H. Janssen

Image guided brachytherapy in locally advanced cervical cancer: Improved pelvic control and survival in RetroEMBRACE, a multicenter cohort study

PURPOSE Image guided brachytherapy (IGBT) for locally advanced cervical cancer allows dose escalation to the high-risk clinical target volume (HRCTV) while sparing organs at risk (OAR). This is the first comprehensive report on clinical outcome in a large multi-institutional cohort. PATIENTS AND METHODS From twelve centres 731 patients, treated with definitive EBRT±concurrent chemotherapy followed by IGBT, were analysed. Kaplan-Meier estimates at 3/5years were calculated for local control (LC, primary endpoint), pelvic control (PC), overall survival (OS), cancer specific survival (CSS). In 610 patients, G3-4 late toxicity (CTCAEv3.0) was reported. RESULTS Median follow up was 43months, percent of patients per FIGO stage IA/IB/IIA 22.8%, IIB 50.4%, IIIA-IVB 26.8%. 84.8% had squamous cell carcinomas; 40.5% lymph node involvement. Mean EBRT dose was 46±2.5Gy; 77.4% received concurrent chemotherapy. Mean D90 HRCTV was 87±15Gy (EQD210), mean D2cc was: bladder 81±22Gy, rectum 64±9Gy, sigmoid 66±10Gy and bowel 64±9Gy (all EQD23). The 3/5-year actuarial LC, PC, CSS, OS were 91%/89%, 87%/84%, 79%/73%, 74%/65%. Actuarial LC at 3/5years for IB, IIB, IIIB was 98%/98%, 93%/91%, 79%/75%. Actuarial PC at 3/5years for IB, IIB, IIIB was 96%/96%, 89%/87%, 73%/67%. Actuarial 5-year G3-G5 morbidity was 5%, 7%, 5% for bladder, gastrointestinal tract, vagina. CONCLUSION IGBT combined with radio-chemotherapy leads to excellent LC (91%), PC (87%), OS (74%), CSS (79%) with limited severe morbidity.

Common Breast Cancer Susceptibility Loci Are Associated with Triple-Negative Breast Cancer

Triple-negative breast cancers are an aggressive subtype of breast cancer with poor survival, but there remains little known about the etiologic factors that promote its initiation and development. Commonly inherited breast cancer risk factors identified through genome-wide association studies display heterogeneity of effect among breast cancer subtypes as defined by the status of estrogen and progesterone receptors. In the Triple Negative Breast Cancer Consortium (TNBCC), 22 common breast cancer susceptibility variants were investigated in 2,980 Caucasian women with triple-negative breast cancer and 4,978 healthy controls. We identified six single-nucleotide polymorphisms, including rs2046210 (ESR1), rs12662670 (ESR1), rs3803662 (TOX3), rs999737 (RAD51L1), rs8170 (19p13.1), and rs8100241 (19p13.1), significantly associated with the risk of triple-negative breast cancer. Together, our results provide convincing evidence of genetic susceptibility for triple-negative breast cancer.

Stellate ganglion block for the management of hot flashes and sleep disturbances in breast cancer survivors: an uncontrolled experimental study with 24 weeks of follow-up

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.

Breathing adapted radiation therapy in comparison with prone position to reduce the doses to the heart, left anterior descending coronary artery, and contralateral breast in whole breast radiation therapy.

PURPOSE To compare 3 different treatment positions in whole breast radiation therapy in terms of target volume coverage and doses to the organs at risk (OAR). METHODS AND MATERIALS Thirty-four breast cancer (BC) patients (17 right-sided and 17 left-sided) were included in this dosimetric planning study. They all underwent a computed tomography (CT) scan in standard supine position in free-breathing (FB), supine position with gating in deep inspiratory breath hold (DIBH)(G), and prone position (P). Three-dimensional treatment plans were made for all 3 CTs. Target coverage and OAR sparing were evaluated. RESULTS Breast volumes varied between 209 and 2814 cm(3). The target coverage, expressed as the mean volume of the breast receiving at least 95% of the prescription dose, was similar for the 3 treatment positions. The mean lung dose and the volume of the lungs receiving >20 Gy were significantly lower in P (1.7 Gy; 2.3%) compared with G (3.4 Gy; 5.6%; P < .0001) and FB (4 Gy; 7.3%; P < .0001). The volume of the contralateral breast receiving >5 Gy was significantly lower in G (P = .001) or FB (P = .004) versus prone. The supine position with gating in DIBH significantly reduced the volume of the heart receiving >30 Gy (V30(heart)), the mean heart (D(heart)), and mean left anterior descending coronary artery (LAD) dose (D(LAD)) for left-sided BC patients (V30(heart) 0.9%, D(heart) 1.6 Gy, DLAD 22.4 Gy) with respect to FB (V30(heart) 4.3%, D(heart) 3.5 Gy, DLAD 30.9 Gy)(V30(heart) and mean D(heart): P ≤ .0001; mean D(LAD): P = .008) and P (V30(heart) 7.9%, D(heart) 5.4 Gy, D(LAD) 36.4 Gy)(V30(heart) and mean D(heart): P = .0004; mean D(LAD): P = .01). CONCLUSIONS The coverage of the planning target volume breast was equal for the 3 treatment positions. The lowest doses to the lungs were achieved in prone. The heart, LAD, and contralateral breast were best spared in the supine position with gating in DIBH.

