Quality of life in women with early-stage and metastatic hormone receptor-positive, HER2-negative breast cancer receiving endocrine therapy.

INTRODUCTION: Early discontinuation of endocrine therapy (ET) is higher among patients with early breast cancer (EBC) compared to patients with metastatic hormone receptor-positive (HR+) breast cancer (MBC). In our clinical experience the reasons for this may include a significant burden of ET side effects impacting quality of life (QOL) in patients with EBC.  We hypothesized that QOL is lower in patients with HR + EBC compared to patients with HR + MBC on ET. METHODS: We conducted a cross-sectional observational study to assess QOL utilizing FACT-ES & EORTC QLQ C30 tools among patients with EBC and MBC receiving ET across 5 Irish hospitals. RESULTS: A total of 417 patients were enrolled-EBC (79% n = 331) and MBC 21% (n = 86). Using the FACT-ES, we found no difference in overall QOL by stage (139.2 vs 141, P  = .33). Patients with HR + MBC had a lower symptom burden from ET compared to HR + EBC (61.4 vs 54, P < .01). In adjusted multivariate linear regression models, there was no difference in QOL for patients with EBC and MBC receiving ET. CONCLUSIONS: There was no significant difference in overall QOL for patients with EBC and MBC. However, patients with EBC experienced more endocrine symptoms. In adjusted multivariate linear regression models, the stage did not predict QOL. Our results suggest that endocrine symptoms are significant contributors to impaired QOL for patients with EBC but the role of other determinants of QOL (eg, stage) is less clear. Future work could include the development of stage-specific QOL tools and utilization of electronic patient-reported outcomes (ePROs) to identify and manage emergent toxicities.

Impact of cyclin dependent kinase 4/6 inhibitors on breast cancer brain metastasis outcomes.

BACKGROUND: Cyclin dependent kinase 4/6 inhibitors (CDK4/6i) are recommended 1st line treatments in HR+HER2- metastatic breast cancer. However, the impact of prior CDK4/6i on the natural history of brain metastases (BM) is not well described. MATERIALS AND METHODS: We reviewed retrospective data for 363 patients with HR+HER2- BM who received a CDK4/6i (CDK-Y) between 1 Jan 2015 to 31 July 2021 and 299 patients with HR+HER2- BM who did not receive a CDK4/6i (CDK-N) between 1 Jan 2010 to 31 Dec 2014. CNS PFS and OS were assessed in patients who received CDK4/6i after BM. OS from the time of BM development was assessed between patients who received CDK4/6i before BM and the CDK-N cohort RESULTS: In the CDK-Y cohort of 363 patients, 203 (56 %) received a CDK4/6i before BM, 133 (37 %) received a CDK4/6i only after BM and 27 (7 %) received a CDK4/6i both before and after BM. Median CNS PFS was 21.4 months for patients receiving a CDK4/6i only after BM and 9.4 months for patients who received CDK4/6i both before and after BM (p = 0.006). Median OS was 24.9 months for patients receiving a CDK4/6i only after BM and 12.1 months for patients who received CDK4/6i both before and after BM (p = 0.0098). Median OS from time of BM development for patients receiving a CDK4/6i before BM versus the CDK-N cohort was 4.3 months and 7.7 months respectively (p = 0.0082). CONCLUSIONS: CDK4/6i exposure prior to BM may lead to development of resistance mechanisms which in turn reduces CNS PFS and OS upon rechallenging with a CDK4/6i after BM development. This motivates investigation of biomarkers for patient selection.

New strategies for the treatment of breast cancer with leptomeningeal metastasis.

