JCO
Sacituzumab govitecan (SG), a first-in-class anti-trophoblast cell surface antigen 2 (Trop-2) antibody-drug conjugate, demonstrated superior efficacy over single-agent chemotherapy (treatment of ...physician's choice TPC) in patients with metastatic triple-negative breast cancer (mTNBC) in the international, multicenter, phase III ASCENT study.Patients were randomly assigned 1:1 to receive SG or TPC until unacceptable toxicity/progression. Final efficacy secondary end point analyses and post hoc analyses of outcomes stratified by Trop-2 expression and human epidermal growth factor receptor 2 status are reported. Updated safety analyses are provided.In this final analysis, SG (n = 267) improved median progression-free survival (PFS; 4.8
1.7 months; hazard ratio (HR), 0.41 95% CI, 0.33 to 0.52) and median overall survival (OS; 11.8
6.9 months; HR, 0.51 95% CI, 0.42 to 0.63) over TPC (n = 262). SG improved PFS over TPC in each Trop-2 expression quartile (n = 168); a trend was observed for improved OS across quartiles. Overall, SG had a manageable safety profile, with ≤5% of treatment-related discontinuations because of adverse events and no treatment-related deaths. The safety profile was consistent across all subgroups.These data confirm the clinical benefit of SG over chemotherapy, reinforcing SG as an effective treatment option in patients with mTNBC in the second line or later.
Abstract
Background. Treatment of triple-negative breast cancer (TNBC) is clinically challenging due to disease heterogeneity and aggressiveness which often result in high recurrence and mortality ...rates. We have previously reported on genomic alterations found in 14 metastatic TNBC tumors (Craig et al 2012) uncovered through whole-genome and transcriptome sequencing and found that majority of tumor changes in our cohort converged on RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways revealing potential therapeutic targets. In this study, we interrogated patients’ matched primary and metastatic cancers using exome sequencing. Differentiating between primary and metastasis-specific genomic alterations will further our understanding of TNBC recurrence.
Methods. Tumor tissue was microdissected from 10uM FFPE sections from primary tumors of nine TNBC patients. DNA was extracted using Qiagen AllPrep kit. Whole-genome libraries were prepared from >250ng of DNA using Kapa-on–Bead method. Exomes were captured using All Exon V5 capture kit (Agilent Technologies) and sequenced on Illumina HiSeq. List of somatic variants (SNVs) in primary tissue was generated using Seurat variant caller and manually compared with the SNVs uncovered previously in metastatic tumors. Presence (or absence) of all reported somatic SNVs was visually confirmed in IGV genome viewer.
Results. Our analysis revealed the majority of somatic mutations found in metastatic lesions were also present in the primary tissue (64.3% on average). Patient TNBC03 had an unusually high number of new mutations in the lung metastatic lesion (72.7%). All TP53 mutations in our cohort were an early event present in both primary and metastatic tissues. In patient TNBC01, acquired mutation in NF1 - an upstream negative regulator of RAS pathway - in addition to pre-existing PTEN deletion, CTNNA1 underexpression and RB1 mutation - suggests RAS pathway addiction which could have been responsible for disease recurrence in this patient. Interestingly, NEDD4 mutation was found in a lung metastasis of another patient whose disease was refractory to BEZ235 (PI3K/mTOR inhibitor) treatment. NEDD4 has recently been shown to be an upstream regulator of the PI3K pathway and a possible therapeutic target in cancers with downregulated PTEN. Additional select acquired mutations in metastatic lesions of our cohort included FGF14, ABCB10, MDM2, KIF1C, ATAD2B, PTPLAD2, MDM20, TDRD1, and USP6. Mutated CDH5 was found in metastases in 2 of 9 patients.
Conclusion. Our findings demonstrate the complexity and variability in somatic events underlying TNBC recurrence, reinforcing the need to re-biopsy metastatic TNBC lesions and to employ combination targeted therapies wherever possible.
Citation Format: Irene Cherni, Maren K Levin, Joyce A O"Shaughnessy, John D Carpten. Comparative analysis of somatic mutations in matched primary vs metastatic triple-negative breast cancers abstract. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-03-04.
Chemoprevention of breast cancer O'Shaughnessy, J A
JAMA : the journal of the American Medical Association,
1996-May-01, Letnik:
275, Številka:
17
Journal Article
Dose-intensive therapy for breast cancer O'Shaughnessy, J A; Cowan, K H
JAMA : the journal of the American Medical Association,
11/1993, Letnik:
270, Številka:
17
Journal Article
A point about stilettos Joyce, C.W; O' Shaughnessy, M
Journal of plastic, reconstructive & aesthetic surgery,
01/2016, Letnik:
69, Številka:
1
Journal Article
Background: Fight bite injuries are typically sustained by young, combative males and are the direct consequence of an aggressive act. Second to fourth digit ratios (2D:4D) are dependent on prenatal ...androgen exposure and lower ratios have been shown to be linked to various psychological and physical traits, including aggression. The aim of this study was to examine the 2D:4D ratios in a cohort of patients with fight bite injuries and compare these to an age and gender-matched control group.
Methods: The 2D:4D ratios were calculated using plain films of the hand from 133 patients (122 males, 11 females) with fight bite injuries. A further 133 radiographs were obtained from patients that did not have fight bite injuries and digit ratios were calculated in the same fashion. Statistical analysis was then carried out to compare the 2D:4D ratios between the different groups.
Results: The 2D:4D ratios for male fight bite patients was significantly smaller than the male control group (p < 0.05). No significant difference was observed between the female fight bite patients and the female control group (p > 0.05).
Conclusions: Fight bite injuries are usually sustained as a result of aggression. 2D:4D ratios are reflect intrauterine androgen exposure and low ratios have been linked to aggressive tendencies. We have demonstrated that male patients who sustained fight bite injuries have a lower 2D:4D ratio then the general population, thereby suggesting that exposure to prenatal androgens can lead to aggressive tendencies in adulthood. This suggests that lower ratios may predict a predisposition to acts of aggression, and as such result in an increased likelihood of sustaining an injury such as a fight bite.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Oral cyclophosphamide is well tolerated and effective. Published data support its use as part of adjuvant and metastatic breast cancer treatment regimens. Cyclophosphamide has generally been ...administered at a higher dose intensity when given orally compared with intravenous infusion. However, there is currently no evidence that oral cyclophosphamide is either more toxic or more or less effective than an equivalent dose of intravenous cyclophosphamide. There is evidence in both the adjuvant and metastatic settings that classical oral cyclophosphamide-methotrexate-fluorouracil (CMF) is more effective than intravenous CMF, possibly because of the greater dose intensity of classical CMF. Prolonged administration of oral cyclophosphamide up to high cumulative doses is associated with an elevated risk of a secondary leukaemia. The rates of chemotherapy-related amenorrhoea with oral cyclophosphamide are directly related to the total dose of cyclophosphamide administered and the patient's age. With the growing availability of other oral cytotoxic agents with demonstrated effectiveness in breast cancer, it is likely that oral cyclophosphamide will be incorporated once again into regimens for both metastatic and adjuvant treatment.
A point about stilettos Joyce, C W; O' Shaughnessy, M
Journal of plastic, reconstructive & aesthetic surgery : JPRAS,
01/2016, Letnik:
69, Številka:
1
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