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Background: Serum biomarkers have been investigated as predictive risk factors for cancer-related cardiovascular (CV) risk, but their analysis is limited to their baseline level rather than their overtime change. Besides historically validated causal factors, inflammatory and oxidative stress (OS) related markers seem to be correlated to CV events but this association needs to be further explored. We conducted an observational study to determine the predictive role of the longitudinal changes of commonly used and OS-related biomarkers during the cancer treatment period. Methods: Patients undergoing anticancer therapies, either aged 75+ years old or younger with an increased CV risk according to European Society of Cardiology guidelines, were enrolled. We assessed the predictive value of biomarkers for the onset of CV events at baseline and during therapy using Cox model, Subpopulation Treatment-Effect Pattern Plot (STEPP) method and repeated measures analysis of longitudinal data. Results: From April 2018 to August 2021, 182 subjects were enrolled, of whom 168 were evaluable. Twenty-eight CV events were recorded after a median follow up of 9.2 months (Interquartile range, IQR: 5.1-14.7). Fibrinogen and troponin levels were independent risk factors for CV events. Specifically, patients with higher than the median levels of fibrinogen and troponin at baseline had higher risk compared with patients with values below the medians, hazard ratio (HR) = 3.95, 95% CI, 1.25-12.45 and HR = 2.48, 0.67-9.25, respectively. STEPP analysis applied to Cox model showed that cumulative event-free survival at 18 and 24 months worsened almost linearly as median values of fibrinogen increased. Repeated measure analysis showed an increase over time of D-Dimer (p-interaction event*time = 0.08), systolic (p = 0.07) and diastolic (p = 0.05) blood pressure and a decrease of left ventricular ejection fraction (p = 0.15) for subjects who experienced a CV event. Conclusions: Higher levels of fibrinogen and troponin at baseline and an increase over time of D-Dimer and blood pressure are associated to a higher risk of CV events in patients undergoing anticancer therapies. The role of OS in fibrinogen increase and the longitudinal monitoring of D-dimer and blood pressure levels should be further assessed.
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PURPOSE: Data from recently trials have provided practice-changing recommendations in management of the axilla in early breast cancer (eBC). However, further controversies have been raised, resulting in heterogeneous diffusion of these recommendations. Our purpose was to obtain a better homogeneity. MATERIAL AND METHODS: In 2021, the Tuscan Breast Network (TBN) established a consensus with the aim to update recommendations in this area. We performed a literature review on axillary management in eBC patients which led to an expert Delphi consensus aiming to explore the gray areas, build consensus and propose evidence-based suggestions for an appropriate management. Thereafter, we investigate their implementation in clinical practice. RESULTS: (1) DCIS patients should have SLN biopsy only in case of mastectomy or in conservative surgery if tumor is in a location that would preclude future nodal sampling or in case of a mass; (2) ALND may be omitted for 1-2 positive SLN patients undergoing BCS in T1-2 tumors with 1-2 SLN positive, eligible for whole-breast irradiation and adjuvant systemic therapies; (3) consider the option of RNI in patients with 1-3 positive lymph nodes and one or more high-risk characteristics; (4) the population identified in 2) should NOT undergo lymph node irradiation as an alternative to axillary surgery and (5) patients with clinically (pre-operatively) positive axilla, or undergoing primary systemic therapy, or outside the criteria reported in 2) must receive additional ALND and/or RT as per local policy. CONCLUSION: This consensus provided a practical tool to stimulate local and national breast surgical and radiotherapy protocols.
Subject(s)
Axilla , Breast Neoplasms , Delphi Technique , Humans , Breast Neoplasms/pathology , Breast Neoplasms/therapy , Female , Sentinel Lymph Node Biopsy , Italy , Lymph Node Excision , Consensus , Lymphatic Metastasis , MastectomyABSTRACT
OBJECTIVE: Recurrent gynecological tumors (e.g., endometrial, and ovarian cancers) are incurable diseases; therefore, new treatment options are urgently needed. The PTEN-AKT-PI3K pathway is frequently altered in these tumors, representing a potential treatment target. Alpelisib is an α-specific PI3K inhibitor approved in PIK3CA-mutated advanced breast cancer. We report outcomes from a large series of patients with PIK3CA-mutated gynecological cancers prospectively treated with alpelisib within a controlled program. METHODS: From April 2021 to December 2022, 36 patients with PIK3CA-mutated advanced gynecological cancers received alpelisib 300 mg orally once daily. Objective response (ORR) and disease control (DCR) rates provided measure of the antitumor activity of alpelisib, the primary objective of the study. RESULTS: Included patients had endometrial (17/36 [47%]), ovarian (10/36 [28%]), or other gynecological cancers (9/36 [25%]). Most patients had received 2-3 prior systemic treatments (endometrial, 47·2%; ovarian, 60%; other, 56%), and presented with visceral metastases at baseline (82%, 70%, and 56%, respectively). Overall, 17 different PIK3CA mutations were found, including 53% in the kinase domain (most commonly H1047R) and 36% in the helical domain (most commonly E545K). Overall, the ORR was 28% and DCR was 61%, with the greatest benefit observed in patients with endometrial cancer (35% and 71%, respectively). CONCLUSION: Alpelisib represents an active treatment option in patients with recurrent gynecological cancers harboring a PIK3CA mutation. These findings support the need of biomarker-driven randomized trials of PI3K inhibitors in gynecological cancers.
