Reclassification of breast cancer: Towards improved diagnosis and outcome.
ABSTRACT: BACKGROUND:The subtyping of breast cancer based on features of tumour biology such as hormonal receptor and HER2 status has led to increasingly patient-specific treatment and thus improved outcomes. However, such subgroups may not be sufficiently informed to best predict outcome and/or treatment response. The incorporation of multi-modal data may identify unexpected and actionable subgroups to enhance disease understanding and improve outcomes. METHODS:This retrospective cross-sectional study used the cancer registry Surveillance, Epidemiology and End Results (SEER), which represents 28% of the U.S. population. We included adult female patients diagnosed with breast cancer in 2010. Latent class analysis (LCA), a data-driven technique, was used to identify clinically homogeneous subgroups ("endophenotypes") of breast cancer from receptor status (hormonal receptor and HER2), clinical, and demographic data and each subgroup was explored using Bayesian networks. RESULTS:Included were 44,346 patients, 1257 (3%) of whom had distant organ metastases at diagnosis. Four endophenotypes were identified with LCA: 1) "Favourable biology" had entirely local disease with favourable biology, 2) "HGHR-" had the highest incidence of HR- receptor status and highest grade but few metastases and relatively good outcomes, 3) "HR+ bone" had isolated bone metastases and uniform receptor status (HR+/HER2-), and 4) "Distant organ spread" had high metastatic burden and poor survival. Bayesian networks revealed clinically intuitive interactions between patient and disease features. CONCLUSIONS:We have identified four distinct subgroups of breast cancer using LCA, including one unexpected group with good outcomes despite having the highest average histologic grade and rate of HR- tumours. Deeper understanding of subgroup characteristics can allow us to 1) identify actionable group properties relating to disease biology and patient features and 2) develop group-specific diagnostics and treatments.
Project description:Reliable predictive and prognostic markers for routine diagnostic purposes are needed for breast cancer patients treated with neoadjuvant chemotherapy. We evaluated protein biomarkers in a cohort of 116 participants of the GeparDuo study on anthracycline/taxane-based neoadjuvant chemotherapy for operable breast cancer to test for associations with pathological complete response (pCR) and disease-free survival (DFS). Particularly, we evaluated if interactions between hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) expression might lead to a different clinical behavior of HR+/HER2+ co-expressing and HR+/HER2- tumors and whether subgroups of triple negative tumors might be identified by the help of Ki67 labeling index, cytokeratin 5/6 (CK5/6), as well as cyclooxygenase-2 (COX-2), and Y-box binding protein 1 (YB-1) expression.Expression analysis was performed using immunohistochemistry and silver-enhanced in situ hybridization on tissue microarrays (TMAs) of pretherapeutic core biopsies.pCR rates were significantly different between the biology-based tumor types (P = 0.044) with HR+/HER2+ and HR-/HER2- tumors having higher pCR rates than HR+/HER2- tumors. Ki67 labeling index, confirmed as significant predictor of pCR in the whole cohort (P = 0.001), identified HR-/HER- (triple negative) carcinomas with a higher chance for a pCR (P = 0.006). Biology-based tumor type (P = 0.046 for HR+/HER2+ vs. HR+/HER2-), Ki67 labeling index (P = 0.028), and treatment arm (P = 0.036) were independent predictors of pCR in a multivariate model. DFS was different in the biology-based tumor types (P < 0.0001) with HR+/HER2- and HR+/HER2+ tumors having the best prognosis and HR-/HER2+ tumors showing the worst outcome. Biology-based tumor type was an independent prognostic factor for DFS in multivariate analysis (P < 0.001).Our data demonstrate that a biology-based breast cancer classification using estrogen receptor (ER), progesterone receptor (PgR), and HER2 bears independent predictive and prognostic potential. The HR+/HER2+ co-expressing carcinomas emerged as a group of tumors with a good response rate to neoadjuvant chemotherapy and a favorable prognosis. HR+/HER2- tumors had a good prognosis irrespective of a pCR, whereas patients with HR-/HER- and HR-/HER+ tumors, especially if they had not achieved a pCR, had an unfavorable prognosis and are in need of additional treatment options.
