ABSTRACT
Genetic abnormalities are present in all tumor types, although the frequency and type can vary. Chromosome abnormalities include highly aberrant structures, particularly chromothriptic chromosomes. The generation of massive sequencing data has illuminated the scope of the mutational burden in cancer genomes, identifying patterns of mutations (mutation signatures), which have the potential to shed light on the relatedness and etiologies of cancers and impact therapy response. Some mutation patterns are clearly attributable to disruptions in pathways that maintain genomic integrity. Here we review recent advances in our understanding of genetic changes occurring in cancers and the roles of genome maintenance pathways.
Subject(s)
Chromosome Aberrations , DNA Damage , DNA Repair , DNA/genetics , Genome , Mutation , Animals , Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/pathology , Chromothripsis , DNA/biosynthesis , DNA/chemistry , Drug Resistance, Neoplasm/genetics , Gene Expression Profiling/methods , Gene Expression Regulation, Neoplastic , Genetic Predisposition to Disease , Humans , Neoplasms/genetics , Neoplasms/metabolism , Neoplasms/pathology , Neoplasms/therapy , Phenotype , TranscriptomeABSTRACT
Mitotic homologous recombination promotes genome stability through the precise repair of DNA double-strand breaks and other lesions that are encountered during normal cellular metabolism and from exogenous insults. As a result, homologous recombination repair is essential during proliferative stages in development and during somatic cell renewal in adults to protect against cell death and mutagenic outcomes from DNA damage. Mutations in mammalian genes encoding homologous recombination proteins, including BRCA1, BRCA2 and PALB2, are associated with developmental abnormalities and tumorigenesis. Recent advances have provided a clearer understanding of the connections between these proteins and of the key steps of homologous recombination and DNA strand exchange.
Subject(s)
Genomic Instability , Mitosis/genetics , Neoplasms/genetics , Recombination, Genetic/genetics , Animals , DNA Breaks, Double-Stranded , DNA Breaks, Single-Stranded , DNA Repair , Humans , Models, Biological , Neoplasms/pathologyABSTRACT
BRCA1 is essential for homology-directed repair (HDR) of DNA double-strand breaks in part through antagonism of the nonhomologous end-joining factor 53BP1. The ATM kinase is involved in various aspects of DNA damage signaling and repair, but how ATM participates in HDR and genetically interacts with BRCA1 in this process is unclear. To investigate this question, we used the Brca1S1598F mouse model carrying a mutation in the BRCA1 C-terminal domain of BRCA1. Whereas ATM loss leads to a mild HDR defect in adult somatic cells, we find that ATM inhibition leads to severely reduced HDR in Brca1S1598F cells. Consistent with a critical role for ATM in HDR in this background, loss of ATM leads to synthetic lethality of Brca1S1598F mice. Whereas both ATM and BRCA1 promote end resection, which can be regulated by 53BP1, 53bp1 deletion does not rescue the HDR defects of Atm mutant cells, in contrast to Brca1 mutant cells. These results demonstrate that ATM has a role in HDR independent of the BRCA1-53BP1 antagonism and that its HDR function can become critical in certain contexts.
Subject(s)
DNA Repair , Synthetic Lethal Mutations , Tumor Suppressor Proteins/genetics , Animals , Ataxia Telangiectasia Mutated Proteins/genetics , BRCA1 Protein , DNA Breaks, Double-Stranded , DNA End-Joining Repair , Embryonic Stem Cells/cytology , Epistasis, Genetic , Fibroblasts/metabolism , Gene Deletion , Green Fluorescent Proteins/metabolism , Homologous Recombination , Mice , Mice, Mutant Strains , Mutation , Phthalazines/pharmacology , Piperazines/pharmacology , Tumor Suppressor p53-Binding Protein 1/geneticsABSTRACT
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
Homology-directed repair (HDR) is a critical pathway for the repair of DNA double-strand breaks (DSBs) in mammalian cells. Efficient HDR is thought to be crucial for maintenance of genomic integrity during organismal development and tumor suppression. However, most mammalian HDR studies have focused on transformed and immortalized cell lines. We report here the generation of a Direct Repeat (DR)-GFP reporter-based mouse model to study HDR in primary cell types derived from diverse lineages. Embryonic and adult fibroblasts from these mice as well as cells derived from mammary epithelium, ovary, and neonatal brain were observed to undergo HDR at I-SceI endonuclease-induced DSBs at similar frequencies. When the DR-GFP reporter was crossed into mice carrying a hypomorphic mutation in the breast cancer susceptibility gene Brca1, a significant reduction in HDR was detected, showing that BRCA1 is critical for HDR in somatic cell types. Consistent with an HDR defect, Brca1 mutant mice are highly sensitive to the cross-linking agent mitomycin C. By contrast, loss of the DSB signaling ataxia telangiectasia-mutated (ATM) kinase did not significantly alter HDR levels, indicating that ATM is dispensable for HDR. Notably, chemical inhibition of ATM interfered with HDR. The DR-GFP mouse provides a powerful tool for dissecting the genetic requirements of HDR in a diverse array of somatic cell types in a normal, nontransformed cellular milieu.