Subject(s)
Class I Phosphatidylinositol 3-Kinases , Genital Neoplasms, Female , Mutation , Thiazoles , Humans , Female , Class I Phosphatidylinositol 3-Kinases/genetics , Middle Aged , Aged , Genital Neoplasms, Female/genetics , Genital Neoplasms, Female/drug therapy , Genital Neoplasms, Female/pathology , Adult , Thiazoles/therapeutic use , Thiazoles/administration & dosage , Aged, 80 and over , Endometrial Neoplasms/genetics , Endometrial Neoplasms/drug therapy , Endometrial Neoplasms/pathology , Ovarian Neoplasms/genetics , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Prospective Studies , Phosphoinositide-3 Kinase Inhibitors/therapeutic use , Phosphoinositide-3 Kinase Inhibitors/administration & dosageABSTRACT
The therapeutic landscape of estrogen receptor (ER)-positive breast cancer includes endocrine treatments with aromatase inhibitors (AIs), selective estrogen receptor modulators (SERMs), and selective estrogen receptor degraders (SERDs). Fulvestrant is the first approved SERD with proven efficacy and good tolerability in clinical practice. However, drug resistance, low receptor affinity, and parental administration stimulated the search for new oral SERDs opening a new therapeutic era in ER + breast cancer. Elacestrant is an orally bioavailable SERD that has been recently approved by the FDA for postmenopausal women with ER+, human epidermal growth factor receptor 2-negative (HER2-), estrogen receptor 1 (ESR1)-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. Other molecules of the same class currently tested in clinical trials are amcenestrant, giredestrant, camizestrant, and imlunestrant. The current review article offers a detailed pharmacological perspective of this emerging drug class, which may help with their possible future clinical applications.
Subject(s)
Breast Neoplasms , Mouth Neoplasms , Female , Humans , Breast Neoplasms/pathology , Fulvestrant , Selective Estrogen Receptor Modulators/pharmacology , Selective Estrogen Receptor Modulators/therapeutic use , Breast/pathology , Estrogen Receptor alpha/metabolism , Mouth Neoplasms/drug therapyABSTRACT
Importance: In spite of the effectiveness of endocrine therapy plus cyclin-dependent kinase (CDK) 4/6 inhibitors as the first-line treatment for estrogen receptor (ER)-positive, erb-b2 receptor tyrosine kinase 2 (ERBB2 [formerly HER2/neu])-negative (ER+/ERBB2-) metastatic breast cancer (MBC), patients eventually develop resistance, and eventually most will receive chemotherapy. The METEORA-II trial compared a metronomic all-oral treatment with intravenous (IV) chemotherapy. Objective: To compare the efficacy of the oral vinorelbine plus cyclophosphamide plus capecitabine (VEX) regimen vs weekly IV paclitaxel among patients with ER+/ERBB2- MBC who are candidates for chemotherapy. Design, Setting, and Participants: This phase 2 randomized clinical trial including 140 women 18 years and older (randomized 1:1) with ER+/ERBB2- MBC was carried out from September 13, 2017, to January 14, 2021 at 15 centers in Italy. Eligible patients could have received 1 prior line of chemotherapy for MBC and/or 2 lines of endocrine therapy (including CDK4/6 inhibitors). Interventions: In 4-week cycles, patients received either metronomic oral VEX or weekly IV paclitaxel. Main Outcomes and Measures: The primary end point was investigator-assessed time to treatment failure (TTF) defined as the interval between the date of randomization to the end of treatment (because of disease progression or lack of tolerability or because further trial treatment was declined). Secondary end points included progression-free survival (PFS), overall survival (OS), and disease control rate (complete or partial response or stable disease lasting for at least 24 weeks). Results: In total, 133 patients received either VEX (n = 70) or paclitaxel (n = 63) in 4-weekly cycles. The median age was 61 (range, 30-80) years. The VEX treatment significantly prolonged TTF vs paclitaxel (hazard ratio [HR], 0.61; 95% CI, 0.42-0.88; P = .008), median TTF was 8.3 (95% CI, 5.6-11.1) months for VEX vs 5.7 (95% CI, 4.1-6.1) months for paclitaxel, and the 12-month TTF was 34.3% for VEX vs 8.6% for paclitaxel. The median PFS was 11.1 (95% CI, 8.3-13.8) months vs 6.9 (95% CI, 5.4-10.1) months favoring VEX (HR, 0.67; 95% CI, 0.46-0.96, P = .03). The 12-month PFS was 43.5% for VEX vs 21.9% for paclitaxel. No difference in OS was found. The TF event for 55.6% of patients was progression of disease; for 23% it was AEs. More patients assigned to VEX had at least 1 grade 3 or 4 targeted adverse event (VEX, 42.9%; 95% CI, 31.1%-55.3% vs paclitaxel, 28.6%; 95% CI, 17.9%-41.3%), but essentially no alopecia. Conclusion and Relevance: This randomized clinical trial found significantly prolonged TTF and PFS for oral VEX but no improvement in OS compared with intravenous paclitaxel, despite increased but still manageable toxic effects. The VEX regimen may provide more prolonged disease control than weekly paclitaxel for ER+/ERBB2- MBC. Trial Registration: ClinicalTrials.gov Identifier: NCT02954055.
