Peripheral immune cells in metastatic breast cancer patients display a systemic immunosuppressed signature consistent with chronic inflammation.

Immunotherapies blocking the PD-1/PD-L1 checkpoint show some efficacy in metastatic breast cancer (mBC) but are often hindered by immunosuppressive mechanisms. Understanding these mechanisms is crucial for personalized treatments, with peripheral blood monitoring representing a practical alternative to repeated biopsies. In the present study, we performed a comprehensive mass cytometry analysis of peripheral blood immune cells in 104 patients with HER2 negative mBC and 20 healthy donors (HD). We found that mBC patients had significantly elevated monocyte levels and reduced levels of CD4+ T cells and plasmacytoid dendritic cells, when compared to HD. Furthermore, mBC patients had more effector T cells and regulatory T cells, increased expression of immune checkpoints and other activation/exhaustion markers, and a shift to a Th2/Th17 phenotype. Furthermore, T-cell phenotypes identified by mass cytometry correlated with functionality as assessed by IFN-γ production. Additional analysis indicated that previous chemotherapy and CDK4/6 inhibition impacted the numbers and phenotype of immune cells. From 63 of the patients, fresh tumor samples were analyzed by flow cytometry. Paired PBMC-tumor analysis showed moderate correlations between peripheral CD4+ T and NK cells with their counterparts in tumors. Further, a CD4+ T cell cluster in PBMCs, that co-expressed multiple checkpoint receptors, was negatively associated with CD4+ T cell tumor infiltration. In conclusion, the identified systemic immune signatures indicate an immune-suppressed environment in mBC patients who had progressed/relapsed on standard treatments, and is consistent with ongoing chronic inflammation. These activated immuno-suppressive mechanisms may be investigated as therapeutic targets, and for use as biomarkers of response or treatment resistance.

Design, Development, and Evaluation of an mHealth App for Reporting of Side Effects During Cytostatic Treatment: Usability Test and Interview Study.

BACKGROUND: Using mobile health (mHealth) interventions such as smartphone apps to deliver health services is an opportunity to engage patients more actively in their own treatment. Usability tests allow for the evaluation of a service by testing it out on the relevant users before implementation in clinical practice. OBJECTIVE: The objective of this study was to design, develop, and evaluate the user interface of an app that would aid patients with cancer in reporting a more comprehensive summary of their side effects. METHODS: The usability test was conducted by exposing patients with cancer to a prototype of an mHealth app that allowed for reporting of side effects from a chemotherapy regimen. After solving a set of 13 tasks, the test participants completed a system usability scale questionnaire and were interviewed using a semistructured interview guide. The interviews were later transcribed and analyzed. RESULTS: The 10 test participants had a mean age of 56.5 (SD 7.11) years. The mean total task completion time for the task-solving session was 240.15 (SD 166.78) seconds. The calculated system usability scale score was 92.5. Most participants solved most of the tasks without any major issues. A minority reported having difficulties using apps on smartphones in general. One patient never achieved a meaningful interaction with our app prototype. Most of those who engaged with the app approved of features that calmed them down, made them more empowered, and put them in control. They preferred to report on side effects in a detailed and concise manner. App features that provided specific advice could provoke both fear and rational action. CONCLUSIONS: The user tests uncovered design flaws that allowed for subsequent refining of an app that has the potential to enhance the safety of patients undergoing home-based chemotherapy. However, a refined version of the app is unlikely to be of value to all patients. Some might not be able to use apps on smartphones in general, or their ability to use apps is impaired because of their disease. This finding should have implications for health care providers' overall design of their follow-up service as the service must allow for all the patients to receive safe treatment whether they can use an mHealth app or not.

Atezolizumab plus anthracycline-based chemotherapy in metastatic triple-negative breast cancer: the randomized, double-blind phase 2b ALICE trial.

Immune checkpoint inhibitors have shown efficacy against metastatic triple-negative breast cancer (mTNBC) but only for PD-L1positive disease. The randomized, placebo-controlled ALICE trial ( NCT03164993 , 24 May 2017) evaluated the addition of atezolizumab (anti-PD-L1) to immune-stimulating chemotherapy in mTNBC. Patients received pegylated liposomal doxorubicin (PLD) and low-dose cyclophosphamide in combination with atezolizumab (atezo-chemo; n = 40) or placebo (placebo-chemo; n = 28). Primary endpoints were descriptive assessment of progression-free survival in the per-protocol population (>3 atezolizumab and >2 PLD doses; n = 59) and safety in the full analysis set (FAS; all patients starting therapy; n = 68). Adverse events leading to drug discontinuation occurred in 18% of patients in the atezo-chemo arm (7/40) and in 7% of patients in the placebo-chemo arm (2/28). Improvement in progression-free survival was indicated in the atezo-chemo arm in the per-protocol population (median 4.3 months versus 3.5 months; hazard ratio (HR) = 0.57; 95% confidence interval (CI) 0.33-0.99; log-rank P = 0.047) and in the FAS (HR = 0.56; 95% CI 0.33-0.95; P = 0.033). A numerical advantage was observed for both the PD-L1positive (n = 27; HR = 0.65; 95% CI 0.27-1.54) and PD-L1negative subgroups (n = 31; HR = 0.57, 95% CI 0.27-1.21). The progression-free proportion after 15 months was 14.7% (5/34; 95% CI 6.4-30.1%) in the atezo-chemo arm versus 0% in the placebo-chemo arm. The addition of atezolizumab to PLD/cyclophosphamide was tolerable with an indication of clinical benefit, and the findings warrant further investigation of PD1/PD-L1 blockers in combination with immunomodulatory chemotherapy.

Long term trends of breast cancer incidence according to proliferation status.