PURPOSE OF REVIEW: Leptomeningeal metastasis is a complication of metastatic breast cancer that has a rising incidence likely due to the increased availability of novel systemic therapies, which have improved survival with better extracranial disease control but with limited intracranial efficacy. A poor prognosis of less than 6 months has historically been associated with leptomeningeal metastasis and it is often an exclusion factor for enrollment in clinical trials. There are limited evidence-based data supporting use of therapeutics in leptomeningeal metastasis patients and recommendations are largely derived from retrospective reports and small prospective studies. However, in recent years, there has been a surge in effective modern therapeutics with promising intracranial activity. RECENT FINDINGS: The study aims to review the most recent updates in the management of leptomeningeal metastasis in breast cancer. We discuss the effectiveness and limitations of intrathecal administration, predictive biomarkers in the cerebrospinal fluid, proton radiation therapy and promising new systemic therapies such as antibody drug conjugates. SUMMARY: Ongoing development of clinical trials that allow inclusion of leptomeningeal metastasis are essential for establishing efficacy potential and discovering new treatment options in this population of great unmet need.

Characterization of Treatments and Disease Course for Women with Breast Cancer Brain Metastases: 5-Year Retrospective Single Institution Experience.

PURPOSE: Around 30% of patients with breast cancer will develop brain metastases (BM). We sought to characterize the disease course, treatments and outcome for our patient cohort. MATERIALS AND METHODS: We extracted clinicopathological data from electronic records from January 2015 to December 2020. Results were generated using SPSS statistics v27. RESULTS: We identified 98 patients. Median overall survival (OS) from BM diagnosis was 3 months [hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)-], 8 months [HR+/HER2+], 7 months [HR-/HER2+] and 2 months [triple negative breast cancer (TNBC)]. Whole brain radiotherapy (WBRT) (n=48, 70%) was most frequently used followed by surgery (n=15, 22%) and stereotactic radiosurgery (n=6, 8%). In patients who received WBRT alone (n=40) the median OS post WBRT was 2.6 months. CONCLUSION: After BM development, half of the patients had systemic therapy and 70% had local therapy, but only the HER2 subgroup had a prolonged OS likely reflecting central nervous system (CNS) activity of anti-HER2 drugs. TNBC patients had the worst prognosis. Although our cohort is small, OS was >1 year for 60% of HER2+ patients who received trastuzumab emtansine after BM development, which is encouraging for antibody drug conjugates and CNS activity. Patients who received WBRT had a higher burden of CNS disease and had an OS of less than 3 months.

SKAP2-BRAF fusion and response to an MEK inhibitor in a patient with metastatic melanoma resistant to immunotherapy.

A woman in her 40s presented to the emergency department with headache and unintentional weight loss in September 2018. Investigations revealed a widely metastatic pan-negative melanoma of unknown primary. She had multiple lines of treatment including combination immunotherapy and chemotherapy. Next-generation sequencing identified an SKAP2-BRAF fusion protein, and she was commenced on an MEK inhibitor in September 2019 with a partial response seen on restaging scans after 6 weeks and a dramatic fall in her lactate dehydrogenase from 2248 IU/L to 576 IU/L. Unfortunately, the response was not maintained and she died from progression of her cancer in January 2020. SKAP2-BRAF fusions have a dimerisation domain that paradoxically activates the mitogen-activated protein kinase pathway, resulting in hyperproliferation if first-generation or second-generation BRAF inhibitors are used. Our knowledge is limited regarding the complex effects of targeted therapy in rare BRAF fusion proteins.

TGFß drives NK cell metabolic dysfunction in human metastatic breast cancer.

