Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options. Although immunotherapy has improved outcomes in selected patients, predictive biomarkers remain scarce. Low-density neutrophils (LDNs), a subpopulation of immunosuppressive neutrophils, have been implicated in resistance to immune checkpoint inhibitors (ICIs), but their longitudinal dynamics and correlation with clinical parameters and immune markers have not been investigated to date, especially in TNBC. We report a case of a 48-year-old woman with early-stage TNBC treated with neoadjuvant chemoimmunotherapy per the KEYNOTE-522 protocol. Circulating LDNs, following density gradient centrifugation, as well as activation status of systemic T lymphocytes, were monitored longitudinally by flow cytometry. Parallel assessments included lactate dehydrogenase (LDH), carcinoembryonic antigen (CEA), cancer antigen 15.3 (CA 15.3), platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR). Tumor-infiltrating lymphocytes (TILs) were characterized by immunohistochemistry, in the surgical specimen. LDNs were absent at baseline but increased during neoadjuvant therapy, peaking before radiologic progression and remaining elevated during palliative treatment. Notably, systemic T lymphocytes markers, such as CD69 and HLA-DR, declined as LDNs rose. This trajectory preceded disease evolution while conventional markers, such as LDH, CA 15.3, PLR and NLR rose later. The patient progressed during adjuvant immunotherapy and partially responded to first-line antibody-drug conjugate therapy. In line with the systemic immunosuppression profile, and resistance to immunotherapy, TIL analysis revealed low CD8 + infiltration and sparse CD20 + B cells. This case illustrates the potential of LDNs as minimally invasive biomarkers for monitoring treatment response and detecting therapy resistance in breast cancer (BC). Their longitudinal profile captured disease progression more precisely than conventional markers, underscoring their translational relevance for patient stratification and therapeutic guidance. Although limited by the single-patient design, these findings warrant investigation of LDNs dynamics in larger cohorts to validate their predictive value and clinical utility in optimizing immunotherapy outcomes in BC.

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) (Ribociclib, Palbociclib or Abemaciclib) plus endocrine therapy (ET) is the standard first line treatment in hormone receptor-positive (HR+) human epidermal growth factor receptor two-negative (HER2-) metastatic breast cancer (MBC) patients (pts). There are no established guidelines on subsequent treatment after disease progression with CDK4/6i, especially in later lines. Methods: We conducted a multicentric retrospective observational study including HR+/HER2- MBC pts who experienced disease progression with a CDK4/6i for metastatic disease, between January 2016 and July 2023. Data were collected from medical records. The primary objectives were to compare Progression-Free Survival (PFS) and Overall Survival (OS) across different treatment options. Survival curves were estimated with Kaplan-Meier method and compared with the pairwise log-rank test. Results: We identified 222 pts (220 women, 2 men) with a mean age of 57.6±13.4 years at the time of metastatic disease diagnosis; 131 (59.5%) were postmenopausal. The majority had visceral disease (172 pts, 77.5%). CDK4/6i were used as a first-line treatment in 182 pts (82.0%), as second-line in 30 (13.5%) and as third-line in 10 (4.5%). After progression with CDK4/6i, the next line of treatment included ET (68 pts, 30.8%), capecitabine (62 pts, 28.1%), paclitaxel (30 pts, 13.5%), rechallenge with a different CDK4/6i (14 pts, 7.7%), other chemotherapies (12 pts, 5.4%) and other treatments (17 pts, 7.6%). After progression with CDK4/6i, PFS was higher for capecitabine treated pts (16.5 months (mo), 95% CI [7.6, 32.1]) and the lowest with paclitaxel (5.6 mo, 95% CI [3.5, 8.2]). However, the OS was higher for pts who were rechallenged with a different CDK4/6i (24.6 mo, 95% CI [18.2, not reached - NR]), followed by those on ET (14.0 mo, 95% CI [12.2, NR]) and capecitabine (15.6 mo, 95% CI [10.4, 20.8]), and it was the lowest for those treated with paclitaxel (9.0 mo, 95% CI [4.8, 15.0], p<0.05). Conclusions: In our cohort, PFS was longer for pts treated with capecitabine, while OS was the highest for those treated with a different CDK4/6i or ET. The main limitation of this study is its retrospective nature and the non-random assignment of treatments. Thus, our findings support emerging data suggesting a benefit in switching ET while maintaining CDK4/6i after progression. Citation Format: Ana Rita Rego Freitas, Inês F. Eiriz, Marta Vaz Batista, Andreia Chaves, Catarina Santos, Tiago Barroso, Sara Cabral, Pedro Meireles, Ana R. Fortuna, Vanessa Patel, João P. Araújo, Tânia Duarte, Tiago P. Cabral, Sandra C. Silva, Joana Gonçalves, Isabel Fernandes, Inês Dunões, Cláudia Viana, Sofia Prada, Sofia Azambuja Braga. Subsequent Treatments After Progression On Cyclin-Dependent Kinase 4/6 Inhibitors - A Multicentric Portuguese Real-world Data Study [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 P5-01-12.

