Exploring the Combined Action of Adding Pertuzumab to Branded Trastuzumab versus Trastuzumab Biosimilars for Treating HER2+ Breast Cancer.

The binding activity of various trastuzumab biosimilars versus the branded trastuzumab towards the glycosylated extracellular domain of the human epidermal growth factor receptor 2 (HER2) target in the presence of pertuzumab was investigated. We employed size exclusion chromatography with tetra-detection methodology to simultaneously determine absolute molecular weight, concentration, molecular size, and intrinsic viscosity. All trastuzumab molecules in solution exhibit analogous behavior in their binary action towards HER2 regardless of the order of addition of trastuzumab/pertuzumab. This analogous behavior of all trastuzumab molecules, including biosimilars, highlights the robustness and consistency of their binding activity towards HER2. Furthermore, the addition of HER2 to a mixture of trastuzumab and pertuzumab leads to increased formation of high-order HER2 complexes, up to concentrations of one order of magnitude higher than in the case of sequential addition. The observed increase suggests a potential synergistic effect between these antibodies, which could enhance their therapeutic efficacy in HER2-positive cancers. These findings underscore the importance of understanding the complex interplay between therapeutic antibodies and their target antigens, providing valuable insights for the development of more effective treatment strategies.

Phase Ia/b Study of Giredestrant ± Palbociclib and ± Luteinizing Hormone-Releasing Hormone Agonists in Estrogen Receptor-Positive, HER2-Negative, Locally Advanced/Metastatic Breast Cancer.

PURPOSE: Giredestrant is an investigational next-generation, oral, selective estrogen receptor antagonist and degrader for the treatment of estrogen receptor-positive (ER+) breast cancer. We present the primary analysis results of the phase Ia/b GO39932 study (NCT03332797). PATIENTS AND METHODS: Patients with ER+, HER2-negative locally advanced/metastatic breast cancer previously treated with endocrine therapy received single-agent giredestrant (10, 30, 90, or 250 mg), or giredestrant (100 mg) ± palbociclib 125 mg ± luteinizing hormone-releasing hormone (LHRH) agonist. Detailed cardiovascular assessment was conducted with giredestrant 100 mg. Endpoints included safety (primary), pharmacokinetics, pharmacodynamics, and efficacy. RESULTS: As of January 28, 2021, with 175 patients enrolled, no dose-limiting toxicity was observed, and the MTD was not reached. Adverse events (AE) related to giredestrant occurred in 64.9% and 59.4% of patients in the single-agent ± LHRH agonist and giredestrant + palbociclib ± LHRH agonist cohorts, respectively (giredestrant-only-related grade 3/4 AEs were reported in 4.5% of patients across the single-agent cohorts and 3.1% of those with giredestrant + palbociclib). Dose-dependent asymptomatic bradycardia was observed, but no clinically significant changes in cardiac-related outcomes: heart rate, blood pressure, or exercise duration. Clinical benefit was observed in all cohorts (48.6% of patients in the single-agent cohort and 81.3% in the giredestrant + palbociclib ± LHRH agonist cohort), with no clear dose relationship, including in patients with ESR1-mutated tumors. CONCLUSIONS: Giredestrant was well tolerated and clinically active in patients who progressed on prior endocrine therapy. Results warrant further evaluation of giredestrant in randomized trials in early- and late-stage ER+ breast cancer.

An international multicentric phase â ¢ randomized controlled trial of time-acupoints-space acupuncture for the prevention of chemotherapy-induced fatigue in patients with early stage breast cancer: a study protocol.

