The Prosigna gene expression assay and responsiveness to adjuvant cyclophosphamide-based chemotherapy in premenopausal high-risk patients with breast cancer.

BACKGROUND: The PAM50-based (Prosigna) risk of recurrence (ROR) score and intrinsic subtypes are prognostic for women with high-risk breast cancer. We investigate the predictive ability of Prosigna regarding the effectiveness of cyclophosphamide-based adjuvant chemotherapy in premenopausal patients with high-risk breast cancer. METHODS: Prosigna assays were performed on the NanoString platform in tumors from participants in Danish Breast Cancer Group (DBCG) 77B, a four-arm trial that randomized premenopausal women with high-risk early breast cancer to no systemic treatment, levamisole, oral cyclophosphamide (C) or cyclophosphamide, methotrexate and fluorouracil (CMF). RESULTS: In total, this retrospective analysis included 460 women (40% of the 1146 randomized patients). The continuous Prosigna ROR score was prognostic in the no systemic treatment group (unadjusted P < 0.001 for disease-free survival (DFS), P = 0.001 for overall survival (OS)). No statistically significant interaction of continuous ROR score and treatment on DFS and OS was found. A highly significant association was observed between intrinsic subtypes and C/CMF treatment for DFS (Pinteraction = 0.003 unadjusted, P = 0.001 adjusted) and OS (Pinteraction = 0.04). In the adjusted analysis treatment with C/CMF was associated with a reduced risk of DFS events in patients with basal-like (hazard ratio (HR) 0.14; 95% CI 0.06; 0.32) and luminal B (HR 0.48; 95% CI 0.27; 0.84) subtypes but not in patients with Human epidermal growth factor receptor-enriched (HR 1.05; 95% CI 0.56; 1.95) or luminal A (HR 0.61; 95% CI 0.32; 1.16) subtypes. CONCLUSION: The Prosigna ROR score and intrinsic subtypes were prognostic in high-risk premenopausal patients with breast cancer, and intrinsic subtypes identify high-risk patients with or without major benefit from adjuvant C/CMF treatment.

The ability of PAM50 risk of recurrence score to predict 10-year distant recurrence in hormone receptor-positive postmenopausal women with special histological subtypes.

INTRODUCTION: The Prosigna-PAM50 risk of recurrence (ROR) score has been validated in randomized clinical trials to predict 10-year distant recurrence (DR) in hormone receptor-positive breast cancer. Here, we examine the ability of Prosigna for predicting DR at 10 years in a subgroup of postmenopausal breast cancer patients with special histological subtypes. METHODS: Using the population based Danish Breast Cancer Group database, follow-up data were collected on all patients diagnosed from 2000 to 2003 with estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2) normal breast cancer who by nationwide guidelines were treated with 5 year of endocrine therapy (N = 2558). Among patients with 1 to 3 positive lymph nodes or a tumor size >20 mm, we identified 1570 with invasive ductal carcinoma (IDC) and 89 with special histological subtypes (apocrine, medullary, mucinous, papillary, secretory, tubular, neuroendocrine) who were tested with Prosigna. Fine and Gray models were applied to determine the prognostic value of the Prosigna-PAM50 ROR score for DR special subtypes as compared to IDC. RESULTS: Median follow-up for DR was 9.2 year and for OS 15.2 year. The 10-year DR rate for the special subtypes was 9.2% (95% CI: 4.0% to 17.2%) as compared to 13.7% (95% CI: 11.9% to 15.7%) for IDC. The 10-year OS was 74.2% (95% CI: 63.7% to 82.0%) for the special subtypes and 75.4% (95% CI: 73.2% to 77.4%) for IDC. Prosigna showed a statistical significant association of the continuous ROR score with risk of DR for both IDC and the special subtypes (IDC: p < .0001; special subtypes: p = .01). CONCLUSION: In the present study, we demonstrated that Prosigna-PAM50 continuous ROR score added significant prognostic information for 10-year DR in postmenopausal patients with special subtypes (tumor size >20 mm or 1 to 3 positive lymph nodes) and ER-positive, HER2-normal early breast cancer.

HER2DX Genomic Assay in HER2-Positive Early Breast Cancer Treated with Trastuzumab and Pertuzumab: A Correlative Analysis from the PHERGain Phase II Trial.

