O Brouckaert

Vitamin D status at breast cancer diagnosis: correlation with tumor characteristics, disease outcome, and genetic determinants of vitamin D insufficiency

We correlated serum 25-hydroxyvitamin D(3) (25OHD) levels with tumor characteristics and clinical disease outcome in breast cancer patients and assessed the impact of genetic determinants of vitamin D insufficiency. We collected serum from 1800 early breast cancer patients at diagnosis, measured 25OHD by radioimmunoassay (RIA), and determined genetic variants in vitamin D-related genes by Sequenom. Multivariable regression models were used to correlate 25OHD levels with tumor characteristics. Cox proportional hazard models were used to assess overall survival (OS), disease-specific survival (DSS), and disease-free interval (DFI). Lower 25OHD serum levels significantly correlated with larger tumor size at diagnosis (P = 0.0063) but not with lymph node invasion, receptor status, or tumor grade. Genetic variants in 25-hydroxylase (CYP2R1) and vitamin D-binding (DBP) protein significantly determined serum 25OHD levels but did not affect the observed association between serum 25OHD and tumor size. High serum 25OHD (>30 ng/mL) at diagnosis significantly correlated with improved OS (P = 0.0101) and DSS (P = 0.0192) and additionally had a modest effect on DFI, which only became apparent after at least 3 years of follow-up. When considering menopausal status, serum 25OHD had a strong impact on breast cancer-specific outcome in postmenopausal patients [hazards ratios for 25OHD >30 ng/mL versus ≤30 ng/mL were 0.15 (P = 0.0097) and 0.43 (P = 0.0172) for DSS and DFI, respectively], whereas no association could be demonstrated in premenopausal patients. In conclusion, high vitamin D levels at early breast cancer diagnosis correlate with lower tumor size and better OS, and improve breast cancer-specific outcome, especially in postmenopausal patients.

Update on triple-negative breast cancer: prognosis and management strategies.

Triple negative breast cancer (TNBC) is a heterogeneous disease comprehending different orphan breast cancers simply defined by the absence of ER/PR/HER-2. Approximately 15%–20% of all breast cancers belong to this phenotype that has distinct risk factors, distinct molecular features, and a particular clinical presentation and outcome. All these features will be discussed in this review. The risk of developing TNBC varies with age, race, genetics, breastfeeding patterns, and parity. Some TNBC are very chemo-sensitive and the majority of patients confronted with and treated for TNBC will never relapse. Some (histological) subgroups of TNBC may have good prognosis even in the absence of chemotherapy. Distinct molecular subgroups within TNBC have been defined now as well. In case metastatic relapse occurs, this is usually within 5 years following surgery, and survival following metastatic relapse is shorter compared to other breast cancer subtypes; treatment options are few and responses lack durability. Novel drug targets and new biomarkers are needed to improve breast cancer care for patients presenting with TNBC. Further molecular/biological unraveling of TNBC is needed.

A critical review why assessment of steroid hormone receptors in breast cancer should be quantitative

Steroid receptors have been around in the field of breast cancer for decades now. Still, controversy remains on how best to report steroid receptors. In this review, we will convince the reader why benefits outweigh pitfalls, when reporting steroid receptors in a quantitative rather than qualitative way. Summarizing decades of research in this field, we will explore the evidence why quantitative reporting is superior in all settings (neoadjuvant, adjuvant and metastatic settings). Furthermore, we will also summarize different staining methods, definitions and pitfalls that have shown to be important points of discussion in earlier debates. Although the molecular unraveling of breast cancer in the past decade has revolutionized the way we think about breast cancer, we should not easily abandon the classical pathological variables such as steroid receptors in favor of molecular tools.

Breast cancer phenotype, nodal status and palpability may be useful in the detection of overdiagnosed screening-detected breast cancers

