Use Of MammaPrint Research Articles

Treatment response and 5-year distant metastasis-free survival outcome in breast cancer patients after the use of MammaPrint and BluePrint to guide preoperative systemic treatment decisions

AimIn the prospective neoadjuvant NBREaST II study, we measured the response to preoperative treatment and 5-year survival outcome in the molecular subgroups as determined by combining the MammaPrint and BluePrint. MethodsBetween 2012 and 2016 we included 256 patients for whom MammaPrint and BluePrint were performed on pre-treatment core needle biopsies. The primary objective of the NBREaST II trial was to measure chemosensitivity or endocrine sensitivity in the molecular subgroups. Distant metastasis-free survival (DMFS), relapse-free survival (RFS) and breast cancer-specific survival (BCSS) were the endpoints for long-term follow-up. ResultsMammaPrint and BluePrint molecular sub-typing reclassified 9% (24/256) of tumours, reassigning more responsive patients to the HER2-Type and Basal-Type, and less responsive patients to the Luminal-Type category. Patients with Luminal A-Type tumours (n = 67, 26% of the total cohort) had a poor response when treated with neoadjuvant chemotherapy (NCT), but had the highest 5-year DMFS outcome (91.4%; 95% CI 78.6–96.7) of all molecular subgroups. Out of the IHC/FISH defined HER2+ tumours (n = 41), 37% were not classified as HER2-Type by BluePrint. Notably, in BluePrint HER2-Type tumours, we observed a higher pCR rate, whereas the 5-year DMFS was lower compared to IHC/FISH-defined HER2+ tumours. The pCR rate and 5-year outcome for patients with Basal-Type tumours were similar to IHC/FISH-defined TN tumours. ConclusionThese findings suggest that MammaPrint and BluePrint can predict chemosensitivity and 5-year outcomes more accurately compared to traditional pathological sub-typing, supporting informed decision-making.

P088 - 5-yr DMFS outcomes on the pre-operative use of MammaPrint and BluePrint for neoadjuvant decisions in the NBREaST II trial

P088 - 5-yr DMFS outcomes on the pre-operative use of MammaPrint and BluePrint for neoadjuvant decisions in the NBREaST II trial

Abstract PS6-30: Combined use of MammaPrint and BluePrint assays to evaluate patients for response to neo-adjuvant chemotherapy for locally advanced breast cancer

Abstract Background: The main goal of the Multi-Institutional Neo-Adjuvant Therapy MammaPrint (MINT) project was to determine the predictive power of the combination of the molecular assays MammaPrint and BluePrint (Agendia Inc., Irvine, CA) for chemosensitivity as measured by complete pathological response (pCR) in patients with locally advanced breast cancer (LABC). MammaPrint is a 70-gene microarray-based assay that classifies each breast cancer patient as low or high risk to develop metastases within 10 years after diagnosis. The BluePrint test is an 80-gene molecular subtyping profile that discriminates between luminal, basal and HER-2 subtypes. Methods: After appropriate IRB approval, 270 female patients with histologically-proven invasive breast cancer and no distant metastases were enrolled in this study. Patients had a clinical tumor classification of T2-T4 with 0-3 positive lymph nodes. DCIS or LCIS was allowed in addition to invasive cancer at the T2 or T3 levels. At least one lesion had to be accurately measured in two dimensions utilizing mammogram, ultrasound, or MRI images to define specific size and validate pCR. Patients were required to have adequate bone marrow reserves, renal function and hepatic function, as determined by standard blood and serum measurements. Patients under 18 years of age or those with confirmed metastatic disease, inflammatory breast cancer, any serious uncontrolled intercurrent infections, or other serious uncontrolled concomitant disease were excluded. Patients with any prior chemotherapy, radiotherapy, or endocrine therapy for the treatment of breast cancer were also excluded. Tumor samples were collected via incisional or core needle biopsy and shipped to Agendia for processing of the MammaPrint and BluePrint gene panels, as well as whole human genome expression microarrays. Comparison of response rates between MammaPrint and BluePrint molecular subtypes was conducted using Pearson Chi-square test with chemo-responsiveness measured as a binary response: pCR or residual disease. Results: Of 270 patients enrolled, 56 did not have TNM or RCB staging information reported in the case report form and/or were not submitted for central pathology review. Of 214 patients evaluated by central pathology review, 68 (32%) exhibited a pCR. Patients with a high risk MammaPrint result had a higher pCR rate (37%) compared to patients with a low risk MammaPrint (0%). And patients with a HER-2 or basal molecular subtype by BluePrint had significantly higher rates of pCR (62%, 37%, respectively). Conclusion: Upfront evaluation of LABC tumors using the combination of MammaPrint and BluePrint can help in the clinico-pathologic evaluation to determine which patients are more likely to benefit from neo-adjuvant chemotherapy, ranging from expected minimal response in Luminal A to substantial responses for HER2-type and Basal-type tumors. Additional studies to evaluate the prognostic and/or predictive values of additional gene panels from the whole human genome microarrays are underway. Rate of pCR in MammaPrint and MammaPrint/BluePrint groupsGroupsResidual DiseasepCRP valueMP Risk GroupLow Risk27 (100%)0 (0%)0.0004High Risk114 (63%)67 (37%)BP subtypeBasal42 (63%)25 (37%)2 x 10-9HER220 (38%)33 (62%)Luminal A26 (100%)0 (0%)Luminal B53 (85%)9 (15%) Citation Format: Brian Longbottom, Steven C Shivers, Geza Acs, Charles E Cox. Combined use of MammaPrint and BluePrint assays to evaluate patients for response to neo-adjuvant chemotherapy for locally advanced breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-30.

