Search Results (99)

Background: Older women represent a significant and increasing population of patients with breast cancer, accounting for over 40% of new cases of breast cancer. However, this growing subgroup of patients is still underrepresented in clinical trials, and treatment is usually selected based on limited data from retrospective subgroup analyses. However, the ESMO guidelines for metastatic breast cancer (mBC) suggest that the management decision should not be based on age alone. Nab-paclitaxel (nab-P) was associated with improved efficacy and a better safety profile than solvent-based taxanes without steroid or antihistamine premedication, making this treatment appealing to elderly patients. Patients and methods: This is an observational, retrospective, multicenter study, evaluating the safety and activity of nab-paclitaxel (nab-P) in elderly patients (≥65 years old) with HER2-negative mBC from 11 Sicilian oncology centers. The primary endpoint of the study was the safety nab-P in elderly mBC patients; secondary endpoints included the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: We included 70 patients, and all were evaluable for safety and efficacy. All patients had previously been pretreated with taxane-based chemotherapy in a (neo)-adjuvant or metastatic setting. One third of the patients received nab-P as a fourth line therapy. Most of the patients were treated with nab-P at doses of 260 mg/m² 3-weekly (87.1%), and 12.9% received a nab-P dose of 125 mg/m² weekly. Patients’ characteristics included a median age of 67 years (range 65–83 years), a median ECOG PS of 1 (range 0–2), and the following intrinsic molecular subtypes: Luminal A (18.8%), Luminal B HER-2 negative (62.5%), and triple negative (18.8%). Nab-P was administered for a median of six cycles (range 1–21), with 35.5% of patients experiencing a dose reduction, and 11.5% treatment discontinuation due to toxicity. Adverse events were mainly G2-G3 and occurred mostly in patients treated with 3-weekly nab-P (85.7%). The ORR was 31.3% (CR in 6.3% and PR in 25% of pts) and the DCR was 70.4%. Median PFS was 6 months (95% CI, 2–38), and median OS was 40.5 months (95% CI, 7–255). Conclusions: Our real-life study showed that nab-P is an effective, well-tolerated regimen in elderly mBC patients, including taxane-pretreated patients, and can be safely administered in elderly mBC patients. Full article

Background: In patients with curatively resected pancreatic adenocarcinoma who have undergone neoadjuvant chemotherapy (NACT), evidence supporting the benefit of additional adjuvant chemotherapy (ACT) remains limited. We aim to identify favorable factors contributing to survival benefits in resected pancreatic adenocarcinoma after NACT. Methods: This is a retrospective cohort study of pancreatic adenocarcinoma patients who underwent NACT followed by curative surgical resection between 2008 and 2023 at a single academic institution. Univariate and multivariable analyses were conducted to identify factors contributing to disease-free survival (DFS) and overall survival (OS). Results: A total of 230 patients with a median age of 68 years (IQR, 62–72 years) were included. All patients underwent curative surgical resection. Of these, 42% received neoadjuvant modified (m) FOLFIRINOX (96/230), 15% received gemcitabine plus nab-paclitaxel (GEM-NAB) (34/230), and 43% received gemcitabine, docetaxel, and capecitabine (GTX) (100/230). In univariate analysis, lower College of American Pathologists (CAP) tumor regression grade (TRG) (0–1 vs. 2–3, median DFS: 29.8 vs. 14.2 months, p = 0.0081) and receipt of ACT (Yes vs. No, median DFS: 22.2 vs. 12.4 months, p < 0.0001) demonstrated significant associations with superior DFS. Multivariable analysis identified receipt of ACT as an independent predictor of superior DFS (HR 0.55, 95% CI: 0.39–0.78, p = 0.0007) and OS (HR 0.49, 95% CI: 0.33–0.71, p = 0.0002). However, the NACT regimen (mFOLFIRINOX vs. GEM-NAB) and the transition between neoadjuvant and adjuvant therapy (de-escalation vs. continuation vs. change) did not correlate with DFS or OS. The duration of perioperative chemotherapy showed a trend toward improved survival outcomes, though not statistically significant (6 months vs. <6 months: DFS, 19.4 vs. 16.2 months, p = 0.1448; OS, 49.6 vs. 30.4 months, p = 0.0623). In the following subgroup analyses, receipt of ACT provided DFS/OS benefits in patients who did not achieve a major pathologic response, pN0, or R0 resection (DFS: p = 0.0003; OS: p < 0.0001). However, it did not provide DFS/OS benefits in those who achieved a major pathologic response with pN0/R0 to NACT (DFS: p = 0.8036; OS: p = 0.1877). Conclusions: In resected pancreatic adenocarcinoma following NACT, receiving ACT was associated with favorable survival outcomes. Additional ACT appears to benefit patients who did not achieve a major pathologic response (pN0 or R0) to neoadjuvant therapy, with limited benefit for those who achieved a major response with pN0/R0. The specific NACT regimen (mFOLFIRINOX vs. GEM-NAB) and changes in ACT from NACT did not significantly influence survival outcomes in our cohort. Full article

