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- Brueffer, Christian, et al.
(författare)
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Abstract P4-09-03: On the development and clinical value of RNA-sequencing-based classifiers for prediction of the five conventional breast cancer biomarkers: A report from the population-based multicenter SCAN-B study
- 2018
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Ingår i: Cancer research. Supplement. - 1538-7445. ; 78:4
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Konferensbidrag (refereegranskat)abstract
- Background:In early breast cancer, five histopathological biomarkers are part of current clinical routines and used for determining prognosis and treatment: estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (ERBB2/HER2), Ki67, and Nottingham histological grade (NHG). We aimed to develop classifiers for these biomarkers based on tumor mRNA-sequencing (RNA-seq), compare classification performance to conventional histopathology, and test whether RNA-seq-based predictors could add value for patient risk-stratification.Patients and Methods:In total, 3678 breast tumors were studied. For 405 breast tumors in the training cohort, a comprehensive histopathological biomarker evaluation was performed by three pathology readings to estimate inter-pathologist variability on the original diagnostic slides as well as on repeat immunostains for this study, and the consensus biomarker status for all five conventional biomarkers was determined. Whole transcriptome gene expression profiling was performed by RNA-sequencing on the Illumina platform. Using RNA-seq-derived tumor gene expression data as input, single-gene classifiers (SGC) and multi-gene classifiers (MGC) were trained on the consensus pathology biomarker labels. The trained classifiers were tested on an independent prospective population-based series of 3273 primary breast cancer cases from the multicenter SCAN-B study with median 41 months follow-up (ClinicalTrials.gov identifier NCT02306096), and classifications were evaluated by agreement statistics and by Kaplan-Meier and Cox regression survival analyses.Results:For the histopathological evaluation, pathologist evaluation concordance was high for ER, PgR, and HER2 (average kappa values of .920, .891, and .899, respectively), but moderate for Ki67 and NHG (.734 and .581). Classification concordance between RNA-seq classifiers and histopathology for the independent 3273-cohort was similar to that within histopathology assessments, with SGCs slightly outperforming MGCs. Importantly, patients with discordant results, classified as hormone responsive (HoR+) by histopathology but non-hormone responsive by MGC, presented with significantly inferior overall survival compared to patients with concordant results. These results extended to patients with no adjuvant systemic therapy (hazard ratio, HR, 4.54; 95% confidence interval, CI, 1.42-14.5), endocrine therapy alone (HR 3.46; 95% CI, 2.01-5.95), or receiving chemotherapy (HR 2.57; 95% CI 1.13-5.86). For HoR+ cases receiving endocrine therapy alone, the MGC HoR classifier remained significant after multivariable adjustment (HR 3.14; 95% CI, 1.75-5.65).Conclusions:RNA-seq-based classifiers for the five key early breast cancer biomarkers were generally equivalent to conventional histopathology with regards to classification error rate. However, when benchmarked using overall survival, our RNA-seq classifiers provided added clinical value in particular for cases that are determined by histopathology to be hormone-responsive but by RNA-seq appear hormone-insensitive and have a significantly poorer outcome when treated with endocrine therapy alone
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- Loman, Niklas, et al.
(författare)
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Abstract P2-02-09: Breast cancer subtype distribution and circulating tumor DNA in response to neoadjuvant chemotherapy: Experiences from a preoperative cohort within SCAN-B
- 2018
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Ingår i: Cancer research. Supplement. - 1538-7445. ; 78:4
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Konferensbidrag (refereegranskat)abstract
- Introduction: Preoperative chemotherapy in early breast cancer increases the rate of breast preservation and provides prognostic information. In the case of residual disease, a change in subtypes may be observed. Sensitive and reproducible biomarkers predicting treatment response early during the treatment course are needed in order to better exploit the potential benefit of an individualized preoperative treatment.Material and Methods: In an ongoing prospective study within the population-based SCAN-B project (NCT02306096), patients undergoing preoperative chemotherapy for early or locally recurrent breast cancer have been treated with iv Epirubicin and Cyclophosphamide q3w x 3 in sequence with either Docetaxel q3w x 3 or Paclitaxel q1w x 9 with a preoperative intent. HER2-positive cases also received HER2-directed treatment. At baseline, patients were staged using sentinel node biopsy for clinically node-negative patients and CT scan for cytologically confirmed node-positive cases. A clinical core needle biopsy as well as tissue from the surgical specimen was collected for determination of conventional biomarkers including ER, PgR, HER2 and Ki67. Tumor biopsies for biomolecule-extraction and RNA-sequencing were taken using ultrasound guidance and collected fresh in RNAlater at baseline, after 2 treatment