Background and purpose: Neoadjuvant therapy (NAT) has become standard therapy for early triple-negative breast cancer (TNBC). The aim of this study was to report real-world outcome of TNBC treated with NAT with or without pembrolizumab and to identify predictive factors for achieving pathologic complete response (pCR) in the pembrolizumab cohort. Patient/material and methods: The data of 75 consecutive TNBC patients treated with neoadjuvant chemotherapy and pembrolizumab at the Helsinki University Hospital Comprehensive Cancer Center were retrospectively collected. Treatment outcome and predictive factors for pCR were analyzed. Additionally, the outcome of nonmatched 102 consecutive TNBC patients treated without pembrolizumab during the preceding years is reported. Results: Forty-two patients (56.0%) achieved pCR to pembrolizumab-based NAT, while 47 patients (46.1%) without pembrolizumab had pCR. Lymph node metastasis (p = 0.011) and multifocality (p < 0.001) were inversely associated with pCR in the pembrolizumab cohort. Thirty-four patients (45.3%) had immune-related adverse events (irAEs), and 11 patients (14.7%) had grade 1–2 myocarditis in the pembrolizumab cohort. Due to adverse events (AEs), pembrolizumab was discontinued in 22 patients (29.3%) in the neoadjuvant setting, not started postoperatively in 21 patients (28%) and discontinued postoperatively in eight patients (10.7%). The number of preoperative pembrolizumab cycles was not associated with pCR. Interpretation: Despite higher incidence of myocarditis and interruption of the systemic therapy due to irAEs, higher pCR rates were seen with pembrolizumab. Even though the number of preoperative pembrolizumab cycles was not associated with pCR monitoring and limiting AEs is important.

As treatment strategies for early triple-negative breast cancer continue to evolve, translating clinical evidence into practice can be challenging, especially as the standard of care also shifts and may differ across studies. The management of patients with triple-negative breast cancer who have residual disease after neoadjuvant therapy exemplifies a complex clinical scenario with emerging yet sometimes difficult-to-interpret evidence. Through a critical appraisal of current data and an expert consensus discussion from the Nordic region, the authors present a perspective on postneoadjuvant treatment options for triple-negative breast cancer and discuss potential approaches based on available evidence and expert opinion.

Background and purpose: This study aimed to assess current treatment strategies for metastatic triple-negative breast cancer (mTNBC) and the perceptions of clinical experts in Sweden, Denmark, Norway, Finland, and Iceland, comparing them to international guidelines to provide insights into how these therapies are implemented and adapted to national Nordic guidelines. Methods: A three-round modified Delphi method was followed with consensus defined as 70% agreement. A steering committee selected 20 experienced oncologists as panellists and developed the questionnaires. Questions included items related to treatment preferences in different treatment lines with different clinical scenarios in mTNBC patients. Results: In the first round, eight out of 33 questions on clinical treatment reached consensus with 14 out of 27 in the second round reaching consensus. In round three, eight out of eight questions reached consensus. The preferred treatment for mTNBC patients with PD-L1 positive was checkpoint inhibitors (CPI) in combination with chemotherapy. For patients with germline BRCA mutation and PD-L1 negative disease, PARP-inhibitors were preferred as 1L and sacituzumab govitecan (SG) in both 2L and later lines. Disagreement was observed for chemotherapy in later lines where evidence is sparse or lacking. Interpretation: The high level of consensus for new treatment strategies, such as CPI and PARP-inhibitors in 1L and SG in 2L or later lines, in comparison with the limited consensus for older treatments, such as chemotherapy, may reflect the growing academic evidence for different treatment strategies. Understanding the treatment patterns across different countries contributes to gaining consensus on the upcoming therapeutic advances.

