Oncogenic Pathways and Targeted Therapies in Ovarian Cancer.

Epithelial ovarian cancer (EOC) is one of the most aggressive forms of gynaecological malignancies. Survival rates for women diagnosed with OC remain poor as most patients are diagnosed with advanced disease. Debulking surgery and platinum-based therapies are the current mainstay for OC treatment. However, and despite achieving initial remission, a significant portion of patients will relapse because of innate and acquired resistance, at which point the disease is considered incurable. In view of this, novel detection strategies and therapeutic approaches are needed to improve outcomes and survival of OC patients. In this review, we summarize our current knowledge of the genetic landscape and molecular pathways underpinning OC and its many subtypes. By examining therapeutic strategies explored in preclinical and clinical settings, we highlight the importance of decoding how single and convergent genetic alterations co-exist and drive OC progression and resistance to current treatments. We also propose that core signalling pathways such as the PI3K and MAPK pathways play critical roles in the origin of diverse OC subtypes and can become new targets in combination with known DNA damage repair pathways for the development of tailored and more effective anti-cancer treatments.

Impact of multidisciplinary team meetings on the management of patients with breast cancer in a large private healthcare facility.

AIMS: Multidisciplinary meetings (MDMs) play a crucial role in decision-making in breast cancer patient care. This study aimed to firstly assess the impact of breast cancer MDMs in decision-making for breast cancer patients and secondly to determine the concordance between MDM recommendations and implementation of clinical practice. METHODS: Patient cases to be presented at the weekly breast cancer MDMs were identified and prospectively enrolled. Management plans were predicted by the treating surgeon with the pre-MDM management plans then compared to MDM recommendations. Changes in decision-making were assessed in the following domains: further surgery, systemic therapy (endocrine, chemotherapy or targeted), radiotherapy, enrolment in a clinical trial, further investigations, and referral to other specialists or services. Patient records were subsequently reviewed at 3 months post-MDM to assess the rate of implementation of MDM recommendations and any reasons for discordance. RESULTS: Out of 50 cases, 66% (CI 53-79%; p < .005) experienced a change in management plan as a result of MDM discussion, with a total of 66 episodes of recorded change per decision-making domain affecting the following: further surgery (7.6%), endocrine therapy (4.5%), chemotherapy (19.7%), targeted therapy (4.5%), radiotherapy (18.2%), enrolment for a clinical trial (12.1%), additional investigations (22.7%), and further referrals (10.6%). MDM recommendations were implemented in 83.7% of cases. CONCLUSION: The breast cancer MDMs were found to substantially impact on the management plans for breast cancer patients, with 83.7% of MDM recommendations being implemented into clinical practice. This study reinforces the importance of MDMs in the management of these patients, as well as highlighting the need for further investigating and addressing the potential barriers to the implementation of MDM recommendations.

A Multicenter, Open-Label, Phase I/II Study of FN-1501 in Patients with Advanced Solid Tumors.

BACKGROUND: FN-1501, a potent inhibitor of receptor FMS-like tyrosine kinase 3 (FLT3) and CDK4/6, KIT, PDGFR, VEGFR2, ALK, and RET tyrosine kinase proteins, has demonstrated significant in vivo activity in various solid tumor and leukemia human xenograft models. Anomalies in FLT3 have an established role as a therapeutic target where the gene has been shown to play a critical role in the growth, differentiation, and survival of various cell types in hematopoietic cancer and have shown promise in various solid tumors. An open-label, Phase I/II study (NCT03690154) was designed to evaluate the safety and PK profile of FN-1501 as monotherapy in patients (pts) with advanced solid tumors and relapsed, refractory (R/R) AML. METHODS: Pts received FN-1501 IV three times a week for 2 weeks, followed by 1 week off treatment in continuous 21-day cycles. Dose escalation followed a standard 3 + 3 design. Primary objectives include the determination of the maximum tolerated dose (MTD), safety, and recommended Phase 2 dose (RP2D). Secondary objectives include pharmacokinetics (PK) and preliminary anti-tumor activity. Exploratory objectives include the relationship between pharmacogenetic mutations (e.g., FLT3, TP53, KRAS, NRAS, etc.), safety, and efficacy; as well as an evaluation of the pharmacodynamic effects of treatment with FN-1501. Dose expansion at RP2D further explored the safety and efficacy of FN-1501 in this treatment setting. RESULTS: A total of 48 adult pts with advanced solid tumors (N = 47) and AML (N = 1) were enrolled at doses ranging from 2.5 to 226 mg IV three times a week for two weeks in 21-day cycles (2 weeks on and 1 week off treatment). The median age was 65 years (range 30-92); 57% were female and 43% were male. The median number of prior lines of treatment was 5 (range 1-12). Forty patients evaluable for dose-limiting toxicity (DLT) assessment had a median exposure of 9.5 cycles (range 1-18 cycles). Treatment-related adverse events (TRAEs) were reported for 64% of the pts. The most common treatment-emergent adverse events (TEAEs), defined as those occurring in ≥20% of pts, primarily consisted of reversible Grade 1-2 fatigue (34%), nausea (32%), and diarrhea (26%). The most common Grade ≥3 events occurring in ≥5% of pts consisted of diarrhea and hyponatremia. Dose escalation was discontinued due to DLTs of Grade 3 thrombocytopenia (N = 1) and Grade 3 infusion-related reaction (N = 1) occurring in 2 pts. The maximum tolerated dose (MTD) was determined to be 170 mg. CONCLUSIONS: FN-1501 demonstrated reasonable safety, tolerability, and preliminary activity against solid tumors in doses up to 170 mg. Dose escalation was terminated based on 2 DLTs occurring at the 226 mg dose level.

