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Endocrine therapy (ET) is recommended as first-line therapy for the majority of patients with hormone receptor-positive (HR+), human epidermal growth factor 2-negative advanced breast cancer (ABC); however, the efficacy of ET in patients with visceral metastases (VM) versus patients whose disease is limited to non-visceral metastases (non-VM) is debated. Meta-analyses including available data from randomised controlled trials of first- and second-line endocrine monotherapies for patients with HR+ ABC were performed to address this question. In one and two-stage meta-analyses, progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR) and duration of clinical benefit (DoCB) outcomes were analysed. In the first-line meta-analysis (seven trials; n = 1988) tamoxifen and fulvestrant significantly improved PFS, OS and CBR for patients with non-VM versus those whose disease included VM. The most substantial hazard ratios were observed for fulvestrant 500 mg; 0.56 (95% confidence interval [CI] 0.45−0.70) and 0.55 (95% CI 0.42−0.72) for PFS and OS, respectively. In the second-line meta-analysis (seven trials; n = 2324), all ET combined was more effective (in terms of PFS, OS and DoCB) for non-VM versus VM. In both meta-analyses, patients with non-liver VM had better clinical outcomes than patients with liver VM for all types of ET. Patients whose disease included non-VM sites had better clinical outcomes with endocrine monotherapy compared with patients whose disease included VM. These findings may facilitate better informed treatment decision-making.

PURPOSE Most distant recurrences (DRs) in women with hormone receptor–positive breast cancer occur after 5 years from diagnosis. The Clinical Treatment Score post-5 years (CTS5) estimates DRs after 5 years of adjuvant endocrine therapy (AET). The aim of this study was to externally validate the CTS5 as a prognostic/predictive tool. METHODS The CTS5 categorizes patients who have been disease free for 5 years into low, intermediate, and high risk and calculates an absolute risk for developing DRs between 5 and 10 years. Discrimination and calibration were assessed using data from the TEAM and IDEAL trials. The predictive value of the CTS5 was tested with data from the IDEAL trial. RESULTS A total of 5,895 patients from the TEAM trial and 1,591 patients from the IDEAL trial were included. When assessing the CTS5 discrimination, significantly more DRs were found at 10 years after diagnosis in the CTS5 high- and intermediate-risk groups than in the low-risk group (hazard ratio, 5.7 [95% CI, 3.6 to 8.8] and 2.8 [95% CI, 1.7 to 4.4], respectively). In low- and intermediate-risk patients, the CTS5-predicted DR rates were higher, although not statistically significantly so, than observed rates. However, in high-risk patients, the CTS5-predicted DR rates were significantly higher than observed rates (29% v 19%, respectively; P < .001). The CTS5 was not predictive for extended AET duration. CONCLUSION The CTS5 score as applied to patients treated in the TEAM and IDEAL cohorts discriminates between risk categories but overestimates the risk of late DRs in high-risk patients. Therefore, the numerical risk assessment from the CTS5 calculator in its current form should be interpreted with caution when used in daily clinical practice, particularly in high-risk patients.

Background Four randomised controlled trials (RCTs) in postmenopausal women with advanced breast cancer (ABC) comparing aromatase inhibitors (AIs) versus the selective estrogen receptor modulator tamoxifen, each individually reported significantly longer progression free survival (PFS) but none showed a significant difference in overall survival (OS). In these trials between 6.8%–55% of tumours were hormone receptor (HR) status unknown or negative. This meta-analysis restricted the comparison to HR-positive (HR+) tumours. MethodsAnonymised individual patient data were obtained from three RCTs, EORTC (exemestane versus tamoxifen), Study 0027 and Study 0030 (both anastrozole versus tamoxifen). For the remaining RCT (Femara Study PO25; letrozole versus tamoxifen), odds ratio (OR) or hazard ratio (HzR), with confidence intervals were obtained from the clinical study report, for patients with HR+ tumours, in addition to published data. In total, data were obtained from 2296 patients; 1560 (68%) had HR+ ABC. FindingsThe OR for clinical benefit rate was 1·56, in favour of AIs (p[less than] 0·001). The duration of clinical benefit was not significantly increased by AIs (hazard ratio [HzR] 0·88; p=0·08). For PFS the HzR (0·82) was in favour of AIs (p=0·007). However, for OS the HzR (1·05) was not significantly different between AIs and tamoxifen (p=0·42).InterpretationAlthough third generation AIs put significantly more patients into ‘clinical benefit’, their tumours were not controlled for significantly longer. Overall, while this resulted in a significantly greater PFS in favour of the AIs, this did not translate into improvement in OS.

Optimal endocrine therapy for postmenopausal, hormone-receptor positive (HR+) early breast cancer remains a point of discussion. The Tamoxifen Exemestane Adjuvant Multinational (TEAM) phase III trial showed no significant differences for disease free survival (DFS) and overall survival (OS) at 5 years between exemestane monotherapy and sequential treatment (tamoxifen followed by exemestane). We now report disease related outcomes at 10 years of follow-up (FU), and an explorative analysis to assess the predictive value of clinicopathological and immune-related biomarkers. In the TEAM trial, postmenopausal women with HR+ positive early breast cancer were randomly assigned to exemestane alone or sequential therapy. For this analysis, TEAM patients from countries that completed 10 years of FU were included. The primary endpoint was DFS at ten years, analyzed by intention to treat. Secondary outcomes were OS and cumulative incidence of relapse. An explorative per protocol analysis for relapse free survival (RFS) was performed to identify predictive pathological and immunological biomarkers, including centrally determined ER (ER-poor 0-6 vs ER-rich 7-8) and PR (0-4 vs 5-8) Allred scores, and the immunological markers CD8, FoxP3, classical HLA class 1 and HLA-G which were described earlier (Engels et al, Breast Cancer Treat Res, 2015). In total, 6120 patients were eligible for the current analysis, 3075 patients with exemestane monotherapy and 3045 patients randomized to sequential treatment. Median follow up was 9.83 years. DFS was 66.8% in the exemestane group and 66.8% in the sequential group (hazard ratio (HR) 0.96, 95% CI 0.88-1.05, p=0.389). OS was 74% in the exemestane, and 73% in the sequential group, respectively (HR 0.98, 95% CI 0.89-1.09, p=0.737). The cumulative incidence of relapse was 20% and 22% in the exemestane and sequential groups, respectively (HR 0.88, 95% CI 0.79-0.99, p=0.031). In the explorative per protocol analysis (n=4041), Allred score were available for 2996 patients; immunological markers for 1754 patients. Patients with above median numbers of FoxP3-positive T-cells showed a benefit of exemestane monotherapy for RFS (HR 0.56, 95% CI 0.42-0.75, p After ten years of follow up, both exemestane monotherapy and sequential therapy remain appropriate options for postmenopausal HR+ early breast cancer patients. Interestingly, the number of regulatory T-cells was a predictive factor for the benefit of exemestane monotherapy, which implies a role of the local immune system in endocrine therapy. Furthermore, data suggested that patients with a higher differentiation grade or ER-rich tumor derive more benefit from exemestane monotherapy. Citation Format: Blok EJ, Derks MGM, Kuppen PJK, Meershoek-Klein Kranenbarg EM, Engels CC, Liefers G-J, Putter H, Seynaeve CM, Kroep JR, Nortier JWR, Rea DW, Hasenburg A, Markopoulos CJ, Paridaens R, Bartlett JMS, van de Velde CJH. 10-year follow-up and biomarker discovery for adjuvant endocrine therapy; results of the TEAM trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD2-07.

Summary Background After 5 years of median follow-up, the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial reported no difference in disease-free survival between exemestane monotherapy and a sequential scheme of tamoxifen followed by exemestane in postmenopausal patients with early-stage, hormone receptor-positive breast cancer. As recurrence risk in hormone receptor-positive breast cancer remains linear beyond 5 years after diagnosis, we analysed long-term follow-up outcomes of this trial. Methods The TEAM trial, a multicentre, open-label, randomised, controlled, phase 3 trial, included postmenopausal patients with early-stage hormone receptor-positive breast cancer from nine countries. Patients were randomly allocated (1:1) by a computer-generated random permuted block method (block sizes 4–8) to either 5 years of oral exemestane monotherapy (25 mg once a day) or a sequential scheme of oral tamoxifen (20 mg once a day) followed by exemestane for a total duration of 5 years. After the publication of the IES trial, the protocol was amended (Dec 13, 2004). Patients assigned to tamoxifen were switched after 2·5–3·0 years to exemestane therapy for a total duration of 5·0 years of treatment. Randomisation was done centrally in each country. Long-term follow-up data for disease recurrence and survival was collected in six participating countries and analysed by intention to treat. The primary endpoint was disease-free survival at 10 years of follow-up. The trial is registered with ClinicalTrials.gov, numbers NCT00279448 and NCT00032136; with Netherlands Trial Register, number NTR 267; and the Ethics Commission Trial, number 27/2001. Findings 6120 patients of the original 9776 patients in the TEAM trial were included in the current intention-to-treat analysis. Median follow-up was 9·8 years (IQR 8·0–10·3). During follow-up, 921 (30%) of 3075 patients in the exemestane group and 929 (31%) of 3045 patients in the sequential group had a disease-free survival event. Disease-free survival at 10 years was 67% (95% CI 65–69) for the exemestane group and 67% (65–69) for the sequential group (hazard ratio 0·96, 0·88–1·05; p=0·39). Interpretation The long-term findings of the TEAM trial confirm that both exemestane alone and sequential treatment with tamoxifen followed by exemestane are reasonable options as adjuvant endocrine therapy in postmenopausal patients with hormone receptor-positive early breast cancer. These results suggest that the opportunity to individualise adjuvant endocrine strategy accordingly, based on patient preferences, comorbidities, and tolerability might be possible. Funding Pfizer, Dutch Cancer Foundation.