Subject(s)
Breast Neoplasms , Female , Humans , Middle Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/pathology , Capecitabine , Cyclophosphamide , Paclitaxel , Receptor, ErbB-2 , Receptors, Estrogen , Vinorelbine/adverse effects , Adult , Aged , Aged, 80 and overABSTRACT
BACKGROUND: In patients with locally advanced rectal cancer (LARC) treated with preoperative (chemo) radiotherapy and surgery, adjuvant chemotherapy is poorly feasible and its benefit is questionable. In the last years, several total neoadjuvant treatment (TNT) strategies, moving the adjuvant chemotherapy to the neoadjuvant setting, have been investigated with the aim of improving compliance to systemic chemotherapy, treating micrometastases earlier and then reducing distant recurrence. PATIENTS AND METHODS: ShorTrip (NTC05253846) is a prospective, multicentre, single-arm phase II trial where 63 patients with LARC will be treated with short-course radiotherapy followed by intensified consolidation chemotherapy with FOLFOXIRI regimen and surgery. Primary endpoint is pCR. Among the first 11 patients who started consolidation chemotherapy, a preliminary safety analysis showed a high rate of grade 3 to 4 neutropenia (N = 7, 64%) during the first cycle of FOLFOXIRI. Therefore, the protocol has been emended with the recommendation to omit irinotecan during the first cycle of consolidation chemotherapy. After amendment, in a subsequent safety analysis focused on the first 9 patients treated with FOLFOX as first cycle and then with FOLFOXIRI, grade 3 to 4 neutropenia was reported in only one case during the second cycle. AIM OF THE STUDY: The aim of this study is to assess the safety and activity of a TNT strategy including SCRT, intensified consolidation treatment with FOLFOXIRI and delayed surgery. After protocol amendment, the treatment seems feasible without safety concern. Results are expected at the end of 2024.
Subject(s)
Neutropenia , Rectal Neoplasms , Humans , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Chemoradiotherapy/methods , Consolidation Chemotherapy/methods , Neoadjuvant Therapy/methods , Prospective Studies , Rectal Neoplasms/drug therapy , Rectal Neoplasms/pathologyABSTRACT
Background Liquid biopsy is mainly used to identify tumor cells in pulmonary neoplasms. It is more often used in research than in clinical practice. The BL-MOL-AR study aims to investigate the efficacy of next-generation sequencing (NGS) and clinical interpretation of the circulating free DNA (cfDNA) levels. This study reports the preliminary results from the first samples analyzed from patients affected by various neoplasms: lung, intestinal, mammary, gastric, biliary, and cutaneous. Methods The Biopsia Liquida-Molecolare-Arezzo study aims to enroll cancer patients affected by various malignancies, including pulmonary, intestinal, advanced urothelial, biliary, breast, cutaneous, and gastric malignancies. Thirty-nine patients were included in this preliminary report. At time zero, a liquid biopsy is executed, and two types of NGS panels are performed, comprising 17 genes in panel 1, which is already used in the routine tissue setting, and 52 genes in panel 2. From the 7th month after enrollment, 10 sequential liquid biopsies are performed up to the 17th month. The variant allele frequency (%) and cfDNA levels (ng/mL) are measured in every plasmatic sample. Results The NGS results obtained by different panels are similar even though the number of mutations is more concordant for lung pathologies. There are no significant differences in the actionability levels of the identified variants. Most of the molecular profiles of liquid biopsies reflect tissue data. Conclusions Preliminary data from this study confirm the need to clarify the limitations and potential of liquid biopsy beyond the lung setting. Overall, parameters related to cfDNA levels and variant allele frequency could provide important indications for prognosis and disease monitoring.
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Cardio-oncology is now part of the standard clinical approach for patients with cancer and cannot be overlooked anymore. While its scientific background is solid and its clinical relevance is well known, its application in daily practice varies greatly among hospitals. To provide the best cardio-oncology care to cancer patients and to make cardio-oncology's clinical use uniform, we developed a shared multidisciplinary proposal for a dedicated clinical pathway. Our proposition presents the minimum requirements needed to which this path caters for, identifies patient categories to be entered into the path, highlights the role of a specific inter-hospital clinical and imaging network and indicates follow-up strategies during and after oncological treatments. The proposed pathway is based on some key elements and is easily adaptable to different hospitals with minimal changes.