OBJECTIVE: To determine the difference in prevention of chemotherapy-induced fatigue between time-acupoints-space acupuncture (ATAS) administered weekly compared to sham acupuncture and non-acupuncture in patients with early breast cancer receiving adjuvant chemotherapy by epirubicine-cyclophosphamide (EC) followed by paclitaxel, as measured by the multi-dimensional fatigue inventory (MFI) over the previous week and Visual Analogue Scale measuring fatigue (VAS-F), and to evaluate the effects of ATAS on self-reported neuropathy pain, sleep, anxiety and depression. METHODS: In this multicenter clinical trial, we have randomized patients into 3 groups: ATAS, Sham and non-acupuncture with an unequal randomization of 2∶1∶1. A cloud related electronical clinical report form and smartphone platform was established for data entry. Patients with a history of stage Ⅰ-Ⅲ breast cancer scheduled to receive adjuvant chemotherapy. Acupuncture will be delivered once a week during chemotherapy with VAS-F evaluation. In order to qualify and quantify the mechanism of fatigue induced by chemotherapy with or without acupuncture, an evaluation of immune profiling was incorporate in this study. RESULTS: The presence and seriousness of chemotherapy-induced fatigue should be considered in therapeutic programs for early breast cancer treatment. Fatigue induced by adjuvant chemotherapy in patients with breast cancer remains a major concern affecting the quality of life significantly. Unfortunately, we do not have effective pharmacological interventions yet. And clinical trials of acupuncture in preventing chemotherapy-induced fatigue in patients with early breast cancer have not been reported. CONCLUSION: The findings of the trial will allow us to determine the effects of acupuncture treatment approach. We will also be able to confirm whether ATAS is better than sham acupuncture and non-acupuncture treatments.

Treatment Exposure and Discontinuation in the PALbociclib CoLlaborative Adjuvant Study of Palbociclib With Adjuvant Endocrine Therapy for Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Early Breast Cancer (PALLAS/AFT-05/ABCSG-42/BIG-14-03).

PURPOSE: The PALLAS study investigated whether the addition of palbociclib, an oral CDK4/6 inhibitor, to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) in early hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. In this analysis, we evaluated palbociclib exposure and discontinuation in PALLAS. METHODS: Patients with stage II-III HR+, HER2- disease were randomly assigned to 2 years of palbociclib with adjuvant ET versus ET alone. The primary objective was to compare iDFS between arms. Continuous monitoring of toxicity, dose modifications, and early discontinuation was performed. Association of baseline covariates with time to palbociclib reduction and discontinuation was analyzed with multivariable competing risk models. Landmark and inverse probability weighted per-protocol analyses were performed to assess the impact of drug persistence and exposure on iDFS. RESULTS: Of the 5,743 patient analysis population (2,840 initiating palbociclib), 1,199 (42.2%) stopped palbociclib before 2 years, the majority (772, 27.2%) for adverse effects, most commonly neutropenia and fatigue. Discontinuation of ET did not differ between arms. Discontinuations for non-protocol-defined reasons were greater in the first 3 months of palbociclib, and in the first calendar year of accrual, and declined over time. No significant relationship was seen between longer palbociclib duration or ≥ 70% exposure intensity and improved iDFS. In the weighted per-protocol analysis, no improvement in iDFS was observed in patients receiving palbociclib versus not (hazard ratio 0.89; 95% CI, 0.72 to 1.11). CONCLUSION: Despite observed rates of discontinuation in PALLAS, analyses suggest that the lack of significant iDFS difference between arms was not directly related to inadequate palbociclib exposure. However, the discontinuation rate illustrates the challenge of introducing novel adjuvant treatments, and the need for interventions to improve persistence with oral cancer therapies.

The Leptin Axis and Its Association With the Adaptive Immune System in Breast Cancer.

Adipose tissue secretes various peptides, including leptin. This hormone acts through the leptin receptor (Ob-R), which is expressed ubiquitously on the surface of various cells, including breast cancer cells and immune cells. Increasing evidence points to an interaction between the tumor microenvironment, tumor cells, and the immune system. Leptin plays an important role in breast cancer tumorigenesis and may be implicated in activation of the immune system. While breast cancer cannot be considered an immunogenic cancer, the triple-negative subtype is an exception. Specific immune cells - tumor infiltrating lymphocytes - are involved in the immune response and act as predictive and prognostic factors in certain breast cancer subtypes. The aim of this article is to review the interaction between adipose tissue, through the expression of leptin and its receptor, and the adaptive immune system in breast cancer.