Background In estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 (HER-2) negative breast cancers, the progesterone receptor (PR) is an independent prognostic marker. Little is known about the prognostic value of PR by tumor grade. We assessed this in two independent datasets. Patients and Methods Women with primary operable, invasive ER+ HER-2 negative breast cancer diagnosed between 2000 and 2012, treated at University Hospitals Leuven, were included. We assessed the association of PR status and subtype (grade 1–2 vs. grade 3) with distant recurrence-free interval (DRFI) and breast cancer-specific survival. The interaction between PR status and subtype was investigated, and associations of PR status by subtype were calculated. The BIG 1-98 data set was used for validation. Results In total, 4,228 patients from Leuven and 5,419 from BIG 1-98 were analyzed. In the Leuven cohort, the adjusted hazard ratio (HR) of PR-positive versus PR-negative tumors for DRFI was 0.66 (95% confidence interval [CI], 0.50–0.89). For the interaction with subtype (p = .34), the HR of PR status was 0.79 (95% CI, 0.61–1.01) in luminal A-like and 0.59 (95% CI, 0.46–0.76) in luminal B-like tumors. In luminal A-like tumors, observed 5-year cumulative incidences of distant recurrence were 4.1% for PR-negative and 2.8% for PR-positive tumors, and in luminal B-like 18.7% and 9.2%, respectively. In the BIG 1-98 cohort, similar results were observed; for the interaction with subtype (p = .12), the adjusted HR of PR status for DRFI was 0.88 (95% CI, 0.57–1.35) in luminal A-like and 0.58 (95% CI, 0.43–0.77) in luminal B-like tumors. Observed 5-year cumulative incidences were similar. Conclusion PR positivity may be more protective against metastatic relapse in luminal B-like versus luminal A-like breast cancer, but no strong conclusions can be made. In absolute risk, results suggest an absent PR is clinically more important in high compared with low proliferative ER+ HER-2 negative tumors. Implications for Practice An absent progesterone receptor (PR) predicts a worse outcome in women treated for an estrogen receptor-positive, human epidermal growth factor receptor 2 negative breast cancer. As low proliferative tumors lacking PR are now also classified high risk, the prognostic value of PR across risk groups was studied. Despite a negative test for interaction of the prognostic value of PR by tumor grade, the magnitude of an absent PR on breast cancer relapse is much larger in high than in low proliferative breast cancers.

Metastatic triple-negative breast cancer (TNBC) is a phenotypic breast cancer subgroup with a very poor prognosis, despite standard treatments. Combined twice-weekly iniparib and gemcitabine/carboplatin (GC+tw-iniparib) showed benefit over gemcitabine/carboplatin in a randomized phase II trial, and a phase III was initiated comparing these regimens. The present phase II study was initiated to compare GC+tw-iniparib with a more practical once-weekly schedule (GC+w-iniparib) in TNBC. Metastatic TNBC patients were randomized to receive iniparib weekly (11.2 mg/kg on days 1 and 8) or twice-weekly (5.6 mg/kg on days 1, 4, 8, and 11) with gemcitabine (1000 mg/m2) and carboplatin (area under the curve 2 on days 1 and 8), every 3 weeks. The primary endpoint was the overall response rate (ORR). Pharmacokinetics of iniparib and its two metabolites were analyzed. A total of 163 patients were randomized, 82 GC+w-iniparib and 81 GC+tw-iniparib. Demographic and baseline characteristics were well balanced. ORR was 34.1% (95% CI 23.9–44.4%) vs. 29.6% (95% CI 19.7–39.6%) and median progression-free survival was 5.5 months (95% CI 4.2–5.7) vs. 4.3 months (95% CI 3.0–5.8) for GC+w-iniparib and GC+tw-iniparib, respectively. Safety was similar across treatment arms in terms of event severity and type. Iniparib plasma concentrations and exposure were two-fold higher with w-iniparib compared to tw-iniparib. Iniparib and its metabolites were cleared rapidly with a terminal half-life of

Goals of work: The aims of this study were to assess chemotherapy treatment characteristics, neutropenic event (NE) occurrence and related risk factors in breast cancer patients in Western Europe. Material and methods: Six retrospective audits of breast cancer chemotherapy were combined into a dataset of 2,860 individuals. NEs were defined as neutropenia-related hospitalisation, dose reduction >= 15% or dose delay >= 7 days. Summation dose intensity (SDI) was calculated to compare different types of chemotherapy regimens on a single scale. Risk factors of NE occurrence and of low relative dose intensity (RDI) >= 85% were identified by multiple logistic regression. Main results: Patient populations were comparable between audits. Until 1998, cyclophosphamide, methotrexate and fluorouracil regimens were most frequently used, but thereafter, anthracycline-based regimens were most common. NEs occurred in 20% of the patients and low RDI in 16%. NE occurrence predicted low RDI and was associated with higher age, bigger body surface area, lower body mass index, regimen type, more chemotherapy cycles planned, normal to high SDI, concomitant radiotherapy and year of treatment. First cycle NE occurrence predicted NEs from cycle 2 onwards. A risk score using age, SDI, number of planned chemotherapy cycles and concomitant radiotherapy differentiated patients with increasing NE risk (9-37%). An alternative score version not using concomitant radiotherapy performed moderately less well. Conclusions: NEs occurred frequently in this combined dataset and they affected treatment delivery. Identifying patients at high NE risk enables targeted prophylaxis and may avoid dose limitations.

Background: There remains a perception among many clinicians that visceral metastases (VMs) from hormone receptor positive (HR) breast cancer (BC) respond less well to endocrine therapy (ET) than non-VMs and so should receive chemotherapy as first line treatment. Patients & Methods: Four phase 3 randomised controlled trials (RCTs) of first line ET, all with tamoxifen (TAM) as their control arm) have been reviewed – Exemestane (Exe), fulvestrant 250mg (F250) and two with anastrozole (Ana); the latter, were study 27 in the Rest of the World (ROW) & study 30 in North America (NA). All reported objective response (OR), clinical benefit (CB), time to progression (TTP) / progression free survival (PFS): all have been published (1-5). Only HR positive tumors were included in this review. Data have been analysed both for Tam control arms alone and also for the four different endocrine agents combined. Results: CB & OR for TAM alone in each study individually and then combined are shown in the Table. The OR and CB rates were similar for non-VMs versus VMs in all studies except study 30 (NA) where CB rates were 59% for non-VM and 33% for VM (Test for heterogeneity of CB rates was p=0.047). For the four studies combined, the CB rates for non-VM versus VMs were 64% and 57% respectively (p=0.06) while the OR rates were 34% versus 30% respectively (p= 0.28). When all endocrine agents were combined the OR rate between non-VMs and VMs was significantly different (p = 0.038) as was the CB rate (p = 0.0015). Rates of CB and OR in study 30 (NA) again appear different between non-VMs and VMs (data not shown). The Median Duration of CB on Tam appear similar between non-VMs versus VMs, both for each study individually and when combined (see Table); when combined the Medians were 420 versus 418 days respectively with a Hazard Ratio (HR)=0.952 (0.748-1.211) (p=0.69). When all endocrine therapies for the combined four studies were assessed the HR for DoCB between non-VMs and VMs was 0.922 (0.779-1.093) (p=0.35). For the TTP the HR of non-VMs versus VMs on Tam alone was 0.851 (0.715-1.011) (p=0.07) and for all endocrine therapies the HR was 0.821 (0.727-0.926) (p=0.001). Conclusions: HR+VMs which achieve clinical benefit on ET remain controlled for as long as non-VMs as shown by the DoCB results for both Tam and all endocrine therapies combined. There was no significant difference in OR rates between VMs and non-VMs with Tamoxifen. There was when all endocrine agents were combined and the difference appears to be primarily due to one study (30 – NA). There is no confirmed explanation for these differences. TTP differences appear to be due primarily to the difference in initial CB rates in study 30 (see Table). HR+ VMs have hormone sensitivity similar to non-visceral mets – they respond as well and for as long as non-VMs. In the absence of visceral crisis (ie immediately life-threatening disease) ET would appear to be the treatment of choice for VMs in the same way as it is for non-VMs. Clinical Outcome by VM and Non VM (Tamoxifen only patients) N (%)StudiesExeAna (EUR)Ana (NA)F250Combined N = 168N = 144N = 162N = 209N=683Without VM (55%)N = 88N = 71N = 82N = 135N=376CB (%)66 (75)42 (59)47 (59)87 (64)242 (64)OR (%)41 (47)26 (37)15 (19)45 (33)127 (34)TTP (Median in days)287254305234277DoCB (Median in days)343360445451420With VM (45%)N = 80N = 73N = 80N = 74N=307CB (%)64 (80)38 (52)27 (33)46 (62)175 (57)OR (%)36 (45)21 (29)13 (16)21 (28)91 (30)TTP (Median in days)340230152281238DoCB (Median in days)376505411339418 Citation Format: John FR Robertson, Robert Paridaens, Jan Bogaerts, Yuri Rukazenkov, Christine Campbell, Ian Bradbury. Visceral metastases from hormone receptor positive breast cancer are as sensitive to endocrine therapy as non-visceral metastases [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-13-02.

Evidence suggests that premenopausal obesity decreases and postmenopausal obesity increases breast cancer risk. Because it is not well known whether this is subtype dependent, we studied the association between body mass index (BMI) and age at breast cancer diagnosis, or the probability of being diagnosed with a specific breast cancer phenotype, by menopausal status. All patients with non-metastatic operable breast cancer from the University Hospital Leuven diagnosed between January 1, 2000 and December 31, 2013 were included (n = 7020) in this cross-sectional study. Linear models and logistic regression were used for statistical analysis. Allowing correction for age-related BMI-increase, we used the age-adjusted BMI score which equals the difference between a patient’s BMI score and the population-average BMI score corresponding to the patient’s age category. The quadratic relationship between the age-adjusted BMI and age at breast cancer diagnosis (p = 0.0207) interacted with menopausal status (p

Purpose The Intergroup Exemestane Study, an investigator-led study of 4,724 postmenopausal patients with early breast cancer (clinical trial information: ISRCTN11883920), has previously demonstrated that a switch from adjuvant endocrine therapy after 2 to 3 years of tamoxifen to exemestane was associated with clinically relevant improvements in efficacy. Here, we report the final efficacy analyses of this cohort. Patients and Methods Patients who remained disease free after 2 to 3 years of adjuvant tamoxifen were randomly assigned to continue tamoxifen or switch to exemestane to complete a total of 5 years of adjuvant endocrine therapy. Given the large number of non–breast cancer–related deaths now reported, breast cancer–free survival (BCFS), with censorship of intercurrent deaths, was the primary survival end point of interest. Analyses focus on patients with estrogen receptor-positive or unknown tumors (n = 4,599). Results At the time of the data snapshot, median follow-up was 120 months. In the population that was estrogen receptor positive or had unknown estrogen receptor status, 1,111 BCFS events were observed with 508 (22.1%) of 2,294 patients in the exemestane group and 603 (26.2%) of 2,305 patients in the tamoxifen group. The data corresponded to an absolute difference (between exemestane and tamoxifen) at 10 years of 4.0% (95% CI, 1.2% to 6.7%), and the hazard ratio (HR) of 0.81 (95% CI, 0.72 to 0.92) favored exemestane. This difference remained in multivariable analysis that was adjusted for nodal status, prior use of hormone replacement therapy, and prior chemotherapy (HR, 0.80; 95% CI, 0.71 to 0.90; P < .001). A modest improvement in overall survival was seen with exemestane; the absolute difference (between exemestane and tamoxifen) at 10 years in the population that was estrogen receptor positive or had unknown estrogen receptor status was 2.1% (95% CI, −0.5% to 4.6%), and the HR was 0.89 (95% CI, 0.78 to 1.01; P = .08). For the intention-to-treat population, the absolute difference was 1.6% (95% CI, −0.9% to 4.1%); the HR was 0.91 (95% CI, 0.80 to 1.03, P = .15). No statistically significant difference was observed in the proportion of patients who reported a fracture event in the post-treatment period. Conclusion The Intergroup Exemestane Study and contemporaneous studies have established that a strategy of switching to an aromatase inhibitor after 2 to 3 years of tamoxifen can lead to sustained benefits in terms of reduction of disease recurrence and breast cancer mortality.

