bluuebunny/crossref_metadata_2025 huggingface dataset:
Absence of racial predilection for aggressive tumor phenotype among low socio-economic status women with breast cancer
Authors: Dookeran K. A. , Wang Y. , Gao X. , Ferrer K. , Sekosan M. , DeLaTorre R. , Radeke E. , McCaskill-Stevens W. , Zaren H.
Published: March 2020

10554

Background: Survival disparity for African-American (AA) women with breast cancer has been associated with more frequent aggressive tumor phenotype, manifested as higher stage, high grade and negative estrogen/progesterone receptor (ER/PR) status. However, AAs more often have low socioeconomic status (SES), and other studies suggest that low SES, not simply race, is associated with these prognostic features. We hypothesized that low SES AAs and non-AAs with breast cancer would demonstrate similar aggressive tumor phenotype and prognosis. Methods: Variables were analyzed for 538 consecutive low SES women treated between 1/00–12/05. Comparison between racial groups was done with independent t-test & Chi-square test. Associations were examined with logistic-regression, and compared as odds ratios (OR) & 95% confidence intervals (CI). Survival was computed using Log-rank test & Kaplan-Meier method. Results: At median follow-up of 32 months, there were 335 AAs & 203 non-AAs. No significant differences occurred between racial groups for tumor size & grade, node status, stage, ER/PR status, and frequency of survival events. HER2+ status was more frequent in non-AAs (25.1% vs. 17.9% AAs; p=0.048). No significant differences occurred between races for treatment with surgery, chemo & endocrine therapy, however radiation was more common in non-AAs (73.4% vs. 62.2% AAs; p=0.012) but AAs were significantly older (p=0.0001) and had more comorbid disease (p=0.0001). See Table for prevalence of aggressive tumor features. Age-adjusted logistic-regression showed no racial predilection for negative ER/PR, high grade and higher stage, but AAs were less likely to be HER2+ (OR=0.644; 95% CI=0.415–1.00; p=0.05). Log-rank tests showed no differences between racial groups for age & stage-specific disease-free & overall survival. Conclusions: These results confirm that among similar low SES women with breast cancer, there is no racial predilection for aggressive tumor phenotype and poor prognosis.

[Table: see text]

No significant financial relationships to disclose.
Polymorphisms in angiogenesis related genes predict clinical outcome in patients (pts) with metastatic colorectal cancer (mCRC) treated with first line 5-FU or capecitabine in combination with oxaliplatin and bevacizumab (FOLFOX/BV or XELOX/BV)
Authors: Shaye O. S. , Chang H. M. , Yang D. Y. , Shriki J. , Schultheis A. M. , Zhang W. , Lurje G. , Iqbal S. , Lenz H. J. , El- Khoueiry A. B.
Published: March 2020

10576

Background: The inhibition of angiogenesis is central to the mechanism of action of BV, a monoclonal antibody to vascular endothelial growth factor (VEGF). We evaluated functionally significant polymorphisms of genes involved in the angiogenesis/VEGF pathway as potential molecular predictors of clinical outcome in pts with mCRC who received BV as part of their frontline therapy. These genes included: VEGF, VEGF receptor 2 (KDR), neuropilin 1 (NRP 1), Interleukin (IL) 6 and 8, IL receptor 1 and 2 (CXCR 1, CXCR 2) adrenomedullin (AM), leptin, fibroblast growth factor receptor 4 (FGFR4), tissue factor (TF), matrix metalloproteinases (MMP 2,7,9), epidermal growth factor receptor (EGFR), aryl hydrocarbon receptor nuclear translocator (ARNT), and nuclear factor kappa b (NFkb). Methods: PCR-RFLP assays were performed on genomic DNA extracted from the blood of 30 pts with mCRC treated with first-line FOLFOX/BV or XELOX/BV at USC. Results: the cohort consisted of 21 males and 9 females with a median age of 56 years (range: 29–81). 20 pts received XELOX/BV as part of an on-going phase II study, 10 pts received FOLFOX/BV. Radiologic response was evaluable in 27/30 pts: 2/27 (7%) complete response (CR), 14/27 (52%) partial response (PR), and 10/27 (37%) stable disease (SD) and 1/28 (4%) progressive disease. At a median follow-up of 19.4 months, 16/30 pts progressed with a median progression free survival (PFS) of 11.8 months. Pts homozygous A/A at the leptin 5'UTR region had a higher probability of response than pts with the G/A or G/G genotypes (p=0.03, Fisher's exact test). Pts with one or more G allele (G/G or A/G) at locus -181 in the promoter region of MMP7 had a higher probability of response than pts with the AA genotype (p=0.014, Fisher's exact test). There were statistically significant associations between genomic polymorphisms of KDR, CXCR2, MMP7 and PFS (<0.05, Log-rank test). Conclusions: This pilot study demonstrated, in a preliminary fashion, the potential predictive and prognostic value of several genomic polymorphisms in pts with mCRC treated with FOLFOX/BV or XELOX/BV.

