Expression of <scp>MAGE</scp>‐A and <scp>NY</scp>‐<scp>ESO</scp>‐1 cancer/testis antigens is enriched in triple‐negative invasive breast cancers

Raghavendra, Ashwini; Croft, Priyakshi Kalita-de; Vargas, Ana Cristina; Smart, Chanel E.; Simpson, Peter T.; Saunus, Jodi M.; Lakhani, Sunil R.

doi:10.1111/his.13498

Cited by 37 publications

(36 citation statements)

References 66 publications

(131 reference statements)

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“…We found no significant association between WHO type and size (Figure E), size and grade (Figure F), or WHO type and age at diagnosis (Figure G). The features of the metaplastic cohort showed limited similarity in distribution when compared with a cohort of grade 2 and grade 3 IC‐NSTs from the Queensland Follow‐Up (QFU) set (Table ). In fact, the only criteria without significant differences were age at diagnosis and presence of in situ disease and lymphovascular invasion.…”

Section: Resultsmentioning

confidence: 99%

“…Table S1 in the supplementary material details the origins of the cohort, as provided by the AP‐MBC Consortium. The Queensland Follow‐Up (QFU) cohort was also employed in this study as a cross‐sectional control cohort. It comprises 527 non‐metaplastic breast tumours sampled in duplicate on tissue microarrays, with detailed clinicopathological annotation and median follow‐up of 21.4 years (censored cases).…”

Section: Methodsmentioning

confidence: 99%

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Phenotypic and molecular dissection of metaplastic breast cancer and the prognostic implications

Reed

Kalaw

Nones

et al. 2018

The Journal of Pathology

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Metaplastic breast carcinoma (MBC) is relatively rare but accounts for a significant proportion of global breast cancer mortality. This group is extremely heterogeneous and by definition exhibits metaplastic change to squamous and/or mesenchymal elements, including spindle, squamous, chondroid, osseous, and rhabdomyoid features. Clinically, patients are more likely to present with large primary tumours (higher stage), distant metastases, and overall, have shorter 5‐year survival compared to invasive carcinomas of no special type. The current World Health Organisation (WHO) diagnostic classification for this cancer type is based purely on morphology – the biological basis and clinical relevance of its seven sub‐categories are currently unclear. By establishing the Asia‐Pacific MBC (AP‐MBC) Consortium, we amassed a large series of MBCs (n = 347) and analysed the mutation profile of a subset, expression of 14 breast cancer biomarkers, and clinicopathological correlates, contextualising our findings within the WHO guidelines. The most significant indicators of poor prognosis were large tumour size (T3; p = 0.004), loss of cytokeratin expression (lack of staining with pan‐cytokeratin AE1/3 antibody; p = 0.007), EGFR overexpression (p = 0.01), and for ‘mixed’ MBC, the presence of more than three distinct morphological entities (p = 0.007). Conversely, fewer morphological components and EGFR negativity were favourable indicators. Exome sequencing of 30 cases confirmed enrichment of TP53 and PTEN mutations, and intriguingly, concurrent mutations of TP53, PTEN, and PIK3CA. Mutations in neurofibromatosis‐1 (NF1) were also overrepresented [16.7% MBCs compared to ∼5% of breast cancers overall; enrichment p = 0.028; mutation significance p = 0.006 (OncodriveFM)], consistent with published case reports implicating germline NF1 mutations in MBC risk. Taken together, we propose a practically minor but clinically significant modification to the guidelines: all WHO_1 mixed‐type tumours should have the number of morphologies present recorded, as a mechanism for refining prognosis, and that EGFR and pan‐cytokeratin expression are important prognostic markers. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Phenotypic and molecular dissection of metaplastic breast cancer and the prognostic implications

Reed

Kalaw

Nones

et al. 2018

The Journal of Pathology

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“…Archival formalin‐fixed, paraffin‐embedded (FFPE) tissue blocks were available for 39 cases: 15 cases with matched primary and metastatic tumours; 4 with only the primary available; 20 with only metastases available. The Queensland Follow‐Up (QFU) cohort was used to compare various clinico‐pathological parameters. This cohort contains 449 consecutive, unselected primary breast cancer cases diagnosed between 1986 and 1993 at the Royal Brisbane and Women's Hospital, with detailed clinical data and a minimum of 25 years clinical follow‐up data.…”

Section: Methodsmentioning

confidence: 99%

Breast cancer metastasis to gynaecological organs: a clinico‐pathological and molecular profiling study

