ABSTRACT
BACKGROUND: Endocrine therapy (ET)-based regimens are the mainstay of treatment for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer. With the introduction of new treatment classes, it is important to examine patient symptoms and health-related quality of life (HRQoL) at the start of this changing therapeutic landscape. This real-world study describes the patient-reported outcomes (PROs) of women with HR+/HER2- advanced breast cancer receiving ET-based regimens who were naïve to systemic treatment in the advanced setting across five European countries (EU5). METHODS: Data were collected between March and July 2017 from surveyed oncologists and their patients at a single time point using the multinational Adelphi Advanced Breast Cancer Disease Specific Programme™. Patients completed PRO questionnaires on HRQoL (EORTC QLQ-C30), pain severity and interference, and work and activity impairment. A multiple linear regression model explored factors associated with HRQoL. RESULTS: Across EU5, 226 physicians provided data on 781 women with HR+/HER2- advanced breast cancer taking their first ET-based regimen for advanced disease, of whom 252 provided PRO data. This subset had a mean age of 67.1 years, 94% were postmenopausal, 89% were diagnosed with advanced breast cancer at initial presentation, 79% had stage IV disease (66% of these patients had bone metastases and 38% had visceral metastases, including 18% with liver metastases) and 77% were on endocrine-only therapy as their initial treatment for advanced disease. The mean EORTC QLQ-C30 global health score (50.9) was worse than the reference value for patients with advanced breast cancer (60.2). Fatigue, pain, and insomnia were the most severe symptoms, and mean functioning scores were also worse than reference values. "Worst pain" and "pain interference" were moderate/severe for 42 and 80% of patients. Mean activity impairment was 44%, and greater activity impairment was associated with poorer HRQoL. CONCLUSIONS: Despite receiving first-line ET-based regimens for advanced disease, these women had a poor HRQoL and high levels of symptoms, pain, pain interference and activity impairment. New treatments that maintain a stable disease state and reduce activity impairment may have a positive effect on the HRQoL of those living with advanced breast cancer.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Bone Neoplasms/drug therapy , Breast Neoplasms/drug therapy , Liver Neoplasms/drug therapy , Adult , Aged , Bone Neoplasms/pathology , Bone Neoplasms/secondary , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Europe/epidemiology , Female , Humans , Liver Neoplasms/pathology , Liver Neoplasms/secondary , Middle Aged , Patient Reported Outcome Measures , Quality of Life , Receptor, ErbB-2/genetics , Surveys and QuestionnairesABSTRACT
The addition of CDK4 and 6 inhibitors (abemaciclib, palbociclib or ribociclib) to endocrine therapy, as first-line treatment or following progression after initial endocrine therapy, significantly increased progression-free survival, objective response rates and in some trials overall survival, compared with endocrine therapy alone in HR+ and HER2- breast metastatic breast cancer. These CDK4 and 6 inhibitors are now approved in this context and have become a new standard of care. A hypothesis-generating exploratory analysis suggested that the addition of abemaciclib to endocrine therapy showed the largest effects in subgroups of women with indicators of poor prognosis, although these data require confirmation. This review provides updated clinical trial data for all three drugs in metastatic breast cancer, focusing on abemaciclib, the most recently approved agent.
Subject(s)
Aminopyridines/therapeutic use , Benzimidazoles/therapeutic use , Breast Neoplasms/drug therapy , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Protein Kinase Inhibitors/therapeutic use , Aminopyridines/pharmacology , Benzimidazoles/pharmacology , Biomarkers, Tumor , Breast Neoplasms/etiology , Breast Neoplasms/metabolism , Breast Neoplasms/mortality , Female , Humans , Molecular Targeted Therapy , Prognosis , Protein Kinase Inhibitors/pharmacology , Treatment OutcomeABSTRACT