No significant financial relationships to disclose.
Biological mechanisms that trigger breast cancer (BC) tumor progression are molecular subtype dependent
Authors: Sotiriou C. , Desmedt C. , Haibe-Kains B. , Harris A. , Larsimont D. , Buyse M. , Wirapati P. , Delorenzi M. , Bontempi G. , Piccart M.
Published: March 2020

10581

Background: We have recently developed several gene expression indices related to hallmarks of breast cancer involving various biological processes such as tumor invasion, impairment of immune response, sustained angiogenesis, evasion of apoptosis and self- sufficiency in growth signal, and investigated their impact on clinical outcome. Here, we aim to refine our biological understanding and the prognostic impact of these indices according to the previously described molecular subtypes based on the estrogen (ER) and ERBB2 receptors. Methods: Each of these indices were developed in a series of 581 BC samples and then computed on several publicly available microarray studies totaling over 2100 BC patients. Multivariate analyses were used to study the dependency patterns between these indices, the molecular subtypes and their impact on survival. Results: ER-/ERBB2- and ERBB2+ subgroups were significantly associated with high expression levels of the proliferation, tumor invasion, angiogenesis and immune response indices. Multivariate analysis showed that in the ER+/ERBB2- subgroup, only tumor size and the proliferation and tumor invasion indices were significantly associated with clinical outcome, with the proliferation index having the largest HR and most significant p-value (HR 3.25; CI 2.31–4.56; p=1.2 10-11). In contrast, in the ER-/ERBB2- subgroup, only tumor size (HR 2.08; CI 1.14–3.81; p=0.01) and immune response index (HR 0.66; CI 0.46–0.95; p=0.02) were associated with prognosis whereas in the ERBB2+ tumors only nodal status (HR 3.40; CI 0.96–12.10; p=0.05) and tumor invasion index (HR 3.03; CI 1.32–6.95; p=0.009) showed significant association with survival. Of interest, proliferation index lost its significance as almost all ER- /ERBB2- and ERBB2 + tumors showed high proliferation levels. Conclusions: Although proliferation seems to be the strongest parameter predicting clinical outcome in ER+/ERBB2- subtype, immune response and tumor invasion appear to be the main molecular mechanisms associated with prognosis in the ER-/ERBB2- and ERBB2+ subgroups respectively. Defining these clinico-genomic models in the specific molecular subgroups will be the key to success for personalized medicine.

No significant financial relationships to disclose.
Activation of the PI3K/AKT signal transduction pathway is inversely associated with estrogen receptor levels and correlates with survival in hormone receptor-positive Her2/neu-negative breast cancer
Authors: Gonzalez-Angulo A. M. , Hennessy B. T. , Meric-Bernstam F. , Lu Y. , Symmans W. F. , Hortobagyi G. N. , Mills G. B.
Published: March 2020

10588

Background: Hormone receptor-positive is the most common subtype of breast cancer. Despite the successes of antihormone therapy alone or combined with chemotherapy, a significant proportion of patients (30–40%) will have primary or acquired resistance to this treatment. There is a need to identify molecular markers to distinguish patients unlikely to benefit from therapy as well as novel targeted therapeutics that increase the response rate. Methods: We used a novel functional proteomics technology, reverse phase protein array (RPPA), to quantify expression and activation of 42 steroid and kinase signaling proteins in 64 hormone receptor-positive-Her2/neu-negative breast cancers from patients with stage I to III tumors managed with non-steroidal aromatase inhibitors ± chemotherapy. Unsupervised clustering analysis was used to molecularly group the tumors. Recurrence-free survival (RFS) was estimated with the Kaplan Meier product limit method and comparison was made using the Log-rank test. Correlation coefficients were used to look at the relationships between two variables. Results: Median age was 57 years (23–79). Sixteen patients (25%) had stage I tumors, 32 (50%) had stage II tumors and 16 (25%) had stage III tumors. There were two well-defined and distinct clusters of tumors: Group 1: ER high (n=25) and Group 2: PI3K/AKT activated (n=39). 3-year RFS estimates were 100% for group 1 and 59% for group 2 (p=0.04). There were thus clear inverse correlations between markers of activation of PI3K pathway and expression of ER (R for pAKT vs ER = -0.26, p=0.03). PIK3CA mutation was detected in 12/58 (21%) of hormone receptor-positive breast cancers and these tumors were found to have a proteomic signature distinct from PTEN loss with the former signature associated with a trend to improved RFS (p=0.06). Conclusion: Activation of the PI3K/AKT pathway in hormone receptor- positive-Her2/neu-negative breast cancer is inversely correlated with ER levels and associated with adverse outcome. At least in some cases, PI3K/AKT pathway activation, may be under the control of genomic aberrations. A validation set of 100 tumors treated with tamoxifen is on- going.

No significant financial relationships to disclose.
β-catenin interacts with heat shock protein Hsp27 and heat shock transcription factor 1 and it is a useful prognostic marker in breast cancer patients
Authors: Gago F. E. , Fanelli M. A. , Montt-Guevara M. M. , Diblasi A. M. , Tello O. , Cuello-Carrión F. D. , Callegari E. , Ciocca D. R.
Published: March 2020

10593

Background: We examined in breast cancer the possible interactions between heat shock proteins (Hsps) and the cadherin- catenin cell adhesion proteins, which have important roles in signaling pathways and tumor cell invasion. The cadherin-catenin proteins, like Hsps, have the capacity to bind other proteins. Moreover, there are common molecular pathways for the Hsp response and for the cadherin- catenin protein system. Methods: β-catenin was immunoprecipitated from breast cancer biopsies and the resulting product was probed with antibodies against Hsp members. LC-ESI-MSMS analysis was performed. Immunohistochemistry was used on paraffin sections. Statistical analyses were performed (Prism computer program): Kaplan-Meier, difference between curves evaluated with the log-rank test for censored survival or event observations, contingency tables analyzed by the Fisher`s exact test and Chi-square. Results: β- catenin interacted with Hsp27 and HSF1 (heat shock transcription factor 1), this is the first demonstration of these specific interactions, β- catenin did not interact with Hsp60, Hsp70, Hsp90, gp96 and CHOP. To confirm this finding, the 27 kDa band was excised and submitted to LC- ESI-MSMS, the band was identified as Hsp27. In addition, β-catenin interacted with P-cadherin and caveolin-1. In the co-localization studies, β- catenin was observed in the same tumor areas and cells that expressed Hsp27. This association was strong when β-catenin was expressed in the cytoplasm, not when β-catenin was expressed at the cell membrane. In addition, β-catenin co-localized with HSF1. Finally, the prognostic significance of cadherin-catenin proteins was examined in breast cancer patients (n=215, follow-up: >10 years). Conclusions: We found that cytoplasmic β-catenin interacted with Hsp27 and HSF1, and that the survival (disease free and overall) was significantly shorter for patients with P-cadherin + and cytoplasmic β-catenin + tumors. The interactions of β-catenin with Hsp27 and with HSF1 may explain some of the molecular pathways that influence tumor cell survival and the clinical significance in the prognosis of the breast cancer patients.