Project description:African American breast cancer patients have lower frequency of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2)-negative disease and higher subtype-specific mortality. Racial differences in molecular subtype within clinically defined subgroups are not well understood.Using data and biospecimens from the population-based Carolina Breast Cancer Study (CBCS) Phase 3 (2008-2013), we classified 980 invasive breast cancers using RNA expression-based PAM50 subtype and recurrence (ROR) score that reflects proliferation and tumor size. Molecular subtypes (Luminal A, Luminal B, HER2-enriched, and Basal-like) and ROR scores (high vs low/medium) were compared by race (blacks vs whites) and age (?50?years vs?>?50?years) using chi-square tests and analysis of variance tests.Black women of all ages had a statistically significantly lower frequency of Luminal A breast cancer (25.4% and 33.6% in blacks vs 42.8% and 52.1% in whites; younger and older, respectively). All other subtype frequencies were higher in black women (case-only odds ratio [OR] = 3.11, 95% confidence interval [CI] = 2.22 to 4.37, for Basal-like; OR?=?1.45, 95% CI?=?1.02 to 2.06, for Luminal B; OR?=?2.04, 95% CI?=?1.33 to 3.13, for HER2-enriched). Among clinically HR+/HER2- cases, Luminal A subtype was less common and ROR scores were statistically significantly higher among black women.Multigene assays highlight racial disparities in tumor subtype distribution that persist even in clinically defined subgroups. Differences in tumor biology (eg, HER2-enriched status) may be targetable to reduce disparities among clinically ER+/HER2- cases.
Project description:Several studies have shown that estrogen receptor (ER) and progesterone receptor (PR) expression and human epidermal growth factor receptor 2 (HER2) expression may vary during tumoral progression. We aimed to describe and compare ER, PR, and HER2 expressions in primary breast tumors and synchronic axillary nodal metastases, and evaluate phenotypic correlations between them.Patients were identified prospectively through surgical procedures between September 2013 and July 2016. The status of ER, PR, HER2, and Ki-67 were pathologically analyzed in breast cancers and axillary nodal metastases; these patients were classified based on the breast cancer phenotypes into five subgroups.Synchronic axillary nodal metastases were observed in 127 patients. In breast cancers and nodal metastases, correlation analyses of ER, PR, and Ki-67 expression showed a statistical dependence and concordance between these samples was unambiguously demonstrated through Bland-Altman plots for each determination. Primary breast tumors were classified as follows: luminal A, 41.6%; luminal B, 40.0%; luminal B/HER2, 9.6%; HER2, 2.4%; triple negative, 6.4%. Alterations in phenotype were observed in 28% of patients. The most frequent phenotypic alteration was from luminal B to A (36.4%). Ten cases (30.3%) showed alterations with therapeutic implications; six gained HER2 overexpression, and four, hormonal receptor (HR) expression. A moderate strength of agreement (Cohen's κ coefficient, 0.59; 95% confidence interval, 0.48-0.71) was observed. In multivariate analyses, high histologic grade (odds ratio [OR], 2.79; p<0.047) and high Ki-67 expression (OR, 1.05; p<0.037) were independent factors predictive of phenotypic alterations.Strong correlations were observed in HR and Ki-67 expressions between primary breast tumors and axillary nodal metastases, and a moderate concordance was observed in their phenotypical characteristics. Nevertheless, alterations did exist, and one-third of these changes may have therapeutic implications. The nodal metastases of tumors with high grade and high Ki-67 expression may need to be analyzed, to obtain complete therapeutic information.