In order to describe the impact of sarcomatoid dedifferentiation on outcome in metastatic clear cell RCC treated with first-line anti-VEGFR-TKIs, we retrospectively reviewed 124 patients files. An important sarco- matoid component, defined as ‡25% involvement of the primary tumor, was associated with poor outcome. Analysis of the extent of sarcomatoid features in resected metastases can also provide additional prognostic information. Introduction: This study aimed to assess the efficacy of antievascular endothelial growth factor receptor tyrosine kinase inhibitors (anti-VEGFR-TKIs) in patients with metastatic clear cell renal cell carcinoma (m-ccRCC) with sar- comatoid dedifferentiation. Patients and Methods: The files of all patients with m-ccRCC consecutively treated with first-line anti-VEGFR-TKIs at the authors' institution were retrospectively reviewed. Pathology slides from nephrec- tomy and metastasectomy were assessed for the presence and extent of sarcomatoid dedifferentiation. Results: A total of 124 patients were included; nephrectomy and metastasectomy specimens were available in 117 and 35 patients, respectively. Thirty percent of the primary nephrectomy specimens had sarcomatoid features, and the median involvement of the sarcomatoid component was 21% (range, 1%-95%). Patients with an important sarco- matoid component, defined as � 25% involvement of the tumor, had a very poor outcome: progression-free survival (PFS) and overall survival (OS) were 3 and 6 months, respectively, and no partial responses (PR) were observed. Patients without sarcomatoid dedifferentiation or with sarcomatoid involvement < 25% had a PFS of 12 months (P < .0001; hazard ratio (HR), 51; 95% CI, 12.58-207.3), an OS of 22 months (P < .0001, HR, 10.72; 95% CI, 3.56- 32.25), and a PR rate of 50% (P ¼ .0015). Patients with a sarcomatoid component � 25% in the metastasectomy also had a poorer PFS and OS on anti-VEGFR-TKIs compared with patients with < 25% of sarcomatoid features at these sites. Conclusion: Patients with m-ccRCC whose tumors contain a component of sarcomatoid dedifferentiation of � 25% of the total tumor volume have a very poor outcome when treated with anti-VEGFR-TKIs. Analysis of the extent of sarcomatoid features in resected metastases can provide additional prognostic information.

To assess the impact of patient-related factors, including genetic variability in genes involved in the metabolism of chemotherapeutic agents, on breast cancer-specific survival (BCSS) and recurrence-free interval (RFI). We selected early breast cancer patients treated between 2000 and 2010 with 4-6 cycles of (neo-)adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) or 3 cycles FEC followed by 3 cycles docetaxel. Tumor stage/subtype; febrile neutropenia and patient-related factors such as selected single nucleotide polymorphisms and baseline laboratory parameters were evaluated. Multivariable Cox regression was performed. Of 991 patients with a mean follow-up of 5.2 years, 152 (15.3 %) patients relapsed and 63 (6.4 %) patients died. Advanced stage and more aggressive subtype were associated with poorer BCSS and RFI in multivariable analysis (p < 0.0001). Associations with worse BCSS in multivariable analysis were: homozygous carriers of the rs1057910 variant C-allele in CYP2C9 (hazard ratio [HR] 30.4; 95 % confidence interval [CI] 6.1-151.5; p < 0.001) and higher white blood cell count (WBC) (HR 1.2; 95 % CI 1.0-1.3; p = 0.014). The GT genotype of the ABCB1 variant rs2032582 was associated with better BCSS (HR 0.5; 95 % CI 0.3-0.9, p = 0.021). Following associations with worse RFI were observed: higher WBC (HR 1.1; 95 % CI 1.0-1.2; p = 0.026), homozygous carriers of the rs1057910 variant C-allele in CYP2C9 (HR 10.9; 95 % CI 2.5-47.9; p = 0.002), CT genotype of the CYBA variant rs4673 (HR 1.8; 95 % CI 1.2-2.7; p = 0.006), and G-allele homozygosity for the UGT2B7 variant rs3924194 (HR 3.4; 95 % CI 1.2-9.7, p = 0.023). Patient-related factors including genetic variability and baseline white blood cell count, impacted on outcome in early breast cancer.

Breast cancer is the most prevalent type of cancer in women and responsible for significant female cancer-related mortality worldwide. In the Western world, over 80% of breast cancers are hormone-receptor positive for which endocrine therapy is administered. The main anti-estrogen treatments in use consist of selective estrogen-receptor modulators, such as tamoxifen, and third-generation aromatase inhibitors (AIs), such as exemestane, letrozole, and anastrozole. In this review, the focus will lie on exemestane, its clinical use, and its side-effect profile. Exemestane is the only third-generation steroidal AI. Its efficacy as a first-line treatment in metastatic breast cancer has been demonstrated. Therefore, exemestane could be considered a valid first-line therapeutic option, but it also can be used in second-line or further situations. Exemestane is mostly used as part of sequential adjuvant treatment following tamoxifen, but in this setting it is also active in monotherapy. Furthermore, this AI has been studied in the neoadjuvant setting as presurgical treatment, and even as chemoprevention in high-risk healthy postmenopausal women. It may reverse side effects of tamoxifen, such as endometrial changes and thromboembolic disease but may also cause some inconvenient side effects itself. Additionally, there is a lack of total cross-resistance between exemestane and nonsteroidal AIs as far as their anti-tumoral efficacy is concerned; moreover the two classes of AIs display a nontotal overlapping toxicity profile. Taking together, exemestane can be considered as a useful treatment option at all stages of breast cancer.

Objective: •To evaluate the impact of baseline serum C-reactive protein (CRP) level on outcome in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib. Patients and Methods: •We reviewed the charts of patients with mRCC who started sunitinib as a first targeted treatment between 2005 and 2012 in three hospitals in Belgium and France. •Collected data included known prognostic factors for mRCC, anatomical location of metastatic sites, response rate (RR), progression-free survival (PFS) and overall survival (OS). Results: •A total of 200 eligible patients were identified by retrospective chart review. The median PFS and OS were 12 and 20 months, respectively. •We observed a clear impact of baseline CRP levels on outcome: the median PFS was 25 months in the group with baseline CRP ≤5 mg/L and 8 months in the group with baseline CRP >5 mg/L (hazard ratio [HR] 2.48, 95% CI 1.74–3.59). The median OS in each group was 50 vs 12 months, respectively (HR 3.17, 2.20–4.68). In the group with baseline CRP ≤5 mg/L, 61% of patients experienced a partial response compared with 32% of patients in the group with baseline CRP >5 mg/L (difference = 29%, 95% CI 15–42). •When adding baseline CRP (with a log transformation) to the six variables of the International Metastatic RCC Database Consortium (IMDC) model in a multivariable Cox regression model, baseline CRP was independently associated with poor PFS (HR for each doubling in CRP level: 1.14, 95% CI 1.03–1.26; P = 0.01) and OS (HR: 1.29, 95% CI 1.16–1.43; P < 0.001). •Adding baseline CRP to the model increased the c-statistic of PFS at 5 years from 0.63 (0.59–0.68) to 0.69 (0.65–0.73), and the c-statistic of OS at 5 years from 0.65 (0.60–0.69) to 0.70 (0.66–0.74). •Patients with elevated baseline CRP levels had a poor prognosis independent of the IMDC risk group, whereas patients with a low baseline CRP in the IMDC favourable risk group had a very good outcome. Conclusion: •Baseline serum CRP level is a strong independent variable linked with RR, PFS and OS in patients with mRCC treated with sunitinib.

BACKGROUND Tamoxifen remains important in the treatment and prevention of estrogen receptor-positive breast cancer. In postmenopausal women, it can lead to endometrial changes such as cystic appearances, hyperplasia, polyps and endometrial cancer. Tamoxifen is metabolized by cytochrome P450 (CYP450) enzymes to the more active metabolite endoxifen. Several genetic variants in the CYP450 enzymes reduce tamoxifen metabolism, leading to reduced endoxifen levels. We hypothesize that carriers of these variants, which are established poor metabolizers of tamoxifen, do not have the typical tamoxifen-induced increase in endometrial thickness. We test the association between genetic variability in CYP450 enzymes and the increase in double endometrial thickness (DET) as measured through transvaginal ultrasound (TVU). PATIENTS AND METHODS We carried out a retrospective study on postmenopausal tamoxifen users for which germline DNA was available and at least one DET measurement was made between January 2000 and October 2011. Genotyping of 33 single nucleotide polymorphisms in CYP450 genes involved in tamoxifen metabolism was carried out using Sequenom MassARRAY. The association between these variants and TVU outcome (DET ≥5 mm) was assessed by proportional hazards regression. RESULTS Data were available for 184 women: 47 with a DET of

Objective Aromatase inhibitors (AIs) frequently induce or enhance musculoskeletal problems, also known as the AI-induced musculoskeletal syndrome (AIMSS). Underlying mechanisms are unknown, likely multiple and induced by low estrogen levels. We hypothesized a role for the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis (Lintermans et al, Ann of Oncol 2011). Recently, Gallicchio et al. (J Cancer Res Clin Oncol 2013) confirmed our hypothesis. Here we report the effect of tamoxifen and AIs on AIMSS, IGF-I, its binding protein and estrogen levels from a prospective study. Material & Methods In this prospective cohort study postmenopausal women with an early breast cancer scheduled to start adjuvant endocrine therapy with any of the third generation AIs or tamoxifen were included. After providing informed consent, a rheumatologic questionnaire was completed and serum was collected. AI-induced musculoskeletal pain was defined as an increase in joint or muscle pain relative to baseline; AIMSS presence was defined as the presence of ≥ 3 out of five features (arthralgia, myalgia, joint stiffness, tingling, carpal tunnel syndrome). IGF-I levels were determined in batch with an inhouse radio-immunoassay; levels of IGF binding protein 3 (IGFBP-3) with a commercial EASIA from DiaSource. A sensitive liquid chromatography dual mass spectrometry was used for assessment of estradiol (E2) and estrone (E1) values, with a limit of quantification of 1.3 and 1.2 ng/l, respectively. SHBG levels were determined with the Roche Modular E170 analyzer. Re-evaluation was done after 3, 6 and 12 months of therapy. Results 84 patients started on tamoxifen (n = 42) or an AI (n = 42; anastrozole n = 6, letrozole n = 36). In the AI group, 4 patients discontinued due to AIMSS. In the tamoxifen group, 1 patient developed a deep vein thrombolic event and discontinued tamoxifen therapy. In all BMI categories, AI and not tamoxifen decreased E1 and E2 levels below limit of quantification from month 3 onwards. SHBG values dropped on AI while they increased on tamoxifen. AI therapy resulted in elevated IGF-I and IGF-I/IGFBP-3 ratio levels, whereas tamoxifen users had a decrease. AI-induced musculoskeletal symptoms were characterized by a higher increase from baseline in IGF-I levels and IGF-I/IGFBP-3 ratio than AI users without any complaints. Patients experiencing AIMSS showed a significant decrease in IGFBP-3 levels (p = 0.0007) and an increase in IGF-I/IGFBP-3 ratio (p = 0.07) compared to patients without AIMSS. This divergence was most pronounced at 3 months following AI start. Conclusion These findings provide preliminary evidence that AI-induced musculoskeletal symptoms are associated with changes in the GH/IGF-I axis. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-13-08.

