H. Wildiers

Association between tumour characteristics and HER-2/neu by immunohistochemistry in 1362 women with primary operable breast cancer

Aims: To investigate the association between tumour characteristics and HER-2/neu by immunohistochemistry in primary operable breast cancer. Methods: The association between HER-2/neu and other clinicopathological factors was evaluated in 1362 consecutive patients with primary breast cancer treated between 2000 and July 2003 in one centre. Microscopic tumour size, tumour grade, lymph node status, patient’s age, oestrogen receptor (ER), progesterone receptor (PR), and joint ER/PR status were evaluated, using the χ2 test for univariate analysis and logistic regression for multivariate analysis. The hormone receptors and HER-2/neu were studied immunohistochemically. Using the HER-2/neu DAKO scoring system, scores of 0, 1+, or 2+ were defined as negative and 3+ as positive. Data for DAKO scores 2+/3+ versus 0/1+ are also presented. Results: Hormone receptor negative breast cancers were more often HER-2/neu positive than hormone receptor positive cancers, both for ER (28.7% v 6.8%) and PR (19.9% v 5.9%). In multivariate analysis, both ER, PR, and tumour grade were independently associated with HER-2/neu. In ER+ tumours, HER-2/neu overexpression was significantly lower in PR+ than in PR− cases (11.5% v 5.4%). HER-2/neu overexpression (2.7%) was lowest in the large subgroup of ER+PR+ tumours with low tumour grade (grade 1–2), comprising 46.1% of all patients. Conclusions: ER, PR, and tumour grade are independent predictors for HER-2/neu overexpression in women with primary operable breast cancer. ER and PR are negatively associated with HER-2/neu, whereas tumour grade is positively associated with HER-2/neu. In women with ER+ tumours, PR status also affects the likelihood of HER-2/neu expression.

Expression profiling of cancerous and normal breast tissues identifies microRNAs that are differentially expressed in serum from patients with (metastatic) breast cancer and healthy volunteers.

IntroductionMicroRNAs (miRNAs) are a group of small noncoding RNAs involved in the regulation of gene expression. As such, they regulate a large number of cellular pathways, and deregulation or altered expression of miRNAs is associated with tumorigenesis. In the current study, we evaluated the feasibility and clinical utility of circulating miRNAs as biomarkers for the detection and staging of breast cancer.MethodsmiRNAs were extracted from a set of 84 tissue samples from patients with breast cancer and eight normal tissue samples obtained after breast-reductive surgery. After reverse transcription and preamplification, 768 miRNAs were profiled by using the TaqMan low-density arrays. After data normalization, unsupervised hierarchical cluster analysis (UHCA) was used to investigate global differences in miRNA expression between cancerous and normal samples. With fold-change analysis, the most discriminating miRNAs between both tissue types were selected, and their expression was analyzed on serum samples from 20 healthy volunteers and 75 patients with breast cancer, including 16 patients with untreated metastatic breast cancer. miRNAs were extracted from 200 μl of serum, reverse transcribed, and analyzed in duplicate by using polymerase chain reaction (qRT-PCR).ResultsUHCA showed major differences in miRNA expression between tissue samples from patients with breast cancer and tissue samples from breast-reductive surgery (P < 0.0001). Generally, miRNA expression in cancerous samples tends to be repressed when compared with miRNA expression in healthy controls (P = 0.0685). The four most discriminating miRNAs by fold-change (miR-215, miR-299-5p, miR-411, and miR-452) were selected for further analysis on serum samples. All miRNAs at least tended to be differentially expressed between serum samples from patients with cancer and serum samples from healthy controls (miR-215, P = 0.094; miR-299-5P, P = 0.019; miR-411, P = 0.002; and miR-452, P = 0.092). For all these miRNAs, except for miR-452, the greatest difference in expression was observed between serum samples from healthy volunteers and serum samples from untreated patients with metastatic breast cancer.ConclusionsOur study provides a basis for the establishment of miRNAs as biomarkers for the detection and eventually staging of breast cancer through blood-borne testing. We identified and tested a set of putative biomarkers of breast cancer and demonstrated that altered levels of these miRNAs in serum from patients with breast cancer are particularly associated with the presence of metastatic disease.

Dysregulation of microRNAs in breast cancer and their potential role as prognostic and predictive biomarkers in patient management.

