A diagnostic gene profile for molecular subtyping of breast cancer associated with treatment response

Krijgsman, Oscar; Roepman, Paul; Zwart, Wilbert; Carroll, Jason S.; Tian, Sun; Snoo, Femke A. de; Bender, Richard A.; Bernards, René; Glas, Annuska M.

doi:10.1007/s10549-011-1683-z

Cited by 129 publications

(139 citation statements)

References 40 publications

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“…[12, 13] Another assay, Agendia’s MammaPrint [10, 11, 14] utilizes a 70-gene expression panel to determine a recurrence risk for early stage breast cancer. However, this assay must be combined with an additional 80-gene molecular subtyping assay, BluePrint [15], to predict neoadjuvant response [16]. …”

Section: Introductionmentioning

confidence: 99%

The E2F4 prognostic signature predicts pathological response to neoadjuvant chemotherapy in breast cancer patients

et al. 2017

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BackgroundNeoadjuvant chemotherapy is a key component of breast cancer treatment regimens and pathologic complete response to this therapy varies among patients. This is presumably due to differences in the molecular mechanisms that underlie each tumor’s disease pathology. Developing genomic clinical assays that accurately categorize responders from non-responders can provide patients with the most effective therapy for their individual disease.MethodsWe applied our previously developed E2F4 genomic signature to predict neoadjuvant chemotherapy response in breast cancer. E2F4 individual regulatory activity scores were calculated for 1129 patient samples across 5 independent breast cancer neoadjuvant chemotherapy datasets. Accuracy of the E2F4 signature in predicting neoadjuvant chemotherapy response was compared to that of the Oncotype DX and MammaPrint predictive signatures.ResultsIn all datasets, E2F4 activity level was an accurate predictor of neoadjuvant chemotherapy response, with high E2F4 scores predictive of achieving pathologic complete response and low scores predictive of residual disease. These results remained significant even after stratifying patients by estrogen receptor (ER) status, tumor stage, and breast cancer molecular subtypes. Compared to the Oncotype DX and MammaPrint signatures, our E2F4 signature achieved similar performance in predicting neoadjuvant chemotherapy response, though all signatures performed better in ER+ tumors compared to ER- ones. The accuracy of our signature was reproducible across datasets and was maintained when refined from a 199-gene signature down to a clinic-friendly 33-gene panel.ConclusionOverall, we show that our E2F4 signature is accurate in predicting patient response to neoadjuvant chemotherapy. As this signature is more refined and comparable in performance to other clinically available gene expression assays in the prediction of neoadjuvant chemotherapy response, it should be considered when evaluating potential treatment options.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3297-2) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

The E2F4 prognostic signature predicts pathological response to neoadjuvant chemotherapy in breast cancer patients

et al. 2017

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“…One recently available molecular profile is BluePrint. The profile determines the mRNA levels of 80 genes that discriminate between three breast cancer subtypes based on functional molecular pathways: Luminal, HER2, and Basal 1. A further stratification of the Luminal group into types A and B is important to identify the risk of metastasis and has been related to tumor grade and/or proliferation (Ki-67 fraction or mitosis) 2.…”

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confidence: 99%

Chemosensitivity Predicted by BluePrint 80-Gene Functional Subtype and MammaPrint in the Prospective Neoadjuvant Breast Registry Symphony Trial (NBRST)

