Detailed DNA methylation characterisation of phyllodes tumours identifies a signature of malignancy and distinguishes phyllodes from metaplastic breast carcinoma.

Phyllodes tumours (PTs) are rare fibroepithelial lesions of the breast that are classified as benign, borderline, or malignant. As little is known about the molecular underpinnings of PTs, current diagnosis relies on histological examination. However, accurate classification is often difficult, particularly for distinguishing borderline from malignant PTs. Furthermore, PTs can be misdiagnosed as other tumour types with shared histological features, such as fibroadenoma and metaplastic breast cancers. As DNA methylation is a recognised hallmark of many cancers, we hypothesised that DNA methylation could provide novel biomarkers for diagnosis and tumour stratification in PTs, whilst also allowing insight into the molecular aetiology of this otherwise understudied tumour. We generated whole-genome methylation data using the Illumina EPIC microarray in a novel PT cohort (n = 33) and curated methylation microarray data from published datasets including PTs and other potentially histopathologically similar tumours (total n = 817 samples). Analyses revealed that PTs have a unique methylome compared to normal breast tissue and to potentially histopathologically similar tumours (metaplastic breast cancer, fibroadenoma and sarcomas), with PT-specific methylation changes enriched in gene sets involved in KRAS signalling and epithelial-mesenchymal transition. Next, we identified 53 differentially methylated regions (DMRs) (false discovery rate < 0.05) that specifically delineated malignant from non-malignant PTs. The top DMR in both discovery and validation cohorts was hypermethylation at the HSD17B8 CpG island promoter. Matched PT single-cell expression data showed that HSD17B8 had minimal expression in fibroblast (putative tumour) cells. Finally, we created a methylation classifier to distinguish PTs from metaplastic breast cancer samples, where we revealed a likely misdiagnosis for two TCGA metaplastic breast cancer samples. In conclusion, DNA methylation alterations are associated with PT histopathology and hold the potential to improve our understanding of PT molecular aetiology, diagnostics, and risk stratification. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Stromal cell diversity associated with immune evasion in human triple-negative breast cancer.

The tumour stroma regulates nearly all stages of carcinogenesis. Stromal heterogeneity in human triple-negative breast cancers (TNBCs) remains poorly understood, limiting the development of stromal-targeted therapies. Single-cell RNA sequencing of five TNBCs revealed two cancer-associated fibroblast (CAF) and two perivascular-like (PVL) subpopulations. CAFs clustered into two states: the first with features of myofibroblasts and the second characterised by high expression of growth factors and immunomodulatory molecules. PVL cells clustered into two states consistent with a differentiated and immature phenotype. We showed that these stromal states have distinct morphologies, spatial relationships and functional properties in regulating the extracellular matrix. Using cell signalling predictions, we provide evidence that stromal-immune crosstalk acts via a diverse array of immunoregulatory molecules. Importantly, the investigation of gene signatures from inflammatory-CAFs and differentiated-PVL cells in independent TNBC patient cohorts revealed strong associations with cytotoxic T-cell dysfunction and exclusion, respectively. Such insights present promising candidates to further investigate for new therapeutic strategies in the treatment of TNBCs.

A novel clinician-delivered intervention to reduce fear of recurrence in breast cancer survivors: Results from a Phase I/II implementation study (CIFeR_2).

OBJECTIVE: Fear of cancer recurrence (FCR) is highly prevalent, however there is no formal training for clinicians to address FCR. A novel brief clinician intervention to help patients manage FCR (Clinician Intervention to Reduce Fear of Recurrence (CIFeR)) was shown to be feasible, acceptable, and reduced FCR in breast cancer patients in a pilot study. We now aim to explore the barriers and facilitators of implementing CIFeR within routine oncology practice in Australia. METHODS: This multicentre, single-arm Phase I/II implementation study recruited surgical, medical and radiation oncologists who treat women with early breast cancer. Participating clinicians completed online CIFeR training and were asked to use CIFeR for the next 6 months. Questionnaires were administered before (T0), immediately after (T1), then 3 (T2) and 6 months (T3) after training to assess confidence in addressing FCR and Proctor Implementation outcomes. The primary outcome was adoption at T2. Secondary outcomes were self-efficacy in FCR management, acceptability, feasibility, costs, barriers and facilitators of implementation. RESULTS: Fifty-two clinicians consented of whom 37 completed the CIFeR intervention training. Median age of participants was 41.5 (range 29-61), 73% were female and 51% were medical oncologists. The primary endpoint was met, with CIFeR adopted by 82%. Clinician intervention delivery took 7.4 min on average and was deemed acceptable, appropriate and feasible. Self-efficacy in managing FCR improved significantly across all domains (p < 0.001). Lack of time was the greatest barrier to routine CIFeR_2 implementation. CONCLUSIONS: A structured brief, low-cost clinician intervention to reduce FCR is useful, acceptable and improved self-efficacy with FCR management. Fear of cancer recurrence training should be incorporated into communication skills training of oncologists and surgeons. TRIAL REGISTRATION: Prospectively registered with the Australian New Zealand Clinical Trials Registry, ACTRN12621001697875. TRIAL SPONSOR: Chris O'Brien Lifehouse.