cycles, as well as at surgery. Blood plasma samples were collected at baseline, after one-, three-, and six- 3w treatment cycles, and post-surgery. Using RNA-sequencing data, somatic mutations were identified in the tumor biopsies and personalized analyses for circulating tumor DNA (ctDNA) were performed. A pathological complete remission (pCR) was defined as the complete disappearance of invasive breast cancer in the breast and axilla at time of definitive surgery. Subtyping was performed using modified St Gallen criteria (2013).Results: Thus far, 45 patients aged 24-74 years have been included, of which 34 (76 %) were clinical stage 2 and 11 (24%) were stage 3. The subtype distribution at baseline was five Luminal A-like (11 %), 21 Luminal B-like (HER2 negative) (47 %), 8 HER2-positive (18 %) and 11 Triple-negative (ductal) (24 %). The rates of pCR in 38 operated cases to date were 0/3 Luminal A-like, 3/19 Luminal B-like (HER2 negative), 2/8 HER2-positive, and 4/7 Triple-negative (overall 24 % pCR rate). One patient did not undergo surgery due to clinically progressive disease. In 25 cases with evaluable residual disease at surgery, there was a shift in the subtype in 13 (52 %), the majority of which represented a transition from Luminal B to Luminal A. No Triple-negative cases underwent a change in subtype during treatment. Results of the ctDNA analyses will be presented at the meeting.Discussion: We have established an infrastructure allowing for an extensive evaluation of preoperative chemotherapy in early breast cancer. The goal is to develop methods to refine response-guided treatment in early breast cancer using molecular responses in the tumor as well as in the blood circulation. The patients continue to be prospectively monitored with iterative ctDNA analyses during follow-up.
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- Morgan, G, et al.
(författare)
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Abstract P3-02-02: Concordance between immunohistochemical and gene-expression based subtyping of early breast cancer using core needle biopsies and surgical specimens - experices from SCAN-B
- 2018
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Ingår i: Cancer research. Supplement. - 1538-7445. ; 78:4
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Konferensbidrag (refereegranskat)abstract
- Introduction: Preoperative chemotherapy in early breast cancer increases the rate of breast preservation and provides prognostic information. Treatment decisions in these cases rely on biomarker assessments and subtyping from tissue acquired through core needle biopsies. Tumor heterogeneity and representativity are pit-falls when limited tissue is available. Biomarker expression may change considerably as a result of preoperative chemotherapy, and in a subset of cases a complete pathological response at time of surgery may even preclude any further assessment. Therefore, the reliability and reproducibility of biomarkers in base-line core biopsies are of utmost importance for patients treated with preoperative chemotherapy.Material and Methods: In an ongoing population-based study of early breast cancer, the SCAN-B (NCT02306096), patients were identified for whom an ultra-sound guided core needle biopsy was analyzed for biomarkers during primary clinical work-up and the patient was offered primary surgery as initial treatment. Clinical biomarker profiles including immunohistochemical (IHC) determinations of ER, PgR, HER2 and Ki67 were translated to subtypes according to modified St Gallen criteria (2013) and compared with paired samples from surgical specimens. In addition, tumor specimens for biomolecule extraction and RNA sequencing were collected fresh in RNAlater.Results: IHC data was available from 51 paired samples. The subtype distribution in core needle biopsies was DCIS in 1 case (2 %), LCIS in 1 case (2 %) Luminal A-like in 16 cases (31 %), Luminal B-like (HER2 negative) in 26 cases (51 %), Luminal B-HER2-like (HER2 positive) in 4 cases (8 %), HER2-positive (non-luminal) in 1 case (2 %) and triple negative (ductal) breast cancer in 2 cases (4 %). The subtype distribution in surgical specimens was DCIS in 0 case (0 %), LCIS in 1 case (2 %) Luminal A-like in 18 cases (35 %), Luminal B-like (HER2negative) in 23 cases (45 %), Luminal B--like (HER2 positive) in 6 cases (12 %), HER2-positive (non-luminal) in 1 case (2 %) and triple negative (ductal) breast cancer in 2 cases (4 %). Notably, 5/16 cases classified as Luminal A-like in the core needle biopsy were reclassified as Luminal B-like (HER2-negative) in the surgical specimen, whereas 9/26 cases classified as Luminal B-like (HER2-negative) in the core needle biopsy were reclassified as either Luminal A-like (7 cases) or Luminal B-like (HER2 positive) (2 cases) in the surgical specimen. In all instances, except one, transition between Luminal A-like and Luminal B-like was due to recorded Ki67 expression. One case that was classified as a DCIS in the core needle was reclassified as Luminal B-like (HER2 negative) at time of surgery.Discussion: In this limited material, discordance between evaluations regarding Luminal A-like and Luminal B-like was considerable. Especially the misclassification of primary HER2-positive breast cancer needs further evaluation. These findings may be caused by tumor heterogeneity, and highlight the risk of both over- and under-treatment upon biomarker assessment from core needle biopsies. Data from gene expression based subtype classifications will be presented during the meeting.