No significant financial relationships to disclose.
Increased expression levels of human telomerase reverse transcriptase (hTERT) mRNA correlates with poor prognosis in resected non-small cell lung cancer (NSCLC) patients
Authors: Carrera S. , López-Vivanco G. , Calvo B. , Aresti U. , Jangi M. S. , Ferreiro J. , Martínez-Bueno A. , Rubio I. , Muñoz A. , Ancizar N.
Published: March 2020

10594

Background: Telomerase adds hexameric TTAGGG nucleotide repeats onto the ends of chromosomal DNAs to compensate for losses of each cell replication. In several tumors, telomerase is expressed in a way that tumoral cell proliferates indefinitely. Correlation between telomerase level expression, clinico-pathological characteristics and survival of lung cancer is not well established in NSCLC. Methods: We studied 149 consecutive patients (140 men/9 women) with resected NSCLC: 37.6% adenocarcinoma, 59 % squamous cell, and 3.4% large cell carcinoma. Pathological stage: I (36.9%), II (32.3%) and III (30.8%). Reverse transcription-polymerase chain reaction (RT-PCR) analysis was used for the detection hTERT expression in lung cancer tissues immediately snap-frozen in liquid nitrogen at -80 °C. Results: Median and mean values of hTERT mRNA were 18.27 and 475.29 (SE 309.76). There were no significant differences on expression according to sex, histology, smoking history and pathological stage (ANOVA). Patients with highest values of hTERT mRNA expression (percentile 95, cut-off value >353) had worse median progression free survival (PFS) (p=0.024) and overall survival (OS) (p=0.020), using Kaplan-Meier method. Multivariate analysis by Cox regression yielded that hTERT level > 353 independently predicted a worse PFS (HR=0.39; 95% CI 0.17–0.93, p=0.034) and OS (HR=0.32; 95% CI 0.12–0.82, p=0.017). Conclusions: A high level of telomerase expression in tumoral tissue is strongly associated with increased risk of recurrence and mortality in resected NSCLC. The level of hTERT mRNA would predict the prognosis of lung cancer patients.

No significant financial relationships to disclose.
Subgroup analysis of GEICAM 9906 trial comparing six cycles of FE90C (FEC) to four cycles of FE90C followed by 8 weekly paclitaxel administrations (FECP): Relevance of HER2 and hormonal status (HR)
Authors: Rodríguez-Lescure Á. , Martín M. , Ruiz A. , Alba E. , Calvo L. , García-Asenjo J. L. , Guitian M. , de la Cruz A. , Aranda I. , de Álava E.
Published: March 2020

10598

Background: GEICAM 9906 interim analysis showed FECP improved disease-free survival (DFS) compared to FEC (SABCS 2005, abstract #39). As a secondary objective, predictive markers were centrally determined and DFS of subgroups analyzed. A prior report from CALGB 9344 trial suggested that patients (pt) with HER2+ tumors get the maximum benefit with adjuvant P (ASCO 2006, abstract #510). We aimed to confirm this finding in our dataset. Methods: 1248 node + pt received 6 q3wk cycles (cy) of FEC (600/90/600 mg/m2) or 4 cy of same FEC followed by 8 wk cy of P (100 mg/m2). Tumor paraffin-embedded blocks were prospectively collected from 889 pt (71%) for Tissue Microarrays. Statistical analysis used Kaplan-Meier estimates for DFS by treatment group at a median follow-up (FU) of 65 months (m). HER2 status was evaluated by FISH. HR status was determined by IHC, following Allred criteria. Results: At a median of 65 m FU, DFS for FECP remains better than FEC (79% vs. 72%; p=0.0042; HR= 0.71). HER2: DFS for HER2+ and HER2- pt were 66% vs. 78% (p=0.0008; HR= 0.60). HER2+ subgroup (n=177): DFS with FECP and FEC were 63% vs. 70% [p=0.5187, HR=1.18 (0.71–1.98)]. HER2- subgroup (n=712): FECP was significantly better than FEC [82% vs. 74%, p=0.0075; HR=0.65 (0.48–0.89)]. HR: DFS for HR+ and HR- pt were 80% vs. 68% (p<0.0001; HR= 0.52). HR+ subgroup (n=561): DFS with FECP and FEC were 82% vs. 79%, [p=0.2162; HR=0.79 (0.54–1.15)]. HR- subgroup (n=311): DFS was 72% vs. 65% [p=0.1633, HR=0.76 (0.51–1.12)]. DFS data in the four HER2/HR subgroups is summarized in the table . Conclusions: FECP is superior to FEC mostly in HER2-HR- (triple negative) tumors. Our subgroup analysis does not support the superiority of the paclitaxel-containing arm (FECP) in pt with HER2 positive tumors.