Subject(s)
Cardiology , Neoplasms , Critical Pathways , Humans , Medical Oncology , Neoplasms/therapy , OutpatientsABSTRACT
Importance: Bone resorption inhibitors (BRIs) are recommended by international guidelines to prevent skeletal-related events (SREs) among patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. Abiraterone acetate with prednisone is currently the most common first-line therapy for the treatment of patients with mCRPC; however, the clinical impact of the addition of BRIs to abiraterone acetate with prednisone in this disease setting is unknown. Objective: To evaluate the association of the use of concomitant BRIs with overall survival (OS) and time to first SRE among patients with mCRPC and bone metastases receiving abiraterone acetate with prednisone as first-line therapy. Design, Setting, and Participants: This retrospective cohort study collected data from 745 consecutive patients who began receiving abiraterone acetate with prednisone as first-line therapy for mCRPC with bone metastases between January 1, 2013, and December 31, 2016. Data were collected from 8 hospitals in Canada, Europe, and the US from June 15 to September 15, 2019. Exposures: Patients were classified by receipt vs nonreceipt of concomitant BRIs and subclassified by volume of disease (high volume or low volume, using definitions from the Chemohormonal Therapy Vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer [CHAARTED] E3805 study) at the initiation of abiraterone acetate with prednisone therapy. Main Outcomes and Measures: The primary end point was OS. The secondary end point was time to first SRE. The Kaplan-Meier method and Cox proportional hazards models were used. Results: Of the 745 men (median age, 77.6 years [interquartile range, 68.1-83.6 years]; 699 White individuals [93.8%]) included in the analysis, 529 men (71.0%) received abiraterone acetate with prednisone alone (abiraterone acetate cohort), and 216 men (29.0%) received abiraterone acetate with prednisone plus BRIs (BRI cohort). A total of 420 men (56.4%) had high-volume disease, and 276 men (37.0%) had low-volume disease. The median follow-up was 23.5 months (95% CI, 19.8-24.9 months). Patients in the BRI cohort experienced significantly longer OS compared with those in the abiraterone acetate cohort (31.8 vs 23.0 months; hazard ratio [HR], 0.65; 95% CI, 0.54-0.79; P < .001). The OS benefit in the BRI cohort was greater for patients with high-volume vs low-volume disease (33.6 vs 19.7 months; HR, 0.51; 95% CI, 0.38-0.68; P < .001). The BRI cohort also had a significantly shorter time to first SRE compared with the abiraterone acetate cohort (32.4 vs 42.7 months; HR, 1.27; 95% CI, 1.00-1.60; P = .04), and the risk of a first SRE was more than double in the subgroup with low-volume disease (HR, 2.29; 95% CI, 1.57-3.35; P < .001). In the multivariable analysis, concomitant BRIs use was independently associated with longer OS (HR, 0.64; 95% CI, 0.52-0.79; P < .001). Conclusions and Relevance: In this study, the addition of BRIs to abiraterone acetate with prednisone as first-line therapy for the treatment of patients with mCRPC and bone metastases was associated with longer OS, particularly in patients with high-volume disease. These results suggest that the use of BRIs in combination with abiraterone acetate with prednisone as first-line therapy for the treatment of mCRPC with bone metastases could be beneficial.
Subject(s)
Abiraterone Acetate/standards , Bone Neoplasms/mortality , Neoplasm Metastasis/drug therapy , Prostatic Neoplasms, Castration-Resistant/drug therapy , Abiraterone Acetate/adverse effects , Abiraterone Acetate/therapeutic use , Aged , Aged, 80 and over , Bone Density Conservation Agents/adverse effects , Bone Density Conservation Agents/standards , Bone Density Conservation Agents/therapeutic use , Bone Neoplasms/drug therapy , Bone Neoplasms/epidemiology , Cohort Studies , Humans , Kaplan-Meier Estimate , Male , Prednisone/therapeutic use , Prostatic Neoplasms, Castration-Resistant/epidemiology , Prostatic Neoplasms, Castration-Resistant/mortality , Registries/statistics & numerical data , Retrospective StudiesABSTRACT
BACKGROUND: Despite endocrine therapy being the mainstay of treatment for hormone receptor positive (HR+)/HER2- metastatic breast cancer, patients at risk of visceral crisis or doubt for endocrine sensitivity are still offered first-line chemotherapy. Maintenance hormonal therapy is generally offered at the discontinuation of chemotherapy. The MAINtenance Afinitor study is a randomised, phase III trial comparing maintenance everolimus combined with aromatase inhibitors (AIs) versus AI monotherapy in patients with disease control after first-line chemotherapy. METHODS: Patients with stable disease, partial response or complete response after first-line chemotherapy were randomised to everolimus plus AIs (exemestane or letrozole or anastrozole) or to AIs alone. Primary aim was progression-free survival (PFS). Secondary aims included response rate, safety and