Subject(s)
BRCA1 Protein/metabolism , DNA Breaks, Double-Stranded , Models, Animal , Recombinational DNA Repair/physiology , Animals , Ataxia Telangiectasia Mutated Proteins , Cell Cycle Proteins/metabolism , DNA-Binding Proteins/metabolism , Deoxyribonucleases, Type II Site-Specific , Electroporation , Fibroblasts , Flow Cytometry , Green Fluorescent Proteins/metabolism , Mice , Protein Serine-Threonine Kinases/metabolism , Repetitive Sequences, Nucleic Acid/genetics , Saccharomyces cerevisiae Proteins , Tumor Suppressor Proteins/metabolismABSTRACT
PIK3CA gene mutations are the most common activating mutations in human breast cancer. Its association with hormone receptor-positive breast cancer makes it a prime target for clinical therapeutic advances to maintain anti-estrogen responsiveness. In anticipation of this therapeutic approach, we have evaluated intratumoral heterogeneity in primary breast cancers with regard to PIK3CA mutation status. In addition, we have assessed for the presence of the mutation in paired pre-invasive breast cancer and metastases. To assess for intratumoral heterogeneity, separate tumor blocks from primary breast cancers (n = 63) were genotyped for PIK3CA mutations. Available paired tissue samples from breast tumors known to harbor mutations underwent massARRAY genotyping (n = 70) to identify PIK3CA and AKT1(E17K) mutations. Cores were macro-dissected from matched tissue, including normal breast, benign lymph nodes (LN), ductal carcinoma in situ, regional LN metastases, and distant metastases. Matched samples underwent genetic fingerprinting by multiple SNP genotyping to confirm genetic identity. Intratumoral heterogeneity is minimal with a concordance rate of 95.2% between two different blocks from primary breast cancers. Complete concordance of PIK3CA mutations is noted between primary breast cancer and DCIS. PIK3CA mutations in primary breast cancer are detected in matched regional LNs (91.7%) and distant metastases (100%). Mutation detection by massARRAY genotyping is sensitive but may be affected by sample quality. Intratumoral heterogeneity as measured by PIK3CA genotype is rare; PIK3CA mutations occur early and are selected for in breast cancer progression. HapMap analysis is an essential control for paired sample analysis. This data is clinically important, particularly, for the design of therapies targeting the PI3K/AKT pathway, as it offers confidence that the detection of PIK3CA mutations in the invasive primary tumor will accurately reflect breast cancer biology.
Subject(s)
Breast Neoplasms/genetics , Mutation , Phosphatidylinositol 3-Kinases/genetics , Breast Neoplasms/enzymology , Breast Neoplasms/pathology , Class I Phosphatidylinositol 3-Kinases , DNA Fingerprinting , DNA Mutational Analysis , Disease Progression , Female , Genetic Predisposition to Disease , Humans , Neoplasm Invasiveness , New York City , Phenotype , Polymorphism, Single Nucleotide , Proto-Oncogene Proteins c-akt/geneticsABSTRACT
Alpelisib is a selective inhibitor of PI3Kα, shown to improve outcomes for PIK3CA mutant, hormone receptor positive (HR+) metastatic breast cancers (MBC) when combined with antiestrogen therapy. To uncover mechanisms of resistance, we conducted a detailed, longitudinal analysis of tumor and plasma circulating tumor DNA among such patients from a phase I/II trial combining alpelisib with an aromatase inhibitor (AI) (NCT01870505). The trial's primary objective was to establish safety with maculopapular rash emerging as the most common grade 3 adverse event (33%). Among 44 evaluable patients, the observed clinical benefit rate was 52%. Correlating genetic alterations with outcome, we identified loss-of-function PTEN mutations in 25% of patients with resistance. ESR1 activating mutations also expanded in number and allele fraction during treatment and were associated with resistance. These data indicate that genomic alterations that mediate resistance to alpelisib or antiestrogen may promote disease progression and highlight PTEN loss as a recurrent mechanism of resistance to PI3Kα inhibition.