Propensity score analysis of the prognostic value of genomic assays for breast cancer in diverse populations using the National Cancer Data Base.

Genomic assays such as Oncotype Dx (ODX) and MammaPrint are used for risk-adapted treatment decisions among patients with early breast cancer. However, to the authors' knowledge, concordance between genomic assays is modest. Using real-world data, the authors performed a comparative analysis of ODX and MammaPrint. A cohort of women diagnosed with early-stage, hormone receptor-positive breast cancer who received ODX or MammaPrint was established using the National Cancer Data Base (NCDB) for 2010 through 2016. Using the propensity score matching method, 2 groups of patients with similar clinical and demographic characteristics were defined: one group received ODX and the other received MammaPrint. The authors examined the association between use of the ODX or MammaPrint assays and overall survival using Cox models. Of the 451,693 eligible patients, approximately 45.3% received ODX and 1.8% received MammaPrint testing. The use of ODX increased from 36.1% in 2010 to 49.9% in 2016, whereas use of MammaPrint increased from 0.5% in 2010 to 3.3% in 2016. The authors matched 5042 patients who received ODX with 5042 patients who received MammaPrint. The 5-year risks of death for the MammaPrint low-risk group and the ODX low-risk group were 3.4% and 4.7%, respectively. The prognostic value of MammaPrint was similar to that of ODX; the C-index was 0.614 (95% confidence interval, 0.572-0.657) for MammaPrint and 0.581 (95% confidence interval, 0.530-0.631) for ODX. There was a difference in the performance of the ODX assay observed across racial and/or ethnic groups (P<.001), with a slightly better performance noted among white compared with African American and Hispanic individuals. Both the ODX and MammaPrint tests are good at identifying low-risk individuals who could be spared chemotherapy. The suboptimal performance of ODX in ethnic minority individuals deserves further investigation.

Prospective Validation of a Genomic Assay in Breast Cancer: The 70-gene MammaPrint Assay and the MINDACT Trial.

MammaPrint was the first genomic assay in breast cancer to be validated with a prospective randomized trial, the MINDACT trial. The 70 gene MammaPrint assay was developed to determine the risk of distant metastasis in early stage breast cancer through gene expression analysis and was the first FDA cleared genomic assay for breast cancer. The assay identifies primary breast cancers likely to metastasize within the first five years of diagnosis and has clinical utility for helping to determine the expected benefit from adjuvant chemotherapy. The MINDACT Trial was the first trial of a genomic assay in breast cancer to provide prospective, randomized evidence of clinical utility for this important clinical question, identifying a significant proportion of patients who could safely forgo chemotherapy within a cohort of patients with high risk clinical characteristics. Nearly half of all patients (46%) who would have been advised chemotherapy according to clinical guidelines were identified genomically by MammaPrint as being low risk and found to have equivalent rates of freedom from metastasis at 5 years with or without chemotherapy. Based upon the MINDACT trial, the ASCO Biomarker Guidelines now approve the use of MammaPrint to inform decisions regarding chemotherapy for women with clinically high-risk ER+ breast cancer, and as the only approved assay for use in women with 1-3 involved lymph nodes. Recent studies suggest information obtained from the 70-gene assay may also help inform decisions regarding endocrine therapy, as well as chemotherapy, targeted therapy and immunotherapy. CONCLUSION: The power of gene expression analysis in breast cancer, effectively illustrated with MammaPrint in the MINDACT trial, is now being explored through examination of the full transcriptome in breast cancer.

