Meta-analyses of visceral versus non-visceral metastatic hormone receptor-positive breast cancer treated by endocrine monotherapies.

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.

Meta-analyses of phase 3 randomised controlled trials of third generation aromatase inhibitors versus tamoxifen as first-line endocrine therapy in postmenopausal women with hormone receptor-positive advanced breast cancer.

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% and 55% of tumours were hormone receptor (HR) status unknown or negative. This meta-analysis restricted the comparison to HR-positive (HR+) tumours. METHODS: Anonymised 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. FINDINGS: The OR for clinical benefit rate was 1.56, in favour of AIs (p < 0.001). The duration of clinical benefit was not significantly increased by AIs (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). INTERPRETATION: Although 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.

Overestimation of Late Distant Recurrences in High-Risk Patients With ER-Positive Breast Cancer: Validity and Accuracy of the CTS5 Risk Score in the TEAM and IDEAL Trials.

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.

Iniparib administered weekly or twice-weekly in combination with gemcitabine/carboplatin in patients with metastatic triple-negative breast cancer: a phase II randomized open-label study with pharmacokinetics.

PURPOSE: 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. METHODS: 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. RESULTS: 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 < 1 h, without accumulation. CONCLUSIONS: Despite a doubled maximum concentration with weekly iniparib, no detectable differences in safety or efficacy were observed between the weekly and twice-weekly administration schedules in this population. TRIAL REGISTRATION: ClinicalTrial.gov Identifier NCT01045304.

Prognostic Value of the Progesterone Receptor by Subtype in Patients with Estrogen Receptor-Positive, HER-2 Negative Breast Cancer.

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.

Tamoxifen Metabolism and Efficacy in Breast Cancer: A Prospective Multicenter Trial.

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

Adjuvant tamoxifen and exemestane in women with postmenopausal early breast cancer (TEAM): 10-year follow-up of a multicentre, open-label, randomised, phase 3 trial.

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.

Long-Term Follow-Up of the Intergroup Exemestane Study.

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.

Androgen deprivation by adrenal suppression using low-dose hydrocortisone for the treatment of breast carcinoma with apocrine features: a case report illustrating this new paradigm.

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.

Clinical and genetic risk factors for epirubicin-induced cardiac toxicity in early breast cancer patients.

Anthracycline-induced cardiotoxicity (ACT) is a well-known serious adverse drug reaction leading to substantial morbidity. The purpose of this study was to assess ACT occurrence and clinical and genetic risk factors in early breast cancer patients. In 6 genes of interest (ABCC1, ABCC2, CYBA, NCF4, RAC2, SLC28A3), 10 single nucleotide polymorphisms (SNPs) involved in ACT were selected based on a literature search. Eight hundred and seventy-seven patients treated between 2000 and 2010 with 3-6 cycles of (neo) adjuvant 5-fluorouracil, epirubicin and cyclophosphamide (FEC) were genotyped for these SNPs using Sequenom MassARRAY. Main outcome measures were asymptomatic decrease of left ventricular ejection fraction (LVEF) > 10 % and cardiac failure grade 3-5 (CTCAE 4.0). To evaluate the impact of these 10 SNPs as well as clinical factors (age, relative dose intensity of epirubicin, left-sided radiotherapy, occurrence of febrile neutropenia, and planned and received cycles of epirubicin) on decrease of LVEF and cardiac failure, we performed uni- and multivariable logistic regression analysis. Additionally, exploratory analyses including 11 additional SNPs related to the metabolism of anthracyclines were performed. After a median follow-up of 3.62 years (range 0.40-9.60), a LVEF decline of > 10 % occurred in 153 patients (17.5 %) and cardiac failure in 16 patients (1.8 %). In multivariable analysis, six cycles of FEC compared to three cycles received and heterozygous carriers of the rs246221 T-allele in ABCC1 relative to homozygous carriers of the T-allele were significantly associated with LVEF decline of > 10 % (OR 1.3, 95 % CI 1.1-1.4, p < 0.001 and OR 1.6, 95 % CI 1.1-2.3, p = 0.02). Radiotherapy for left-sided breast cancer was associated with cardiac failure (OR 3.7, 95 % CI 1.2-11.5, p 0.026). The other 9 SNPs and clinical factors tested were not significantly associated. In our exploratory analysis, no other SNPs related to anthracycline metabolism were retained in the multivariate model for prediction of LVEF decline. ACT in breast cancer patients is related to number of received cycles of epirubicin and left-sided radiotherapy. Additional studies should be performed to independently confirm the potential association between rs246221 in ABCC1 and LVEF.

