bluuebunny/crossref_metadata_2025 huggingface dataset:
Breast cancer risks in individuals testing negative for known family mutations in BRCA1 or BRCA2
Authors: Domchek S. M. , Gaudet M. M. , Stopfer J. E. , Kemel Y. , Powers J. , Balistreri L. , Tigges-Cardwell J. , Nathanson K. L. , Offit K. , Robson M. E.
Published: August 2020

11044

Background: Genetic testing for BRCA1 and BRCA2 mutations in individuals from families with known deleterious mutations can identify both those at high risk of disease and those who are not. Recent studies have raised concern that women who test negative for mutations previously identified in their families (“true negatives,” TN), may nonetheless have a higher incidence of breast cancer than women in the general population. To evaluate this question, we have examined a prospectively followed cohort of TN to assess their risk of breast cancer. Methods: The women included were first and second degree relatives of known BRCA1 and BRCA2 mutation carriers, had undergone genetic testing and were negative for the known familial mutation, and were unaffected at the time of genetic testing. Standardized incidence ratios (SIR) and 95% confidence intervals (CI) were calculated using SEER incidence rates from 1992–2005. Results: Among 375 TN women followed for a mean of 4.9 years (total 1,962 person-years), 2 invasive and 2 in situ breast cancers were diagnosed. Four invasive breast cancers were expected, whereas 2 were observed, for an age-adjusted SIR of 0.52 (95% confidence interval 0.13–2.09). One case of in situ breast cancer was expected, whereas 2 were observed (SIR=2.30; 95% CI 0.57–9.19). There were no cases of ovarian cancer observed, whereas 0.4 cases were expected. Conclusions: In this prospective study of women who were unaffected at the time of genetic testing and who were negative for a known familial mutation in BRCA1 or BRCA2, no excess risk of invasive breast cancer was observed. Although we cannot exclude a modest increase in risk (RR<2), our data suggest that such women should adhere to population based guidelines for breast cancer screening.

No significant financial relationships to disclose.
Evaluation of tumor-associated lymphocytes as a predictor of response to neoadjuvant chemotherapy in breast cancer: Results from the GeparDuo and GeparTrio trial
Authors: Denkert C. , Loibl S. , Noske A. , Müller B. M. , Kronenwett R. , Budczies J. , von Törne C. , Engels K. , Solbach C. , von Minckwitz G.
Published: August 2020

11054

Background: Preclinical investigations suggest an involvement of the immune system in chemotherapy response; however, this contribution has not been validated in prospective clinical trials so far. Methods: We investigated the inflammatory infiltrate in a total of 1058 pretherapeutic breast cancer core biopsies from two neoadjuvant anthracycline-taxane-based studies. As a training cohort, we used 218 core biopsies from the GeparDuo study. The results were validated in a completely independent cohort of 840 samples from the GeparTrio study. In addition, molecular parameters of lymphocyte recruitment and activation in breast cancer tissue were evaluated by kinetic PCR. Results: While the overall rate of pathological complete response (pCR) in the GeparDuo cohort was 12.8%, it was significantly increased to 42.7% in the tumors with more than 60% intratumoral or stromal lymphocytes. In a multivariate regression analysis, the percentage of intratumoral lymphocytes (iTu-Ly) was an independent significant parameter for pCR (P = 0.013) in the GeparDuo cohort. In the validation set from the GeparTrio trial, the inflammatory infiltrate was a strong predictor of pCR in univariate (P < 0.0005) and multivariate logistic regression (P < 0.0005). For tumors with 60% iTu-Ly the pCR rate was 40% with an odds ratio (OR) of 8.5 (4.0–18.2) which were similar to those values in hormone receptor negative samples (pCR: 36%; OR: 6.0 [4.0–9.1]). The expression of inflammatory marker genes and chemokines related to B and T infiltration in tumor tissue was significantly linked to the presence of a lymphocytic infiltrate and mRNA expression data showed a significant association of T cell markers with a pCR (P < 0.003). Conclusions: An increased lymphocytic inflammatory infiltrate in breast cancer is a new independent predictor of response to anthracyclin-taxane neoadjuvant chemotherapy and might be helpful to identify patients with benefit from cytotoxic chemotherapy.