Ectopic adrenocorticotropic hormone syndrome (EAS) occurs when a tumor develops neuroendocrine differentiation with the secretion of ACTH resulting in hypercortisolism and possibly Cushing’s syndrome (CS). Only 5–10% of CS cases are attributed to EAS; of these, breast tumors comprise less than 1%. Two known variants of breast neuroendocrine tumors include neuroendocrine-differentiated carcinoma and ductal carcinoma with neuroendocrine features. Currently, guidelines for treatment are limited and EAS is associated with significant morbidity and mortality. A 39-year-old female presented with a rapidly enlarging breast mass. Biopsy demonstrated invasive poorly differentiated breast carcinoma with high-grade neuroendocrine features and necrosis. Staging at diagnosis confirmed metastatic disease of the liver and bone. First-line chemotherapy (Cisplatin/Etoposide/Durvalumab) was initiated with evidence of disease progression after four cycles. Given a poor response to therapy, a simple mastectomy was performed for local control and complete pathologic analysis, demonstrating high-grade neuroendocrine carcinoma with large-cell features. Second-line therapy (Adriamycin/Cyclophosphamide) was initiated for three cycles after which the patient required admission for severe and refractory hypokalemia. Workup confirmed elevated ACTH consistent with paraneoplastic EAS and further evidence of disease progression. Third-line therapy (Nab-Paclitaxel) was initiated, and genetic testing was completed, confirming the PIK3 mutation, for which access to Alpelisib therapy was requested. Given symptoms of progressive severe CS with significant liver disease limiting medical therapies, the patient underwent urgent bilateral laparoscopic adrenalectomy after which she was able to be discharged home while awaiting additional systemic therapy. EAS resulting in CS secondary to breast neuroendocrine carcinoma is a rare and challenging diagnosis. Further research is needed to inform treatment guidelines to improve outcomes. While patient survival is dependent upon the underlying disease process, laparoscopic bilateral adrenalectomy is an accepted, definitive treatment option. Full article

There is a growing prevalence of pancreatic cancer, accompanied by accelerated disease progression and diminished survival rates. Radical resection with clear margins remains the sole viable option for achieving a long-term cure in patients. In cases of advanced, unresectable, and metastatic disease, chemotherapy based on leucovorin, 5-fluorouracil, irinotecan, oxaliplatin, gemcitabine, or nab-paclitaxel represents the cornerstone of the treatment. Considering the limited treatment options available following initial therapy, the strategy of repurposing commonly prescribed drugs such as antihypertensives into anti-cancer therapies in palliative treatment represents a promising avenue for enhancing survival in patients with pancreatic ductal adenocarcinoma. The repurposing of existing drugs is typically a more cost-effective and expedient strategy than the development of new ones. The potential for antihypertensive drugs to be employed as adjunctive therapies could facilitate a more comprehensive treatment approach by targeting multiple pathways involved in cancer progression and acquired resistance to treatment. Antihypertensive medications, particularly those belonging to the pharmacological classes of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and calcium channel blockers, are commonly prescribed and have well-established safety profiles, particularly among patients with pancreatic cancer who are affected by multiple comorbidities. Therefore, we emphasize the preclinical and clinical evidence supporting the use of antihypertensive agents in the treatment of pancreatic cancer, emphasizing their beneficial chemosensitizing effects. Full article