Assessing citric acid-derived luminescent probes for pH and ammonia sensing: A comprehensive experimental and theoretical study.

The present work reports on the assessment of luminescent probes derived from citric acid (CA) and ß-aminothiols (namely, l-cysteine (Cys) and cysteamine) for instrumental and smartphone-based fluorimetric sensing purposes. Remarkably, the evaluated luminescent probes derived from natural compounds showed pH-dependent dual excitation/dual emission features. Both fluorophores hold promise for the ratiometric fluorimetric sensing of pH, being especially convenient for the smartphone-based sensing of pH via ratiometric analysis by proper selection of B and G color channels. Time dependent density functional theory (TDDFT) calculations allowed to substantiate the pH dependent structure-property relationship and to unveil the critical role of the CA derived carboxyl group, these findings contributing to the fundamental knowledge on these systems for the rational design of new fluorophores and in establishing fluorescence sensing mechanisms of CA-derived systems. Besides, paper-based devices modified with CA-Cys were implemented in a three-phase separation approach for sensitive and selective ammonia sensing, yielding a remarkable enrichment factor of 389 and a limit of detection of 37 µM under optimal conditions. The proposed approach was successfully applied to the determination of ammonia nitrogen and extractable ammonium in water samples and marine sediments, respectively.

Obesity and Breast Cancer: A Paradoxical and Controversial Relationship Influenced by Menopausal Status.

Breast cancer is the most common tumor in women worldwide, and an increasing public health concern. Knowledge of both protective and negative risk factors is essential for a better understanding of this heterogenous disease. We undertook a review of the recent literature and evaluated the relationship between obesity mediators and breast cancer development depending on menopausal status. Excess weight is now pandemic and has replaced tobacco as the main lifestyle-related risk factor for premature death. Although the prevalence of obesity/overweight has increased globally over the last 50 years, the potential harm attributable to excess fat has generally been underestimated. The relationship between overweight/obesity, breast cancer and overall risk appears to be highly dependent on menopausal status. Thus, obesity increases the risk of breast cancer in postmenopausal women but, conversely, it appears to be protective in premenopausal women. We evaluate the role of different clinical factors potentially involved in this seemingly contradictory relationship, including estrogen, mammogram density, adipokines, insulin-signaling pathway activation, and inflammatory status. A key focus of this review is to better understand the impact of body mass index and menopausal status on these clinical factors and, hence, provide some clarity into the inter-relationships involved in this controversial issue.

Insights into Paraben Adsorption by Metal-Organic Frameworks for Analytical Applications.

Metal-organic frameworks (MOFs) are attractive materials used as sorbents in analytical microextraction applications for contaminants of emerging concern (CECs) from environmental liquid matrices. The demanding specs for a sorbent in the analytical application can be comprehensively studied by considering the interactions of the target analytes with the frameworks by the use of single-crystal X-ray diffraction, computational analysis, and adsorption studies, including the kinetic ones. The current study intends a better understanding of the interactions of target CECs (particularly, propylparaben (PPB) as a model) and three Zn-based layered pillared MOFs: CIM-81 [Zn2(tz)2(bdc)] (Htz = 1,2,4-triazole and H2bdc = 1,4-benzenedicarboxylic acid) and their amino derivatives [Zn2(NH2-tz)2(bdc)] CIM-82 and [Zn2(tz)2(NH2-bdc)] CIM-83 (NH2-Htz = 3-amino-1,2,4-triazole and NH2-H2bdc = 2-amino-1,4-benzenedicarboxylic acid). The crystal structures of the two solvate compounds (dma@CIM-81 (dma = dimethylacetamide) and acetone@CIM-81) were solved by single-crystal X-ray diffraction to determine the points of interaction between the framework and the guest molecules. They also served as a starting point for the computational modeling of the PPB@CIM-81 compound, showing that up to two PPB molecules can be hosted in one of the pores, while only one can be trapped in the second pore type, leading to a maximum theoretical capacity of 291.9 mg g-1. This value is close to the value obtained by the adsorption isotherm experiment for CIM-81 (283 mg g-1). This value is, by far, higher than those previously reported for other materials for the removal of PPB from water, and also higher than the experimental values obtained for CIM-82 (54 mg g-1) and CIM-83 (153 mg g-1). The kinetics of adsorption is not very fast, with uptake of about 40% in 3 h, although a 70% release in methanol is achieved in 1 h. In addition, a further comparison of performance in analytical microextraction (requiring only 10 mg of CIM-81) was carried out together with chromatographic analysis to support all insights attained, with the method being able to monitor CECs as low as µg L-1 levels in complex environmental water samples, thus performing successfully for water monitoring even in multicomponent scenarios.