Platinum-based chemotherapy for early triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer associated with shorter survival and a higher likelihood of the cancer returning. In early TNBC, platinum-based chemotherapy has been shown to improve pathological complete response (pCR); however, its effect on long-term survival outcomes has not been fully elucidated and recommendations to include platinum chemotherapy are not consistent in international guidelines. OBJECTIVES: To evaluate the benefits and harms of platinum-based chemotherapy as adjuvant and neoadjuvant treatment in people with early triple-negative breast cancer. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 4 April 2022. SELECTION CRITERIA: We included randomised controlled trials examining neoadjuvant or adjuvant platinum chemotherapy for early TNBC. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were disease-free survival (DFS) and overall survival (OS). Our secondary outcomes were pCR, treatment adherence, grade III or IV toxicity related to chemotherapy, and quality of life. Prespecified subgroups included BRCA mutation status, homologous recombination deficiency (HRD) status, frequency of chemotherapy, type of platinum agent used, and the presence or absence of anthracycline chemotherapy. We assessed risk of bias using Cochrane's RoB 1 tool and certainty of evidence using the GRADE approach. MAIN RESULTS: From 3972 records, we included 20 published studies involving 21 treatment comparisons, and 25 ongoing studies. For most domains, risk of bias was low across studies. There were 16 neoadjuvant chemotherapy studies (one of which combined neoadjuvant and adjuvant therapy) and four adjuvant chemotherapy trials. Most studies used carboplatin (17 studies) followed by cisplatin (two), and lobaplatin (one). Eight studies had an anthracycline-free intervention arm, five of which had a carboplatin-taxane intervention compared to an anthracycline-taxane control. All studies reporting DFS and OS used carboplatin. Inclusion of platinum chemotherapy improved DFS in neoadjuvant and adjuvant settings (neoadjuvant: hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.53 to 0.75; 7 studies, 8 treatment comparisons, 1966 participants; high-certainty evidence; adjuvant: HR 0.69, 95% CI 0.54 to 0.88; 4 studies, 1256 participants; high-certainty evidence). Platinum chemotherapy in the regimen improved OS (neoadjuvant: HR 0.69, 95% CI 0.55 to 0.86; 7 studies, 8 treatment comparisons, 1973 participants; high-certainty evidence; adjuvant: 0.70, 95% CI 0.50 to 0.96; 4 studies, 1256 participants; high-certainty evidence). Median follow-up for survival outcomes ranged from 36 to 97.6 months. Our analysis confirmed platinum chemotherapy increased pCR rates (risk ratio (RR) 1.44, 95% CI 1.31 to 1.59; 15 studies, 16 treatment comparisons, 3083 participants; high-certainty evidence). Subgroup analyses showed no evidence of differences in DFS according to BRCA mutation status, HRD status, lymph node status, or whether the intervention arm contained anthracycline chemotherapy or not. Platinum chemotherapy was associated with reduced dose intensity, with participants more likely to require chemotherapy delays (RR 2.23, 95% CI 1.70 to 2.94; 4 studies, 5 treatment comparisons, 1053 participants; moderate-certainty evidence), dose reductions (RR 1.77, 95% CI 1.56 to 2.02; 7 studies, 8 treatment comparisons, 2055 participants; moderate-certainty evidence) and early cessation of treatment (RR 1.20, 95% CI 1.04 to 1.38; 16 studies, 17 treatment comparisons, 4178 participants; moderate-certainty evidence). Increased haematological toxicity occurred in the platinum group who were more likely to experience grade III/IV neutropenia (RR 1.53, 95% CI 1.43 to 1.63; 19 studies, 20 treatment comparisons, 4849 participants; moderate-certainty evidence), anaemia (RR 8.20, 95% CI 5.66 to 11.89; 18 studies, 19 treatment comparisons, 4757 participants; moderate-certainty evidence) and thrombocytopenia (RR 7.59, 95% CI 5.10 to 11.29; 18 studies, 19 treatment comparisons, 4731 participants; moderate-certainty evidence). There was no evidence of a difference between chemotherapy groups in febrile neutropenia (RR 1.16, 95% CI 0.89 to 1.49; 11 studies, 3771 participants; moderate-certainty evidence). Renal impairment was very rare (0.4%, 2 events in 463 participants; note 3 studies reported 0 events in both arms; 4 studies; high-certainty evidence). Treatment-related death was very rare (0.2%, 7 events in 3176 participants and similar across treatment groups; RR 0.58, 95% 0.14 to 2.33; 10 studies, 11 treatment comparisons; note 8 studies reported treatment-related deaths but recorded 0 events in both groups. Thus, the RR and CIs were calculated from 3 studies rather than 11; 3176 participants; high-certainty evidence). Five studies collected quality of life data but did not report them. AUTHORS' CONCLUSIONS: Platinum-based chemotherapy using carboplatin in the adjuvant or neoadjuvant setting improves long-term outcomes of DFS and OS in early TNBC, with no evidence of differences by subgroup. This was at the cost of more frequent chemotherapy delays and dose reductions, and greater haematological toxicity, though serious adverse events including neuropathy, febrile neutropenia or treatment-related death were not increased. These findings support the use of platinum-based chemotherapy for people with early TNBC. The optimal dose and regimen are not defined by this analysis, but there is a suggestion that similar relative benefits result from the addition of carboplatin to either anthracycline-free regimens or those containing anthracycline agents.