Abstract P4-08-12: Comparative analyses of the prognostic value of oncotype and mammaprint using the National Cancer Database

Abstract INTRODUCTION: Majority of the approximately 40,610 deaths from metastatic breast cancer in the US each year occur in women with hormone receptor positive breast cancer who recur after treatment for early stage disease. Genomic analysis is increasingly used to personalize breast cancer treatment for women with early breast cancer resulting in AJCC 8 modification of TNM staging. The 70-gene Mammaprint was developed using both ER- and ER+ breast tissue samples, while the 21-gene Oncotype DX (ODX) assay was developed using only ER+ breast tissue. Previous studies found that the two genomic assays gave discordant testing results. OBJECTIVE: To compare the performance of Mammaprint and Oncotype DX in assigning prognosis in early stage hormone receptor positive breast cancer. METHOD: A retrospective cohort of women diagnosed with early stage, hormone receptor positive breast cancer who received ODX or Mammaprint was established using the National Cancer Data Base (NCDB), 2010-2014. Using the propensity score matching method, we defined two groups of patients with similar clinical and demographic characteristics; one group received ODX and another received Mammaprint. The groups were matched by clinicopathologic and demographic factors. We examined the association between ODX or Mammaprint and overall survival using Log-rank test and Cox models in the two groups separately. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated as strength of association. The prognostic values were evaluated using c-index (i.e. area under ROC curve). RESULTS: Of 320,276 eligible patients with breast cancer, 41.5% received ODX and 1.3% received Mammaprint testing. The use of ODX increased from 34.3% in 2010 to 45.2% in 2014, while the use of Mammaprint increased from 0.5% in 2010 to 2.0% in 2014. After propensity score matching, we identified 3319 patients who received ODX and matched to 3319 patients who received Mammaprint. Compared to patients with a low risk Mammaprint score (n=1915), patients with a high risk Mammaprint score (n=1404) had 4.53-fold increased risk of dying (95% CI 2.79-7.36). The c-index for Mammaprint was 0.683. Relative to patients with a low ODX recurrence score (n=1927), the HR for intermediate ODX score was 1.23 (95% CI 0.76-1.98) and the HR for high ODX score was 3.62 (95% CI 2.21-5.94). The c-index for ODX was 0.601. In patients with ODX testing, 28.2% received chemotherapy. In patients with Mammaprint testing, 42.4% received chemotherapy. Based on MINDACT's modification of Adjuvant!Online, 49.2% patients were assigned to the clinical high risk group, including 22.3% to the clinical high risk/genomic low risk (C-high/G-low) subgroup and 26.9% to the C-high/G-high subgroup. The percentage of patients receiving chemotherapy with C-low/G-low, C-low/G-high, C-high/G-low, and C-high/G-high were 4.3%, 70.4%, 32.2%, and 84.9%, respectively. CONCLUSION: The findings from our preliminary study suggest that Mammaprint may achieve better separation of high risk from low risk patients. However, it is possible that having more genes in multigene assays would better capture the heterogeneity of hormone receptor positive breast cancer and guide choice of optimal systemic therapy to reduce risk of metastases. Citation Format: Ibraheem AF, Olopade O, Huo D. Comparative analyses of the prognostic value of oncotype and mammaprint using the National Cancer Database [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-08-12.

Mammaprint™: a comprehensive review.

The number of breast cancer (BC) cases is growing worldwide, being most frequently diagnosed in the early-setting. Mammaprint™ is a 70-gene-expression signature, originally designed for selecting early BC patients with low risk of developing metastasis, so that they could be spared adjuvant chemotherapy. Its use as a prognostic biomarker has been extensively validated, both retrospectively and prospectively. However, its value as a predictive tool and as a clinically useful tool remains controversial. This review will describe how the test works, its application in the clinic and its limitations. Cost-effectiveness studies will be summarized. Finally, we will provide a perspective on the use of Mammaprint in the near future, as a valuable tool for personalizing the treatment of early BC patients.

Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Focused Update.