overall survival (OS). RESULTS: In total, 110 patients were randomised to everolimus + AIs (n = 52) or to AIs (n = 58). Median PFS was 11.0 months (95% confidence interval [CI] 8.1-13.8) in the everolimus + AI arm and 7.2 months (95% CI 4.7-10.9) in the AI monotherapy arm (hazard ratio [HR] 0.71, 95% CI 0.47-1.06). Objective response rate was 22.4% in everolimus + AI arm and 19.2% in AI monotherapy arm. A higher proportion of disease progression as best response was reported in the AI monotherapy arm (28.8% versus 14.3%). Median OS was 35.7 months (95% CI 26.0-47.8) in the combination arm versus 33.5 (95% CI 26.4-42.7) in the AI alone arm (HR 1.0, 95% CI 0.61-1.62). CONCLUSIONS: EVE + AIs did not significantly impact on the outcome of metastatic breast cancer patients deemed suitable for first-line chemotherapy. Also taking into account treatment tolerability, maintenance endocrine therapy remains the standard. TRIAL REGISTRATION: EudraCT: 2013-004153-24.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Aromatase Inhibitors/administration & dosage , Breast Neoplasms/drug therapy , Everolimus/administration & dosage , Adult , Aged , Aged, 80 and over , Aromatase Inhibitors/adverse effects , Breast Neoplasms/mortality , Everolimus/adverse effects , Female , Humans , Middle AgedABSTRACT
BACKGROUND: Although the efficacy of molecularly target agents in vitro, their use in routine setting is limited mainly to the use of anti-HER2 and antiEGFR agents in vivo. Moreover, core biopsy of a single cancer site may not be representative of the whole expanding clones and cancer molecular profile at relapse may differ with respect to the primary tumor. METHODS: We assessed the status of a large panel of cancer driver genes by cell-free DNA (cfDNA) analysis in a cohort of 68 patients with 13 different solid tumors at disease progression. Whenever possible, a second cfDNA analysis was performed after a mean of 2.5 months, in order to confirm the identified clone(s) and to check the correlation with clinical evolution. RESULTS: The approach was able to identify clones plausibly involved in the disease progression mechanism in about 65% of cases. A mean of 1.4 mutated genes (range 1-3) for each tumor was found. Point mutations in TP53, PIK3CA, and KRAS and copy number variations in FGFR3 were the gene alterations more commonly observed, with a rate of 48%, 20%, 16%, and 20%, respectively. Two-points-Next-Generation Sequencing (NGS) analysis demonstrated statistically significant correlation between allele frequency variation and clinical outcome (P = .026). CONCLUSIONS: Irrespective of the primary tumor mutational burden, few mutated genes are present at disease progression. Clinical outcome is consistent with variation of allele frequency of specific clones indicating that cfDNA two-point-NGS analysis of cancer driver genes could be an efficacy tool for precision oncology.
Subject(s)
Biomarkers, Tumor/genetics , Circulating Tumor DNA/genetics , DNA Mutational Analysis , High-Throughput Nucleotide Sequencing , Neoplasms/diagnosis , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/blood , Child , Child, Preschool , Circulating Tumor DNA/blood , Clonal Evolution , DNA Copy Number Variations , Disease Progression , Feasibility Studies , Female , Follow-Up Studies , Humans , Infant , Male , Middle Aged , Mutation , Neoplasms/blood , Neoplasms/genetics , Neoplasms/therapy , Point Mutation , Precision Medicine/methods , Prospective Studies , Young AdultABSTRACT
BACKGROUND: Subcutaneous trastuzumab (H SC) is a valuable alternative to the intravenous formulation. This study assessed H SC safety and tolerability in human epidermal growth factor receptor 2 (HER2)+ early/locally advanced breast cancer (EBC/LABC). METHODS: SCHEARLY is a prospective, two-cohort, non-randomised, multicentre Italian trial included in the umbrella study UmbHER1, planning a 1-year treatment with H SC 600 mg in HER2+ EBC/LABC. Patients were sequentially assigned to cohort A (N = 121) and B (N = 119) to receive H SC via a handheld syringe and a single-use injection device, respectively. Adjuvant or neoadjuvant treatment included anthracycline-containing regimens followed by H SC plus taxanes and then alone for 18 cycles totally. RESULTS: Two hundred forty patients were enrolled (adjuvant therapy: 81.7%; neoadjuvant therapy: 18.3%), and 201 completed the treatment (early discontinuation was mainly due to intercurrent adverse events [AEs], 7.5%). Overall, the two cohorts displayed similar safety profiles. From H SC start, the rate of treatment-related AEs in the safety population (N = 228) was 3.9% for grade ≥3 AEs; 0.9% for serious AEs (one pleuropericarditis and one anaphylactic shock, both resolved) and 14.5% for cardiac AEs, the most common being the decreased left ventricular ejection fraction (7.9%; mean reduction from the screening to the follow-up visit was 2.9%). No cases of congestive heart failure occurred. The rate of systemic administration-related reactions and local injection site reactions was 68.0% and 21.9%, respectively, mostly of grade 1-2. CONCLUSIONS: H SC 600 mg confirmed to be a safe and tolerable option as adjuvant/neoadjuvant therapy in patients with HER2+ EBC and LABC. CLINICALTRIALS. GOV IDENTIFIER: NCT01940497.