Metastatic Breast Cancer Patients Research Articles

Discovery of a sushi domain-containing protein 2-positive phenotype in circulating tumor cells of metastatic breast cancer patients

Cell lines derived from circulating tumor cells (CTCs) in the blood provide important biological information on cancer metastasis. CTC-ITB-01 is a CTC cell line derived from a patient with metastatic estrogen receptor-alpha (ER-alpha) positive breast cancer two months before the death of the patient. After a LC-MC/MS based proteomics analysis of CTC-ITB-01, we found extraordinary high levels of the poorly characterized protein SUSD2 (sushi domain-containing protein 2) in CTC-ITB-01. Expression of SUSD2 on subsets of CTCs was validated on clinical blood samples of patients with metastatic breast cancer. SUSD2-positive CTCs could be captured specifically by a MACS-based approach. We overexpressed SUSD2 in the poorly-metastatic cell line MCF-7. This resulted in upregulation of ER-alpha, the tumor progression protein GRP78 (78-kDa glucose-regulated protein) and downregulation of the tumor suppressor protein PDCD4 (programmed cell death protein 4). We observed downregulation of SUSD2 and PDCD4 after hypoxia and simulation of re-oxygenation in the blood in MCF-7 and MDA-MB-468, while in CTC-ITB-01 SUSD2 levels remained unchanged, and only PDCD4 was downregulated under hypoxia. In conclusion, we show, for the first time, that SUSD2 is expressed in CTCs and appears to affect key proteins in tumor progression and survival.

Understanding metastasis mixed-treatment responses through genomic analyses

Early-stage and metastatic breast cancers (MBC) can exhibit genomic heterogeneity, even within the same individual. Response to therapy in metastatic breast cancer patients with multiple metastases can also be heterogeneous, with different degrees of responsiveness to the same drug(s) across metastatic sites, termed “mixed response,” within the same patient. Whether this treatment response variability is influenced by factors such as intrinsic tumor characteristics of metastatic lesions and/or the microenvironment is unknown. Through genomic analysis of multiple metastases from the same patient, assayed in 6 different patients who had exhibited mixed response on imaging, we identified that higher regulatory T cells (T reg) and CDKN2A gene expression values correlate with non-response, while the KRAS gene, KRAS amplicon, and CD8T cells were associated with response in individual metastases. These genomic features may explain mixed clinical responses and provide valuable insights into intrapatient variations in treatment sensitivity.

Dihydropyrimidine Dehydrogenase Deficiency (DPYD) Genotyping-Guided Fluoropyrimidine-Based Adjuvant Chemotherapy for Breast Cancer. A Cost-Effectiveness Analysis.

While standard doses of adjuvant fluoropyrimidine-based chemotherapies are generally safe for most patients, the risk of severe adverse drug reactions (ADRs) is increased for those with dihydropyrimidine dehydrogenase deficiency (DPYD), a genetic variation that affects drug metabolism. The objective of this study was to examine the cost effectiveness of offering DPYD pharmacogenetic-guided care, where genetic testing informs personalized dosing versus the current standard of care (SoC), which involves administering fluoropyrimidine-based therapies without prior genetic screening, for local or metastatic breast cancer patients in Qatar. We developed a two-stage decision analysis, with an analytic tree model over a 6-month period, followed by a life-table Markov model over a lifetime horizon. We compared the current SoC with the alternate strategy of DPYD genetic screening in patients living in Qatar with local or metastatic breast cancer who were eligible for adjuvant fluoropyrimidine therapy. Clinical outcomes and utilities were obtained from published studies, while healthcare costs were estimated from Hamad Medical Corporation, Qatar. The short-term outcome included the incremental cost-effectiveness ratio (ICER), defined as cost per success (survival without grade III/IV ADRs) at 6 months. The long-term outcome was the ICER, defined as cost per quality-adjusted life year (QALY) gained, with a 3% annual discount rate. The study adopted a public healthcare perspective in Qatar. Sensitivity analyses were conducted to explore the impact of key input parameters on the robustness of the model. In the short-term model, at its base case, DPYD genomic screening was dominant over SoC with a mean cost-saving of QAR84,585 (95% confidence interval [CI], 45,270-151,657). This cost saving reflects the overall economic benefits associated with the implementation of DPYD genomic screening. In the long-term model, compared to the current SoC, DPYD genetic screening would result in an ICER of QAR21,107 (95% CI -59,382-145,664) per QALY gained. Based on our model, implementing DPYD genetic screening to detect DPYD mutations in breast cancer patients before therapy initiation seems to be a cost-saving and cost-effective strategy in Qatar.

