promising effects of novel agents, whose safety and efficacy need to be confirmed by prospective clinical trials. Among BTA, adjuvant bisphosphonates have also been shown to reduce the risk of BM in selected breast cancer patients, but failed to reduce the incidence of BM from lung and prostate cancer. Moreover, adjuvant denosumab did not improve BM free survival in patients with breast cancer, suggesting the need for further investigation to clarify BTA role in early-stage malignancies. The aim of this review is to describe BM pathogenesis and current treatment options in different clinical settings, as well as to explore the mechanism of action of novel potential therapeutic agents for which further investigation is needed.

Bone metastases are common in advanced cancer and may cause major morbidity including fractures, pain, nerve compression and hypercalcemia. Through optimum multidisciplinary management and use of both systemic treatments to treat the underlying cancer and bone-targeted treatments such as potent bisphosphonates or denosumab to improve the structural integrity of bone, the experience of advanced cancer patients has been transformed with a major reduction in skeletal complications, less bone pain and improved quality of life.

Adjuvant bisphosphonates improve disease outcomes in postmenopausal early breast cancer (EBC) but the long-term effects are poorly described. The AZURE trial (ISRCTN79831382) was designed to determine whether adjuvant zoledronic acid (ZOL) improves disease outcomes in EBC. Previous analyses showed no effect on overall outcomes but identified benefits in postmenopausal women. Here we present the long-term risks and benefits of adjuvant ZOL with 10-years follow-up. Patients and methods: 3360 patients with stage II/III breast cancer were included in an academic, international, phase III, randomized, open label trial. Patients were followed up on a regular schedule until 10 years. Patients were randomized on a 1:1 basis to standard adjuvant systemic therapy +/− intravenous ZOL 4 mg every 3–4 weeks x6, and then at reduced frequency to complete 5 years treatment. The primary outcome was disease free survival (DFS). Secondary outcomes included invasive DFS (IDFS), overall survival (OS), sites of recurrence, skeletal morbidity and treatment outcomes according to primary tumor amplification of the transcription factor, MAF. Pre-planned subgroup analyses focused on interactions between menopausal status and treatment effects. Results: With a median follow up of 117 months [IQR 70.4–120.4), DFS and IDFS were similar in both arms (HRDFS = 0.94, 95%CI = 0.84–1.06, p = 0.340; HRIDFS = 0.91, 95%CI = 0.82–1.02, p = 0.116). However, outcomes remain improved with ZOL in postmenopausal women (HRDFS = 0.82, 95%CI = 0.67–1.00; HRIDFS = 0.78, 95%CI = 0.64–0.94). In the 79% of tested women with a MAF FISH negative tumor, ZOL improved IDFS (HRIDFS = 0.75, 95%CI = 0.58–0.97) and OS HROS = 0.69, 95%CI = 0.50–0.94), irrespective of menopause. ZOL did not improve disease outcomes in MAF FISH + tumors. Bone metastases as a first DFS recurrence (BDFS) were reduced with ZOL (HRB-DFS = 0.76, 95%CI = 0.63–0.92, p = 0.005). ZOL reduced skeletal morbidity with fewer fractures and skeletal events after disease recurrence. 30 cases of osteonecrosis of the jaw in the ZOL arm (1.8%) have occurred. Conclusions: Disease benefits with adjuvant ZOL in postmenopausal early breast cancer persist at 10 years of follow-up. The biomarker MAF identified a patient subgroup that derived benefit from ZOL irrespective of menopausal status.

Background: The Ovarian Protection Trial In Premenopausal Breast Cancer Patients “OPTION” trial\ud (NCT00427245) was a prospective, multicenter, randomised, open label study evaluating the frequency of\ud primary ovarian insufficiency (POI) at 12 months in women randomised to 6–8 cycles of (neo)adjuvant\ud chemotherapy (CT) þ/ goserelin (G). Here we report the results of a secondary endpoint analysis of the\ud effects of CTþ/-G on markers of bone turnover.\ud Methods: Serum for bone alkaline phosphatase (BALP) and urine for N-terminal telopeptide (NTX) were\ud collected at baseline, 6, 12, 18, 24 and 36 months. Changes in median levels of bone turnover markers\ud were evaluated for the overall population, according to age stratification at randomisation (r40 vs 440\ud years) and with exploratory analysis according to POI rates at 12 months.\ud Results: In the overall population, there was a significant increase in NTX at 6 months compared to\ud baseline in patients treated with CTþG (40.81 vs 57.82 p¼0.0074) with normalisation of levels thereafter.\ud BALP was significantly increased compared to baseline at 6 months and 12 months in those receiving\ud CTþG, but normalised thereafter. BALP remained significantly higher compared to baseline at 12, 24 and\ud 36 months in patients receiving CT, resulting in a significant difference between treatment groups at 36\ud months (CTþG 5.845 vs CT 8.5 p¼0.0006). These changes were predominantly seen in women 440\ud years. Women with POI at 12 months showed altered bone formation compared to baseline levels for a\ud longer duration than women who maintained menses.\ud Conclusion: Addition of G to CT increases bone turnover during treatment with normalisation after\ud cessation of treatment suggesting G may offer sufficient ovarian protection against CT induced POI to\ud negate longstanding altered bone turnover associated with POI.\ud

