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.

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.

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.

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.

Efficacy and safety results by menopausal status in monarchE: adjuvant abemaciclib combined with endocrine therapy in patients with HR+, HER2-, node-positive, high-risk early breast cancer.

Background: Abemaciclib is the first and only cyclin-dependent kinases 4 and 6 inhibitor approved for adjuvant treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), node-positive, and high-risk early breast cancer (EBC), with indications varying by geography. Premenopausal patients with HR+, HER2- tumors may have different tumor biology and treatment response compared to postmenopausal patients. Objectives: We describe the efficacy and safety of abemaciclib plus endocrine therapy (ET) for the large subgroup of premenopausal patients with HR+, HER2- EBC in monarchE. Design: Randomized patients (1:1) received adjuvant ET with or without abemaciclib for 2 years plus at least 3 additional years of ET as clinically indicated. Methods: Patients were stratified by menopausal status (premenopausal versus postmenopausal) at diagnosis. Standard ET (tamoxifen or aromatase inhibitor) with or without gonadotropin-releasing hormone agonist was determined by physician's choice. Invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) by menopausal status were assessed at data cutoff on 1 April 2021 (median follow-up of 27 months). Results: Among randomized patients, 2451 (43.5%) were premenopausal and 3181 (56.4%) were postmenopausal. The choice of ET for premenopausal patients varied considerably between countries. Treatment benefit was consistent across menopausal status, with a numerically greater effect size in premenopausal patients. For premenopausal patients, abemaciclib with ET resulted in a 42.2% and 40.3% reduction in the risk of developing IDFS and DRFS events, respectively. Absolute improvement at 3 years was 5.7% for IDFS and 4.4% for DRFS rates. Safety profile for premenopausal patients was consistent with the overall safety population. Conclusion: Abemaciclib with ET demonstrated clinically meaningful treatment benefit for IDFS and DRFS versus ET alone regardless of menopausal status and first ET, with a numerically greater benefit in the premenopausal compared to the postmenopausal population. Safety data in premenopausal patients are consistent with the overall safety profile of abemaciclib.

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.

Feasibility and preliminary efficacy of iConquerFear: a self-guided digital intervention for fear of cancer recurrence.

PURPOSE: Approximately 50% of cancer survivors experience moderate-severe fear of cancer recurrence (FCR). Self-guided digital interventions have potential to address the high level of FCR-related unmet needs at scale, but existing digital interventions have demonstrated variable engagement and efficacy. This study aimed to evaluate the feasibility and preliminary efficacy of iConquerFear, a five-module self-guided digital FCR intervention. METHODS: Eligible curatively treated breast cancer survivors were recruited. Participants reporting clinically significant FCR (≥ 13 on the Fear of Cancer Recurrence Inventory-Short Form; FCRI-SF) were given access to iConquerFear. Feasibility was indicated by > 50% of eligible participants enrolling in iConquerFear and recording moderate (≥ 120 min) or greater usage. Preliminary efficacy was evaluated via changes in self-reported FCR severity, anxiety, depression, intrusions and metacognitions from baseline to immediately and 3 months post-intervention. RESULTS: Fifty-four (83%) of 65 eligible participants enrolled in iConquerFear; six subsequently withdrew. Thirty-nine (83%) participants recorded moderate (n = 24; 120-599 min) or high (n = 15; ≥ 600 min) usage. Engagement levels increased with participant age (p = 0.043), but were lower in participants with higher baseline FCR (p = 0.028). Qualitative feedback indicated engagement was sometimes limited by difficulties with navigation and relating to featured survivors. Participants reported significantly improved FCR (mean reduction (95%CI): baseline to post-intervention - 3.44 (- 5.18, - 1.71), baseline to 3-month follow-up - 4.52 (- 6.25, - 2.78), p = < 0.001). CONCLUSION: iConquerFear is a feasible and potentially efficacious intervention for reducing FCR in breast cancer survivors. Easier navigation and more relatable examples may enhance engagement. IMPLICATIONS FOR CANCER SURVIVORS: iConquerFear may help address moderate but burdensome FCR levels in cancer survivors.

Patient satisfaction with telehealth consultations in medical oncology clinics: A cross-sectional study at a metropolitan centre during the COVID-19 pandemic.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic has resulted in a widespread adoption of telehealth (phone and video consultations) in cancer care worldwide. The aim of this study was to determine patient satisfaction with telehealth consultations with their medical oncologist at a tertiary cancer centre in Sydney, Australia. METHODS: Patients who attended a routine telehealth appointment at the medical oncology outpatient clinic were recruited to complete a questionnaire containing 16 items, each on a 5-point Likert scale regarding satisfaction levels in various aspects of telehealth and their willingness to continue telehealth after the pandemic. Patients were also invited to provide suggestions for improvement. RESULTS: In total, 150 patients were invited to participate, and 103 valid questionnaires were returned. Median age was 63 years (range: 25-90), 49% of patients were male, 63% of patients had advanced cancer and 81% were on active treatment. In total, 95% of participants indicated that they were satisfied (score ≥4) with telehealth. 82% of participants preferred to continue telehealth consultations after the coronavirus disease 2019 pandemic, but ideally with a mix of telehealth and in-person consultations. Phone appointments (vs. video, p < 0.002), patients with advanced cancer (vs. early, p < 0.036) and pre-chemotherapy/immunotherapy/targeted therapy treatment reviews (vs. follow-up appointments, p < 0.001) were significantly associated with a willingness to continue telehealth. DISCUSSION: Patients were overwhelmingly satisfied with telehealth during the study period and were willing to continue telehealth for some appointments beyond the coronavirus disease 2019 pandemic. More research into the effectiveness, safety and implementation of telehealth to compliment traditional face-to-face services for patient-centred cancer care is required.