Subject(s)
Aromatase Inhibitors , Breast Neoplasms , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Aromatase Inhibitors/pharmacology , Breast Neoplasms/drug therapy , Estrogen Receptor Modulators/therapeutic use , Female , Humans , PTEN Phosphohydrolase/genetics , Receptor, ErbB-2/genetics , Receptors, Estrogen/genetics , ThiazolesABSTRACT
PURPOSE: We conducted a pilot study of dose-dense epirubicin/cyclophosphamide (EC) x 6 --> paclitaxel (P) x 6 with pegfilgrastim. A previous dose-dense trial of FEC (5-fluorouracil [5-FU]/EC) x 6 with filgrastim --> by weekly paclitaxel alternating with docetaxel x 18 was not feasible because of pneumonitis (with dose-dense FEC) and pericardial/pleural effusion (taxane phase). Dose-dense EC (without the 5-FU) is not associated with pneumonitis, and dose-dense paclitaxel (alone) is feasible. Primary objective was feasibility. PATIENTS AND METHODS: Patients with resectable breast cancer were enrolled, regardless of surgery status, tumor size, or nodal status. Treatment regimen consisted of every-2-week EC (100/600 mg/m2) x 6 --> by 2-weekly P (175 mg/m2) x 6 with pegfilgrastim 6 mg on day 2. RESULTS: Between November 2004 and May 2005, 38 patients were enrolled. The median age was 47 years (range, 30-72 years); 33 of 38 (87%) were treated in the adjuvant setting and 27 of 33 (81%) had involved nodes (range, 1-46); 5 of 38 (13%) were treated pre-operatively; 33 of 38 (87%) completed all chemotherapy as planned; the remaining patients (13%) had treatment modifications for toxicity. Febrile neutropenia occurred in 6 of 38 patients (16 %) and only during EC. There were 12 hospitalizations in 9 of 38 patients (24%) enrolled. CONCLUSION: Dose-dense every-2-week EC x 6 --> P x 6 with pegfilgrastim is feasible based on our prospective definition.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Breast Neoplasms/drug therapy , Adult , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Epirubicin/administration & dosage , Epirubicin/adverse effects , Female , Humans , Middle Aged , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Pilot ProjectsABSTRACT
Purpose Phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha ( PIK3CA) mutations are frequently observed in primary breast cancer. We evaluated their prognostic relevance by performing a pooled analysis of individual patient data. Patients and Methods Associations between PIK3CA status and clinicopathologic characteristics were tested by applying Cox regression models adjusted for age, tumor size, nodes, grade, estrogen receptor (ER) status, human epidermal growth factor receptor 2 (HER2) status, treatment, and study. Invasive disease-free survival (IDFS) was the primary end point; distant disease-free survival (DDFS) and overall survival (OS) were also assessed, overall and by breast cancer subtypes. Results Data from 10,319 patients from 19 studies were included (median OS follow-up, 6.9 years); 1,787 patients (17%) received chemotherapy, 4,036 (39%) received endocrine monotherapy, 3,583 (35%) received both, and 913 (9%) received none or their treatment was unknown. PIK3CA mutations occurred in 32% of patients, with significant associations with ER positivity, increasing age, lower grade, and smaller size (all P < .001). Prevalence of PIK3CA mutations was 18%, 22%, and 37% in the ER-negative/HER2-negative, HER2-positive, and ER-positive/HER2-negative subtypes, respectively. In univariable analysis, PIK3CA mutations were associated with better IDFS (HR, 0.77; 95% CI, 0.71 to 0.84; P < .001), with evidence for a stronger effect in the first years of follow-up (0 to 5 years: HR, 0.73; 95% CI, 0.66 to 0.81; P < .001; 5 to 10 years: HR, 0.82; 95% CI, 0.68 to 0.99; P = .037); > 10 years: (HR, 1.15; 95% CI, 0.84 to 1.58; P = .38; P heterogeneity = .02). In multivariable analysis, PIK3CA genotype remained significant for improved IDFS ( P = .043), but not for the DDFS and OS end points. Conclusion In this large pooled analysis, PIK3CA mutations were significantly associated with a better IDFS, DDFS, and OS, but had a lesser prognostic effect after adjustment for other prognostic factors.