Kutasovic

Reed

Males

et al. 2018

The Journal of Pathology CR

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Breast cancer metastasis to gynaecological organs is an understudied pattern of tumour spread. We explored clinico‐pathological and molecular features of these metastases to better understand whether this pattern of dissemination is organotropic or a consequence of wider metastatic dissemination. Primary and metastatic tumours from 54 breast cancer patients with gynaecological metastases were analysed using immunohistochemistry, DNA copy‐number profiling, and targeted sequencing of 386 cancer‐related genes. The median age of primary tumour diagnosis amongst patients with gynaecological metastases was significantly younger compared to a general breast cancer population (46.5 versus 60 years; p < 0.0001). Median age at metastatic diagnosis was 54.4, time to progression was 4.8 years (range 0–20 years), and survival following a diagnosis of metastasis was 1.95 years (range 0–18 years). Patients had an average of five involved sites (most frequently ovary, fallopian tube, omentum/peritoneum), with fewer instances of spread to the lungs, liver, or brain. Invasive lobular histology and luminal A‐like phenotype were over‐represented in this group (42.8 and 87.5%, respectively) and most patients had involved axillary lymph nodes (p < 0.001). Primary tumours frequently co‐expressed oestrogen receptor cofactors (GATA3, FOXA1) and harboured amplifications at 8p12, 8q24, and 11q13. In terms of phenotype conversion, oestrogen receptor status was generally maintained in metastases, FOXA1 increased, and expression of progesterone receptor, androgen receptor, and GATA3 decreased. ESR1 and novel AR mutations were identified. Metastasis to gynaecological organs is a complication frequently affecting young women with invasive lobular carcinoma and luminal A‐like breast cancer, and hence may be driven by sustained hormonal signalling. Molecular analyses reveal a spectrum of factors that could contribute to de novo or acquired resistance to therapy and disease progression.

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“…Tumours were sampled in tissue microarrays (TMAs) for IHC analysis of proteins in the HER4-YAP pathway, and other biomarkers of interest ( and survival data were assembled in a database linked by the TMA position of each case. We assessed clinical biomarkers by IHC (see in the following) according to diagnostic reporting standards, as described previously 46 : (i) oestrogen and progesterone receptors (hormone receptors, HR); (ii) human epidermal growth factor receptor 2 (HER2).…”

Section: Methodsmentioning

confidence: 99%

Clinicopathologic significance of nuclear HER4 and phospho-YAP(S¹²⁷) in human breast cancers and matching brain metastases

et al. 2020

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Background: Human epidermal growth factor receptor-4 (HER4) and yes-associated protein-1 (YAP) are candidate therapeutic targets in oncology. YAP’s transcriptional coactivation function is modulated by the HER4 intracellular domain (HER4-ICD) in vitro, but the clinical relevance of this has not been established. This study investigated the potential for targeting the HER4-YAP pathway in brain metastatic breast cancer. Methods: We performed immuno-phenotypic profiling of pathway markers in a consecutive breast cancer series with 25 years of clinical follow up ( n = 371), and patient-matched breast and metastatic brain tumours ( n = 91; 30 pairs). Results: Membrane localisation of phospho-HER4 [pHER4(Y1162)] was infrequent in primary breast cancer, but very frequent in brain metastases (5.9% versus 75% positive), where it was usually co-expressed with pHER3(Y1289) ( p < 0.05). The presence of YAP in tumour cell nuclei was associated directly with nuclear pERK5(T218/Y210) ( p = 0.003). However, relationships with disease-specific survival depended on oestrogen receptor (ER) status. Nuclear pYAP(S127) was associated with smaller, good prognostic ER+ breast tumours (log-rank hazard-ratio 0.53; p = 9.6E−03), but larger, poor prognostic triple-negative cancers (log-rank hazard-ratio 2.78; p = 1.7E−02), particularly when co-expressed with nuclear HER4-ICD ( p = 0.02). This phenotype was associated with stemness and mitotic instability markers (vimentin, SOX9, ID1, SPAG5, TTK, geminin; p < 0.05). YAP expression in brain metastases was higher than matched primary tumours; specifically, nuclear pYAP(S127) in ER-negative cases ( p < 0.05). Nuclear YAP was detected in ~70% of ER-negative, HER4-activated brain metastases. Discussion: Our findings suggest that the canonical-mechanism where Hippo pathway-mediated phosphorylation of YAP ostensibly excludes it from the nucleus is dysfunctional in breast cancer. The data are consistent with pYAP(S127) having independent transcriptional functions, which may include transducing neuregulin signals in brain metastases. Consistent with mechanistic studies implicating it as an ER co-factor, nuclear pYAP(S127) associations with breast cancer clinical outcomes were dependent on ER status. Conclusion: Preclinical studies investigating HER4 and nuclear YAP combination therapy strategies are warranted.

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Expression of MAGE‐A and NY‐ESO‐1 cancer/testis antigens is enriched in triple‐negative invasive breast cancers

Cited by 37 publications

References 66 publications

Phenotypic and molecular dissection of metaplastic breast cancer and the prognostic implications

Phenotypic and molecular dissection of metaplastic breast cancer and the prognostic implications

Breast cancer metastasis to gynaecological organs: a clinico‐pathological and molecular profiling study

Clinicopathologic significance of nuclear HER4 and phospho-YAP(S¹²⁷) in human breast cancers and matching brain metastases

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Expression of MAGE‐A and NY‐ESO‐1 cancer/testis antigens is enriched in triple‐negative invasive breast cancers

Cited by 37 publications

References 66 publications

Phenotypic and molecular dissection of metaplastic breast cancer and the prognostic implications

Phenotypic and molecular dissection of metaplastic breast cancer and the prognostic implications

Breast cancer metastasis to gynaecological organs: a clinico‐pathological and molecular profiling study

Clinicopathologic significance of nuclear HER4 and phospho-YAP(S127) in human breast cancers and matching brain metastases

Contact Info

Product

Resources

About

Clinicopathologic significance of nuclear HER4 and phospho-YAP(S¹²⁷) in human breast cancers and matching brain metastases