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents, Immunological/adverse effects , Breast Neoplasms/drug therapy , Chemotherapy, Adjuvant , Genes, erbB-2 , Heart Diseases/chemically induced , Molecular Targeted Therapy , Neoadjuvant Therapy , Trastuzumab/adverse effects , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cyclophosphamide/administration & dosage , Docetaxel/administration & dosage , Doxorubicin/administration & dosage , Female , Fluorouracil/administration & dosage , Follow-Up Studies , Humans , Injections, Subcutaneous , Middle Aged , Neoplasm Invasiveness , Paclitaxel/administration & dosage , Prospective Studies , Receptor, ErbB-2/analysis , Receptor, ErbB-2/genetics , Stroke Volume , Trastuzumab/administration & dosageABSTRACT
OBJECTIVES:: Never-smokers may be a distinct subgroup among patients with advanced non-small cell lung cancer, appearing to benefit less from immunotherapy than smokers. We report results from never-smokers enrolled in the Italian cohort of the nivolumab expanded access program in pre-treated patients with advanced squamous non-small cell lung cancer. MATERIALS AND METHODS:: Nivolumab (3 mg/kg every 2 weeks for ≤24 months) was available on physician request. Efficacy data included objective tumor response, date of progression, and survival information. Safety was monitored. RESULTS:: Overall, 371 patients received at least one dose of nivolumab, including 31 never-smokers (8%). Objective response rate, disease-control rate, and median overall survival were 23%, 45%, and 12.1 months (95% confidence interval: 3.7-20.4), respectively, in never-smokers, and 18%, 47%, and 7.9 months (95% confidence interval: 6.2-9.6), respectively, in the overall expanded access program population. Any-grade and grade 3-4 treatment-related adverse events were reported in 12 (39%) and 3 (10%) never-smokers, respectively, and in 109 (29%) and 21 (6%) patients, respectively, in the overall expanded access program population. Grade 3-4 treatment-related adverse events in non-smokers were increased transaminases (n = 2; 6%) and diarrhea (n = 1; 3%). Treatment-related adverse events led to treatment discontinuation in 4 non-smokers (17%) and in 26 patients (9%) overall. CONCLUSION:: Pre-treated never-smokers with advanced squamous non-small cell lung cancer in this Italian expanded access program demonstrated efficacy and safety that were consistent with those in the overall expanded access program population and clinical trials. These results suggest that a proportion of never-smoker patients with squamous non-small cell lung cancer may be responsive to immunotherapy. Other factors, such as the tumor mutational load and the status of programmed death-ligand 1, anaplastic lymphoma kinase, and epidermal growth factor receptor, might play a potential key role.
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Squamous Cell/drug therapy , Health Services Accessibility , Lung Neoplasms/drug therapy , Nivolumab/therapeutic use , Non-Smokers/statistics & numerical data , Adult , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Squamous Cell/pathology , Case-Control Studies , Cohort Studies , Disease Progression , Female , Follow-Up Studies , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Prognosis , Survival RateABSTRACT
BACKGROUND: Results from phase III clinical trial CheckMate 025 have established nivolumab as the standard of care for treatment of metastatic renal-cell carcinoma (mRCC) after VEGF inhibitor failure; however, elderly patients are under-represented in the registration trial and little is known about the activity of nivolumab in this subgroup. The purpose of the Expanded Access Program was to provide nivolumab to patients with mRCC who had progressed despite treatment with other agents that were considered standard of care. METHODS: Nivolumab 3 mg/kg was administered intravenously every 2 weeks to a maximum of 24 months or until progression or unacceptable toxicity. The current analysis included all patients from the EAP Italian cohort who had received ≥1 dose of nivolumab. Adverse events (AEs) were monitored using Common Terminology Criteria for Adverse Events v4.0. RESULTS: A total of 389 patients with advanced RCC were enrolled in the Italian cohort of the EAP and treated with nivolumab. Of these patients, 125 (32%) were at least 70 years of age and 70 (18%) were at least 75 years of age. Efficacy with nivolumab in the elderly patients was similar to that observed in the overall EAP population and in the CheckMate 025 trial. Safety was comparable between the elderly patients and the overall EAP population, and was consistent with what previously reported. CONCLUSION: The final results suggest that elderly patients with pretreated metastatic RCC may benefit from therapy with nivolumab.
Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/pathology , Kidney Neoplasms/drug therapy , Kidney Neoplasms/pathology , Nivolumab/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/adverse effects , Carcinoma, Renal Cell/mortality , Female , Humans , Italy , Kidney Neoplasms/mortality , Male , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Nivolumab/administration & dosage , Nivolumab/adverse effects , Retreatment , Survival Analysis , Treatment OutcomeABSTRACT
INTRODUCTION: Nivolumab is the first checkpoint inhibitor approved for the treatment of nonsquamous NSCLC. We report results from the nivolumab Italian expanded access program focusing on never-smokers and patients with EGFR-mutant nonsqamous NSCLC. METHODS: Nivolumab (3 mg/kg intravenously every 2 weeks) was administered upon physicians' request to patients who had relapsed after one or more prior systemic treatments for stage IIIB/IV nonsquamous NSCLC. Efficacy and safety were evaluated in patients who received at least one dose of nivolumab. RESULTS: Of 1588 patients with nonsquamous NSCLC, 305 (19.2%) were never-smokers. EGFR status was available for 1395 patients. Of the 102 patients (6.4%) with EGFR mutation-positive tumors, 51 (50%) were never-smokers. The objective response rate was significantly higher in patients with wild-type EGFR than patients with EGFR-mutant tumors (19.6% versus 8.8% [p = 0.007]), in former and current smokers than in never-smokers (21.5% versus 9.2% [p = 0.0001]), and in never-smokers with wild-type EGFR than in never-smokers with mutant EGFR (11.0% versus 1.9% [p = 0.04]). There was no significant difference in objective response rate between smokers with wild-type EGFR and smokers with mutant EGFR (22.0% versus 20.6%). There was no statistically significant difference in median progression-free survival or in median overall survival. The median overall survival times were 11 months in patients with EGFR wild-type tumors versus 8.3 months in patients with EGFR-mutant tumors, 11.6 months in smokers versus 10.0 months in never-smokers, 11.0 months in never-smokers with EGFR wild-type tumors versus 5.6 months in never-smokers with EGFR-mutant tumors, and 14.1 months in smokers with EGFR-mutant tumors versus 11.3 months in smokers with EGFR wild-type tumors. CONCLUSIONS: The data on the Italian expanded access program in populations with nonsquamous NSCLC suggest that subgroups of patients could benefit differently from nivolumab according to their EGFR mutational status and smoking habits. These results warrant further investigation.
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Mutation , Nivolumab/therapeutic use , Adult , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/pathology , ErbB Receptors/genetics , Female , Humans , Italy , Lung Neoplasms/pathology , Male , Middle Aged , Nivolumab/pharmacology , Non-SmokersABSTRACT
Over the years, thanks to the addition of new generation systemic agents, as well as the use of more advanced and precise radiotherapy techniques, it was able to obtain a high curability rate for breast cancer. Anthracyclines play a key role in the treatment of breast disease, with a well-known benefit on disease-free survival of patients with positive nodal status. Trastuzumab have shown a significant outcome advantage after 1-year administration in case of HER2-positive disease. Unfortunately, significant increase in cardiotoxicity has been observed after anthracyclines and trastuzumab therapies. Even though the cardiology and oncology community strongly recommend a cardiotoxicity prevention strategy for this subset of patients, there is still no consensus on the optimal patient's approach. We aimed to review the published and ongoing researches on cardioprevention strategies and to present the SAFE trial (CT registry ID: NCT2236806; EudraCT number: 2015-000914-23). It is a randomized phase 3, four-arm, single-blind, placebo-controlled study that aims to evaluate the effect of bisoprolol, ramipril or both drugs, compared to placebo, on subclinical heart damage evaluated by speckle tracking cardiac ultrasound in non-metastatic breast cancer patients.
Subject(s)
Anthracyclines/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/drug therapy , Cardiotonic Agents/therapeutic use , Cardiotoxicity/prevention & control , Trastuzumab/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bisoprolol/therapeutic use , Clinical Trials, Phase III as Topic , Female , Humans , Ramipril/therapeutic use , Randomized Controlled Trials as Topic , Trastuzumab/administration & dosageABSTRACT
The aim of this retrospective study was to assess toxicity and efficacy of adjuvant high-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation (AHSCT) in 583 high-risk breast cancer (BC) patients (>3 positive nodes) who were transplanted between 1995 and 2005 in Europe. All patients received surgery before transplant, and 55 patients (9.5%) received neoadjuvant treatment before surgery. Median age was 47.1 years, 57.3% of patients were premenopausal at treatment, 56.5% had endocrine-responsive tumors, 19.5% had a human epidermal growth factor receptor 2 (HER2)-negative tumor, and 72.4% had ≥10 positive lymph nodes at surgery. Seventy-nine percent received a single HDC procedure. Overall transplant-related mortality was 1.9%, at .9% between 2001 and 2005, whereas secondary tumor-related mortality was .9%. With a median follow-up of 120 months, overall survival and disease-free survival rates at 5 and 10 years in the whole population were 75% and 64% and 58% and 44%, respectively. Subgroup analysis demonstrated that rates of overall survival were significantly better in patients with endocrine-responsive tumors, <10 positive lymph nodes, and smaller tumor size. HER2 status did not affect survival probability. Adjuvant HDC with AHSCT has a low mortality rate and provides impressive long-term survival rates in patients with high-risk BC. Our results suggest that this treatment modality should be considered in selected high-risk BC patients and further investigated in clinical trials.