BACKGROUND AND PURPOSE:We evaluated the impact of the coronavirus disease 2019 (COVID-19) pandemic on health-related quality of life (HRQoL) in early-stage breast cancer patients receiving adjuvant chemotherapy. PATIENTS AND METHODS:The study involved 180 patients with stage I-III breast cancer who initiated adjuvant chemotherapy between June 2020 and May 2021. The pre-pandemic comparison data included 113 early breast cancer patients who began adjuvant chemotherapy between November 2018 and August 2019. HRQoL was assessed using the EORTC QLQ-C30 at baseline and again after 3 and 6 months. The subscales were compared between the COVID-19 pandemic and the pre-pandemic eras. RESULTS:We observed deterioration on almost all HRQoL subscales of the patients treated during the pandemic from baseline to 3 months. After the chemotherapy at 6 months, the scales remained deteriorated, whereas only appetite loss and emotional functioning improved. A comparison between the pandemic and the pre-pandemic eras revealed that several HRQoL subscales showed better results during chemotherapy in the pandemic era. Global health and role functioning at 6 months presented declined levels during the pandemic. INTERPRETATION:The well-being of breast cancer patients during the chemotherapy treatment in the pandemic era was moderately better than in the pre-pandemic era. Patients in the pandemic era might have reported fewer symptoms during the treatment, as the focus was on the COVID-19 pandemic and its restrictions.

Dysregulated metabolism, a hallmark of cancer, creates unique metabolic features that can be employed to elucidate cancer prognosis, personalized treatment, and therapeutic response. Metabolomics has emerged as a powerful tool for profiling biomarkers in cancer studies. Most cancer metabolomic research on extracellular vesicles (EVs) has focused on human biofluids as samples. The metabolome of fecal EVs, a connecting link for host-microbiome interactions in cancer, has not been extensively studied. In this controlled study, we investigated the metabolomic signatures of fecal EVs in patients with solid tumors. Fecal samples were collected from adult patients with solid tumors (n = 28) and healthy controls (n = 7). After the isolation of EVs from fecal samples, EV metabolites were identified using targeted metabolomics profiling based on liquid chromatography-mass spectrometry (LC-MS). The metabolomic profiles of the fecal EVs from both patients and controls were compared using R and Metabolite Set Enrichment Analysis was done using Metaboanalyst 6.0. The metabolomic profiles of fecal EVs showed several differences between patients with solid tumors and control subjects. L-glutamic acid was identified as the most significantly enriched metabolite in patients with solid tumors. Conversely, guanine and N-acetylneuraminate were the most significantly depleted metabolites in the fecal EVs of these patients. Metabolite Set Enrichment Analysis linked the identified EV metabolites to key metabolic pathways, including arginine biosynthesis, glyoxylate and dicarboxylate metabolism, and the biosynthesis of branched-chain amino acids and unsaturated fatty acids. Receiver operating characteristic (ROC) revealed that glutamic acid is the most effective metabolite in distinguishing cancer patients from healthy controls. Some of these metabolites may also have plausible bacterial origins, as described in previous studies. Distinct metabolic phenotypes were identified in patients with solid tumors by analyzing fecal EVs in this study. The metabolomic profiling of fecal EVs offers valuable insights into the interactions between the gut microbiome and the host as well as unique metabolic snapshot of the disease status in the context of cancer. Thus, fecal EVs should be included in advanced multi-omics analyses of cancer research, alongside other human biofluids.

