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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. A multi-omic atlas of breast cancers, integrating single-cell RNA sequencing, spatial transcriptomics and immunophenotyping, identifies nine ecotypes associated with cellular heterogeneity and prognosis.

Background Women living with metastatic breast cancer can benefit from physical activity. Presently, there is an absence of research outside of quantitative investigations on the benefits of structured programs. To enable effective physical activity advice and services, it is important to understand factors that may facilitate or prevent engagement. We therefore explored with women with metastatic breast cancer: (i) personal and behavioural factors that influenced physical activity, and (ii) the role of healthcare services in influencing engagement in being physically active. Methods Recruitment took place at a metropolitan cancer centre from November 2019 to January 2020. Women living with metastatic breast cancer were asked to participate in semi-structured interviews about physical activity, covering health-specific factors, goals, barriers, enablers, and interests. Interviews were recorded, transcribed and thematically analysed. Results Twenty-three women completed the interview, with a median age of 60 years (IQR: 20) and median time since metastatic diagnosis of 3.3 years (IQR: 3.0). Physical activity ranged from regular participation in structured exercise to simple incidental activity. Seven themes organised into three categories were identified. The category ‘personal context’ incorporated themes on: (1) both cancer and non-cancer related health factors; (2) time, work and family factors; and (3) exercise history and preferences. The category ‘strategies for physical activity’ incorporated themes on: (4) self-efficacy, and (5) routine and incidental activity. The category ‘role of health and physical activity services’ incorporated themes on: (6) tailored education and services, and (7) specific metastatic cancer services and considerations. Conclusions Participants expressed diverse experiences with physical activity, with common notions on how physical activity is beneficial but difficult in which to adhere. Whilst some barriers to engagement in physical activity were unique to having cancer, many were not specific to metastatic breast cancer. For example, some participants emphasised specific considerations resulting from their disease, while others primarily reported on general factors such as being time-poor or having conflicting priorities. A patient-centred approach tailored to this group’s health and behavioural context may be effective for women who are currently inactive to engage in physical activity.

Background The beneficial role of physical activity for people living with cancer is well established. However, the importance of physical activity to women living with metastatic breast cancer is not known. As motivations and perceptions around physical activity influence behavioural uptake, a qualitative study was undertaken to explore the motivations and perceptions towards physical activity of this group. Methods Women living with metastatic breast cancer were recruited through a metropolitan cancer centre in Australia to participate in semi-structured interviews about their physical activity. Open-ended questions explored health-specific factors, goals, barriers, enablers, and interests. Interviews were recorded, transcribed and thematically analysed. Results Twenty-three women participated; median age was 60 years (IQR: 20) and median time since metastatic diagnosis was 3.3 years (IQR: 3.0). Twelve women were engaged with physical activity, seven reported intentions to be active but found it challenging, and four reported nominal interest in physical activity. Four categories, covering nine themes, were identified: (i) predispositions towards physical activity, incorporating themes on enjoyment and energy, and positivity and mental resilience; (ii) health-related motivations behind physical activity, incorporating themes on physical and mental health benefits; (iii) social motivations behind physical activity, incorporating themes on enjoying exercise with others, role models and social support, and others’ negative perceptions of metastatic breast cancer; and (iv) connections between physical activity and metastatic breast cancer, incorporating themes on prognosis uncertainty, and reframing limiting perceptions. Conclusions Participants described a wide-ranging spectrum of experiences and perceptions toward physical activity. Whilst most women perceived improved physical and mental well-being from being physically active, some women were not engaged in being physically active. Behaviour change strategies that target both their attitudes and those around them may address this gap.

Shoulder movement impairment is a commonly reported consequence of surgery for breast cancer. The aim of this study was to determine whether shoulder girdle kinematics, including those of the scapula, spine, and upper limb, in women who have undergone a unilateral mastectomy for breast cancer are different from those demonstrated by an age-matched control group. An observational study using 3-dimensional kinematic analysis was performed. Women who had a unilateral mastectomy on their dominant-arm side (n=29, mean [+/-SD] age=62.4+/-8.9 years) or nondominant-arm side (n=24, mean [+/-SD] age=59.8+/-9.9 years), as well as a control group of age-matched women without upper-limb, shoulder, or spinal problems (n=22, mean [+/-SD] age=58.1+/-11.5 years), were measured while performing bilateral arm movements in the sagittal, scapular, and coronal planes. All of the women were free of shoulder pain at the time of testing. Data were collected from the glenohumeral joint, the scapulothoracic articulation, and the spine (upper and lower thoracic and lumbar regions) using an electromagnetic tracking system. Women following mastectomy displayed altered patterns of scapular rotation compared with controls in all planes of movement. In particular, the scapula on the mastectomy side rotated upward to a markedly greater extent than that on the nonmastectomy side, and women following mastectomy displayed greater scapular excursion than controls. The findings suggest that altered motor patterns of the scapula are associated with mastectomy on the same side. Whether these changes are harmful or not is unclear. Investigation of interventions designed to restore normal scapulohumeral relationships on the affected side following unilateral mastectomy for breast cancer is warranted.