Palliative Radiotherapy in Metastatic Breast Cancer Patients on CDK4/6 Inhibitors: Safety Analysis

Purpose: CDK4/6 inhibitors require meticulous monitoring due to their potential to cause hematological toxicities and hepatotoxicity. This study evaluates the safety of combining CDK4/6 inhibitors with palliative radiotherapy in patients with metastatic hormone receptor-positive and HER2-negative breast cancer. Patients and Methods: This study included 188 patients treated with CDK4/6 inhibitors between January 2021 and June 2024. Data on patient demographics, tumor characteristics, and treatment interventions were extracted from medical records. The primary focus was on the incidence of grade ≥ 3 hematologic toxicities and hepatotoxicity, assessed according to CTCAE 5.0 criteria, in those receiving concurrent palliative radiotherapy. Results: With a median follow-up of 18.5 months, the 18-month PFS and OS rates were 67% and 85%, respectively. The median age was 57.5 years, and 79% of patients were post-menopausal. Bone and liver metastases were present in 66% and 23% of patients, respectively. Concurrent palliative radiotherapy was administered in 25% of the cohort. The incidence of grade ≥ 3 hematologic toxicity was comparable between those who received radiotherapy and those who did not. Ribociclib use was associated with lower rates of grade 3 hematologic toxicity (OR: 0.37), neutropenia (OR: 0.41), dose interruptions (OR: 0.30), and dose reductions (OR: 0.37). Pre-menopausal status was linked to fewer dose reductions (OR: 0.17). Rates of treatment interruption, dose reduction, and withdrawal were 55%, 24%, and 2%, respectively. Conclusions: The concurrent use of CDK4/6 inhibitors and palliative radiotherapy does not increase the incidence of hematological adverse events in patients with metastatic breast cancer.

Intrapatient 16α-[18F]Fluoro-17β-Estradiol PET Heterogeneity as a Prognostic Factor for Endocrine Therapy Response and Survival in Patients with Estrogen Receptor-Positive Metastatic Breast Cancer.

Intrapatient heterogeneity of estrogen receptor (ER) expression on 16α-[18F]fluoro-17β-estradiol ([18F]FES) PET is related to outcome in patients with ER-positive metastatic breast cancer (MBC), but a validated and practical method to support clinical decision-making is lacking. Therefore, the [18F]FES PET heterogeneity score (i.e., percentage of [18F]FES-positive metastases) was validated as a prognostic factor for endocrine therapy response and survival in a large cohort of patients with newly diagnosed MBC. Furthermore, we explored 2 less laborious methods to predict the [18F]FES PET heterogeneity score. Methods: Patients with ER-positive MBC included in the IMPACT-MBC study, who received baseline [18F]FES and [18F]FDG PET and first-line endocrine therapy, were included in this subanalysis. ER homogeneous (100% [18F]FES-positive lesions) and ER heterogeneous (both [18F]FES-positive and [18F]FES-negative lesions) MBC was distinguished by manual segmentation of all lesions on [18F]FES PET and related to progression-free survival (PFS) and overall survival (OS). In addition, the positive predictive value of the visual assessment and the 5-largest-lesions assessment to predict homogeneous MBC in all lesions on [18F]FES PET was determined. Results: From the 102 MBC patients eligible for the present retrospective subanalysis, 46 had ER homogeneous MBC and 56 had ER heterogeneous MBC. Differences were found between ER homogeneous and ER heterogeneous MBC for median PFS (19.8 vs. 15.0 mo; hazard ratio, 0.63; 95% CI, 0.41-0.96; P = 0.03) and median OS (62.5 vs. 34.7 mo; hazard ratio, 0.65; 95% CI, 0.38-1.08; P = 0.09). Twenty-one (38%) of 61 patients with ER homogeneous MBC by visual analysis and 37 (45%) of 83 patients with ER homogeneous MBC by the 5-largest-lesions method had ER heterogeneous MBC by manual segmentation of all lesions on [18F]FES PET (positive predictive value, 0.66 and 0.55, respectively). Conclusion: Patients with ER-positive homogeneous MBC showed a trend toward superior PFS and OS compared with patients with ER heterogeneous MBC. This analysis confirmed and validated the prognostic value of the [18F]FES PET heterogeneity score for endocrine therapy response and survival in a large cohort of MBC patients. The less laborious visual and 5-largest-lesions methods were inferior compared with assessment based on the [18F]FES PET heterogeneity score in all lesions.