[Table: see text]

[Table: see text]
Superior survival of breast cancer BRCA1 /2 mutation carriers harboringG/G at the -309 position at the MDM2 promoter compared to those harboring T/T or G/T at this SNP
Authors: Nechushtan H. , Hamburger T. , Mendelson S. , Kadouri L. , Sharon N. , Pikarsky E. , Peretz T.
Published: March 2020

10600

Background: A germ line single polymorphism in the promoter of the gene encoding the important modulator of P53, MDM2 has been described. The findings of G/G nucleotides at this position in contrast to G/Tor T/T were demonstrated to increase MDM2 transcriptional levels and were correlated with younger onset of cancers in patients with the Li-Fraumeni syndrome. Furhtermore gastric cancer patients harboring T/T at this position and treated with chemotherapy were found to have decresed survival compared to the other SNP carriers. P53 mutations appear in high frequency in tumors associated with BRCA1/2 mutations. Indeed it has been suggested that mutations in the p53 gene are a necessary step in tumorigenesis in BRCA tumors. Methods: Here we investigate the effect of the MDM2 SNP309 on overall survival and age of onset in breast cancer patients. MDM2 SNP309 was evaluated in Breast cancer Ashkenazy patients analyzed for the three common mutations in BRCA1/2- 180 patients who are positive for either of these mutation and 272 negative ones. 194 negative, Disease onset age and survival were analyzed for the different subgroups Results: Around a quarter of the whole population analyzed were identified as carriers of G/G at the -309 MDM2. There was no correlation between age of disease onset in either BRCA1/2mutation carriers and the specific genotype. In the BRCA1/2 mutation carriers we found a survival advantage in patients harboring the SNP309 G/G genotype(p-0.001 log rank test). Such an effect was not demonstrated in patients tested negative for the known Ashkenazy mutations Conclusions: In specific subgroups of breast cancer patients SNP309 G/G is associated with improved patient survival. A possible explanation for this finding could be the presence of a P53 which can be reactivated in the MDM2 SNP309 G/G carriers.

No significant financial relationships to disclose.
Fulvestrant in the treatment of HER2-positive advanced breast cancer (ABC)
Authors: Robertson J. F. , Steger G. G. , Neven P. , Barni S.
Published: March 2020

1061

Background: Patients with HER2-positive (HER2+) disease are regarded as less responsive to endocrine therapy, although there are data to suggest activity in some patients. Fulvestrant is a novel estrogen receptor (ER) antagonist with no agonist effects, and is licensed for the treatment of postmenopausal women with ABC after progression on prior endocrine therapy. Here we pool clinical experience data from HER2+ patients who received fulvestrant. Methods: Postmenopausal women with HER2+ disease were treated with fulvestrant 250 mg/month IM until progression/other reason for discontinuation. Clinical response was assessed monthly using RECIST or UICC criteria, or the clinical judgment of the physician. Clinical benefit (CB) was defined as the proportion of patients experiencing a response (complete or partial response [PR]) or stable disease (SD) lasting =6 months. Results: Fifty-three patients with HER2+ ABC and a median age of 61 years (range 30–85 years) received fulvestrant. Patients received a median of two prior endocrine therapies (range 0–3) and one chemotherapy (range 0–5) for ABC. ER and/or progesterone receptor (PgR) status was assessed in 52 patients. Twenty-two patients experienced CB (4 PR and 18 SD =6 months) with fulvestrant, giving a CB rate of 41.5% (n=53), with activity observed up to 4th-line endocrine therapy. CB rate was 47.8% amongst ER+/PgR+ patients (n=23) and 45.0% amongst ER+/PgR- patients (n=20). Sixteen adverse events (AEs) were reported (30.2%), with one considered severe (restlessness). No patients discontinued due to AEs. Conclusions: From these data, fulvestrant appears to demonstrate activity in patients with HER2+ ABC. Observed activity was independent of PgR status and is consistent with fulvestrant efficacy demonstrated in the overall ABC population. These are encouraging data, warranting further exploration of the use of fulvestrant in HER2+ disease.

No significant financial relationships to disclose.
Clodronate compared to ibandronate breast cancer bone metastases patient preference study
Authors: Jagdev S. , Berry H. , Newsham A. , Smith A. , Flanagan L. , Perren T. , Dodwell D. , Velikova G.
Published: March 2020

1068

Background: The use of bisphosphonates for patients with breast cancer bone metastases confers significant benefits. Prolonged IV bisphosphonate use burdens both patients and services and oral clodronate is often used. Ibandronate is a potent oral third generation bisphosphonate which is effective and well tolerated in patients with metastastic breast cancer. In Phase III studies, the incidence of adverse events for oral ibandronate was similar to placebo. Clodronate requires prolonged fasting and size of tablets and gastric irritation may be problematic, therefore ibandronate may provide advantages. The aim of this study was to investigate patients’ preferences between oral ibandronate and oral clodronate and to assess the reasons for preference. Methods: This randomised, open-label, cross-over study recruited 46 women with breast cancer bone metastases who were starting or established on IV bisphosphonates. Patients were randomised to receive one drug for two months then crossed over to the second for two months. 23 patients received ibandronate then clodronate and 23 received clodronate first. Patients completed questionnaires on pain and symptoms at baseline, at crossover and on completion of the study. Patient preferences were assessed at the end of the study. Results: Data on 41 patients were available for preference assessment in this initial analysis. 5 patients discontinued the study. 26/41 patients preferred ibandronate (63.4%) and 14/41 preferred clodronate (34.5%) (c2=3.10, p=0.078). 1 patient did not state a preference. Significantly more patients receiving ibandronate first preferred ibandronate (13/18), compared with those receiving clodronate first expressing a preference for clodronate (10/23) (c2 =6.44, p= 0.011). Tablet size (p=0.001) and number (p<0.001) scored highly as reasons for preference for ibandronate. The following toxicities were reported on ibandronate and clodronate respectively: nausea (17%, 9.7%), indigestion (9.7%, 4.8%) and pain flare (7.3%, 4.8%). Conclusions: Significantly more patients preferred oral ibandronate compared with oral clodronate, with size and number of tablets being important reasons for preference.