Purpose This focused update addresses the use of MammaPrint (Agendia, Irvine, CA) to guide decisions on the use of adjuvant systemic therapy. Methods ASCO uses a signals approach to facilitate guideline updates. For this focused update, the publication of the phase III randomized MINDACT (Microarray in Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy) study to evaluate the MammaPrint assay in 6,693 women with early-stage breast cancer provided a signal. An expert panel reviewed the results of the MINDACT study along with other published literature on the MammaPrint assay to assess for evidence of clinical utility. Recommendations If a patient has hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-negative breast cancer, the MammaPrint assay may be used in those with high clinical risk to inform decisions on withholding adjuvant systemic chemotherapy due to its ability to identify a good-prognosis population with potentially limited chemotherapy benefit. Women in the low clinical risk category did not benefit from chemotherapy regardless of genomic MammaPrint risk group. Therefore, the MammaPrint assay does not have clinical utility in such patients. If a patient has hormone receptor-positive, HER2-negative, node-positive breast cancer, the MammaPrint assay may be used in patients with one to three positive nodes and a high clinical risk to inform decisions on withholding adjuvant systemic chemotherapy. However, such patients should be informed that a benefit from chemotherapy cannot be excluded, particularly in patients with greater than one involved lymph node. The clinician should not use the MammaPrint assay to guide decisions on adjuvant systemic therapy in patients with hormone receptor-positive, HER2-negative, node-positive breast cancer at low clinical risk, nor any patient with HER2-positive or triple-negative breast cancer, because of the lack of definitive data in these populations. Additional information can be found at www.asco.org/breast-cancer-guidelines and www.asco.org/guidelineswiki .

Abstract P6-11-04: Use of Mammaprint© (MMP) genetic signature in early breast cancer patients. Economic analisys of a 129 patient cohort treated in three Spanish hospitals

Abstract Introduction: Benefit derived from adjuvant chemotherapy (CT) is doubtful in a high percentage of patients with early breast cancer. The 70-genes platform MMP improves prognostic classification and has been proven useful when it comes to individualizing treatment options. At our institution we use this test to try to avoid overtreatment in those patients in which CT benefit is unclear. We defined some criteria in order to discriminate better which patients would benefit most from the MMP assessment as well as to identify a group of subjects where the test would be more cost-effective. These criteria were: age between 35-70 years, tumor size from 1 to 3 cm, histological grade 2, absence of macrometastatic disease in axillary nodes, hormone receptors positive, HER2 negative and Ki67 between 11-25%. Objective: To analyze the impact of using MMP to help selecting adjuvant treatment, both in clinical and economical aspects. Material and Methods: Since August 2012 to January 2015, MMP genetic signature was performed in 129 early tumors samples. Most cases met the criteria explained above. Some that did not were also included by decision of the institution multidisciplinary committee when the individual characteristics of the cases where taken into account. We compiled the adjuvant treatment initially planned according to our institution protocol and usual clinical practice and compared it with the actual treatment given after the results of the test were known. We calculated the direct economic costs of chemotherapy and of the diagnostic test. Results: The clinical characteristics of the patients and the adjuvant therapy they received are shown in Table 1. Patients Characteristicsn=129 Age, median (range)54.5 (20-76)Histology Infiltrating ductal carcinoma115 (89%)Infiltrating lobular carcinoma14 (11%)pT (mm) Median (range)15 (8-60)Mean (range)18.55 (8-60)pN pN087 (67.4%)pN1mic30 (23.2%)pN17 (5.4%)pN21 (0.8%)Histological grade I24 (18.8%)II100 (78.1%)III4 (3.1%)Hormone receptors ER 50-100%129 (100%)PR &amp;lt;20%21 (16.3%)PR &amp;gt;20%108 (83.7%)Ki 67 &amp;lt;=20%74 (57.8%)&amp;gt; 20%54 (42.2%)Median (range)20 (1-35)Mean (range)19.95 (1-35)Her 2 negative129 (100%)Adjuvant treatment FEC-paclitaxel + Hormonotherapy18TAC + Hormonotherapy27Hormonotherapy84 119 Patients (92.2%) would have received adjuvant CT without MMP risk determination. After the results only 45 patients (34.9%) received it. The cost of the genetic study was 306.725€. Direct costs savings estimated from the reduction in CT treatment were 494.771,48 €. Conclusion: The use of the MMP test in a selected group of patients reduced the administration of adjuvant CT in a 57.3%. This represented a saving of 188.046,48€. Citation Format: Rullan AJ, Pernas S, Margelí M, Joan D, Quiroga V, Stradella A, Petit A, Germà JR, Calle C, Falo C, Ponton JL, Gil-Gil M. Use of Mammaprint© (MMP) genetic signature in early breast cancer patients. Economic analisys of a 129 patient cohort treated in three Spanish hospitals. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-11-04.