Background/Objectives: The study objective was to determine the physicochemical stability of nab-paclitaxel (Pazenir) ready-to-use (RTU) dispersion for infusion in original glass vials and ready-to-administer (RTA) infusion dispersion in EVA infusion bags. Methods: Triplicate test dispersions were prepared and stored light protected for a maximum of 28 days either in the original glass vials (RTU) at 2–8 °C or in EVA infusion bags (RTA) at 2–8 °C and at 25 °C. Directly after reconstitution and on days 1, 3, 5, 7, 14, 21, and 28 samples were withdrawn and paclitaxel concentrations assayed by a stability-indicating HPLC method. In parallel, pH and osmolality were measured. In a second series, test dispersions were stored over a 14-day period and inspected daily for visible particles and colour changes. Samples were taken daily for particle size analysis. Integrity and particle size distribution of the nanoparticles were determined by dynamic light scattering (DLS) and albumin monomers, dimers, oligomers, or polymers by size-exclusion-chromatography (SEC). Results: Non-redispersible particles were observed in test dispersions on day 5 (RTA 25 °C), day 7 (RTA 2–8 °C), and day 11 (RTU 2–8 °C). DLS analysis revealed out-of-specification results for the polydispersity index from day 7 (RTA 25 °C) and day 12 (RTU, RTA refrigerated). Paclitaxel concentrations remained >95% of the initial concentrations for 7 days (RTU 2–8 °C, RTA 25 °C) and for 14 days (RTA 2–8 °C). All test dispersions met the specifications regarding the oligomeric status of albumin, pH, and osmolality over the investigation periods. Conclusions: Stability of nab-paclitaxel dispersions is limited by the release of water-insoluble paclitaxel from the nanoparticles and subsequent crystallisation and by formation of insoluble albumin aggregates. Based on our overall results, shelf life of refrigerated RTU and RTA nab-paclitaxel dispersions is limited to 7 days. Shelf life of RTA nab-paclitaxel dispersions stored at room temperature is limited to 4 days. Careful visual inspection of nab-paclitaxel dispersions after reconstitution and prior to administration is highly recommended to detect non-redispersible particles. Full article

The primary treatment for operable pancreatic cancer (PC) involves surgery followed by adjuvant therapy. Nevertheless, perioperative or neoadjuvant chemotherapy (CT) may be used to mitigate the likelihood of recurrence and mortality. This network meta-analysis (NMA) assesses the comparative efficacy of various treatment approaches for resectable PC. A thorough search was carried out on January 31, 2023, encompassing PubMed/MEDLINE, Cochrane Library, and Embase databases. We incorporated randomized clinical trials (RCTs) that compared surgical interventions with or without (neo)adjuvant or perioperative therapies for operable PC. We conducted a fixed-effects Bayesian NMA. We presented the effect sizes in terms of hazard ratios (HRs) for overall survival (OS) along with 95% credible intervals (95% CrIs). The treatment was deemed statistically superior when the 95% credible interval (CrI) did not encompass a null value (hazard ratio < 1). Treatment rankings were established based on the surface under the cumulative ranking curve (SUCRA). A total of 24 studies were incorporated, comparing 21 treatments with surgery in isolation. Eleven treatments showed superior efficacy compared to surgery alone, with HRs ranging from 0.38 for perioperative treatments to 0.73 for adjuvant 5-fluorouracil. After the exclusion of studies conducted in Asia, it was found that the perioperative regimen of gemcitabine combined with nab-paclitaxel was the most effective regimen (SUCRA, p = 0.99). The findings endorse the utilization of perioperative CT, especially multi-agent CT, as the favored intervention for operable PC in Western nations. Full article

