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Background: Numerous retrospective analyses of prospective randomized clinical trials of patients treated with adjuvant tamoxifen and chemotherapy have demonstrated that the breast cancer intrinsic subtype Luminal A tumors generally have favorable early initial outcomes, while basal-like tumors are associated with a marked risk of early relapse. To determine the extended natural history of the intrinsic subtypes across two decades of follow up the PAM50 "non-commercial open source bioinformatics" qPCR assay was conducted on node negative tumors accrued through the Cooperative Breast Cancer Tissue Registry (CBCTR) from patients who did not receive systemic therapy. Methods: Intrinsic subtype calls were obtained from 331 CBCTR cases treated with local interventions only. Tumors were classified into Luminal A (LumA), Luminal B (LumB), HER2-enriched (HER2-E) and Basal-like (BLBC), and correlated relapse-free (RFS). Patient survival and hazard rate were estimated using Kaplan-Meier plots and log-rank test. Multivariable Cox regression analyses were used to determine the significance of the intrinsic subtypes, adjusted with standard clinicopathological variables including tumor size, age at diagnosis, grade, radiation therapy treatment, centralized reviewed estrogen receptor, progesterone receptor and human epidermal growth factor 2 status measured by immunohistochemistry. Patients were diagnosed from 1978 to 1992, with a mean follow-up time of 13 years (range 0.5-31). Results: Of the 331 tumors tested, 51% of cases were classified as LumA, 18% as LumB, 11 % as HER2-E and 20% as BLBC. Although LumA was associated with the best outcome for the first 10-year of follow-up, the final number of RFS events were eventually comparable with those observed for BLBC with prolonged follow up (Table 1). In the multivariable Cox model, only BLBC tumors were associated with worse prognosis than LumA with borderline significance (Hazard ratio: 2.0 (95% Cl 0.9-5), p = 0.07). BLBC had the highest hazard rates for the first 5 years (7% at first year to 5% at 5 yr), consistent with previous observations. Interestingly, in the absence of treatment, the slow growing LumA subtype had a gradual increase of hazard for an RFS event from 3% at 5 yrs to 4% at 10 yrs to 7% at 20 yrs. The hazard rates of LumA cross with those of BLBC at 10 years. Conclusions: Basal-like breast cancers are associated with an early risk of relapse that decreases over time. In contrast, Luminal A breast cancer has a low risk of relapse at the outset but the risk of relapse increases over time and is responsible of the majority of the RFS events after 20 years of follow up. Luminal A breast cancers are therefore not truly low risk, particularly if they do not receive endocrine therapy; and may experience the consequences of inadequate treatment decades after diagnosis. [ABSTRACT FROM AUTHOR]

Background: Between 1978-1986, 318 premenopausal women treated with mastectomy for lymph node positive breast cancer, were randomized to CMF chemotherapy alone vs. CMF chemotherapy and adjuvant radiotherapy (RT) to the chest wall and regional lymph nodes. After 15 years of follow-up, post-mastectomy RT was associated with a statistically significant 29% relative risk reduction in mortality. Recent evidence suggests that Luminal A tumors, identified using hormone receptors and Ki67, have a particularly favorable prognosis. We retrospectively identified the Luminal A tumors from this clinical trial cohort to determine if the response to postmastectomy RT differed among Luminal A and non- Luminal A tumors. Methods: 203 archival breast tumor samples from this study were used to construct a tissue microarray. Luminal A tumors were identified using an immunopanel consisting of: estrogen receptor, progestorone receptor, Her2, and Ki67. Luminal A tumors were defined as either ER or PR positive, Her2 negative, and Ki67 < 14%. Kaplan-Meier estimates and the log-rank test were used to test the differences in locoregional relapse free survival (LRFS) and breast cancer specific survival (BCSS). Interaction between treatment and Luminal A/Non-luminal A were tested using Cox regression analysis. Results: The intrinsic subtype was successfully determined in 144 breast tumors, and 49 were classified as Luminal A (34%). Survival outcomes at 10 years are summarized in Table 1: Conclusion: Our study examines the outcome of Luminal A tumors in patients with higher risk (premenopausal and lymph node positive) breast cancer treated with CMF chemotherapy. We observed that both subjects with Luminal A tumors and non-Luminal A tumors appear to demonstrate improved locoregional control with post-mastectomy RT, although this was only significant for Luminal A tumors. The non-significant interaction test suggests that there is no observable difference in radiosensitivity in this limited study population. However, the improvement in BCSS with post-mastectomy RT was only significant in the subjects with Luminal A tumors, and the interaction test was statistically significant. Our results raise the possibility that patients with non-Luminal A breast tumors are at higher risk of occult metastatic disease at presentation, and may not derive a survival benefit with improved locoregional control in the setting of CMF chemotherapy. In contrast, locoregional control has a significant effect on survival with Luminal A tumors. Our study suggests that a favorable Luminal A diagnosis should not be a reason to omit regional radiotherapy in node positive patients, as it is this subgroup that may derive the greatest benefit. [ABSTRACT FROM AUTHOR]