BACKGROUND:Substantial improvements in survival have been observed in HER2 (human epidermal growth factor receptor 2)-positive (HER2+) inoperable or metastatic breast cancer (advanced breast cancer [ABC]) in recent years, driven by the introduction and widespread use of multiple novel agents. The DESTINY-Breast02 trial compared the efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients with HER2+ ABC formerly treated with trastuzumab emtansine (T-DM1), demonstrating significant improvements in both overall survival (OS) and progression-free survival (PFS). METHODS:We conducted a national, multicentric, retrospective study to describe real-world treatment patterns, PFS, OS, safety, and key toxicities associated with T-DXd use in Portugal, following the DESTINY-Breast02 inclusion criteria. RESULTS:A total of 100 women with HER2+ ABC from 17 centers were included, all of whom had received at least two prior treatments for advanced disease and were treated with T-DXd between July 2021 and May 2023. The mean age was 53.9 years n(standard deviation: 9.9). Thirty-six patients presented with synchronous metastatic disease. The most common metastatic site was bone, in 61 (61%) patients; 72 (72%) had visceral metastases, and 21 patients (21%) had brain metastases. The median follow-up was 10 months, with a median of 11 T-DXd cycles administered. Prior treatments included pertuzumab in 71 (71%) patients and T-DM1 in 84 (84%). T-DXd was administered as third-line therapy in 52 (52%) patients, as fourth-line therapy in 15 (15%), and as fifth-line therapy and beyond in 23 (23%) patients. The overall response rate (ORR) was 44%, and the clinical benefit rate (CBR) was 80%. The most frequent toxicities of any grade were nausea in 49 patients (49%), neutropenia in 37 (37%), and alopecia in 34 (34%). Serious adverse events (grade ≥ 3) occurred in 16 (16%) patients, with treatment discontinuation or delays due to adverse events observed in 46 cases (46%). Median OS was not reached, with a 12-month OS rate of 74%. The median PFS was 13 months (95% CI: 10-16 months), and the 12-month PFS rate was 54%. CONCLUSIONS:This real-world analysis revealed that the efficacy, safety, and tolerability of T-DXd in the Portuguese population are consistent with the outcomes observed in the DESTINY-Breast02 clinical trial.