The aim of this study was to determine whether an exercise program, commencing 4–6 weeks post-operatively, reduces upper limb impairments in women treated for early breast cancer. Women ( n  = 160) were randomized to either an 8-week exercise program ( n  = 81) or to a control group ( n  = 79) following stratification for axillary surgery. The exercise program comprised a weekly session and home program of passive stretching and progressive resistance training for shoulder muscles. The control group attended fortnightly assessments but no exercises were provided. The primary outcome was self-reported arm symptoms derived from the EORTC breast cancer-specific questionnaire (BR23), scored out of 100 with a low score indicative of fewer symptoms. The secondary outcomes included physical measures of shoulder range of motion, strength, and swelling (i.e., lymphedema). Women were assessed immediately following the intervention and at 6 months post-intervention. The change in symptoms from baseline was not significantly different between groups immediately following the intervention or at 6 m post-intervention. The between group difference immediately following the intervention was 4 (95% CI −1 to 9) and 6 months post-intervention was 4 (−2 to 10). However, the change in range of motion for flexion and abduction was significantly greater in the exercise group immediately following the intervention, as was change in shoulder abductor strength. In conclusion, a supervised exercise program provided some, albeit small, additional benefit at 6 months post-intervention to women who had been provided with written information and reminders to use their arm. Both the groups reported few impairments including swelling immediately following the intervention and 6 months post-intervention. Notably, resistance training in the post-operative period did not precipitate lymphedema.

Dysregulation of histone modifications promotes carcinogenesis by altering transcription. Breast cancers frequently overexpress the histone methyltransferase EZH2, the catalytic subunit of Polycomb Repressor Complex 2 (PRC2). However, the role of EZH2 in this setting is unclear due to the context-dependent functions of PRC2 and the heterogeneity of breast cancer. Moreover, the mechanisms underlying PRC2 overexpression in cancer are obscure. Here, using multiple models of breast cancer driven by the oncogene ErbB2, we show that the tyrosine kinase c-Src links energy sufficiency with PRC2 overexpression via control of mRNA translation. By stimulating mitochondrial ATP production, c-Src suppresses energy stress, permitting sustained activation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which increases the translation of mRNAs encoding the PRC2 subunits Ezh2 and Suz12. We show that Ezh2 overexpression and activity are pivotal in ErbB2-mediated mammary tumourigenesis. These results reveal the hitherto unknown c-Src/mTORC1/PRC2 axis, which is essential for ErbB2-driven carcinogenesis. Polycomb Repressor Complex 2 (PRC2) is frequently up-regulated in cancers. Here, the authors show that the tyrosine kinase c-Src stimulates mitochondrial function to signal energy sufficiency to mTORC1, increasing translation of the PRC2 subunits EZH2 and SUZ12 to support ErbB2-dependent tumours.

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 C linician I ntervention to Reduce Fe ar of R ecurrence (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.

The aim of this systematic review was to identify the prevalence and severity of upper limb problems following surgery and radiation for early breast cancer. Additionally, the independent prognostic contribution of radiation, type of breast surgery, type of axillary surgery, age and body mass index (BMI) was evaluated. Searches of electronic databases were conducted to identify articles that reported upper limb and quality of life outcomes after breast cancer surgery and external radiation. Eligible studies for prognosis were longitudinal in design, with ≥95% of patients treated by surgery and radiation that excluded the axilla. Cross-sectional studies were also included for identification of prognostic factors. Where possible, the contribution of independent prognostic factors was analyzed. The review identified 32 relevant studies. Shoulder restriction was reported in between <1% and 67% of participants, lymphedema was reported in between 0 and 34% of participants, shoulder/arm pain was reported in between 9 and 68% of participants and arm weakness was reported in between 9 and 28% of participants. Quality of life was high across studies. Irradiated patients had slightly increased odds of lymphedema (OR = 1.46, 95% CI 1.16–1.84) and shoulder restriction (OR = 1.67, 95% CI 0.98–2.86) compared with non-irradiated patients. For patients undergoing surgery and radiation for breast cancer, the prognosis is good in terms of the upper limb and quality of life. Radiation that excludes the axilla does not appear to be a strong prognostic indicator of adverse upper limb outcomes.

Purpose This study aimed to explore differences in physical activity and fitness between women with metastatic breast cancer compared to healthy controls and factors associated with their physical activity levels. Methods Seventy-one women with metastatic breast cancer, aged (mean (SD)) 57.7 (9.5) and 2.9 (3.1) years after the onset of metastatic disease, and 71 healthy controls aged 55.0 (9.4) years participated. Of those with metastatic disease, 27 % had bone-only metastases, 35 % visceral-only metastases and 38 % bone and visceral metastases. Patient-reported outcomes and physical measures of muscle strength and aerobic fitness assessments were obtained. Participants wore a SenseWear® physical activity monitor over 7 days, and the average steps/day and the time spent in moderate-to-vigorous intensity physical activity were determined. Results Women with metastases were significantly (i) less aerobically fit than the control group (25.3 (5.4) vs. 31.9 (6.1) mL • kg −1  • min −1 ; P  < 0.001); (ii) weaker (e.g. lower limb strength for the metastatic and control groups was 53.5 (23.7) vs. 76.0 (27.4) kg, respectively; P  < 0.001); (iii) less active, with the metastatic group attaining only 56 % of the mean daily step counts of the healthy women; and (iv) more symptomatic, reporting higher levels of fatigue and dyspnoea ( P  < 0.001). Conclusion Women living in the community with metastatic breast cancer possessed lower aerobic fitness, reduced muscular strength and less daily physical activity compared to healthy counterparts. They also experienced poorer functioning and higher symptom burden. Implications for Cancer Survivors Women living with metastatic breast cancer may benefit from a physical activity programme to address their physical impairments.

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.