No significant financial relationships to disclose.
Dental care and tooth extraction as a risk factor for developing osteonecrosis of the jaw after long-term bisphosphonate therapy in patients with metastatic breast cancer
Authors: Spadaro P. , Pitini V. , Altavilla G. , Ingemi M. , Dottore G.
Published: March 2020

1076

Background: Association between osteonecrosis of the jaw (ONJ) and bisphosphonate treatment in patients (pts.)with Multiple Myeloma, breast cancer and prostate cancer has been increasingly reported in the literature. Risk factor for this complication include presence of infection, recent dental extraction and any oral surgical procedure with bone exposure. Methods: This is a retrospective review of our experience with patients diagnosed with bone metastasis secondary to breast cancer, who developed ONJ while treated with bisphosphonates, between January 2002 and December 2006. Presentation, age, dental status, and outcome were reviewed. Logistic Regression was used to test for statistical significance. Results: 100 pts. with bone metastasis secondary to breast cancer, median age 63 years, treated with bisphosphonates were reviewed. ONJ developed in 5 (5%) pts. Age did not impact occurrence of ONJ. All 5 patients developed ONJ after a minimum of 100mg of Zoledronic Acid and 2700mg of Pamidronate. All pts. had a history of previous tooth extraction and inadequate dental care. Three pts. were treated with debridement and antibiotics and their lesions healed. Two pts. ended up suffering from a chronically exposed bone. Conclusions: ONJ is a serious complication of bisphosphonate therapy and it affected a significant proportion of our patients. Our data suggests a strong association between dental care, tooth extraction, and the development of ONJ.

No significant financial relationships to disclose.
Gemcitabine and cisplatin in metastatic breast cancer
Authors: Moura G. L. , Pasquini R. , Frare A. , Vianna K. , Albini L. , Padilha S.
Published: March 2020

1084

Background: Gemcitabine plus cisplatin have synergistic activity and have been tested in several schedules and doses in metastatic breast cancer. Our objectives were to assesss the efficacy and toxicity of gemcitabine and cisplatin in pretreated patients. Methods: Measurable disease and at least two prior anthracycline and /or taxane-containing regimen in either metastatic or adjuvant setting was required. Treatment consisted of gemcitabine 700mg/m(2) IV infusion over 30 min plus cisplatin 30mg(2) given on day1 and 8 every 3 weeks. Results: Seventy four patients with median age of 48 years (range 26- 73) were recruited. A median of six cycles of the study treatment was delivered. The overal response rate was 30% (95% confidence interval, 12–53%). Median time to progreesion was 30.6 weeks (95%CI, 12.6–44 weeks). Median survival was 73.2 weeks (95% CI, 47.1–93.2 weeks). Toxicities included grade 3 and 4 leukopenia in 27(36.4%), anemia in 19 (25.6%) and oral mucositis in 4 (5.4%). No grade 3 or 4 peripheral neurophaty, hepatic or renal dysfunction was observed. No treatment-related death ocurred. Conclusions: Gemcitabine plus cisplatin is a well tollerated and active treatment in heavily pretreated patients with metastatic breast cancer.

No significant financial relationships to disclose.
Lipid lowering effect of fulvestrant in hormone-sensitive metastatic breast cancer patients
Authors: Camerini A. , Amoroso D. , Garrone O. , Vincenti M. , Tartarelli G. , Donati S. , Valsuani C. , Siclari O. , Mattiot V. Polla , Sgambato A.
Published: March 2020

1085

Background: Fulvestrant (F) is a pure anti-estrogen agent available for the HT of post-menopausal ormone-sensitive advanced breast cancer (ABC). Aim of the study is to analyze the effect(s) of F treatment on lipid profile, endometrial mucosa and coagulation indices (CI). Methods: 24 pts (mean age 66.2 ± 9.5 yrs) with hormone-sensitive ABC were enrolled. All patients (data on 21 pts) received at least one previous HT course, with 90.5% receiving =2 HT courses. Last HT was exemestane in 13/21, letrozole in 5/21 and other in 3/21 with a median withdrawal time of 19 days (range 3–1,456). All pts but one received at least one previous CT regimen, with 60% receiving =2 CT regimens. Complete fasting lipid blood profile and CI were assessed before F administration, every 3 months and at discontinuation. Endometrial mucosa thickness was evaluated before F administration and at end-study time. All patients referred no significant dietary changes during treatment. Pts receiving statins were excluded. Results: pts received a median of 6 F injections (range 3–14). We observed SD in 10/21 pts and PD in 11/21 pts with a mean TTP of 6.2 ± 2.9 months. Total cholesterol (C) levels significantly decreased during F treatment (214.1 ± 48.7 vs 194.0 ± 41.0 mg/dl; p=0.0084) together with LDL-C (119.5 ± 40.7 vs 104.2 ± 30.4 mg/dl; p=0.0067). HDL-C (62.4 ± 17.8 vs 64.3 ± 19.5 mg/dl; p = ns) and triglycerides (152.4 ± 64.5 vs 148.2 ± 61.6 mg/dl; p=ns) did not show significant changes. Subgroup analysis demonstrated a reduction in both pts receiving = 6 (n=17) or >6 (n=11) injections (204.6 ± 45.3 vs 186.6 ± 41.2 mg/dl, p=0.014 and 219.5 ± 48.9 vs 203.9 ± 33.3 mg/dl, p=ns respectively). All CI and mean endometrial mucosa thickness value did not vary. Conclusions: We observed a clear lipid lowering effect of F in our study population. We suggest a possible effect of F on lipid metabolism. Lipid lowering effect of F it’s evident during the first six months of treatment lasting in pts continuing therapy.