[Table: see text]
MicroRNA-based assay for differential diagnosis of squamous from non-squamous non-small cell lung carcinoma
Authors: Lebanony D. , Benjamin H. , Gilad S. , Ashkenazi K. , Nonaka D. , Feinmesser M. , Rosenfeld N. , Chajut A. , Cohen D. , Aharonov R.
Published: August 2020

11069

Background: Recent advances in biologically directed therapies for non-small cell lung carcinoma (NSCLC) emphasize the need for more accurate sub-classification of NSCLC, as treatment may be dictated by histologic subtype. In particular, squamous histology can be a counter-indication for treatment by VEGF inhibitors. MicroRNAs are highly tissue-specific biomarkers with potential clinical applicability for defining cancer type and origin. MicroRNAs are well preserved in formalin fixed tissue, making them ideal candidates for molecular markers for use in routinely processed material. Here we report on the development and performance of a microRNA-based assay for the differential diagnosis of squamous from non-squamous NSCLC. Methods: We developed protocols for extraction of high-quality RNA that retain the microRNA fraction from FFPE archival tissue samples. MicroRNA microarrays were used to profile more than a hundred NSCLC samples. Specific microRNA qRT-PCR was used to validate results, and to develop a diagnostic assay. Results: We identified a microRNA biomarker that is strongly overexpressed in squamous cell NSCLC. A diagnostic assay (miRview squamous) was developed, that utilizes qRT-PCR measurement of this microRNA, normalized by an additional microRNA and a small nuclear RNA. This assay was validated on a blinded test set of 64 tumor samples, and had sensitivity of 97% and specificity of 91%. More than ¾ of the samples were classified with high confidence, and these classifications were accurate in 96% of the cases. Conclusions: MicroRNAs are becoming an important tool for classification of cancers. A diagnostic assay based on the specificity of a single microRNA accurately identifies squamous from non-squamous NSCLC. This assay provides an important new tool for the classification of NSCLC.

[Table: see text]
Role of Galectin-3 in the activation of p-ERK and in resistance to radiotherapy in glioblastoma through the activation of p-ERK independent of Ras activity
Authors: El-Jawahri A. R. , Lautenschlaeger T. , Patel D. , Chakravarti A.
Published: August 2020

11073

Background: There has been a growing interest in investigating the molecular mechanisms leading to treatment resistance in glioblastoma (GBM). The MAPK pathway has been shown to be involved in mediating treatment resistance. Galectin-3 (Gal3) is commonly overexpressed in astrocytic tumors of the brain and has been associated with adverse clinical outcomes. We investigated the role and mechanisms of Gal3 in mediating treatment resistance in GBM through modulating the MAPK pathway. Methods: We investigated Gal3 expression in GBM cell lines (U87, LN18, LN229). We created stable Gal3 knockdown cell lines (Gal3KD), ERK-knockdown (lentiviral shRNA) and constitutively active MEK(MEK2DD plasmid obtained from Dr. Brugge) cell lines. We then evaluated the radiosensitivity, apoptosis, and cell viability of control cell lines treated by non-targeting (NT) vectors as compared to Gal3KD, ERKKD and MEK2DD using clonogenic survival, Annexin V/PI apoptosis, COMET, and cell cycle assays. Signaling cascades were evaluated using Western blot and a GTP-ras pull down assay. Gal3 was also transiently knocked down in MEK2DD and NT cell lines and signaling cascades were analyzed using western blotting. Gal3 binding interactions were identified using co-immunoprecipitation. Results: Gal3 expression was induced in all GBM cell lines following irradiation. Gal3KD showed increased radiosensitivity similar to ERKKD as compared to controls with decreased clonogenic survival, increased DNA damage, increased apoptosis, and increased cell cycle arrest in G1 and G2, while MEK2DD showed enhanced radioresistance. Gal3KD showed reduced p-ERK at baseline followed by a minimal induction of p-ERK with irradiation as compared to controls which have a high level of p-ERK. Overall p-Akt, ERK and Ras-GTP levels were equivalent in Gal3KD and controls. When Gal3 was transiently knocked down in MEK2DD cell line, p-ERK was drastically reduced similar to controls. Gal3 co-immunoprecipitated with ERK. Conclusions: Our results suggest a possible direct novel interaction between Gal3 and ERK in GBMs that is essential for the expression of p-ERK and mediating treatment resistance in GBMs.

