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Whitworth P.,Nashville Breast Center | Stork-Sloots L.,Agendia Inc. | de Snoo F.A.,Agendia Inc. | Richards P.,Blue Ridge | And 10 more authors.
Annals of Surgical Oncology | Year: 2014

Purpose: The 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. Methods: The 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. Results: A 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. Conclusions: BluePrint 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. © 2014, The Author(s).


Wesseling J.,Netherlands Cancer Institute | Tinterri C.,Instituto Clinico Humanitas IRCCS | Sapino A.,University of Turin | Zanconati F.,University of Trieste | And 15 more authors.
Virchows Archiv | Year: 2016

To compare results from messenger RNA (mRNA)-based TargetPrint testing with those from immunohistochemistry (IHC) and in situ hybridization (ISH) conducted according to local standard procedures at hospitals worldwide. Tumor samples were prospectively obtained from 806 patients at 22 hospitals. The mRNA level of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) was assessed by TargetPrint quantitative gene expression readouts. IHC/ISH assessments were performed according to local standards at the participating hospitals. TargetPrint readout showed a high concordance with IHC/ISH of 95 % (kappa 0.81) for ER, 81 % (kappa 0.56) for PR, and 94 % (kappa 0.76) for HER2. The positive/negative agreement between TargetPrint and IHC for ER, PR, and HER2 was 96 %/87 %, 84 %/74 %, and 74 %/98 %, respectively. The concordance rate in IHC/ISH results between hospitals varied: 88–100 % for ER (kappa 0.50–1.00); 50–100 % for PR (kappa 0.20–1.00); and 90–100 % for HER2 (kappa 0.59–1.00). mRNA readout of ER, PR, and HER2 status by TargetPrint was largely comparable to local IHC/ISH analysis. However, there was substantial discordance in IHC/ISH results between different hospitals. When results are discordant, the use of TargetPrint would improve the reliability of hormone receptor and HER2 results by prompting retesting in a reference laboratory. © 2016 Springer-Verlag Berlin Heidelberg


Nagourney R.A.,Todd Cancer Institute | Blitzer J.B.,Todd Cancer Institute | Shuman R.L.,Todd Cancer Institute | Asciuto T.J.,Todd Cancer Institute | And 4 more authors.
Anticancer Research | Year: 2012

Background/Aim: To assess the impact of drug selection upon the treatment of advanced and metastatic non-small cell lung cancer (NSCLC), we applied a functional platform that measures drug-induced cell death in human tumor primary-culture micro-spheroids isolated from surgical specimens. Patients and Methods: At diagnosis, microspheroids isolated by mechanical and enzymatic disaggregation were examined for drug-induced cell-death by morphology and staining characteristics. Drugs were administered using standard protocols. Thirty-one patients, who received at least one cycle of therapy, were evaluable. All patients signed informed consent. Results: Twenty out of 31 patients responded (64.5%), 1 completely and 19 partially, providing a two-fold improvement over historical control of 30% (p=0.00015), a median time-to-progression of 8.5 months and a median overall survival of 21.3 months. Conclusion: This functional platform is feasible and provides a favorable objective response rate, time-to-progression and survival in advanced, metastatic, untreated NSCLC, and warrants further evaluation.


Nguyen B.,Todd Cancer Institute | Cusumano P.G.,CHC | Deck K.,The Surgical Center | Kerlin D.,John Muir | And 8 more authors.
Annals of Surgical Oncology | Year: 2012