Purpose To investigate the clinical behavior of triple negative breast cancer (TNC), including age distribution, occurrence of LN (lymph node) invasion and prognosis in different histological subtypes. Methods For this cohort study we used data on 476 patients with newly diagnosed TNC at the University Hospitals Leuven (Belgium) between 1999 and 2009. Of these, 395 received upfront surgery, 68 neoadjuvant chemotherapy and 21 had metastases at diagnosis. Results Apocrine and invasive lobular TNC occur more often in older patients compared to IDC-NOS. Of the primarily operated patients with TNC, 35.1% has pathological LN involvement. There were no significant differences in nodal invasion between different histological subtypes, but most subtypes contained few patients. In contrast to previous reports, 6/14 of apocrine TNC had LN involvement. Disease free survival (DFS) was different in different histological subtypes, but group sizes were insufficient to be able to draw firm conclusions. Within the histologically ‘homogeneous’ IDC-NOS group with primary surgery and outcome data (n = 300), DFS with 3.5 year median follow-up decreased with increasing age, but chemotherapy and radiotherapy were much less frequently given with increasing age. In multivariable analysis, lower age, presence of LN involvement, lack of administration of chemotherapy and radiotherapy were significant predictors of relapse. Conclusion TNC is not a uniform disease. Different histological subtypes have different age distribution and behavior. The prognosis of the most common histological subgroup, IDC-NOS, is better in older patients, but this is counterbalanced by significantly decreased use of chemotherapy and radiotherapy.

Lymph node involvement is the most important prognostic factor in breast cancer. It is a multifactorial event determined by patient and tumour characteristics. The purpose of this study was to determine clinical and pathological factors predictive for axillary lymph node metastasis (ALNM) in patients with early breast cancer and to build a model to portend lymph node involvement.We evaluated 1300 consecutive patients surgically treated in our institution (2007-2009) for cT1-T2 invasive breast cancer. The patient and tumour characteristics evaluated included: age at diagnosis, number of foci, histologic grade, location, tumour size, histologic subtype, lymphovascular invasion (LVI), estrogen-receptor (ER), progesterone-receptor (PR) and Her-2 status. Univariate and multivariate analyses were performed. Factors significantly associated with ALNM by univariate analysis plus histologic subtype were included in the multivariate analysis.By univariate analysis, the incidence of ALNM was significantly associated with the presence of LVI (P 0.0001), larger tumour size (P 0.0001), higher histologic grade (P 0.0001), retroareolar or lateral location in the breast (P 0.0001), multiple foci (P = 0.0002) and in patients who underwent an axillary lymph node dissection. We found no effect of age, ER⁄PR nor HER-2 status. By multivariate analysis, ALNM was significantly associated with the presence of LVI (P 0.0001), larger tumour size (P 0.0001), axillary lymph node dissection (P = 0.0003), retroareolar and lateral tumour location in the breast (P = 0.0019) and the presence of multiple foci (P = 0.0155).LVI and tumour size emerged as the most powerful independent predictors of ALNM, followed by the location of the tumour in the breast and the presence of multiple foci.

Background: There are no validated markers that predict response in metastatic renal cell cancer (RCC) patients treated with sunitinib. We aim to study the impact of single-nucleotide polymorphisms (SNPs) that have recently been proposed as predictors of outcome to anti-VEGF-targeted therapy in metastatic RCC in an independent cohort of patients. Methods: We genotyped 16 key SNPs in 10 genes involved in sunitinib pharmacokinetics, pharmacodynamics and VEGF-independent angiogenesis in patients with metastatic clear-cell RCC treated with sunitinib as the first-line targeted therapy. Association between SNPs, progression-free survival (PFS) and overall survival (OS) were studied by multivariate Cox regression using relevant clinical factors associated with PFS and OS as covariates. Results: In a series of 88 patients, both PFS and OS were associated significantly with SNP rs1128503 in ABCB1 (P=0.027 and P=0.025), rs4073054 in NR1/3 (P=0.025 and P=0.035) and rs307821 in VEGFR3 (P=0.032 and P=0.011). Progression-free survival alone was associated with rs2981582 in FGFR2 (P=0.031) and rs2276707 in NR1/2 (P=0.047), whereas OS alone was associated with rs2307424 in NR1/3 (P=0.048) and rs307826 in VEGFR3 (P=0.013). Conclusion: Our results confirm former communications regarding the association between SNPs in ABCB1, NR1/2, NR1/3 and VEGFR3 and sunitinib outcome in clear-cell RCC. Prospective validation of these SNPs is now required.

Background Aromatase inhibitors (AIs) frequently lead to the AI-induced musculoskeletal syndrome (AIMSS). Looking into its pathophysiology, 6 months of AI therapy thickens the tendon sheath with intra-articular fluid (IAF) retention and loss of grip strength. We here report 24-month follow-up data. Patients and methods A prospective cohort study of 33 postmenopausal breast cancer patients received adjuvant endocrine therapy; 27 received an AI and 6 received tamoxifen. At baseline, 6 and 24 months patients had a rheumatologic examination, including a grip strength test, and magnetic resonance imaging of both hands and wrists. The primary end point was tenosynovial changes; secondary end points were changes in morning stiffness, grip strength and IAF. Results Twenty-three AI and 5 tamoxifen patients completed all investigations. Between month 6 and 24, IAF further increased in AI users (P = 0.04) but not in tamoxifen users, and grip strength further decreased in both groups. The worsened tenosynovial changes were strongly correlated with a decrease in grip strength. At 24 months, morning stiffness continued to be present in over a third of AI users. Conclusion AIMSS represents a substantial problem in breast cancer patients. It is associated with tenosynovial changes, IAF retention, joint stiffness and loss of grip strength that do not improve with prolonged use.

Introduction. For postmenopausal patients with hormone-sensitive breast cancer, outcome is worse with increasing age at diagnosis. The aim of this study was to assess the incidence of breast cancer recurrence (locoregional and distant), and contralateral breast cancer by age at diagnosis. Methods. Patients enrolled in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial were included. Primary endpoints were locoregional recurrence, distant recurrence, and contralateral breast cancer. Age at diagnosis was categorized as younger than 65 years, 65–74 years, and 75 years or older. Results. Overall, 9,766 patients were included, of which 5,349 were younger than 65 years (reference group), 3,060 were 65–74 years, and 1,357 were 75 years or older. With increasing age, a decreased administration of radiotherapy after breast conserving surgery (94%, 92%, and 88%, respectively) and adjuvant chemotherapy (51%, 23%, and 5%, respectively) was observed. Risk of distant recurrence increased with age at diagnosis; multivariable hazard ratio for patients aged 65–74 years was 1.20 (95% confidence interval [CI]: 1.00–1.44), hazard ratio for patients aged 75 years or older was 1.39 (95% CI: 1.08–1.79). Risks of locoregional recurrence and contralateral breast cancer were not significantly different across age groups. Conclusion. Elderly patients with breast cancer were at increased risk for distant recurrence. Other studies have shown that the risk of distant recurrence is mainly affected by adjuvant systemic therapy. All TEAM patients received adjuvant endocrine treatment; however, chemotherapy was administered less often in elderly patients. These findings are suggestive for consideration of chemotherapy in relatively fit elderly breast cancer patients with hormone-sensitive disease.

Purpose: This study aims to investigate the impact of comprehensive Geriatric Assessment (CGA) on treatment decisions in a large cohort of older breast cancer patients. We also studied the functional evolution during treatment and the development of severe toxicity in patients receiving chemotherapy and we looked for predictive baseline markers of functional decline and toxicity. Patients and methods: This study is part of a study on CGA in older cancer patients in 6 tumor types. We selected the breast cancer cohort for this presentation: 379 older breast cancer patients were recruited in 2 Belgian university hospitals. Patients aged 70 years or older with a newly diagnosed or progressive breast cancer for which treatment initiation or change was considered, were eligible. At baseline, an evaluation was performed of the oncological parameters as well as a CGA including geriatric screening with G8 and Flemish version of the TRST, pain, social situation, Activities of Daily Living (ADL), Instrumental Activities of Daily Living (IADL), presence of falls, MNA, GDS-15, MOB-T for fatigue, MMSE, polypharmacy, and Charlson Comorbidity Index (CCI). CGA results were communicated to the treating physician and after treatment decision, the physician was interviewed by a trained healthcare worker using a predefined questionnaire focusing on unknown geriatric problems revealed by CGA, subsequent planning of geriatric interventions, and impact on treatment decision. At 2–3 months follow-up, functionality was reassessed and severe toxicity in patients receiving chemotherapy (n = 98) was recorded. Predictors for functional decline (ADL increase of ≥2 points and IADL decrease of ≥1 point compared to baseline) and severe haematological and non-haematological toxicity were identified by multivariate analysis. Results: 79,2% of treating physicians were aware of CGA results at the time of treatment decision. CGA revealed unknown geriatric problems in 70,5% of cases, leading to geriatric intervention in 5,4% of patients. Treatment was adapted according to age and standard clinical approach (without CGA taken into account) in 41,1% of cases and CGA results led to an additional change of treatment decision in 5,4%. At follow-up, 47,9% of patients was dependent on at least one of the activities of ADL (compared to 54,1% at baseline) and 64,7% was dependent on at least one of IADL (compared to 58,1% at baseline). Functional decline at 2–3 months was predicted by baseline ADL, IADL and ECOG-PS, but no markers were found to predict chemotherapy toxicity (which occurred in 22/98 pts: 14 hematological toxicity gr III-IV, and 10 non-hematological toxicity gr III-IV) Conclusion: CGA revealed unknown information in the majority (70.5%) of breast cancer patients but led to a geriatric intervention and a change in treatment decision in a minority of pts (both 5.4%). Baseline functionality measures (ADL, IADL, ECOG-PS) were found to be predictive for functional decline at 2–3 months, but predictors for severe chemotherapy toxicity could not be identified. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-09-07.