No significant financial relationships to disclose.
Combining multigene profiling of molecular subtypes with the 70-gene profile for classification of breast cancer
Authors: Stork-Sloots L. , Krijgsman O. , Roepman P. , de Snoo F. A. , Bender R. A. , Glas A. M.
Published: August 2020

11083

Background: Classification of breast cancers into molecular subtypes may be important for accurate selection of therapy for patients. Herein we report a multigene profile for classification of breast cancer into molecular subtypes. The profile separates tumors into hormone receptor (HR)+/luminal-like, HER2+/ERBB2-like, and triple negative/basal-like subclasses. Methods: A multi-gene profile was developed based on a series of 200 tumor samples of known ER, PR and HER2 receptor status (concordant IHC and gene expression result) hybridized on 44k microarrays. The profile classifies 96% concordant to the molecular subtypes named luminal-, ERBB2- or basal-type as published by Perou et al (Perou et al, Nature, 2000; Fan et al, NEJM, 2005). The profile was validated using 469 independent samples as well as on two publically available gene expression datasets (n=251 and n=159). Results: The profile classified 66% (712) as luminal-like, 18% (194) ERBB2-like, and 16% (173) as basal-like. As compared to single-marker readout for the presence of ER, PR and HER2, 13% of the samples that were scored positive for presence of ER/PR did not express a luminal-like gene profile. Samples with a ERBB2-like or basal-like gene profile showed equally poor 5-year survival rates of ∼65%. However, the ERBB2-like subset of MammaPrint low risk patients (15%) showed an 89% (95%CI, 71–100) survival rate without trastuzumab treatment. When the luminal-like subtype was separated into “high-” and “low-risk” by MammaPrint the survival rate was 56% (95%CI, 46–68) for high-risk luminal-like samples and 94% (95%CI, 90–99) for low-risk samples. Conclusions: The developed multigene profile can classify breast tumors into luminal-, ERBB2- and basal-like subgroups. By combining this molecular subtyping with MammaPrint risk-classification specific groups of patients can be recognized that that are at high risk of recurrence. The low risk patients within the luminal- and ERBB2-like subclasses have a very low risk of recurrence. Implementation of this knowledge can improve the clinical management of breast cancer patients.

[Table: see text]
Adjuvant UK: Validation of a UK prognostic model for early breast cancer
Authors: Wishart G. , Greenberg D. , Rashbass J. , Ravdin P. , Lawrence G. , Caldas C. , Pharoah P.
Published: August 2020

11086

Background: To develop and validate a prognostication model to predict overall survival for women treated for early breast cancer in the UK based on cancer registry data. The main advantages are that unlike SEER, this dataset includes accurate information on mode of detection as well as systemic therapy. Methods: Using the Eastern Cancer Registration & Information Centre (ECRIC) dataset, information was collated for 5,818 women diagnosed with invasive breast cancer in East Anglia from 1999–2003. All patients underwent surgery, had records of pathological staging (tumour size, grade, lymph node status, ER status) and systemic treatment (chemotherapy, hormone therapy, both), mode of detection (screen-detected, symptomatic) and were followed up to December 2007. A model was derived from these data using Cox proportional hazards and this was subsequently validated in an external dataset of 5,468 patients from the West Midlands Cancer Intelligence Unit (WMCIU). Validation was performed by comparing (a) observed and predicted mortality - overall and by risk group decile - and (b) receiver operating characteristic (ROC) curves in both ECRIC & WMCIU datasets. Results: ECRIC dataset: Observed/predicted deaths were: 2 years (262/267), 5 years (868/867), 8 years (1108/1093). Area under ROC curve was 0.800WMCIU dataset: Observed/predicted deaths were: 2 years (317/298), 5 years (862/919), 8 years (955/999). Area under ROC curve was 0.783. The model and validation worked equally well at all time points (2, 5, 8 years) and in all risk group deciles. In the validation dataset the observed and predicted 8-year OS was within 1% (17.5% versus 18.3%). There was no significant statistical difference between the ROC curves (X2 = 2.35, P=.12) for prediction at 8 years in ECRIC and WMCIU data. Conclusions: We have developed a prognostication model for early breast cancer based on data from a UK cancer registry and validated the model using data from another UK registry. The model was well calibrated and provides a high degree of discrimination. This model will underpin the first web-based prognostication and treatment benefit tool for early breast cancer in the UK (Adjuvant UK).

No significant financial relationships to disclose.
Prognostic value of the genomic grade index (GGi) as compared to centrally measured Ki-67 IHC and mitotic index in early breast cancer patients
Authors: Bertucci F. , Le Doussal J. M. , Birnbaum D. , Tagett R. , Martinec A. , Hermitte F. , Marisa L. , Martin A. L. , Geneve J. , Roché H. , Penault-Llorca F.
Published: August 2020