BACKGROUND: The current exploratory analysis was performed to evaluate the efficacy and safety of everolimus for treatment of human epidermal growth factor receptor 2-positive (HER2+) advanced breast cancer in the Asian subset of patients in the BOLERO-1 trial. METHODS: Postmenopausal women with HER2+ advanced breast cancer, who had not received systemic therapy for advanced disease, were randomized 2:1 to receive everolimus or placebo, plus trastuzumab and paclitaxel. The two primary end points were investigator-assessed progression-free survival (PFS) in the full population and in the hormone receptor-negative (HR-) subpopulation. Secondary end points included assessment of the objective response rate, the clinical benefit rate, and safety. RESULTS: In the Asian subset, median PFS was similar in the everolimus (n = 198) and placebo (n = 105) arms in the full analysis set (hazard ratio = 0.82 (95% CI 0.61-1.11)). In the HR- subpopulation, everolimus prolonged median PFS by 10.97 months vs placebo (25.46 vs 14.49 months; hazard ratio = 0.48 (95% CI 0.29-0.79)). In the everolimus arm of the Asian subset, the most common adverse events of any grade were stomatitis (62.2%), diarrhea (48.0%), rash (43.4%) and neutropenia (42.3%). Neutropenia (grade 3: 27.6%; grade 4: 4.6%) and decreased neutrophil count (grade 3: 11.2%; grade 4: 3.6%) were the most frequent grade 3/4 adverse events. Serious adverse events included pneumonia (5.1%), pneumonitis (3.1%), and interstitial lung disease (3.1%). There were three deaths (1.5%) during treatment in the everolimus arm vs none in the placebo arm. CONCLUSIONS: The efficacy and safety of everolimus plus trastuzumab and paclitaxel as first-line treatment for HER2+ advanced breast cancer in the Asian subset was consistent with that reported previously in the overall population. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00876395 . Registered on 2 April 2009.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/metabolism , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Everolimus/administration & dosage , Female , Humans , Kaplan-Meier Estimate , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Paclitaxel/administration & dosage , Proportional Hazards Models , Receptor, ErbB-2/metabolism , Retreatment , Trastuzumab/administration & dosage , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: The current analysis was performed to evaluate the impact of PIK3CA hotspot mutations on everolimus efficacy in BOLERO-2 participants, using cell-free DNA (cfDNA) from plasma samples collected at the time of patient randomisation. METHODS: PIK3CA H1047R, E545K, and E542K mutations in plasma-derived cfDNA were analysed by droplet digital PCR (ddPCR). Median PFS was estimated for patient subgroups defined by PIK3CA mutations in each treatment arm. RESULTS: Among 550 patients included in cfDNA analysis, median PFS in everolimus vs placebo arms was similar in patients with tumours that had wild-type or mutant PIK3CA (hazard ratio (HR), 0.43 and 0.37, respectively). Everolimus also prolonged median PFS in patients with PIK3CA H1047R (HR, 0.37) and E545K/E542K mutations (HR=0.30) with a similar magnitude. CONCLUSIONS: Mutation analysis of plasma-derived cfDNA by ddPCR suggests that PFS benefit of everolimus was maintained irrespective of PIK3CA genotypes, consistent with the previous analysis of archival tumour DNA by next-generation sequencing.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/genetics , Breast Neoplasms/genetics , DNA, Neoplasm/blood , DNA, Neoplasm/genetics , Mutation/genetics , Phosphatidylinositol 3-Kinases/genetics , Androstadienes/administration & dosage , Biomarkers, Tumor/blood , Biomarkers, Tumor/metabolism , Breast Neoplasms/blood , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cell-Free System , Class I Phosphatidylinositol 3-Kinases , DNA Mutational Analysis , Everolimus/administration & dosage , Female , Follow-Up Studies , Humans , Immunoenzyme Techniques , Neoplasm Metastasis , Neoplasm Staging , Prognosis , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Survival RateABSTRACT
The present exploratory analysis examined the efficacy, safety, and quality-of-life effects of everolimus (EVE) + exemestane (EXE) in the subgroup of patients in BOLERO-2 whose last treatment before study entry was in the (neo)adjuvant setting. In BOLERO-2, patients with hormone-receptor-positive (HR(+)), human epidermal growth factor receptor-2-negative (HER2(-)) advanced breast cancer recurring/progressing after a nonsteroidal aromatase inhibitor (NSAI) were randomly assigned (2:1) to receive EVE (10 mg/day) + EXE (25 mg/day) or placebo (PBO) + EXE. The primary endpoint was progression-free survival (PFS) by local assessment. Overall, 137 patients received first-line EVE + EXE (n = 100) or PBO + EXE (n = 37). Median PFS by local investigator assessment nearly tripled to 11.5 months with EVE + EXE from 4.1 months with PBO + EXE (hazard ratio = 0.39; 95 % CI 0.25-0.62), while maintaining quality of life. This was confirmed by central assessment (15.2 vs 4.2 months; hazard ratio = 0.32; 95 % CI 0.18-0.57). The marked PFS improvement in patients receiving EVE + EXE as first-line therapy for disease recurrence during or after (neo)adjuvant NSAI therapy supports the efficacy of this combination in the first-line setting. Furthermore, the results highlight the potential benefit of early introduction of EVE + EXE in the management of HR(+), HER2(-) advanced breast cancer in postmenopausal patients.