The insulin-like growth factor-1 (IGF-1) and insulin axes are upregulated in obesity and obesity-associated esophageal adenocarcinoma (EAC). Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a contemporary nanotechnology-based paclitaxel (PT) bound to human albumin, ensuring its solubility in water rather than a toxic solvent. Here, we examined the benefits of inhibiting insulin-like growth factor-1 receptor/insulin receptor (IGF-1/IR) signaling and the enhancement of nab-paclitaxel effects by inclusion of the small-molecule inhibitor BMS-754807 using both in vitro and in vivo models of EAC. Using multiple EAC cell lines, BMS-754807 and nab-paclitaxel were evaluated as mono and combination therapies for in vitro effects on cell proliferation, cell death, and cell movement. We then analyzed the in vivo anticancer potency with survival improvement with BMS-754807 and nab-paclitaxel mono and combination therapies. BMS-754807 monotherapy suppressed in vitro cell proliferation and wound healing while increasing apoptosis. BMS-754807, when combined with nab-paclitaxel, enhanced those effects on the inhibition of cell proliferation, increment in cell apoptosis, and inhibition of wound healing. BMS-754807 with nab-paclitaxel produced substantially greater antitumor effects by increasing in vivo apoptosis, leading to increased mice survival compared to those of BMS-754807 or nab-paclitaxel monotherapy. Our outcomes support the use of BMS-754807, alone and in combination with nab-paclitaxel, as an efficient and innovative treatment choice for EAC. Full article

Background/Objectives: This nationwide population-based study investigated the overall survival (OS) of patients with metastatic pancreatic cancer (mPC) receiving first-line chemotherapy. Methods: Data from the National Health Insurance Service linked to the Korea Central Cancer Registry were used. Patients with mPC receiving first-line chemotherapy (2012–2019) were included and followed up until 2020. The gemcitabine plus nab-paclitaxel (GnP) and FOLFIRINOX groups were matched according to age, sex, and comorbidities. Results: In total, 8652 patients with mPC were treated with chemotherapy. GnP and FOLFIRINOX have been administered since 2016 and 2017, respectively. The median OS increased annually from 6 months in 2012–2013 to 10 months in 2018–2019. The median OSs in the GnP and FOLFIRINOX groups were significantly longer than those in patients receiving gemcitabine ± erlotinib. A total of 1134 patients from both the GnP and FOLFIRINOX groups were selected using propensity score matching. Before matching, the median OS was longer in the FOLFIRINOX group than in the GnP group (p = 0.0029). After matching, however, there was no significant difference in the median OS between the two groups (11 vs. 11 months, respectively, p = 0.2438). Conclusions: Patients with mPC receiving chemotherapy have shown improved OS since the introduction of GnP and FOLFIRINOX. After matching, OS did not differ between the GnP and FOLFIRINOX groups. Full article

Pancreatic malignancy is the fourth cause of cancer-related death in Western countries and is predicted to become the second leading cause of cancer-related mortality by 2030. The standard therapies (FOLFIRINOX and gemcitabine with nab-paclitaxel) are not resolutive because this type of cancer is also characterized by a high chemoresistance, due in part to the activity of the ATP Binding Cassette (ABC) pumps accounting for the reduction in the intracellular concentration of the drugs. In this work, we analyze the occurrence of single-nucleotide polymorphisms (SNPs) in the MDR-1 gene, in different pancreatic cancer cell lines, and in tissues from pancreatic cancer patients by DNA sequencing, as well as the expression levels of MDR-1 mRNA and protein, by qRT-PCR and Western Blot analysis. We found that gemcitabine-resistant cells, in conjunction with homozygosis of analyzed SNPs, showed high MDR-1 basal levels with further increases after gemcitabine treatment. Nevertheless, we did not observe in the human PDAC samples a correlation between the level of MDR-1 mRNA and protein expression and SNPs. Preliminary, we conclude that in our small cohort, these SNPs cannot be used as molecular markers for predicting the levels of MDR-1 mRNA/protein levels and drug responses in patients with PDAC. Full article