11094

Background: Genomic grading has been proposed to improve tumor grading. The genomic grade index (GGi) is a 97-gene continuous measure which resolves 80% of histological grade 2 (HG 2) tumors into HG 1 and HG 3 risk categories. GGi has higher prognostic value than HG in patients treated with and without systemic adjuvant endocrine and chemotherapy. A key issue is whether the GGi adds prognostic information to centrally-determined mitotic index and Ki-67 IHC. Methods: The control arm of the PACS 01 trial included 996 women with node-positive (N+) early breast cancer treated with six cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) and tamoxifen as required. 128 genomic profiles could be obtained from available frozen tumor samples using Affymetrix U133 Plus 2.0 gene chips through the “Carte d'Identite des Tumeurs” program of the French Ligue Nationale contre le Cancer. The Genomic Grade index (GGi) was computed using Ipsogen MapQuant Dx(R). Central Elston-Ellis grade, mitotic index (mitosis / mm2), and Ki-67 IHC (% positive cells) were available for 125 patients. The GGi and histological parameters were correlated to the 5-year metastasis status (MFS-5) by ROC analysis and to the metastasis hazard (follow-up of 6.2 ± years) by Cox regression. Results: In ER+ patients (n=93), the GGi was the only significant correlate to metastasis hazard in multivariate Cox regression with histological parameters (HR = 3.5 [1.7–7.5], p<0.001). It was the best predictor of MFS-5 (ROC AUC = 0.83, p=1E-6) when compared to histological parameters (ROC AUC = 0.71, 0.72 and 0.66 resp. p=0.003 to 0.03). In HG 2 subgroup (n=43), the GGi was the only significant predictor of MFS-5 (ROC AUC = 0.81, p=0.016). Conclusions: In our sample of N+ ER+ breast cancer patients, the GGi improved prognostication compared to centrally-measured mitotic index and Ki-67 IHC used alone and in combination. Moreover, the GGi was the only prognostic factor in histological grade 2 patients.

[Table: see text]
Thymidylate synthase polymorphisms and immunohistochemistry in non-small cell lung cancer
Authors: Stoehlmacher J. , Goekkurt E. , Hoeffken G. , Zinsky R. , Lynch F. , Buettner H. , Scheil-Bertram S. , Schirren J. , Ehninger G. , Fisseler-Eckhoff A.
Published: August 2020

11101

Background: Recently, pemetrexed has been introduced into the treatment of non-small cell lung cancer (NSCLC). There's evidence that pemetrexed appears to be more efficient in non squamous NSCLC including adenocarcinoma (AC) and large cell carcinoma (LCC). TS represents a major target enzyme of pemetrexed. We evaluated the expression of TS among different histological types of NSCLC and its association with functional genetic polymorphisms of the TS gene. Methods: Archived tumor samples from 312 individuals with NSCLC were analyzed. Immunohistochemistry (IHC) was performed using a mouse monoclonal antibody to TS. TS stained sections were scored for cytoplasmic and nuclear localization. For each compartment, the tumor was evaluated for the estimated percentage of positive cells with the greatest intensity within the tumor. Intensity was scored on a scale of 0–4. A score of 3–4 was classified as high expression. Genotyping of TS-VNTR including the G/C SNP and TS1394del6 was performed by PCR based RFLP techniques. Genotypes supposed to be associated with low expression were grouped (group A: 2R/2R or 2R/3RC or 3RC/3RC + -6/-6) and compared to genotype groups associated with high expression (group B: 2R/3RG or 3RC/3RG or 3RG/3RG + -6/+6 or +6/+6). Results: IHC and polymorphisms could be performed successfully in 312 (100%) and 287 (92%), respectively. Distribution of histology was as follows: 50% AC, 42% squamous cell carcinoma (SCC), 3% LCC and 5% mixed or other histological subtypes. Group B genotypes were significantly more present in SCC than in AC (49% vs 23%, p=.002). Tumors with group B genotypes were more likely to display high nuclear staining intensity than group A tumors (30% vs. 17%, p=.077). A similar but not significant trend was seen for cytoplasmic staining intensity. There was no significant difference between histological subtypes of NSCLC with respect to TS protein expression. AC were more common than SCC to show a G1 differentiated tumors (8% vs 1%, p<.001). No difference between genotype groups were observed with respect to grading. Conclusions: TS polymorphisms are significantly associated with histology subtypes in NSCLC. These results represent a potential explanation for efficacy differences of pemetrexed in NSCLC and warrants further investigations.