BACKGROUND: The five prognostic surrogate phenotypes, defined by the 2011 St Gallen consensus, predict metastatic relapse following early breast cancer treatment (Brouckaert et al Ann Oncol 2012). It is unknown to what extent these surrogate phenotypes defined on the primary tumor predict metastatic survival (MS) in a cohort of consecutive women with metachronous metastases. PATIENTS & METHODS: All 4318 patients with primary operable breast cancer, diagnosed between 01–01-2000 and 31–12-2009 and treated in our center were prospectively entered in our institutional database. We included 345 patients with a (distant) metastatic relapse during their follow-up. We observed metastatic survival as the time between the diagnosis of the relapse and death. Tumor subtype was defined according to the 2011 St Gallen recommendations in 5 groups: luminal A (ER+/HER2−, grade 1–2), luminal B1 (ER+/HER2−, grade 3), luminal B2 or luminal-HER2 (ER+/HER2+), HER2-like (ER−/HER2−) and triple-negative. We focused on the value of the primary tumor subtype as a major prognostic determinant, but also assessed age at diagnosis, tumor size, lymph node involvement, tumor subtype, PR-status, primary detection (screening vs. palpation), histology, adjuvant therapy, distant-metastasis free interval (DMFI), first-line metastatic hormonal therapy, recurrence sites (isolate or multiple) and metastasis detection (clinical vs. biochemical). RESULTS: In our cohort, we recorded a median metastatic survival (MS) of 22.3 months (95% CI: 19.7–25.6) and a 5-year survival probability of 15%. Significant differences in median MS were noted when considering the primary tumor subtype (cf. table). We observed an independent prognostic effect for multiple recurrence sites (HR = 1.78, 95% CI 1.37–2.32), first-line metastatic hormonal therapy (HR = 0.30, 95% CI 0.18–0.49), DMFI (HR = 0.92 CI 0.85–0.98) and, finally, primary tumor subtype. CONCLUSION: Our results showed that primary tumor subtype, DMFI, solitary recurrence and first-line metastatic hormonal therapy act as independent prognostic factors in metastatic breast cancer. In order to overcome the biological complexity of metastatic breast cancer, we must appreciate the primary tumor subtype in our therapeutic approach. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-12.

Background: Many adverse events (AEs) associated with aromatase inhibitors (AIs) involve symptoms related to the depletion of circulating estrogens, and may be related to efficacy. We assessed the relationship between specific AEs [hot flashes (HF) and musculoskeletal AEs (MSAE)] and survival outcomes in Dutch and Belgian patients treated with exemestane (EXE) in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. Additionally, the relationship between hormone receptor expression and AEs was assessed. Methods: Efficacy end points were relapse-free survival (RFS), overall survival (OS) and breast cancer-specific mortality (BCSM), starting at 6 months after starting EXE treatment. AEs reported in the first 6 months of treatment were included. Specific AEs comprised HF and/or MSAE. Landmark analyses and Cox proportional hazards models assessed survival differences up to 5 years. Results: A total of 1485 EXE patients were included. Patients with HF had a better RFS than patients without HF [multivariate hazard ratio (HR) 0.393, 95% confidence interval (CI) 0.19–0.813; P= 0.012]. The occurrence of MSAE versus no MSAE did not relate to better RFS (multivariate HR 0.677, 95% CI 0.392–1.169; P = 0.162). Trends were maintained for OS and BCSM. Quantitative hormone receptor expression was not associated with specific AEs. Conclusions: Some AEs associated with estrogen depletion are related to better outcomes and may be valuable

Background: Outside clinical trials, long term follow-up data from large series of women treated with adjuvant trastuzumab are lacking. We here report such data from a Belgian cohort for premature trastuzumab discontinuation and 5 year outcome. Patients and Methods: A year prior to its reimbursement (June 1st 2007), the Belgian health authorities offered adjuvant trastuzumab to women with a HER-2 amplified breast cancer as given in HERA: following completion of loco-regional therapy, at least 4 cycles of chemotherapy (CT) (neo-adjuvant or adjuvant) or radiotherapy whichever was last. Demographics, histopathologic features, baseline (≥55%) and follow-up left ventricular ejection fraction (LVEF) together with 5 yr breast cancer related events (BCRE) were centrally recorded. Outcome was reported by grade (< or > grade 3), lymph node (pN) status (neg/pos), hormone receptor (HR) status (neg/pos) and timing of CT (adjuvant/neo-adjuvant). Results: 917 pts were included. Files on histopathology, demographics, LVEF and therapy are available for 887 (97%) pts, outcome for 738 (80%). Median age at diagnosis was 53 years (25–81); 56% of tumors were >pT1, 57% pN+, 72% grade 3, 59% HR-positive for estrogen receptor (ER) and/or progesterone receptor (PR). CT was neo-adjuvant in 20% and adjuvant in 80%. Radiotherapy and endocrine therapy were given respectively in 86% and 50%. Median follow-up was 63 (range 8–90) months. Premature ( We here focus on 636 pts with outcome data. Breast cancer related events (119, 19%) occurred on average 31 months (4–74) after diagnosis and was mainly metastatic, with preference for liver or lungs only (17%), bone only (15%) or brain only (14%). 44 (7%) pts died of breast cancer. Patients who had chemotherapy administered in the neoadjuvant setting (20%) clearly had more advanced disease with more chance to develop a distant relapse (24%) and breast cancer related death (17%). These figures were respectively 11% and 4% when chemotherapy was given in the adjuvant setting (80%). In both populations, the following variables were most prognostic for metastatic relapse: lymph node involvement (28% vs 16% neo; 13% vs 7% adj), grade 3 (24% vs 18% neo; 14% vs 8% adj), a negative HR-status (26% vs 21% neo; 14% vs 9% adj) and a negative PR status (27% vs 16% neo; 13% vs 7% adj). Discussion: Outside a clinical trial, ≥ 80% of patients eligible for adjuvant trastuzumab are able to complete treatment. Outcome at 5 years is favorable with low symptomatic cardiac toxicity and a 13% incidence of metastatic relapse, being lowest in pN−, < grade 3, HR+ and ER+/PR+ tumors. Longer follow-up is needed to differentiate a relapse pattern by HR-status as PR positive cases might relapse at a later moment. This work is funded by the Belgian National Institute for Health and Disability Insurance (INAMI-RIZIV). Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-19.

We report on a postmenopausal patient with a secondary metastatic apocrine breast cancer successfully treated with low-dose hydrocortisone only following several lines of chemotherapy. The tumor cells in the primary and metastatic lesion exhibited a 'triple-negative' status (estrogen receptor (ER)-, progesterone receptor (PR)-, and human epidermal growth factor receptor 2 (HER2)-negative); the androgen receptor (AR) was strongly expressed. Twenty milligrams of hydrocortisone, a low substitution dose known to suppress adrenal steroid production, twice daily led to a clinical benefit lasting for one year, with symptom control, radiologically stable disease, and steady decrease in CA15.3. Our observation demonstrates that an AR-expressing apocrine breast cancer may respond to androgen deprivation, as an ER-positive breast cancer may benefit from estrogen deprivation. It highlights the importance of further research targeting the AR pathway in apocrine carcinoma, for which androgens represent the sole (known) steroid hormone stimulating tumor growth. Future clinical trials should not only focus on AR inhibitors like enzalutamide, but also on ablative modalities like low-dose hydrocortisone aiming at medical adrenalectomy. This method of androgen deprivation is largely available, cheap, and nearly devoid of toxicity.

Background Many easily measurable and readily available factors are now established as being prognostic in primary operable breast cancer. We here applied the 2011 St Gallen surrogate definition for breast cancer subclassification using tumor grade instead of Ki67. Patients and methods Four thousand three hundred and eighteen consecutive patients who had surgery for primary operable breast cancer (1 January 2000 and 31 December 2009) in UZ Leuven excluding primary metastastic male breast cancers and those receiving neoadjuvant therapy. Five different surrogate phenotypes were created using the combined expression of estrogen receptor, progesterone receptor, human epidermal growth factor receptor-2 together with tumor grade. Disease-free interval (DFI), distant metastastis-free interval (DMFI), locoregional relapse-free interval (LRRFI), breast cancer-specific survival (BCSS) and overall survival (OS) were calculated. Results Surrogate phenotypes present with significant differences in DFI, DMFI, LRRFI, BCSS and OS. ‘Luminal A’ tumors presented with the best outcome parameters but the effect weakened at longer follow-up. Conclusions The four surrogate markers, agreed upon by the 2011 St Gallen consensus, defined five prognostic surrogate phenotypes in a large series of consecutively treated breast cancer patients. Their prognostic value changed with longer follow-up. The added value of gene expression profile over classical pathological assessment remains to be defined.

Introduction Worldwide, breast cancer is the most frequently diagnosed cancer in women and the leading cause of cancer death, accounting for 23% of total cancer cases and 14% of cancer deaths. Lymph node involvement is the most important prognostic factor and varies with several tumor and patient characteristics (ie, age at diagnosis, tumor size, tumor type, tumor grade, lymphovascular invasion, multifocality, and estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 [HER-2] status). Factors o be considered in clinical decision making include not only

To determine the recommended dose (RD) of vinflunine in combination with trastuzumab in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and to investigate potential pharmacokinetic (PK) interactions.In the first part of the study, two dose levels of vinflunine given every 3 weeks were explored (280 and 320 mg/m(2)) combined with trastuzumab (4 mg/kg loading dose and 2 mg/kg weekly). For each level of dose, six patients were enrolled to determine the RD for phase 2 studies (RP2S). In the second part of the study, 18 additional patients at RP2S have been evaluated to confirm safety and investigate preliminary antitumor activity.The RD was 320 mg/m(2) according to the dose escalation plan. Eleven of 15 additional patients who received this dose experienced dose-limiting toxicities, leading to a reduction in the RD to 280 mg/m(2). When compared to prior trials when vinflunine was used as a single agent, neither vinflunine total blood clearance nor trastuzumab serum concentrations were modified when the drugs were combined. All patients were evaluable, and the overall response rate was 73.3 % (95 % CI 54.1-87.7). The median progression-free survival was 11.3 months (95 % CI 9.4-21.0). At the dose of 280 mg/m(2), grade 3-4 neutropenia were seen in 4 patients (44.4 %) without febrile neutropenia. Non-hematologic grade 4 toxicities were not reported while grade 3 peripheral sensory neuropathy concerned 2 patients (22.2 %).The RD of vinflunine in combination with the standard regimen of trastuzumab is 280 mg/m(2) every 3 weeks. No mutual PK drug-drug interaction was seen. This regimen appears to be active with a favorable safety profile. Its role in HER2-positive MBC treatment needs to be defined in prospective comparative clinical trials.