BACKGROUND AND PURPOSE:The prognosis for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer has significantly improved over the past few decades. However, a substantial number of patients still face an elevated risk of recurrence. Due to the high prevalence and cumulative mortality of HR+/HER2- breast cancer, it poses a global health challenge. MATERIAL AND METHODS:This is a narrative review on the post-chemotherapy treatment options in patients with HR+/HER2- breast cancer. RESULTS:Endocrine therapy remains the cornerstone of adjuvant treatment, with extended durations of tamoxifen and aromatase inhibitors demonstrating survival benefits. Several novel post-chemotherapy adjuvant treatments have recently been introduced for high-risk patients, and now most patients with HR+/HER2- breast cancer are eligible for non-endocrine adjuvant therapies. Bisphosphonates help to reduce bone recurrence and enhance overall survival in postmenopausal women, though the evidence remains somewhat inconsistent. CDK4/6 inhibitors abemaciclib and ribociclib have also emerged as adjuvant therapies, while the poly ADP ribose polymerase (PARP) inhibitor olaparib provides clinically meaningful benefits for patients with germline BRCA1/2 mutations. INTERPRETATION:Optimal patient selection for these often toxic treatments remains partially unclear and is the focus of intensive research. In the near future, monitoring ctDNA may enable treatment de-escalation for selected high-risk patients. The rise of perioperative immunological therapies, new CDK4-specific inhibitors, and targeted endocrine treatments can lead to a notably favorable prognosis for many previously high-risk HR+/HER2- breast cancers. Future research should prioritize predictive biomarkers and personalized approaches to optimize treatment efficacy, ensure more equal access to treatments, and minimize overtreatment.

Anti-PD-(L)1 therapies are widely used for the treatment of distinct cancers, but the proportion of patients who benefit from the treatment remains low, and tools for patient selection are suboptimal. In this study, we investigated whether plasma proteomics could explore the benefit of anti-PD-(L)1 antibodies. This prospective study enrolled 56 patients with multiple solid tumor types treated with anti-PD-(L)1 therapies. Pre-treatment plasma samples were profiled with a 92-plex immuno-oncology proximity extension assay panel. Associations with radiographic outcomes and survival were examined. Prediction models for ORR, DCR and OS were evaluated. Analyses were performed in a pooled hypothesis-generating framework. Several proteins, including ADGRG1 and ARG1, were linked to radiographic response. ARG1 achieved ROC-AUCs 0.68 (ORR) and 0.53 (DCR). We generated machine learning models for predicting both radiographic responses and long-term survival (≥ 720 days). For overall survival, the six-protein Cox proportional model separated risk groups (hazard ratio (HR) 4.8; CI 95

Extracellular vesicles (EVs), nanoparticles secreted by both gram-negative and gram-positive bacteria, carry various biomolecules and cross biological barriers. Gut microbiota-derived EVs are currently being investigated as a communication mechanism between the microbiota and the host. Few clinical studies, however, have investigated gut microbiota-derived EVs. Here, we show that machine learning models were able to accurately distinguish gut microbiota and respective microbiota-derived EV samples according to their taxonomic composition both within each data set (area under the curve [AUC] 0.764-1.00) and in a cross-study setting (AUC 0.701-0.997). These results show that gut microbiota-derived EVs form a distinct taxonomic entity from gut microbiota. Thus, conventional gut microbiota composition may not correctly reflect communication between the gut microbiota and the host unless microbiota-derived EVs are reported separately.IMPORTANCEGut microbiota-derived extracellular vesicles (EVs) have been suggested to be a communication mechanism between the gut microbiota and the human body. However, the data on EV secretion from the gut microbiota remain limited. To investigate and compare the composition of gut microbiota-derived EVs to gut microbiota composition, we used a machine learning approach to classify 16S rRNA gene sequencing data in seven clinical data sets incorporating both gut microbiota and gut microbiota-derived EV samples. The results of the study show that microbiota-derived EVs form a separate taxonomic entity from the gut microbiota. Gut microbiota-derived EVs should be included in clinical studies that investigate gut microbiota to gain more comprehensive insight into gut microbiota-host communication.