Protocol of an implementation study of a clinician intervention to reduce fear of recurrence in cancer survivors (CIFeR_2 implementation study).

BACKGROUND: Fear of cancer recurrence (FCR) affects 50-70% of cancer survivors with 30% reporting an unmet need for help with managing FCR. Patients indicate desire to discuss FCR with clinicians, however clinicians indicate discomfort with managing FCR and no formal educational interventions on how to discuss FCR or worry exists for oncology clinicians. Our team developed a novel clinician-driven brief education intervention to help patients manage FCR (the Clinician Intervention to Reduce Fear of Recurrence (CIFeR) intervention). In earlier work, we demonstrated the feasibility, acceptability, and efficacy of CIFeR in reducing FCR in breast cancer patients. We now aim to explore the barriers and facilitators to implementing this low-cost brief intervention within routine oncology practice in Australia. The primary objective is to assess the adoption of CIFeR in routine clinical practice. Secondary objectives are to identify the uptake and sustainability, perceived acceptability, feasibility, costs, barriers and facilitators of implementation of CIFeR in routine clinical practice, and to assess whether training in CIFeR increases clinicians' self-efficacy in managing FCR with their patients. METHODS: This multicentre, single-arm Phase I/II implementation study will recruit medical and radiation oncologists and oncology surgeons who treat women with early breast cancer. Participants will complete online CIFeR training. They will then be asked to use CIFeR with suitable patients for the next 6 months. Participants will complete questionnaires prior to, immediately after and 3 and 6 months after training to assess confidence addressing FCR, and 3 and 6 months after training to assess Proctor Implementation outcomes. At 6 months, they will also be asked to participate in a semi-structured telephone interview to elicit their feedback about barriers and facilitators to using CIFeR in routine clinical practice. DISCUSSION: This study will provide further data to support the routine use of an evidence-based, clinician-lead educational intervention to reduce FCR in breast cancer patients. Additionally, this study will identify any barriers and facilitators to implementing the CIFeR intervention in routine care and evidence for integration of FCR training into oncology communication skills education. TRIAL REGISTRATION: Prospectively registered with the Australian New Zealand Clinical Trials Registry, ACTRN12621001697875. TRIAL SPONSOR: Chris O'Brien Lifehouse. PROTOCOL VERSION: 2.6, Dated 28th February 2023.

Long term risk of distant metastasis in women with non-metastatic breast cancer and survival after metastasis detection: a population-based linked health records study.

OBJECTIVES: To estimate the long term risk of distant metastases (DM) for women with initial diagnoses of non-metastatic breast cancer; to estimate breast cancer-specific and overall survival for women with DM. DESIGN: Population-based health record linkage study. SETTING, PARTICIPANTS: Women diagnosed with localised or regional primary breast cancer recorded in the NSW Cancer Registry, 2001-2002. MAJOR OUTCOME MEASURES: Time from breast cancer diagnosis to first DM, time from first DM to death from breast cancer. SECONDARY OUTCOME: time to death from any cause. RESULTS: 6338 women were diagnosed with non-metastatic breast cancer (localised, 3885; regional, 2453; median age, 59 years [IQR, 49-69 years]). DM were recorded (to 30 September 2016) for 1432 women (23%; median age, 62 years [IQR, 51-73 years]). The 14-year cumulative DM incidence was 22.2% (95% CI, 21.1-23.2%; localised disease: 14.3% [95% CI, 13.2-15.4%]; regional disease: 34.7% [95% CI, 32.8-36.6%]). Annual hazard of DM was highest during the second year after breast cancer diagnosis (localised disease: 2.8%; 95% CI, 2.3-3.3%; regional disease: 9.1%; 95% CI, 7.8-10.3%); from year five it was about 1% for those with localised disease, from year seven about 2% for women with regional disease at diagnosis. Five years after diagnosis, the 5-year conditional probability of DM was 4.4% (95% CI, 3.7-5.1%) for women with localised and 10.4% (95% CI, 9.1-12.0%) for those with regional disease at diagnosis. Median breast cancer-specific survival from first DM record date was 28 months (95% CI, 25-31 months); the annual hazard of breast cancer death after the first DM record declined from 36% (95% CI, 33-40%) during the first year to 14% (95% CI, 11-18%) during the fourth year since detection. CONCLUSIONS: DM risk declines with time from diagnosis of non-metastatic breast cancer, and the annual risk of dying from breast cancer declines with time from initial DM detection. These findings can be used to inform patients at follow-up about changes in risk over time since diagnosis and for planning health services.

Patients' and oncologists' perspectives on a novel Clinician-led Fear of Cancer Recurrence (CIFeR) Intervention.

