Immune-checkpoint inhibitors for metastatic colorectal cancer : a systematic review of clinical outcomes

Background. Colorectal cancer (CRC) is the fourth most deadly cancer worldwide. Unfortunately, a quarter of the patients are diagnosed at late stages, when surgical options are limited. Targeted therapies, particularly immune-checkpoint inhibitors (ICIs), are the latest addition and have been studied herein regarding their efficacy outcomes. Methods. Clinical studies were identified through the PubMed, Scopus and Cochrane databases. Any trial that evaluated ICIs in patients with metastatic CRC (mCRC) and reported the objective response rate was deemed eligible. Data analysis was performed by employing the random-effects model in STATA v.17. Results. A total of 461 articles were identified; 13 clinical trials were included, encompassing a total cohort of 1209 patients. Our study determined that a single PD-1/PD-L1 checkpoint blockade provides durable clinical response in mCRC patients with high microsatellite instability (MSI-H). The combinatorial therapy of CTLA-4 + PD-1 inhibitors also showed high response rates in pre-treated MSI-H patients. The single-arm REGONIVO trial reported durable clinical response in patients with microsatellite stable (MSS) status. Conclusions. Our study surmises that PD-1/PD-L1 inhibitors as well as combination therapy with CTLA-4 and PD-1 inhibitors show encouraging response rates in mCRC patients, albeit exclusively in patients with cancer that are of MSI-H status. A single study suggests that nivolumab + regorafenib can reach a durable response rate in MSS patients; however, further studies in larger randomized settings are required

A mixed methods approach to developing and evaluating oncology trainee education around minimization of adverse events and improved patient quality and safety

BACKGROUND: Adverse events are a significant quality and safety issue in the hospital setting due to their direct impact on patients. Additionally, such events are often handled by junior doctors due to their direct involvement with patients. As such, it is important for health care organizations to prioritize education and training for junior doctors on identifying adverse events and handling them when they occur. The Cancer Cup Challenge is an educational program focuses on quality improvement and adverse event awareness targeting for junior oncology doctors across three international sites. METHODS: A mixed methodology was used to develop and evaluate the program. The Qstream spaced learning platform was used to disseminate information to participants, as it has been demonstrated to impact on both knowledge and behavior. Eight short case based scenarios with expert feedback were developed by a multidisciplinary advisory committee containing representatives from the international sites. At the conclusion of the course impact on participant knowledge was evaluated using analysis of the metrics collected by the Qstream platform. Additionally, an online survey and semi-structured interviews were used to evaluate engagement and perceived value by participants. RESULTS: A total of 35 junior doctors registered to undertake the Qstream program, with 31 (88.57 %) successfully completing it. Analysis of the Qstream metrics revealed 76.57 % of cases were answered correctly on first attempt. The post-program survey received 17 responses, with 76.47 % indicating cases for the course were interesting and 82.35 % feeling cases were relevant. Finally, 14 participants consented to participate in semi-structured interviews about the program, with feedback towards the course being generally very positive. CONCLUSIONS: Our study demonstrates that an online game is well accepted by junior doctors as a method to increase their quality improvement awareness. Developing effective and sustainable training for doctors is important to ensure positive patient outcomes are maintained in the hospital setting. This is particularly important for junior doctors as they are working closely with patients and learning skills and behaviors, which will influence their practice throughout their careers