BACKGROUND: Natural killer (NK) cells provide important immune protection from cancer and are a key requirement for particular immunotherapies. There is accumulating evidence that NK cells become dysfunctional during cancer. Overcoming NK cell exhaustion would be an important step to allow them to function optimally in a range of NK cell therapies, including those that depend on autologos circulating NK cells. We have previously demonstrated that NK cells undergo a normal metabolic reprogramming in response to cytokine activation and that this is required for optimal function. The objective of this work was to investigate if cellular metabolism of circulating NK cells is dysregulated in patients with metastatic breast cancer and if so, to gain insights into potential mechanisms underpinning this. Such discoveries would provide important insights into how to unleash the full activity of NK cells for maximum immunotherapy output. METHODS: Single-cell analysis, metabolic flux and confocal analysis of NK cells from patients with metastatic breast cancer and healthy controls RESULTS: In addition to reduced interferon-γ production and cytotoxicity, peripheral blood NK cells from patients had clear metabolic deficits including reduced glycolysis and oxidative phosphorylation. There were also distinct morphologically alterations in the mitochondria with increased mitochondrial fragmentation observed. Transforminggrowth factor-ß (TGFß) was identified as a key driver of this phenotype as blocking its activity reversed many metabolic and functional readouts. Expression of glycoprotein-A repetitions predominant (GARP) and latency associated peptide (LAP), which are involved with a novel TGFß processing pathway, was increased on NK cells from some patients. Blocking the GARP-TGFß axis recapitulated the effects of TGFß neutralization, highlighting GARP as a novel NK cell immunotherapy target for the first time. CONCLUSIONS: TGFß contributes to metabolic dysfunction of circulating NK cells in patients with metastatic breast cancer. Blocking TGFß and/or GARP can restore NK cell metabolism and function and is an important target for improving NK cell-based immunotherapies.

Virtual oncology clinics during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has resulted in radical changes in the delivery of healthcare worldwide. Our oncology service (at an Irish national cancer centre) rapidly transitioned to the use of telemedicine or virtual clinics (VC) to minimise potential risk of exposure to COVID-19 amongst an immunosuppressed, high-risk population. Our study aimed to evaluate the use of VC in this setting. METHODS: An 18-point questionnaire was designed to investigate the patient experience of VC during the COVID-19 pandemic in Ireland and compliance with guidelines developed in Ireland to conduct VC and the role of VC in the future. Questionnaires were distributed following the receipt of verbal consent from patients during the VC. Descriptive statistics were utilised for data analysis using SPSS®. RESULTS: One hundred and four patients returned completed surveys (n = 104/164, 63% response rate). Overall satisfaction levels were high with most patients (n = 58/100, 58%; no answer provided (NAP), n = 4) equally satisfied or nearly equally satisfied with VC in comparison to a usual clinic encounter. The majority of patients felt that there should be a role for VC in the future (n = 84/102, 82%; NAP, n = 2). The majority of patients (n = 61/99, 61%; NAP, n = 5) were very relieved to avoid a hospital visit due to perceived risk of potential exposure to COVID-19. CONCLUSION: The majority of oncology patients were satisfied with a VC encounter. VC may have a role in the future of medical care in Ireland post the COVID-19 pandemic.

Unusual Sites of High-Grade Neuroendocrine Carcinomas: A Case Series and Review of the Literature.

BACKGROUND Neuroendocrine tumors (NETs) encompass a diverse group of varying clinicopathological entities arising from cells of the endocrine and nervous systems. The presentation of these unique tumors can range from occult disease discovered incidentally to hyperactive, metastatic secretory tumors. NETs most commonly originate in the gastrointestinal and respiratory tract, although they may occur at any site in the body due to the wide distribution of neuroendocrine cells. Their classification system is complex and continues to evolve, and the current system uses histological grade in defining these subtypes. Neuroendocrine carcinomas (NECs), or high-grade, poorly-differentiated NETs, are the most aggressive subtype. Surgical resection remains the primary treatment modality and may be curative, thus early diagnosis is paramount. Management of advanced NETs remains both a diagnostic and therapeutic challenge; however, advances in our understanding of these unique neoplasms as well as an evolving classification system has led to the development of adjunctive therapeutic approaches aimed to minimize morbidity and improve patient outcomes. CASE REPORT We present 6 cases of unusual sites of high-grade neuroendocrine carcinomas involving the cervix, gallbladder, oesophagus, ovary, prostate, and urinary bladder. CONCLUSIONS Our case series highlights the heterogenous and aggressive nature of this subtype of NETs as well as their diagnostic and therapeutic difficulties. We also review the evolution of the NET classification system and its impact on the management of these malignancies.