Background/Objectives: Breast cancer is the most common malignant neoplasm in women and the leading cause of cancer-related death. Approximately 50% of HER2-negative breast cancers exhibit low expression of this protein (HER2-low). Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate targeting the HER2 receptor which has shown benefit in patients with HER2-low metastatic breast cancer in the DESTINY-Breast04 study. However, few data are available on its efficacy in real-world practice. Methods: We conducted a retrospective multicenter national study (eight centers) including patients with advanced HER2-low breast cancer (immunohistochemistry 1+ or 2+/ in situ hybridization negative) who started T-DXd treatment between January 2022 and March 2024. Patients had received at least one previous line of treatment. The primary endpoint was real-world progression-free survival (rwPFS) in patients with metastatic HER2-low breast cancer treated with T-DXd. The secondary endpoints were real-world overall survival (OS) and objective response rate (ORR). Results: The study included 35 patients (34 female and 1 male patient), with a median age of 54 years at the start of T-DXd. All patients had an ECOG-PS 0-1, and 26 patients (74%) had hormone receptor (HR)-positive disease. The median number of prior lines of treatment was 4 [1-7], and 23 patients (65.8%) had metastases in three or more sites. With a median follow-up of 7.8 months, rwPFS was 6 months (95% CI, 2.3-9.7), and OS was 15 months (95% CI, 4.7-25.3). In HR-positive patients, the median rwPFS was 6 months (95% CI, 1.2-10.7), compared to 4 months (95% CI, 2.1-5.9) in HR-negative patients. The overall ORR was 52.9%. Adverse events of grade 3 or higher were neutropenia (2.9%) and fatigue (2.9%). Conclusions: This study provides real-world data on T-DXd in the treatment of advanced HER2-low breast cancer. It is noteworthy that the population was heavily pre-treated and had a higher proportion of HR-negative patients, which may explain the lower efficacy compared to the DESTINY-Breast04 study.

Substantial improvement in survival has been seen in HER2+ advanced breast cancer (ABC) over the past years with the introduction and widespread use of multiple novel agents. The DESTINY-Breast02 trial compared the efficacy and safety of T-DXd versus physician's choice therapy in HER2+ unresectable and/or metastatic breast cancer previously treated with trastuzumab emtansine (T-DM1). It showed a significant improvement in overall survival (OS) and progression-free survival (PFS). We conducted a national, multicentric, retrospective study describing real-world treatment patterns and related PFS, OS, treatment safety and main toxicities of T-DXd in Portugal, as per DESTINY-Breast02 criteria. IBM SPSS Statistics 28.0.1 was used for analyzing procedures. One hundred women, from 17 different centers, with HER2+ ABC who had received at least 2 previous treatments for advanced disease and received T-DXd were included from July 2021 to May 2023. The median age were 53 years old. A total of 32 patients (pts) (34, 8%) had metastatic disease at the time of the diagnosis. The most common metastatic sites were bone (61%), visceral disease (72%) and brain (21%). The median follow-up was 10 months with 11 median cycles administered. The majority, 77, 2%, had received pertuzumab and 91, 7% T-DM1 previously. T-DXd was administered in a second-line setting in 52% and 3rd line setting in 15% (range 1-7 lines). The objective response rate (ORR) was 44% and the clinical benefit rate (CBR) was 80%. The most frequent toxicities of any grade were emesis (49%), neutropenia (37%), alopecia (34%), pneumonitis (12%) and reduced ejection fraction (5%). Serious adverse events (AEs) (CTCAE ≥ grade 3) were observed in 16 pts (16%). Discontinuation or delay of T-DXd treatment because of AEs occurred in 46% of pts. Median OS was not reached. OS rate at 12 months (m) was 74%. Median PFS was 13 m (95% CI, 10-16 m). PFS rate at 12 m was 53, 7%. In this analysis we found similarities between clinical trial efficacy and real-world effectiveness as well as safety, tolerability and adverse events in the Portuguese population treated with T-DXd after at least 2 previous lines for HER2+ ABC.