Molecular Pathways in Low-Grade Serous Ovarian Cancer

Low-grade serous cancer (LGSC) is a distinct subtype of ovarian cancer (OC), characterised by younger age at diagnosis and low chemotherapy response rates compared with the most common subtype, high-grade serous. Most women are diagnosed with advanced stage disease and there are few effective treatment options beyond surgery. We aimed to increase the understanding of the clinical and molecular features of LGSC and shed light on new treatment options. Applying stringent criteria, LGSC cases (n=99) were identified from >4,000 women being investigated for OC, representing one of the largest LGSC cohorts described to date. Tumour mutations were found in KRAS (26/99, 26.3%), BRAF (13/99, 13.1%) and NRAS (10/99, 10.1%). Few clinical differences were associated with RAS/RAF mutations, although, RAS/RAF-wildtype (WT) cases were more commonly primary peritoneal, and had worse survival compared with RAS/RAF-mutated cases. LGSC were resistant to carboplatin, in patients and in cell lines, and women who received neoadjuvant chemotherapy rather than upfront surgical debulking, had worse outcomes. Responses to paclitaxel, gemcitabine and liposomal doxorubicin were variable in LGSC cell lines, and although case numbers were small, there were more responses to these agents compared with carboplatin. This suggests that these agents could be used in preference to carboplatin in some women with LGSC. Targeting the RAS-MAPK pathway in LGSC shows promise. Sustained responses to BRAF inhibitors were seen in two women with BRAFV600 LGSC, and a second-generation RAF inhibitor decreased proliferation in KRAS-mutant cell lines suggesting activity beyond BRAFV600E LGSC. The effect of MEK inhibition differed markedly between LGSC cell lines, and RAS/RAF mutations alone did not predict response. In women, responses were seen in KRAS- and NRAS-mutation positive cases and interestingly, in RAS/RAF-WT LGSC. Rational combination approaches were explored and MEK in combination with PI3K/mTOR, CDK4/6 or RAF inhibitors were synergistic in some LGSC cell lines. In summary, the work presented advances the understanding of LGSC and highlights heterogeneous responses to treatment. Molecular characterisation, novel clinical trial designs and rationally targeted treatments are needed to improve outcomes for women with LGSC

Dual-energy x-ray absorptiometry assessment of bone health in Australian men with prostate cancer commencing androgen deprivation therapy

Objective: To determine the prevalence in Australia of bone health assessment of men with prostate cancer by dual-energy x-ray absorptiometry (DXA), from six months before to twelve months after initiation of androgen deprivation therapy (ADT). Design, setting: Cross-sectional national study; linkage of de-identified Medicare Benefits Schedule (MBS) and Pharmaceutical Benefits Scheme (PBS) data. Participants: Men (18 years or older) first dispensed PBS-subsidised ADT during 1 May 2017 – 31 July 2020. Main outcome measures: Prevalence of MBS-subsidised DXA assessments undertaken from six months before to twelve months after first ADT prescription. Results: Of 33 836 men with prostate cancer commencing ADT therapy during 2017–20, 6683 (19.8%) underwent DXA bone heath assessments between six months before and twelve months after commencing ADT; the mean time from first ADT dispensing to DXA scanning was +90 days (standard deviation, 134 days). The proportion of men aged 54 years or younger who had scans (66 of 639, 10%) was smaller than that of men aged 70–84 years (4528 of 19 378, 23.4%; adjusted odds ratio, 0.36; 95% CI, 0.28–0.47). Conclusions: For about 80% of men with prostate cancer commencing ADT in Australia, therapy initiation was not accompanied by DXA assessment of bone health. Given the excellent long term prognosis for men with prostate cancer and the availability of bone protective therapy, bone health monitoring should be a routine component of prostate cancer care for men receiving ADT

PARAGON: A Phase II study of anastrozole in patients with estrogen receptor-positive recurrent/metastatic low-grade ovarian cancers and serous borderline ovarian tumors