Arthralgia induced by endocrine treatment for breast cancer: A prospective study of serum levels of insulin like growth factor-I, its binding protein and oestrogens.

BACKGROUND: Aromatase inhibitors (AIs) frequently induce or enhance musculoskeletal problems (AI-induced musculoskeletal syndrome (AIMSS)) which sometimes are debilitating. Apart from low oestrogen levels, underlying mechanisms are unknown and likely multiple. We previously hypothesised a role for the growth hormone/insulin like growth factor-I (IGF-I) axis. Here, we report the effect of tamoxifen and AI on IGF-I, IGF binding protein-3 (IGFBP-3) and oestrogen levels from a prospective study. MATERIALS AND METHODS: Postmenopausal women with an early breast cancer scheduled to start adjuvant endocrine therapy with an AI or tamoxifen were recruited. A rheumatologic questionnaire was completed and serum was collected for assessment of IGF-I, IGFBP-3 and oestrogen levels. Re-evaluation was done after 3, 6 and 1 2months of therapy. RESULTS: 84 patients started on tamoxifen (n=42) or an AI (n=42). 66% of the latter group experienced worsening of pre-existing or de novo complaints in joint and/or muscle, compared to 29% of tamoxifen-treated patients. AI therapy resulted in elevated IGF-I levels with a statistically significant increase at 6months (p=0.0088), whereas tamoxifen users were characterised by a decrease in IGF-I levels at all follow-up times (p<0.0004). No effect on IGFBP-3 was seen in the latter group. AI-users, however, showed decreased IGFBP-3 levels at 12 months (p=0.0467). AIMSS was characterised by a decrease in IGFBP-3 levels (p=0.0007) and a trend towards increased IGF-I/IGFBP-3 ratio (p=0.0710). CONCLUSION: These findings provide preliminary evidence that AI-induced musculoskeletal symptoms are associated with changes in the growth hormone (GH)/IGF-I axis.

Sarcomatoid dedifferentiation in metastatic clear cell renal cell carcinoma and outcome on treatment with anti-vascular endothelial growth factor receptor tyrosine kinase inhibitors: a retrospective analysis.

INTRODUCTION: This study aimed to assess the efficacy of anti-vascular endothelial growth factor receptor tyrosine kinase inhibitors (anti-VEGFR-TKIs) in patients with metastatic clear cell renal cell carcinoma (m-ccRCC) with sarcomatoid 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 nephrectomy 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 sarcomatoid 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 = .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.

Efflux pump ABCB1 single nucleotide polymorphisms and dose reductions in patients with metastatic renal cell carcinoma treated with sunitinib.

UNLABELLED: There is growing evidence that sunitinib plasma levels have an impact on treatment outcome in patients with metastatic renal cell carcinoma (mRCC). We studied the impact of single nucleotide polymorphisms (SNPs) in genes involved in sunitinib pharmacokinetics, and additionally, sunitinib pharmacodynamics on dose reductions of the tyrosine kinase inhibitor. METHODS: We retrospectively analyzed germ-line DNA retrieved from mRCC patients receiving sunitinib as first-line therapy. We genotyped 11 key SNPs, respectively, in ABCB1, NR1/2, NR1/3 and CYP3A5, involved in sunitinib pharmacokinetics as well as VEGFR1 and VEGFR3, which have been suggested as regulators of sunitinib pharmacodynamics. Association between these SNPs and time-to-dose-reduction (TTDR) was studied by Cox regression. RESULTS: We identified 96 patients who were treated with sunitinib and from whom germ-line DNA and data on dose reductions were available. We observed an increased TTDR in patients carrying the TT-genotype in ABCB1 rs1125803 compared to patients with CC- or CT-genotypes (19 vs. 7 cycles; p = 0.031 on univariate analysis and p = 0.012 on multivariate analysis) and an increased TTDR in patients carrying the TT/TA-variant in ABCB1 rs2032582 compared to patients with the GG- or GT/GA-variant (19 vs. 7 cycles; p = 0.046 on univariate analysis and p = 0.024 on multivariate analysis). CONCLUSION: mRCC patients carrying the rs1128503 TT-variant or the TT/TA-variant in rs2032582 in ABCB1, which encodes for an efflux pump, do require less dose reductions due to adverse events compared to patients with the wild type or heterozygote variants in these genes.

Multivariable regression analysis of febrile neutropenia occurrence in early breast cancer patients receiving chemotherapy assessing patient-related, chemotherapy-related and genetic risk factors.