One third of ABC pts is currently represented by women aged over 70. However, this population remains under-represented in clinical trials. Recently, T-DXd revolutionized the treatment of HER2 positive ABC, demonstrating its efficacy in DESTINY-Breast trials. Its safety profile was manageable and most adverse events (AEs) were gastrointestinal in nature. Nevertheless, T-DXd was associated with the development of interstitial lung disease (ILD) in 10-15% of pts. Thus, some concerns could raise regarding those outcomes in elderly patients. The aim of this retrospective analysis was to evaluate the safety and efficacy of T-DXd in ABC pts over 70 in a real-life setting. TREX-Old is an European retrospective registry evaluating the real-life use of T-DXd in ABC pts aged ≥ 70 among 4 centers across Austria, France, Italy and Portugal. Clinical and pathological characteristics, previous treatments and AEs were collected. Overall, to date, 27 pts were enrolled. Median age was 74 years (range 70-81), with 10 patients over 75 (37%). The ECOG performance status was 0, 1 and ≥ 2 in 22%, 56% and 22% of pts, respectively. Among them, 37% had cardiovascular comorbidities. The median number of lines before T-DXd was 3 (1-13). At treatment initiation, 71% and 29% of pts had a visceral and non-visceral (bone only, skin or lymph nodes) disease, respectively. Eight pts (30%) started with a dose-reduction, and 8 pts (30%) had secondary dose adjustment. Overall, any-grade treatment-related AEs occurred in 19 pts (70%). Among them, nausea was the most common AE (37%), followed by asthenia (18%). Three out 27 pts (11%) developed ILD. Finally, at a median follow-up of 9.5 months (1-29), median PFS was 12 months, considering that only 8 pts progressed at time of current analysis. With the limit of number and follow-up, our data suggest that T-DXd is not associated with new safety signals in pts ≥ 70 years. ILD occurrence was in line with previously reported data. Therefore, age should not be a criterion to discourage treatment with T-DXd. This registry is ongoing, and updated data will be presented.

The better survival of Human Epidermal growth factor receptor-type 2 positive (HER2+) breast cancer (BC) patients unmasked the biological predilection of this BC subtype for development of brain metastasis (BM). Indeed, central nervous system (CNS) is a frequent metastatic site for HER2+ advanced BC patients. Over the last years, new therapeutic strategies targeting the HER2 protein have been introduced for systemic treatment of HER2+ BC - either tyrosine kinase inhibitors, monoclonal antibodies, or antibody-drug conjugates. Patients with BMs have a poorer outcome, compared with patients without BMs, but their prognosis is also improving with the introduction of new anti HER2+ - targeted therapies. The

Breast Cancer patients with germline Breast Cancer Gene (BRCA) mutations have a greater advantage from targeted therapy with Poly (ADP-ribose) Polymerase (PARP) inhibitors (PARPi). The identification of patients with homologous recombination deficiency (HRD) tumors that may be sensitive to PARPi besides those with germline BRCA1/2 mutations remains an important point of research. There is increasing evidence demonstrating that breast tumors with BRCAness may benefit from PARPi and there are studies ongoing to identify those subtypes which may benefit the most. Pancreatic cancer with HRD non-BRCA mutations seem to have very little benefit from PARPi, but in HRD non-BRCA ovarian and prostate cancer, PARP inhibition appears to be a reasonable therapeutic target. Also, there is data showing that genomic instability caused by mutations in HRD genes, potentially makes cancer cells susceptible to chemotherapeutic drugs, such as anthracyclines or platinum salts. Widespread use of next generation sequencing could increase the role of hallmarks influencing the DNA repair system and therefore increase the therapeutic possibilities for cancer patients. In this review we evaluate the latest advances with PARPi in BRCAness Breast Cancer patients.

[This corrects the article DOI: 10.7759/cureus.31144.].