Molecular subtyping improves diagnostic stratification of patients with primary breast cancer into prognostically defined risk groups.

Combined use of MammaPrint and a molecular subtyping profile (BluePrint) identifies disease subgroups with marked differences in long-term outcome and response to neo-adjuvant therapy. The aim of this study was to evaluate the prognostic value of molecular subtyping using MammaPrint and BluePrint in women with early-stage breast cancer (BC) treated at US institutions following National Comprehensive Cancer Network standard guidelines. Tumor samples were collected from stage 1-2B consecutively diagnosed BC patients (n = 373) who underwent lumpectomy or mastectomy with an axillary staging procedure between 1992 and 2010 at two institutes (NorthShore University HealthSystem and Fox Chase Cancer Center) in the United States of America, with a median follow-up time of 9.5 years. MammaPrint low-risk patients had a 10-year DMFS of 96 % (95 %CI 92.8–99.4), while MammaPrint high-risk patients had a 10-year DMFS of 87 % (95 %CI 81.9–92.1) with a hazard ratio of 3.62 (95 %CI 1.38–9.50) (p = 0.005). Uni- and multivariate analyses included age, tumor size, grade, ER, and Her2; in multivariate analysis, MammaPrint reached near-significance (HR 3.01; p 0.08). When comparing BluePrint molecular subtyping with clinical stratification, the prognosis (10-year DMFS) was significantly different in 10-year DMFS between the different molecular subtypes (p < 0.001). This retrospective study with 10-year follow-up data provides valuable insight into prognosis of patients with primary BC comparing clinical with molecular subtyping. The BluePrint molecular stratification assay identifies patients with significantly different outcomes compared with standard clinical molecular stratification.

Abstract P2-11-23: MammaPrint and BluePrint in early breast cancer: Clinical implications of prognostic stratification and molecular subtyping

Abstract Background: Combined use of MammaPrint and a molecular subtyping profile (BluePrint) identifies disease subgroups with marked differences in long-term outcome and response to neo-adjuvant therapy [Glück et al. BCRT 2013]. The aim of this study is to compare tumor subtyping between clinical immunohistochemistry (IHC)/fluorescent in-situ (FISH) hybridization and MammaPrint and BluePrint and to determine which method of subtyping most accurately predicts long term outcome. Methods: 325 frozen/FFPE tumor samples from patients with AJCC stage TI-III, N0-Ib breast cancers were obtained from two separate cancer centers (NorthShore and Fox Chase Cancer Center) in the United States from 1992-2010. Median follow-up was 10.2 years. All patients underwent surgical excision and adjuvant therapy according to NCCN guidelines. Clinical subtyping included IHC and FISH whereas MammaPrint and BluePrint included microarray analysis. Results: Median age at diagnosis was 55 years (range 28-89 years) and 138 (42%) were AJCC Stage I, 119 (37%) Stage IIA, and 68 (21%) Stage IIB. One hundred three (33%) patients received adjuvant endocrine therapy (ET) alone, 84 (27%) received adjuvant chemotherapy (CT) alone, 104 (33%) received both modalities and 25 (7%) did not receive adjuvant treatment. Clinical Hormone Receptor (HR) and HER2 status assessment revealed that 208 (64%) of all tumors examined were luminal-like (ER/PR positive, HER2 negative), 52 (16%) were classified as HER2 positive and 65 (20%) as triple negative. Molecular classification using BluePrint demonstrated discordance in the following clinical groups: 20 out of 208 (10%) originally classified as luminal-like were reclassified as HER2-type (35%, n = 7) and as Basal-type (65%, n = 13) by BluePrint; 26 out of 52 (50%) previously identified as HER2 positive were reclassified as Luminal A (19%, n = 5), Luminal B (50%, n = 13), and 8 (31%) as Basal-type by BluePrint; 14 out of 65 (22%) patients originally identified as triple negative were reclassified as Luminal A (14%, n = 2), 5 (36%) as Luminal B and 7 (50%) as Basal-type by BluePrint. Molecular classification with BluePrint and MammaPrint identifies 40% of patients as Luminal A-type with 99% distant metastases free survival (DMFS) at 5 years. DMFS at 5-years for Luminal B tumors and HER2-type tumors was similar between clinical subtyping and BluePrint/MammaPrint subtyping but for triple negative tumors was different. For tumors using clinical subtyping, the DMFS for triple negative tumors was 84% compared to 93% for BluePrint/MammaPrint subtyping. Discordant cases are being centrally re-assessed for ER, PR and HER2. Conclusions: Molecular subtyping with BluePrint and MammaPrint leads to a more accurate molecular classification with clinically significant prognostic stratification. The use of MammaPrint and BluePrint in the management of patients with primary breast cancer should be considered to select adjuvant therapy in this era of personalized medicine. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-11-23.