Background: Current evidence from both randomized trials and real-world evidence studies suggests that older patients with advanced hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer derive clinical benefit from the addition of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors to endocrine therapy. However, a higher risk for adverse events due to CDK4/6 inhibitors among older patients is evident, leading to a trend of initiating CDK4/6 inhibitors at a lower dose in clinical practice, though without evidence. The aim of the present randomized trial is to investigate whether lower initial dose of CDK4/6 inhibitors combined with endocrine therapy is comparable to full dose in older patients with advanced HR+/HER2-breast cancer that are assessed as vulnerable/frail based on comprehensive geriatric assessment (CGA). Trial Design: We designed a multi-national, open-label, pragmatic randomized controlled trial with non-inferiority approach. Patients ≥70 years old with advanced HR+/HER2- breast cancer with no curative intention, no prior treatment in an advanced setting, and suitable to receive a combination of CDK4/6 inhibitors plus endocrine therapy according to treating physician, are eligible for study inclusion. After informed consent, included patients fill out a self-administered CGA tool and categorized accordingly to fit, vulnerable, or frail, depending on the number of impaired CGA domains. Fit patients receive full dose of CDK4/6 inhibitors and endocrine therapy whereas vulnerable/frail patients are randomized to either -1 level lower CDK4/6 inhibitor dose or full dose and endocrine therapy. The randomization is stratified by type of CDK 4/6 inhibitor, type of endocrine therapy, and level of vulnerability. The treating physician decides on the choice of CDK4/6 inhibitor (abemaciclib, ribociclib, palbociclib) and endocrine therapy (aromatase inhibitors, fulvestrant). The primary endpoint is time to treatment failure whereas secondary endpoints include overall treatment utility, progression-free survival, overall survival, time to chemotherapy initiation, toxicity, quality-of-life, time to quality-of-life deterioration and cost-effectiveness. The evaluation of disease progression, toxicity assessment, and the follow-up strategy resembles clinical practice to enhance the pragmatic design approach of IMPORTANT trial. The trial also enables a hybrid decentralized approach where the initial patient visit is in-person whereas the visits for efficacy and toxicity evaluation can be performed digitally according to local practices. In total, 495 patients are planned to be included to allow 346 vulnerable/frail patients to be randomized. Enrolment: The trial is open for recruitment since February 2024 with a recruitment period of 30 months. Clinical Trial Registration: NCT06044623 (ClinicalTrials.gov) Citation Format: Emanuela Risi, Laura Biganzoli, Athina Christopoulou, Fjermeros, Elena Fountzilas, Jürgen Geisler, Raquel Gomez-Bravo, Peeter Karihtala, Paris Kosmidis, Angelos Koutras, Helena Linardou, Henrik Lindman, Iván Martínez-Ballestero, Anna Belén Rodríguez, Icro Meattini, Montserrat Munoz-Mateu, Mukhrizah Othman, Amanda Psyrri, Aglaia Schiza, Nikolaos Spathas, Meri Utriainen, Luca Visani, Thanos Kosmidis, Antonis Valachis. Implementing geriatric assessment for dose Optimization of CDK 4/6-inhibitors in older Breast Cancer patients (IMPORTANT trial) – a pragmatic randomized-controlled trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-08-28.

Metformin and statin use have been associated with an improved prognosis for colorectal cancer in persons with type 2 diabetes (T2D). Data regarding rectal cancer (RC) have been inconclusive; therefore, we investigated the issue with high-quality data and a robust study design. We identified 1271 eligible patients with T2D and incident RC between 1998 and 2011 from the Diabetes in Finland (FinDM) database. Cox models were fitted for cause-specific mortality rates to obtain adjusted estimates of the hazard ratios (HR) with 95% confidence intervals (CI) in relation to use of antidiabetic medication (ADM) and statins before the RC diagnosis and for post-diagnostic use in a time-dependent exposure manner. No sufficient evidence was found for either pre- or post-diagnostic metformin use and RC mortality (HR 0.96, 95% CI 0.67–1.38, and 0.70, 95% CI 0.45–1.10, respectively) when compared to other oral ADMs. Both pre- and post-diagnostic statin use appeared to be inversely associated with mortality from RC (HR 0.77 95% CI 0.63–0.94, and 0.57, 95% CI 0.42–0.78, respectively). Our study was inconclusive as to the association of metformin use with the prognosis of RC, but statin use was found to predict reduced mortality, both from RC and from other causes of death in persons with T2D.

