The prognostic significance of the aberrant extremes of p53 immunophenotypes in breast cancer

Boyle, David P.; McArt, Darragh G.; Irwin, Gareth; Wilhelm-Benartzi, Charlotte S.; Lioe, T. F.; Sebastián, Elena; McQuaid, Stephen; Hamilton, Peter; James, Jacqueline; Mullan, Paul B.; Catherwood, Mark; Harkin, D. Paul; Salto-Tellez, Manuel

doi:10.1111/his.12398

Cited by 64 publications

(85 citation statements)

References 33 publications

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“…Full clinical and pathological follow-up was available for each patient, and full details regarding the cohort have been published previously. 8 Of note, 169 cases were Grade 3 (58%), 119 cases Grade 2 (41%) and 5 cases Grade 1 (2%), while at time of diagnosis 175 tumors were ER +ve (60%), 115 ER -ve (39%) and 3 had unknown ER status (1%). All patients received anthracycline-based chemotherapy, with or without radiotherapy.…”

Section: Materials and Methods Study Designmentioning

confidence: 96%

“…8 Immunohistochemistry All IHC was performed in a hybrid laboratory (Northern Ireland Molecular Pathology Laboratory) that has UK Clinical Pathology Accreditation, using established protocols described in detail elsewhere. 8 The antibodies used were as follows: anti-ER (clone 6F11 mouse monoclonal antibody; Leica); anti-PR (clone PgR 636 mouse monoclonal antibody; Dako); anti-HER2 (clone CB11 mouse monoclonal antibody; Leica); anti-p53 (clone DO-7 mouse monoclonal antibody; Dako, Cambridgeshire, UK). In the case of Ki67, the original data set was stained with NCL-Ki67-MM1 antibody on a Leica staining platform with a polymer-based detection system.…”

Section: Materials and Methods Study Designmentioning

confidence: 99%

“…All biomarkers in this data set were scored manually by a pathologist as described previously, 8 and the pathologist also selected appropriate clinical cutoff thresholds that should be applied to these scores following standard guidelines in the literature. 8 This allowed us to obtain a binary 'clinical score' variable distinguishing between positive and negative cases, which is not necessarily the modus operandi in clinical practice for some of these biomarkers but allowed a clear-cut comparison of the results.…”

Section: Manual Scoringmentioning

confidence: 99%

“…8 This allowed us to obtain a binary 'clinical score' variable distinguishing between positive and negative cases, which is not necessarily the modus operandi in clinical practice for some of these biomarkers but allowed a clear-cut comparison of the results. Briefly, ER and PR were evaluated using the Allred scoring method, giving scores in the range 0-8, where a score ≥ 3 was considered positive provided the proportion score was at least 2.…”

Section: Manual Scoringmentioning

confidence: 99%

“…8 Consequently, DIA scores were also generated here with two cutoffs. Nevertheless, the continuous nature of the H-score provided by DIA makes it amenable to alternative approaches to cutoff selection, which may be particularly valuable when biologically derived cutoffs are not available.…”

Section: Application Of Multiple Cutoffs To P53mentioning

confidence: 99%

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Integrated tumor identification and automated scoring minimizes pathologist involvement and provides new insights to key biomarkers in breast cancer

Bankhead

Fernández

McArt

et al. 2018

Laboratory Investigation

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Digital image analysis (DIA) is becoming central to the quantitative evaluation of tissue biomarkers for discovery, diagnosis and therapeutic selection for the delivery of precision medicine. In this study, automated DIA using a new purpose-built software platform (QuPath) is applied to a cohort of 293 breast cancer patients to score five biomarkers in tissue microarrays (TMAs): ER, PR, HER2, Ki67 and p53. This software is able to measure IHC expression following fully automated tumor recognition in the same immunohistochemical (IHC)-stained tissue section, as part of a rapid workflow to ensure objectivity and accelerate biomarker analysis. The digital scores produced by QuPath were compared with manual scores by a pathologist and shown to have a good level of concordance in all cases (Cohen's κ40.6), and almost perfect agreement for the clinically relevant biomarkers ER, PR and HER2 (κ40.86). To assess prognostic value, cutoff thresholds could be applied to both manual and automated scores using the QuPath software, and survival analysis performed for 5-year overall survival. DIA was shown to be capable of replicating the statistically significant stratification of patients achieved using manual scoring across all biomarkers (Po0.01, log-rank test). Furthermore, the image analysis scores were shown to consistently lead to statistical significance across a wide range of potential cutoff thresholds, indicating the robustness of the method, and identify sub-populations of cases exhibiting different expression patterns within the p53 and Ki67 data sets that warrant further investigation. These findings have demonstrated QuPath's suitability for fast, reproducible, high-throughput TMA analysis across a range of important biomarkers. This was achieved using our tumor recognition algorithms for IHC-stained sections, trained interactively without the need for any additional tumor recognition markers, for example, cytokeratin, to obtain greater insight into the relationship between biomarker expression and clinical outcome applicable to a range of cancer types.