BACKGROUND:Perioperative fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT) improves prognosis in locally advanced gastric cancer (LAGC). Neutrophil-to-lymphocyte (NLR), lymphocyte-to-monocyte (LMR), and platelet-to-lymphocyte (PLR) ratios are prognostic biomarkers but not predictive factors.AIM:To assess blood ratios' (NLR, LMR and PLR) potential predictive response to FLOT and survival outcomes in resectable LAGC patients.METHODS:This was a multicentric retrospective study investigating the clinical potential of NLR, LMR, and PLR in resectable LAGC patients, treated with at least one preoperative FLOT cycle, from 12 Portuguese hospitals. Means were compared through non-parametric Mann-Whitney tests. Receiver operating characteristic curve analysis defined the cut-off values as: High PLR > 141 for progression and > 144 for mortality; high LMR > 3.56 for T stage regression (TSR). Poisson and Cox regression models the calculated relative risks/hazard ratios, using NLR, pathologic complete response, TSR, and tumor regression grade (TRG) as independent variables, and overall survival (OS) as the dependent variable.RESULTS:This study included 295 patients (mean age, 63.7 years; 59.7% males). NLR was correlated with survival time (r = 0.143, P = 0.014). PLR was associated with systemic progression during FLOT (P = 0.022) and mortality (P = 0.013), with high PLR patients having a 2.2-times higher risk of progression [95% confidence interval (CI): 0.89-5.26] and 1.5-times higher risk of mortality (95%CI: 0.92-2.55). LMR was associated with TSR, and high LMR patients had a 1.4-times higher risk of achieving TSR (95%CI: 1.01-1.99). OS benefit was found with TSR (P = 0.015) and partial/complete TRG (P < 0.001). Patients without TSR and with no evidence of pathological response had 2.1-times (95%CI: 1.14-3.96) and 2.8-times (95%CI: 1.6-5) higher risk of death.CONCLUSION:Higher NLR is correlated with longer survival time. High LMR patients have a higher risk of decreasing T stage, whereas high PLR patients have higher odds of progressing under FLOT and dying. Patients with TSR and a pathological response have better OS and lower risk of dying.

Background: Brain metastasis (BM) is a major clinical problem in metastatic breast cancer (MBC), occurring in 50% of patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer. Historically omitted from clinical trials, recent studies of novel HER2-targeted agents have focused on HER2+ BM patients, addressing stable but also progressing BM and leptomeningeal carcinomatosis (LMC). Summary: This review aimed to summarize the most relevant data on treating patients with HER2+ BM and LMC. Key Messages: The treatment paradigm for patients with HER2+ MBC has changed. Local therapies play an important role, but accumulating evidence on the intracranial activity and clinical benefit of anti-HER2 targeting therapies might lead to a shift in the paradigm on treating BM in the next few years towards more widespread use of systemic therapy.

The presence of tumor-infiltrating lymphocytes (TILs) is related to antitumoral immune response and has been associated with better clinical outcomes in several solid malignancies, including colorectal cancer (CRC), regardless of mismatch repair (MMR) status. Besides nonuniform scoring methodologies between studies, evaluation and quantification of TILs density is considered a prognostic marker. Retrospective analysis of patients diagnosed with stage II and III CRC between 2016 and 2019, with an evaluation of TILs grade score (minimal, moderate, abundant or Chron-like infiltrate) was conducted. Overall survival (OS) and disease free-survival (DFS) curves were estimated using the Kaplan–Meier method. From 544 patients with CRC, 307 (56.7%) were male with a median age of 70 years (range 25-96). One hundred and sixty-seven patients (30.8%) had right colon cancer, 50.5% had left colon cancer and 18.8% had rectal cancer. Regarding histology 92.5% of patients had adenocarcinoma, 7.4% mucinous carcinoma; 21.9% had a high-grade carcinoma, 32.2% had vascular invasion and 16.9% had perineural invasion. Two hundred and sixty-six patients (48.9%) had stage II disease and 278 (51.1%) had stage III disease. Chemotherapy was used in 50% of patients, from which 61.5% used a doublet scheme. Eighty-eight patients had disease progression and eighty-two patients died during the period of analysis. TILs were present in 359 patients (66%) with a classification moderate/abundant/Chron-like in 167 patients (30.7%). Median DFS was 51.6 months (95% CI 48.8 - 54.4) in moderate/abundant/Chronlike TILs group and 46.9 months (95% CI 44.5 - 49.3) in absent or minimal TILs group (p=0.012). Multivariate analysis showed that elevated TILs (HR=1.8, 95% CI 1.0 – 3.0, p=0.034) is a prognostic factor independent from conventional prognostic factors. We found a similar overall survival for two groups of TILs. The presence and density of an immune activation are related with better outcomes in CRC. Despite the limitations of a retrospective study, our results are in agreement with previous studies showing that the presence of increased TILs appears to be a predictive marker for better DFS. Prospective studies with a defined analysis method of TILs are required to validate these findings.