No significant financial relationships to disclose.
Efficacy of i.v. and oral ibandronate in bone metastases breast cancer patients and some clinical aspects of bisphosphonates studies: Clinical experience of one trial center
Authors: Lichinitser M. , Semenov N. N.
Published: March 2020

1096

Background: Ibandronate is the only bisphosphonate that has both i.v. and oral formulation. Previously similar effectiveness of 6 mg i.v. and 50 mg oral Ibandronate compared with placebo in breast cancer metastatic bone disease was demonstrated. Methods: Due to similar inc/excl criteria in both (MF 4265 and MF4414–34) trials, we directly compare frequency of pathological fractures, hypercalcemia and osteolisys markers dynamics for patients, who received ibandronate 6 mg i.v. monthly or 50 mg per os daily (n=58) with placebo (n=53) during 2 years. Results: The frequency of pathological fractures (PF) and hypercalcemia (HC) is strongly depending on the efficacy of antitumor treatment: in periods of progression PF were 42%, in periods without progression only 6,8%, p<0.0001. Ibandronate decrease frequency of PF and HC, as acute bone pain and narcotics requirement in progression periods. Hypercalcemia was observed in progression periods only. Ibandronate effectively suppressed osteolysis in periods of disease progression: level of dPyr decreased by 3% and CTx by 60%, while in placebo group dPyr increased by 25% and CTx by 58%. Conclusions: Ibandronate is effective in periods of disease progression. Development of new clinical research methodology of bisphosphonate trials is thus actual.

No significant financial relationships to disclose.
Dose-dense docetaxel, carboplatinum and trastuzumab (ddTCH) as neoadjuvant therapy for human epidermal receptor 2 (HER2) positive breast cancer
Authors: Han H. S. , Doliny P. , Blaya M. , Gluck S. , Slingerland J. , Silva O. , Welsh C. , Hurley J.
Published: March 2020

11003

Background: Docetaxel, cisplatin, and trastuzumab given every 21 days in Her 2-postitive breast cancer demonstrates a pathologic complete response (pCR) rate of 23%. Decreasing the interval between doses of chemotherapy has lead to improvement in survival in the adjuvant setting. In one study dose dense chemotherapy improved response only in patients whose tumors overexpressed her-2. We conducted a phase II trial to evaluate the efficacy and safety of neoadjuvant dose-dense TCH for HER 2-positive breast cancer. Methods: Patients with T2–4 N0–3 M0 HER-2 positive (by FISH) breast cancers were eligible. Neoadjuvant therapy consisted of carboplatinum (AUC 6) Day 1,15,29,43, docetaxel (75mg/m2) Day 1,15,29, 43 and weekly trastuzumab for 10 weeks 4mg/kg Day 1 then 2mg/kg Day 8,15,22,29,36,43,50,57,64, Pegfilgastrim Day 2,16,30,44. The primary end point was the rate of pCR. Results: Twenty patients are evaluable for response. The median age was 51.5 years (range 29–73). Mean tumor size was 5.6 cm. Patients had stage IIA (30%), IIB (15%), IIIA (45%), IIIB (5%), and IIIC (5%). Estrogen receptors were positive in 36% of tumors. No grade 4 or 5 toxicity occurred. The most frequent toxicity was hand-foot syndrome (Grade I 15%, Grade II 10%, Grade III 15%). Neutropenia occurred in 5 patients (Grade II 10%, Grade III 15%) There were no episodes of febrile neutropenia or hospitalizations. Grade I cardiotoxicity was seen in 30%. The rate of pCR was 40% in the breast and 35% in both breast and axilla. 16/20 patients (80%) had pathologically negative lymph nodes. Conclusions: Changing the scheduling of TCH from every 21 days to every 14 days improves the pCR rate from 23 to 40%. The regimen was well tolerated.

No significant financial relationships to disclose.
Evaluation of the tumor marker Ca27.29 for risk stratification and treatment monitoring in primary breast cancer
Authors: Genss E. M. , Rack B. , Sommer H. L. , Schrader I. , Lorenz R. , Tesch H. , Söling U. , Noeding S. , Beckmann M. W. , Lichtenegger W.
Published: March 2020

11005

Background: Several trials have shown an earlier detection of metast. disease in breast cancer pts by the use of TU- markers. Whether this lead time advantage can be translated into improved outcome is discussed controversially. We prospectively evaluated the role of Ca27.29 in breast cancer pts at primary diagnosis and during adjuvant systemic treatment within the German SUCCESS-Trial (n=3658 pts planned). Methods: The SUCCESS-Trial compares sequential chemotherapy with FEC-Docetaxel(Doc) vs. FEC- DocGemcitabine, followed by zoledronate 2 vs. 5 years in primary high risk N0 and N+ breast cancer pts. Ca27.29 levels were assessed using the specific ST AIA-PACK Ca27.29 reagents directed against MUC-1 for AIA-600II (Tosoh Bioscience, Tessenderlo, Belgium). Cut-off levels for the assay was 24 U/ml. Results: We analyzed 1098 breast cancer pts prospectively before start and after completion of chemotherapy. 21% of pts (n=226; median 17U/ml; range 4–410) had tumor marker elevation = 24 U/ml before and 48% (n=524; median 23U/ml; range 4–198) after completion of chemotherapy. Ca27.29 levels before and after chemo correl. significantly (p<.001). Of those pts who presented with elevated values initially, 14% remained positive, while 84% had normal Ca27.29 after chemo. Those pts with initially negative blood sampling, returned with high Ca27.29 in 38% and normal values in 62% of cases. While Ca27.29 was well balanced between the two treatment arms at primary diagnosis with a rate of 10% with elevated Ca27.29 in each arm, significantly more pts showed high Ca27.29 with FEC-DocGemcitabine compared to FEC-Doc (27% vs. 21%, p<.001). Ca27.29 elevation did not correl. with most conventional prognostic factors such as tumor size (p=.23), histopath. grading (p=.98) or HR-status (p=.46). However, we found a significant correlation of Ca 27.29 with the presence of lymph node metastases (p=.01) and Her2/neu-over-expression of the primary tumor (p=.04). Conclusions: Measurement Ca27.29 in peripheral blood of primary breast cancer is feasible and reproducible. Whether it can be used for risk stratification leading to more tailored treatment approaches and for the monitoring of treatment efficacy in individual pts will show further follow-up of the SUCCESS-Study.