PURPOSE: Despite strong demand from breast cancer survivors, there is a dearth of flexibly delivered, accessible psychological interventions addressing fear of cancer recurrence (FCR). This study aimed to explore patients' and clinicians' perspectives concerning the experience, utility and barriers to a novel clinician-led FCR intervention (CIFeR). METHODS: Twenty female participants (mean age, 59.8, SD = 11.43), diagnosed with early-stage breast cancer (mean years since diagnosis = 2.8, SD = 1.37 years) participated in telephone interviews, and their five oncologists completed a semi-structured electronic survey. Thematic qualitative analyses were performed on interview transcripts and survey responses. RESULTS: Findings indicated both patients and clinicians were positive about CIFeR with perceived cognitive, behavioural and emotional benefits of CIFeR most pronounced for patients with clinically significant FCR. All patients, however, found that receiving CIFeR (especially the tailored prognostic information) from their oncologists with whom they had a long-standing relationship added a much-needed human element to addressing FCR. Similarly, clinicians valued CIFeR as a clear and consistent way to address unmet needs around FCR, with some barriers around time, language and cultural issues noted. CONCLUSION: Overall, all participants perceived CIFeR as strongly beneficial in reducing FCR and related worries, thus warranting further evaluation of its utility in clinical practice.

Development and usability evaluation of an online self-management intervention for fear of cancer recurrence (iConquerFear).

OBJECTIVE: To develop and evaluate the usability of iConquerFear, an online self-management adaptation of an efficacious face-to-face therapist-delivered treatment for fear of cancer recurrence (FCR). METHODS: iConquerFear development was theory based and person based. Development was guided by Ritterband et al's behaviour change model for internet interventions. iConquerFear end users (cancer survivors) provided iterative feedback in accordance with Yardley et al's person-based approach to maximise engagement and usability. Online focus groups and cognitive interviews were conducted to evaluate the usability of iConquerFear. Discussions were recorded, transcribed verbatim, and thematically analysed. RESULTS: Five online FCR modules were developed. Twenty-three cancer survivors (47% of those eligible) participated; 11/23 (58%) were breast cancer survivors, and average age was 53 years (SD = 10.8). Thematic saturation was reached after six focus groups (n = 16) and seven individual think-aloud interviews. Thematic analysis produced five overarching themes: easy navigation essential; satisfaction and engagement with content; flexible access is key; normalising and empowering; and a useful first step. CONCLUSIONS: Online self-management interventions like iConquerFear have the potential to address the unmet supportive care needs reported by burgeoning numbers of cancer survivors. However, that potential may not be realised unless interventions are rigorously developed and user tested, as benefits are constrained by limited engagement. Themes from the usability testing of iConquerFear highlight the importance of developing flexible, tailored, interactive, and contextual online self-management interventions for people with cancer.

Ovarian suppression for adjuvant treatment of hormone receptor-positive early breast cancer.