Predictive Role of Leptin Receptor (Ob-R) Overexpression in Patients with Early Breast Cancer Receiving Neoadjuvant Systemic Treatment.

The primary aim of this retrospective study was to investigate the correlation between the immunohistochemical expression of Ob-R (leptin receptor) with pCR (pathological complete response) in early breast cancer patients receiving neoadjuvant systemic treatment (NST). A total of 100 women with breast cancer receiving NST (2017-2020) followed by surgical resection were retrospectively obtained. Demographic parameters and clinicopathological factors (e.g., treatment modalities, immunohistochemistry (IHC), and cancer subtype) were obtained from the patient's clinical records. In the analyzed breast cancer cohort, high expression of Ob-R was found in 52% of tumors and there was a significantly higher incidence in the HER2+ and TNBC subgroups. Overall, a significantly greater percentage of patients with Ob-R positive tumors achieved pCR compared with Ob-R negative patients (57.7% vs. 27.1%; p = 0.002). This result was observed in most breast cancer subtypes. In patients with HER2+ breast cancer, there was no difference in Ob-R expression in relation to the HR status. Ob-R cell positivity was significantly higher in younger breast cancer patients (p = 0.008), those who were premenopausal (p = 0.011), and in those with a BMI > 25 kg/m2 (p = 0.019). A significantly greater percentage of early breast cancer patients with Ob-R positive tumors achieved pCR compared with Ob-R negative patients. Furthermore, breast cancer patients with positive Ob-R expression were significantly younger than those with negative Ob-R expression. This association was not explained by differences in BMI between young and old patients.

First Characterization of the Formation of Anthocyanin-Ge and Anthocyanin-B Complexes through UV-Vis Spectroscopy and Density Functional Theory Quantum Chemical Calculations.

The occurrence of anthocyanin (ACN) and metal (Me) complexes has been widely supported by many research works while the possibility that ACNs bind to metalloids (Mds) is yet to be proven. Here, metalloids (H3BO3 for B; GeO2 for Ge) were added to cyanidin-based solutions at pH 5, 6, and 7 and ACN-Md stoichiometric ratios of 1:1, 1:10, 1:100, and 1:500, and UV-vis transmittance spectroscopy as well as density functional theory (DFT) calculations were performed to test this hypothesis. Ge and B addition caused bathochromic and hyperchromic shifts on ACN UV-vis spectra, particularly pronounced at pH 5 and a 1:500 (ACN:Md) ratio. ACN-Me complexation reactions have been evaluated where Ge showed a higher capability to bind to ACNs than B. Among the complexes envisioned, those labeled as b1, b2, and b3 feature UV-vis spectra compatible with experiments. The combination of experimental and computational data offers for the first time evidence of the formation of ACN-Md complexes.

A Randomized Placebo Controlled Phase II Trial Evaluating Exemestane with or without Enzalutamide in Patients with Hormone Receptor-Positive Breast Cancer.