Real-world clinical multi-omics analyses reveal bifurcation of ER-independent and ER-dependent drug resistance to CDK4/6 inhibitors

To better understand drug resistance mechanisms to CDK4/6 inhibitors and inform precision medicine, we analyze real-world multi-omics data from 400 HR+/HER2- metastatic breast cancer patients treated with CDK4/6 inhibitors plus endocrine therapies, including 200 pre-treatment and 227 post-progression samples. The prevalences of ESR1 and RB1 alterations significantly increase in post-progression samples. Integrative clustering analysis identifies three subgroups harboring different resistance mechanisms: ER driven, ER co-driven and ER independent. The ER independent subgroup, growing from 5% pre-treatment to 21% post-progression, is characterized by down-regulated estrogen signaling and enrichment of resistance markers including TP53 mutations, CCNE1 over-expression and Her2/Basal subtypes. Trajectory inference analyses identify a pseudotime variable strongly correlated with ER independence and disease progression; and revealed bifurcated evolutionary trajectories for ER-independent vs. ER-dependent drug resistance mechanisms. Machine learning models predict therapeutic dependency on ESR1 and CDK4 among ER-dependent tumors and CDK2 dependency among ER-independent tumors, confirmed by experimental validation.

Bone-Induced Her2 Promotes Secondary Metastasis in HR+/Her2- Breast Cancer.

Bone metastases can disseminate to secondary sites and promote breast cancer progression creating additional clinical challenges. The mechanisms contributing to secondary metastasis are barely understood. Here, we evaluate the prediction power of Her2-expressing (Her2E) circulating tumor cells (CTCs) after analyzing over 13,000 CTCs from a cohort of 137 metastatic breast cancer (MBC) patients with initial HR+/Her2- status and employ preclinical models of bone metastasis (BM) to validate the role of Her2E CTCs in multi-organ metastases. While Her2 expression was higher in patients with bone metastasis, experimental analyses revealed that Her2E CTCs derived from bone lesions were more dependent on Her2 activity and more susceptible to anti-Her2 therapy. Targeting the bone-mediated Her2 induction reduces CTC detection and abrogates secondary metastasis from bone. Overall, we elucidate that Her2E CTCs can serve as a non-invasive biomarker for BM formation with high therapeutic benefit for HR+ MBC patients.

Lerociclib plus fulvestrant in patients with HR+/HER2− locally advanced or metastatic breast cancer who have progressed on prior endocrine therapy: LEONARDA-1 a phase III randomized trial

Lerociclib (GB491), a highly selective oral CDK4/6 inhibitor, has displayed anti-tumor activity and differentiated safety and tolerability profile in previous ph1/2 clinical trials. The LEONARDA-1, a randomized, double-blind, phase III study, was conducted to evaluate the efficacy and safety of lerociclib in HR+/HER2− locally advanced or metastatic breast cancer patients, who had relapsed or progressed on prior endocrine therapy. A total of 275 patients were randomized at 1:1 ratio to receive lerociclib (137 patients, 150 mg twice daily) or placebo (138 patients) plus fulvestrant. Progression-free survival (PFS) assessed by investigators was significantly improved in lerociclib arm versus placebo arm (11.07 vs 5.49 months; hazard ratio, 0.451, 95% CI: 0.311-0.656, P = 0.000016), meeting the pre-specified primary endpoint. The secondary endpoints included PFS assessed by Blinded Independent Central Review (BICR), objective response rate (ORR), duration of response (DOR), disease control rate (DCR), clinical benefit rate (CBR), overall survival (OS), safety and tolerability and pharmacokinetic profile. DOR is not reported, and OS data was immature at the data cut-off but unplanned ad hoc analysis is reported. These findings support lerociclib plus fulvestrant as a treatment option for patients with HR+/HER2− endocrine-resistant advanced breast cancer (ABC). (Funded by Genor Biopharma; LEONARDA-1 ClinicalTrials.gov identifier, NCT05054751.)