Project description:Breast cancer is a highly heterogeneous disease at the molecular level and >90% of mortalities are due to metastasis and its associated complications. The present study determined the impact of molecular subtypes on metastatic behavior and overall survival (OS) of patients with metastatic breast cancer. The influence of molecular subtypes on the sites and number of metastases in 166 patients with metastatic breast cancer from a single center were assessed; and the influence of molecular subtypes on the sites and number of metastases and OS in 15,322 metastatic cases among 329,770 patients with primary breast cancer from the Surveillance, Epidemiology and End Results database were assessed. Analysis of both datasets revealed that different molecular subtypes exhibited differences in the prevalence of different metastatic sites and number of metastases. A larger proportion of bone metastasis was observed in the hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)+ subtype than in other subtypes, more lung metastasis was observed in the HR-/HER2+ subtype and more liver metastasis occurred in the HR+/HER2+ and HR-/HER2+ subtypes. Single-site metastasis was more common for the HR+/HER2- subtype than in other subtypes, while 2-3 sites of metastases were more common for the HR+/HER2+ subtype and ?4 sites of metastases were more frequent in the HR-/HER2+ and HR-/HER2- subtypes. The mean OS of patients with primary breast cancer in the HR+/HER2- subtype group was the longest (78.5 months), while the HR-/HER2- group had the shortest mean OS (69.1 months). The mean OS of the metastatic HR+/HER2+ group was the longest (46.0 months), while the mean OS of the metastatic HR-/HER2- group was the shortest (18.5 months). In conclusion, the results of the present study suggested that different molecular subtypes of breast cancer have different metastatic behavior, as well as mean OS.
Project description:Importance:Capecitabine is not considered a standard agent in the adjuvant treatment of early breast cancer. The results of this study suggest that addition of adjuvant capecitabine to a regimen that contains docetaxel, epirubicin, and cyclophosphamide improves survival outcomes of patients with triple-negative breast cancer (TNBC). Objective:To investigate the effect of capecitabine on long-term survival outcomes of patients with early breast cancer, particularly in subgroups defined by cancer estrogen receptor (ER) and progesterone receptor (PR) content, and HER2 content (human epidermal growth factor receptor 2). Design, Setting, and Participants:This is an exploratory analysis of the multicenter FinXX randomized clinical trial that accrued 1500 women in Finland and Sweden between January 27, 2004, and May 29, 2007. About half received 3 cycles of docetaxel followed by 3 cycles of cyclophosphamide, epirubicin, and fluorouracil (T+CEF), while the other half received 3 cycles of docetaxel plus capecitabine followed by 3 cycles of cyclophosphamide, epirubicin, and capecitabine (TX+CEX). Data analysis took place between January 27, 2004, and December 31, 2015. Main Outcomes and Measures:Recurrence-free survival (RFS). Results:Following random allocation, 747 women received T+CEF, and 753 women received TX+CEX. Five patients were excluded from the intention-to-treat population (3 had overt distant metastases at the time of randomization; 2 withdrew consent). The median age of the remaining 1495 patients was 53 years at the time of study entry; 157 (11%) had axillary node-negative disease; 1142 (76%) had ER-positive cancer; and 282 (19%) had HER2-positive cancer. The median follow-up time after random allocation was 10.3 years. There was no significant difference in RFS or overall survival between the groups (hazard ratio [HR], 0.88; 95% CI, 0.71-1.08; P = .23; and HR, 0.84, 95% CI, 0.66-1.07; P = .15; respectively). Breast cancer-specific survival tended to favor the capecitabine group (HR, 0.79; 95% CI, 0.60-1.04; P = .10). When RFS and survival of the patients were compared within the subgroups defined by cancer steroid hormone receptor status (ER and/or PR positive vs ER and PR negative) and HER2 status (positive vs negative), TX+CEX was more effective than T+CEF in the subset of patients with TNBC (HR, 0.53; 95% CI, 0.31-0.92; P = .02; and HR, 0.55, 95% CI, 0.31-0.96; P = .03; respectively). Conclusions and Relevance:Capecitabine administration with docetaxel, epirubicin, and cyclophosphamide did not prolong RFS or survival compared with a regimen that contained only standard agents. Patients with TNBC had favorable survival outcomes when treated with the capecitabine-containing regimen in an exploratory subgroup analysis. Trial Registration:clinicaltrials.gov Identifier: NCT00114816.