BACKGROUND: Approximately 80% of breast cancers amongst premenopausal women are hormone receptor-positive. Adjuvant endocrine therapy is an integral component of care for hormone receptor-positive breast cancer and in premenopausal women includes oestrogen receptor blockade with tamoxifen, temporary suppression of ovarian oestrogen synthesis by luteinising hormone releasing hormone (LHRH) agonists, and permanent interruption of ovarian oestrogen synthesis with oophorectomy or radiotherapy. Recent international consensus statements recommend single-agent tamoxifen or aromatase inhibitors with ovarian function suppression (OFS) as the current standard adjuvant endocrine therapy for premenopausal women (often preceded by chemotherapy). This review examined the role of adding OFS to another treatment (i.e. chemotherapy, endocrine therapy, or both) or comparing OFS to no further adjuvant treatment. OBJECTIVES: To assess effects of OFS for treatment of premenopausal women with hormone receptor-positive early breast cancer. SEARCH METHODS: For this review update, we searched the Specialised Register of the Cochrane Breast Cancer Group, MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 8), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and ClinicalTrials.gov on 26 September 2019. We screened the reference lists of related articles, contacted trial authors, and applied no language restrictions. SELECTION CRITERIA: We included all randomised trials assessing any method of OFS, that is, oophorectomy, radiation-induced ovarian ablation, or LHRH agonists, as adjuvant treatment for premenopausal women with early-stage breast cancer. We included studies that compared (1) OFS versus observation, (2) OFS + chemotherapy versus chemotherapy, (3) OFS + tamoxifen versus tamoxifen, and (4) OFS + chemotherapy + tamoxifen versus chemotherapy + tamoxifen. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias and certainty of evidence using the GRADE approach. Hazard ratios (HRs) were derived for time-to-event outcomes, and meta-analysis was performed using a fixed-effect model. The primary outcome measures were overall survival (OS) and disease-free survival (DFS). Toxicity, contralateral breast cancer, and second malignancy were represented as risk ratios (RRs), and quality of life data were extracted when provided. MAIN RESULTS: This review update included 15 studies involving 11,538 premenopausal women with hormone receptor-positive early breast cancer; these studies were conducted from 1978 to 2014. Some of these treatments are not current standard of care, and early studies did not assess HER2 receptor status. Studies tested OFS versus observation (one study), OFS plus chemotherapy versus chemotherapy (six studies), OFS plus tamoxifen versus tamoxifen (six studies), and OFS plus chemotherapy and tamoxifen versus chemotherapy and tamoxifen (two studies). Of those studies that reported the chemotherapy regimen, an estimated 72% of women received an anthracycline. The results described below relate to the overall comparison of OFS versus no OFS. High-certainty evidence shows that adding OFS to treatment resulted in a reduction in mortality (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.78 to 0.94; 11 studies; 10,374 women; 1933 reported events). This treatment effect was seen when OFS was added to observation, to tamoxifen, or to chemotherapy and tamoxifen. The effect on mortality was not observed when OFS was added to chemotherapy without tamoxifen therapy (HR 0.95, 95% CI 0.82 to 1.09; 5 studies; 3087 women; median follow-up: range 7.7 to 12.1 years). The addition of OFS resulted in improved DFS (HR 0.83, 95% CI 0.77 to 0.90; 10 studies; 8899 women; 2757 reported events; high-certainty evidence). The DFS treatment effect persisted when OFS was added to observation, to tamoxifen, and to chemotherapy and tamoxifen. The effect on DFS was reduced when OFS was added to chemotherapy without tamoxifen therapy (HR 0.90, 95% CI 0.79 to 1.01; 5 studies; 2450 women). Heterogeneity was low to moderate across studies for DFS and OS (respectively). Evidence suggests that adding OFS slightly increases the incidence of hot flushes (grade 3/4 or any grade; risk ratio (RR) 1.60, 95% CI 1.41 to 1.82; 6 studies; 5581 women; low-certainty evidence, as this may have been under-reported in these studies). Two other studies that could not be included in the meta-analysis reported a higher number of hot flushes in the OFS group than in the no-OFS group. Seven studies involving 5354 women collected information related to mood; however this information was reported as grade 3 or 4 depression, anxiety, or neuropsychiatric symptoms, or symptoms were reported without the grade. Two studies reported an increase in depression, anxiety, and neuropsychiatric symptoms in the OFS group compared to the no-OFS group, and five studies indicated an increase in anxiety in both treatment groups (but no difference between groups) or no difference overall in symptoms over time or between treatment groups. A single study reported bone health as osteoporosis (defined as T score < -2.5); this limited evidence suggests that OFS increases the risk of osteoporosis compared to no-OFS at median follow-up of 5.6 years (RR 1.16, 95% CI 1.10 to 28.82; 2011 women; low-certainty evidence). Adding OFS to treatment likely reduces the risk of contralateral breast cancer (HR 0.75, 95% CI 0.57 to 0.97; 9 studies; 9138 women; moderate-certainty evidence). Quality of life was assessed in five studies; four studies used validated tools, and the fifth study provided no information on how data were collected. Two studies reported worse quality of life indicators (i.e. vaginal dryness, day and night sweats) for women receiving OFS compared to those in the no-OFS group. The other two studies indicated worsening of symptoms (e.g. vasomotor, gynaecological, vaginal dryness, decline in sexual interest, bone and joint pain, weight gain); however these side effects were reported in both OFS and no-OFS groups. The study that did not use a validated quality of life tool described no considerable differences between groups. AUTHORS' CONCLUSIONS: This review found evidence that supports adding OFS for premenopausal women with early, hormone receptor-positive breast cancers. The benefit of OFS persisted when compared to observation, and when added to endocrine therapy (tamoxifen) or chemotherapy and endocrine therapy (tamoxifen). The decision to use OFS may depend on the overall risk assessment based on tumour and patient characteristics, and may follow consideration of all side effects that occur with the addition of OFS.

A psychological intervention (ConquerFear) for treating fear of cancer recurrence: Views of study therapists regarding sustainability.

OBJECTIVE: ConquerFear is a metacognitive intervention for fear of cancer recurrence (FCR) with proven efficacy immmediately and 6 months post-treatment. This qualitative study documented barriers and facilitators to the sustainability of ConquerFear from the perspective of study therapists. METHODS: Fourteen therapists who had delivered ConquerFear in a randomised controlled trial completed a semi-structured phone interview, reaching theoretical saturation. Themes from thematic analysis were mapped to the Promoting Action on Research Implementation in Health Services (PARiHS) implementation framework. RESULTS: Participants were 13 males and one female with, on average, 14 years psycho-oncology experience. Nine over-arching themes were identified, falling into three domains, which when present, were facilitators, and if absent, were barriers: evidence (intervention credibility, experienced efficacy, perceived need for intervention); context (positive attitude to and capacity for survivorship/FCR care, favourable therapist orientation and flexibility, strong referral pathways); and facilitation of implementation (intervention/service fit, intervention/patient fit, and training, support, and provided resources). CONCLUSIONS: ConquerFear is a sustainable intervention in routine clinical practise. Facilitators included a sound evidence base; a receptive context; good fit between the intervention, therapist orientation, and patient need; and flexibility of delivery. Where absent, these factors served as barriers. These results have implications for enhancing uptake of psycho-oncology interventions in routine care.

Systematic review of interventions by non-mental health specialists for managing fear of cancer recurrence in adult cancer survivors.