Bone represents a common site of metastasis from several solid tumours, including breast, prostate and lung malignancies. The onset of bone metastases (BM) is associated not only with serious skeletal complications, but also shortened overall survival, owing to the lack of curative treatment options for late-stage cancer.Despite the diagnostic advances, BM detection often occurs in the symptomatic stage, underlining the need for novel strategies aimed at the early identification of high-risk patients. To this purpose, both bone turnover and tumour-derived markers are being investigated for their potential diagnostic, prognostic and predictive roles.In this review, we summarize the pathogenesis of BM in breast, prostate and lung tumours, while exploring the current research focused on the identification and clinical validation of BM biomarkers. Keywords: Bone metastasis, Biomarkers, Bone turnover markers, Breast cancer, Prostate cancer, Lung cancer

Bone targeted treatments have transformed the quality of life and physical functioning of patients with metastatic bone disease and, in certain circumstances, have been shown to prevent the development of bone metastases and improve survival. However, the steps in development of these agents have been somewhat disjointed and based on good fortune as well as scientific endeavour and rational clinical development.

Symptomatic skeletal events (SSEs) commonly occur in patients with bone metastases,\ud often leading to hospitalisations and decreased quality-of-life. In the ALSYMPCA trial,\ud radium-223 significantly improved overall survival (hazard ratio 0.70, 95% confidence interval\ud [CI] 0.58e0.83, P < 0.001) and prolonged time to first SSE (hazard ratio 0.66, 95% CI 0.52\ud e0.83, P Z 0.00037) and subsequent SSE (hazard ratio 0.65, 95% CI 0.51e0.83,\ud P Z 0.00039) versus placebo in patients with castration-resistant prostate cancer with symptomatic\ud bone metastases and no known visceral metastases. Health care resource use (HCRU),\ud including hospitalisation events and days, were prospectively collected in ALSYMPCA. We\ud assessed health care resource use for the first 12 months post-randomisation. Significantly\ud fewer radium-223 (218/589; 37.0%) versus placebo patients (133/292; 45.5%) had at least\ud one hospitalisation event (P Z 0.016). However, mean number of hospitalisation events per\ud patient was similar (radium-223 0.69 versus placebo 0.79, P Z 0.226), likely due to the significantly\ud longer follow-up time for radium-223 (7.82 months versus 6.92 months for placebo;P < 0.001). There were significantly fewer hospitalisation days per patient for radium-223\ud (4.44 versus 6.68, respectively, P Z 0.004). The reduction in hospitalisation days with\ud radium-223 was observed both before first SSE (2.35 days versus 3.36 days, respectively)\ud and after SSE (7.74 days versus 9.19 days, respectively). Our data suggest that this reduced\ud hospital days along with the survival benefit and reduction in time to SSEs with radium-\ud 223 treatment may contribute to improvements in health-related quality-of-life in patients with\ud castration-resistant prostate cancer with symptomatic bone metastases (ALSYMPCA ClinicalTrials.gov\ud number, NCT00699751.).