(1) Background: Pancreatic ductal adenocarcinoma (PDAC) has low survival rates despite treatment advancements. Aim: This study aims to show how molecular profiling could possibly guide personalized treatment strategies, which may help improve survival outcomes in patients with PDAC. (2) Materials and Methods: A retrospective analysis of 142 PDAC patients from a single academic center was conducted. Patients underwent chemotherapy and next-generation sequencing for molecular profiling. Key oncogenic pathways were identified using the Reactome pathway database. Survival analysis was performed using Kaplan–Meier curves and Cox Proportional Hazards Regression. (3) Results: Patients mainly received FOLFIRINOX (n = 62) or gemcitabine nab-paclitaxel (n = 62) as initial chemotherapy. The median OS was 13.6 months. Longer median OS was noted in patients with NOTCH (15 vs. 12.3 months, p = 0.007) and KIT pathway mutations (21.3 vs. 12.12 months, p = 0.04). Combinatorial pathway analysis indicated potential synergistic effects on survival. In the PFS, PI3K pathway (6.6 vs. 5.7 months, p = 0.03) and KIT pathway (10.3 vs. 6.2 months, p = 0.03) mutations correlated with improved PFS within the gemcitabine nab-paclitaxel subgroup. (4) Conclusions: Molecular profiling could play a role in PDAC for predicting outcomes and responses to therapies like FOLFIRINOX and gemcitabine nab-paclitaxel. Integrating genomic data into clinical decision-making can benefit PDAC treatment, though further validation is needed to fully utilize precision oncology in PDAC management. Full article

The novel Oxathiazinane derivative GP-2250 (Misetionamide) displays antineoplastic activity in vitro and in vivo, as previously shown in pancreatic cancer cells and in patient-derived mouse xenografts (PDX). Currently, GP 2250 is under phase I clinical trial in pancreatic ductal adenocarcinoma (PDAC). GP-2250 in combination with Gemcitabine displays a high synergistic capacity in various primary and established pancreatic cancer cell lines. Additionally, in the eight PDX models tested, the drug combination was superior in reducing tumor volume with an aggregate tumor regression (ATR) of 74% compared to Gemcitabine alone (ATR: 10%). Similarly, in a PDX maintenance setting following two weeks of treatment with nab-Paclitaxel plus Gemcitabine, the combination of GP-2250 plus Gemcitabine resulted in outstanding tumor control (ATR: 79%) compared to treatment with Gemcitabine alone (ATR: 60%). Furthermore, GP-2250 reduced the ratio of tumor-initiating CD133⁺ markers on the surface of PDAC cells in spheroid cultures, indicating a possible mechanism for the synergistic effect of both substances. Considering the high tolerability of GP 2250, these results may open up a new approach to maintenance therapy with GP-2250/Gemcitabine combination following nab-Paclitaxel plus Gemcitabine as first-line treatment. Full article

The efficacy and safety of olaratumab plus nabpaclitaxel and gemcitabine in treatment-naïve participants with metastatic pancreatic ductal adenocarcinoma was evaluated. An initial phase 1b dose-escalation trial was conducted to determine the olaratumab dose for the phase 2 trial, a randomized, double-blind, placebo-controlled trial to compare overall survival (OS) in the olaratumab arm vs. placebo arms. In phase 1b, 22 participants received olaratumab at doses of 15 and 20 mg/kg with a fixed dose of nabpaclitaxel and gemcitabine. In phase 2, 159 participants were randomized to receive olaratumab 20 mg/kg in cycle 1 followed by 15 mg/kg in the subsequent cycles (n = 81) or the placebo (n = 78) on days 1, 8, and 15 of a 28-day cycle, plus nabpaclitaxel and gemcitabine. The primary objective of the trial was not met, with a median OS of 9.1 vs. 10.8 months (hazard ratio [HR] = 1.05; 95% confidence interval [CI]: 0.728, 1.527; p = 0.79) and the median progression-free survival (PFS) was 5.5 vs. 6.4 months (HR = 1.19; 95% CI: 0.806, 1.764; p = 0.38), in the olaratumab vs. placebo arms, respectively. The most common treatment-emergent adverse event of any grade across both arms was fatigue. Olaratumab plus chemotherapy failed to improve the OS or PFS in participants with metastatic PDAC. There were no new safety signals. Full article

Immunotherapy has shown clinical benefit in patients with non-small-cell lung cancer (NSCLC). Due to the limited response of monotherapy, combining immune checkpoint inhibitors (ICIs) and chemotherapy is considered a treatment option for advanced NSCLC. However, the mechanism of combined therapy and the potential patient population that could benefit from combined therapy remain undetermined. Here, we developed an NSCLC model based on the published quantitative systems pharmacology (QSP)-immuno-oncology platform by making necessary adjustments. After calibration and validation, the established QSP model could adequately characterise the biological mechanisms of action of the triple combination of atezolizumab, nab-paclitaxel, and carboplatin in patients with NSCLC, and identify predictive biomarkers for precision dosing. The established model could efficiently characterise the objective response rate and duration of response of the IMpower131 trial, reproducing the efficacy of alternative dosing. Furthermore, CD8+ and CD4+ T cell densities in tumours were found to be significantly related to the response status. This significant extension of the QSP model not only broadens its applicability but also more accurately reflects real-world clinical settings. Importantly, it positions the model as a critical foundation for model-informed drug development and the customisation of treatment plans, especially in the context of combining single-agent ICIs with platinum-doublet chemotherapy. Full article