Immune and genomic biomarkers of immunotherapy response in cancer of unknown primary.

BACKGROUND: Cancer of unknown primary (CUP) is a heterogeneous group of metastatic cancers where a primary tissue of origin (TOO) is uncertain. Most patients with CUP have limited treatment options and poor survival outcomes. Immune checkpoint inhibitors (ICIs) can be efficacious in some patients with CUP, but the optimal predictive biomarkers are unknown. We therefore assessed immune and genomic biomarkers as well as predicted TOO in patients with CUP, including a subset treated with ICIs. METHODS: Patients with CUP were subject to gene-expression profiling (GEP) and DNA panel sequencing. Immune and stromal-related gene expression was explored by NanoString, including genes associated with immunotherapy response (IR) in other solid malignancies. ICI responsive cancer types were assigned based on Food and Drug Administration-approved indications, and either detection of a latent primary tumor or the TOO was suspected based on genomics informed pathology review. Tumor mutation burden (TMB) and gene mutations were also assessed. RESULTS: A total of 219 patients with CUP were included, 215 assessed for TOO in a previous study, with the majority (163) receiving both RNA and DNA tests. Of GEP profiled cases, 33% (59/175) had a high IR gene-expression score. Of the DNA sequenced cases, 16% (32/203) had high TMB (>10 mutations/Mb), including two with mismatch repair deficiency. Low correlation was observed between TMB and an IR score (R=0.26, p<0.001). Among 110 CUPs with a latent primary or suspected TOO, 47% (52/110) belonged to ICI-responsive cancer types. More than half of the CUPs had at least one feature that may predict ICI response (high IR score, high TMB, ICI-responsive cancer type). Among patients with CUP treated with ICIs, 8/28 (29%) responded (2 complete responses and 6 partial responses). Among non-responders, 9 had stable and 11 had progressive disease. All responders had a high IR score (7/8) and/or high TMB (3/8), while most (5/8) belonged to ICI-responsive cancer types. These features were detected at a lower frequency in non-responders and mostly in patients with stable disease. CONCLUSIONS: A significant fraction of CUP tumors had genomic features previously associated with ICI response. High IR score was the most sensitive predictive feature of ICI response, warranting evaluation in a larger patient series.

A comparison of DNA sequencing and gene expression profiling to assist tissue of origin diagnosis in cancer of unknown primary.

Cancer of unknown primary (CUP) is a syndrome defined by clinical absence of a primary cancer after standardised investigations. Gene expression profiling (GEP) and DNA sequencing have been used to predict primary tissue of origin (TOO) in CUP and find molecularly guided treatments; however, a detailed comparison of the diagnostic yield from these two tests has not been described. Here, we compared the diagnostic utility of RNA and DNA tests in 215 CUP patients (82% received both tests) in a prospective Australian study. Based on retrospective assessment of clinicopathological data, 77% (166/215) of CUPs had insufficient evidence to support TOO diagnosis (clinicopathology unresolved). The remainder had either a latent primary diagnosis (10%) or clinicopathological evidence to support a likely TOO diagnosis (13%) (clinicopathology resolved). We applied a microarray (CUPGuide) or custom NanoString 18-class GEP test to 191 CUPs with an accuracy of 91.5% in known metastatic cancers for high-medium confidence predictions. Classification performance was similar in clinicopathology-resolved CUPs - 80% had high-medium predictions and 94% were concordant with pathology. Notably, only 56% of the clinicopathology-unresolved CUPs had high-medium confidence GEP predictions. Diagnostic DNA features were interrogated in 201 CUP tumours guided by the cancer type specificity of mutations observed across 22 cancer types from the AACR Project GENIE database (77,058 tumours) as well as mutational signatures (e.g. smoking). Among the clinicopathology-unresolved CUPs, mutations and mutational signatures provided additional diagnostic evidence in 31% of cases. GEP classification was useful in only 13% of cases and oncoviral detection in 4%. Among CUPs where genomics informed TOO, lung and biliary cancers were the most frequently identified types, while kidney tumours were another identifiable subset. In conclusion, DNA and RNA profiling supported an unconfirmed TOO diagnosis in one-third of CUPs otherwise unresolved by clinicopathology assessment alone. DNA mutation profiling was the more diagnostically informative assay. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Is There a Relationship Between Frequency of Port-Care Maintenance and Related Complications in Patients With Cancer?