No significant financial relationships to disclose.
A prospective study of the impact of the 21-gene recurrence score assay on treatment decisions in N-, ER+ early stage breast cancer patients
Authors: Ben-Baruch N. , Hammerman A. , Klang S. , Liebermann N.
Published: March 2020

11008

Background: The Oncotype DX™ Recurrence Score (RS) assay predicts distant recurrence risk and benefit of chemotherapy (CT) in N-, ER+ breast cancer patients (pts). In February 2006, Clalit Health Services in Israel (CHS) was the first public health insurer to reimburse the assay outside the USA. Methods: CHS requires a pre-authorization form with data on biological parameters and specification of treatment (Rx) recommendation (1) before knowledge of RS and (2) the Rx planned according to each of 3 possible RS risk levels. For the first 200 reimbursed assays, we compared: (1) the Rx offered without RS knowledge, (2) the Rx the patient actually received after RS, and (3) the planned Rx stated on the form to be given according to the RS. Results: 200 pts. Median age: 57 yrs (34–81). RS: Low risk (RS<18), 37.5%; Intermediate (int) risk (RS 18–30), 44.5%; High risk (RS≥31), 18%. In 20 pts, Rx recommendations before RS were not specified. Before the RS, CT was offered in 106/180 (59%) and hormonal therapy (HT) in 74/180 (41%). In 71/180 pts (39%) the actual Rx changed from the recommendation before RS - CT to HT in 62 pts (low risk: 37, int risk: 21, high risk: 4) and HT to CT in 9 pts (int risk: 4, high risk: 5). Suggested therapy by RS was not specified in 19 pts. In 30/181 (17%) actual Rx differed from planned - CT to HT in 20 pts (int risk: 17, high risk: 3) and HT to CT in 10 pts (low risk: 4, int risk: 6). Conclusions: RS changed the treatment decision in a significant proportion of pts (39%), mostly from CT to HT. In 58% of pts originally offered CT, knowledge of RS changed the Rx to HT. 12% of pts originally offered HT were treated with CT. Rx decisions in intermediate RS are sometimes not obvious. In 26% of intermediate RS, final Rx differed from original plan; in these cases, patients’ preferences might have had a major impact on decision making.

No significant financial relationships to disclose.
Sensitivity of surveillance mammography for contralateral breast cancers and ipsilateral recurrences in survivors under 50
Authors: Weinstock C. , Bigenwald R. , Narod S. , Sun P. , Hochman T. , Warner E.
Published: March 2020

11009

Background: Annual mammography is currently the gold standard for surveillance of breast cancer survivors for both ipsilateral recurrence and contralateral new primaries. The risk of either of these events occurring has been found to be inversely proportional to age and is at least 1% per year if breast cancer was diagnosed before age 50. (Chen et al 1999) (Komoike et al 2006). However, the sensitivity of screening mammography is significantly lower in young women. We therefore sought to determine the effectiveness of surveillance mammography according to age of diagnosis using a prospective database. Methods: The Henrietta Banting Database prospectively follows all new cases of operable breast cancer diagnosed from 1987 - 2004 at Women’s College Hospital. From the 1992 women in the database, we selected all patients diagnosed before age 60 who subsequently developed non-metastatic contralateral cancers (n=71 ) or ipsilateral recurrences (n=11 ). Records were obtainable for 59 of these 82 patients. Results: Method of detection and stage of diagnosis are listed in table below for the 59 patients according to age of diagnosis of second cancers. Overall, mammography was less effective at detecting contralateral and recurrent breast cancers in younger women, detecting only 24% of these cancers in women under 50 compared to 74% in patients 50 and older (Chi-Square, p<0.001). In addition, 77% of patients under 50 whose second cancers were detected by methods other than mammography had negative surveillance mammograms in the 15 months prior to diagnosis. Conclusion: Since mammography detected only 24% of second primary breast cancers/ recurrences in survivors < age 50 and almost one third of all detected cancers were locally advanced, more sensitive imaging modalities such as breast MRI should be considered for surveillance of young survivors.

[Table: see text]

No significant financial relationships to disclose.
3-D irradiated lung and heart volume predictions from 2-D datasets: Value of CT-based treatment planning in postmastectomy tangential beam radiation therapy
Authors: Shankar V. , Haritha C. , Prajapati H. J. , Bhatt R. , Parmar J. , Shanubhogue A.
Published: March 2020