Project description:INTRODUCTION:Population-based data on the incidence and prognosis of bone metastases at diagnosis of breast cancer are currently limited. Hence, we conducted this study to analyze the incidence proportions and prognostic factors of patients with breast cancer and bone metastases at the time of cancer diagnosis. MATERIALS AND METHODS:Patients with primary invasive breast cancer and bone metastases at initial diagnosis between 2010 and 2014 were identified using the Surveillance, Epidemiology, and End Results (SEER) dataset and Fudan University Shanghai Cancer Center (FUSCC) cohort. Multivariable logistic regression was performed to identify predictors of the presence of bone metastases at diagnosis. Univariate and multivariate analyses were performed to determine the effects of each variable on survival. RESULTS:Of 229, 195 patients from SEER database included in the analysis, 8295 patients had bone metastases at initial diagnosis, reflecting 3.6% of the entire study population, and 65.1% of the subset with metastatic disease to any distant site. Patients with hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative represented the highest incidence proportions among patients with metastatic disease (73.9%). Among entire cohort, multivariable logistic regression identified eight factors as predictors of the presence of bone metastases at diagnosis. Median OS for the patients with bone metastases in SEER and FUSCC cohorts was 30.0 and 68.2 months, respectively. Patients with HR-positive HER2-positive subtype had the longest median OS, and patients with triple-negative subtype showed the shortest median OS. Multivariable Cox model in SEER cohort confirmed age, histology, grade, tumor subtype, extraosseous metastatic sites, history of primary surgery, insurance status, marital status, and income as independent prognostic factors for both OS and BCSS. CONCLUSIONS:The findings of this study provide population-based estimates of the incidence and prognosis for patients with bone metastases at initial diagnosis of breast cancer.
Project description:This study aimed to analyze the factors affecting brain metastases free survival (BMFS) and the survival after brain metastases (SABM). The data of 215 patients with breast cancer brain metastases (BCBM) in Sun Yat-sen University Cancer Center from January 2000 to August 2017 were retrospectively analyzed. The clinicopathological features of BCBM were analyzed, and their effects on BMFS and SABM were analyzed by univariate and multivariate COX regression. Finally, it was analyzed whether the receptor status of the brain metastases and the primary lesions were consistent. The median age of the entire cohort was 46 years old. The median BMFS, SABM and overall survival were 31, 9 and 44.2 months, respectively. Clinical stage, molecular subtypes and bone metastasis were independent prognostic factors affecting BMFS. TNM stage IV (HR, 4.99 [95% CI, 2.13-11.7]) and triple negative subtype (HR, 2.06 [95% CI, 1.35-3.14]) was significantly associated with shorter BMFS, but the presence of bone metastases (HR, 0.63 [95% CI, 0.45-0.88]) was a favorable factor for BMFS. Molecular subtypes, resection of BCBM and whole brain radiotherapy (WBRT) were independent factors for SABM. The triple negative subtype (HR, 2.02[95% CI, 1.12-3.64]) was significantly associated with shorter SABM. However, resection of BCBM (HR, 0.31 [95% CI, 0.15-0.65]) and WBRT (HR, 0.57 [95% CI, 0.35-0.93]) were independent factors in improving SABM. The conversion rate of ER was 11.1%, PR was 29.6%, and HER2 was 3.7% between paired breast cancer and brain metastases. BMFS and SABM have different influencing factors. Resection of BCBM and WBRT can significantly improve SABM. The frequency of HER2 status changes between the paired BCBM and the primary lesions is low.