Erythrocyte modified controlling nutritional status as a biomarker for predicting poor prognosis in post-surgery breast cancer patients

Nutrition and inflammation are closely related to prognosis in breast cancer patients. However, current nutritional and inflammatory measures predict disease free survival (DFS) of breast cancer are still different, and the most predictive measures remain unknown. This study aimed to compare the predictive effects of commonly used nutritional and inflammatory measures on DFS and to improve existing nutritional or inflammatory measures in order to develop a new model that is more effective for predicting postoperative recurrence and metastasis in breast cancer patients. The clinical data of 536 female breast cancer patients with invasive ductal carcinoma who underwent surgery at Shaoxing People’s Hospital from January 2012 to December 2018 were retrospectively evaluated. The predictive effects of nutritional and inflammatory indicators on DFS were evaluated. Machine learning was used to evaluate and rank laboratory indicators, select relatively important variables to modify nutritional or inflammatory indicators with the best predictive power, and evaluate their predictive role in patients’ postoperative recurrence and metastasis. Among various metrics predicting DFS, the CONUT score emerged paramount with an area under the curve (AUC) of 0.667. Interestingly, the combination of the erythrocyte levels with the CONUT score (ECONUT) achieved the highest AUC (0.722). The Kaplan-Meier survival analysis showed that the group exhibiting high ECONUT scores experiencing a notably poorer DFS. ECONUT was identified as an independent risk factor for postoperative DFS (P < 0.001). The ECONUT model could provide an effective assessment tool for predicting DFS in breast cancer patients.

Predicting Axillary Metastasis of Breast Cancer Patients with MRI Relaxometry.

Background: Breast cancer is a leading cause of cancer-related mortality among women worldwide. Accurate staging, including the detection of axillary metastases, is vital for treatment planning. This study evaluates the efficacy of MRI relaxometry as a diagnostic tool for axillary lymph node metastases in breast cancer patients. Methods: A prospective study was conducted on 67 consecutive breast cancer patients. Relaxometry parameters, including T2Max, T2Min, and 1HAv, were assessed using 1.5 Tesla MRI. All axillary metastases were histologically confirmed using core-needle biopsy or surgical specimens. Statistical analyses included ROC curves, chi-square tests, and multivariate analysis to determine correlations between imaging findings and pathological results. Results: Significant associations were found between T2Min-ipsilateral (p = 0.018), 1HAv-ipsilateral (p = 0.003), and axillary metastases. ROC analysis demonstrated that T2Min-ipsilateral and 1HAv-ipsilateral have modest to acceptable discriminatory abilities (AUC = 0.681 and AUC = 0.740, respectively). Combined clinical and imaging models enhanced diagnostic accuracy (AUC = 0.749). Conclusions: MRI relaxometry improves the detection of axillary metastases in breast cancer, particularly when integrated with clinical and pathological evaluations.

The Cost-Effectiveness of CDK4/6 Inhibitors in Treating HR+/HER2- Metastatic Breast Cancer Patients in the USA: When Non-medication Expenses are Considered.