PURPOSE: Totally implantable ports require regular maintenance to prevent port-related complications. Manufacturers recommend monthly maintenance port flushes for patients for the life of the port. Previous studies show that extending intervals between maintenance port flushes up to 16 weeks does not increase incidence of port-related complications. To date, no prospective study has been conducted to evaluate the medical safety of extending flush intervals from monthly to every 12 weeks within a heterogeneous disease cohort. Research Question: Is it feasible and medically safe to extend intervals between maintenance port flushes to every 12 weeks in patients with cancer not on active treatment? PATIENTS AND METHODS: This study enrolled oncology and hematology patients who had retained their port following completion of anticancer treatment. Clinical data were extracted for 1,059 participants. The primary end points of this study were the overall number of ports removed and incidence of port-related complications reported between cohorts 1 and 2 (flushes every 4-8 weeks), and cohort 3 (flushes every 12 weeks). RESULTS: Data were allocated into three study cohorts on the basis of year and duration between port flushes. No difference was observed in the overall percentage of ports removed because of physician-reported complications across all cohorts (25%-30%). No change in the incidence of port-related complications including suspected infection and malfunction was observed between cohorts 1 and 2 (8%), or cohort 3 (5%). CONCLUSION: Our findings show that extending maintenance port flush intervals to 12 weeks does not increase the incidence of port-related adverse events and is medically safe.

The role of depression and other psychological factors in work ability among breast cancer survivors in Australia.

OBJECTIVE: Identifying modifiable factors affecting work ability among cancer survivors is important. The primary aim of the present study was to examine the effects of depression and related psychological factors on work ability among breast cancer survivors in Australia. METHODS: In this cross-sectional electronic and postal survey, Australian breast cancer survivors were investigated. Work status and conditions before and after cancer treatment were analysed. Work ability was measured using the Work Limitation Questionnaire©-Short Form (WLQ-SF) with its four domains (time management, physical tasks, mental-interpersonal tasks, and output tasks). Three psychological factors were investigated: depression, fear of cancer recurrence, and demoralisation. Sociodemographic and clinical data were also collected. Multivariate regression analysis was used to identify the associations of psychological factors with WLQ-SF. RESULTS: Among eligible survivors, 310 (50%) responded to the survey and were analysed. Nearly one third reported their work conditions had changed after cancer treatment. The depressed group reported limited work ability in 35%-44% of the four domains of WLQ-SF, while the non-depressed group reported limited work ability in only 8%-13%. At-work productivity loss was approximately fourfold higher in the depressed group than in the non-depressed group. In multivariate analysis, at-work productivity loss was associated with depression, demoralisation, and past history of anxiety. CONCLUSIONS: After breast cancer treatment, work conditions changed toward lower wages and working hours. Depression, demoralisation, and past history of anxiety were associated with lower work ability. Further evaluations of work rehabilitation in breast cancer survivors are warranted.

Evaluation of FGFR targeting in breast cancer through interrogation of patient-derived models.