MicroRNAs (miRNAs) are an emerging class of gene expression modulators with relevant roles in several biological processes, including cell differentiation, development, apoptosis, and regulation of the cell cycle. Deregulation of those tiny RNA molecules has been described frequently as a major determinant for the initiation and progression of diseases, including cancer. Not only miRNAs but also the enzymes responsible for miRNA processing could be deregulated in cancer. In this review, we address the role of miRNAs in the pathogenesis of breast cancer, since there are oncogenic, tumor-suppressive, and metastatic-influencing miRNAs. Additionally, the different detection platforms and normalization strategies for miRNAs will be discussed. The major part of this review, however, will focus on the capability of miRNAs to act as diagnostic, predictive, or prognostic biomarkers. We will give an overview of their potential to correlate with response to or benefit from a given treatment and we will consider their ability to give information on prognosis in breast cancer. We will focus on miRNAs validated by more than one study or verified in independent cohorts or where results rely on preclinical as well as clinical evidence. As such, we will discuss their potential use in the personalized management of breast cancer.

Detection and monitoring of cardiotoxicity-what does modern cardiology offer?

IntroductionWith new anticancer therapies, many patients can have a long life expectancy. Treatment-related comorbidities become an issue for cancer survivors. Cardiac toxicity remains an important side effect of anticancer therapies. Myocardial dysfunction can become apparent early or long after end of therapy and may be irreversible. Detection of cardiac injury is crucial since it may facilitate early therapeutic measures. Traditionally, chemotherapy-induced cardiotoxicity has been detected by measuring changes in left ventricular ejection fraction. This parameter is, however, insensitive to subtle changes in myocardial function as they occur in early cardiotoxicity.DiscussionThis review will discuss conventional and modern cardiologic approaches of assessing myocardial function. It will focus on Doppler myocardial imaging, a method which allows to sensitively measure myocardial function parameters like myocardial velocity, deformation (strain), or deformation rate (strain rate) and which has been shown to reliably detect early abnormalities in both regional and global myocardial function in an early stage.Other newer echocardiographic function estimators are based on automated border detection algorithms and ultrasonic integrated backscatter analysis. A further technique to be discussed is dobutamine stress echocardiography. The use of new biomarkers like B-type natriuretic peptide and troponin and less often used imaging techniques like magnetic resonance imaging and computed tomography will also be mentioned.

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

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

Biology and prognosis by age of primary operable breast cancer.

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

Abstract P4-07-08: Age-related microRNAs and their biomarker potential in chemotherapy-treated older breast cancer patients

BD and SH contributed equally to this study. Background MicroRNAs (miRNAs) are important regulators of cellular function and have been associated with both aging and cancer, while the impact of chemotherapy on miRNAs has barely been studied. Patients and Methods To examine whether chemotherapy accelerates the aging process, we have monitored age-related circulating miRNAs in 89 older breast cancer patients (≥70y), receiving adjuvant chemotherapy (N= 46; chemo group, ChG) or no chemotherapy (N= 43; control group, CoG). Patients and associated blood samples belonged to the cohort of our recently published study (Brouwers et al., Oncotarget. 2016.) All patients underwent geriatric assessment at inclusion (T0), after 3 months (T1) and 1 year (T2). At each timepoint we analysed the serum expression of nine age-related miRNAs (miR-20a, miR-30b, miR-34a, miR-106b, miR-191, miR-301a, miR320b, miR374a, miR-378a). Our primary aim was to assess miRNA changes during the study period, including differences between groups. Secondary endpoints included association of microRNAs with: chronological age, clinical geriatric assessment parameters and aging biomarkers assessed in the above-mentioned study. We then investigated the predictive role of miRNAs at T0 on: decline in functionality and quality of life, toxicity and unexpected hospitalization during or after chemotherapy. We also performed clustering of patients according to specific miRNA signatures. Results Except for miR-106b, which appeared to behave slightly different in ChG compared to CoG, all other miRNAs underwent moderate fluctuations during the study course with no significant differences between both groups. Also within the older cohort, several age-related miRNAs significantly (p Moreover, based on their 9aging miRNA9 profiles, patients clustered into two distinct groups, cluster A (CA) and cluster B (CB), exhibiting significantly different results for several biological/clinical aging parameters. CA (N=43, miR-20a, miR-30b, miR-191, miR-301a and miR-374a underexpressed, miR-378a overexpressed) was characterized by older age, higher geriatric risk profile, as well as elevated IL-6, TNFα and MCP-1 levels compared to CB (N=45, inverse expression pattern). Moreover, 31.9% of CA patients but only 7.4% of CB patients experienced decline in quality of life after chemotherapy (p=0.051). Conclusions These results further corroborate our recent findings, stating that adjuvant chemotherapy does not significantly boost aging progression in elderly breast cancer patients. Our data also endorsed specific age-related miRNAs as promising aging/frailty biomarkers in oncogeriatric populations. Citation Format: Dalmasso B, Hatse S, Brouwers B, Laenen A, Berben L, Kenis C, Smeets A, Neven P, Schoffski P, Wildiers H. Age-related microRNAs and their biomarker potential in chemotherapy-treated older breast cancer patients [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 P4-07-08.