[Table: see text]
Evaluation of aldehyde dehydrogenase 1 (ALDH1) as a marker of non-small cell lung cancer (NSCLC) stem cells (SCs) and correlation with prognosis
Authors: Zhou R. , Liu Q. , Todd N. W. , Deepak J. , Liu Z. , Stass S. A. , Edelman M. J. , Katz R. L. , Jiang F.
Published: August 2020

11105

Background: ALDH1 is a cytosolic enzyme responsible for oxidizing intracellular aldehydes, and conversion of retinol to retinoic acid in SCs. ALDH1 has been previously demonstrated to be a marker for SCs in breast cancer (Ginestier C, et al., Cell Stem Cell. 2007 Nov; 1(5):555–67). The Aldefluor assay is based on conversion of a synthetic substrate BAAA, when passively infused into cytosol, to brightly fluorescent BAA by ALDH1. Combined with fluorescence-activated cell sorting (FACS), it has been used successfully in hematopoietic and breast cancer SCs isolation. ALDH1 is also found in NSCLC. We hypothesized that ALDH1 would be a marker for NSCLC SCs and a potential prognostic marker. Methods: NSCLC SCs were isolated from human NSCLC cell lines using the Aldefluor assay and FACS. ALDH1-positive cells were analyzed extensively for SC characteristics. ALDH1 expression in 303 NSCLC biopsy specimens from three independent cohorts of NSCLC patients was then analyzed by immunohistochemisty (IHC) using an ALDH1 antibody (Santa Cruz Biotechnology) and commercially available negative controls. Results: Isolated cancer cells with high ALDH1 activity displayed cancer SCs features, including capacities for proliferation, self-renewal, differentiation; resistance to chemotherapeutic agents including cisplatin, vinorelbine, gemcitabine and docetaxel; expression of the SC surface marker CD133, and high invasiveness. ALDH1-positive cells generated tumors in vivo recapitulating heterogeneity of parental cells. Xenograft tumors derived from ALDH1-positive cells (103 each) were 36±2.9 mm3 on average in size, with some of the cells having lost ALDH1 expression. Xenograft tumors derived from ALDH1-negative cells (105 each) were 4 mm3 on average in size, without ALDH1 reactivation. Statistical analysis of quantitative IHC and clinical data showed ALDH1 expression was correlated with higher stage and grade of NSCLC (p = 0.02). Expression of ALDH1 in stage I NSCLC patients was linked to decreased 5 year cancer-specific survival (62% vs. 96%, p = 0.006) and overall survival (32% vs. 72%, p = 0.009). Conclusions: 1. ALDH1 is a NSCLC SC-associated tumor marker. 2. ALDH1 expression is a negative prognostic marker in early stage NSCLC.

No significant financial relationships to disclose.
Topographical analysis of telomere length and correlation with genomic instability in whole mount prostatectomies
Authors: Joshua A. M. , Marrano P. , Evans A. , Van der Kwast T. , Zielenska M. , Squire J.
Published: August 2020

11107

Background: Many critical events in prostatic carcinogenesis appear to relate to the emergence of chromosomal instability and acquisition of genomic rearrangements. Characteristic abnormalities such as 8p loss, 8q gain, trisomy 7, PTEN microdeletions and TMPRSS2-ERG gene fusions appear to mediate mechanisms to increase neoplastic transformation in prostate cancer. Current evidence suggests that telomere dysfunction is a likely causative factor for some of these abnormalities on the basis of its relationship to mechanisms such as the break-fusion-bridge cycle that can lead to the onset of chromosomal instability. Methods: In this study, we correlated telomere length in various prostatic histologies by quantitative FISH with genomic markers of chromosomal instability by standard FISH and immunohistochemical measures of proliferation in 3 whole mount prostatectomies. Results: After analysing approximately 25,000 cells, we found that telomere shortening was correlated with an increase in the number of cells with abnormalities on chromosome 8, such as an increase in the average number of c-myc signals (r∼0.35, p∼0.02). However, there were no significant correlations with abnormalities such as trisomy 7 or abnormalities of the PTEN locus in any sample. Additional findings included; associations found with the probability of C-MYC aberrations in stroma with greater proximity to cancer (<1,000 um), a correlation between telomere length in a number of prostatic histologies (normal, atrophy, HPIN and cancer) with the adjacent stroma, and a lack of correlation between the Ki67 index of various histologies and their telomere length - all suggesting the importance of microenvironmental effects on telomere maintenance in the prostate. Finally, we also report significant telomere shortening in BPH in 2 cases, a phenomenon that has not been noted previously. Conclusions: This is the first study to directly link a mechanism of chromosomal instability with specific chromosomal abnormalities in prostatic carcinogenesis and also suggests that the microenvironmental milieu is of critical importance in the evolution of in vivo telomere homeostasis.