Subject(s)
Androstadienes/administration & dosage , Breast Neoplasms/drug therapy , Neoplasms, Hormone-Dependent/drug therapy , Sirolimus/analogs & derivatives , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Clinical Trials as Topic , Disease-Free Survival , Everolimus , Female , Humans , Kaplan-Meier Estimate , Middle Aged , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology , Neoplasms, Hormone-Dependent/genetics , Neoplasms, Hormone-Dependent/pathology , Receptors, Estrogen/genetics , Receptors, Progesterone/genetics , Sirolimus/administration & dosageABSTRACT
MUC1 over-expression in renal clear-cell carcinoma (RCC) is associated with poor prognosis. This phase II study determined the efficacy and tolerability of TG4010, a cancer vaccine based on a modified vaccinia virus expressing MUC1 and interleukin-2, in combination with cytokines, as first-line therapy in metastatic RCC. Thirty-seven patients with progressive, MUC1-positive RCC received TG4010 10(8) pfu/inj weekly for 6 weeks, then every 3 weeks until progression, when TG4010 was continued in combination with interferon-α2a and interleukin-2. Assessments included clinical response (primary endpoint), safety, time to treatment failure (TTF), overall survival (OS), and immune response. No objective clinical responses occurred. Five of the 27 evaluable patients (18%) had stable disease for >6 months with TG4010 alone and six of 20 patients (30%) had stable disease for >6 months with TG4010 plus cytokines. Median TTF was 4.1, 3.6, and 9.3 months for monotherapy, combination therapy, and overall, respectively. Median OS was 19.3 months for all patients and 22.4 months combination therapy recipients. The most frequent TG4010-related adverse events were minor-to-moderate injection-site reactions, fatigue, and flu-like symptoms. Six of 28 patients showed a MUC1 CD4+ T cell proliferative response during therapy. Anti-MUC1 CD8+ T cells were detected before and after therapy in 3 and 4 patients, respectively. MUC1-specific CD8+ T cell responses were associated with longer survival. Therapy with TG4010 plus cytokines appears to be feasible and well tolerated in patients with metastatic RCC. However, these data should be interpreted with caution, as additional prospective studies are necessary to clarify the clinical efficacy of this therapy.
Subject(s)
Cancer Vaccines/immunology , Cancer Vaccines/therapeutic use , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/therapy , Cytokines/immunology , Cytokines/therapeutic use , Kidney Neoplasms/pathology , Kidney Neoplasms/therapy , Membrane Glycoproteins/immunology , Membrane Glycoproteins/therapeutic use , Adolescent , Adult , Aged , Cancer Vaccines/administration & dosage , Carcinoma, Renal Cell/immunology , Cell Proliferation , Cytokines/administration & dosage , Disease Progression , Drug-Related Side Effects and Adverse Reactions , Female , Humans , Kidney Neoplasms/immunology , Male , Membrane Glycoproteins/administration & dosage , Middle Aged , Mucin-1/biosynthesis , Mucin-1/immunology , Neoplasm Metastasis/pathology , Neoplasm Metastasis/therapy , Treatment Outcome , Young AdultABSTRACT
OBJECTIVE: This phase II investigated efficacy and tolerability of gefitinib in combination with paclitaxel (P) and carboplatin (C) for second-line treatment of patients (pts) with ovarian, tubal or peritoneal adenocarcinoma. PATIENTS AND METHODS: Women (>18 years) with platinum-resistant/refractory (relapsed<6 months), or platinum-sensitive (relapsed >6 months) disease after first-line platinum-based and P chemotherapy. Pts received 6-8 cycles of gefitinib (500 mg/day), P (175 mg/m(2) 3 h infusion) and C (AUC 5) every 3 weeks, followed by gefitinib alone. The primary endpoint was objective response rate (ORR) (RECIST or Rustin criteria). RESULTS: Sixty-eight patients (26 resistant/refractory and 42 sensitive) were enrolled (median age: 57 years). ORR and disease control rates were 19.2% and 69.2% for resistant/refractory, and 61.9% and 81.0%, for sensitive disease. Median time to progression and overall median survivals were 6.1 and 16.9 months for resistant/refractory and 9.2 and 25.7 months for sensitive disease. Grade 3/4 toxicities (in > or = 10% patients) were neutropenia (59%), diarrhea (25%), leukopenia (22%), anemia (13%), and acne (13%). Two secondary myelodysplastic syndromes (MDS) and one secondary acute leukemia occurred during treatment, and one MDS 34 months after treatment discontinuation. CONCLUSION: Gefitinib, administered in combination with paclitaxel and carboplatin, provides a good clinical response but associated with an increased risk of hematologic disorders.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Fallopian Tube Neoplasms/drug therapy , Ovarian Neoplasms/drug therapy , Peritoneal Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin/administration & dosage , Carboplatin/adverse effects , Disease-Free Survival , Female , Gefitinib , Humans , Middle Aged , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Quinazolines/administration & dosage , Quinazolines/adverse effectsABSTRACT
Many genomic abnormalities have been identified in various subsets of prostate cancer, but until now, few genes have been associated with the progression of this cancer. High activity of protein serine/threonine kinase CK2 has been observed in various solid tumours and this alteration has been linked both to growth-related functions and to suppression of cellular apoptosis. Here, we provide the first evidence for a strong association between a nuclear localization of CK2alpha, evaluated by immunohistochemistry, and poor prognostic factors in a retrospective cohort of 131 human prostate adenocarcinomas. Nuclear CK2alpha localization is significantly correlated with higher Gleason score, more locally advanced disease (cT3-T4) and more perineural or lymphatic invasion (p<0.0019 to 0.046). In contrast, despite a strong trend, no significant relationship was found between higher initial PSA and nuclear CK2alpha localization. Thus, this previously undescribed molecular heterogeneity is the first step in defining CK2 as both a potential biomarker and a promising target in human prostate cancer.