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Section: Materials and Methods Study Designmentioning

confidence: 96%

Section: Materials and Methods Study Designmentioning

confidence: 99%

Section: Manual Scoringmentioning

confidence: 99%

Section: Manual Scoringmentioning

confidence: 99%

Section: Application Of Multiple Cutoffs To P53mentioning

confidence: 99%

See 3 more Smart Citations

Integrated tumor identification and automated scoring minimizes pathologist involvement and provides new insights to key biomarkers in breast cancer

Bankhead

Fernández

McArt

et al. 2018

Laboratory Investigation

Self Cite

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Orthogonal MET analysis in a population‐representative stage II–III colon cancer cohort: prognostic and potential therapeutic implications

et al. 2021

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Clinical trials for MET inhibitors have demonstrated limited success for their use in colon cancer (CC). However, clinical efficacy may be obscured by a lack of standardisation in MET assessment for patient stratification. In this study, we aimed to determine the molecular context in which MET is deregulated in CC using a series of genomic and proteomic tests to define MET expression and identify patient subgroups that should be considered in future studies with MET-targeted agents. To this aim, orthogonal expression analysis of MET was conducted in a population-representative cohort of stage II/III CC patients (n=240) diagnosed in Northern Ireland from 2004 to 2008. Targeted sequencing was used to determine the relative incidence of MET R970C and MET T992I mutations within the cohort. MET amplification was assessed using dual-color dual-

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Subsets of salivary duct carcinoma defined by morphologic evidence of pleomorphic adenoma, PLAG1 or HMGA2 rearrangements, and common genetic alterations

Chiosea

Thompson

Weinreb

et al. 2016

Cancer

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Background We hypothesized that histogenetic classification of salivary duct carcinoma (SDC) could account for de novo cases and those with morphologic or molecular evidence (PLAG1, HMGA2 rearrangement, amplification) of pleomorphic adenoma (PA). Methods SDCs (n=66) were reviewed for morphologic evidence of PA. PLAG1 and HMGA2 alterations were detected by fluorescence in situ hybridization (FISH). PLAG1 positive cases were tested for FGFR1 rearrangement (by FISH). Thirty-nine cases were analyzed by the Ion Ampliseq Cancer HotSpot panel v2 for mutations and copy number variation in 50 cancer-related genes. Results Based on combined morphologic and molecular evidence of PA, four subsets of SDC emerged: 1) carcinomas with morphologic evidence of PA, but intact PLAG1 and HMGA2 (n=22); 2) carcinomas with PLAG1 (n=18), or 3) HMGA2 alteration (n=12); and 4) de novo carcinomas, without morphologic or molecular evidence of PA (n=14). The median disease free survival was 37 months (95% confidence interval, 28.4 – 45.6 months). Disease free survival and other clinicopathologic parameters did not differ by above defined subsets. Combined HRAS/PIK3CA mutations were seen predominantly in de novo carcinomas (5/8 vs 2/31, p = 0.035). ERBB2 copy number gain was not seen in de novo carcinoma (0/8 vs. 12/31, p = 0.08). TP53 mutations were more common in SDC ex PA than in de novo cases (17/31 vs. 1/8, p = 0.033). Conclusion The genetic profile of SDC varies with the absence or presence of pre-existing PA and its cytogenetic signature. Most de novo SDCs harbor combined HRAS/PIK3CA mutations and no ERBB2 amplification.

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The prognostic significance of the aberrant extremes of p53 immunophenotypes in breast cancer

Cited by 64 publications

References 33 publications

Integrated tumor identification and automated scoring minimizes pathologist involvement and provides new insights to key biomarkers in breast cancer

Integrated tumor identification and automated scoring minimizes pathologist involvement and provides new insights to key biomarkers in breast cancer

Orthogonal MET analysis in a population‐representative stage II–III colon cancer cohort: prognostic and potential therapeutic implications

Subsets of salivary duct carcinoma defined by morphologic evidence of pleomorphic adenoma, PLAG1 or HMGA2 rearrangements, and common genetic alterations

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