BACKGROUND: Particular breast cancer subtypes pose a clinical challenge due to limited targeted therapeutic options and/or poor responses to the existing targeted therapies. While cell lines provide useful pre-clinical models, patient-derived xenografts (PDX) and organoids (PDO) provide significant advantages, including maintenance of genetic and phenotypic heterogeneity, 3D architecture and for PDX, tumor-stroma interactions. In this study, we applied an integrated multi-omic approach across panels of breast cancer PDXs and PDOs in order to identify candidate therapeutic targets, with a major focus on specific FGFRs. METHODS: MS-based phosphoproteomics, RNAseq, WES and Western blotting were used to characterize aberrantly activated protein kinases and effects of specific FGFR inhibitors. PDX and PDO were treated with the selective tyrosine kinase inhibitors AZD4547 (FGFR1-3) and BLU9931 (FGFR4). FGFR4 expression in cancer tissue samples and PDOs was assessed by immunohistochemistry. METABRIC and TCGA datasets were interrogated to identify specific FGFR alterations and their association with breast cancer subtype and patient survival. RESULTS: Phosphoproteomic profiling across 18 triple-negative breast cancers (TNBC) and 1 luminal B PDX revealed considerable heterogeneity in kinase activation, but 1/3 of PDX exhibited enhanced phosphorylation of FGFR1, FGFR2 or FGFR4. One TNBC PDX with high FGFR2 activation was exquisitely sensitive to AZD4547. Integrated 'omic analysis revealed a novel FGFR2-SKI fusion that comprised the majority of FGFR2 joined to the C-terminal region of SKI containing the coiled-coil domains. High FGFR4 phosphorylation characterized a luminal B PDX model and treatment with BLU9931 significantly decreased tumor growth. Phosphoproteomic and transcriptomic analyses confirmed on-target action of the two anti-FGFR drugs and also revealed novel effects on the spliceosome, metabolism and extracellular matrix (AZD4547) and RIG-I-like and NOD-like receptor signaling (BLU9931). Interrogation of public datasets revealed FGFR2 amplification, fusion or mutation in TNBC and other breast cancer subtypes, while FGFR4 overexpression and amplification occurred in all breast cancer subtypes and were associated with poor prognosis. Characterization of a PDO panel identified a luminal A PDO with high FGFR4 expression that was sensitive to BLU9931 treatment, further highlighting FGFR4 as a potential therapeutic target. CONCLUSIONS: This work highlights how patient-derived models of human breast cancer provide powerful platforms for therapeutic target identification and analysis of drug action, and also the potential of specific FGFRs, including FGFR4, as targets for precision treatment.

Avelumab alone or in combination with chemotherapy versus chemotherapy alone in platinum-resistant or platinum-refractory ovarian cancer (JAVELIN Ovarian 200): an open-label, three-arm, randomised, phase 3 study.

BACKGROUND: Most patients with ovarian cancer will relapse after receiving frontline platinum-based chemotherapy and eventually develop platinum-resistant or platinum-refractory disease. We report results of avelumab alone or avelumab plus pegylated liposomal doxorubicin (PLD) compared with PLD alone in patients with platinum-resistant or platinum-refractory ovarian cancer. METHODS: JAVELIN Ovarian 200 was an open-label, parallel-group, three-arm, randomised, phase 3 trial, done at 149 hospitals and cancer treatment centres in 24 countries. Eligible patients were aged 18 years or older with epithelial ovarian, fallopian tube, or peritoneal cancer (maximum of three previous lines for platinum-sensitive disease, none for platinum-resistant disease) and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1:1) via interactive response technology to avelumab (10 mg/kg intravenously every 2 weeks), avelumab plus PLD (40 mg/m2 intravenously every 4 weeks), or PLD and stratified by disease platinum status, number of previous anticancer regimens, and bulky disease. Primary endpoints were progression-free survival by blinded independent central review and overall survival in all randomly assigned patients, with the objective to show whether avelumab alone or avelumab plus PLD is superior to PLD. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02580058. The trial is no longer enrolling patients and this is the final analysis of both primary endpoints. FINDINGS: Between Jan 5, 2016, and May 16, 2017, 566 patients were enrolled and randomly assigned (combination n=188; PLD n=190, avelumab n=188). At data cutoff (Sept 19, 2018), median duration of follow-up for overall survival was 18·4 months (IQR 15·6-21·9) for the combination group, 17·4 months (15·2-21·3) for the PLD group, and 18·2 months (15·8-21·2) for the avelumab group. Median progression-free survival by blinded independent central review was 3·7 months (95% CI 3·3-5·1) in the combination group, 3·5 months (2·1-4·0) in the PLD group, and 1·9 months (1·8-1·9) in the avelumab group (combination vs PLD: stratified HR 0·78 [repeated 93·1% CI 0·59-1·24], one-sided p=0·030; avelumab vs PLD: 1·68 [1·32-2·60], one-sided p>0·99). Median overall survival was 15·7 months (95% CI 12·7-18·7) in the combination group, 13·1 months (11·8-15·5) in the PLD group, and 11·8 months (8·9-14·1) in the avelumab group (combination vs PLD: stratified HR 0·89 [repeated 88·85% CI 0·74-1·24], one-sided p=0·21; avelumab vs PLD: 1·14 [0·95-1·58], one-sided p=0·83]). The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysesthesia syndrome (18 [10%] in the combination group vs nine [5%] in the PLD group vs none in the avelumab group), rash (11 [6%] vs three [2%] vs none), fatigue (ten [5%] vs three [2%] vs none), stomatitis (ten [5%] vs five [3%] vs none), anaemia (six [3%] vs nine [5%] vs three [2%]), neutropenia (nine [5%] vs nine [5%] vs none), and neutrophil count decreased (eight [5%] vs seven [4%] vs none). Serious treatment-related adverse events occurred in 32 (18%) patients in the combination group, 19 (11%) in the PLD group, and 14 (7%) in the avelumab group. Treatment-related adverse events resulted in death in one patient each in the PLD group (sepsis) and avelumab group (intestinal obstruction). INTERPRETATION: Neither avelumab plus PLD nor avelumab alone significantly improved progression-free survival or overall survival versus PLD. These results provide insights for patient selection in future studies of immune checkpoint inhibitors in platinum-resistant or platinum-refractory ovarian cancer. FUNDING: Pfizer and Merck KGaA, Darmstadt, Germany.