Subject(s)
Casein Kinase II/metabolism , Neoplasm Proteins/metabolism , Prostate/pathology , Prostatic Neoplasms/metabolism , Aged , Aged, 80 and over , Biopsy , Blotting, Western , Catalytic Domain , Humans , Immunohistochemistry , Male , Middle Aged , Prognosis , RNA, Small Interfering/metabolismABSTRACT
Purpose This two-part, first-in-human study was initiated in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors (FGFRs) to determine the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), and the schedule, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of oral BGJ398, a selective FGFR1-3 tyrosine kinase inhibitor. Patients and Methods Adult patients were treated with escalating dosages of BGJ398 5 to 150 mg once daily or 50 mg twice daily continuously in 28-day cycles. During expansion at the MTD, patients with FGFR1-amplified squamous cell non-small-cell lung cancer (sqNSCLC; arm 1) or other solid tumors with FGFR genetic alterations (mutations/amplifications/fusions) received BGJ398 daily on a continuous schedule (arm 2), or on a 3-weeks-on/1-week-off schedule (arm 3). Results Data in 132 patients from the escalation and expansion arms are reported (May 15, 2015, cutoff). The MTD, 125 mg daily, was determined on the basis of dose-limiting toxicities in four patients (100 mg, grade 3 aminotransferase elevations [n = 1]; 125 mg, hyperphosphatemia [n = 1]; 150 mg, grade 1 corneal toxicity [n = 1] and grade 3 aminotransferase elevations [n = 1]). Common adverse events in patients treated at the MTD (n = 57) included hyperphosphatemia (82.5%), constipation (50.9%), decreased appetite (45.6%), and stomatitis (45.6%). A similar safety profile was observed using the 3-weeks-on/1-week-off schedule (RP2D). However, adverse event-related dose adjustments/interruptions were less frequent with the 3-weeks-on/1-week-off (50.0%) versus the continuous (73.7%) schedule. Antitumor activity (seven partial responses [six confirmed]) was demonstrated with BGJ398 doses ≥ 100 mg in patients with FGFR1-amplified sqNSCLC and FGFR3-mutant bladder/urothelial cancer. Conclusion BGJ398 at the MTD/RP2D had a tolerable and manageable safety profile and showed antitumor activity in several tumor types, including FGFR1-amplified sqNSCLC and FGFR3-mutant bladder/urothelial cancers.
Subject(s)
Antineoplastic Agents/administration & dosage , Phenylurea Compounds/administration & dosage , Pyrimidines/administration & dosage , Receptors, Fibroblast Growth Factor/genetics , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Antineoplastic Agents/blood , Antineoplastic Agents/pharmacokinetics , Female , Humans , Hyperphosphatemia/chemically induced , Male , Maximum Tolerated Dose , Middle Aged , Phenylurea Compounds/adverse effects , Phenylurea Compounds/blood , Phenylurea Compounds/pharmacokinetics , Pyrimidines/adverse effects , Pyrimidines/blood , Pyrimidines/pharmacokineticsABSTRACT
Neuroendocrine differentiation can be identified in a subset of human breast carcinomas, either as scattered cells or as a predominant neuroendocrine component. We report a case of an invasive breast carcinoma largely composed of neuroendocrine cells. Eight years after a left mammary lumpectomy for a pT2N1MO SBR III invasive ductal carcinoma, a 67-years-old woman presented with a metastastic neuroendocrine sternal mass. To establish a relationship between mammary carcinoma and bone metastasis, histological slides of both the breast tumor and axillary lymph nodes were reviewed, and an immunohistochemical study was performed. They showed that: a) the mammary carcinoma was composed of a majority of small and large neuroendocrine cells synaptophysin +, NCAM+, chromogranin - (80%), associated with 2 other differentiated non endocrine components, one of metaplastic squamous carcinoma (10%) and the other of ductal carcinoma (10%); b) 4 axillary lymph nodes were involved by the ductal component which contained few NCAM + but synaptophysin - cells; c) Estrogen and progesterone receptors and HER2 were negative in the breast tumor and the metastatic nodes. We discuss the histogenesis of composite mammary carcinomas with neuroendocrine differentiation, the outcome of each component and the prognostic relevance of such a diagnosis.