BACKGROUND Breast cancer remains the leading cause of female cancer death despite improvements in treatment and screening. Screening is often criticized for leading to overdiagnosis and overtreatment. However, few have attempted to identify overdiagnosed cases. PATIENTS AND METHODS A large, consecutive series of patients treated for primary operable, screening-detected, breast cancer (n = 1610). Details from pathology and clinical reports, treatment and follow-up were available from our prospectively managed database. Univariate and multivariate Cox proportional models were used to study the prognostic variables in screening-detected breast cancers for distant metastatic and breast cancer-specific survival. RESULTS We included 1610 patients. The mean/median follow-up was 6.0/6.0 years. Univariate analysis: tumor size, palpability, breast cancer phenotype and nodal status were predictors of distant metastasis and breast cancer-specific death. Multivariate analysis: palpability, breast cancer phenotype and nodal status remained independent prognostic variables. Palpability differed by breast cancer phenotype. CONCLUSION Screening-detected breast cancer is associated with excellent outcome. Palpability, nodal status and breast cancer phenotype are independent prognostic variables that may select patients at increased risk for distant metastatic relapse and breast cancer-specific death. Overdiagnosed cases reside most likely in the nonpalpable node negative subgroup with a Luminal A phenotype.BACKGROUND Breast cancer remains the leading cause of female cancer death despite improvements in treatment and screening. Screening is often criticized for leading to overdiagnosis and overtreatment. However, few have attempted to identify overdiagnosed cases. PATIENTS AND METHODS A large, consecutive series of patients treated for primary operable, screening-detected, breast cancer (n = 1610). Details from pathology and clinical reports, treatment and follow-up were available from our prospectively managed database. Univariate and multivariate Cox proportional models were used to study the prognostic variables in screening-detected breast cancers for distant metastatic and breast cancer-specific survival. RESULTS We included 1610 patients. The mean/median follow-up was 6.0/6.0 years. Univariate analysis: tumor size, palpability, breast cancer phenotype and nodal status were predictors of distant metastasis and breast cancer-specific death. Multivariate analysis: palpability, breast cancer phenotype and nodal status remained independent prognostic variables. Palpability differed by breast cancer phenotype. CONCLUSION Screening-detected breast cancer is associated with excellent outcome. Palpability, nodal status and breast cancer phenotype are independent prognostic variables that may select patients at increased risk for distant metastatic relapse and breast cancer-specific death. Overdiagnosed cases reside most likely in the nonpalpable node negative subgroup with a Luminal A phenotype.

Lobular and non-lobular breast cancers differ regarding axillary lymph node metastasis: a cross-sectional study on 4,292 consecutive patients

Invasive lobular carcinoma (ILC) accounts for 8–14% of all breast cancers and carries distinct prognostic and biologic implications. The goal of our study was to investigate the impact of lobular histology on axillary lymph node (ALN) involvement. This is a cross-sectional study of 4,292 consecutive patients surgically treated for breast carcinoma at the University Hospitals Leuven. Logistic regression analysis was used to relate ILC to lymph node involvement while controlling for the following clinicopathologic features: tumor size, multifocal disease, tumor grade, lobular subtype and the combined steroid, and Her-2 status. Odds ratios (ORs) and 95% confidence intervals (CIS) were computed. A subgroup analysis was performed for patients that underwent a sentinel lymph node (SLN) procedure. The observed incidence of ILC was 13%. ILCs were larger, were more often grade II, multifocal, steroid receptor positive and Her-2 negative, and tended to be present in older patients. Incidence of ALN involvement was 42.0% for ILCs versus 38.3% for other tumors (OR 1.17, 95% CI 0.97–1.40). For the SLN subgroup, ILCs were less often ALN positive than non-ILCs (20.5% versus 28.3%, OR 0.66, 95% CI: 0.41–1.00). In the multivariable analysis, the lobular subtype was identified as less likely to have ALN involvement (adjusted OR 0.66, 95% CI 0.53–0.82). The analysis for the SLN subgroup showed comparable results (adjusted OR 0.49, 95% CI 0.30–0.78). This study has demonstrated that the lobular subtype is an independent predictor of lymph node involvement with ILC having a lower incidence of involved lymph nodes. The mildly higher incidence of ALN metastasis in lobular cancers in univariable analysis is not due to the lobular subtype, but due to confounding factors that interact with lymph node involvement.

Tamoxifen metabolism and efficacy in breast cancer- a prospective multicentre trial

Purpose: Levels of endoxifen, the most active metabolite of tamoxifen, vary by the highly polymorphic cytochrome P450 (CYP) 2D6 enzyme. We prospectively investigated tamoxifen efficacy by serum endoxifen levels and the tamoxifen activity score (TAS). Experimental Design: A prospective observational multicenter study included postmenopausal women with an estrogen receptor–positive breast cancer receiving first-line tamoxifen, 20 mg daily in the neoadjuvant or metastatic setting, recruited between February 2009 and May 2014. The primary endpoint was the objective response rate (ORR) using RECIST criteria 1.0. Secondary endpoints were clinical benefit (CB), progression-free survival (PFS), and tolerability of tamoxifen. The main analysis used logistic regression to relate ORR to serum endoxifen levels after 3 months. Endpoints were also related to other tamoxifen metabolites and to TAS. Results: Endoxifen levels were available for 247 of all 297 patients (83%), of which 209 with target lesions (85%). Median follow-up time for PFS was 32.5 months, and 62% progressed. ORR and CB were 45% and 84%, respectively. ORR was not related to endoxifen, and the OR of ORR was 1.008 per μg/L increase in endoxifen (95% confidence interval, 0.971–1.046; P = 0.56). In general, none of the endpoints was associated with endoxifen levels, tamoxifen metabolites, or TAS. Conclusions: Under the prespecified assumptions, the results from this prospective clinical trial do not suggest therapeutic drug monitoring of endoxifen to be of clinical value in postmenopausal women treated with tamoxifen for breast cancer in the neoadjuvant or metastatic setting. Clin Cancer Res; 24(10); 2312–8. ©2018 AACR.