A single-cell and spatially resolved atlas of human breast cancers.

Breast cancers are complex cellular ecosystems where heterotypic interactions play central roles in disease progression and response to therapy. However, our knowledge of their cellular composition and organization is limited. Here we present a single-cell and spatially resolved transcriptomics analysis of human breast cancers. We developed a single-cell method of intrinsic subtype classification (SCSubtype) to reveal recurrent neoplastic cell heterogeneity. Immunophenotyping using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) provides high-resolution immune profiles, including new PD-L1/PD-L2+ macrophage populations associated with clinical outcome. Mesenchymal cells displayed diverse functions and cell-surface protein expression through differentiation within three major lineages. Stromal-immune niches were spatially organized in tumors, offering insights into antitumor immune regulation. Using single-cell signatures, we deconvoluted large breast cancer cohorts to stratify them into nine clusters, termed 'ecotypes', with unique cellular compositions and clinical outcomes. This study provides a comprehensive transcriptional atlas of the cellular architecture of breast cancer.

SP142 PD-L1 Scoring Shows High Interobserver and Intraobserver Agreement in Triple-negative Breast Carcinoma But Overall Low Percentage Agreement With Other PD-L1 Clones SP263 and 22C3.

SP142 programmed cell death ligand 1 (PD-L1) status predicts response to atezolizumab in triple-negative breast carcinoma (TNBC). Prevalence of VENTANA PD-L1 (SP142) Assay positivity, concordance with the VENTANA PD-L1 (SP263) Assay and Dako PD-L1 IHC 22C3 pharmDx assay, and association with clinicopathologic features were assessed in 447 TNBCs. SP142 PD-L1 intraobserver and interobserver agreement was investigated in a subset of 60 TNBCs, with scores enriched around the 1% cutoff. The effect of a 1-hour training video on pretraining and posttraining scores was ascertained. At a 1% cutoff, 34.2% of tumors were SP142 PD-L1 positive. SP142 PD-L1 positivity was significantly associated with tumor-infiltrating lymphocytes (P <0.01), and node negativity (P=0.02), but not with tumor grade (P=0.35), tumor size (P=0.58), or BRCA mutation (P=0.53). Overall percentage agreement (OPA) for intraobserver and interobserver agreement was 95.0% and 93.7%, respectively, among 5 pathologists trained in TNBC SP142 PD-L1 scoring. In 5 TNBC SP142 PD-L1-naive pathologists, significantly higher OPA to the reference score was achieved after video training (posttraining OPA 85.7%, pretraining OPA 81.5%, P<0.05). PD-L1 status at a 1% cutoff was assessed by SP142 and SP263 in 420 cases, and by SP142 and 22C3 in 423 cases, with OPA of 88.1% and 85.8%, respectively. The VENTANA PD-L1 (SP142) Assay is reproducible for classifying TNBC PD-L1 status by trained observers; however, it is not analytically equivalent to the VENTANA PD-L1 (SP263) Assay and Dako PD-L1 IHC 22C3 pharmDx assay.

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.

Novel Clinician-Lead Intervention to Address Fear of Cancer Recurrence in Breast Cancer Survivors.

PURPOSE: Fear of cancer recurrence (FCR) affects 50%-70% of cancer survivors. This multicenter, single-arm study sought to determine the participant-rated usefulness of an oncologist-delivered FCR intervention. METHODS: Women who completed treatment for early breast cancer (could be receiving endocrine therapy) with baseline FCR > 0 were invited to participate. FCR was measured using a validated 42-item FCR Inventory. The brief oncologist-delivered intervention entailed (1) FCR normalization; (2) provision of personalized prognostic information; (3) recurrence symptoms education, (4) advice on managing worry, and (5) referral to psycho-oncologist if FCR was high. FCR, depression, and anxiety were assessed preintervention (T0), at 1 week (T1), and 3 months (T2) postintervention. The primary outcome was participant-rated usefulness. Secondary outcomes included feasibility and efficacy. RESULTS: Five oncologists delivered the intervention to 61/255 women invited. Mean age was 58 ± 12 years. Mean time since breast cancer diagnosis was 2.5 ± 1.3 years. Forty-three women (71%) were on adjuvant endocrine therapy. Of 58 women who completed T1 assessment, 56 (97%) found the intervention to be useful. FCR severity decreased significantly at T1 (F = 18.5, effect size = 0.39, P < .0001) and T2 (F = 24, effect size = 0.68, P < .0001) compared with baseline. There were no changes in unmet need or depression or anxiety. Mean consultation length was 22 minutes (range, 7-47 minutes), and mean intervention length was 8 minutes (range, 2-20 minutes). The intervention was perceived as useful and feasible by oncologists. CONCLUSION: A brief oncologist-delivered intervention to address FCR is useful and feasible, and has preliminary efficacy in reducing FCR. Plans for a cluster randomized trial are underway.

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.

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.

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.