No significant financial relationships to disclose.
Use of the ErbB2/CEP17 ratio to predict prognosis and response to trastuzumab-based therapy in the metastatic breast cancer setting
Authors: Fuchs E. , Köstler W. , Horvath R. , Hudelist G. , Kubista E. , Attems J. , Zielinski C. , Singer C. F.
Published: August 2020

11110

Background: Despite patient selection based upon detection of Her-2/neu overexpression by immunohistochemistry (IHC) and/or presence of amplification of the Her-2/neu-encoding erbB2 oncogene measured by FISH, response to trastuzumab-based therapy is only achieved in a subset of patients with Her-2/neu overexpressing breast carcinomas. Exact quantification of erbB2 copy-number relative to chromosome 17 (CEP17) (ErbB2/CEP17 ratio “R”) probably adds further important predictive information. Methods: Clinical data of 137 patients receiving trastuzumab based treatment for Her-2/neu overexpressing (IHC) metastatic breast cancer were analysed. ErbB2/CEP17 ratio (R) was determined by quantitative FISH analysis in original tumor tissue using Vysis PathVysion DNA-based FISH technology. Results: ErbB2/CEP17 (R) provided additional predictive value for progression free survival (PFS) and time to first metastasis (TTM), but not for overall survival (OS) (all from start of trastuzumab containing treatment). The following cutoffs of Her-2/neu were identified: group A: 0–2.2 R (TTM: 49.8; OS: 6.7; PFS: 6.2); group B: 2.2- 6 R (TTM: 26.2; OS: 5.3; PFS: 9.3); group C: >6 CN (TTM: 20.1; OS: 3.9; PFS: 13.7) Kaplan-Maier analysis showed significant longer TTM for group A (p<0.01 vs. B/C), significant longer PFS for group C (p<0.01 vs. A/B). Significant differences in complete response (B/C: 16.9% vs C:44.4%), partial response (B/C: 20.2% vs. C: 33.3%) and progressive disease (B/C: 27% vs. 11.1%) were noted. No significant difference in overall survival between the groups was seen. Conclusions: ErbB/CEP17 R provides important prognostic information and, in metastatic patients, allows one to better predict response to trastuzumab-based treatment than the widely used binary classification of ErbB2 amplification that is based on a cut-off at a copy number of >2.2.

No significant financial relationships to disclose.
The prognostic factors for the recurred breast cancer patients with isolated, limited number of lung metastasis, and the implication of pulmonary metastasectomy
Authors: Yhim H. , Han S. , Oh D. , Han W. , Im S. , Kim T. , Kim Y. , Noh D. , Ha S. , Bang Y.
Published: August 2020

1112

Background: In recurred breast cancer (BC) with isolated lung metastasis, the role of pulmonary metastasectomy (PM) is not established. Methods: We consecutively enrolled recurred BC patients (pts) with isolated lung metastasis from 1997 to 2007 in Seoul National University Hospital. Among 140 recurred pts with isolated lung metastasis, 45 had metastatic lesions less than 4. We analyzed the clinical outcomes of these 45 pts. Results: The median age was 49.0 (range 32–67) years. The median disease-free interval (DFI, Time from initial BC diagnosis to recur) was 26.1 (range 4.2–168.0) months, and the pts with DFI of less than 24 months were 20 (44%). The pts who had biologic subtypes (BS) of hormone receptor (HR)(+), HER-2(+), triple negative (TN) were 16 (36%), 14 (31%,) and 15 (33%), respectively. Fifteen (33%) had PM then followed by systemic treatment (PM group), and 30 received systemic treatment without PM (no PM group). There was no difference in terms of clinical factors such as DFI and BS between two groups. The median progression-free survival (PFS) and overall survival (OS) were 13.0 months (95% CI, 10.05–15.95) and 41.7 months (95% CI, 23.82–59.58), respectively. In univariate analysis, PFS was significantly longer in pts with PM (p < 0.001), DFI of more than 24 months (p < 0.001), and was marginally significant according to BS (p = 0.084). In multivariate analysis, DFI of less than 24 months (hazard ratio [H], 4.53; 95% CI, 1.72–11.90), no PM (H, 9.52; 95% CI, 3.34–27.18) and BS such as HER-2(+) (H, 3.00; 95% CI, 1.04–8.64) and TN (H, 3.92; 95% CI, 1.32–11.59) were independent prognostic factors for shorter PFS. In univariate analysis, OS was significantly longer in pts with PM (p = 0.011), DFI of more than 24 months (p < 0.001), HR(+) BS (p = 0.009). In multivariate analysis, DFI of less than 24 months (H, 7.67; 95% CI, 2.00–29.43) and BS such as HER-2(+) (H, 3.70; 95% CI, 1.03–13.24) and TN (H, 3.27; 95% CI, 1.02–10.44) were independent prognostic factors for shorter OS. Conclusions: In recurred BC with isolated, limited number (less than 4) of lung metastasis, DFI and BS were prognostic factors for PFS and OS. PM also prolonged PFS, and, for OS, more follow-up is needed. Further prospective studies to define the role of PM are warranted.

