Prognostic Significance of Nottingham Histologic Grade in Invasive Breast Carcinoma

Rakha, Emad A.; El-Sayed, Maysa E.; Lee, Andrew H.S.; Elston, C.W.; Grainge, Matthew J.; Hodi, Zsolt; Blamey, R.W.; Ellis, Ian O.

doi:10.1200/jco.2007.15.5986

Cited by 517 publications

(424 citation statements)

References 29 publications

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“…[26][27][28] Importantly, histological grade and type provide complementary information about the features of breast cancers. 14,29 Indeed, the main reason for recognizing special types of breast carcinoma is the improvement of prediction of the likely biological behavior beyond that provided by traditional prognostic factors. 26,28,30 Women diagnosed with most special type (ie, tubular, cribriform or mucinous) carcinomas have an excellent prognosis, often approaching that of the general population of the same age.…”

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confidence: 99%

A mitotically active, cellular tumor stroma and/or inflammatory cells associated with tumor cells may contribute to intermediate or high Oncotype DX Recurrence Scores in low-grade invasive breast carcinomas

et al. 2012

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Oncotype DX is an RT-PCR-based 21-gene assay validated to provide prognostic and predictive information in the form of a Recurrence Score in patients with estrogen receptor-positive, lymph node-negative breast cancer. Although the Recurrence Score was shown to correlate with several histopathological tumor features, there is a significant proportion of cases showing an apparent discrepancy between Recurrence Score and risk estimates based on the traditional clinicopathological tumor features. In this study, we tested whether a proliferating, cellular stroma and/or admixed inflammatory cells may result in an artificially increased Recurrence Score in low-grade invasive breast cancers. We analyzed the histopathological features in 141 low-grade invasive breast carcinomas, including 41 special type (tubular, cribriform and mucinous) carcinomas, with available Recurrence Score. The tumor stroma was evaluated for increased cellularity and presence of inflammatory cells. Double immunohistochemical stains for pancytokeratin and Ki-67 was performed to assess the cell proliferation in tumor vs stromal/inflammatory cells. The clinicopathological features of tumors with Recurrence Score o18 (low risk) were compared with those with Recurrence Score Z18 (intermediate/high risk). Carcinomas associated with Recurrence Score Z18 showed lower progesterone receptor immunoreactivity, increased stromal cellularity and presence of inflammatory cells associated with the tumor. Double immunohistochemical stains showed significantly increased proliferation in stromal/inflammatory cells compared with carcinoma cells in cases associated with Recurrence Score Z18. A Ki-67-positive stromal/ tumor cells ratio of 41 predicted Recurrence Score Z18 with an area under the curve of 0.8967 on receiver operator curve analysis (Po0.0001). Our results suggest that the presence of increased stromal cellularity and/ or associated inflammatory cells in low-grade invasive breast carcinomas may contribute to an apparently increased risk of recurrence according to Oncotype DX Recurrence Score. Careful assessment and correlation with histopathological features in such cases may help in determining the appropriate patient management.

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confidence: 99%

A mitotically active, cellular tumor stroma and/or inflammatory cells associated with tumor cells may contribute to intermediate or high Oncotype DX Recurrence Scores in low-grade invasive breast carcinomas

et al. 2012

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“…24 Several other large studies have also shown that patients with early stage, lowgrade invasive breast carcinoma have an excellent outcome with over 95% survival. [35][36][37] Indeed, we did not observe any recurrence in our series of lowgrade, early stage breast cancers, although the mean follow-up time was relatively short (54.3 months).…”

Section: Discussionmentioning

confidence: 44%

“…33,34 A compelling body of evidence suggests that histologic grade can accurately predict tumor behavior, particularly in early stage, small tumors, such as those included in this study. 25,29,35 Specifically, patients with breast cancers in the excellent and good Nottingham Prognostic Index groups (104 of 106 cases in this study) were reported to have excellent (96 ± 2 and 93 ± 2%, respectively) 10-year survival rates. 24 Several other large studies have also shown that patients with early stage, lowgrade invasive breast carcinoma have an excellent outcome with over 95% survival.…”