Subject(s)
Breast Neoplasms/genetics , Class I Phosphatidylinositol 3-Kinases/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Breast Neoplasms/therapy , Disease-Free Survival , Female , Genotype , Humans , Middle Aged , Mutation , Neoplasm Staging , Prognosis , Proportional Hazards Models , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Survival Rate , Young AdultABSTRACT
The BRCA1 tumor suppressor has been implicated in the maintenance of chromosomal stability through homology-directed repair of DNA double-strand breaks. Much of the BRCA1 in cells forms a heterodimeric complex with a structurally related protein BARD1. We report that expression of truncated mouse or human BARD1 peptides capable of interacting with Brca1 results in a homologous-repair deficiency. Repair is mildly reduced in Brca1 wild-type cells and severely reduced in cells that harbor a Brca1 splice product deleted for exon 11. Nuclear localization of the Brca1 or BARD1 peptides is not compromised, implying that the repair deficiency is caused by a more direct effect on repair. The tumor suppressor activity of BRCA1 may require the participation of BARD1 to maintain chromosome integrity through the homologous-repair pathway.
Subject(s)
BRCA1 Protein/metabolism , Carrier Proteins/metabolism , Chromosomes/metabolism , Tumor Suppressor Proteins , Ubiquitin-Protein Ligases , Animals , BRCA1 Protein/genetics , Carrier Proteins/genetics , Cell Line , DNA Damage , DNA Repair , Genes, Reporter , Humans , Macromolecular Substances , Mice , Mice, Knockout , Mitomycin/metabolism , Nucleic Acid Synthesis Inhibitors/metabolism , Peptides/genetics , Peptides/metabolism , Protein BindingABSTRACT
Poly(ADP-ribose) polymerases (PARPs) are the first proteins involved in cellular DNA repair pathways to be targeted by specific inhibitors for clinical benefit. Tumors harboring genetic defects in homologous recombination (HR), a DNA double-strand break (DSB) repair pathway, are hypersensitive to PARP inhibitors (PARPi). Early phase clinical trials with PARPi have been promising in patients with advanced BRCA1 or BRCA2-associated breast, ovary and prostate cancer and have led to limited approval for treatment of BRCA-deficient ovary cancer. Unlike HR-defective cells, HR-proficient cells manifest very low cytotoxicity when exposed to PARPi, although they mount a DNA damage response. However, the genotoxic effects on normal human cells when agents including PARPi disturb proficient cellular repair processes have not been substantially investigated. We quantified cytogenetic alterations of human cells, including primary lymphoid cells and non-tumorigenic and tumorigenic epithelial cell lines, exposed to PARPi at clinically relevant doses by both sister chromatid exchange (SCE) assays and chromosome spreading. As expected, both olaparib and veliparib effectively inhibited poly-ADP-ribosylation (PAR), and caused marked hypersensitivity in HR-deficient cells. Significant dose-dependent increases in SCEs were observed in normal and non-tumorigenic cells with minimal residual PAR activity. Clinically relevant doses of the FDA-approved olaparib led to a marked increase of SCEs (5-10-fold) and chromatid aberrations (2-6-fold). Furthermore, olaparib potentiated SCE induction by cisplatin in normal human cells. Our data have important implications for therapies with regard to sustained genotoxicity to normal cells. Genomic instability arising from PARPi warrants consideration, especially if these agents will be used in people with early stage cancers, in prevention strategies or for non-oncologic indications.
Subject(s)
Benzimidazoles/adverse effects , Chromosome Aberrations/drug effects , Genomic Instability/drug effects , Phthalazines/adverse effects , Piperazines/adverse effects , Poly(ADP-ribose) Polymerase Inhibitors/adverse effects , Sister Chromatid Exchange/drug effects , Cisplatin/pharmacology , DNA Damage/drug effects , DNA Repair/drug effects , Dose-Response Relationship, Drug , Drug Synergism , Female , Gene Expression , Homologous Recombination , Humans , Karyotyping , Poly(ADP-ribose) Polymerases/genetics , Poly(ADP-ribose) Polymerases/metabolismABSTRACT
The mammary gland undergoes significant proliferative stages after birth, but little is known about how the developmental changes impact DNA double-strand break (DSB) repair. Mutations in multiple genes involved in homology-directed repair (HDR), considered a particularly accurate pathway for repairing DSBs, are linked to breast cancer susceptibility, including BRCA2. Using reporter mice that express an inducible endonuclease, we find that HDR is particularly robust in mammary tissue during puberty and pregnancy, accounting for 34-40% of detected repair events, more than in other tissues examined. Brca2 hypomorphic mutation leads to HDR defects in mammary epithelium during puberty and pregnancy, including in different epithelial lineages. Notably, a similar dependence on Brca2 is observed in other proliferative tissues, including small intestine epithelium. Our results suggest that the greater reliance on HDR in the proliferating mammary gland, rather than a specific dependence on BRCA2, may increase its susceptibility to tumorigenesis incurred by BRCA2 mutation.