Background We studied the stellate ganglion block (SGB) recently suggested for the treatment of severe vasomotor symptoms and sleep disturbances in breast cancer survivors. Following an initial pilot study, which focused on the acceptability and safety of SGB for this important problem, we evaluated its short- and long-term efficacy. Materials and methods Postmenopausal breast cancer survivors with severe vasomotor symptoms resistant to standard nonhormonal pharmacological intervention were eligible. Diaries were used to measure daily hot flash scores (frequency and intensity) and sleep quality (Pittsburgh Sleep Quality Index) during scheduled visits at baseline, 1, 4, 12 and 24 weeks following the SGB. Efficacy data were analyzed using longitudinal regression models. Results Thirty-four patients participated and none refused the SGB procedure. Most patients received more than one SGB. The pilot study found SGB to be safe. In the main study, hot flash scores were reduced from baseline by 64% [95% confidence interval (CI) -74% to -49%] and 47% (95% CI -62% to -27%) at weeks 1 and 24, respectively. The odds ratio of better sleep quality relative to baseline was 3.4 at week 1 (95% CI 1.6–7.2) and 4.3 at week 24 (95% CI 1.9–9.8). Conclusion In the short term, SGB appears to be an effective treatment with acceptable morbidity for some breast cancer survivors with therapy-resistant vasomotor symptoms and/or sleep disturbances. Although sleep quality was maintained out to 24 weeks the efficacy of SGB for hot flashes was reduced over time. A randomized controlled trial is needed to confirm these findings.

We correlated serum 25-hydroxyvitamin D3 (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.

Introduction: We previously reported that molecular prognostic subgroup classification of operable breast cancers resembles the classification based on combined immunohistochemical expression of ER, PR and HER-2 receptors. This update represents a larger cohort with more detailed follow-up (median 5.5y). Patients and methods: A prospective cohort of 4334 breast-cancer patients primary operated at our institution between 2000 and 2009. Steroid receptors were considered positive for any nuclear staining, HER-2 for strong (3+) membrane staining or positive fluorescence in situ hybridization. Survival curves were calculated for six predefined breast cancer subgroups: ER + PR + HER-2 - (PPN), ER + PR - HER-2 - (PNN), ER + PR + HER-2 + (PPP), ER - PR - HER-2 - (NNN), ER - PR - HER-2 + (NNP), and ER + PR - HER-2 + (PNP) (figures not allowed in abstract). Disease free interval (DFI), distant metastatis free interval (DMFI), overall survival (OS) and breast cancer specific survival (BCSS) were calculated. A long-rank test was used for testing the null hypothesis of no difference between the groups. Results: Conclusion: Combined receptor expression for ER/PR/HER2 determines specific breast cancer subtypes with significant different clinical behavior. Both predictive and prognostic factors need to be considered when interpreting these results. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-09-07.

Introduction: The objective of the sentinel lymph node (SLN) procedure in breast cancer is to perform an accurate axillary staging and provide good local control, while sparing the patients the morbidity of an axillary lymph node dissection (ALND). Since its routine clinical use, questions have been raised concerning the upstaging of a subgroup of node-negative patients and an increase in the overall percentage of node-positive patients. The goal of our study was to investigate the impact of the SLN procedure on the detection of positive lymph nodes. Patients and methods: We included 1119 consecutive breast cancer patients from one center (2007-2009) who underwent primary surgery for a breast cancer smaller than 5 cm diameter without clinical involvement of axillary lymph nodes. 31 patients had a bilateral breast cancer. Logistic regression models were used to analyze the effect of various predictors on the presence of positive lymph nodes. First, we fitted univariable models for a number of predictors of which the relationship with lymph node involvement was to be expected. (multifocality, tumor location in the breast, tumor size, LVI, ER, PR, Her-2, tumor grade, age and histologic subtype). In a second stage, we fitted a multivariable model including the procedure (SLN biopsy or ALND) and the predictors that have been shown to be related to lymph node involvement in univariable analysis or for which this relationship has been suggested in the literature. The probability of finding positive lymph nodes was thus calculated in both groups correcting for relevant predictors of lymph node involvement. Results: The SLN biopsy group includes 830 patients, the ALND group 320. Tumors in the ALND group are larger (mean 26.65 mm versus 18.43mm) and more frequently multifocal (24.44% versus 8.19%). 33% of patients in the ALND group were lymph node positive, 28% in the SLN procedure group. Univariable and multivariable analyses revealed that LVI, tumor size and multifocality are the most significant predictors of lymph node involvement (table 1). The AUC for the multivariate model is 0.754. By comparing ALND en SLN biopsy an odds ratio (OR) of 0.7635 (95% confidence interval: 0.5334−1.0930) is observed, suggesting a higher probability of finding positive lymph nodes with SLN procedure. However, the difference between the procedures is not significant (p= 0.1404). Conclusion: For comparable tumors, the chance of detecting positive lymph nodes is not lower when applying SLN procedure compared to ALND. The results even point in the direction of a higher detection rate with SLN. However, care should be taken in making this conclusion given a non-significant result. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-07-40.

Background Iniparib (BSI-201) is an investigational anticancer agent whose precise mechanism of action is under active investigation. In breast cancer cell lines and xenograft models of triple-negative breast cancer (TNBC), iniparib exhibits anti-proliferative activity and potentiates the cell cycle effects of some DNA damaging agents. In a randomized, open-label phase 2 study in pts with metastatic TNBC (mTNBC), iniparib combined with gemcitabine (G) and carboplatin (C) (GC) improved efficacy outcomes compared with GC alone. A confirmatory phase 3 study with GCI failed to meet pre-specified criteria for PFS and OS; however, an exploratory subset analysis demonstrated a potential benefit amongst 2nd/3rd line pts (O'Shaughnessy et al. ASCO 2011). Here we report results of a randomized phase 2 study (NCT01045304) in pts with mTNBC, which assesses efficacy and pharmacokinetics (PK) of iniparib administered either biw or qw in combination with GC. Patients and methods: Eligible pts (N=163; median age 49 yrs) had documented and measurable TNBC, ECOG PS 0–1, normal organ/marrow function, and had received ≤2 prior chemotherapy (CT) regimens for metastatic disease. Pts were randomized (1:1) to receive G (1,000 mg/m2, IV, d 1, 8) plus C (AUC 2, IV, d 1, 8) and iniparib either biw (5.6 mg/kg, IV d 1,4,8,11) or qw (11.2 mg/kg, IV d 1,8) on a 21 d cycle. Pts were stratified according to prior CT for mTNBC (0 vs. 1–2). The primary efficacy endpoint was overall response rate (ORR; CR + PR); secondary endpoints included: clinical benefit rate (CBR; CR + PR + SD for 24 weeks), PFS, OS and PK. Results: At the time of analysis, 23% of patients were still on treatment. The median number of cycles administered per patient was 6 in both arms; exposure to iniparib was identical. Safety data are not fully validated. All pts experienced at least 1 treatment emergent adverse event (TEAE). Grade (Gr) ≥3 TEAEs occurred in 94% and 85% of pts in the biw and qw arms, respectively. TEAEs Gr ≥3 occurring in ≥5% of pts regardless of relationship to study drug (biw vs qw) are as follows: blood and lymphatic 71% vs 67%; hepatobiliary 7.5% vs 9.8%; asthenia/fatigue 7.5% vs 11%; GI 8.8% vs 8.5%; infections 7.5% vs 3.7%; respiratory, thoracic and mediastinal 5% vs 8.5%, metabolism and nutrition 4% vs 6%. For response data see table. No major difference was observed in drug exposure (based on AUC within one cycle) between the two dosing regimens. Conclusion: Dosing of GCI on a qw schedule produced a similar ORR to that obtained with the biw schedule. A comparable safety profile in both arms, and consistency with results of previous studies, suggests that the weekly combination of GCI may be an appropriate schedule for further studies evaluating this combination. OS and PFS data are not yet mature; updated efficacy and safety data will be presented. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-16-08.

Background The 3rd generation aromatase inhibitors (AIs) induce or enhance musculoskeletal problems. Underlying mechanisms are probably multiple, but remain unknown. We have previously reported that loss of grip strength together with tenosynovial abnormalities are more important in AI- than in tamoxifen-users (Morales et al, JCO 2008) and that musculoskeletal changes in AI-users are more pronounced in women with extremes in baseline BMI (Lintermans et al, Ann Oncol 2011) We here report preliminary results from a larger population and plan to validate findings in patients from University of Michigan. Patients and methods In this prospective observational study, postmenopausal early breast cancer patients scheduled to start adjuvant hormonal therapy with any of the third generation AIs or tamoxifen were recruited. After providing informed consent, a functional assessment test of grip strength was performed with a modified sphygmomanometer. Re-evaluation was done after 3, 6 and 12 months of therapy. BMI and waist to hip ratio (WHR) were assessed and a rheumatological questionnaire was completed at each visit. Results Ninety-four (79 AI; 15 tamoxifen) of the planned 200 patients were included in this preliminary study. 18% of AI-users discontinued their treatment due to musculoskeletal symptoms compared with none of the tamoxifen-users. 62% of patients on AI and 35% of tamoxifen patients complained of new or worsened joint pain. Table 1 shows the proportion of patients that attribute their complaints to their endocrine therapy. Grip strength significantly decreased over time (p=0.03), with patients under AI treatment having a larger loss of grip strength than patients under tamoxifen treatment (p=0.04). We confirm our previously reported results on the shape of the curve “BMI AI-induced loss of grip strength”. Years past menopause and age showed a significant effect on grip strength (p Conclusion Our preliminary results confirm that a majority of patients treated with an AI experience musculoskeletal problems, which are considered due to the therapy by most patients. Grip strength decreased over time, with a significantly larger loss of grip strength in the AI-users compared with the tamoxifen-users. AI-induced loss of grip strength and baseline BMI showed an inverted U-shaped association, although differences between quartiles were small. Further results should be awaited as this is only a preliminary analysis. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-17-09.