PURPOSE: Fear of cancer recurrence (FCR) affects 50-70% of cancer survivors. Evidence-based psychological interventions for FCR are effective but resource-/time-consuming. This systematic review identified interventions by non-mental health specialists addressing FCR, evidence of a relationship between specialist communication and FCR and stakeholder perspectives on how specialist communication can address FCR. METHODS: A systematic literature review was conducted using nine databases (Medline Ovid, EMBASE, Cochrane, CINAHL, Scopus, PsychINFO, Informit, Web of Science and Google Scholar). Included studies were English, published 1997-2018, on adult cancer patients examining 'fear'/'worry' and 'cancer recurrence'/'progression' and 'health communication'/'medical encounter'/'interventions'. Data was extracted, summarised and rated for quality by two authors. RESULTS: Of 6248 articles screened, 16 were included. No phase III randomised controlled trials were found. Five studies piloted an intervention, three were correlational studies, five were cross-sectional patient surveys and three were specialist surveys. Four out of five interventional studies were nurse-led: one trained patients in discussing FCR with their specialist while three delivered supportive counselling and/or taught strategies to manage FCR. The last intervention trained mixed health professionals to manage FCR through normalisation, education and lifestyle strategies. Three intervention studies measured FCR objectively, and two demonstrated a reduction in FCR in the short term. Consultation duration, empathy and clear information delivery were associated with FCR. Patients indicated desire to discuss FCR; however, specialists indicated discomfort with managing FCR. CONCLUSIONS: Research on non-mental health practitioner-led interventions to address FCR is lacking. Further studies on whether specialist interventions delivered during follow-up consultations are useful in managing FCR are required.

Risk of emergency hospitalisation and survival outcomes following adjuvant chemotherapy for early breast cancer in New South Wales, Australia.

OBJECTIVE: To examine risk of emergency hospital admission and survival following adjuvant chemotherapy for early breast cancer. METHODS: Linked data from New South Wales population-based and clinical cancer registries (2008-2012), hospital admissions, official death records and pharmaceutical benefit claims. Women aged ≥18 years receiving adjuvant chemotherapy for early-stage operable breast cancer in NSW public hospitals were included. Odds ratios (OR) for emergency hospitalisation within 6 months following chemotherapy initiation were estimated using logistic regression and survival using Kaplan-Meier and Cox proportional hazards methods. RESULTS: A total of 3,950 women were included and 30.6% were hospitalised. The most common principal diagnosis at admission was neutropenia (30.8%). Women receiving docetaxel/carboplatin/trastuzumab (TCH) and docetaxel/cyclophosphamide (TC) were the most frequently hospitalised. After adjustment for demographic and clinical factors, the increased risk of hospitalisation for TCH and TC remained compared with doxorubicin/cyclophosphamide 3-weekly (OR 1.71, 95% confidence interval [CI] 1.24-2.37 and OR 1.47, 95% CI 1.17-1.85 respectively). Five-year overall survival was similar for women who were (92.2%, 95% CI 90.7-93.8) and were not hospitalised (93.1%, 95% CI 92.1-94.1). CONCLUSION: Emergency hospitalisations following chemotherapy for early breast cancer were relatively common, especially following docetaxel-containing protocols. Further examination of reasons for admission is needed to inform actions to improve patient safety.

Fear of Cancer Recurrence: A Practical Guide for Clinicians.

With increasing cancer survival, fear of cancer recurrence (FCR) is becoming a prominent clinical issue. FCR is prevalent, distressing, and long-lasting, and can negatively impact patients' quality of life, use of health services, and adherence to follow-up recommendations. Novel targeted therapies may increase risk of FCR because of longer treatment duration and follow-up, increased prognostic precision, and omission of treatment based on genomic status. Oncologists can assess and screen for FCR using validated measures; provide adequate information about prognosis, signs and symptoms of recurrence, and behavioral strategies for risk reduction and follow-up; and warn patients and families that FCR may be an issue in survivorship. It is important to normalize FCR and encourage patients to discuss it if it is a concern. Patients with severe FCR should be referred to psycho-oncology staff, who can apply some of the novel psychotherapeutic interventions that have emerged to address this condition.

Medical, demographic and psychological correlates of fear of cancer recurrence (FCR) morbidity in breast, colorectal and melanoma cancer survivors with probable clinically significant FCR seeking psychological treatment through the ConquerFear study.

PURPOSE: Despite the prevalence of fear of cancer recurrence (FCR), understanding of factors underlying clinically significant FCR is limited. This study examined factors associated with greater FCR morbidity, according to a cognitive processing model, in cancer survivors who screened positively for clinically significant FCR seeking psychological treatment through the ConquerFear trial. METHODS: Participants had completed treatment for breast, colorectal or melanoma cancer 2 months to 5 years previously and scored ≥ 13/36 on the Fear of Cancer Recurrence Inventory-Short Form (FCRI-SF). Hierarchical regression analyses examined associations between demographic, medical and psychological variables, namely metacognitions (MCQ-30), post-traumatic stress symptoms (IES-R) and FCR (FCRI total score). RESULTS: Two hundred and ten (95%) of the 222 cancer survivors who consented to the ConquerFear trial completed the baseline questionnaire. Participants were predominantly (89%) breast cancer survivors. The final regression model accounted for 68% of the variance in FCR (demographic and medical variables 13%, metacognitions 26%, post-traumatic stress symptoms 28%). Negative metacognitive beliefs about worry and intrusive post-traumatic stress symptoms were significant individual correlates of FCR, but negative beliefs about worry did not significantly moderate the impact of intrusions on FCR morbidity. CONCLUSIONS: Results provide partial support for the cognitive processing model of FCR. Psychological factors were found to play an important role in FCR morbidity after controlling for demographic/medical factors. More intrusive thoughts and negative beliefs about worry were strong independent predictors of FCR morbidity. Cancer survivors with clinically significant FCR may benefit from assessment for intrusive thoughts and metacognitions and delivery of trauma- and/or metacognitive-based interventions accordingly.

