Triple-negative breast cancer: therapeutic options

Cleator, Susan; Heller, W.; Coombes, R. Charles

doi:10.1016/s1470-2045(07)70074-8

Cited by 777 publications

(713 citation statements)

References 66 publications

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“…Under such conditions, the DDR machinery including the ATM-Chk2-p53 cascade is activated and this environment selects for inactivation of the activated DDR barrier including ATM and p53 for example. This concept is consistent with the preferential association of ATM defects with BRCA1/ 2-deficient cancers reported in this study and with the enhanced frequency of p53 and ATM-aberrations in the triple-negative breast cancers that share some features of 'BRCAness' (Turner et al, 2004;Cleator et al, 2007). From the clinical point of view, the DNA-damagethreshold-related differences might be beneficial in response to PARP1 inhibitors and analogous drugs.…”

Section: Resultssupporting

confidence: 90%

“…The triple-negative tumours are typically highly proliferative, poorly differentiated and display extensive genetic instability. Interestingly, the triple-negative cancers share these and multiple additional features with the BRCA1-associated breast tumours including high incidence of p53 mutations, broadly similar mRNA expression profiles and poor prognosis (Cleator et al, 2007). Our present results indicate that the increased frequency of aberrant ATM Kilpivaara et al, 2005,).…”

Section: Resultssupporting

confidence: 60%

“…The p53 tumour suppressor protein is involved in the DDR and, -like BRCA1, it is also a direct substrate of the ATM kinase (Kastan and Bartek, 2004). Furthermore, like ATM, p53 was also found activated in early human lesions as part of the anticancer barrier (Bartkova et al, 2005a) and it is a marker which is reportedly elevated in BRCA1-deficient breast cancer and the triple-negative subset of breast tumours (Honrado et al, 2005;Cleator et al, 2007). As can be seen from the data in Table 2, there was no significant association of p53 overabundance (scored as positive when 20% or more cancer cells in a tumour were stained) with normal or aberrantly reduced ATM among the non-BRCA1/2 series.…”

Section: Resultsmentioning

confidence: 99%

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The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer

et al. 2007

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The ataxia-telangiectasia-mutated (ATM) kinase is a key transducer of DNA damage signals within the genome maintenance machinery and a tumour suppressor whose germline mutations predispose to familial breast cancer. ATM signalling is constitutively activated in early stages of diverse types of human malignancies and cell culture models in response to oncogene-induced DNA damage providing a barrier against tumour progression. As BRCA1 and BRCA2 are also components of the genome maintenance network and their mutations predispose to breast cancer, we have examined the ATM expression in human breast carcinomas of BRCA1/2 mutation carriers, sporadic cases and familial non-BRCA1/2 patients. Our results show that ATM protein expression is aberrantly reduced more frequently among BRCA1 (33%; P ¼ 0.0003) and BRCA2 (30%; P ¼ 0.0009) tumours than in non-BRCA1/2 tumours (10.7%). Furthermore, the non-BRCA1/2 tumours with reduced ATM expression were more often estrogen receptor (ER) negative (P ¼ 0.0002), progesterone receptor (PR) negative (P ¼ 0.004) and were of higher grade (P ¼ 0.0004). In our series of 1013 non-BRCA1/2 cases, ATM was more commonly deficient (20%; P ¼ 0.0006) and p53 was overabundant (47%; Po0.0000000001) among the difficult-to-treat ER/PR/ ERBB2-triple-negative subset of tumours compared with cases that expressed at least one of these receptors (10 and 16% of aberrant ATM and p53, respectively). We propose a model of 'conditional haploinsufficiency' for BRCA1/2 under conditions of enhanced DNA damage in precancerous lesions resulting in more robust activation and hence increased selection for inactivation or loss of ATM in tumours of BRCA1/2 mutation carriers, with implications for genomic instability and curability of diverse subsets of human breast cancer.

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Section: Resultssupporting

confidence: 90%

Section: Resultssupporting

confidence: 60%

Section: Resultsmentioning

confidence: 99%

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The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer

et al. 2007

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“…In our series, women with a triple negative tumour presented with a better short-term DFI compared with women with any of the three HER-2-positive subgroups; the literature frequently emphasizes the poor prognosis of this subgroup [48,53]. HER-2 as a poor prognostic marker is already now being affected by adjuvant trastuzumab therapy and triple negative tumors may, anyway, eventually become the subgroup with the worst DFI.…”

Section: Discussionmentioning

confidence: 60%

“…The proportion of breast cancers defined as ER-positive (87.47%) or PR-positive (75.18%) is higher than literaturereported proportions for ER (75%) and PR (55%) [7,14,48,49]. Improved laboratory sensitivity for detecting ER, different quantification techniques, and dichotomous cutoff values for assessing ER and PR account for important interlaboratory variability [36,50,51].…”

Section: Discussionmentioning

confidence: 88%

Short-term outcome of primary operated early breast cancer by hormone and HER-2 receptors

Brouckaert

Pintens

Belle

et al. 2008

Breast Cancer Res Treat

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Introduction Prognostic subgroup classification of operable breast cancers using cDNA clustering of breast cancer-related genes resembles the classification based on the combined immunohistochemical (IHC) expression of the hormone and HER-2 receptors. We here report the shortterm disease-free interval (DFI) of operable breast cancers by their joint hormone receptor/HER-2 phenotype. Patients and methods Short-term follow-up (FU) of a prospective cohort of 1,958 breast-cancer patients primary operated at our institution between 2000 and 2005. Receptors were evaluated using IHC. Steroid receptors were considered positive for any nuclear staining; HER-2 for strong (3+) membrane staining or positive fluorescence in situ hybridization (FISH). Kaplan-Meier (KM) DFI curves were calculated for any relapse defined as a local, regional, contralateral, or distant breast cancer event for the six predefined breast cancer subgroups: ER + PR + HER-2 -(PPN), ER + PR -HER-2 -(PNN), ER + PR + HER-2 + (PPP), ER -PR -HER-2 -(NNN), ER -PR -HER-2 + (NNP), and ER + PR -HER-2 + (PNP). P-values were calculated for comparison of the six different survival curves using two possible adaptations for multiple testing. A multivariate model for the receptors predicting DFI did incorporate local and systemic adjuvant therapy. Results Median patient age was 57 years (ranges 26-96) and median FU was 3.35 years. Overall, DFI at median FU was 91%; 94% for PPN, 89% for PNN, 86% for NNN, 81% for PPP, 80% for PNP, and 76% for NNP cases. Some receptor subgroups had a significantly better DFI than others based on multiple testing, especially when the PPN group was compared against the four most frequent subtypes. The multivariate model with local and systemic adjuvant therapy confirmed the prognostic value of ER, PR, and HER-2 for short-term DFI. Conclusion It is possible to distinguish short-term prognostic breast cancer subgroups only on the basis of ER, PR, and HER-2 even when stratified for local and systemic adjuvant therapy. While gene expression profiles based on microarray data of over hundreds of genes will probably teach us much about breast cancer biology, heterogeneity, and prognosis, we emphasize the important short-term prognostic value of currently used IHC markers for ER, PR, and HER-2.

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