0192 Does the stellate ganglion block reduce severe hot flushes and sleep disturbances in breast cancer patients

Therefore, we conducted a retrospective analysis to investigate the equivalent efficacy and safety of using the LH−RH analogue during CTx for Japanese breast cancer pts using a case–control study. Methods: Patients under 45-years-old receiving anthracycline (A) alone, taxane (T) alone or A followed by T combined CTx for more than 6 cycles were eligible for this case–control study. Each pt in the case group, who had given informed consent, was given the LH−RH analogue (Zoladex) 3.6mg s.c, every day for 28 days from 2−4weeks prior to the first CTx and to the last course of the planned regimen. The control data were obtained from a questionnaire survey from pts who did not receive an LH−RH analogue during their CTx over almost the same period. Results: Between November 2003 and June 2006, 28 pts and 41 controls were evaluated (median follow-up time: 42 months after CTx). In the control group, 37 pts had CIA (90.2%). Amenorrhea was observed in 60% of those who received only T vs 94% with A-based CTx. All pts completed 6−8 courses of CTx and the addition of the LH−RH analogue caused no severe adverse events. There was no significant difference in disease-free-survival between two groups. In the patient group with the LH−RH analogue, menses recovered significantly earlier than controls (Mean 290 vs 496 days, P=0.0129); however, there was no difference in the recovery rates. Among 48 pts over 35-yearsold, addition of the LH−RH analogue significantly shortened the median time to menses resumption (Mean 321 vs 531 days, P=0.0174), but in patients under 35-yr, LH−RH analogue use had no beneficial effect on the recovery of menses (P=0.9064). Moreover, Tamoxifen appeared to delay menses resumption (Mean 518 vs 316 days, P=0.0202). Out of 24 pts who recovered menses and had E2 levels in serum continuously measured after chemotherapy, 23 pts recovered their E2 levels within 1000 days. Conclusion: The addition of an LH−RH analogue to CTx for POF was safe and had a beneficial effect on the patients’ internal hormonal environments. POF may have a greater benefit for pts over 35-years-old. E2 levels may help to predict menses resumption.

A double blind randomized phase II study on the efficacy of topical eye treatment in the prevention of docetaxel induced dacryostenosis.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #6144 Introduction : Weekly docetaxel, which is secreted in lacrimal tears, can cause dacryostenosis and eye tearing in up to 60% of patients. We hypothesized that eye drops containing corticosteroids may prevent the formation of fibrosis and hence stenosis of the lacrimal system. In addition, eye drops may wash out Docetaxel from the ocular surface and therefore decrease the occurrence of dacryostenosis. This study was designed to determine the efficacy of corticosteroid (CS) versus artificial tears (AT) topical eye treatment in patients on a weekly Docetaxel regimen. Patients and methods : Prospective, double-blind randomised, single-centre trial. Twenty patients who received a weekly Docetaxel (Doc) regimen for locally advanced or metastatic cancer, were enrolled. In a double blinded fashion, AT (Lacrystat®) were administered in one eye and dexamethasone sodium phosphate (CS)(Maxidex®) in the other eye, 6 times daily, from day 1 of cycle 1, continued throughout the Docetaxel administration, and stopped 2 weeks after the last Docetaxel administration. Before therapy and at week 3, 6 and 9, the patients were assessed for the following: watering, eye adnexes, irrigation and probing of the lacrimal drainage apparatus, and intra-ocular eye pressure. The primary endpoint was the incidence of dacryostenosis in each arm at 9 weeks in one eye treated with corticosteroid eye drops versus the other eye treated with artificial tears. Results: 1 pt with prostate cancer (Doc 36 mg/m2 qw 8w consecutively) and 19 pts with breast cancer entered the study (3 with LABC treated with Doc 36 mg/m2 d1-8 q3w plus capecitabine, +/- trastuzumab, 16 with metastatic BC treated with Doc 36 mg/m2 qw 8w consecutively). 9/20 eyes treated with CS and also 9/20 eyes treated with AT developed dacryostenosis at 9 week evaluation. Most cases of stenosis were grade 1 (narrowed punctum and/or canaliculus or impaired syringing of the outflow system after dilation of punctum) while only 2 eyes in CS and 1 eye in AT developed gr II stenosis (narrowed punctum impossible to dilate or narrowed canaliculus impossible to probe). Eye watering at week 9 was present in 9/20 eyes in CS (2 eyes discordant with stenosis) and 8/20 eyes in AT group (2 eyes discordant with stenosis). Conclusion: When prophylactic eye drops are administered during chemotherapy with weekly docetaxel, 45% of patients develop dacryostenosis after 9 weeks of docetaxel treatment. Although this study does not allow a comparison with a group without eye drops, the percentage of dacryostenosis in the eye drop group is quite high. There was no difference in the development of dacryostenosis in pts receiving corticosteroid or artificial tears (45% in both groups). This prospective double blind randomized phase II study does not confirm the hypothesis that eye drops containing corticosteroids prevent the formation of fibrosis and hence stenosis of the lacrimal system. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6144.