PURPOSE: To determine whether the androgen receptor (AR) inhibitor, enzalutamide, improves effectiveness of endocrine therapy (ET) in hormone receptor-positive (HR+) breast cancer. PATIENTS AND METHODS: In this phase II trial, patients with HR+/HER2 normal advanced/metastatic breast cancer were randomized 1:1 to exemestane 25 mg with placebo or exemestane 50 mg with enzalutamide 160 mg daily (NCT02007512). Two parallel cohorts enrolled patients with 0 (cohort 1) or 1 (cohort 2) prior ET for advanced disease. Progression-free survival (PFS) was the primary endpoint in the intent-to-treat (ITT) population of each cohort. Biomarkers were evaluated in an exploratory analysis. RESULTS: Overall, 247 patients were randomized (cohort 1, n = 127 and cohort 2, n = 120). PFS was not improved in either cohort of the ITT population [HR, 0.82 (95% confidence interval (CI), 0.54-1.26); P = 0.3631 for cohort 1 and HR, 1.02 (95% CI, 0.66-1.59); P = 0.9212 for cohort 2]. In cohort 1, high levels of AR mRNA were associated with greater benefit of enzalutamide (P interaction = 0.0048). This effect was particularly apparent in patients with both high levels of AR mRNA and low levels of ESR1 mRNA [HR, 0.24 (95% CI, 0.10-0.60); P = 0.0011]. The most common any grade adverse events in the enzalutamide arms were nausea (39%) in cohort 1 and fatigue (37%) in cohort 2. CONCLUSIONS: Enzalutamide with exemestane was well tolerated. While PFS was not improved by the addition of enzalutamide to exemestane in an unselected population, ET-naïve patients with high AR mRNA levels, particularly in combination with low ESR1 mRNA levels, may benefit from enzalutamide with exemestane.

C-HAu interactions and optical properties of [(P,P)4Au6]2+ molecular gold nanoclusters.

Two hexagold diphosphine-stabilized [(P,P)4Au6]2+ molecular nanoclusters with the same [core + exo] arrangement differing in the linker (phenylene or trimethylene) connecting the two P-donor sites have been subjected to theoretical studies with the aim of shedding light on two main questions. On one hand, from a previous study [J. Vícha, C. Foroutan-Nejadand M. Straka,Nat. Commun., 2019, 10, 1643], it is still unclear whether short C-H2Au contacts revealed in the corresponding crystal structures are just forced by bulky P(Ph)2 groups and, on the other hand, to what extent the linker affects the visible band position [M. A. Bakar, M. Sugiuchi, M. Iwasaki, Y. Shichibuand K. Konishi, Nat. Commun., 2017, 8, 576]. Here, it is demonstrated that even in simpler model systems in which bulky groups were replaced by PH2 groups, C-H2Au hydrogen bonding interactions are retained and show comparable values, as measured by NBO and QTAIM analyses, to those of 1 and 2. These analyses further confirmed a stronger HB in 1 than in 2. Also, the comparison of model systems without and with a linker connecting the phosphine groups showed a bathochromic shift of 47 and 60 nm, revealing the key role of the linker. The Δρ(r)EE-GS plots of 1 and 2 revealed electron density depletion in the inter-nuclear C-H2 region upon electronic transition unveiling its contribution to their optical properties.

Enhancing global access to cancer medicines.

Globally, cancer is the second leading cause of death, with numbers greatly exceeding those for human immunodeficiency virus/acquired immunodeficiency syndrome, tuberculosis, and malaria combined. Limited access to timely diagnosis, to affordable, effective treatment, and to high-quality care are just some of the factors that lead to disparities in cancer survival between countries and within countries. In this article, the authors consider various factors that prevent access to cancer medicines (particularly access to essential cancer medicines). Even if an essential cancer medicine is included on a national medicines list, cost might preclude its use, it might be prescribed or used inappropriately, weak infrastructure might prevent it being accessed by those who could benefit, or quality might not be guaranteed. Potential strategies to address the access problems are discussed, including universal health coverage for essential cancer medicines, fairer methods for pricing cancer medicines, reducing development costs, optimizing regulation, and improving reliability in the global supply chain. Optimizing schedules for cancer therapy could reduce not only costs, but also adverse events, and improve access. More and better biomarkers are required to target patients who are most likely to benefit from cancer medicines. The optimum use of cancer medicines depends on the effective delivery of several services allied to oncology (including laboratory, imaging, surgery, and radiotherapy). Investment is necessary in all aspects of cancer care, from these supportive services to technologies, and the training of health care workers and other staff.