No significant financial relationships to disclose.
A multicenter randomized phase II study of nonpegylated liposomal doxorubicin plus vinorelbine versus nonpegylated liposomal doxorubicin plus cyclophosphamide as first line in locally advanced breast cancer (LABC) or metastatic breast cancer (MBC): Safety results
Authors: Lorusso V. , Leo S. , Ciccarese M. , Giotta F. , Bordonaro R. , Filippelli G. , Del Prete S. , Piano A. , Gebbia V. , Pisconti S. , Colucci G.
Published: August 2020

1116

Background: We conducted a multicenter randomized phase II trial to assess activity and tolerability of the combination of nonpegylated liposomal doxorubicin plus vinorelbine versus standard nonpegylated liposomal doxorubicin plus cyclophosphamide. Methods: This multicenter randomized phase II study was planned to enrol 140 patients (pts). Elegibile pts must have LABC or MBC, PS (ECOG) ≤ 2, and measurable disease. Adjuvant or neoadjuvant chemotherapy with anthracyclines was allowed as well as prior endocrine therapy. Pts assigned to arm A received nonpegylated liposomal doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 on day 1 of a 21-day cycle. Pts assigned to arm B received nonpegylated liposomal doxorubicin 50 mg/m2 plus vinorelbine 25 mg/m2 iv on day 1, and 60 mg/m2 on day 8 po, every 3 weeks. The primary outcome measure was response rate (RR), whereas safety was one of the secondary endpoints. Results: Between July 2006 and July 2008 110 women were treated; for 80 of these, safety results are available. Patient characteristics: Arm A pts (N=41): median age, 59 (range 37–69); ER status ±/unk, 26/15/0; Her-2 status ±/unk, 5/34/2; PS 0/1/2, 26/14/1; prior adjuvant treatment with anthracyclines 10 pts (24%); dominant site of disease visceral 31 pts (76%). Arm B pts (N=39): median age, 61 (range 25–70); Er status ±/unk, 29/10/0; Her-2 status ±/unk, 3/35/1; prior adjuvant treatment with anthracyclines 14 pts (36%); dominant site of disease visceral in 28 pts (72%). There was no study discontinuation due to AE either in arm A or in arm B, nor study-related deaths. Conclusions: The combination regimen of nonpegylated liposomal doxorubicin plus vinorelbine appears to be associated with a slight increase of hematological and nonhematological toxicity when compared with nonpegylated liposomal doxorubicin plus cyclophosphamide. No increase in cardiotoxicity was seen. The trial is ongoing and we plan to give preliminary efficacy results at the time of the Meeting.

[Table: see text]

No significant financial relationships to disclose.
A phase I study of oral metronomic vinorelbine plus capecitabine in patients with metastatic breast cancer
Authors: Kalykaki A. , Agelaki S. , Kotsakis A. , Vamvakas L. , Bozionelou V. , Kalbakis K. , Androulakis N. , Georgoulias V. , Mavroudis D.
Published: August 2020

1127

Background: The combination of capecitabine plus intravenous vinorelbine has shown substantial activity in anthracycline and/or taxane pretreated patients with metastatic breast cancer (MBC). The metronomic administration may be associated with reduced toxicity and enhanced efficacy. We conducted a phase I study to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of capecitabine plus oral vinorelbine administered metronomically in patients with MBC. Methods: Patients were treated with vinorelbine (30–60 mg total dose) p.o three times per week continuously and capecitabine (800–1250 mg/m2 twice a day) from day 1 to 14 in three week cycles. DLT was defined during the first cycle as grade (G) 4 neutropenia or thrombocytopenia, febrile neutropenia, any ≥ G 3 non-hematological toxicity, and any delay of treatment due to toxicity. Results: To date 27 patients have been enrolled on 7 different dose levels. Treatment was first line for 16 and second line for 11 patients. DLTs included G3 febrile neutropenia and treatment delay due to G2 neutropenia occurring in 1 patient each, at dose level 4 and G3 diarrhea and treatment delay due to G2 neutropenia in 1 patient each, at dose level 7. The MTD has not yet been reached. Hematologic and nonhematological toxicities were generally mild to moderate. Most common were myelosuppression, asthenia, nausea, and diarrhea. Nine objective responses were observed with 2 complete and 7 partial. Conclusions: Vinorelbine 60 mg three times a week in combination with capecitabine 1250mg/m2 twice a day, has been well tolerated. Enrollment is ongoing. Updated data will be presented at the meeting.