Subject(s)
BRCA2 Protein/genetics , DNA Breaks, Double-Stranded , Mammary Glands, Animal/metabolism , Recombinational DNA Repair , Animals , BRCA2 Protein/metabolism , Cells, Cultured , Female , Mammary Glands, Animal/cytology , Mice, Knockout , Mice, Transgenic , Mutation , Pregnancy , Sexual Maturation/geneticsABSTRACT
IMPORTANCE: Estrogen receptor α (ESR1) mutations found in metastatic breast cancer (MBC) promote ligand-independent receptor activation and resistance to estrogen-deprivation therapy in laboratory models. The prevalence of these mutations and their potential impact on clinical outcomes has not been established. OBJECTIVE: To determine the prevalence of ESR1 mutations (Y537S and D538G) in estrogen receptor (ER)-positive MBC and determine whether mutation is associated with inferior outcomes. DESIGN, SETTING, AND PARTICIPANTS: From December 16, 2014, to August 26, 2015, we analyzed cell-free DNA (cfDNA) from baseline plasma samples from participants in the BOLERO-2 double-blind phase 3 study that randomized patients from 189 centers in 24 countries with MBC to exemestane plus placebo or exemestane plus everolimus. The study enrolled postmenopausal women with a diagnosis of MBC and prior exposure to an aromatase inhibitor. Baseline plasma samples were available from 541 of 724 patients (74.7%). We assessed the effect of mutation on overall survival of the population and the effect of mutation on progression-free survival (PFS) by treatment arm. INTERVENTIONS: Patients were randomized to treatment with exemestane (25 mg oral daily) together with everolimus (10 mg oral daily) or with placebo. MAIN OUTCOMES AND MEASURES: The 2 most frequent mutations in ESR1 (Y537S and D538G) were analyzed from cfDNA using droplet digital polymerase chain reaction and samples scored as wild-type, D538G, Y537S, or double mutant. Cox-proportional hazards model was used to assess PFS in patient subgroups defined by mutations, and the effect of each mutation on overall survival. RESULTS: Of 541 evaluable patients, 156 (28.8%) had ESR1 mutation D538G (21.1%) and/or Y537S (13.3%), and 30 had both. These mutations were associated with shorter overall survival (wild-type, 32.1 months [95% CI, 28.09-36.40 months]; D538G, 25.99 months [95% CI, 19.19-32.36 months]; Y537S, 19.98 months [13.01-29.31 months]; both mutations, 15.15 months [95% CI, 10.87-27.43 months]). The D538G group (hazard ratio, 0.34 [95% CI, 0.02-0.57]) derived a similar PFS benefit as wild type from addition of everolimus to exemestane. CONCLUSIONS AND RELEVANCE: ESR1 mutations are prevalent in ER-positive aromatase inhibitor-treated MBC. Both Y537S and D538G mutations are associated with more aggressive disease biology. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00863655.
Subject(s)
Breast Neoplasms/genetics , Estrogen Receptor alpha/genetics , Breast Neoplasms/drug therapy , Breast Neoplasms/mortality , Breast Neoplasms/pathology , DNA Mutational Analysis , DNA, Neoplasm/blood , DNA, Neoplasm/genetics , Disease-Free Survival , Female , Humans , Multicenter Studies as Topic , Mutation, Missense , Neoplasm Metastasis , Proportional Hazards Models , Randomized Controlled Trials as TopicABSTRACT
PURPOSE: To investigate whether anti-vascular endothelial growth factor therapy with bevacizumab prolongs progression-free survival (PFS) when added to first-line letrozole as treatment of hormone receptor-positive metastatic breast cancer (MBC). PATIENTS AND METHODS: Women with hormone receptor-positive MBC were randomly assigned 1:1 in a multicenter, open-label, phase III trial of letrozole (2.5 mg orally per day) with or without bevacizumab (15 mg/kg intravenously once every 3 weeks) within strata defined by measurable disease and disease-free interval. This trial had 90% power to detect a 50% improvement in median PFS from 6 to 9 months. Using a one-sided α = .025, a target sample size of 352 patients was planned. RESULTS: From May 2008 to November 2011, 350 women were recruited; 343 received treatment and were observed for efficacy and safety. Median age was 58 years (range, 25 to 87 years). Sixty-two percent had measurable disease, and 45% had de novo MBC. At a median follow-up of 39 months, the addition of bevacizumab resulted in a significant reduction in the hazard of progression (hazard ratio, 0.75; 95% CI, 0.59 to 0.96; P = .016) and a prolongation in median PFS from 15.6 months with letrozole to 20.2 months with letrozole plus bevacizumab. There was no significant difference in overall survival (hazard ratio, 0.87; 95% CI, 0.65 to 1.18; P = .188), with median overall survival of 43.9 months with letrozole versus 47.2 months with letrozole plus bevacizumab. The largest increases in incidence of grade 3 to 4 treatment-related toxicities with the addition of bevacizumab were hypertension (24% v 2%) and proteinuria (11% v 0%). CONCLUSION: The addition of bevacizumab to letrozole improved PFS in hormone receptor-positive MBC, but this benefit was associated with a markedly increased risk of grade 3 to 4 toxicities. Research on predictive markers will be required to clarify the role of bevacizumab in this setting.