Cyclin-dependent kinase (CDK)4/6 inhibitors in combination with endocrine therapy (ET) significantly enhance progression-free survival and overall survival in patients diagnosed with HR+/HER2- metastatic breast cancer (MBC). However, they are highly expensive, and their economic impact has not been fully evaluated. This is a retrospective secondary analysis evaluating the cost effectiveness of these drugs, differentiating between medication-related and non-medication costs from a healthcare perspective. We identified 3879 patients diagnosed with MBC who received either CDK4/6i+ET (N = 2137) or ET alone (N = 1742) as first-line treatment between February 2015 and November 2021 using a USA-wide electronic health record-derived de-identified database. SEER-Medicare claims spending data were used to quantify monthly costs as a supplement to the database. Relevant costs included prescribed medications (ET and/or CDK4/6i) and overall other costs. The effectiveness was measured as progression-free duration in months. The incremental cost effectiveness ratio (ICER) analysis was conducted to examine the cost effectiveness of first-line CDK4/6i as compared with first-line ET alone. For medication costs, CDK4/6i+ET (mean cost: $240,723.7; mean effect: 19.2 months of delayed progression) compared with ET alone (mean cost: $5159.7; mean effect: 16 months without progression) resulted in an ICER of $73,098 per month of delayed progression. For non-medication costs, CDK4/6i+ET (mean cost: $43,656.6) compared with ET alone (mean cost: $66,083.5) resulted in an ICER of -$7178 per month of delayed progression. The cost of treating HR+/HER2- MBC is driven by the cost of CDK4/6i. Using CDK4/6i+ET reduces non-medication costs compared to ET alone, but these savings are offset by high CDK4/6i medication costs. Lowering the market cost of CDK4/6i or targeting those who can benefit the most could improve the cost effectiveness of CDK4/6i from Medicare perspective.

Prediction of axillary lymph node metastasis in breast cancer patients based on ultrasonograhic-clinicopathologic features.

Determination of axillary lymph-node status plays a pivotal role in decision making for breast cancer treatment. Biopsy is the current standard of care but hold risks of complications as well. We aimed to find out the correlation of sonographic features of lymph node and histo-pathological findings, to predict axillary lymph-node metastasis in breast cancer patients. This retrospective observational study included 176 breast cancer patients at a private tertiary care hospital from January 2019 to December 2023. The study calculated sensitivity, specificity and accuracy of ultrasound (US) in identifying ALN metastasis. Also, binary logistic regression analysis was used to demonstrate the association between suspicious findings on axillary US with pathology report. Patients who never had undergone axillary surgery or with insufficient data, were excluded from our study. In our study Axillary US was found to be 84.2% sensitive, 48.1% specific, and 67.6% accurate in identifying nodal metastases. In this context, ALN metastases was strongly and independently correlated with cortical thickness > 3 mm and the absence of a fatty hilum (P <.05). Ultrasound was found to be highly sensitive but not specific in predicting metastatic lymph nodes in patients with breast cancer.

Combined pyrotinib and fulvestrant for hormone receptor-positive and HER2-positive metastatic breast cancer: A multicenter, single-arm, phase II trial.

This multicenter, single-arm, phase II clinical trial (NCT04034589) evaluated the efficacy and safety of pyrotinib combined with fulvestrant in patients with HR-positive/HER2-positive metastatic breast cancer who had experienced trastuzumab treatment failure. A total of 46 patients were enrolled, receiving pyrotinib orally once daily and fulvestrant intramuscularly on days 1 and 15 of cycle 1, followed by monthly doses on day 1. The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. The median PFS was 18.2 months (95% CI, 11.9-31.1) overall, 19.5 months (95% CI, 10.6-NA) for those receiving the combination as first-line therapy, and 18.4 months (95% CI, 16.7-NA) for patients with brain metastases. Median OS was not reached, with a 3-year OS rate of 75.2% (95% CI, 62.8-90.2%). The ORR was 32.5%, and the DCR was 97.5%. Responses were observed in patients with low tumor mutation burden and ZNF217 mutation. Importantly, no grade 4 or higher treatment-related adverse events or deaths were reported, indicating a favorable safety profile. In conclusion, the combination of pyrotinib and fulvestrant demonstrated promising antitumor activity and acceptable safety in HR-positive/HER2-positive metastatic breast cancer patients.

Acceptability of the Fit2ThriveMB mHealth physical activity promotion intervention in women with metastatic breast cancer.