Whitworth¹,

Stork‐Sloots

Snoo

et al. 2014

Ann Surg Oncol

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PurposeThe purpose of the NBRST study is to compare a multigene classifier to conventional immunohistochemistry (IHC)/fluorescence in situ hybridization (FISH) subtyping to predict chemosensitivity as defined by pathological complete response (pCR) or endocrine sensitivity as defined by partial response.MethodsThe study includes women with histologically proven breast cancer, who will receive neoadjuvant chemotherapy (NCT) or neoadjuvant endocrine therapy. BluePrint in combination with MammaPrint classifies patients into four molecular subgroups: Luminal A, Luminal B, HER2, and Basal.ResultsA total of 426 patients had definitive surgery. Thirty-seven of 211 (18 %) IHC/FISH hormone receptor (HR)+/HER2− patients were reclassified by Blueprint as Basal (n = 35) or HER2 (n = 2). Fifty-three of 123 (43 %) IHC/FISH HER2+ patients were reclassified as Luminal (n = 36) or Basal (n = 17). Four of 92 (4 %) IHC/FISH triple-negative (TN) patients were reclassified as Luminal (n = 2) or HER2 (n = 2). NCT pCR rates were 2 % in Luminal A and 7 % Luminal B patients versus 10 % pCR in IHC/FISH HR+/HER2− patients. The NCT pCR rate was 53 % in BluePrint HER2 patients. This is significantly superior (p = 0.047) to the pCR rate in IHC/FISH HER2+ patients (38 %). The pCR rate of 36 of 75 IHC/FISH HER2+/HR+ patients reclassified as BPLuminal is 3 %. NCT pCR for BluePrint Basal patients was 49 of 140 (35 %), comparable to the 34 of 92 pCR rate (37 %) in IHC/FISH TN patients.ConclusionsBluePrint molecular subtyping reclassifies 22 % (94/426) of tumors, reassigning more responsive patients to the HER2 and Basal categories while reassigning less responsive patients to the Luminal category. These findings suggest that compared with IHC/FISH, BluePrint more accurately identifies patients likely to respond (or not respond) to NCT.

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“…Examples of FDA-approved kitted CDxs are the Roche COBAS 4800 test for BRAF V600E mutation detection as a CDx for vemurafenib (Zelboraf) and the Abbott Vysis ALK Break Apart FISH Probe test to identify ALK-positive NSCLC patients for Pfizer’s approved NSCLC therapy Xalkori (Crizotinib) (108, 109, 113, 125). There is a separate class of lab-based, FDA-cleared IVDs, e.g., the Agendia MammaPrint assay (126) and the XDx AlloMap assay (127). The largest class of genetic tests is currently unregulated clinical lab-developed tests.…”

Section: Strategic Challenges For Drug and Diagnostic Developersmentioning

confidence: 99%

Navigating the Rapids: The Development of Regulated Next-Generation Sequencing-Based Clinical Trial Assays and Companion Diagnostics

2014

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Over the past decade, next-generation sequencing (NGS) technology has experienced meteoric growth in the aspects of platform, technology, and supporting bioinformatics development allowing its widespread and rapid uptake in research settings. More recently, NGS-based genomic data have been exploited to better understand disease development and patient characteristics that influence response to a given therapeutic intervention. Cancer, as a disease characterized by and driven by the tumor genetic landscape, is particularly amenable to NGS-based diagnostic (Dx) approaches. NGS-based technologies are particularly well suited to studying cancer disease development, progression and emergence of resistance, all key factors in the development of next-generation cancer Dxs. Yet, to achieve the promise of NGS-based patient treatment, drug developers will need to overcome a number of operational, technical, regulatory, and strategic challenges. Here, we provide a succinct overview of the state of the clinical NGS field in terms of the available clinically targeted platforms and sequencing technologies. We discuss the various operational and practical aspects of clinical NGS testing that will facilitate or limit the uptake of such assays in routine clinical care. We examine the current strategies for analytical validation and Food and Drug Administration (FDA)-approval of NGS-based assays and ongoing efforts to standardize clinical NGS and build quality control standards for the same. The rapidly evolving companion diagnostic (CDx) landscape for NGS-based assays will be reviewed, highlighting the key areas of concern and suggesting strategies to mitigate risk. The review will conclude with a series of strategic questions that face drug developers and a discussion of the likely future course of NGS-based CDx development efforts.

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A diagnostic gene profile for molecular subtyping of breast cancer associated with treatment response

Cited by 129 publications

References 40 publications

The E2F4 prognostic signature predicts pathological response to neoadjuvant chemotherapy in breast cancer patients

The E2F4 prognostic signature predicts pathological response to neoadjuvant chemotherapy in breast cancer patients

Chemosensitivity Predicted by BluePrint 80-Gene Functional Subtype and MammaPrint in the Prospective Neoadjuvant Breast Registry Symphony Trial (NBRST)

Navigating the Rapids: The Development of Regulated Next-Generation Sequencing-Based Clinical Trial Assays and Companion Diagnostics

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