Objective: Treatment options are limited for patients with recurrent/metastatic low-grade ovarian cancers (LGOCs) and serous borderline ovarian tumors (SBOTs) as response rates to chemotherapy are low. A subset of patients appears to derive clinical benefit from antiestrogens, but most studies have been retrospective and clinical benefit rates (CBR) remain uncertain. The primary aim of PARAGON was to prospectively investigate the CBR of anastrozole, an aromatase inhibitor, in patients with estrogen receptor (ER) and/or progesterone receptor (PR) positive LGOC and SBOT. Methods: Post-menopausal women with ER-positive and/or PR-positive recurrent/metastatic LGOCs and SBOTs and evaluable disease by RECIST v1.1 or GCIG CA125 criteria were treated with anastrozole 1 mg daily until progression or unacceptable toxicity. Results: Thirty-six patients were enrolled. Clinical benefit at 3 months (primary endpoint) was observed in 23 patients (64%, 95% CI 48%–78%) and was similar at 6 months (61%, 95% CI 43%–75%). The median duration of clinical benefit was 9.5 months (95% CI 8.3–25.8). Best study response was partial response by RECIST in 5 patients (14%), stable disease in 18 patients (50%) with progressive disease in 13 patients (36%). Median PFS was 11.1 months (95% CI 3.2–11.9). Anastrozole was well-tolerated. Patients with evidence of clinical benefit at 3 months reported less pain, fatigue, and improved physical and role functioning as early as 1 month of commencing treatment. Conclusions: Anastrozole was associated with a CBR of 61% of patients with recurrent ER-positive and/or PR-positive LGOC or SBOT for at least 6 months with acceptable toxicity

EIF1AX and NRAS Mutations Co-occur and Cooperate in Low-Grade Serous Ovarian Carcinomas.

Low-grade serous ovarian carcinomas (LGSC) are associated with a poor response to chemotherapy and are molecularly characterized by RAS pathway activation. Using exome and whole genome sequencing, we identified recurrent mutations in the protein translational regulator EIF1AX and in NF1, USP9X, KRAS, BRAF, and NRAS RAS pathway mutations were mutually exclusive; however, we found significant co-occurrence of mutations in NRAS and EIF1AX Missense EIF1AX mutations were clustered at the N-terminus of the protein in a region associated with its role in ensuring translational initiation fidelity. Coexpression of mutant NRAS and EIF1AX proteins promoted proliferation and clonogenic survival in LGSC cells, providing the first example of co-occurring, growth-promoting mutational events in ovarian cancer. Cancer Res; 77(16); 4268-78. ©2017 AACR

BRAF mutations in low-grade serous ovarian cancer and response to BRAF inhibition

Purpose Low-grade serous ovarian carcinoma (LGSC) responds poorly to chemotherapy and is characterized by activating mutations in the Ras sarcoma-mitogen-activated protein kinase (RAS-MAPK) pathway, including oncogenic BRAF. However, response to BRAF inhibitors is tumor-type specific. Significant improvement in survival is seen in patients with BRAF-mutant melanoma, but other cancer types, such as colorectal cancers, are generally less sensitive. We examined the frequency and characteristics of BRAF-mutated LGSC and described the response to treatment with BRAF inhibitors. Patients and Methods Mutations were assessed in LGSC (N = 65) by using targeted, exome, and whole-genome sequencing. Patient characteristics, treatment, and clinical outcome were assessed, and the median follow-up time was more than 5 years. BRAF inhibitors were trialed in two patients with a somatic BRAF V600E mutation: one patient received dabrafenib monotherapy and was monitored clinically, biochemically (cancer antigen [CA]-125 levels), and with positron emission tomography (PET) imaging. Expression of the BRAF V600E protein in this patient was assessed by immunohistochemistry. Results Among patients with LGSC, nine (13.8%) of 65 had a somatic BRAF mutation. Of the nine patients with BRAF mutation-positive LGSC, four experienced progressive disease that did not respond to conventional chemotherapy. Two of the patients experienced progression quickly and died as a result of disease progression, and two received targeted treatment. Two patients with BRAF V600E mutation received BRAF inhibitors at relapse and both achieved durable responses. Conclusion BRAF mutations are not uncommon in patients with LGSC and should be routinely tested, because BRAF inhibitors can be an effective treatment for these patients. The results highlight the need for targeted treatment in this rare tumor type, and a prospective study is needed to formally assess the response rate and clinical benefit