Abstract P3-05-01: Molecular subtyping improves stratification of patients into diagnostically more meaningful risk groups

Abstract Background: Microarray-based gene expression profiling demonstrated that breast cancer is a heterogeneous group of different diseases characterized by distinct molecular aberrations, rather than one disease. Improved understanding of the molecular phenotypes of the disease has already shown prognostic and predictive value and, when prospectively applied, could have dramatic implications in establishing a more personalized approach to the management of early-stage breast cancer. Combined use of MammaPrint and a molecular subtyping profile (BluePrint) identifies disease subgroups with marked differences in long-term outcome and response to neo-adjuvant therapy [Glück et al. ASCO 2012]. The aim of this study was to evaluate the implication of accurate molecular subtyping using MammaPrint and BluePrint in women with early-stage breast cancer treated at US Institutions following National Comprehensive Cancer Network (NCCN) standard guidelines. Methods: 208 frozen tumor samples from consecutive BC patients (TI-III, N0-Ib) were obtained from 2 US centers. Median age at diagnosis was 56 years (range 28–89 years). Between 1992 and 2010 patients were treated either with breast-conserving therapy or mastectomy with axillary lymph node dissection followed by systemic adjuvant therapy when indicated. Sixty-three percent of patients received adjuvant endocrine therapy (ET), 58% received adjuvant chemotherapy (CT) and 32% received both. Hormone Receptor (HR) and HER2 status were assessed by immunohistochemistry (IHC) and fluorescent in-situ hybridization (FISH), following standard guidelines. Median follow-up was 11.3 years. Survival was assessed for patient groups according to local pathological assessment and compared with molecular classification of patients (centrally assessed full genome expression at Agendia laboratory). Results: Standard HR and HER2 status assessment revealed that 57% of all tumors examined were luminal-like (ER/PR positive, HER2 negative), 20% HER2 positive and 24% triple negative. Molecular classification demonstrated discordance in the following clinical groups: 16 out of 41 patients previously identified as HER2 positive were reclassified as Luminal-type, with 97% 5-year distant metastases-free survival (DMFS) for Luminal A (MammaPrint Low Risk/Luminal-type) and 98% for Luminal B (MammaPrint High Risk/Luminal-type). Ten patients identified with clinical triple-negative tumors were reclassified with molecular subtyping as HER2 positive (n = 6) and Luminal-type (n = 4). Of the patients classified with BluePrint Basal-type tumors, 58 (28%) had a 5-year DMFS of 82% (81% received adjuvant CT). Of those with HER2-type tumors, 25 (12%) had a 5-year DMFS of 76% (88% received adjuvant CT without trastuzumab). Discordant cases are being centrally re-assessed for ER, PR and HER2. Conclusions: This retrospective study showed that Molecular Subtyping with BluePrint and MammaPrint leads to clinically significant prognostic and molecular stratification. The use of MammaPrint and BluePrint in the management of patients with primary breast cancer should be considered for a more accurate selection of adjuvant therapies in this era of personalized medicine. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-05-01.

Molecular subtyping using MammaPrint and BluePrint as an outcome predictor in U.S. breast cancer (BC) patients.