A group of 27 patients diagnosed with metastatic triple-negative breast cancer (mTNBC) was randomly distributed into two groups and underwent different lines of metronomic treatment (mCHT). The former group (N 14) received first-line mCHT and showed a higher overall survival rate than the second group (N 13), which underwent second-line mCHT. Analysis of one patient still alive from the first group, diagnosed with mTNBC in 2019, showed a complete metabolic response (CMR) after a composite approach implicating first-line mCHT followed by second-line epirubicin and third-line nab-paclitaxel, and was chosen for subsequent molecular characterization. We found altered expression in the cancer stemness-associated gene NOTCH-1 and its corresponding protein. Additionally, we found changes in the expression of oncogenes, such as MYC and AKT, along with their respective proteins. Overall, our data suggest that a first-line treatment with mCHT followed by MTD might be effective by negatively regulating stemness traits usually associated with the emergence of drug resistance. Full article

Immediate hypersensitivity reactions (iHSRs) to taxanes are observed in 6% and 4% of gynecologic and breast cancer patients, respectively. Drug desensitization is the only option, as no comparable alternative therapy is available. Surfactants in the taxane formulation have been implicated in the immunopathogenesis of iHSRs, although sporadic skin test (ST) positivity and iHSRs to nab-paclitaxel have suggested the involvement of the taxane moiety and/or IgE-mediated pathomechanisms. In vitro diagnostic tests might offer insights into mechanisms underlying iHSRs to taxanes. The aim of the present study was to address this unmet need by developing a novel basophil activation test (BAT). The study included patients (n = 31) undergoing paclitaxel/carboplatin therapy. Seventeen patients presented with iHSRs to paclitaxel (iHSR-Tax^pos), and eleven were tolerant (iHSR-Tax^neg). Fourteen patients presented with iHSRs to carboplatin (iHSR-Pl^pos), and fourteen were tolerant (iHSR-Pl^neg). The BAT median stimulation index (SI) values were 1.563 (range, 0.02–4.11; n = 11) and −0.28 (range −4.88–0.07, n = 11) in iHSR-Tax^pos and iHSR-Tax^neg, respectively. The BAT median SI values were 4.45 (range, 0.1–26.7; n = 14) and 0 (range, −0.51–1.65; n = 12) in iHSR-Pl^pos and iHSR-Pl^neg, respectively. SI levels were not associated with iHSR severity grading. Comparing BAT results in iHSR-Tax^pos and iHSR-Tax^neg showed the area under the receiver operator characteristic (ROC) curve to be 0.9752 (p = 0.0002). The cutoff calculated by the maximized likelihood ratio identified 90.91% of iHSR-Tax^pos patients and 90.91% of iHSR-Tax^neg patients. Comparing BAT results for iHSR-Pl^pos and iHSR-Pl^neg showed the area under the ROC curve to be 0.9286 (p = 0.0002). The cutoff calculated by the maximized likelihood ratio identified 78.57% of iHSR-Pl^pos patients and 91.67% of iHSR-Pl^neg patients. Most iHSR-Tax^pos patients for which ST was available (10/11) scored ST-negative and BAT-positive, whereas most iHSR-Pl^pos patients for which ST was available (14/14) scored both BAT- and ST-positive. This suggested the intervention of non-IgE-mediated mechanisms in iHSR-Tax^pos patients. Consistent with this view, an in silico molecular docking analysis predicted the high affinity of paclitaxel to the degranulation-competent MRGPRX2 receptor. This hypothesis warrants further in vitro investigations. In conclusion, the present study provides preliminary proof-of-concept evidence that this novel BAT has potential utility in understanding mechanisms underlying iHSRs to taxanes. Full article