Purpose: Several studies have evaluated the prognostic effect of bone marrow micrometastases at the time of surgery in early breast cancer, but few studies have long term outcome data. We report here a cohort with more than ten years follow-up. Materials and methods: 131 patients with primary operable invasive breast cancer were enrolled in the protocol from February 1998 to September 1999. Bone marrow aspirates, obtained from the iliac crest or the sternum, were analyzed with real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR) for the presence of cytokeratin 19 (CK19) mRNA. All patients received standard therapy and follow-up. After a median follow-up of 133 months, data about disease recurrence (invasive disease free survival, IDFS) and survival (breast cancer specific survival (BCSS) and overall survival (OS)) were collected. A control group consisted of archived cDNA samples from 38 patients with hematological malignant antecedents in complete remission and without known gene arrangements. The upper limit of the 95% confidence interval of the level of CK19 positive cells is this group was used as cut-off (260 cytokeratin 19+ cells / 5 × 106 leucocytes) to determine bone marrow status in breast cancer patients. Results: 69 bone marrow samples from breast cancer patients (52,7 %) were considered CK19 positive. IDFS was 60.9 % and 79 % for CK19+ and CK19- patients, respectively (log-rank p-value = 0,036). When CK19 was evaluated as a continuous variable, IDFS also correlated significantly with the level of CK19 mRNA in bone marrow aspirates (p-value = 0,019). Except for lymph node status (ANOVA linear regression p-value = 0.022), there was no significant correlation between the level of CK19+ cells in the bone marrow and classical prognostic factors (pathological tumor stage, tumor size, differentiation grade, hormonal receptor status). In multivariate Cox-regression analysis correcting for tumor size, differentiation grade, lymph node status, hormone receptor status, tumor stage and treatment modalities (surgical procedure, chemotherapy, radiotherapy and antihormonal therapy), the CK19 bone marrow status still was a significant predictor of IDFS. (p-value = 0.042) Differences in BCSS (78 % of CK19 + patients and 84 % of CK19 — patients) and OS (75 % in CK 19 + patients and 74 % in CK 19 — patients) were not statistically significant. (log rank p-values 0.087 and 0.883, respectively). Conclusion: This study demonstrates the long term (>ten years) prognostic effect of CK19 mRNA detection with RT-PCR in the bone marrow of operable breast cancer patients. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-14-24.

Background Inoperable, locally advanced breast cancer (LABC) is common in the elderly. Studies have shown good responses with neoadjuvant chemo- and endocrine therapy. However, studies targeting the elderly population are rare. Aim: To assess complete pathological response rate (pCR) following neoadjuvant chemotherapy (NACT) and to evaluate the effectiveness of this therapeutic option in elderly women with LABC. Patients: Women (≥70 years) diagnosed at our University Hospital with LABC between 1999 and 2010 and treated with neoadjuvant chemotherapy. After neoadjuvant systemic treatment pCR was assessed if surgery was performed. Results: 44 women with a mean age of 74.9 (70-93) years were included. Most tumors were ductal (IDA 88.6%), of grade 3 (79.5%) and hormone-receptor (HR) negative (61.4%). Among the 21 tumors (47.7%) that were HER2+ (immunohistochemistry (IHC) 3+ or 2+ and FISH+), all but 3 received neoadjuvant Trastuzumab. Only 4 patients had no surgery (clinical decision or personal choice) while the remaining 40 patients underwent either breast-conserving surgery (17.5%) or mastectomy (82.5%). 23 patients (52.3%) had pathological partial response, 14 patients (31.8%) pCR and 3 patients no response. pCR was more frequently achieved in HR-negative (44.4%) than in HR- positive patients (11.8%). In both groups HER2 positive tumors had better pathological response than HER2 negative tumors. After a mean follow-up of 41 months (5-120) 29 patients (65.9%) had no evidence of disease, 6 patients (13.6%) had (loco)regional recurrence, 12 patients (27.2%) developed metastatic disease and 6 patients (13.6%) died because of breast cancer. Relapse was more frequently seen in patients with a pPR (47.8%) versus patients with a pCR (14.3%). Conclusion: In a selected population of elderly patients with LABC and treated with neoadjuvant chemotherapy, a reasonable percentage of pCR can be achieved. Concordant with younger populations, this percentage is higher in HR-/HER2 positive breast cancer. Neoadjuvant chemotherapeutic treatment can thus be as beneficial for the older patient as for younger ones. In fit elderly patients, neoadjuvant chemotherapy should therefore not be omitted solely on the basis of advanced age. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-22.

Purpose. Lymph node involvement is the most important prognostic factor in breast cancer. It is a multifactorial event determined by tumour and patient characteristics. Several predictors of axillary lymph node metastasis (ALNM) in breast cancer have been described. The purpose of this study was to determine clinical and pathological factors predictive for ALNM in patients with early breast cancer and to build a model to portend lymph node involvement. Methods. We evaluated 1300 consecutive patients surgically treated in our institution (2007-2009) for cT1-T2 invasive breast cancer. The patient and tumour characteristics evaluated included: age at diagnosis, number of foci, histologic grade, location, tumour size, histologic subtype, lymphovascular invasion (LVI), estrogen-receptor (ER), progesterone-receptor (PR) and Her2 status. Univariate and multivariate analyses were performed. Factors significantly associated with lymph node metastasis by univariate analysis and histologic subtype were included in the multivariate model. We validated our model with the same 1300 patients on the basis of a multivariable logistic regression model containing the variables, using a correction factor. Results. By univariate analysis, the incidence of ALNM was significantly higher in patients with a tumour with LVI (P < 0.0001), larger tumours (P < 0.0001), tumours with a higher histologic grade (P < 0.0001), tumours located retroareolar or lateral in the breast (P < 0.0001), tumours with multiple foci (P = 0.0002) and in patients who underwent an axillary lymph node dissection. We found no effect of ER/PR nor HER-2 status. By multivariate analysis, lymph node involvement was significantly associated with the presence of lymphovascular invasion (P < 0.0001), larger tumour size (P < 0.0001), axillary lymph node dissection (P = 0.0003), retroareolar and lateral tumour location in the breast (P = 0.0019) and the presence of multiple foci (P = 0.0155). The discrimination of the model, calculated by the area under the curve (AUC), was 0.778. Conclusions. LVI and tumour size emerged as most powerful independent predictors of ALNM. A model with an AUC of 0.50 is equivalent to the toss of a coin, a model with an AUC > 0.70 is considered as good. In conclusion, our result is not perfect in discrimination which raises further questions. It is clear that underlying mechanisms of ALNM remain to be elucidated. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-14-21.

Background Epidemiologic studies show an age related decrease in the frequency that breast cancers are triple negative (TN) (estrogen receptor, progesterone receptor and HER-2 negative). Parity increases the risk of TN breast cancer as a previous full-term pregnancy mainly protects against ER+ breast cancer. It is unknown whether this protective affect appears at all ages of breast cancer diagnosis. We study the frequency of triple negative breast cancers by parity and age at breast cancer diagnosis. Methods We performed a retrospective case-case analysis including 1583 consecutive female patients with primary diagnosis of invasive breast cancer, < 51 years at diagnosis. We compared the frequency of TN tumors between parous (N = 1271) and nulliparous (N = 312) women in three age categories (21 to 30 yrs, 31 to 40 yrs and 41 to 50 yrs). For statistical analysis we used a logistic regression model. Results We confirmed a decrease of TN breast cancer with age (p < 0.0001). This decrease is stronger pronounced in the nulliparous group. Parity favors TN tumors only in women > 40 years at breast cancer diagnosis. Discussion: Although several other factors may affect the frequency breast cancers are TN, age at breast cancer diagnosis interacts with the effect of a previous pregnancy on the frequency breast cancers are TN. Breast cancers in young women (< age 40) may have been initiated long before pregnancy can induce a protective effect against ER-positive cases. The international BCAC has recently accepted to validate our UZ Leuven findings. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-08-20.

On average, aromatase inhibitors are better than tamoxifen when used as initial or sequential therapy for postmenopausal women with endocrine-responsive early breast cancer. Because there may be contraindications to their use based on side-effects or cost, we investigated subgroups in which aromatase inhibitors may be more or less important.Breast International Group 1-98 trial randomized 6182 women among four groups comparing letrozole and tamoxifen with sequences of each agent; 5177 (84%) had centrally confirmed estrogen receptor (ER) positivity. We assessed whether centrally determined ER, progesterone receptor (PgR), human epidermal growth factor receptor 2, and Ki-67 labeling index, alone or in combination with other prognostic features, predicted the magnitude of letrozole effectiveness compared with either sequence or tamoxifen monotherapy.Individually, none of the markers significantly predicted differential treatment effects. Subpopulation treatment effect pattern plot analysis of a composite measure of prognostic risk revealed three patterns. Estimated 5-year disease-free survival for letrozole monotherapy, letrozole→tamoxifen, tamoxifen→letrozole, and tamoxifen monotherapy were 96%, 94%, 93%, and 94%, respectively, for patients at lowest risk; 90%, 91%, 93%, and 86%, respectively, for patients at intermediate risk; and 80%, 76%, 74%, and 69%, respectively, for patients at highest risk.A composite measure of risk informs treatment selection better than individual biomarkers and supports the choice of 5 years of letrozole for patients at highest risk for recurrence.

Background Our preliminary results showed that tenosynovial changes and decrease in grip strength are associated with the aromatase inhibitor-induced musculoskeletal syndrome (AIMSS). Here, we report the final results and assess the relationship between grip strength and body mass index (BMI). Patients and methods We conducted a prospective study including postmenopausal early breast cancer patients receiving either an aromatase inhibitor (AI) or tamoxifen. Primary end point was change from baseline in tenosynovial abnormalities. Secondary end points were changes from baseline in morning stiffness, intra-articular fluid and grip strength and its association with BMI. Results After 6 months of therapy, 74% [95% confidence interval (CI) 51% to 89%] of AI-treated patients had worsened tenosynovial abnormalities, 56% (95% CI 34% to 75%) had increased intra-articular fluid, and 22% (95% CI 9% to 45%) had increased morning stiffness. Grip strength decreased 8% for the left hand (95% CI 2% to 21%) and 11% for the right (95% CI 4% to 17%). Regression analysis suggested that grip strength decreased more for subjects with high or with low BMI. Conclusions AIMSS is characterized by tenosynovial changes, intra-articular fluid and morning stiffness. We hypothesize that the quadratic association between BMI and loss of grip strength reflects AI-induced changes on the endocrine control of the growth hormone insulin-like growth factor-I pathway.