A comparison of three different radiotherapy boost techniques after breast conserving therapy for breast cancer

PURPOSE Compare different boost techniques after breast conserving therapy (BCT) in terms of local and loco-regional recurrences. MATERIALS AND METHODS From 2000 to 2005, patients treated with BCT for invasive breast cancer (BC) were included. An electron boost (EB) was performed for a superficial boost-volume (less than 29 mm under the epidermis), in all other cases a brachytherapy boost (BTB) was proposed. When patients refused a BTB or it was not possible for technical reasons, a photon boost (PB) was given. The primary endpoints were local and loco-regional recurrences. Secondary endpoints were metastasis-free and overall survival. RESULTS 1379 patients were eligible for analysis. Most patients (1052) received an EB, 225 a BTB and 76 a PB. At a median follow-up of 8.8 years, 35 (2.5%) patients developed a local or loco-regional recurrence. Ten years local relapse-free rate was 97.9%. No differences between boost techniques were observed in relapse risk, metastasis-free and overall survival after multivariate analyses. CONCLUSION In women treated with BCT followed by a boost irradiation to the tumor bed, no difference in local and loco-regional recurrence, metastasis-free and overall survival was observed comparing three different boost techniques. Outcome was excellent regardless of the boost technique.

Cellular transformation of NIH3T3 fibroblasts by CIZ/NMP4 fusions

Molecular cloning of the translocations t(12;22)(p13;q12) and t(12;17)(p13;q11) in acute leukaemia showed that either EWSR1 or its homologue TAF15 are fused to the transcription factor CIZ. EWSR1 and TAF15 belong to the TET family (TLS/FUS, EWSR1 and TAF15) of proteins. TET fusions have been identified in both solid tumours and acute myeloid leukaemia. The novel 12p translocations directly implicated TET fusions in acute lymphoblastic leukaemia as well, and demonstrated the involvement of CIZ in haematopoietic malignancies. In addition, a new fusion E2A‐CIZ was recently cloned as a result of a t(12;19)(p13;p13) in a patient with acute lymphoblastic leukaemia. NIH3T3 cells stably expressing TET‐CIZ fusions display a transformed phenotype in a focus formation assay. We show here that E2A‐CIZ also transforms 3T3 fibroblasts, suggesting that the addition of a transactivation domain to the CIZ protein is involved in this phenotype. An artificial VP16‐CIZ construct reveals similar transforming properties, supporting this. We have then analysed the domains within TAF15‐CIZ that are necessary for 3T3 fibroblast transformation. Deletion of the zinc fingers of CIZ resulted in loss of both DNA‐binding and transforming properties of TAF15‐CIZ, whereas deletion of the other functional domains of CIZ had no effect. Fusion of a transactivation domain to CIZ is suggestive for a transactivating function in transformation. Luciferase experiments indeed showed that E2A‐CIZ as well as VP16‐CIZ transactivates the MMP7 promoter. Taken together, our results reported here suggest that transformation of 3T3 fibroblasts by CIZ fusions is dependent on DNA‐binding and might involve transactivation of CIZ target genes.

RAD51B in Familial Breast Cancer

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11–1.19, P = 8.88 x 10−16) and among familial cases (OR: 1.24, 95% CI: 1.16–1.32, P = 6.19 x 10−11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.

Does the Stellate Ganglion Block Reduce Severe Hot Flushes and Sleep Disturbances in Breast Cancer Patients