Weekly paclitaxel versus weekly docetaxel in elderly and frail patients with metastatic breast carcinoma having failed previous anthracyclines: a randomised phase II study of the Belgian Society of Medical Oncology.

Abstract #6115 Rationale: Taxanes are considered as standard 2nd-line chemotherapy after anthracyclines in metastatic breast carcinoma (MBC). In one large randomized trial, Jones et al. (JCO 2005;23:5542) reported a mean objective remission rate (RR) of 32% with a median time to progression (TTP) of 24.6 weeks (wks) for 3-weekly docetaxel 100mg/m², while the corresponding figures for paclitaxel 175mg/m² were 25% and 15.6wks respectively. Nevertheless, excessive toxicity, especially myelosuppression, precludes their use in frail and/or elderly patients (pts). For the latter, weekly schemes were developed, which proved tolerable without losing efficacy. This randomized phase II trial investigated the efficacy and the tolerability of weekly docetaxel or paclitaxel in MBC pts considered unfit for a 3-weekly therapy. Eligibility criteria were age >70 years, particular risk for myelosuppression (febrile neutropenia during previous chemotherapy, extensive radiation therapy, proven bone marrow invasion) or impaired hepatic function.
 Study design: 70pts accrued from Jan. 2002 to Aug. 2005 were randomized between arm A (33pts) receiving paclitaxel 80mg/m² weekly x8, and arm B (37pts), receiving docetaxel 36mg/m² weekly x8 after which a clinical response evaluation including CT-scan was performed. Pts with objective remission or stable disease (SD) pursued treatment 3/4 or 2/3 wks untill progression or unacceptable toxicity. For all pts, this was the first exposure to taxanes, unless they had received it in an adjuvant scheme, or in a palliative scheme with at least a 4 months lasting response. Study-endpoints were RR, TTP, overall survival (OS) and tolerability.
 Results: With paclitaxel, we obtained a RR of 55.2%, SD in 27.6% and progressive disease (PD) in 17.2% of the pts; median TTP was 21.1wks (95% CI:14.9-29.0) and median survival 55.7wks (95% CI:28.6-79.0). Corresponding results for docetaxel were: a RR of 45.2%, SD in 19.4% and PD in 35.4%; median TTP was 12.7wks (95% CI:8.4-29.3) and median survival 32wks (95% CI:19.4-50.9). Docetaxel and paclitaxel are known to have a different toxicity profile in 3-weekly regimens, with more hematotoxicity for docetaxel. In our study, boths products had a similar toxicity profile with more anemia, neutropenia and febrile neutropenia in the paclitaxel arm.
 Conclusions: Our study demonstrates that in pts with MBC unfit for 3-weekly docetaxel or paclitaxel, weekly administration of either compound may certainly be considered after anthracycline failure. They display different, but acceptable toxicity profiles, with levels of antitumoral efficacy comparable to those previously reported for 3-weekly regimens. A true valid comparison would require extension into a phase III trial. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6115.