Subject(s)
Angiogenesis Inhibitors/administration & dosage , Antineoplastic Agents/administration & dosage , Bevacizumab/administration & dosage , Breast Neoplasms/drug therapy , Nitriles/therapeutic use , Postmenopause , Triazoles/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols , Disease-Free Survival , Female , Humans , Letrozole , Middle Aged , Nitriles/administration & dosage , Treatment Outcome , Triazoles/administration & dosageABSTRACT
BRCA1 and BRCA2 mutations are estimated to be responsible for the great majority of familial breast and ovarian cancers. Much progress has been made toward the understanding of the function of these proteins through genetic, biochemical, and structural studies. The embryonic lethality encountered in the knockout mouse initially hindered the development of mouse models aimed at studying tumor suppression. However, mice that harbor hypomorphic Brca1 and Brca2 alleles and cre-mediated tissue-specific deletions for Brca1 and Brca2 have been generated. Mice deficient for either Brca1 or Brca2 sustain a wide range of carcinoma and mammary epithelium deleted for Brca1 or Brca2 is highly susceptible to mammary tumorigenesis. Mammary (and other) tumors occur at long latency as compared to oncogene-induced mouse tumors. p53 deficiency is highly cooperative with both Brca1 and Brca2 in promoting tumorigenesis. Analysis of Brca1-associated mammary tumors reveals significant similarities to BRCA1-associated breast cancer in regard to high tumor grade, hormone receptor negativity, a high incidence of p53 mutations and genetic instability.
Subject(s)
BRCA1 Protein/genetics , BRCA2 Protein/genetics , Neoplasms, Experimental/genetics , Animals , BRCA1 Protein/metabolism , BRCA2 Protein/metabolism , Breast Neoplasms/genetics , Disease Models, Animal , Fetal Death/genetics , Humans , Mammary Neoplasms, Experimental/genetics , Mammary Neoplasms, Experimental/pathology , Mice , Mutation , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolismABSTRACT
PURPOSE: The CLEOPATRA (Clinical Evaluation of Trastuzumab and Pertuzumab) study demonstrated superior progression-free survival (PFS) and overall survival when pertuzumab was added to trastuzumab and docetaxel. Paclitaxel given once per week is effective and less toxic than docetaxel. We performed a phase II study to evaluate the efficacy and safety of pertuzumab and trastuzumab with paclitaxel given once per week. PATIENTS AND METHODS: Patients with metastatic human epidermal growth factor receptor 2-positive breast cancer with zero to one prior therapy were enrolled. Treatment consisted of paclitaxel 80 mg/m(2) once per week plus trastuzumab (8 mg/kg loading dose â 6 mg/kg) once every 3 weeks plus pertuzumab (840 mg loading dose â 420 mg) once every 3 weeks, all given intravenously. The primary end point was 6-month PFS assessed by Kaplan-Meier methods. RESULTS: From January 2011 to December 2013, we enrolled 69 patients: 51 (74%) and 18 (26%) treated in first- and second-line metastatic settings, respectively. At a median follow-up of 21 months (range, 3 to 38 months), 6-month PFS was 86% (95% CI, 75% to 92%). The median PFS was 19.5 months (95% CI, 14 to 26 months) overall. PFS was 24.2 months (95% CI, 14 months to not reached [NR]) and 16.4 months (95% CI, 8.5 months to NR) for those without and with prior treatment, respectively. At 1 year, Kaplan-Meier PFS was 70% (95% CI, 56% to 79%) overall, 71% (95% CI, 55% to 82%) for those without prior therapy, and 66% (95% CI, 40% to 83%) for those with prior therapy. Treatment was well-tolerated; there was no febrile neutropenia or symptomatic left ventricular systolic dysfunction. CONCLUSION: Paclitaxel given once per week with trastuzumab and pertuzumab is highly active and well tolerated and seems to be an effective alternative to docetaxel-based combination therapy.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/analysis , Breast Neoplasms/chemistry , Breast Neoplasms/drug therapy , Receptor, ErbB-2/analysis , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/administration & dosage , Disease-Free Survival , Drug Administration Schedule , Female , Follow-Up Studies , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Infusions, Intravenous , Kaplan-Meier Estimate , Middle Aged , Paclitaxel/administration & dosage , Trastuzumab , Treatment OutcomeABSTRACT