Prediction of non-sentinel lymph node involvement in breast cancer patients with a positive sentinel lymph node

Completion axillary lymph node dissection (cALND) is the golden standard if breast cancer involves the sentinel lymph node (SLN). However, most non-sentinel lymph nodes (NSLN) are not involved, cALND has a considerable complication rate and does not improve outcome. We here present and validate our predictive model for positive NSLNs in the cALND if the SLN is positive. Consecutive early breast cancer patients from one center undergoing cALND for a positive SLN were included. We assessed demographic and clinicopathological variables for NSLN involvement. Uni- and multivariate analysis was performed. A predictive model was built and validated in two external centers. 21.9% of 470 patients had at least one involved NSLN. In univariate analysis, seven variables were significantly correlated with NSLN involvement: tumor size, grade, lymphovascular invasion (LVI), number of positive and negative SLNs, size of SLN metastasis and intraoperative positive SLN. In multivariate analysis, LVI, number of negative SLNs, size of SLN metastasis and intraoperative positive pathological evaluation were independent predictors for NSLN involvement. The calculated risk resulted in an AUC of 0.76. Applied to the external data, the model was accurate and discriminating for one (AUC = 0.75) and less for the other center (AUC = 0.58). A discriminative predictive model was constructed to calculate the risk of NSLN involvement in case of a positive SLN. External validation of our model reveals differences in performance when applied to data from other institutions concluding that such a predictive model requires validation prior to use.

Prognostic implications of lobular breast cancer histology: new insights from a single hospital cross-sectional study and SEER data.

BACKGROUND Invasive lobular breast cancer (ILC) is generally believed to have an increased risk for late relapse compared to invasive ductal breast cancer (IDC). However, the study most often referred to is a chemotherapy trial that mainly included node positive patients. We hypothesize that nodal status may influence the hazard of relapse since time of diagnosis differently in invasive ductal carcinoma (IDC) and ILC. METHODS Primary operable breast cancer patients from our institution diagnosed between 2000 and 2009 were studied. Multivariable analysis and subgroup analyses were performed to assess whether ILC carries a different prognosis compared to IDC. SEER data were used for external validation. RESULTS In lymph node negative patients, ILC carries a better prognosis regarding distant metastasis free interval (DMFI) (HR 3.242 (1.380-7.614), p = 0.0069) with a trend towards improved breast cancer specific survival (BCSS), over the entire study frame (UZ Leuven data). In lymph node positive patients, both DMFI (HR 0.466 (0.309-0.703), p = 0.0003) and BCSS (HR 0.441 (0.247-0.788), p = 0.0057) are significantly worse for ILC, especially after longer follow-up (>4-5 years) (UZ Leuven data). Similar results were found in the SEER cohort. Results remained identical when excluding screen detected cases (data not shown). CONCLUSION The prognostic impact of lobular histology not only depends on time since diagnosis but also on nodal status. The general believe that ILC have compromised late-term outcome compared to IDC seems untrue for the majority ( = node negative) of ILCs.

Short-Term Prognostic Index for Breast Cancer: NPI or Lpi

Axillary lymph node involvement is an important prognostic factor for breast cancer survival but is confounded by the number of nodes examined. We compare the performance of the log odds prognostic index (Lpi), using a ratio of the positive versus negative lymph nodes, with the Nottingham Prognostic Index (NPI) for short-term breast cancer specific disease free survival. A total of 1818 operable breast cancer patients treated in the University Hospital of Leuven between 2000 and 2005 were included. The performance of the NPI and Lpi were compared on two levels: calibration and discrimination. The latter was evaluated using the concordance index (cindex), the number of patients in the extreme groups, and difference in event rates between these. The NPI had a significant higher cindex, but a significant lower percentage of patients in the extreme risk groups. After updating both indices, no significant differences between NPI and Lpi were noted.

Biology and prognosis by age of primary operable breast cancer.

Abstract #2082 Introduction Breast cancer (BC) biology and prognosis are age dependent. We studied the effect of age on BC biology, treatment and prognosis.
 Methods Data from 2059 consecutive patients, primary operated for invasive BC in UZ Leuven (01/01/00–01/06/05), were used. Patients with ≥ 3.5 yrs follow-up were included (n=1064) to study relapse in relation to age (logistic regression).
 Results Early relapse in BC is age-related, decreasing 3.2% each yr for patients 60 yrs: early relapse increases 5.5% each yr (p=0.0007, 95% CI OR: 1.021-1.082). The positive lymph node status is decreasing 3.5% each yr 60 years. For the progesterone receptor (PR), this depends quadratically on the age at diagnosis (p=0.0108, 95% CI OR=0.999-1.000), decreasing Conclusion Early relapse was higher with increasing/decreasing age, starting from age 60. This goes in parallel with the U-shape curve of lymph node involvement (Fig1). Increased relapse and lymph node positivity in elderly might partially be a reflection of the fact that BC is diagnosed in a later stage in elderly patients but might also be related to different biological behavior or to decreased use of adjuvant systemic treatment. HER-2 overexpression decreases with age and age related differences in ER and PR expression as well as tumor grading are observed (Fig 2).
 Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2082.