Transduction optimization of AAV vectors for human gene therapy of glaucoma and their reversed cell entry characteristics.

The trabecular meshwork (TM) of the eye is responsible for maintaining physiological intraocular pressure (IOP). Dysfunction of this tissue results in elevated IOP, subsequent optic nerve damage and glaucoma, the world's leading cause of irreversible blindness. IOP regulation by delivering candidate TM genes would offer an enormous clinical advantage to the current daily-drops/surgery treatment. Initially, we showed that a double-stranded AAV2 (scAAV2) transduced the human TM very efficiently, while its single-stranded form (ssAAV2) did not. Here, we quantified transduction and entry of single- and double-strand serotypes 1, 2.5, 5, 6, 8, and 9 in primary, single individual-derived human TM cells (HTM). scAAV2 exhibited highest transduction in all individuals, distantly followed by scAAV2.5, scAAV6, and scAAV5. Transduction of scAAV1, scAAV8, and scAAV9 was negligible. None of the ssAAV serotypes transduced, but their cell entries were significantly higher than those of their corresponding scAAV. Tyrosine scAAV2 capsid mutants increased transduction in HTM cultured cells and all TM-outflow layers of perfused postmortem human eyes. These studies provide the first serotype optimization for gene therapy of glaucoma in humans. They further reveal biological differences between the AAV forms in HTM cells, whose understanding could contribute to the development of gene therapy of glaucoma.

Contextualizing pertuzumab approval in the treatment of HER2-positive breast cancer patients.

The use of adjuvant pertuzumab in HER2-positive early-stage breast cancer has recently been approved by the EMA on the basis of data from the APHINITY trial. Accordingly, we have produced this opinion article with the aim of putting the study data in perspective against other add-on therapeutic strategies, to clarify methodological or statistical doubts about the study, and to define the population of high-risk patients with hormone receptor-negative breast cancer that we agree, in general, should be treated. With this approval, physicians must be well prepared to place the APHINITY study data in context. It is now up to each country to ratify the EMA-approved indications and to agree on reimbursement, and doctors must optimize their use based on knowledge and discussion with patients.

Comunicación de las enfermeras con los pacientes. Validación de la escala "Interpersonal Communication Assessment Scale" (ICAS) / Communication of nurses with patients. Validation the "interpersonal communication assessment scale" (ICAS)

OBJETIVO: Adaptar culturalmente la escala "Interpersonal Communication Assessment Scale" en el contexto español de la práctica enfermera. METODOLOGÍA: Estudio trasversal con metodología de traducción directa e inversa, para obtener la adaptación lingüística-cultural. Participaron enfermeras de hospital general universitario. Para analizar las propiedades psicométricas, se valoró fiabilidad analizando la consistencia interna y validez mediante análisis de la estructura factorial. RESULTADOS: Participaron 188 enfermeras, el coeficiente alfa de Cronbach para el cuestionario total fue de 0,881 con coeficientes entre 0,816 y 0,622 en las subescalas. El test KMO mostró índice de 0,850, la prueba de esfericidad de Barlett con Chi cuadrado de 1208,714 con p = 0,000 y análisis factorial con 4 factores que explicaban el 49,268% de la varianza total. CONCLUSIÓN: El cuestionario obtenido comprende todos los aspectos necesarios para evaluar competencias en comunicación de estos profesionales con sus pacientes, con suficiente evidencia y características psicométricas para su utilización en población española