BACKGROUND: Ganetespib is a small molecule, nongeldanamycin HSP90 inhibitor with potent inhibitory effects on HSP90-dependent oncoproteins of relevance to breast cancer pathogenesis. We therefore tested ganetespib in an unselected cohort of patients with MBC. PATIENTS AND METHODS: Patients were treated with single agent ganetespib at 200 mg/m(2) once weekly for 3 weeks, on a 28-day cycle. Therapy was continued until disease progression. The primary end point was ORR using Reponse Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Twenty-two patients were enrolled with a median age of 51(range, 38-70) years and a median Eastern Cooperative Oncology Group performance status of 0 (range, 0-1). Most patients had at least 2 previous lines of chemotherapy in the metastatic setting. Most common toxicities, largely grade 1/2, were diarrhea, fatigue, nausea, and hypersensitivity reaction. The ORR in this unselected population was 9%, with all responses coming from the subset of patients with HER2-positive MBC (2/13; 15%). One patient with TNBC had objective tumor regression in the lung metastases. The clinical benefit rate (complete response + partial response + stable disease > 6 months) was 9%, median progression-free survival was 7 weeks (95% confidence interval [CI], 7-19), and median overall survival was 46 weeks (95% CI, 27-not applicable). CONCLUSION: The study did not meet the prespecified criteria for ORR in the first stage of the Simon 2-stage model in this heavily pretreated unselected population of MBC. However, activity was observed in trastuzumab-refractory HER2-positive and TNBC. Ganetespib was well tolerated and responses in more targeted populations harboring specific HSP90-dependent oncoproteins justifies its further study, particularly as part of rational combinations.
Subject(s)
Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Triazoles/therapeutic use , Adult , Aged , Breast Neoplasms/mortality , Disease-Free Survival , Female , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Humans , Kaplan-Meier Estimate , Middle Aged , Neoplasm MetastasisABSTRACT
BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-P) and bevacizumab have each demonstrated efficacy in patients with MBC. This trial was designed to further develop nab-P by evaluating its efficacy and safety using every 3 weeks (q3w), every 2 weeks (q2w), or weekly scheduling in combination with bevacizumab as first-line treatment of MBC. PATIENTS AND METHODS: This open-label phase II study randomized patients to nab-P 260 mg/m(2) q3w (arm A) vs. 260 mg/m(2) q2w with filgrastim (arm B) vs. 130 mg/m(2) weekly uninterrupted, all with bevacizumab (15 mg/kg q3w arm A, 10 mg/kg q2w arms B and C). The primary endpoints were overall response rate (ORR) and toxicity. Time to tumor progression (TTP) and overall survival were secondary endpoints. RESULTS: Of 212 patients randomized, 208 (arm A, 75; arm B, 54; arm C, 79) were treated. Arm B was closed early due to toxicity, with more grade ≥ 2 fatigue (arm A, 46%; arm B, 62%; arm C, 62%) and bone pain (arm A, 11%; arm B, 23%; arm C, 5%). Neurotoxicity grade ≥ 2 was equivalent across the arms (> 50%) and reversible for most patients. Febrile neutropenia occurred in ≤ 3% of patients in all arms. ORR was similar among the arms (arm A, 45%; arm B, 41%; arm C, 46%). Median TTP was slightly longer in arm C (9.0 months) vs. arms A (8.0 months) and B (5.8 months) (overall, P = .105). CONCLUSIONS: Significant antitumor activity was observed in all the arms. Weekly nab-P with bevacizumab appeared to have the highest therapeutic index. However, sensory neuropathy was treatment limiting, which suggests that a 3 weeks on and 1 week off schedule should be explored.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Albumin-Bound Paclitaxel , Albumins/administration & dosage , Antibodies, Monoclonal, Humanized/administration & dosage , Bevacizumab , Breast Neoplasms/mortality , Female , Follow-Up Studies , Humans , Middle Aged , Neoplasm Metastasis , Paclitaxel/administration & dosage , Prognosis , Survival RateABSTRACT