Project description:We sought to investigate the impact of hormone receptor (HR) status and distant recurrence-free interval (DRFI) on the degree of overall survival (OS) benefit from palliative trastuzumab-containing treatment in HER2-positive metastatic breast cancer (MBC). Here, we retrospectively identified 588 eligible HER2-positive patients with postoperative distant recurrence. DRFI of HR+HER2+ MBC patients (median: 30.7 months, IQR: 18.5-45.9, P?<?0.001) was significant longer compared with HR-HER2+ patients. Patients were categorized into four subgroups based on HR status and palliative trastuzumab (trast+) received. The most superior outcome was observed in the HR+HER2+trast+ subgroup, with a median OS of 48.3 months. Moreover, DRFI?>?24 months is an independent favourable prognostic factor for both HR-HER2+ patients (Hazard Ratio (HzR)?=?0.55, 95%?CI: 0.39-0.76, P?<?0.001) and HR+HER2+ patients (HzR?=?0.45, 95%?CI: 0.32-0.64, P? <? 0.001). Upon further analysis of the interaction between trastuzumab and DRFI, the degree of trastuzumab benefits in HR-HER2+ MBC patients remained basically unchanged regardless of DRFI length. Unlikely, the degree in HR+HER2+ MBC patients decreased gradually along with DRFI extending, indicating that trastuzumab failed to translate into an OS benefit for late recurrent (DRFI?>?5years) HR+HER2+ MBC patients.
Project description:The aim of this study was to evaluate the outcomes of patients with inflammatory breast cancer (IBC), with emphasis on the role of molecular subtypes and radiotherapy.A retrospective cohort study to investigate overall survival (OS) and breast cancer-specific mortality (BCSM) in patients with IBC was conducted using data obtained by the Surveillance, Epidemiology, and End Results (SEER) program from 2010-2013. Cox multivariate regression was used to calculate the adjusted Hazard Ratios (aHR).403 patients were eligible for this study. Patients in the group with hormone receptors (HR)+/HER2- subtype had an OS of 79.6% compared with 89.0 % in the group with (HR)+/HER2+ subtype and 76.8% in the HR-/HER2+ group and 62.9% in the triple-negative (TN) group. BCSM was 16.3% for the HR+/HER2- group, 9.8% for the HR+/HER2+ group, 21.7% for the HR-/HER2+ group, and 30.5% for the TN group. For distant metastases, the results showed that there was a high probability of bone metastasis in HR-positive groups, brain and liver metastasis in HER2-positive groups, and lung metastasis in the TN group. Multivariate analysis demonstrated that estrogen receptor and HER2 positivity were associated with better survival and that the TN subtype had a poorer OS and BCSM compared with other subtypes (P<0.05). Furthermore, patients who received radiotherapy were more likely to have improved survival (P< 0.05).Inflammatory breast cancer appears to alter the prognosis in association with the receptor status and molecular subtypes. Radiotherapy was still considered to be a crucial treatment for patients with IBC.
Project description:This study aimed to access possible relationships between breast cancer subtypes and sites of distant metastasis in breast cancer.A total of 243,896 patients, including 226,451 cases in control groups were identified. Bone metastasis was found in 8848 cases, compared with 1,000 brain metastasis cases, 3434 liver metastasis cases and 4167 lung metastasis cases. Patients with all subtypes were most prone to bone metastases, the incidence of bone metastasis in HR+/HER2+ subtype was up to 5.1 %. Further, HR-/HER2+ subtype patients had a higher probability of brain (OR = 1.978) metastasis compared to HR+/HER2- subtype patients. In addition, liver metastasis was more frequently observed in the HER2 positive subtypes compared with HER2 negative subtypes. Patients with TN primarily presented lung metastasis, but it made no difference in the probability of lung metastases of all subtypes.Using the 2010-2013 Surveillance, Epidemiology, and End Results Program(SEER) data, a retrospective, population-based cohort study to investigate tumor subtypes-specific differences in the sites of distant metastasis. Metastatic patterns information was provided for bone, brain, liver and lung. The breast cancer was classified into four subtypes: hormone receptor (HR) +/ human epidermal growth factor receptor 2 (HER2) -, HR+/HER2+, HR-/HER2+ and triple negative (TN).The pathological subtypes of breast cancer are clearly different in metastatic behavior with regard to the sites of distant metastasis, emphasizing that this knowledge may help to determine the appropriate strategy for follow-up and guide personalized medicine.