11013

Background: Lung and heart complications in breast cancer treatment are directly related to the irradiated volumes, technique, total radiation dose and type of chemotherapy. 3D dose calcuations allow computation of the DVH’s & a realistic NTCP associated with breast cancer RT. 1) Study aims to evaluate the impact of the 2-D radiographic parameters on the volumetric dose of the lung and heart, for patients undergoing postmastectomy,postchemo radiation therapy. (2)To deduce the analytical equations for the quick estimation of the irradiated volume based on the distances obtained from the digitally reconstructed radiographs. Methods: Between August 2002–2006, 162 postmastectomy patients underwent 5wk course of tangential CW irradiation ± Axillary / SCL radiation to a total dose of 50gy/25#. After adequate immobilization on the CT compatable breast board, CT scans with 1cm slice intervalsof the chest were performed, covering lung apex to lung base. The ipsilateral total lung area and the lung area included within the treatment port were countered on each CT slice.It is multiplied by slice thickness, and then integrated in all CT slices to give volumes.Parameters used to deduce irradited lung volume (n=104) studied from the DRR included Central lung distance-CLD, Maximum perpendicular distance-MPD, Length of the lung-L & Parameters related to heart are measured only in left breast irradiation (n=58) included: Maximum heart distance-MHD, Maximum heart length MHL.Linear regression analysis is applied to test relationship between the percentage of ipsilateral lung volume involved and the CLD / MPD / L and similarly between MHD / MHL and the cardiac volume in irradiation. Results: Predicted irradiated volume for: Right Lung = 4.0118+6.6474(CLD) OR -5.965 + 6.827(MLD) Left Lung = 6.6395(CLD) OR 5.431(MLD) Heart = 7.325(MHD) OR 6.742(CLD) Conclusions: The conclusion of the present study, to the best of our knowledge, is the largest series reported so far in the literature. CLD and MLD deduced from the DRR, are the direct measures of the lung volumes irradiated in tangential breast irradiation ( r2=0.91 & 0.79).While MHD and CLD appear to be direct measure of the irraidiated heart volume (r2=0.98 & 0.91).

No significant financial relationships to disclose.
Pathological characteristics and clinical outcome in triple-negative breast cancer (BC) patients (PTS): Results from the NORA study
Authors: Cazzaniga M. E. , Mustacchi G. , Pronzato P. , Di Costanzo F. , De Matteis A. , Ravaioli A. , Gamucci T. , Brugia M. , Bari M. , Rulli E.
Published: March 2020

11014

Background: Different studies have recently focused the attention on the so-called triple-negative pts, defined as ER-/PR- /HER2-. Although triple-negative tumours have been reported to be more aggressive, there are limited long-term data evaluating outcome as a function of this classification. Methods: NORA is an observational study aimed at investigating treatment modalities and clinical outcome of 3515 patients (pts) with early breast cancer (EBC) treated in 77 Oncological Centres in Italy from to 2000 to 2003, whose overall results have been already published. We now compare pathological characteristics and clinical outcome of pts for whom ER and PR andHER2 tests are negative with remaining pts (OTH). Results: 123 (4.1%) of 2968 evaluable pts resulted triple-negative. Out of these 123, 76 pts (61.7% vs 63.2% of OTH) were treated with conservative surgery (CS). Pathological T stage was T1 in55.3% pts (OTH: 59.6%), 47.9% were pN+ (OTH: 45.3%), 63.2 had G3 tumours (OTH: 34.1%). Chemotherapy alone was administered in 89.4% pts, mainly anthracycline-based (54.1%). At a median follow up of 27 months, all triple-negative pts were alive, 11 (8.9%) with relapse. No difference has been observed between two groups both in DFS (HR=0.74; 95%CI: 0.39–1.40; p=0.35) and OS (HR not estimated, p=0.99). Conclusions: Our results suggest that triple-negative pts have pathological characteristics similar to what observed in the other pts, receive CS in the same percentage of the cases, but have a 3-fold increase of undifferentiated tumours. On the contrary to what observed by other Authors, our data show that triple- negative pts do not have worse prognosis. Longer follow up is required to confirm these data.

No significant financial relationships to disclose.
Meta-analysis of side effects (SEs) of aromatase inhibitors (AI) and of tamoxifen (TAM) in large randomized clinical trials (RCT)
Authors: Vakaet L. A.
Published: March 2020

11015

Background: The published data from large RCTs for the endocrine adjuvant treatment of postmenopausal breast cancer patients (ATAC and BIG 1–98) have shown us the difference in SEs between an AI vs TAM. Observed SEs in these trials are the result of an effect of both drugs: e.g. AIs induce bone loss and lead to an increase in fracture risk whereas TAM reduces fracture risk. We did a meta- analysis of comparable SEs in ATAC and BIG and combined this information with a second meta-analysis comparing an AI vs nil and a third meta-analysis comparing TAM vs nil. Methods: A relative risk (RR) meta-analysis was done on published data of SEs comparing AI vs TAM (ATAC Lancet 2002; BIG 1–98 NEJM 2005). SEs studied were: (1) fracture risk; (2) ischemic cerebrovascular events; (3) hypercholesterolemia; (4) hot flushes; (5) venous thromboembolic events and (6) any musculoskeletal events. Data for the comparison of AI vs nil were taken from MA.17 (NEJM 2003) and the combined arm of ATAC (Lancet 2002). Data for the comparison of TAM vs nil were taken from the P1 (JNCI 1998) and IBIS 1 (Lancet 2002). The assumption of a fixed effects model was used unless significant heterogeneity (Cochran Q test) was found. Results: In the comparison of fractures (ATAC and BIG combined) there was a 50% increase in RR for fractures in the AI arm. Our second meta-analysis showed that half of this increase was due to an effect of the AI and (according to the third meta- analysis) about half was due to a decrease of the RR for fractures thanks to TAM. Significant differences in cerebrovascular, hypercholesterolemia and hot flushes related events were due to a TAM effect. Concerning musculoskeletal events, significant heterogeneity was found when comparing the effect of an AI in the presence or absence of TAM. When patients get TAM together with an AI (ATAC combined arm) there is no increase in musculoskeletal events compared to the TAM alone arm. When an AI was compared to nil (MA.17) a significant increase in events was observed. We hypothesize that this heterogeneity is due to an estrogenic effect of TAM. Conclusion: This RR analysis allowed us to dissect the SEs profile of an AI and of TAM. The results for musculoskeletal events generate a new biological hypothesis.

No significant financial relationships to disclose.