Subject(s)
Breast Neoplasms/mortality , Breast Neoplasms/therapy , Hematopoietic Stem Cell Transplantation , Adult , Aged , Autografts , Chemotherapy, Adjuvant/methods , Disease-Free Survival , Europe/epidemiology , Female , Humans , Middle Aged , Registries , Survival RateABSTRACT
The efficacy of high-dose chemotherapy (HDC) and autologous hemopoietic progenitor cell transplantation (AHPCT) for breast cancer (BC) patients has been an area of intense controversy among the medical oncology community. The aim of this study was to assess toxicity and efficacy of this procedure in a large cohort of high-risk primary BC patients who underwent AHPCT in Italy. A total of 1183 patients receiving HDC for high-risk BC (HRBC) (>3 positive nodes) were identified in the Italian registry. The median age was 46 years, 62% of patients were premenopausal at treatment, 60.1% had endocrine-responsive tumors, and 20.7% had a human epidermal growth factor receptor 2 (HER2)-positive tumor. The median number of positive lymph nodes (LN) at surgery was 15, with 71.5% of patients having ≥ 10 positive nodes. Seventy-three percent received an alkylating agent-based HDC as a single procedure, whereas 27% received epirubicin or mitoxantrone-containing HDC, usually within a multitransplantation program. The source of stem cells was peripheral blood in the vast majority of patients. Transplantation-related mortality was .8%, whereas late cardiac and secondary tumor-related mortality were around 1%, overall. With a median follow-up of 79 months, median disease-free and overall survival (OS) in the entire population were 101 and 134 months, respectively. Subgroup analysis demonstrated that OS was significantly better in patients with endocrine-responsive tumors and in patients receiving multiple transplantation procedures. HER2 status did not affect survival probability. The size of the primary tumor and number of involved LN negatively affected OS. Adjuvant HDC with AHPCT has a low mortality rate and provides impressive long-term survival rates in patients with high-risk primary BC. Our results suggest that this treatment modality should be proposed in selected HRBC patients and further investigated in clinical trials.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Breast Neoplasms/therapy , Peripheral Blood Stem Cell Transplantation , Registries , Adult , Aged , Antineoplastic Agents, Alkylating/administration & dosage , Breast Neoplasms/immunology , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Drug Administration Schedule , Epirubicin/administration & dosage , Female , Gene Expression , Humans , Italy , Lymphatic Metastasis , Middle Aged , Mitoxantrone/administration & dosage , Receptor, ErbB-2/genetics , Receptor, ErbB-2/immunology , Risk , Survival Analysis , Transplantation, AutologousABSTRACT
PURPOSE: Dasatinib is a potent, oral SRC-family kinase inhibitor with preclinical antiproliferative, antimetastatic, and antiosteoclastic activity suggesting dasatinib sensitivity in triple-negative, or basal-like, breast cancer cell lines. This phase 2 trial assessed efficacy and safety of single-agent dasatinib in patients with advanced triple-negative breast cancer (TNBC). EXPERIMENTAL DESIGN: Female patients with measurable, locally advanced or metastatic TNBC initially received dasatinib 100 mg twice daily (BID); to improve tolerability, the protocol was amended and subsequent patients received 70 mg BID. Primary endpoint was Response Evaluation Criteria in Solid Tumors-defined objective response rate (ORR); secondary endpoints included progression-free survival (PFS), disease control rate (DCR), safety, and limited pharmacokinetics. RESULTS: Of the 44 treated patients, 43 were response evaluable. ORR was 4.7%: two patients had confirmed partial responses lasting 14 and 58 weeks, respectively. Of 11 patients with stable disease, two continued for more than 16 weeks, thus protocol-defined DCR was 9.3%. Median PFS was 8.3 weeks (95% CI: 7.3-15.3). Five patients discontinued before first tumor assessment. No grade 4 adverse events (AE) were reported; grade 3 AEs occurring in more than 5% of patients were fatigue (9.1%), diarrhea, pleural effusion, and dyspnea (all 6.8%). Laboratory abnormalities were uncommon. Dasatinib at 100 mg BID was not well tolerated; rates of treatment interruption, dose reduction, and serious AEs were lower with dasatinib 70 mg BID. CONCLUSIONS: Single-agent dasatinib has limited activity in unselected patients with TNBC. Dasatinib 70 mg BID was better tolerated than 100 mg BID. Future studies will investigate dasatinib in other breast cancer settings, including chemotherapy combinations.
Subject(s)
Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Thiazoles/therapeutic use , Administration, Oral , Adult , Aged , Dasatinib , Female , Humans , Middle Aged , Protein Kinase Inhibitors/adverse effects , Pyrimidines/adverse effects , Receptor, ErbB-2/biosynthesis , Receptors, Estrogen/biosynthesis , Receptors, Progesterone/biosynthesis , Thiazoles/adverse effects , src-Family Kinases/antagonists & inhibitors , src-Family Kinases/metabolismABSTRACT
Triple-negative breast cancer (TNBC) has been recently recognized as an important subgroup of breast cancer with a distinct outcome and therapeutic approach compared with other breast cancer subgroups. Because TNBC is defined by the absence of a target (either hormone receptors or HER-2), conventional cytotoxic therapy is still the mainstay of treatment. This report focuses on the current state and recent advances in managing TNBC.