Subject(s)
Bone Neoplasms/secondary , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/pathology , Carcinoma, Neuroendocrine/secondary , Neoplastic Stem Cells/pathology , Sternum/pathology , Biomarkers, Tumor/analysis , Bone Neoplasms/chemistry , Breast Neoplasms/chemistry , Breast Neoplasms/drug therapy , Breast Neoplasms/radiotherapy , Breast Neoplasms/surgery , Carcinoma, Ductal, Breast/chemistry , Carcinoma, Neuroendocrine/chemistry , Carcinoma, Neuroendocrine/pathology , Cell Differentiation , Chemotherapy, Adjuvant , Chromogranin A , Chromogranins/analysis , Combined Modality Therapy , Disease Progression , Female , Humans , Lymphatic Metastasis , Mastectomy, Segmental , Middle Aged , Neoplasm Proteins/analysis , Neural Cell Adhesion Molecules/analysis , Radiotherapy, Adjuvant , Sternum/chemistry , Synaptophysin/analysisABSTRACT
UNLABELLED: The 8p12 locus (containing the FGFR1 tyrosine kinase gene) is frequently amplified in squamous cell lung cancer. However, it is currently unknown which of the 8p12-amplified tumors are also sensitive to fibroblast growth factor receptor (FGFR) inhibition. We found that, in contrast with other recurrent amplifications, the 8p12 region included multiple centers of amplification, suggesting marked genomic heterogeneity. FGFR1-amplified tumor cells were dependent on FGFR ligands in vitro and in vivo. Furthermore, ectopic expression of FGFR1 was oncogenic, which was enhanced by expression of MYC. We found that MYC was coexpressed in 40% of FGFR1-amplified tumors. Tumor cells coexpressing MYC were more sensitive to FGFR inhibition, suggesting that patients with FGFR1-amplified and MYC-overexpressing tumors may benefit from FGFR inhibitor therapy. Thus, both cell-autonomous and non-cell-autonomous mechanisms of transformation modulate FGFR dependency in FGFR1-amplified lung cancer, which may have implications for patient selection for treatment with FGFR inhibitors. SIGNIFICANCE: Amplification of FGFR1 is one of the most frequent candidate targets in lung cancer. Here, we show that multiple factors affect the tumorigenic potential of FGFR1, thus providing clinical hypotheses for refinement of patient selection.
Subject(s)
Cell Transformation, Neoplastic/genetics , Gene Amplification , Lung Neoplasms/genetics , Receptor, Fibroblast Growth Factor, Type 1/genetics , Animals , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/metabolism , Cell Line , Cell Transformation, Neoplastic/metabolism , Chromosomes, Human, Pair 8 , Disease Models, Animal , Gene Expression , Gene Expression Profiling , Genes, myc , Genetic Heterogeneity , Heterografts , Humans , Ligands , Lung Neoplasms/diagnosis , Lung Neoplasms/metabolism , Lung Neoplasms/therapy , Mice , Receptor, Fibroblast Growth Factor, Type 1/metabolism , Signal Transduction , Treatment OutcomeABSTRACT
RTOG and EORTC trials have paved the way of the combination of radiation therapy and androgen suppression. Localized carcinoma with intermediate prognostic factors (cT2b, Gleason 7, or baseline PSA ranging between 10 and 20 ng/mL) may be submitted to a 4-month complete androgene blockade with 2 months before irradiation, unless to include patients in ongoing randomized trials. High risk cancers (cT2c, or Gleason > 7, or PSA > 20 ng/ml) should receive a 4-month or 6-month complete androgen blockade (RTOG trial 86-10), knowing that the results of EORTC trial 22961 are eagerly expected to tell us whether a 3- year androgen suppression is preferable. Very high risk prostate cancers, T3-4 N0 M0 or pelvic lymph node involvement (c or pN1) whatever the UICC T stage, need a long term androgen suppression of 3 years or more.