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- Staaf, Johan, et al.
(författare)
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Abstract P1-06-01: Putting multigene signatures to the test: Prognostic assessment in population-based contemporary clinical breast cancer
- 2018
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Ingår i: Cancer research. Supplement. - 1538-7445. ; 78:4
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Konferensbidrag (refereegranskat)abstract
- Background Gene expression signatures hold promise for a molecularly driven division of primary breast cancer with clinical implications. A gap still remains in the application/validation of such signatures in actual clinical treatment groups from unselected, population-based, primary breast cancer receiving current standard of care therapy. We analyzed classification proportions and overall survival (OS) of 14 reported gene expression phenotypes (GEPs) and risk predictors (RPs) in seven clinical treatments groups from an 3273-sample breast cancer cohort representative of population-based disease in the South Swedish healthcare region. Patients and methods Between 2010-09-01 to 2015-03-31, 5101 (87%) of 5892 patients with invasive primary disease in the healthcare region were included in the SCAN-B study (ClinicalTrials.gov ID: NCT02306096). Inclusion criteria included no generalized/prior contralateral disease and known surgery/treatment status (neo- or adjuvant). 3273 tumors were profiled by RNA sequencing and matched to clinicopathological patient data from the National Breast Cancer Register, with distribution of clinicopathological characteristics reflecting proportions in the catchment region. RNA profiles were classified according to 14 reported gene signatures featuring both GEPs (PAM50, IC10, CIT, TNBCtype) and specific risk predictors (e.g. Oncotype Dx, 70-gene, 76-gene, ROR-variants, genomic grade index). Classifications were investigated for association with patient OS by univariate and multivariate analyses in seven adjuvant clinical treatment groups: TNBC-ACT (adjuvant chemotherapy, n=228), TNBC-untreated (n=83), HER2+/ER- with trastuzumab + ACT treatment (n=101), HER2+/ER+ with trastuzumab + ACT + endocrine treatment (n=210), ER+/HER2- with endocrine treatment (n=1477), ER+/HER2- with endocrine + ACT treatment (n=637), and ER+/HER2- untreated (n=216). Results For the majority of signatures, analysis of classification demonstrated prognostic value limited to ER+/HER2- tumors given follow-up time. Several signatures (including Oncotype Dx, 70-gene, ROR-variants) showed strong predictive value in identifying a subset of ER+/HER2- patients receiving a combination of endocrine and ACT therapy with excellent overall survival (>96%), indicating appropriate therapy selection. In addition, for both ER+/HER2- treatment groups signature analysis identified high-risk groups of patients in clear need of additional treatment beyond standard therapeutic regimes, even with less than 5-years of follow-up. Conclusions Our results support the prognostic association of gene expression signatures in large unselected population-based primary breast cancer cohorts even with a short follow-up of OS.Importantly, prognostic associations are limited to specific subgroups for different classifiers and in population-based breast cancer some clinically important subgroups constitute a small proportion of cases. In this context, continued population-based inclusion and broad transcriptional profiling of breast cancer patients provides an opportunity for application to broader patient groups (e.g. TNBC and HER2+), and for consensus classification of individual risk assessments that could potentially provide more stable predictions.
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- Cunha, Sara I., et al.
(författare)
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Endothelial ALK1 Is a Therapeutic Target to Block Metastatic Dissemination of Breast Cancer.
- 2015
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Ingår i: Cancer Research. - 1538-7445 .- 0008-5472. ; 75:12, s. 2445-2456
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Tidskriftsartikel (refereegranskat)abstract
- Exploration of new strategies for the prevention of breast cancer metastasis is justifiably at the center of clinical attention. In this study, we combined a computational biology approach with mechanism-based preclinical trials to identify inhibitors of activin-like receptor kinase (ALK) 1 as effective agents for blocking angiogenesis and metastasis in breast cancer. Pharmacologic targeting of ALK1 provided long-term therapeutic benefit in mouse models of mammary carcinoma, accompanied by strikingly reduced metastatic colonization as a monotherapy or part of combinations with chemotherapy. Gene-expression analysis of breast cancer specimens from a population-based nested case-control study encompassing 768 subjects defined endothelial expression of ALK1 as an independent and highly specific prognostic factor for metastatic manifestation, a finding that was corroborated in an independent clinical cohort. Overall, our results suggest that pharmacologic inhibition of endothelial ALK1 constitutes a tractable strategy for interfering with metastatic dissemination of breast cancer. Cancer Res; 75(12); 2445-56. ©2015 AACR.
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