BACKGROUND: Long-term breast cancer incidence trends according to proliferation status are poorly described. We studied time-trends in breast cancer incidence, using mitotic count and Ki-67 as markers of proliferation. METHODS: Among 83,298 Norwegian women followed for breast cancer occurrence 1961-2012, 2995 incident breast cancers were diagnosed. Ki-67 was assessed using immunohistochemistry on tissue microarrays and mitoses were counted on whole sections. We compared incidence rates according to proliferation status among women born 1886-1928 and 1929-1977, estimating age-specific incidence rate ratios. We performed multiple imputations to account for unknown proliferation status. Mean values of Ki-67 and mitotic counts were calculated, according to age and birth year. We performed separate incidence analyses for HER2+ and triple negative breast cancers. RESULTS: Among women aged 40-69 years, incidence rates of tumours with low-proliferative activity were higher among those born in 1929 or later, compared to before 1929, according to Ki-67 and mitotic count. Incidence rates of tumours with high-proliferative activity were also higher in women born in 1929 or later compared to before 1929 according to Ki-67, but not according to mitotic count. Mean values of Ki-67 and mitotic count varied according to age and birth year. In subtype-specific analyses we found an increase of high-proliferative HER2+ tumours according to Ki-67 in women born in 1929 or later, compared to before 1929. CONCLUSIONS: There has been a temporal increase in both low- and high-proliferative breast cancers.

Training, validation, and clinical implementation of a deep-learning segmentation model for radiotherapy of loco-regional breast cancer.

AIM: To train and validate a comprehensive deep-learning (DL) segmentation model for loco-regional breast cancer with the aim of clinical implementation. METHODS: DL segmentation models for 7 clinical target volumes (CTVs) and 11 organs at risk (OARs) were trained on 170 left-sided breast cancer cases from two radiotherapy centres in Norway. Another 30 patient cases were used for validation, which included the evaluation of Dice similarity coefficient and Hausdorff distance, qualitative scoring according to clinical usability, and relevant dosimetric parameters. The manual inter-observer variation (IOV) was also evaluated and served as a benchmark. Delineation of the target volumes followed the ESTRO guidelines. RESULTS: Based on the geometric similarity metrics, the model performed significantly better than IOV for most structures. Qualitatively, no or only minor corrections were required for 14% and 71% of the CTVs and 72% and 26% of the OARs, respectively. Major corrections were required for 15% of the CTVs and 2% of the OARs. The most frequent corrections occurred in the cranial and caudal parts of the structures. The dose coverage, based on D98 > 95%, was fulfilled for 100% and 89% of the breast and lymph node CTVs, respectively. No differences in OAR dose parameters were considered clinically relevant. The model was implemented in a commercial treatment planning system, which generates the structures in 1.5 min. CONCLUSION: Convincing results from the validation led to the decision of clinical implementation. The clinical use will be monitored regarding applicability, standardization and efficiency.

Fully Integrated Oncology and Palliative Care Services at a Local Hospital in Mid-Norway: Development and Operation of an Innovative Care Delivery Model.

INTRODUCTION: Early access to cancer palliative care is recommended. Descriptions of structures and processes of outpatient palliative care clinics operated within smaller hospitals are scarce. This paper presents the development and operation of a fully integrated cancer and palliative care outpatient clinic at a local hospital in a rural region of Mid-Norway offering palliative care concurrent with cancer treatment. A standardized care pathway was applied. METHODS: Palliative care is in Norway part of the public healthcare system. Official recommendations recent years point out action points to improve delivery of palliative care. An integrated cancer and palliative care outpatient clinic at a local hospital and an innovative care delivery model was developed and operated in this setting. Patients were recruited for a descriptive study of the patient population. Clinical data were collected by clinical staff and 13 symptom intensities were reported by the patients. RESULTS: Cancer and palliative care were provided by one team of healthcare professionals trained in both fields. There was a close collaboration with the other departments at the hospital, with its affiliated tertiary hospital, and with community health and care services to provide timely referral, enhanced continuity, and improved coordination of care. Eighty-eight patients were included. Mean age was 65.6 years, the most common cancer diagnoses were digestive organs (22.7%), male genital organs (20.5%) or breast (25.0%), 75.0% had metastatic or locally advanced cancer, 59.1% were treated with non-curative intention and 93.1% had Karnofsky Performance Status ≥ 80%. Median scores of individual symptoms ranged from 0 to 3 (numerical rating scale, 0-10) and 61.0% reported at least one clinically significant symptom rating (≥ 4). CONCLUSION: This delivery model of integrated outpatient cancer and palliative care is particularly relevant in rural regions allowing cancer patients access to palliative care earlier in the disease trajectory and closer to home.

Palliative care is an important part of cancer care which aims at improving cancer patients' symptom burden and quality of life and support their carers. Palliative care has traditionally been separated from cancer care. During the last decade, one has become aware of the benefits of introducing palliative care early and concurrent with cancer treatment. Most cancer patients are nowadays treated as outpatients. Availability of palliative care as a routine part of outpatient cancer clinics is therefore important. Most of the described models of early palliative care in cancer care are within large tertiary hospitals. Here it is described how early palliative care was delivered to cancer patients in an outpatient clinic in a smaller hospital in a rural region of Mid-Norway. In this integrated cancer and palliative care outpatient clinic, cancer and palliative care were provided by one team of healthcare professionals trained in both fields. The integrated outpatient clinic collaborated closely with the other hospital departments and with community health and care services. This was needed to be able to offer palliative care to all cancer patients in need of it, and closer to their home. Many of the patients attending the integrated outpatient clinic could not be cured for their cancer. They did not have many symptoms of their cancer, and they had a high functional status. This demonstrated that the integrated outpatient clinic in this local hospital was a relevant place to offer palliative care early and concurrent with cancer treatment before symptoms became severe.