9 Background: Combined use of MammaPrint and a molecular subtyping profile (BluePrint) identifies disease subgroups with marked differences in long-term outcome and response to neo-adjuvant therapy (Glück SABCS2011). The aim of this study was to evaluate the prognostic value of Molecular Subtyping using MammaPrint and BluePrint in women with early stage BC treated at U.S. institutions following National Comprehensive Cancer Network (NCCN) standard guidelines. Methods: Frozen tumor samples from 180 BC patients (TI-III, N0-Ib) median age 57 years at diagnosis (range 28-89) were suitable for hybridization on full genome array. MammaPrint and BluePrint Molecular Subtypes were determined and survival for Luminal A (MammaPrint Low Risk), Luminal B (MammaPrint High Risk), HER2-type and Basal-type patients was assessed. Patients were treated either with breast conserving therapy or mastectomy with axillary lymph node dissection between 1992 and 2005. The median follow-up is 12.7 years. 71% was ER positive and 20% Her2 positive by IHC/FISH. 58% received adjuvant endocrine therapy (ET) (excluding 13 patients unknown treatment), 64% received adjuvant chemotherapy (CT) (excluding 12 patients unknown treatment) and 33% received both. Results: 61 (34%) Patients with MammaPrint Low Risk/Luminal-type (Luminal A) showed 5-year DFS of 97% (34% received CT and 69% ET) and 50 (28%) patients with MammaPrint High Risk/Luminal-type (Luminal B) had a 5-year DFS of 98% (60% received CT and 68% ET). Patients with BluePrint Basal-type tumors (46 (26%)) had a 5-year DFS of 80% (78% received CT); HER2-type (23 (13%)) had a 5-year DFS of 78% (87% received CT without HER2 targeted therapy). Conclusions: In this retrospective study evaluating 180 US patients with early BC treated according to standard guidelines we showed how combining BluePrint with MammaPrint can detect molecularly defined subgroups of patients who are at high risk of recurrence (HER2 and Basal-type). Furthermore, we confirmed that molecularly defined Luminal type disease is associated with excellent disease-free survival. MammaPrint and BluePrint molecular and prognostic stratification should be prospectively evaluated for therapeutic selection.

Molecular subtyping using MammaPrint and BluePrint as an outcome predictor in 180 U.S. breast cancer (BC) patients.

577 Background: Combined use of MammaPrint and a molecular subtyping profile (BluePrint) identifies disease subgroups with marked differences in long-term outcome and response to neo-adjuvant therapy (Glück SABCS2011). The aim of this study was to evaluate the prognostic value of Molecular Subtyping using MammaPrint and BluePrint in women with early stage BC treated at US Institutions following National Comprehensive Cancer Network (NCCN) standard guidelines. Methods: Frozen tumor samples from 180 BC patients (TI-III, N0-Ib) median age 57 years at diagnosis (range 28-89) were suitable for hybridization on full genome array. MammaPrint and BluePrint Molecular Subtypes were determined and survival for Luminal A (MammaPrint Low Risk), Luminal B (MammaPrint High Risk), HER2-type and Basal-type patients was assessed. Patients were treated either with breast conserving therapy or mastectomy with axillary lymph node dissection between 1992 and 2005. The median follow-up is 12.7 years. 71% was ER positive and 20% Her2 positive by IHC/FISH. 58% received adjuvant endocrine therapy (ET) (excluding 13 patients unknown treatment), 64% received adjuvant chemotherapy (CT) (excluding 12 patients unknown treatment) and 33% received both. Results: 61 (34%) Patients with MammaPrint Low Risk/Luminal-type (Luminal A) showed 5-year DFS of 97% (34% received CT and 69% ET) and 50 (28%) patients with MammaPrint High Risk/Luminal-type (Luminal B) had a 5-year DFS of 98% (60% received CT and 68% ET). Patients with BluePrint Basal-type tumors (46 (26%)) had a 5-year DFS of 80% (78% received CT); HER2-type (23 (13%)) had a 5-year DFS of 78% (87% received CT without HER-2 targeted therapy). Conclusions: In this retrospective study evaluating 180 US patients with early BC treated according to standard guidelines we showed how combining BluePrint with MammaPrint can detect molecularly defined subgroups of patients who are at high risk of recurrence (HER2 and Basal-type). Furthermore, we confirmed that molecularly defined Luminal type disease is associated with excellent disease-free survival. MammaPrint and BluePrint molecular and prognostic stratification should be prospectively evaluated for therapeutic selection.

Combined use of MammaPrint and molecular subtyping profile (BluePrint) to identify subgroups with marked differences in response to neoadjuvant treatment.