Impact of prior (neo)adjuvant trastuzumab (NAT) exposure on the efficacy of HER2-targeted therapy for metastatic breast cancer.

PURPOSE: Trastuzumab, pertuzumab, and docetaxel are the standard first-line therapy for HER2-positive (HER2+) metastatic breast cancer (MBC). However, only 10% of patients received neoadjuvant and/or adjuvant trastuzumab (NAT) in the registration trial (NCT00567190). In contemporary practice, the majority of recurrent HER2+ MBC patients had prior NAT. We explore any impact of prior therapy on the efficacy of dual HER2-targeted antibody with taxane therapy for metastatic disease. METHODS: Utilising a prospective national registry, clinico-pathological, treatment, and outcome data for HER2+ MBC patients diagnosed between October 2006 and January 2019 were collected. Survival was estimated by the Kaplan-Meier method and compared among groups by log-rank test. RESULTS: Of 287 HER2+ MBC patients, 222 (77%) received first-line trastuzumab, pertuzumab, and taxane therapy. There were 130 (45%) with de novo MBC. Of the recurrent MBC patients 107/157 (68%) had received NAT. The median progression-free survival (PFS) among patients who received NAT was 15.8 months compared with 24.3 months without prior NAT (hazard ratio [HR] 1.45, 95% CI 1.05-2.03, p = 0.03). The median overall survival (OS) was 42.7 months in patients who had NAT, and was not reached in those who did not (HR 1.80, 95% CI 1.12-2.90, p = 0.02). However, when excluding de novo MBC patients, prior NAT exposure was no longer significantly associated with survival (p = 0.11). De novo MBC patients had the longest median PFS (25.2 months) and OS (91.2 months). CONCLUSIONS: Prior receipt of NAT was associated with inferior median PFS following first-line HER2-based therapy in the metastatic setting. However, prior NAT exposure did not significantly impact OS, supporting the efficacy of taxane, trastuzumab, pertuzumab combination for first-line HER2+ MBC regardless of prior NAT exposure. Patients with de novo MBC had the longest survival, suggesting stratification for synchronous versus metachronous disease in prospective clinical trials of MBC should be considered.

Phase I, Open-Label, Dose-Escalation/Dose-Expansion Study of Lifirafenib (BGB-283), an RAF Family Kinase Inhibitor, in Patients With Solid Tumors.