Increasing physical activity (PA) is safe and associated with improved health outcomes in patients with metastatic breast cancer (MBC). Mobile health (mHealth) PA interventions that allow for remote monitoring and tailoring to abilities may be particularly useful for MBC patients. However, limited data exist on the acceptability of these interventions for MBC patients. This study examined the acceptability of Fit2ThriveMB, a highly tailored mHealth intervention targeting increased daily steps in MBC patients. Insufficiently active women with MBC ((N = 25) Mage = 57.2, SD = 11.9) received the Fit2ThriveMB intervention (Fit2ThrviveMB app, Fitbit, weekly coaching calls) for 12weeks. Participants completed an online questionnaire (n = 22) and semi-structured interview (n = 23) at 12weeks to assess intervention acceptability. Quantitative data were analyzed using descriptive statistics. Interviews were analyzed and coded using thematic content analysis and consensus review. All (n = 23) participants indicated they were satisfied with the intervention, Fit2ThriveMB app design, and Fitbit usability via questionnaire. Four themes emerged from qualitative interview data: (1) Overall satisfaction with implementation, (2) Social interaction is important, but within-app social features need improvement, (3) Fit2ThriveMB was encouraging and enhanced accountability, (4) Fit2ThriveMB helped form sustainable habits. Participants were generally satisfied with the intervention. However, areas for improvement were identified for some study features. Findings indicate Fit2ThriveMB was acceptable among people with MBC. Further refinement of Fit2ThriveMB social feed features and step count goals is warranted for future testing in fully powered trials with a larger sample size.

Large Unstained Cells (LUC): A Novel Predictor of CDK4/6 Inhibitor Outcomes in HR+ HER2-Negative Metastatic Breast Cancer.

Background: Although CDK4/6 inhibitors combined with endocrine therapies have improved outcomes in HR+ HER2-negative metastatic breast cancer, predictive biomarkers for treatment response and adverse effects remain limited. This study assessed the prognostic and predictive value of large unstained cells (LUC), a subset of white blood cells that may reflect immune status or treatment response. Methods: A retrospective analysis of 210 patients with HR+ HER2-negative metastatic breast cancer treated with CDK 4/6 inhibitors between 2021 and 2024 was conducted. Clinical data, including demographics, tumor characteristics, and treatment regimens, were analyzed. Based on LUC levels, progression-free survival (PFS), overall survival (OS), and adverse events were evaluated. Results: The cohort had a median age of 57, of which 78% were postmenopausal. Common metastatic sites included bone (67%) and liver (24%). At a median follow-up of 18.5 months, the PFS and OS rates were 65% and 83%. Patients with low LUC levels had significantly shorter PFS (OR: 1.91; p = 0.014) and OS (OR: 2.39; p = 0.012), while high LUC levels correlated with a lower incidence of grade 3 neutropenia (OR: 0.49; p = 0.017). Liver metastasis and prior treatments were also linked to shorter survival. Conclusions: LUC levels emerge as a promising biomarker for predicting survival outcomes and the risk of neutropenia in HR+ HER2-negative metastatic breast cancer patients treated with CDK 4/6 inhibitors and endocrine therapy, showing their potential to guide personalized treatment approaches.

ST6GAL1-Mediated Sialylation of PECAM-1 Promotes a Transcellular Diapedesis-Like Process that Directs Lung Tropism of Metastatic Breast Cancer.