Background: Invalidating hot flushes and night sweats leading to sleep dysfunction and poor quality of life are difficult to treat, especially in postmenopausal breast cancer patients likely to take an anti-estrogen. Lipov et al. (Lancet Oncology 2008; 9: 523-32) recently reported on the therapeutic value of the ganglion stellatum block (GSB) in 13 patients. We here report results from a pilot and prospectively planned study using the GSB in symptomatic breast cancer patients. Methods and Patients: Both studies were approved by our ethical committee and included postmenopausal women with severe hot flushes and/or night sweats and no contra-indication for GSB. Patients had to sign a consent form after information and were recruited from the follow-up breast cancer clinic. Hot flushes were recorded in a daily diary by use of the hot-flash score (Lipov et al.) and night awakenings by use of the Pittsburgh Sleep Quality Index. Improvement was estimated by the patient from 0-100 %. The pilot cohort compared both instruments between baseline and after 1 month whereas the prospective study compared baseline, weeks 1, 12 & 24 following the GSB. Patients were treated as out-patients in the pain clinic with a right side GSB at the anterolateral aspect of C6 vertebra under fluoroscopy by an experienced anesthetist injecting 10 cc Chirocaine. A contralateral block was placed when no satisfactory result. Results: The pilot study included 9 patients and as of today, 18 of 25 patients are included in the prospective study. The temporary Horner syndrome confirmed the GSB in all. In the pilot study, 5/9 patients had the GSB unilateral and 4/9 bilateral. Three of 9 patients had no improvement in either endpoint while 6/9 reported an improvement in severity of hot flushes and in quality of sleep. Two patients had a complete disappearance of the hot flushes and perfect sleep quality following a unilateral GSB. Three patients with contralateral GSB experienced an 80%, 70% and 50% improvement. Another patient with GSB unilateral experienced improvement by 20% in both instruments. We report results of 6 patients in the prospective study, 3 required a contralateral GSB. Their mean baseline hot flash score was 2.5 down to 2.2 after one week of GSB. Mean sleep hours improved from 6 to 7.25 hours per night even at week 1 after the GSB. One reported a hot flash score of 2.5/1.6/1.5/1.9 respectively mentioned follow up period. Because of rising hot flash score she asked for a third GSB after 24 weeks. Conclusion: This pilot and prospectively planned study to test efficacy of GSB on hot flushes and/or night sweats confirmed that breast cancer patients suffering from invalidating symptoms may benefit with no short term harm. Further results of the patients in both studies will be presented during the meeting. This will also answer the question whether long term efficacy remains. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 809.

Is the use of a preoperative computed tomography beneficial to reduce the interobserver variability of the CTVboost delineation for breast radiation therapy

PURPOSE To determine whether the use of a preoperative (preop) computed tomography (CT) reduces (1) the clinical target volume boost (CTVboost) and (2) the interobserver variability (IOV) of the delineated CTVboost in breast radiation therapy. METHODS AND MATERIALS In patients treated with breast-conserving therapy, 3 CT scans in treatment position were performed: (1) preop; (2) after surgery, prechemotherapy (postop); and (3) postchemotherapy (postchemo). Six radiation-oncologists delineated the tumor bed and CTVboost before and after fusion of the preop CT. To assess the IOV, the Jaccard index was used. Linear mixed models were performedfor all analyses. RESULTS Eighty-two lumpectomy cavities were evaluated in 22 patients. No difference in CTVboost using the fusion of the preop CT (50.0 cm3; 95% confidence interval [CI], 35.6-64.4) compared with no fusion (49.0 cm3; 95% CI, 34.6-63.4) (P = .6) was observed. A significant increase in IOV was shown with the fusion of the preop CT; the mean Jaccard index of the CTVboost delineation of postop and postchemo CT together without the fusion of the preop CT was 0.53 (95% CI, 0.49-0.57) versus 0.50 (95% CI, 0.46-0.53) with fusion (P < .0001). CONCLUSIONS There is no benefit of using a preop CT to reduce the volume or the interobserver variability of the delineated CTVboost for breast radiation therapy.

Boost delineation in breast radiation therapy: Isotropic versus anisotropic margin expansion

PURPOSE The purpose of this article is to compare isotropic and anisotropic margin expansion with regard to the size of the clinical target volume boost (CTVboost) and the interobserver variability (IOV). METHODS AND MATERIALS Lumpectomy cavities marked with 3 or more surgical clips were delineated by 6 radiation oncologists who specialized in breast radiation therapy. CTVboost anisotropic was created by manually expanding the tumor bed with an anisotropic margin of 15 mm (20 mm in case of extensive intraductal component) minus the surgical free margins in 6 directions (anteroposterior, craniocaudal, and superoinferior). For the CTVboost isotropic, the tumor bed was enlarged with an isotropic margin of 15 mm (20 mm in case of extensive intraductal component) minus the minimal surgical free margin. The volumes of the delineated CTVboost (cm3) were measured. To assess the IOV, the Jaccard index (JI), defined as the intersection divided by the size of the union of the sample sets, was used (ideal value = 1). The JI was calculated for each case and each observer pair. Linear mixed models were used for all analyses. RESULTS A total of 444 delineated tumor beds were evaluated. The mean volume of the CTVboost almost doubled by expanding the tumor bed with an isotropic margin compared with anisotropic margins (CTVboost isotropic 94 mL [12.5-331.0] vs CTVboost anisotropic 50 mL [3.2-332.7]; P = .0006). The IOV, assessed by the JI, significantly decreased by using isotropic versus anisotropic margin expansion (JICTV boost isotropic 0.73 [0.02-0.92] vs JICTV boost anisotropic 0.51 [0.0-0.8]; P< .0001). Because of the known positive correlation of the IOV and larger volumes, we corrected for CTVboost volumes. With this correction, the difference in IOV remains highly significant (P < .0001) in favor of isotropic margin expansion. CONCLUSIONS The use of anisotropic margin expansion from tumorbed to CTVboost isotropic significantly reduced the volume of the delineated CTVboost with a factor of 1.9 compared with isotropic margin expansion, but it substantially increased the interobserver variability.