Programmed death ligand 1 expression in triple-negative breast cancer is associated with tumour-infiltrating lymphocytes and improved outcome.

AIMS: Triple-negative breast cancer (TNBC) patients generally have a poor outcome; there is a pressing need to identify more effective therapeutic strategies. Clinical trials targeting programmed death 1/programmed death ligand 1 (PD1/PDL1) in melanoma and non-small-cell lung cancer have reported high response rates, and tumoral PDL1 expression has been suggested as a potential biomarker to enrich for patient response to these treatments. There are only very limited data to date reporting the expression of PDL1 in TNBC. METHODS AND RESULTS: PDL1 immunohistochemistry was performed on 161 primary TNBCs and assessed in the tumour as well as immune cells in the stromal compartment. PDL1 expression was very common in TNBC, expressed in the tumour cell membrane (64%), cytoplasm (80%) and stromal (93%) cellular compartments. Cytoplasmic tumoral expression of PDL1 was associated with a lower risk of breast cancer-specific death [hazard ratio (HR) 0.45, P = 0.035] while stromal PDL1 expression was associated with a lower rate of deaths from all causes (HR 0.305, P = 0.0042). Membranous expression of PDL1 was not associated with outcome. While both PDL1 expression and tumour-infiltrating lymphocytes were associated with a better outcome, only lymphovascular invasion and high tumour-infiltrating lymphocytes were independently prognostic for breast cancer-specific death. CONCLUSION: While PDL1 expression is frequent in TNBC, it was not independently prognostic. There were differences in outcome depending on the cellular compartment of PDL1 expression. These data provide further impetus for investigating the utility of immune checkpoint therapies in TNBC, given the clinical significance of tumour-infiltrating lymphocytes (TILs) and PDL1 expression in this cohort.

Platinum chemotherapy for early triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer associated with shorter survival and a higher likelihood of recurrence. In early TNBC, platinum chemotherapy has been shown to improve pathological complete response (pCR); however, its effect on long-term survival outcomes has not been fully elucidated. METHODS: Randomised controlled trials examining neoadjuvant or adjuvant platinum chemotherapy for early TNBC were included. Primary outcomes were disease-free survival (DFS) and overall survival (OS). Secondary outcomes were pCR, treatment adherence, grade III or IV toxicity related to chemotherapy, and quality of life. RESULTS: From 3972 records, we included 20 published studies. All studies reporting DFS and OS used carboplatin. Inclusion of platinum chemotherapy improved DFS (neoadjuvant: hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.53 to 0.75; adjuvant: HR 0.69, 95% CI 0.54 to 0.88) and OS (neoadjuvant: HR 0.69, 95% CI 0.55 to 0.86; adjuvant: 0.70, 95% CI 0.50 to 0.96). Our analysis confirmed platinum chemotherapy increased pCR rates (risk ratio (RR) 1.44, 95% CI 1.31 to 1.59). There were no differences seen in examined subgroups. Platinum chemotherapy was associated with reduced dose intensity and increased haematological toxicity. CONCLUSIONS: Platinum-based chemotherapy using carboplatin in the adjuvant or neoadjuvant setting improves long-term outcomes of DFS and OS in early TNBC, with no evidence of differences by subgroup. This was at the cost of more frequent chemotherapy delays and dose reductions, and greater haematological toxicity. These findings support the use of platinum-based chemotherapy for people with early TNBC.

Characteristics and post-metastasis survival of recurrent metastatic breast cancer over time - An Australian population-based record linkage study, 2001-2016.