Objective Knowledge of the menopause status of a woman with breast cancer is important for good clinical practice. Long-lasting amenorrhea is frequent in this population, often for reasons other than definitive menopause. Antiestrogens like tamoxifen or oral aromatase inhibitors (AIs) may reactivate the ovary causing vaginal bleeding, menstruation, pregnancy, and unopposed endometrial stimulation. In contrast to tamoxifen, AIs are not active against breast cancer in the presence of functional ovaries. Antimullerian hormone (AMH) is a potential marker of residual ovarian function that can predict not only the onset of menopause but also chemotherapy-induced amenorrhea (CIA) and fertility. We assess the value of AMH in women who recovered from CIA on an AI. Methods This is a series of six women with clinical and biochemical evidence of ovarian recovery during AI treatment. All six were premenopausal at breast cancer diagnosis and developed CIA. AMH, follicle-stimulating hormone, and estradiol levels were measured when patients developed clinical signs of ovarian recovery and/or when a gynecological procedure showed evidence of this. Results In all six AI-treated women, AMH levels were undetectable despite clinical, biochemical, or pathological evidence of ovarian reactivation after a long period of amenorrhea and sensitive biochemical markers indicating definitive menopause status. Conclusions Repeated biochemical monitoring of ovarian function remains important in women with breast cancer undergoing AI treatment because ovarian function can recover, AIs are not active with functional ovaries, and amenorrhea does not, by itself, confirm definitive menopause. Undetectable AMH levels do not exclude residual ovarian function in women with breast cancer on an AI.

BACKGROUND: Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors. METHODS: We pooled tumor marker and epidemiological risk factor data from 35,568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case-case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case-control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided. RESULTS: In case-case analyses, of the epidemiological risk factors examined, early age at menarche (≤12 years) was less frequent in case patients with PR(-) than PR(+) tumors (P = .001). Nulliparity (P = 3 × 10(-6)) and increasing age at first birth (P = 2 × 10(-9)) were less frequent in ER(-) than in ER(+) tumors. Obesity (body mass index [BMI] ≥ 30 kg/m(2)) in younger women (≤50 years) was more frequent in ER(-)/PR(-) than in ER(+)/PR(+) tumors (P = 1 × 10(-7)), whereas obesity in older women (>50 years) was less frequent in PR(-) than in PR(+) tumors (P = 6 × 10(-4)). The triple-negative (ER(-)/PR(-)/HER2(-)) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6(+) and/or epidermal growth factor receptor [EGFR](+)) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case-control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER(+) or PR(+) tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P = .09) or CBP tumors. CONCLUSIONS: This study shows that reproductive factors and BMI are most clearly associated with hormone receptor-positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology.

Purpose: To study clinical characteristics of different histological subtypes of triple negative breast cancer (TNC). TNC are often considered as one group, but consist of many different histological subtypes with different biology and behavior. We decided to analyze a large cohort of TNC in a single centre and focus on clinical behavior including age distribution, occurrence of lymph node invasion, and outcome in different histological subtypes. Patients and methods: We used data from the breast cancer database from UH Leuven, containing 479 newly diagnosed TNC from January 1999 till November 2009, of which 396 received upfront surgery, 64 neoadjuvant chemotherapy, and 18 with metastases at diagnosis. Univariate and multivariate relations were studied between age, lymph node status, histological subtype, treatment and outcome. Results: Apocrine and invasive lobular TNC occur more often in older patients compared to IDC-NOS (resp. P = 0.0004, P = 0.0496), the latter being by far the most common subtype (80,2%). Although TNC are considered as an aggressive subtype of breast cancer with a bad prognosis, only 35.1% have lymph nodal involvement. There were no significant differences in nodal invasion between subtypes, but most subtypes contained few patients. In contrast to previous reports, 7/14 (50%) of apocrine TNC had lymph node involvement. DFS was different in different histological subtypes, but most of the histological subgroups contained insufficient numbers to be able to draw firm conclusions. Within the histologically ‘homogeneous’ IDC-NOS group with primary surgery and outcome data (n=308), DFS with 3.5 year median FUP decreased with increasing age, but chemotherapy and also radiotherapy were much less frequently given with increasing age (in age Conclusion: TNC is not a uniform disease. Different histological subtypes have different age distribution and outcome. The prognosis of the most common group of TNC, IDA-NOS is unexpectedly better in older patients, but this is counterbalanced by the significantly decreased use of chemotherapy and radiotherapy in this population. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-05.

Background: Histologic grade 2 breast cancer may benefit most from molecular classification for prognosis. We studied the prognostic value of ‘detection mode’ and ‘palpability’ together with other prognostic variables in a consecutive series of grade 2 lesions. Patients and methods: We used follow-up data from new diagnosed and primary operable grade 2 breast cancers from UH Leuven (January 2000 - May 2005). Endocrine, chemo-and radiotherapy were given when indicated. The first appearing breast cancer related event (BCRE) was calculated as local (local, regional or contra-lateral) or metastatic (metastatic if both appeared together). These prognostic variables were assessed: age at diagnosis (per decade increase), tumor size (per cm increase), screening (yes/no), palpability (yes/no), lobular type (yes/no), chemotherapy (yes/no), endocrine therapy (yes/no), lymph node status (0, 1, 2-4, >4), combined expression of IHC-measured ER (pos = any expression), PgR (pos if any expression) and HER-2 (positive = IHC2/3+ and FISH pos), architectural, nuclear and mitotic score. Univariable and multivariable proportional hazards Cox regression using the Firth's penalization method to reduce bias in the parameter estimates were used. Results: Of the 1013 patients in the dataset, 14 had missing values (1.4%). With a median follow-up of 80 months, we observed 116 BCRE (11.6%); 43 local and 73 metastatic. In univariable analysis, screen detected cancers showed better (HR 0.63, 95% CI 0.42-0.93) and palpable cancers worse prognosis (HR 1.96, 95% CI 1.13-3.71) than non-screen detected and non-palpable cases respectively. The beneficial univariable effect of screening weakened in the multivariable analysis (HR 0.83, 95% CI 0.52-1.31) as 582/602 (97%) of non-screen detected cancers were palpable vs 227/397 (57%) for screen-detected cancers. If palpable was omitted from the multivariable model the HR of screening decreased to 0.68 (95% CI 0.44-1.03) thereby approximating its univariable result. Conclusion: Overall, palpability is more strongly related to prognosis, but detection method also has an effect even though we do not have enough events to show this with a convincing level of reliability. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-08-09.

To evaluate retrospectively the accuracy of integrated PET/CT, against PET, CT, or conventional staging in breast cancer. Seventy consecutive biopsy proven clinical stage IIB and III breast cancer patients were included. Descriptive statistics of integrated PET/CT for the primary tumor, nodal status and metastasis detection were compared to PET, CT with contrast, and conventional staging (biochemistry, chest X-ray, liver ultrasound, and bone scintigraphy). Sensitivity of PET/CT for primary tumor and nodal status was 97.1% and 62.5%, respectively. Specificity and negative predictive value for nodal status were 100% and 66.6%, respectively. The values for conventional staging for nodal involvement were 100% and 85.7% with a sensitivity of 87.5%. PET/CT showed metastatic disease in seven women despite normal conventional staging. PET/CT is able to visualize most clinical stage IIB and III primary breast cancers. PET/CT is superior to conventional staging for detecting internal mammary chain nodes and metastatic disease, but not for axillary staging. Future studies will have to test whether therapy adjustment based on PET/CT has the potential to improve survival.

Purpose To investigate whether the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) can improve the Nottingham Prognostic Index (NPI) in the classification of patients with primary operable breast cancer for disease-free survival (DFS). Patients and Methods The analysis is based on 1,927 patients with breast cancer treated between 2000 and 2005 at the University Hospitals, Leuven. We compared performances of NPI with and without ER, PR and/or HER2. Validation was done on two external data sets containing 862 and 2,805 patients from Oslo (Norway) and Auckland (New Zealand), respectively. Results In the Leuven cohort, median follow-up was 66 months, and 13.7% of patients experienced a breast cancer–related event. Positive staining for ER, PR, and HER2 was detected, respectively, in 86.9%, 75.5%, and 11.9% of patients. Based on multivariate Cox regression modeling, the improved NPI (iNPI) was derived as NPI − PR positivity + HER2 positivity. Validation results showed a risk group reclassification of 20% to 30% of patients when using iNPI with its optimal risk boundaries versus NPI, in a majority of patients to more appropriate risk groups. An additional 10% of patients were classified into the extreme risk groups, where clinical actions are less ambiguous. Survival curves of reclassified patients resembled more closely those for patients in the same iNPI group than those for patients in the same NPI group. Conclusion The addition of PR and HER2 to NPI increases its 5-year prognostic accuracy. The iNPI can be considered as a clinically useful tool for stratification of patients with breast cancer receiving standard of care.

The aim of this study is to test the hypothesis that antiangiogenic treatment with sunitinib consolidation can prolong remissions induced by taxane-based chemotherapy in women with metastatic breast cancer. The method involves a two-arm open-label (2:1 randomization) multicenter, randomized phase II trial evaluating the efficacy of sunitinib (arm A) versus no therapy (arm B) in patients with HER-2-negative metastatic breast cancer who achieved an objective response to taxane-based chemotherapy. The results of this study indicates that the primary endpoint of progression-free survival (PFS) > or =5 months was achieved in 10 of 36 patients (28%) in arm A and 4 of 19 patients (21%) in arm B. The median PFS was 2.8 and 3.1 months, respectively. A protocol amendment to the sunitinib dosing schedule was made because 53% (17/32) of patients treated at a starting dose of 50 mg (4 weeks on/2 weeks off) required dose reduction. Changing the starting dose to sunitinib 37.5 mg continuously resulted in dose reductions in 44% (7/16) of patients. Grades III-IV toxicity occurred in 69% of patients in arm A (fatigue 31%, musculoskeletal pain 11%, neutropenia and thrombopenia 8%) and 11% in arm B. The proof-of-principle study does not confirm the hypothesis that sunitinib consolidation therapy can lead to a predefined clinically relevant proportion of patients with PFS of > or =5 months after an objective response to taxanes. Furthermore, toxicity was significant.

This randomized phase-II trial investigated the efficacy and tolerability of weekly docetaxel or paclitaxel in metastatic breast cancer (MBC) patients considered unfit for a 3-weekly therapy. The primary study endpoint was antitumor activity, the second endpoint was tolerability, time to progression (TTP) and overall survival (OS). In intent-to-treat analysis, we observed for paclitaxel and docetaxel respectively partial response (PR) in 48% versus 38%, stable disease (SD) in 24% versus 16%, PD in 15% versus 30%. Median TTP was 21.1 weeks versus 12.7 weeks and median OS 55.7 weeks versus 32 weeks. Toxicity profiles were acceptable with more anemia and neurotoxicity for paclitaxel and more edema and fatigue for docetaxel. In patients with MBC unfit for 3-weekly docetaxel or paclitaxel, weekly administration of either compound may certainly be considered. They display different, but acceptable toxicity profiles, with levels of antitumoral efficacy comparable to those previously reported for 3-weekly regimens.