PURPOSE: Lifirafenib is an investigational, reversible inhibitor of B-RAFV600E, wild-type A-RAF, B-RAF, C-RAF, and EGFR. This first-in-human, phase I, dose-escalation/dose-expansion study evaluated the safety, tolerability, and efficacy of lifirafenib in patients with B-RAF- or K-RAS/N-RAS-mutated solid tumors. METHODS: During dose escalation, adult patients with histologically/cytologically confirmed advanced solid tumors received escalating doses of lifirafenib. Primary end points were safety/tolerability during dose escalation and objective response rate in preselected patients with B-RAF and K-RAS/N-RAS mutations during dose expansion. RESULTS: The maximum tolerated dose was established as 40 mg/d; dose-limiting toxicities included reversible thrombocytopenia and nonhematologic toxicity. Across the entire study, the most common grade ≥ 3 treatment-emergent adverse events were hypertension (n = 23; 17.6%) and fatigue (n = 13; 9.9%). One patient with B-RAF-mutated melanoma achieved complete response, and 8 patients with B-RAF mutations had confirmed objective responses: B-RAFV600E/K melanoma (n = 5, including 1 patient treated with prior B-RAF/MEK inhibitor therapy), B-RAFV600E thyroid cancer/papillary thyroid cancer (PTC; n = 2), and B-RAFV600E low-grade serous ovarian cancer (LGSOC; n = 1). One patient with B-RAF-mutated non-small-cell lung cancer (NSCLC) had unconfirmed partial response (PR). Patients with K-RAS-mutated endometrial cancer and K-RAS codon 12-mutated NSCLC had confirmed PR (n = 1 each). No responses were seen in patients with K-RAS/N-RAS-mutated colorectal cancer (n = 20). CONCLUSION: Lifirafenib is a novel inhibitor of key RAF family kinases and EGFR, with an acceptable risk-benefit profile and antitumor activity in patients with B-RAFV600-mutated solid tumors, including melanoma, PTC, and LGSOC, as well as K-RAS-mutated NSCLC and endometrial carcinoma. Future comparisons with first-generation B-RAF inhibitors and exploration of lifirafenib alone or as combination therapy in patients with selected RAS mutations who are resistant/refractory to first-generation B-RAF inhibitors are warranted.

Chemotherapy and biologic use in the routine management of metastatic colorectal cancer in Australia: is clinical practice following the evidence?

BACKGROUND: Emerging evidence on the optimal use of chemotherapy and biologics in patients with metastatic colorectal cancer should impact management in routine care. Recent studies have demonstrated benefits for initial triplet chemotherapy (5-fluorouracil, oxaliplatin and irinotecan, FOLFOXIRI) and for initial treatment with an epidermal growth factor receptor inhibitor (EGFRi) in patients with a RAS wild-type tumour and a left-sided primary tumour. AIM: To explore evolving pattern of metastatic colorectal cancer care over time in Australia. METHODS: We analysed data from the Treatment of Recurrent and Advanced Colorectal Cancer registry. RESULTS: From July 2009 to December 2017, 2552 metastatic colorectal cancer patients were entered into the Treatment of Recurrent and Advanced Colorectal Cancer registry. Of 1585 patients who initially underwent chemotherapy, treatment was with a doublet in 76%. FOLFOXIRI was given to 22 patients (1.4%), mostly young patients and those with potentially resectable disease. Along with first-line chemotherapy, 61% received bevacizumab, while 3.3% received an EGFRi, predominantly over the last 2 years. Within the KRAS wild-type left-sided tumour cohort, EGFRi use increased from 9% in 2015 to 37% in 2017. Across treatment sites, there was a wide variation in the utilisation of FOLFOXIRI and EGFRi therapy; bevacizumab use was more consistent. A clear impact on survival outcomes from these regimens is not evident, potentially due to multiple confounders. CONCLUSION: Doublet chemotherapy + bevacizumab remains the dominant initial strategy, with limited uptake of triplet chemotherapy and of EGFRi. Potential explanations include uncertainty about the significance of post hoc analyses for EGFRi and concerns regarding adverse events for both strategies.

How Should Remote Clinical Monitoring Be Used to Treat Alcohol Use Disorders?: Initial Findings From an Expert Round Table Discussion.

Scientific evidence combined with new health insurance coverage now enable a chronic illness management approach to the treatment of alcohol use disorders (AUDs), including regular monitoring of blood alcohol content (BAC), as a useful indicator of disease control. Recent technical advances now permit many different types of remote, real-time monitoring of BAC. However, there is no body of research to empirically guide clinicians in how to maximize the clinical potential of remote BAC monitoring.As an initial step in guiding and supporting such research, the manufacturer of one remote BAC monitoring system sponsored a group of experienced clinicians and clinical researchers to discuss 8 issues that generally affect remote, clinical BAC monitoring of "adults in outpatient AUD treatment."The expert panel unanimously agreed that remote BAC monitoring for at least 12 months during and after the outpatient treatment of AUD was a clinically viable deterrent to relapse. There was also consensus that positive test results (ie, recent alcohol use) should lead to intensified care and monitoring. However, there was no agreement on specific types of clinical intensification after a positive test. The panel agreed that sharing positive and negative test results with members of the patient support group was helpful in reinforcing abstinence, yet they noted many practical issues regarding information sharing that remain concerning. Significant differences within the panel on several important clinical issues underline the need for more clinical and implementation research to produce empirically-supported guidelines for the use of remote BAC monitoring in AUD treatment.