PURPOSE: The purpose of this study was to assess the predictive capability of HER2DX assay following (neo)adjuvant trastuzumab-pertuzumab (HP)-based therapy in HER2-positive (HER2+) early breast cancer. EXPERIMENTAL DESIGN: HER2DX was analyzed in baseline pretreatment tumors from the PHERGain trial. Patients with stage I-IIIA HER2+ early breast cancer were randomized to group A [docetaxel, carboplatin, and HP (TCHP)] and group B (HP ± endocrine therapy). PET response was evaluated after two cycles. Group A received TCHP for six cycles regardless of PET response. Group B continued with HP ± endocrine therapy for six cycles (PET responders) or with TCHP for six cycles (PET nonresponders). The primary objective of this retrospective study was to associate the HER2DX pathologic complete response (pCR) score with pCR. The secondary objective was the association of the HER2DX risk score with 3-year invasive disease-free survival (iDFS). RESULTS: HER2DX was performed on 292 (82.0%) tumors. The overall pCR rate was 38.0%, with pCR rates of 56.4% in group A and 33.8% in group B. In multivariable analysis including treatment and clinicopathologic factors, the HER2DX pCR score (continuous variable) significantly correlated with pCR [OR, 1.29; 95% confidence interval (CI), 1.10-1.54; P < 0.001]. HER2DX-defined pCR-high, -med, and -low groups exhibited pCR rates of 50.4%, 35.8%, and 23.2%, respectively (pCR-high vs. pCR-low OR, 3.27; 95% CI, 1.54-7.09; P < 0.001). In patients with residual disease, the HER2DX high-risk group demonstrated numerically worse 3-year iDFS than the low-risk group (89.8% vs. 100%; HR, 2.70; 95% CI, 0.60-12.18; P = 0.197). CONCLUSIONS: HER2DX predicts pCR in the context of neoadjuvant HP-based therapy, regardless of chemotherapy addition, and might identify patients at higher risk of recurrence among patients with residual disease.

Population-based Study of Prosigna-PAM50 and Outcome Among Postmenopausal Women With Estrogen Receptor-positive and HER2-negative Operable Invasive Lobular or Ductal Breast Cancer.

PURPOSE: The Prosigna-PAM50 risk of recurrence (ROR) score has documented clinical utility for the prediction of 10-year distant recurrence (DR). The present study investigated the value of Prosigna-PAM50 for predicting 10-year DR and overall survival after 5 years of endocrine treatment for postmenopausal patients with invasive lobular carcinoma. PATIENTS AND METHODS: Using the Danish Breast Cancer Group database, we identified patients with a diagnosis from 2000 to 2003 of estrogen receptor-positive, human epidermal growth factor receptor 2-negative invasive ductal (n = 1570) or lobular (n = 341) cancer > 20 mm or 1 to 3 positive lymph nodes and applied multivariate Cox models. RESULTS: The median follow-up for DR was 9.3 years and for overall survival 15.2 years. Of the 341 lobular and 1570 ductal cases, 140 (41%) and 349 (22%) were classified as low ROR, with a 10-year DR rate of 7.7% (95% confidence interval [CI], 3.7%-13.6%) and 3.5% (95% CI, 1.8%-6.2%), respectively. The 10-year DR rate for the intermediate ROR group for those with lobular cancer was 18% (95% CI, 10.1%-27.9%) compared with 9.7% (95% CI, 6.7%-13.4%) for those with ductal cancer. Luminal B tumors had a significantly worse outcome than luminal A tumors in both lobular (hazard ratio, 1.89; 95% CI, 1.03%-3.45%; P = .04) and ductal (hazard ratio, 3.18; 95% CI, 2.29%-4.43%; P < .0001) cancer. CONCLUSION: Prosigna PAM-50 provides significant prognostic information beyond the clinicopathologic factors in patients with invasive lobular breast cancer. Those with lobular cancer had worse 10-year DR rates compared with those with ductal cancer in the same ROR category. Our results could have an effect on the treatment decisions regarding the addition of chemotherapy for those in the intermediate ROR group.

The Prosigna 50-gene profile and responsiveness to adjuvant anthracycline-based chemotherapy in high-risk breast cancer patients.

The DBCG89D trial randomized high-risk early breast cancer patients to adjuvant CMF (cyclophosphamide, methotrexate and fluorouracil) or CEF (cyclophosphamide, epirubicin and fluorouracil). Prosigna assays were performed by researchers with no access to clinical data. Time to distant recurrence (DR) was the primary endpoint, time to recurrence (TR) and overall survival (OS) secondary. Among the 980 Danish patients enrolled, Prosigna results were obtained in 686. Continuous ROR score was associated with DR for CMF (adjusted hazard ratio (HR) 1.20, 95% CI 1.09-1.33), and for CEF (HR 1.04, 95% CI 0.92-1.18), P interaction = 0.06. DR was significantly longer in CEF compared to CMF treated patients with Her2-enriched tumors (HR 0.58, 95% CI 0.38-0.86), but not in patients with luminal tumors. Heterogeneity of treatment effect was significant for TR and OS. In this prospective-retrospective analysis, patients with Her2-enriched breast cancer derived substantial benefit from anthracycline chemotherapy whereas anthracyclines are not an essential component of chemotherapy for patients with luminal subtypes. The benefit of CEF vs. CMF correlated with increasing ROR Score.