Section: Discussionmentioning

confidence: 63%

“…26,35,39 Based on our results in this highly selected group of low-grade, ER-positive, early stage breast cancers, the agreement between the Oncotype DX Recurrence Score and the Mammostrat Prognostic Index is poor, worse than agreement rates between pathologists regarding tumor grading, 26,35,39 and might be even poorer if cancers of all grades had been included. Several reasons may exist accounting for the discordance between the assays examined.…”

Section: Rs <18mentioning

confidence: 87%

“…Nevertheless, based on reported outcome data in small, low-grade, node-negative, ER-positive breast cancers, 35,36 we expect an excellent outcome in the cases included in this study.…”

Section: Rs <18mentioning

confidence: 90%

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Comparison of Oncotype DX and Mammostrat risk estimations and correlations with histologic tumor features in low-grade, estrogen receptor-positive invasive breast carcinomas

et al. 2013

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associated with increased stromal cellularity, presence of inflammatory cells and increased proliferation in stromal/inflammatory cells, compared with concordant cases showing low risk by both assays. Our results suggest that low-grade ER-positive breast carcinomas with increased stromal/ inflammatory cell proliferation may show an apparent increased risk of distant recurrence as assessed by Oncotype DX, which uses RNA extracted from a mixture of tumor and stromal/inflammatory cells in the assay. Mammostrat, which examines cancer cells only, may provide a better estimation of likely tumor behavior in a subgroup of low-grade breast carcinomas.

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Integrated multi‐omics profiling of high‐grade estrogen receptor‐positive, HER2‐negative breast cancer

Wang

Franch-Expósito

et al. 2021

Molecular Oncology

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Estrogen-receptor-positive, and human epidermal growth factor receptor 2-negative (ER+HER2−) breast cancer accounts for ~60−70% of all cases of invasive breast carcinoma. High-grade ER+HER2− tumors respond poorly to endocrine therapy. In this study, we systematically analyzed clinical and multi-omics data to find potential strategies for personalized therapy of patients with high-grade ER+HER2− disease. Six different cohorts were analyzed, for which multi-omics data were available. Grade III ER+HER2-cases harbored higher proportions of large tumor size (>5cm), lymph nodes metastasis, chemotherapy use and luminal B subtypes defined by PAM50, as compared with grade I/II tumors. DNA methylation (HM450) data and methylation specific PCR indicated that the cg18629132 locus in the MKI67 promoter was hypermethylated in grade I/II cases and normal tissue, but hypomethylated in grade III cases or triple negative breast cancer (TNBC), resulting in higher expression of MKI67. Mutations in ESR1 and TP53 were detected in post-endocrine−treatment metastatic samples at a higher rate than in treatment-naive tumors in grade III cases. We identified 42 and 20 focal copy number events in non-metastatic and metastatic high-grade ER+HER2− cases, respectively, with either MYC or MDM2 amplification representing an independent prognostic event in grade III cases. Transcriptional profiling within grade III tumors, highlighted ER signaling downregulation and upregulation of immune-related pathways in non-luminal-like tumors defined by PAM50. Recursive partitioning analysis (RPA) was employed to construct a decision tree of an endocrine-resistant subgroup (GATA3-negative and AGR-negative) of two genes that was validated by immunohistochemistry in a Chinese cohort. All together, these data suggest that grade III ER+HER2− tumors have distinct clinical and molecular characteristics compared with low-grade tumors, particularly in cases with non-luminal-like biology. Due to the dismal prognosis in this group, clinical trials are warranted to test the efficacy of potential novel therapies.

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Prognostic Significance of Nottingham Histologic Grade in Invasive Breast Carcinoma

Abstract: Histologic grade, as assessed by the Nottingham grading system, provides a strong predictor of outcome in patients with invasive breast cancer and should be incorporated in breast cancer staging systems.

Cited by 517 publications

References 29 publications

A mitotically active, cellular tumor stroma and/or inflammatory cells associated with tumor cells may contribute to intermediate or high Oncotype DX Recurrence Scores in low-grade invasive breast carcinomas

A mitotically active, cellular tumor stroma and/or inflammatory cells associated with tumor cells may contribute to intermediate or high Oncotype DX Recurrence Scores in low-grade invasive breast carcinomas

Comparison of Oncotype DX and Mammostrat risk estimations and correlations with histologic tumor features in low-grade, estrogen receptor-positive invasive breast carcinomas

Integrated multi‐omics profiling of high‐grade estrogen receptor‐positive, HER2‐negative breast cancer

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