Radium-223 was minimally myelosuppressive. Multivariate analyses of data from ALSYMPCA patients identified baseline factors that may increase hematologic toxicity risk with radium-223. Extent of disease and degree of prostate-specific antigen elevation were predictive of grade 2-4 anemia; prior docetaxel, and decreased hemoglobin and platelets were predictive of grade 2-4 thrombocytopenia. Patients with these factors should be closely monitored during radium-223 therapy. Background: Myelosuppression is common in patients with progressive castration-resistant prostate cancer and bone metastases. Radium-223 prolongs overall survival in these patients but may cause myelosuppression; understanding risk factors will improve clinical decision making. We describe hematologic safety of radium-223 in ALSYMPCA and post hoc analyses identifying patients at increased risk for hematologic toxicity. Patients and Methods: Hematologic parameters and adverse events were analyzed. Multivariate analyses assessing baseline risk factors for hematologic toxicities were performed separately for radium-223 and placebo patients. Results: Nine hundred one patients received radium-223 (n = 600) or placebo (n = 301); 65% of radium-223 and 48% of placebo patients had the full 6 cycles. Grade 3/4 thrombocytopenia was more common in radium-223 versus placebo patients (6% vs. 2%). Logistic regression analyses identified significant baseline predictors for grade 2-4 hematologic toxicities related to radium-223 treatment: extent of disease (6-20 vs. < 6 bone metastases; odds ratio [OR] = 2.76; P = .022) and elevated prostate-specific antigen (OR = 1.65; P = .006) for anemia; prior docetaxel (OR = 2.16; P = .035), decreased hemoglobin (OR = 1.35; P = .008), and decreased platelets (OR = 1.44; P = .030) for thrombocytopenia. Neutropenia events were too few in placebo patients for a comparative analysis. There were no significant associations between hematologic toxicities and number of radium-223 injections received (4-6 vs. 1-3). Conclusion: Radium-223 has a favorable safety profile with a low myelosuppression incidence. Understanding baseline factors associated with myelosuppression may assist clinicians in avoiding severe myelosuppression events with radium-223.

Purpose: The ARIBON trial is a double blind, randomised, placebo controlled study designed to evaluate the impact of ibandronate on bone mineral density (BMD) in women taking anastrozole for adjuvant treatment of breast cancer. \ud \ud Methods: 131 postmenopausal women with early breast cancer were recruited to the study. Of these, 13 had osteoporosis, 50 osteopenia and 68 normal BMD. Patients with osteoporosis at baseline were treated with monthly oral ibandronate 150 mg for 5 years; osteopenic patients were randomised to receive either ibandronate or placebo for two years and offered open label ibandronate depending upon the results of their 2-year BMD result. \ud \ud Results: Of the 20 patients with osteopenia who were randomised to ibandronate and evaluable at the 2 year visit, 17/20 were not offered a bisphosphonate and the improvements in BMD accrued during the first 2 years were lost both at the LS (-3.21%) and TH (-5.0%). Of the 16 patients randomised to placebo 8/16 with high rates of bone loss during years 0-2 received ibandronate over the next 3 years with improvements in BMD of +5.01 and +1.19 at the LS and TH respectively. The 8 patients who were not offered a bisphosphonate experienced relatively little change in BMD throughout the 5 years of the study (LS +0.15%, TH -2.72%). BMD increased steadily in the 9/13 patients initially identified as having osteoporosis (LS +9.65%, TH +2.72%). \ud \ud Conclusions: Monthly oral ibandronate provides an option to clinicians considering use of a bispho-sphonate to prevent bone loss during aromatase inhibitor therapy.

The impact of cancer on the skeleton can be devastating and typically results in a major decline in quality of life as well as reduced survival. Over the last decade or more we have learnt a great deal about the cellular interactions that lead to the colonization of bone by tumor cells and subsequent formation of metastases. This improved knowledge has helped the development of a range of bone-targeted treatments that have profoundly affected the clinical course of metastatic bone disease across the range of primary tumors that can affect the skeleton. These agents have complemented the improvements in specific drug treatments for cancer, radiation treatments and orthopedic surgery and become part of the standard of care for patients with spread of cancer to bone. We now have a range of agents with proven efficacy. Ongoing research is trying to define the most cost-effective and safe use of these agents while at the same time trying to identify new classes of agents that can further improve the clinical course of patients with metastatic bone disease or multiple myeloma.

Hormone-ablative therapies for breast cancer can cause marked and rapid reductions in circulating estrogen levels. Cancer treatment-induced bone loss (CTIBL) is generally more rapid and severe than bone loss associated with menopause in women or aging in women and men. In premenopausal women with breast cancer, CTIBL is mainly caused by chemotherapy with resultant ovarian failure, through the use of gonadotropin-releasing hormone (GnRH) agonists or by tamoxifen. In postmenopausal women, steroidal and nonsteroidal aromatase inhibitors (AIs) increase bone turnover, decrease bone mass, and increase fracture rate. Oral bisphosphonates and intravenous zoledronic acid can prevent bone loss in pre- and postmenopausal women. Subcutaneous denosumab has been shown to increase bone mineral density significantly in postmenopausal women receiving AIs. Finally, there is increasing evidence to support a disease modifying effect of bone-targeted treatment with improvements in disease-free and overall survival in some disease settings.