The impact of bevacizumab in metastatic colorectal cancer with an intact primary tumor: Results from a large prospective cohort study.

BACKGROUND: Debate continues regarding the benefits versus risks of initial resection of the primary tumor in metastatic colorectal cancer (mCRC) patients with an asymptomatic primary tumor. Although the benefit of the anti-vascular endothelial growth factor agent bevacizumab alongside first-line chemotherapy in mCRC is established, the impact of bevacizumab on the intact primary tumor (IPT) is less well understood. METHODS: Data from an Australian mCRC registry were used to assess the impact of bevacizumab-based regimens in the presence of an IPT, to see if this differs from effects in resected primary tumor (RPT) patients and to understand the safety profile of bevacizumab in patients with IPT. Progression-free survival (PFS), overall survival (OS) and safety endpoints were analyzed. RESULTS: Of 1204 mCRC patients, 826 (69%) were eligible for inclusion. Bevacizumab use was similar in both arms (IPT (64%) versus RPT (70%)); compared with chemotherapy alone, bevacizumab use was associated with significantly longer PFS (IPT: 8.5 months vs 4.7 months, P = 0.017; RPT: 10.8 months vs 5.8 months, P < 0.001) and OS (IPT: 20 months vs 14.8 months, P = 0.005; RPT: 24.4 months vs 17.3 months, P = 0.004)).1 Bevacizumab use in an IPT was associated with more GI perforations (4.5% vs 1.8%, P = 0.210) but less frequent bleeding (1.5% vs 5.3%, P = 0.050) and thrombosis (1.5% vs 2.7%, P = 0.470), versus chemotherapy alone. Median survival was equivalent between patients that did or did not experience bevacizumab-related adverse events - 20.0 months versus 19.9 months, hazard ratio = 0.98, P = 0.623.1 CONCLUSIONS: The addition of bevacizumab significantly improved survival outcomes in mCRC with an IPT. The occurrence of bevacizumab-related adverse events did not significantly impact survival outcomes.

Final results of a phase 3 study of trebananib plus weekly paclitaxel in recurrent ovarian cancer (TRINOVA-1): Long-term survival, impact of ascites, and progression-free survival-2.

PURPOSE: Trebananib, a peptibody that blocks binding of angiopoietin-1 and -2 to Tie2, significantly prolonged progression-free survival (PFS) in patients with recurrent epithelial ovarian cancer in the phase 3 TRINOVA-1 study. We report overall survival (OS) in the intent-to-treat population and clinically relevant subgroups and time to second disease progression (PFS-2). PATIENTS AND METHODS: Women with recurrent disease (platinum-free interval<12months) were randomized to receive intravenous paclitaxel 80mg/m(2) (3weeks on/1week off) plus intravenous trebananib 15mg/kg or placebo, weekly. OS in the intent-to-treat population was a key secondary endpoint. Exploratory analysis of PFS-2 was conducted according to guidance by the European Medicines Agency. RESULTS: Median OS was not significantly improved with trebananib compared with placebo (19.3 versus 18.3months; HR, 0.95; 95% CI, 0.81-1.11; P=0.52) in the intent-to-treat population (n=919). In subgroup analysis, trebananib improved median OS compared with placebo (14.5 versus 12.3months; HR, 0.72; 95% CI, 0.55-0.93; P=0.011) in patients with ascites at baseline (n=295). In the intent-to-treat population, trebananib significantly improved median PFS-2 compared with placebo (12.5 versus 10.9months; HR, 0.85; 95% CI, 0.74-0.98; P=0.024). The incidence and type of adverse events in this updated analysis was consistent with that described in the primary analysis; no new safety signals were detected. CONCLUSIONS: OS was not significantly longer in the intent-to-treat population, although there was an improvement in OS in patients with ascites receiving trebananib. PFS-2 confirmed that the PFS benefit associated with trebananib was maintained through the second disease progression independent of the choice of subsequent therapy.

Impact of Primary Tumor Site on Bevacizumab Efficacy in Metastatic Colorectal Cancer.