Different endogenous and exogenous mutational processes cause specific patterns of somatic mutations and mutational signatures. Although their biological research has been intensive, there are only rare studies assessing the possible prognostic role of mutational signatures. We used data from The Cancer Genome Atlas to study the associations between the activity of the mutational signatures and four survival endpoints in 18 types of malignancies. We further explored the prognostic differences according to, for example, the HPV status in head and neck squamous cell carcinomas and smoking status in lung cancers. The predictive power of the signatures over time was evaluated with a dynamic area under the curve model, and the links between mutational signature activities and differences in gene expression patterns were analyzed. In 12 of 18 studied cancer types, we identified at least one mutational signature whose activity predicted survival outcomes after adjusting for the established prognostic factors. For example, overall survival was associated with the activity of mutational signatures in nine cancer types and disease-specific survival in seven cancer types. The clock-like signatures SBS5 and SBS40 were most commonly associated with survival endpoints. The genes of the myosin binding protein and melanoma antigen families were among the most substantially dysregulated genes between the signatures of low and high activity. The differences in gene expression also revealed various enriched pathways. Based on these data, specific mutational signatures associate with the gene expression and have the potential to serve as strong prognostic factors in several cancer types.

TPS1132 Background: Current evidence from both randomized trials and real-world evidence studies suggests that older patients with advanced hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer derive clinical benefit from the addition of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors to endocrine therapy. However, a higher risk for adverse events due to CDK4/6 inhibitors among older patients is evident, leading to a trend of initiating CDK4/6 inhibitors at a lower dose in clinical practice, though without evidence. The aim of the present randomized trial is to investigate whether lower initial dose of CDK4/6 inhibitors combined with endocrine therapy is comparable to full dose in older patients with advanced HR+/HER2-breast cancer that are assessed as vulnerable/frail based on comprehensive geriatric assessment (CGA). Methods: We designed a multi-national, open-label, pragmatic randomized controlled trial with non-inferiority approach. Patients ≥70 years old with advanced HR+/HER2- breast cancer with no curative intention, no prior treatment in an advanced setting, and suitable to receive a combination of CDK4/6 inhibitors plus endocrine therapy according to treating physician, are eligible for study inclusion. After informed consent, included patients fill out a self-administered CGA tool and categorized accordingly to fit, vulnerable, or frail, depending on the number of impaired CGA domains. Fit patients receive full dose of CDK4/6 inhibitors and endocrine therapy whereas vulnerable/frail patients are randomized to either -1 level lower CDK4/6 inhibitor dose or full dose and endocrine therapy. The randomization is stratified by type of CDK 4/6 inhibitor, type of endocrine therapy, and level of vulnerability. The treating physician decides on the choice of CDK4/6 inhibitor (abemaciclib, ribociclib, palbociclib) and endocrine therapy (aromatase inhibitors, fulvestrant). The primary endpoint is time to treatment failure whereas secondary endpoints include overall treatment utility, progression-free survival, overall survival, time to chemotherapy initiation, toxicity, quality-of-life, time to quality-of-life deterioration and cost-effectiveness. The evaluation of disease progression, toxicity assessment, and the follow-up strategy resembles clinical practice to enhance the pragmatic design approach of IMPORTANT trial. The trial also enables a hybrid decentralized approach where the initial patient visit is in-person whereas the visits for efficacy and toxicity evaluation can be performed digitally according to local practices. In total, 495 patients are planned to be included to allow 346 vulnerable/frail patients to be randomized. Enrollment: The trial is open for recruitment since February 2024 with a recruitment period of 30 months. Clinical trial information: NCT06044623 .