Metastasis is the leading cause of mortality in breast cancer, with lung metastasis being particularly detrimental. Identification of the processes determining metastatic organotropism could enable the development of approaches to prevent and treat breast cancer metastasis. Here, we found that lung-tropic and non-lung-tropic breast cancer cells differ in their response to sialic acids, affecting the sialylation of surface proteins. Lung-tropic cells showed higher levels of ST6GAL1, while non-lung-tropic cells had more ST3GAL1. ST6GAL1-mediated α-2,6-sialylation, unlike ST3GAL1-mediated α-2,3-sialylation, increased lung metastasis by promoting cancer cell migration through pulmonary endothelial layers and reducing junction protein levels. α-2,6-sialylated PECAM-1 on breast cancer cells facilitated extravasation through the pulmonary endothelium, a critical step in lung metastasis. Knockdown of ST6GAL1 or PECAM-1 significantly reduced lung metastasis. Human pulmonary endothelium displayed high PECAM-1 levels. Through transhomophilic interaction with pulmonary PECAM-1, α-2,6-sialylated PECAM-1 on ST6GAL1-positive cancer cells increased pulmonary extravasation in a diapedesis-like, cell-autonomous manner. Additionally, lung-tropic cells and their exosomes increased the permeability of pulmonary endothelial cells, promoting metastasis in a non-cell-autonomous manner. Analysis of human breast cancer samples showed a correlation between elevated ST6GAL1/PECAM-1 expression and lung metastasis. These results suggest that targeting ST6GAL1-mediated α-2,6-sialylation could be a potential therapeutic strategy to prevent lung metastasis in breast cancer patients.

T cell induced expression of Coronin-1A facilitates blood-brain barrier transmigration of breast cancer cells

In previous work we discovered that T lymphocytes play a prominent role in the rise of brain metastases of ER-negative breast cancers. In the present study we explored how T lymphocytes promote breast cancer cell penetration through the blood brain barrier (BBB). An in vitro BBB model was employed to study the effects of T lymphocytes on BBB trespassing capacity of three different breast carcinoma cell lines. Differential protein expression was explored by comparing the proteomes of the breast cancer cells before and after co-culture with activated T lymphocytes using liquid chromatography-mass spectrometry (LC-MS). siRNA was used to silence protein expression in the breast cancer cells to study contribution to in vitro BBB passage. Furthermore, protein expression in primary breast cancer tissues was explored and related to brain-metastatic potential. Co-culturing with activated T lymphocytes or their conditioned medium (CM) resulted in increased passage through the in vitro BBB. The effects were less for cell line MDA-MB-231-B2M2 (brain affinity) as compared to MDA-MB-231 and SK-BR-7. Mass spectrometry-based proteomics revealed significant alterations in the expression of 35 proteins by the breast cancer cell lines upon T cell contact. Among the proteins is coronin-1 A, a protein related to cell motility. Knockdown of CORO1A in the breast cancer cells reduced their ability to cross the artificial BBB to 60%. The effects were significantly less for the cell line derived from breast cancer with affinity for brain. The expression of coronin-1A was confirmed by immunohistochemistry and RT-PCR of 52 breast cancer samples of patients with metastasized breast cancers, with and without brain locations. Lastly, CORO1A upregulation was validated in a publicly available mRNA expression database from 204 primary breast cancers with known metastatic sites. We conclude that T lymphocytes trigger cancer cells to express proteins including coronin-1A that enable the cancer cells to cross an in vitro BBB. In addition, a prominent role of coronin-1A in the formation of cerebral metastases in breast cancer patients is strongly suggestive by its upregulation in tissue samples of breast cancer patients with brain metastases.

Cell-free tumor DNA analysis in advanced or metastatic breast cancer patients: mutation frequencies, testing intention, and clinical impact.

Circulating cell-free tumor DNA (ctDNA) provides a non-invasive approach for assessing somatic alterations. The German PRAEGNANT registry study aims to explore molecular biomarkers and investigate their integration into clinical practice. In this context, ctDNA testing was included to understand the motivations of clinicians to initiate testing, to identify somatic alterations, and to assess the clinical impact of the results obtained. Patients with advanced/metastatic breast cancer were prospectively enrolled in the Prospective Academic Translational Research Network for the Optimization of Oncological Health Care Quality in the Adjuvant and Advanced/Metastatic Setting (PRAEGNANT study; NCT02338167). The FDA-approved and CE-marked GUARDANT360 CDx test was used to assess somatic alterations. A ctDNA-analysis report was provided to the treating physician along with a questionnaire about the intent for testing and the clinical implications of test results. ctDNA from 49 patients was analyzed prospectively: 37 (76%) had at least one somatic alteration in the analyzed geneset; 14 patients (29%) harbored alterations in TP53, 12 (24%) in PIK3CA, and 6 (12%) in ESR1. Somatic mutations in BRCA1 or BRCA2 were detected in 3 (6%) and 4 (8%) patients, respectively, and 59% of patients had hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. Questionnaires regarding test intentions and clinical impact were completed for 48 (98%) patients. These showed that ctDNA testing influenced treatment decisions for 35% of patients. The high prevalence of somatic alterations in TP53, PIK3CA, ESR1, and BRCA1/2 genes, identified by ctDNA genotyping, highlights their potential as biomarkers for targeted therapies. Detection of specific mutations affected treatment decisions, such as eligibility for alpelisib, and might further facilitate treatment with e.g. elacestrant or capiversatib in future treatment lines.