42 Background: Concordance between the IHC receptor status and the molecular subtype suggests that molecular profiles represent oncogenic processes that are driven by pathways in which ER, PR and HER2 play pivotal roles. It is, therefore, likely that the use of gene expression arrays will enable the identification of previously unappreciated subtypes of breast cancer that differ in clinical outcomes. Methods: The cohort consists of 133 (T1-4, N0-3) breast cancer patients treated with T/FAC neoadjuvant chemotherapy. Genome wide expression data was publicly available and downloaded from bioinformatics.mdanderson.org/pubdata.html. The data was used to determine the response to T/FAC neoadjuvant chemotherapy for patients stratified by MammaPrint and molecular subtype (BluePrint). The MammaPrint and BluePrint result were used to subtype the patients into 4 groups: MammaPrint Low-risk/Luminal-type, MammaPrint High-risk/Luminal-type, Basal-type and ERBB2-type. Results: Within this patient cohort, 20% (n=27) were classified as Basal-type, 62% (n=82) as Luminal-type, and 18% (n=24) as ERBB2-type. The overall pCR of this patient cohort was 26% and differed substantially among the subgroups. pCR was observed in 9% of all Luminal-type samples (i.e. 3% of MammaPrint Low Risk/Luminal-type and 11% of MammaPrint High Risk/Luminal-type), in 50% of the ERBB2-type samples and in 56% of the Basal-type samples. The pCR rates observed for the ERBB2-type and Basal-type patient groups were higher compared to classification based on IHC/CISH assessed ER and HER2 receptor status: 50% for ERBB2-type versus 39% for HER2+ and 56% for Basal-type versus 47% for ER-/HER2- samples. Conclusions: We observed marked differences in response to neo-adjuvant treatment in groups stratified by MammaPrint and BluePrint. These findings confirm differences in chemotherapy response among molecular subgroups and indicate that the BluePrint profile described here will help to further establish a clinical correlation between molecular subtyping and treatment response.

Combined use of MammaPrint and molecular subtyping profile (BluePrint) to identify subgroups with marked differences in response to neoadjuvant treatment.

10613 Background: Concordance between the IHC receptor status and the molecular subtype suggests that molecular profiles represent oncogenic processes that are driven by pathways in which ER, PR and HER2 play pivotal roles. It is, therefore, likely that the use of gene expression arrays will enable the identification of previously unappreciated subtypes of breast cancer that differ in clinical outcomes. Methods: The cohort consists of 133 (T1-4, N0-3) breast cancer patients treated with T/FAC neoadjuvant chemotherapy. Genome wide expression data was publicly available and downloaded from http://bioinformatics.mdanderson.org/pubdata.html. The data was used to determine the response to T/FAC neoadjuvant chemotherapy for patients stratified by MammaPrint and molecular subtype (BluePrint). The MammaPrint and BluePrint result were used to subtype the patients into 4 groups: MammaPrint Low-risk/Luminal-type, MammaPrint High-risk/Luminal-type, Basal-type and ERBB2-type. Results: Within this patient cohort, 20% (n=27) were classified as Basal-type, 62% (n=82) as Luminal-type, and 18% (n=24) as ERBB2-type. The overall pCR of this patient cohort was 26% and differed substantially among the subgroups. pCR was observed in 9% of all Luminal-type samples (i.e. 3% of MammaPrint Low Risk/Luminal-type and 11% of MammaPrint High Risk/Luminal-type), in 50% of the ERBB2-type samples and in 56% of the Basal-type samples. The pCR rates observed for the ERBB2-type and Basal-type patient groups were higher compared to classification based on IHC/CISH assessed ER and HER2 receptor status: 50% for ERBB2-type versus 39% for HER2+ and 56% for Basal-type versus 47% for ER-/HER2- samples. Conclusions: We observed marked differences in response to neo-adjuvant treatment in groups stratified by MammaPrint and BluePrint. These findings confirm differences in chemotherapy response among molecular subgroups and indicate that the BluePrint profile described here will help to further establish a clinical correlation between molecular subtyping and treatment response.

Conquering cancer through discovery research

Cancer is a leading cause of death worldwide. Cancer research improves our understanding of cancer biology, which leads to the discoveries of novel detection approaches and effective therapies for cancer. Translational cancer medicine changes essential science breakthroughs to the practice of medicine and uses clinical result to supply back into basic research. This article covers some studies in the field of translational cancer medicine including the identification of 319 driver genes and the 12 core cancer pathways, the use of MammaPrint in breast cancer, the development of OncoMap, the progress in genome-wide association studies, as well as the generation of microRNA networks in cancer and leukemia. Apart from cancer genome, cancer stem cells, immune and tumor microenvironment are also discussed. In addition, some innovations in translational cancer medicine are introduced. A number of targeted agents have been developed, such as the histone deacetylases inhibitors, poly(ADP-ribose) polymerase inhibitors, anti-mammalian target of rapamycin agents, and PI3K pathway inhibitors. There are also reports of the results from some important clinical trials, including the STAR P-2 trial, NeoBIG program, and BATTLE trial. This review focuses on discussions that emphasize the marriage between curiosity-driven basic research and patient care-focused clinical investigations. With highlights on the most up-to-date molecular, cellular, clinical, and therapeutic cancer research findings, this article tends to provide a wealth of insights into better understanding of the complexity of cancer.