Our simulations suggest that the presence of non-luminal tumors within ER+/HER2-unknown disease is augmenting the apparent benefit of chemotherapy in NSABP B20 and SWOG 8814, but does not appear to be responsible for the entire effect. These simulations provide information about the potential influence of contamination by unexpected tumor subtypes on the future results of TAILORx and RxPONDER trials.Background Retrospective analyses of NSABP B20 and SWOG 8814 showed a large benefit of chemotherapy in patients with ER-positive tumors and high OncotypeDX Recurrence Score (RS≥31). However, it might be possible that both studies may be contaminated by non-luminal tumors, especially in high-risk RS group. Methods We conducted simulations in order to obtain a better understanding of how the NSABP B20 and SWOG 8814 results would have been if non-luminal breast cancer would have been excluded. Simulations were done separately for the node-negative and node-positive cohorts. Results and conclusion The results of the simulations suggest that the non-luminal tumors are augmenting the apparent benefit of chemotherapy, but do not appear to be responsible for the entire effect. These simulations could provide information about the potential influence of contamination by unexpected tumor subtypes on the future results of TAILORx and RxPONDER clinical trials [ABSTRACT FROM PUBLISHER]

Background:In this study, we evaluated the ability of gene expression profiles to predict chemotherapy response and survival in triple-negative breast cancer (TNBC).Methods:Gene expression and clinical-pathological data were evaluated in five independent cohorts, including three randomised clinical trials for a total of 1055 patients with TNBC, basal-like disease (BLBC) or both. Previously defined intrinsic molecular subtype and a proliferation signature were determined and tested. Each signature was tested using multivariable logistic regression models (for pCR (pathological complete response)) and Cox models (for survival). Within TNBC, interactions between each signature and the basal-like subtype (vs other subtypes) for predicting either pCR or survival were investigated.Results:Within TNBC, all intrinsic subtypes were identified but BLBC predominated (55-81%). Significant associations between genomic signatures and response and survival after chemotherapy were only identified within BLBC and not within TNBC as a whole. In particular, high expression of a previously identified proliferation signature, or low expression of the luminal A signature, was found independently associated with pCR and improved survival following chemotherapy across different cohorts. Significant interaction tests were only obtained between each signature and the BLBC subtype for prediction of chemotherapy response or survival.Conclusions:The proliferation signature predicts response and improved survival after chemotherapy, but only within BLBC. This highlights the clinical implications of TNBC heterogeneity, and suggests that future clinical trials focused on this phenotypic subtype should consider stratifying patients as having BLBC or not. [ABSTRACT FROM AUTHOR]

Background ER-positive (ER+ ) breast cancer includes all of the intrinsic molecular subtypes, although the luminal A and B subtypes predominate. In this study, we evaluated the ability of six clinically relevant genomic signatures to predict relapse in patients with ER+ tumors treated with adjuvant tamoxifen only. Methods Four microarray datasets were combined and research-based versions of PAM50 intrinsic subtyping and risk of relapse (PAM50-ROR) score, 21-gene recurrence score (OncotypeDX), Mammaprint, Rotterdam 76 gene, index of sensitivity to endocrine therapy (SET) and an estrogen-induced gene set were evaluated. Distant relapse-free survival (DRFS) was estimated by Kaplan–Meier and log-rank tests, and multivariable analyses were done using Cox regression analysis. Harrell's C-index was also used to estimate performance. Results All signatures were prognostic in patients with ER+ node-negative tumors, whereas most were prognostic in ER+ node-positive disease. Among the signatures evaluated, PAM50-ROR, OncotypeDX, Mammaprint and SET were consistently found to be independent predictors of relapse. A combination of all signatures significantly increased the performance prediction. Importantly, low-risk tumors (>90% DRFS at 8.5 years) were identified by the majority of signatures only within node-negative disease, and these tumors were mostly luminal A (78%–100%). Conclusions Most established genomic signatures were successful in outcome predictions in ER+ breast cancer and provided statistically independent information. From a clinical perspective, multiple signatures combined together most accurately predicted outcome, but a common finding was that each signature identified a subset of luminal A patients with node-negative disease who might be considered suitable candidates for adjuvant endocrine therapy alone. [ABSTRACT FROM AUTHOR]