BACKGROUND: Febrile neutropenia (FN) is common in breast cancer patients undergoing chemotherapy. Risk factors for FN have been reported, but risk models that include genetic variability have yet to be described. This study aimed to evaluate the predictive value of patient-related, chemotherapy-related, and genetic risk factors. METHODS: Data from consecutive breast cancer patients receiving chemotherapy with 4-6 cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) or three cycles of FEC and docetaxel were retrospectively recorded. Multivariable logistic regression was carried out to assess risk of FN during FEC chemotherapy cycles. RESULTS: Overall, 166 (16.7%) out of 994 patients developed FN. Significant risk factors for FN in any cycle and the first cycle were lower platelet count (OR = 0.78 [0.65; 0.93]) and haemoglobin (OR = 0.81 [0.67; 0.98]) and homozygous carriers of the rs4148350 variant T-allele (OR = 6.7 [1.04; 43.17]) in MRP1. Other significant factors for FN in any cycle were higher alanine aminotransferase (OR = 1.02 [1.01; 1.03]), carriers of the rs246221 variant C-allele (OR = 2.0 [1.03; 3.86]) in MRP1 and the rs351855 variant C-allele (OR = 2.48 [1.13; 5.44]) in FGFR4. Lower height (OR = 0.62 [0.41; 0.92]) increased risk of FN in the first cycle. CONCLUSIONS: Both established clinical risk factors and genetic factors predicted FN in breast cancer patients. Prediction was improved by adding genetic information but overall remained limited. Internal validity was satisfactory. Further independent validation is required to confirm these findings.

Aromatase inhibitors in the breast cancer clinic: focus on exemestane.

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.

Prognostic impact of baseline serum C-reactive protein in patients with metastatic renal cell carcinoma (RCC) treated with sunitinib.

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.

VEGFR1 single nucleotide polymorphisms associated with outcome in patients with metastatic renal cell carcinoma treated with sunitinib - a multicentric retrospective analysis.

BACKGROUND: There are no validated markers that predict outcome in metastatic renal cell cancer (mRCC) patients treated with sunitinib. Recently, single nucleotide polymorphism (SNP) rs9582036 in VEGFR1 has been proposed as a predictor of progression-free survival (PFS) and overall survival (OS) to bevacizumab in patients with pancreatic cancer and rs7993418 in VEGFR1 as predictor for PFS in mRCC-patients treated with bevacizumab. Here, we aim to study the impact of these SNPs in mRCC patients treated with sunitinib. METHODS: We included patients with mRCC treated in 15 institutions in France and Belgium. Patients received sunitinib as first-line targeted therapy. We assessed response, time-to-tumor progression (TTP), OS, and clinical and biochemical parameters associated with outcome. We genotyped rs9582036 and rs7993418 as well as three other surrounding SNPs in VEGFR1: rs9554320, rs9554316 and rs9513070. Association between SNPs and treatment outcome were studied by univariate analysis and by multivariate Cox regression using relevant clinical factors associated with TTP and OS as covariates. FINDINGS: Ninety-one patients were included. We found that mRCC patients with the CC-variant in rs9582036 in VEGFR1 have a poorer response rate (RR) (0% vs. 46%, p = 0.028), a poorer PFS (10 vs. 18 months, p = 0.033 on univariate and 0.06 on multivariate analysis) and a poorer OS (14 vs. 31 months, p = 0.019 on univariate and 0.008 on multivariate analysis) compared to patients with the AC- and AA-genotypes. mRCC patients with the AA-variant in rs9554320 in VEGFR1 have a poorer PFS (12 vs. 21 months, p = 0.0066 on univariate and 0.005 on multivariate analysis) and a poorer OS (22 vs. 34 months, p = 0.019 on univariate and 0.067 on multivariate analysis) compared to patients with the AC- and CC-genotypes. Interpretation. mRCC patients with the CC-genotype in VEGFR1 SNP rs9582036 have a poorer response rate, PFS and OS when treated with sunitinib. These findings are in agreement with the association of rs9582036 and outcome observed in bevacizumab treated pancreatic cancer patients. Prospective validation of this SNP is warranted.

Effect of local therapy on locoregional recurrence in postmenopausal women with breast cancer in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial.