Purpose. To compare breast cancer subtyping with the three centrally assessed microarray-based assays BluePrint, MammaPrint, and TargetPrint with locally assessed clinical subtyping using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Methods. BluePrint, MammaPrint, and TargetPrint were all performed on fresh tumor samples. Microarray analysis was performed at Agendia Laboratories, blinded for clinical and pathological data. IHC/FISH assessments were performed according to local practice at each institution; estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) assessments were performed on 132 samples, and Ki-67 on 79 samples. Results. The concordance between BluePrint and IHC/ FISH subtyping was 94 % for the Luminal-type, 95 % for the HER2-type, and 94 % for the Basal-type subgroups. The concordance of BluePrint with subtyping using mRNA single gene readout (TargetPrint) was 96 % for the Luminal- type, 97 % for the HER2-type, and 98 % for the Basal-type subgroups. The concordance for substratification into Luminal A and B using MammaPrint and Ki-67 was 68 %. The concordance between TargetPrint and IHC/FISH was 97 % for ER, 80 % for PR, and 95 % for HER2. Conclusions. The implementation of multigene assays such as TargetPrint, BluePrint, and MammaPrint may improve the clinical management of breast cancer patients. High discordance between Luminal A and B substratification based on MammaPrint versus locally assessed Ki- 67 or grade indicates that chemotherapy decisions should not be based on the basis of Ki-67 readout or tumor grade alone. TargetPrint serves as a second opinion for those local pathology settings where high-quality standardization is harder to maintain. © Society of Surgical Oncology 2012.


Sapino A.,University of Turin | Roepman P.,Agendia Inc. | Linn S.C.,Netherlands Cancer Institute | Linn S.C.,University Utrecht | And 15 more authors.
Journal of Molecular Diagnostics | Year: 2014

MammaPrint, a prognostic 70-gene profile for early-stage breast cancer, has been available for fresh tissue. Improvements in RNA processing have enabled microarray diagnostics for formalin-fixed, paraffin-embedded (FFPE) tissue. Here, we describe method optimization, validation, and performance of MammaPrint using analyte from FFPE tissue. Laboratory procedures for enabling the assay to be run on FFPE tissue were determined using 157 samples, and the assay was established using 125 matched FFPE and fresh tissues. Validation of MammaPrint-FFPE, compared with MammaPrint-fresh, was performed on an independent series of matched tissue from five hospitals (n = 211). Reproducibility, repeatability, and precision of the FFPE assay (n = 87) was established for duplicate analysis of the same tumor, interlaboratory performance, 20-day repeat experiments, and repeated analyses over 12 months. FFPE sample processing had a success rate of 97%. The MammaPrint assay using FFPE analyte demonstrated an overall equivalence of 91.5% (95% confidence interval, 86.9% to 94.5%) between the 211 independent matched FFPE and fresh tumor samples. Precision was 97.3%, and repeatability was 97.8%, with highly reproducible results between replicate samples of the same tumor and between two laboratories (concordance, 96%). Thus, with 580 tumor samples, MammaPrint was successfully translated to FFPE tissue. The assay has high precision and reproducibility, and FFPE results are substantially equivalent to results derived from fresh tissue. © 2014 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.


PubMed | University of Turin, Agendia Inc., University of South Florida, Netherlands Cancer Institute and Todd Cancer Institute
Type: Journal Article | Journal: The Journal of molecular diagnostics : JMD | Year: 2014

MammaPrint, a prognostic 70-gene profile for early-stage breast cancer, has been available for fresh tissue. Improvements in RNA processing have enabled microarray diagnostics for formalin-fixed, paraffin-embedded (FFPE) tissue. Here, we describe method optimization, validation, and performance of MammaPrint using analyte from FFPE tissue. Laboratory procedures for enabling the assay to be run on FFPE tissue were determined using 157 samples, and the assay was established using 125 matched FFPE and fresh tissues. Validation of MammaPrint-FFPE, compared with MammaPrint-fresh, was performed on an independent series of matched tissue from five hospitals (n = 211). Reproducibility, repeatability, and precision of the FFPE assay (n = 87) was established for duplicate analysis of the same tumor, interlaboratory performance, 20-day repeat experiments, and repeated analyses over 12 months. FFPE sample processing had a success rate of 97%. The MammaPrint assay using FFPE analyte demonstrated an overall equivalence of 91.5% (95% confidence interval, 86.9% to 94.5%) between the 211 independent matched FFPE and fresh tumor samples. Precision was 97.3%, and repeatability was 97.8%, with highly reproducible results between replicate samples of the same tumor and between two laboratories (concordance, 96%). Thus, with 580 tumor samples, MammaPrint was successfully translated to FFPE tissue. The assay has high precision and reproducibility, and FFPE results are substantially equivalent to results derived from fresh tissue.