Background and objective With the increasing incidence of cancer and the rise in the survival rates of cancer patients, more and more oncological candidates are being considered for admission to intensive care units (ICU). Several studies have demonstrated no difference in the outcomes of cancer patients compared to non-cancer patients. Our study aimed to describe and analyze the outcomes related to cancer patients in a polyvalent ICU. Methods We conducted a retrospective study of consecutive oncological patients admitted to a polyvalent ICU (2013-2017). Cox model and receiver operating characteristic (ROC) curve analysis were performed to analyze the results. Results A total of 236 patients were included in the study; the mean age of the patients was 53.5 ± 15.3 years, and 65% of them were male. The main cancer types were those related to the central nervous system (CNS; 31%), as well as gastrointestinal (18%), genitourinary (17%), and hematological (15%). Curative/diagnostic surgeries (49%) and sepsis/septic shock (17%) were the main reasons for admission. The Acute Physiology and Chronic Health Evaluation II (APACHE II) and Simplified Acute Physiology Score II (SAPS II) scores in hematological patients vs. solid tumors were as follows: 30 vs. 20 and 63 vs. 38, respectively (p<0.005). Vasopressors, invasive mechanical ventilation (IMV), and renal replacement therapy (RRT) were used more widely in hematological patients compared to solid-tumor patients. Length of stay was longer in hematological patients vs. solid-tumor patients (12.8 vs. 7 days, p=0.002). The median overall survival in hematological patients was one month and that in solid-tumor patients was 5.8 months (p<0.005). The survival rate at six months was better than described in the existing literature (48 vs. 32.4%). Conclusion Both SAPS II and APACHE II scores were reasonably accurate in predicting mortality, demonstrating their value in cancer patients.

Background and objective Uterine sarcomas are rare tumors, and they account for 4% of all uterine malignancies. These tumors are characterized by a great diversity of histological types, and current knowledge regarding their treatment is limited. The aim of our study was to analyze a cohort of patients with uterine sarcomas with respect to the histological types of their tumors, as well as their prognosis and treatment. Materials and methods This was a retrospective analysis involving patients diagnosed at a single center with uterine sarcoma between 2003 and 2017. Results The study included 62 patients; the mean age of the patients was 62 ±13 years. Carcinosarcoma was identified in 44% of cases, leiomyosarcoma in 40%, and endometrial stromal sarcoma in 13%. Endometrial stromal sarcoma was found to occur in younger women compared to carcinosarcoma (52 ±13 vs. 66 ±12 years, p=0.016); 90% of patients underwent surgery, and medical treatment was implemented in 42%. The mean overall survival (OS) was 93 ±10.65 months, and the median progression-free survival (PFS) was 12 months. There was a significant association between the stage of the disease at diagnosis and the probability of survival: mean OS was 118 months for locoregional disease vs. 44 months for metastatic disease (p<0.001). The overall five-year survival rate was 39%. Discussion and conclusions Uterine sarcomas are rare cancers, and they are very heterogeneous. They are also associated with a high mortality rate. Further investigational studies are required so that a more effective treatment method and individualized treatment plans can be implemented for patients with uterine sarcoma.