OBJECTIVE: The adaptation of ICAS in the Spanish context of nursing practice. METHODS: A cross-sectional study was carried, using the bidirectional translation method for linguistic-cultural adaptation. It was applied to the nursing staff in a universitary hospital. Reliability, internal consistence and construct validity were calculated to evaluate the psychometrics properties of the Spanish version. RESULTS: Participation was of 188 nurses. Cronbach's alpha coefficient for the total scale was 0,881, with coefficients between 0,816 and 0,622 in the subscales. Exploratory factor analysis resulted in four factors, which explained 49,268% of total variance, and Kaiser-Meyer-Olkin measure was 0,850. CONCLUSIONS: The Spanish version showed high internal consistency and psychometrics characteristics like appropriate tool for assessing interpersonal communications skills between nurses and patients

Updating the role of obesity and cholesterol in breast cancer.

BACKGROUND: Breast cancer is the second most common cause of cancer-related death among women. Advances in our understanding of the disease have translated into better diagnostics and more effective therapeutics, leading to earlier detection and improved outcomes. Several studies have pointed at lifestyle and environmental factors as contributory for the onset and progression of the disease. Obesity and cholesterol stand out for their potential causal relationship with breast cancer and ease of modification. MAIN TEXT: Obesity and cholesterol represent risk factors for breast cancer, but their impact is largely affected by cofounding variables including menopausal status, disease subtype, and inflammation. Establishing a causal relationship between lifestyle factors and clinical outcomes may be challenging. Epidemiological studies and meta-analyses have rendered conflicting or sometimes contradictory results, possibly owing to the multifactorial nature of the disease. We discuss the supporting evidence and limitations in our understanding of obesity and cholesterol as risk factors for breast cancer. CONCLUSIONS: There is sufficient evidence that obesity and cholesterol impact clinical outcomes. Physicians are advised to take steps to help patients with their weight, such as recommending dietary and lifestyle interventions.

A Phase II Randomized Study of Neoadjuvant Letrozole Plus Alpelisib for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer (NEO-ORB).

PURPOSE: Addition of alpelisib to fulvestrant significantly extended progression-free survival in PIK3CA-mutant, hormone receptor-positive (HR+) advanced/metastatic breast cancer in the phase III SOLAR-1 study. The combination of alpelisib and letrozole also had promising activity in phase I studies of HR+ advanced/metastatic breast cancer. NEO-ORB aimed to determine whether addition of alpelisib to letrozole could increase response rates in the neoadjuvant setting.Patients and Methods: Postmenopausal women with HR+, human epidermal growth factor receptor 2-negative, T1c-T3 breast cancer were assigned to the PIK3CA-wild-type or PIK3CA-mutant cohort according to their tumor PIK3CA status, and randomized (1:1) to 2.5 mg/day letrozole with 300 mg/day alpelisib or placebo for 24 weeks. Primary endpoints were objective response rate (ORR) and pathologic complete response (pCR) rate for both PIK3CA cohorts. RESULTS: In total, 257 patients were assigned to letrozole plus alpelisib (131 patients) or placebo (126 patients). Grade ≥3 adverse events (≥5% of patients) in the alpelisib arm were hyperglycemia (27%), rash (12%), and maculo-papular rash (8%). The primary objective was not met; ORR in the alpelisib versus placebo arm was 43% versus 45% and 63% versus 61% in the PIK3CA-mutant and wild-type cohorts, respectively. pCR rates were low in all groups. Decreases in Ki-67 were similar across treatment arms and cohorts. In PIK3CA-mutant tumors, alpelisib plus letrozole treatment induced a greater decrease in phosphorylated AKT versus placebo plus letrozole. CONCLUSIONS: In contrast to initial results in advanced/metastatic disease, addition of alpelisib to 24-week neoadjuvant letrozole treatment did not improve response in patients with HR+ early breast cancer.

Randomized phase II study evaluating weekly oral vinorelbine versus weekly paclitaxel in estrogen receptor-positive, HER2-negative patients with advanced breast cancer (NorBreast-231 trial).