Amini A.,University of California at Irvine | Kakkis J.,Cancer Institute | Reitherman R.,Cancer Institute | Ibarra J.,Cancer Institute | And 3 more authors.
Anti-Cancer Drugs | Year: 2013

Metaplastic breast carcinoma (MBC) is a rare form of breast cancer comprising less than 1% of all invasive breast carcinomas. There are no clinical studies available for the management of this rare disease and MBC is associated with a poor prognosis. We present a case of a 50-year-old female patient with MBC who showed a favorable response with preoperative chemotherapy. The patient presented with a palpable left breast mass, and diagnostic breast imaging showed a 4.4 cm mass in the left breast, which was biopsied. Pathological review led to a diagnosis of MBC. Staging workup for distant metastasis was negative. She received four cycles of dose-dense AC (doxorubicin and cyclophosphamide), followed by 10 weekly doses of carboplatin (area under the curve=2) and paclitaxel (80 mg/m). The patient underwent partial mastectomy and sentinel lymph node sampling, and pathological review indicated a near-complete pathological response, with few scattered malignant cells at the tumor bed. A current review of the literature on MBC is summarized in this report. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Amini A.,University of California at Irvine | Sanati H.,University of California at Irvine | Sanati H.,Todd Cancer Institute
Anti-Cancer Drugs | Year: 2011

Management of gastric cancer in older adults is challenging. Perioperative treatment with epirubicin, cisplatin, and 5-fluorouracil combination chemotherapy and surgery is considered the standard treatment of locally advanced gastric adenocarcinoma. However, this chemotherapy regimen is not well tolerated in older adults. Here, we report a case of an older patient with locally advanced gastric cancer who was treated with modified FOLFOX-6 (oxaliplatin, leucovorin, and 5-fluorouracil) regimen and achieved a complete pathological response. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.


PubMed | Todd Cancer Institute
Type: Comparative Study | Journal: Annals of surgical oncology | Year: 2012

To compare breast cancer subtyping with the three centrally assessed microarray-based assays BluePrint, MammaPrint, and TargetPrint with locally assessed clinical subtyping using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH).BluePrint, MammaPrint, and TargetPrint were all performed on fresh tumor samples. Microarray analysis was performed at Agendia Laboratories, blinded for clinical and pathological data. IHC/FISH assessments were performed according to local practice at each institution; estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) assessments were performed on 132 samples, and Ki-67 on 79 samples.The concordance between BluePrint and IHC/FISH subtyping was 94 % for the Luminal-type, 95 % for the HER2-type, and 94 % for the Basal-type subgroups. The concordance of BluePrint with subtyping using mRNA single gene readout (TargetPrint) was 96 % for the Luminal-type, 97 % for the HER2-type, and 98 % for the Basal-type subgroups. The concordance for substratification into Luminal A and B using MammaPrint and Ki-67 was 68 %. The concordance between TargetPrint and IHC/FISH was 97 % for ER, 80 % for PR, and 95 % for HER2.The implementation of multigene assays such as TargetPrint, BluePrint, and MammaPrint may improve the clinical management of breast cancer patients. High discordance between Luminal A and B substratification based on MammaPrint versus locally assessed Ki-67 or grade indicates that chemotherapy decisions should not be based on the basis of Ki-67 readout or tumor grade alone. TargetPrint serves as a second opinion for those local pathology settings where high-quality standardization is harder to maintain.


PubMed | Todd Cancer Institute
Type: Journal Article | Journal: Anticancer research | Year: 2012

To assess the impact of drug selection upon the treatment of advanced and metastatic non-small cell lung cancer (NSCLC), we applied a functional platform that measures drug-induced cell death in human tumor primary-culture micro-spheroids isolated from surgical specimens.At diagnosis, microspheroids isolated by mechanical and enzymatic disaggregation were examined for drug-induced cell-death by morphology and staining characteristics. Drugs were administered using standard protocols. Thirty-one patients, who received at least one cycle of therapy, were evaluable. All patients signed informed consent.Twenty out of 31 patients responded (64.5%), 1 completely and 19 partially, providing a two-fold improvement over historical control of 30% (p=0.00015), a median time-to-progression of 8.5 months and a median overall survival of 21.3 months.This functional platform is feasible and provides a favorable objective response rate, time-to-progression and survival in advanced, metastatic, untreated NSCLC, and warrants further evaluation.

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