BACKGROUND: With an ever-increasing focus on personalized medicine, all factors known to affect treatment response need to be considered when defining optimal therapy for individual patients. While the prognostic impact of primary tumor site on colorectal cancer (CRC) outcomes is established, emerging data suggest potential differences in response to biologic therapies. We studied the impact of tumor site on bevacizumab efficacy in patients with metastatic CRC. PATIENTS AND METHODS: We analyzed data of patients in an Australian prospective multicenter metastatic CRC (mCRC) registry who received first-line chemotherapy. Tumor site was defined as right colon, cecum to transverse; left colon, splenic flexure to rectosigmoid; and rectum. Kaplan-Meier and Cox models were used for survival analyses. RESULTS: Of 926 patients, 297 had right colon, 354 left colon, and 275 rectum primary disease. Median age was 68.6, 65.9, and 63.3 years, respectively (P = .001). Right colon disease was significantly associated with intraperitoneal spread (P < .0001), while left colon and rectum disease preferentially metastasized to the liver and lungs, respectively (P < .0001 in both settings). A total of 636 patients (68.7%) received bevacizumab. Progression-free survival was superior for bevacizumab-treated patients in all groups but appeared greatest in right colon disease (hazard ratio, 0.46; 95% confidence interval, 0.36-0.60; P ≤ .001). Overall survival was longest in patients with disease of the rectum, followed by left colon and right colon (median, 26.2, 23.6, and 18.2 months, respectively; P = .0004). CONCLUSION: Tumor site appears to be prognostic in mCRC, with rectum and right colon disease associated with the best and worst outcomes, respectively. Patients who received bevacizumab in addition to chemotherapy had superior outcomes, with the effect appearing greatest in patients with right colon disease.

Primary Tumor Resection and Overall Survival in Patients With Metastatic Colorectal Cancer Treated With Palliative Intent.

BACKGROUND: The survival impact of primary tumor resection in patients with metastatic colorectal cancer (mCRC) treated with palliative intent remains uncertain. In the absence of randomized data, the objectives of the present study were to examine the effect of primary tumor resection (PTR) and major prognostic variables on overall survival (OS) of patients with de novo mCRC. PATIENTS AND METHODS: Consecutive patients from the Australian 'Treatment of Recurrent and Advanced Colorectal Cancer' registry were examined from June 2009 to March 2015. Univariate and multivariate Cox proportional hazards regression analyses were used to identify associations between multiple patient or clinical variables and OS. Patients with metachronous mCRC were excluded from the analyses. RESULTS: A total of 690 patients de novo and 373 metachronous mCRC patients treated with palliative intent were identified. The median follow-up period was 30 months. The median age of de novo patients was 66 years; 57% were male; 77% had an Eastern Cooperative Oncology Group performance status of 0 to 1; and 76% had a colon primary. A total of 216 de novo mCRC patients treated with palliative intent underwent PTR at diagnosis and were more likely to have a colon primary (odds ratio [OR], 15.4), a lower carcinoembryonic antigen level (OR, 2.08), and peritoneal involvement (OR, 2.58; P < .001). On multivariate analysis, PTR at diagnosis in de novo patients was not associated with significantly improved OS (hazard ratio [HR], 0.82; 99% confidence interval [CI], 0.62-1.09; P = .068). PTR at diagnosis did not correlate with outcome in de novo patients with a colon primary (HR, 0.74; 99% CI, 0.54-1.01; P = .014) or a rectal primary (HR, 0.81; 99% CI, 0.27-2.44; P = .621). CONCLUSION: For de novo mCRC patients treated with palliative intent, PTR at diagnosis does not significantly improve OS when adjusting for known major prognostic factors. The outcomes of randomized trials examining the survival impact of PTR are awaited.

"Cancer 2015": A Prospective, Population-Based Cancer Cohort-Phase 1: Feasibility of Genomics-Guided Precision Medicine in the Clinic.

"Cancer 2015" is a longitudinal and prospective cohort. It is a phased study whose aim was to pilot recruiting 1000 patients during phase 1 to establish the feasibility of providing a population-based genomics cohort. Newly diagnosed adult patients with solid cancers, with residual tumour material for molecular genomics testing, were recruited into the cohort for the collection of a dataset containing clinical, molecular pathology, health resource use and outcomes data. 1685 patients have been recruited over almost 3 years from five hospitals. Thirty-two percent are aged between 61-70 years old, with a median age of 63 years. Diagnostic tumour samples were obtained for 90% of these patients for multiple parallel sequencing. Patients identified with somatic mutations of potentially "actionable" variants represented almost 10% of those tumours sequenced, while 42% of the cohort had no mutations identified. These genomic data were annotated with information such as cancer site, stage, morphology, treatment and patient outcomes and health resource use and cost. This cohort has delivered its main objective of establishing an upscalable genomics cohort within a clinical setting and in phase 2 aims to develop a protocol for how genomics testing can be used in real-time clinical decision-making, providing evidence on the value of precision medicine to clinical practice.