Breast cancer prognostic classification in the molecular era: the role of histological grade

Rakha, Emad A.; Reis‐Filho, Jorge S.; Baehner, Frederick L.; Dabbs, David J.; Decker, Thomas; Eusebi, Vincenzo; Fox, Stephen B.; Ichihara, Shu; Jacquemier, Jocelyne; Lakhani, Sunil R.; Palacios, José; Richardson, Andrea L.; Schnitt, Stuart J.; Schmitt, Fernando; Tan, Puay Hoon; Tse, Gary M.; Badve, Sunil; Ellis, Ian O.

doi:10.1186/bcr2607

Cited by 777 publications

(664 citation statements)

References 69 publications

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“…These developments and subsequent implementation of molecular classifications into routine diagnostics led to guidelines 21 which attribute a less important prognostic and particularly predictive power to classic morphology‐based parameters, that is, typing, grading and staging 13, 14, 20, 21, 22.…”

Section: Introductionmentioning

confidence: 99%

Classical pathology and mutational load of breast cancer – integration of two worlds

Budczies

Bockmayr

Denkert

et al. 2015

The Journal of Pathology CR

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Breast cancer is a complex molecular disease comprising several biological subtypes. However, daily routine diagnosis is still based on a small set of well‐characterized clinico‐pathological variables. Here, we try to link the two worlds of surgical pathology and multilayered molecular profiling by analyzing the relationships between clinico‐pathological phenotypes and mutational loads of breast cancer. We evaluated the number of mutated genes with somatic non‐silent mutations in different subgroups of breast cancer based on clinico‐pathological, including immunohistochemical and tumour characteristics. The analysis was performed for a cohort of 687 primary breast cancer patients with mutational profiling, gene expression and clinico‐pathological data available from The Cancer Genome Atlas (TCGA) project. The number of mutated genes was strongly positively associated with higher tumour grade (p = 1.4e−14) and with the different immunohistochemical and PAM50 molecular subtypes of breast cancer (p = 1.4e−10 and p = 4.3e−10, respectively). We observed significant associations (|R| > 0.4) between the abundance of mutated genes and expression levels of genes related to proliferation in the overall cohort and hormone receptor positive cohort, including the Recurrence Score gene signature (e.g., MYBL2 and BIRC5). Specific mutated genes (TP53, NCOR1, NF1, PTPRD and RB1) were highly significantly associated with high loads of mutated genes. Multivariate analysis for overall survival (OS) revealed a worse survival for patients with high numbers of mutated genes (hazard ratio = 4.6, 95% CI: 1.0 – 20.0, p = 0.044). Here, we report a strong association of the number of mutated genes with immunohistochemical and PAM50 subtypes and tumour grade in breast cancer. We provide evidence that specific levels of the mutational load underlie different morphological and biological phenotypes, which collectively constitute the current basis of pathological diagnosis. Our study is a step towards genomics‐informed breast pathology and will provide a basis for future studies in this field bridging the gap between morphology, tumour biology and medical oncology.

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Section: Introductionmentioning

confidence: 99%

Classical pathology and mutational load of breast cancer – integration of two worlds

Budczies

Bockmayr

Denkert

et al. 2015

The Journal of Pathology CR

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“…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: 84%

“…7,26 and emphasized its relevance in breast cancer biology and behavior. 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.…”

Section: Discussionmentioning

confidence: 99%

“…38 However, in order to critically evaluate their role in breast cancer management, we must understand the limitations of the available molecular prognostic/predictive tests, 2 apart from the recognized subjectivity of the biostatistical approaches they employ. 26 Recent studies comparing various algorithms for molecular classification showed less than optimal agreement, comparing unfavorably with agreement a 15 …”

Section: Discussionmentioning

confidence: 99%

“…The Recurrence Score is based on expression levels of genes related to hormone receptor/HER2 signaling and cell proliferation to predict a 10-year distant recurrence risk as a continuous variable, assuming that patients receive adjuvant hormonal manipulation. It is also subdivided into three risk categories: low (o18), intermediate (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) and high (430) scores.…”

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confidence: 99%

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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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Multicenter Survival Analysis and Application of an Olfactory Neuroblastoma Staging Modification Incorporating Hyams Grade

Choby

Geltzeiler

Almeida

et al. 2023

JAMA Otolaryngol Head Neck Surg

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ImportanceCurrent olfactory neuroblastoma (ONB) staging systems inadequately delineate locally advanced tumors, do not incorporate tumor grade, and poorly estimate survival and recurrence.ObjectiveThe primary aims of this study were to (1) examine the clinical covariates associated with survival and recurrence of ONB in a modern-era multicenter cohort and (2) incorporate Hyams tumor grade into existing staging systems to assess its ability to estimate survival and recurrence.Design, Setting, and ParticipantsThis retrospective, multicenter, case-control study included patients with ONB who underwent treatment between January 1, 2005, and December 31, 2021, at 9 North American academic medical centers.InterventionStandard-of-care ONB treatment.Main Outcome and MeasuresThe main outcomes were overall survival (OS), disease-free survival (DFS), and disease-specific survival (DSS) as C statistics for model prediction.ResultsA total of 256 patients with ONB (mean [SD] age, 52.0 [15.6] years; 115 female [44.9%]; 141 male [55.1%]) were included. The 5-year rate for OS was 83.5% (95% CI, 78.3%-89.1%); for DFS, 70.8% (95% CI, 64.3%-78.0%); and for DSS, 94.1% (95% CI, 90.5%-97.8%). On multivariable analysis, age, American Joint Committee on Cancer (AJCC) stage, involvement of bilateral maxillary sinuses, and positive margins were associated with OS. Only AJCC stage was associated with DFS. Only N stage was associated with DSS. When assessing the ability of staging systems to estimate OS, the best-performing model was the novel modification of the Dulguerov system (C statistic, 0.66; 95% CI, 0.59-0.76), and the Kadish system performed most poorly (C statistic, 0.57; 95% CI, 0.50-0.63). Regarding estimation of DFS, the modified Kadish system performed most poorly (C statistic, 0.55; 95% CI, 0.51-0.66), while the novel modification of the AJCC system performed the best (C statistic, 0.70; 95% CI, 0.66-0.80). Regarding estimation of DSS, the modified Kadish system was the best-performing model (C statistic, 0.79; 95% CI, 0.70-0.94), and the unmodified Kadish performed the worst (C statistic, 0.56; 95% CI, 0.51-0.68). The ability for novel ONB staging systems to estimate disease progression across stages was also assessed. In the novel Kadish staging system, patients with stage VI disease were approximately 7 times as likely to experience disease progression as patients with stage I disease (hazard ratio [HR], 6.84; 95% CI, 1.60-29.20). Results were similar for the novel modified Kadish system (HR, 8.99; 95% CI, 1.62-49.85) and the novel Dulguerov system (HR, 6.86; 95% CI, 2.74-17.18).Conclusions and RelevanceThe study findings indicate that 5-year OS for ONB is favorable and that incorporation of Hyams grade into traditional ONB staging systems is associated with improved estimation of disease progression.

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Breast cancer prognostic classification in the molecular era: the role of histological grade

Cited by 777 publications

References 69 publications

Classical pathology and mutational load of breast cancer – integration of two worlds

Classical pathology and mutational load of breast cancer – integration of two worlds

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

Multicenter Survival Analysis and Application of an Olfactory Neuroblastoma Staging Modification Incorporating Hyams Grade

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