BACKGROUND AND PURPOSE: The TEAM trial investigated the efficacy and safety of adjuvant endocrine therapy consisting of either exemestane or the sequence of tamoxifen followed by exemestane in postmenopausal hormone-sensitive breast cancer. The present analyses explored the association between locoregional therapy and recurrence (LRR) in this population. MATERIAL AND METHODS: Between 2001 and 2006, 9779 patients were randomized. Local treatment was breast conserving surgery plus radiotherapy (BCS+RT), mastectomy without radiotherapy (MST-only), or mastectomy plus radiotherapy (MST+RT). Patients with unknown data on surgery, radiotherapy, tumor or nodal stage (n=199), and patients treated by lumpectomy without radiotherapy (n=349) were excluded. RESULTS: After a median follow-up of 5.2 years, 270 LRRs occurred (2.9%) among 9231 patients. The 5-years actuarial incidence of LRR was 4.2% (95% CI 3.3-4.9%) for MST-only, 3.4% (95% CI 2.4-4.2%) for MST+RT and 1.9% (95% CI 1.5-2.3%) for BCS+RT. After adjustment for prognostic factors, the hazard ratio (HR, reference BCS+RT) for LRR remained significantly higher for MST-only (HR 1.53; 95% CI 1.10-2.11), not for MST+RT (HR 0.78; 95% CI 0.50-1.22). CONCLUSION: This explorative analysis showed a higher LRR risk after MST-only than after BCS+RT, even after adjustment for prognostic factors. As this effect was not seen for MST+RT versus BCS+RT, it might be explained by the beneficial effects of radiation treatment.

Is the sentinel lymph node biopsy more sensitive for the identification of positive lymph nodes in breast cancer than the axillary lymph node dissection?

Since the routine clinical use of the sentinel lymph node (SLN) procedure, questions have been raised concerning an increase in the overall percentage of node-positive patients. The goal of our study was to compare the sensitivity of the SLN procedure and the axillary lymph node dissection (ALND) for the identification of positive lymph nodes in breast cancer. The incidence of axillary node metastasis in SLNB and ALND specimens from patients undergoing operative treatment of a primary breast carcinoma was compared retrospectively. Logistic regression models were used to analyze the effect of various predictors on the presence of positive lymph nodes. We constructed a multivariate model including the procedure and these predictors that have shown to be related to lymph node involvement in univariate analysis. The probability of finding positive lymph nodes was thus calculated in both groups correcting for relevant predictors of lymph node involvement. The SLNB group included 830 patients, the ALND group 320. In a multivariate analysis, adjusting for the number of foci, tumor location in the breast, tumor size, LVI, ER, PR, tumor grade and histological subtype, the probability of finding positive lymph nodes was higher with SLNB procedure than with an ALND. However, this difference was not statistically significant (OR 0.7635; CI 0.5334-1.0930, p 0.1404). For comparable tumors, SLNB procedure is at least as sensitive as ALND for detecting positive lymph nodes.

Specific adverse events predict survival benefit in patients treated with tamoxifen or aromatase inhibitors: an international tamoxifen exemestane adjuvant multinational trial analysis.

PURPOSE: Specific adverse events (AEs) associated with endocrine therapy and related to depletion or blocking of circulating estrogens may be related to treatment efficacy. We investigated the relationship between survival outcomes and specific AEs including vasomotor symptoms (VMSs), musculoskeletal adverse events (MSAEs), and vulvovaginal symptoms (VVSs) in postmenopausal patients with breast cancer participating in the international Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. PATIENTS AND METHODS: Primary efficacy end points were disease-free survival (DFS), overall survival (OS), and distant metastases (DM). VMSs, MSAEs, and VVSs arising in the first year of endocrine treatment were considered. Patients who did not start or who discontinued their allocated therapy and/or had an event (recurrence/death) within 1 year after randomization were excluded. Landmark analyses and time-dependent multivariate Cox proportional hazards models assessed survival differences up to 5 years from the start of treatment. RESULTS: A total of 9,325 patients were included. Patients with specific AEs (v nonspecific or no AEs) had better DFS and OS (multivariate hazard ratio [HR] for DFS: VMSs, 0.731 [95% CI, 0.618 to 0.866]; MSAEs, 0.826 [95% CI, 0.694 to 0.982]; VVSs, 0.769 [95% CI, 0.585 to 1.01]; multivariate HR for OS: VMSs, 0.583 [95% CI, 0.424 to 0.803]; MSAEs, 0.811 [95% CI, 0.654 to 1.005]; VVSs, 0.570 [95% CI, 0.391 to 0.831]) and fewer DM (VMSs, 0.813 [95% CI, 0.664 to 0.996]; MSAEs, 0.749 [95% CI, 0.601 to 0.934]; VVSs, 0.687 [95% CI, 0.436 to 1.085]) than patients not reporting these symptoms. Increasing numbers of specific AEs were also associated with better survival outcomes. Outcomes were unrelated to treatment allocation. CONCLUSION: Certain specific AEs are associated with superior survival outcomes and may therefore be useful in predicting treatment responses in patients with breast cancer treated with endocrine therapy.