AIM: To assess population-level characteristics and post-metastasis survival of people with recurrent metastatic breast cancer (rMBC) during a period when new publicly-subsidised adjuvant and metastatic systemic therapies became available. METHODS: Record linkage study of females in NSW Cancer Registry (NSWCR) diagnosed with non-metastatic breast cancer (BC) in 2001-2002 (C1) and 2006-2007 (C2). We identified first rMBC from NSWCR, administrative hospital records, dispensed medicines and radiotherapy services (2001-2016). We used death registrations to estimate cumulative incidence of BC death. RESULTS: The analysis included 2267 women with rMBC (C1:1210, C2:1057). Compared to C1, C2 had access to adjuvant HER2-targeted therapy and were more likely to have received adjuvant chemotherapy (C1:38%, C2:47%) and aromatase inhibitors (C1:52%, C2:73%, of those dispensed endocrine therapy). Five-year probability of BC death was 65% (95%CI:62-68%) in C1 and 63% (95%CI:60-66%) in C2. Regional disease (T4 or N + ) at initial BC diagnosis (C1:62%, C2:68%), and age ≥ 70 years at first metastasis (C1:27%, C2:31%) were more common in C2 and had poorer prognosis. Five-year probability of BC death was lower in C2 than C1 for treatment-defined HER2-positive BC (C1:72% 95%CI:63-79%; C2:52% 95%CI 45-60%) and those dispensed chemotherapy alone (C1:76% 95%CI:69-82, C2:67% 95%CI:59-74%, p = 0.01), but not treatment-defined hormone receptor-positive HER2-negative BC (C1:60% 95%CI 56-63%, C2:64% 95%CI 60-68%). CONCLUSIONS: Despite less favourable prognostic characteristics in C2, BC-related survival following rMBC was similar between the two cohorts; and improved for women with HER2-positive tumours. These findings support the real-world benefits of newer treatments for rMBC.

Decline in the Incidence of Distant Recurrence of Breast Cancer: A Population-Based Health Record Linkage Study, Australia 2001-2016.

BACKGROUND: We investigated differences in cumulative incidence of first distant recurrence (DR) following non-metastatic breast cancer over a time period when new adjuvant therapies became available in Australia. METHODS: We conducted a health record linkage study of females with localized (T1-3N0) or regional (T4 or N+) breast cancer in the New South Wales Cancer Registry in 2001 to 2002 and 2006 to 2007. We linked cancer registry records with administrative records from hospitals, dispensed medicines, radiotherapy services, and death registrations to estimate the 9-year cumulative incidence of DR and describe use of adjuvant treatment. RESULTS: The study included 13,170 women (2001-2002 n = 6,338, 2006-2007 n = 6,832). The 9-year cumulative incidence of DR was 3.6% [95% confidence interval (CI), 2.3%-4.9%] lower for 2006-2007 diagnoses (15.0%) than 2001-2002 (18.6%). Differences in the annual hazard of DR between cohorts were largest in year two. DR incidence declined for localized and regional disease. Decline was largest for ages <40 years (absolute difference, 14.4%; 95% CI, 8.3%-20.6%), whereas their use of adjuvant chemotherapy (2001-2002 49%, 2006-2007 75%) and HER2-targeted therapy (2001-2002 0%, 2006-2007 16%) increased. DR did not decline for ages ≥70 years (absolute difference, 0.9%; 95% CI, -3.6%-1.8%) who had low use of adjuvant chemotherapy and HER2-targeted therapy. CONCLUSIONS: This whole-of-population study suggests that DR incidence declined over time. Decline was largest for younger ages, coinciding with changes to adjuvant breast cancer therapy. IMPACT: Study findings support the need for trials addressing questions relevant to older people and cancer registry surveillance of DR to inform cancer control programs.

Conquer fear: protocol of a randomised controlled trial of a psychological intervention to reduce fear of cancer recurrence.

BACKGROUND: Up to 70% of cancer survivors report clinically significant levels of fear of cancer recurrence (FCR). Despite the known negative impact of FCR on psychological wellbeing and quality of life, little research has investigated interventions for high FCR. Our team has developed and piloted a novel intervention (Conquer Fear) based on the Self-Regulatory Executive Function Model and Relational Frame Theory and is evaluating Conquer Fear in a randomised controlled trial (RCT). We aim to compare the efficacy and cost-efficacy of the Conquer Fear Intervention and relaxation training in reducing the impact of FCR. METHODS/DESIGN: This study is a multi-centre RCT with 260 participants randomised either to the Conquer Fear Intervention or relaxation training. Both interventions will be delivered in five sessions over 10 weeks by trained psychologists, psychiatrists and social workers with five or more years experience in oncology. Conquer Fear sessions use attentional training, detached mindfulness, meta-cognitive therapy, values clarification and psycho-education to help patients change the way they regulate and respond to thoughts about cancer recurrence. Relaxation training includes training in progressive and passive muscle relaxation, meditative relaxation, visualisation and "quick relaxation" techniques. Relaxation was chosen to control for therapist time and attention and has good face-validity as an intervention. The primary outcome is fear of cancer recurrence. Secondary outcomes include distress, quality of life, unmet needs, and health care utilisation. Participants complete questionnaires prior to starting the intervention, immediately after completing the intervention, 3 and 6 months later. Eligible participants are early-stage breast or colorectal cancer survivors who have completed hospital-based treatment between 2 months and 5 years prior to study entry and report a score in the clinical range on the Fear of Cancer Recurrence Inventory. The biostatistician is blinded to group allocation and participants are blinded to which intervention is being evaluated. Randomisation is computer generated, stratified by therapist, and uses sequentially numbered sealed envelopes. DISCUSSION: If successful, the study will provide an evidence-based intervention to reduce psychological morbidity in cancer survivors, and reduce overall health care costs due to more appropriate use of follow-up care and other health services in this very large population. TRIAL REGISTRATION: ACTRN12612000404820.