PURPOSE: Patients with hormone receptor-negative breast cancer generally do not benefit from endocrine-targeted therapies. However, a subset with androgen receptor (AR) expression is predicted to respond to antiandrogen therapies. This phase II study explored bicalutamide in AR-positive, estrogen receptor (ER), and progesterone receptor (PgR)-negative metastatic breast cancer. EXPERIMENTAL DESIGN: Tumors from patients with ER/PgR-negative advanced breast cancer were tested centrally for AR [immunohistochemistry (IHC) > 10% nuclear staining considered positive]. If either the primary or a metastatic site was positive, patients were eligible to receive the AR antagonist bicalutamide at a dose of 150 mg daily. Clinical benefit rate (CBR), the primary endpoint, was defined as the total number of patients who show a complete response (CR), partial response (PR), or stable disease (SD) > 6 months; secondary endpoints included progression-free survival (PFS) and toxicity. Correlative studies included measurement of circulating endocrine markers and IHC surrogates for basal-like breast cancer. RESULTS: Of 424 patients with ER/PgR-negative breast cancer, 12% tested AR-positive. The 6-month CBR was 19% [95% confidence interval (CI), 7%-39%] for bicalutamide. The median PFS was 12 weeks (95% CI, 11-22 weeks). Bicalutamide was well-tolerated with no grade 4/5 treatment-related adverse events observed. CONCLUSION: AR was expressed in 12% of patients with ER/PgR-negative breast cancer screened for this trial. The CBR of 19% observed with bicalutamide shows proof of principle for the efficacy of minimally toxic androgen blockade in a select group of patients with ER/PgR-negative, AR-positive breast cancer.
Subject(s)
Androgen Antagonists/therapeutic use , Anilides/therapeutic use , Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Nitriles/therapeutic use , Receptors, Androgen/metabolism , Receptors, Estrogen/metabolism , Tosyl Compounds/therapeutic use , Adult , Aged , Aged, 80 and over , Androgen Antagonists/administration & dosage , Androgen Antagonists/adverse effects , Anilides/administration & dosage , Anilides/adverse effects , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Female , Hormones/blood , Humans , Middle Aged , Neoplasm Metastasis , Nitriles/administration & dosage , Nitriles/adverse effects , Tosyl Compounds/administration & dosage , Tosyl Compounds/adverse effects , Treatment OutcomeABSTRACT
Testicular Germ Cell Tumors (TGCT) and patient-derived cell lines are extremely sensitive to cisplatin and other interstrand cross-link (ICL) inducing agents. Nevertheless, a subset of TGCTs are either innately resistant or acquire resistance to cisplatin during treatment. Understanding the mechanisms underlying TGCT sensitivity/resistance to cisplatin as well as the identification of novel strategies to target cisplatin-resistant TGCTs have major clinical implications. Herein, we have examined the proficiency of five embryonal carcinoma (EC) cell lines to repair cisplatin-induced ICLs. Using γH2AX staining as a marker of double strand break formation, we found that EC cell lines were either incapable of or had a reduced ability to repair ICL-induced damage. The defect correlated with reduced Homologous Recombination (HR) repair, as demonstrated by the reduction of RAD51 foci formation and by direct evaluation of HR efficiency using a GFP-reporter substrate. HR-defective tumors cells are known to be sensitive to the treatment with poly(ADP-ribose) polymerase (PARP) inhibitor. In line with this observation, we found that EC cell lines were also sensitive to PARP inhibitor monotherapy. The magnitude of sensitivity correlated with HR-repair reduced proficiency and with the expression levels and activity of PARP1 protein. In addition, we found that PARP inhibition strongly enhanced the response of the most resistant EC cells to cisplatin, by reducing their ability to overcome the damage. These results point to a reduced proficiency of HR repair as a source of sensitivity of ECs to ICL-inducing agents and PARP inhibitor monotherapy, and suggest that pharmacological inhibition of PARP can be exploited to target the stem cell component of the TGCTs (namely ECs) and to enhance the sensitivity of cisplatin-resistant TGCTs to standard treatments.