BACKGROUND: Single-agent paclitaxel and vinorelbine are recommended treatments for advanced breast cancer (ABC) non-responsive to hormone therapy and without visceral crisis. This phase II trial compared first-line oral vinorelbine versus weekly paclitaxel for ABC. METHODS: Eligible female patients had measurable locally recurrent/metastatic estrogen receptor-positive HER2-negative breast cancer and had received prior endocrine therapy (any setting) but no chemotherapy for ABC. Patients were stratified by prior taxane and visceral metastases and randomized to either oral vinorelbine 80 mg/m2 (first cycle at 60 mg/m2, escalated to 80 mg/m2 in the absence of grade 3/4 toxicity) or intravenous paclitaxel 80 mg/m2 on days 1, 8, and 15 every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was disease control rate (DCR; confirmed complete or partial response, or stable disease for ≥6 weeks). RESULTS: The 131 randomized patients had received a median of 2 prior endocrine therapies; >70% had prior (neo)adjuvant chemotherapy and 79% visceral metastases. DCR was 75.8% (95% confidence interval: 63.6-85.5%) with vinorelbine and 75.4% (63.1-85.2%) with paclitaxel. The most common grade 3/4 adverse events were neutropenia (52%), fatigue (11%), and vomiting (5%) with vinorelbine, and neutropenia (17%), dyspnea (6%), hypertension (6%), and peripheral sensory neuropathy (5%) with paclitaxel. Grade 2 alopecia occurred in 2% of vinorelbine-treated and 34% of paclitaxel-treated patients. Neither arm showed relevant global health status changes. CONCLUSION: Oral vinorelbine and paclitaxel demonstrated similar DCRs (∼75%). Safety profiles differed and, together with administration route and convenience, may influence treatment choice (EudraCT number, 2012-003530-16).

Paclitaxel With Inhibitor of Apoptosis Antagonist, LCL161, for Localized Triple-Negative Breast Cancer, Prospectively Stratified by Gene Signature in a Biomarker-Driven Neoadjuvant Trial.

PURPOSE: There are currently no targeted therapies approved for triple-negative breast cancer (TNBC). A tumor necrosis factor α ( TNFα)-based gene expression signature (GS) predictive of sensitivity to LCL161, inhibitor of apoptosis antagonist, was translated into a clinical assay and evaluated in a neoadjuvant trial. PATIENTS AND METHODS: Women with localized TNBC (T2/N0-2/M0) were prospectively stratified by GS status and randomly assigned (1:1) to receive oral LCL161 (1,800 mg once per week) and intravenous paclitaxel (80 mg/m2 once per week; combination arm) or paclitaxel alone (control arm) for 12 weeks, followed by surgery. The primary objective was to determine whether neoadjuvant LCL161 enhances efficacy of paclitaxel, defined by > 7.5% increase in the pathologic complete response (pCR, breast) rate, stratified by GS. RESULTS: Of 209 patients enrolled (207 with valid GS scores), 30.4% had GS-positive TNBC. In the GS-positive group, pCR was higher in the combination versus the control arm (38.2% v 17.2%), with 88.8% posterior probability of > 7.5% increase in pCR. However, in the GS-negative group, the pCR was lower in the combination group (5.6% v 16.4%), with 0% posterior probability of > 7.5% increase in pCR. A higher incidence of grade 3 or 4 adverse events in the combination arm included neutropenia (24.5%) and diarrhea (5.7%). Overall, 19 patients (18.1%) in the combination arm discontinued treatment because of adverse events, including pyrexia (n = 5), pneumonia (n = 4), and pneumonitis (n = 4), versus five patients (4.9%) in the control arm. CONCLUSION: This neoadjuvant trial provides evidence supporting a biomarker-driven targeted therapy approach for selected patients with GS-positive TNBC and demonstrates the utility of a neoadjuvant trial for biomarker validation and drug development, but also highlights toxicity risk. Future neoadjuvant clinical trials should carefully weigh these considerations for targeted therapy development in biomarker-defined TNBC.