Objective:The aim of the study was to explore depressive, anxiety, and mental-health related somatic symptoms among young breast-cancer survivors by considering symptoms before and after cancer onset. Materials and Methods:The study sample included females from the prospective Northern Finland Birth Cohort 1966. Symptoms were assessed with the Hopkins Symptom Checklist-25 at the age of 31 and 46 years. We studied both subscales of depressive, anxiety, and somatic symptoms and single symptoms in secondary analyses. Results:Thirty-one cases and 3.077 controls were included. Females diagnosed with breast cancer 3-8 years before the 46-year follow-up had increased depressive (p = 0.005) and somatic symptoms (p = 0.028) at the 46-year follow-up compared with the 31-year follow-up. This was not observed among those diagnosed <3 or >8 years before or among controls. Females diagnosed with breast cancer reported more lack of strength or energy compared with controls at the 46-year follow-up (p = 0.047). Among females who did not report feeling that the future is hopeless at the 31-year follow-up, significantly more females diagnosed with breast cancer reported this feeling at the 46-year follow-up compared with controls (p = 0.006). Conclusion:Depressive and somatic symptoms increased significantly among young females at 3-8 years after breast-cancer diagnosis compared with the time before the cancer diagnosis. Psychosocial measures of support for breast-cancer survivors should be provided over the long-term.

Background Most studies on palliative medicine (PM) undergraduate education have focused on contents and organizational issues but not the outcome. Students’ learning outcomes should be studied to improve teaching in medical schools. Methods A questionnaire about perceived PM education and attitudes on palliative care (PC) was sent to 543 last year students in all five Finnish medical schools in 2018–2019. In total, 175 (32 %) responses were received from four universities. The students evaluated both the quantity and quality of their PM teaching, implementation of European Association for Palliative Care (EAPC) guidelines and their satisfaction to the training. There were two palliative case scenarios, and the students were asked to find the best treatment option. In addition, students´ attitudes towards end-of-life (EOL) care issues were examined. Results In the Finnish universities, PM education was available mainly integrated with oncology, geriatrics, and general medicine. A total of two universities also offered a specific PM course. In average, 50–70% of the EAPC curriculum was covered by lectures, small-group teaching, seminars, and bedside teaching with significant differences between faculties. Only 30–60 % of students were satisfied with the education received. The highest rankings were given in the universities with a special PM course. Students from these universities expressed less anxiety in facing EOL issues. Conclusions In Finland, the coverage of EAPC curriculum is satisfactory, but the PM education is mainly given integrated with other specialties. The dedicated course on PM was associated with increased perceived knowledge and satisfaction of PM education. However, PM training was not associated with students’ attitudes on PC.

Background and purpose: Data on real-world prevalence and outcomes in patients diagnosed with pathogenic germline variants in BRCA1 or BRCA2 (gBRCAm) breast cancer is sparse. Material and methods: An observational cohort study including all patients diagnosed with incident early-stage breast cancer and recorded in Helsinki University Hospital data lake 2012–2022, accounting for one-third of the Finnish breast cancer patient population. Results: Among 14,696 incident early-stage breast cancer patients, 11.2% (n = 1,644) were tested for gBRCAm. Of the tested population, 7.4% (n = 122) carried gBRCAm. Of the 122 gBRCAm patients, 95.1% (n = 116) were women, with a median age at diagnosis of 46.4 years. Among the same patient group, HER2 status was available for 87.7% (n = 107) of the patients. Among these, 49.5% (n = 53) had hormone receptor-positive (HR+), HER2-negative breast cancer, 13.1% were (n = 14) HER2-positive, and 37.3% (n = 40) of patients had triple-negative breast cancer. The tested patients were significantly younger compared with non-tested patients. No significant differences in overall survival or healthcare resource utilization between the tested patients with gBRCAm and gBRCA wild-type (gBRCAwt) were observed. Interpretation: This comprehensive observational study supports previous findings of gBRCAm prevalence in the Western early-stage breast cancer population. While no differences in survival were observed between patients with gBRCAm and gBRCAwt, it is important to consider the potential influence of selection bias, particularly due to the younger gBRCAm testing target population and the overall low frequency of testing. Therefore, a substantial proportion of the patients carrying gBRCAm likely remained undiagnosed, and wider screening criteria are warranted.