PAM50 Risk of Recurrence Score Predicts 10-Year Distant Recurrence in a Comprehensive Danish Cohort of Postmenopausal Women Allocated to 5 Years of Endocrine Therapy for Hormone Receptor-Positive Early Breast Cancer.

Purpose The PAM50-based Prosigna risk of recurrence (ROR) score has been validated in randomized clinical trials to predict 10-year distant recurrence (DR). The value of Prosigna for predicting DR was examined in a comprehensive nationwide Danish cohort consisting of postmenopausal women with hormone receptor-positive early breast cancer treated with 5 years of endocrine therapy alone. Patients and Methods Using the population-based Danish Breast Cancer Cooperative Group database, follow-up data were collected on all patients diagnosed from 2000 through 2003 who, by nationwide guidelines, were treated with endocrine therapy for 5 years. Primary tumor blocks from 2,740 patients were tested with Prosigna and, after determination of human epidermal growth factor receptor 2 (HER2) status, data from 2,558 hormone receptor-positive/HER2-negative samples were analyzed, including 1,395 node-positive patients. Fine and Gray models were applied to determine the prognostic value of ROR for DR. Results Median follow-up for recurrence was 9.2 years. Twenty-six percent of the node-positive patients were classified as low ROR (n = 359) with a DR risk of 3.5% (95% confidence interval [CI], 1.9% to 6.1%) versus a DR risk of 22.1% (95% CI, 18.6% to 25.8%) at 10 years for patients classified as high ROR (n = 648). Node-negative patients classified as low and high ROR had a risk of DR of 5.0% (95% CI, 2.9% to 8.0%) and 17.8% (95% CI, 14.0% to 22.0%), respectively. Luminal B tumors (n = 947; DR risk, 18.4% [95% CI: 15.7% to 21.3%]) had a significantly worse outcome than luminal A tumors (n = 1,474,;DR risk, 7.6% [95% CI: 6.1% to 9.2%]; P < .001). Conclusion Prosigna ROR score improved the prediction of outcome in this nationwide Danish population. In a real-world setting, Prosigna can reliably identify node-negative patients and a significant proportion of patients with one to three positive nodes who can be spared treatment with adjuvant chemotherapy.

Prediction of Response to Neoadjuvant Chemotherapy Using Core Needle Biopsy Samples with the Prosigna Assay.

PURPOSE: Most hormone receptor (HR)(+)/HER2(-) breast cancer patients respond unfavorably to neoadjuvant chemotherapy (NAC); however, genomic tests may identify those patients who are likely to benefit. Using the Prosigna assay, we first evaluated the technical performance of core needle biopsy (CNB) tissues. We then determined whether Prosigna risk of relapse (ROR) score and intrinsic subtype predicted response to NAC in HR(+)/HER2(-) patients using CNB samples. EXPERIMENTAL DESIGN: Using the NanoString's nCounter Dx analysis system and a development tissue sample set, we established tissue requirements and assay output variance. We then evaluated the concordance in subtype and correlation in ROR between CNBs and corresponding surgical resection specimens (SRS) in a second independent sample set. Finally, we analyzed 180 independent CNB samples from HR(+)/HER2(-) patients who were treated with NAC and correlated ROR and intrinsic subtype with pathologic response. RESULTS: Intra- and interbiopsy variabilities were 2.2 and 6.8 ROR units, respectively. Subtype concordance within multiple CNBs was high for the 4- and 3-subtype classifications (k = 0.885 and 0.889, respectively). Correlation in Prosigna ROR score observed between paired CNBs and SRS was high (r ≥ 0.90), and subtype concordance was also high for the 4- and 3-subtype classifications (kappa = 0.81 and 0.91, respectively). Prosigna results obtained from the HR(+)/HER2(-) patient samples showed that both ROR (P = 0.047) and intrinsic subtype (OR LumA vs. non-LumA = 0.341, P = 0.037) were significant predictors of response to NAC. CONCLUSIONS: Prosigna ROR and intrinsic subtype are readily obtained from CNB samples in normal practice and reliably predict response to NAC in HR(+)/HER2(-) patients.