Publisher Summary This chapter provides details on the study of two natural products—azinomycins A and B—that possess intricate and unusual structures and that exhibit potent and effective antitumor activity. These agents have presented a synthetic challenge that is notably greater than their size and functionality. The project discusses in the chapter began in the summer of 1988, with a research proposal prepared as part of an academic job search and has continued through the successful total synthesis of azinomycin A in 2001 and beyond. In 1954, there was a report on the isolation of a new antitumor agent from Streptomyces sahachiroi , named “carzinophilin.” The compound exhibited effective and notable single-dose antitumor activity against several tumor cell lines implanted in mice and possessed significant antibiotic activity. Three decades later, Lown proposed the dimeric and C2-symmetric structure for carzinophilin that was based partly on degradation work. The 1 H(nuclear magnetic resonance (NMR) spectra showed only 29 different protons.

The skeleton and bone marrow microenvironment within bone acts as a critical organ for the development and spread of metastatic cancer. Bone metastases are common and have major impact on the physical function and quality of life of cancer patients. Over the last decade, as our understanding of the processes involved in metastasis has increased, it has become clear that bone marrow derived stem cells are intimately involved in the development of metastases both within and outside bone, and interactions between cancer and bone cells underpin the development of skeletal metastases. Additionally, as survival in many cancers improves, the long-term effects of treatment on bone health are of increasing importance. Coupled with the increasing recognition of the biological and clinical importance of the skeleton in the outcomes for cancer patients, rapid developments in bone targeted treatments, skeletal imaging and bone biomarkers have occurred. The therapeutic advances, notably bisphosphonates and denosumab, have had a profoundly positive effect on the care of patients with advanced malignancy and may have an important role in modifying the clinical course of certain cancers, especially those arising in the breast and prostate as well as for patients with multiple myeloma. Consequently, bone oncology has emerged as a new discipline and, in recognition of this, a new journal that brings together all aspects of the biology and clinical management of bone disease in cancer patients has been created. The Journal of Bone Oncology is a peer-reviewed international journal aimed at presenting basic, translational and clinical high-quality research related to bone and cancer. As the first journal dedicated to cancer induced bone diseases, we believe it fills an important gap in the available literature that adequately addresses this important research area and are very excited to have the enthusiastic support of a world class international editorial board. The areas covered by the journal include: • Pathophysiology, epidemiology, clinical features, prevention and treatment of bone metastases. • Preclinical models of metastasis. • The bone microenvironment in cancer and the role of stem cell, bone cell and cancer cell interactions in the development and spread of malignancy. • The pharmacology, therapeutic targets, drug development, clinical trials, side-effects, and health economics of bone targeted therapy. • Causes, prevention and management of cancer treatment induced bone loss. • Preclinical and clinical imaging of the skeleton and developments in skeletal interventional radiology. • Discovery, validation and clinical and translational applications of bone biomarkers. • Radiotherapy and radio-isotopes for the prevention and treatment of bone metastases. • Skeletal complications of malignancy including fracture, hypercalcaemia, and spinal cord compression. • Mechanisms and management of bone pain. • Orthopaedic cancer surgery. • Primary malignant bone tumours. • Clinical guidelines of relevance to bone health in oncology. • Multidisciplinary patient care. We are delighted, in partnership with Elsevier, to bring you this first issue of the Journal of Bone Oncology. Initially, 4 issues a year will be published and be made available via Science Direct. Our vision is to provide a journal to scientists and clinicians that bridges oncology and bone biology and is of broad appeal to all involved in cancer research and treatment. We do hope you will want to help make this journal a success by submitting relevant original research articles, review articles, editorials, case reports and opinion pieces.

This chapter describes a p -Adic inner product on elliptic modular forms. It presents a cohomology class in the first crystalline cohomology group. It is not true however that the map is always an injection. It is found that if F is an eigenform with complex multiplication such that its eigenvalue has valuation 1, it can be shown that the image is zero. This will follow from the theorem as the q invariant of the p -divisible group of an ordinary CM elliptic curve is a root of unity. It is not known whether this map is an injection when restricted to new forms or equivalently whether the inner product is nondegenerate when restricted to new forms. If W is assumed to be a basic wide open and y be a minimal underlying affinoid of W , W is a rigid space isomorphic to a complete curve C with good reduction X minus an affinoid, which after a finite etale base extension becomes a finite nonzero disjoint union of closed disks lieing in distinct residue classes of C .