Incidence of patient-reported fatigue developing on palbociclib and endocrine therapy for advanced HR+ HER2- breast cancer.

Fatigue is a common nonhematologic toxicity of the CDK4/6 inhibitor palbociclib in metastatic breast cancer (MBC) patients with prevalence rates of clinician-rated all-grade and grade 3/4 fatigue of 39.2% and 2.5%, respectively. We prospectively assessed the incidence of fatigue emerging on palbociclib using patient-reported measures and explored potential predictors. Eighty-eight patients with HR+ HER2- MBC without fatigue initiating palbociclib with endocrine therapy were assessed before and monthly across the initial 6 cycles. Clinically meaningful levels of patient-reported fatigue (Functional Assessment of Chronic Illness Therapy Fatigue Scale, FACIT-F < 34), severity of, and functional interference due to fatigue (NCI Patient-Reported Outcomes for CTCAE, PRO-CTCAE) were assessed. Hematologic and nonhematologic predictors were examined pretreatment and concurrent with fatigue assessments. Patient-reported fatigue emerged in 21/88 patients [incidence rate 23.9% (95%CI, 15.4%-34.1%)] within 2.8 ± 1.7 treatment cycles. PRO-CTCAE-rated incidence rate of severe fatigue and fatigue interference was 14.8% (95%CI, 8.1%-23.9%) and 10.2% (95%CI, 4.8%-18.5%), respectively. Lower pretreatment absolute neutrophil count (ANC) levels predicted treatment-emergent fatigue (P =.01), but ANC levels on treatment did not (P =.78). Other pretreatment predictors were long sleep duration (P =.02) and low physical activity (trend, P =.07). Treatment-emergent fatigue was associated with objectively measured long sleep duration on treatment (P =.02), but not other measures (P ≥.35). One-quarter of patients with HR+ HER2- MBC initiating palbociclib report rapidly emergent clinically meaningful fatigue, often with severe symptoms and functional interference. Treatment-emergent fatigue is associated with both pretreatment (lower ANC levels, longer sleep duration) and on-treatment (long sleep duration) hematologic and nonhematologic profiles.

Metastatic breast cancer patients' preferences for exercise programs: a latent class analysis using data from a survey in five European countries.

We aimed to identify metastatic breast cancer (MBC) patients' preferences for exercise programs and identify patients' characteristics associated with these preferences, to facilitate implementation of exercise programs for MBC patients. We used data from a multinational cross-sectional survey conducted among MBC patients. Patients reported their preferred exercise frequency, intensity, type, session duration, and supervision mode. We used latent class analysis to identify subgroups with similar preferences and descriptive statistics to compare demographic and clinical characteristics of patients within subgroups. Four distinct classes were identified based on data from 409 participants. Class 1 (47% of participants) is characterized by a preference for moderate exercise with supervision within the health care setting. Most participants in this class had bone metastases. Class 2 (30%) is characterized by a preference for vigorous exercise with supervision. This class included participants who were, on average, younger, and had a higher education level. Class 3 (13%) is characterized by a preference for active walking. These participants were less likely to have bone metastases or comorbidities. Class 4 (10%) is characterized by a preference for recreational walking and included participants who were, on average, older, and less likely to be employed. We identified four classes of patients with different preferences for exercise programs. Many patients with MBC express exercise preferences that meet the current guideline recommendations. Some patients with MBC may benefit from targeted education to align their preferences and behavior with the amount of exercise that is necessary to gain health benefits.