No significant financial relationships to disclose.
Effect of simvastatin on the pharmacokinetics of anastrozole
Authors: Bao T. , Slater S. A. , Blackford A. , Jeter S. C. , Wright L. , Rudek M. A. , Desta Z. , Stearns V.
Published: August 2020

1517

Background: When used in the adjuvant setting, aromatase inhibitors (AIs) reduce the incidence of contralateral breast cancer and are therefore under investigation for primary breast cancer prevention. Statins hold promise for chemoprevention based on preclinical and epidemiological data. Adding statin to AI has the potential to enhance breast cancer prevention and to protect women from AI-related side effects. Prior to initiating a chemoprevention trial of combination therapy, we evaluated the potential for pharmacokinetic drug-drug interaction between anastrozole and simvastatin in postmenopausal women taking adjuvant anastrozole to ensure that the combination will not influence anastrozole concentration or affect its ability to reduce estrogen. Methods: Postmenopausal women with hormone receptor-positive, stage 0-III breast cancer who had been on adjuvant anastrozole (1 mg/day) for at least 30 days were prescribed 14 days of simvastatin (40 mg/day). We collected serum at baseline (anastrozole alone) and after 14 days of simvastatin initiation (combination therapy). Anastrozole and hydroxyanastrozole, its hydroxylated metabolite, concentrations were determined using liquid chromatography-tandem mass spectrometry assay. Estrogen concentrations will be determined using radio-immunoassay. Significant change in anastrozole was predetermined to be greater than a 30% decrease in concentrations. Percent changes from baseline in anastrozole and hydroxyanastrozole were evaluated using Wilcoxon signed-rank tests. Results: From December 2006 to September 2008, 11 women (10 Caucasian, 1 Black, all reported non-Hispanic with a mean age of 60 yrs [range 51–69]) were enrolled in the study. Of these women, nine had evaluable anastrozole concentrations. After 14 days of simvastatin, there were nonsignificant changes in anastrozole (median percentage difference = 10.1% [-13.5%, 38.4%], p = 0.36) and hydroxyanastrozole (median percentage difference = -3.0% [-19.1%, 11.2%], p = 0.65). Estrogen data will be available for presentation. Conclusions: Simvastatin is unlikely to alter the pharmacokinetics of anastrozole in a clinically meaningful way. Combination studies to assess chemopreventive properties of the combination are planned.

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Randomized phase II trial of budesonide versus placebo in high-risk population with screening-detected lung nodules: Update on secondary endpoints
Authors: Bonanni B. , Guerrieri-Gonzaga A. , Radice D. , Serrano D. , Varricchio C. , Ferretti S. , Johansson H. , Szabo E. , Decensi A. , Veronesi G.
Published: August 2020

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Background: Lung cancer phase II chemoprevention trials have not focused so far on the peripheral lung. CT discovers small, undetermined peripheral nodules, which may be preinvasive lesions. In a recent phase II trial the glucocorticoid Budesonide reduced peripheral nodules at spiral CT. Methods: We performed a randomized, double-blind, placebo-controlled, phase IIb clinical trial of inhaled budesonide in current (CS) or former smokers (FS) with CT-detected peripheral nodules. Primary endpoint: shrinkage effect on nodules. Secondary endpoints: decrease in size/number of the target lesions, modulation of tumor markers in sputum and plasma, toxicity, effect on pulmonary function. Two hundred and two subjects received 800μg budesonide (B) twice daily or placebo (P) for 1 year. CT scans at 0 and 12 months (mts), and clinical evaluation + serum/plasma collection at 0, 3, 6, and 12 months were performed. Subjects were stratified according to gender, smoking habits (CS vs. FS), and nodule characteristics (solid vs. non-solid). Results: Preliminary data had shown no shrinkage of the nodules in the B treated arm in a per subject analysis (primary objective). We present now results on serum markers (ultrasensitive C-reactive protein, CRP), emphysema and pulmonary function. As compared to baseline, CRP median levels show at 12 months a nonsignificant (p = 0.85) reduction: -0.25 ± 0.63 (B) vs. -1.16 ± 0.97 (P). 12-month values are significantly (p = 0.01) associated with baseline values and smoking status, with higher mean values at 12 months in FS (B 2.1 ± 2.0 vs. P 3.4 ± 1.9). Emphysema values at 12 months are significantly higher (p = 0.0022) in the B (+ 0.29 ± 0.06) versus P arm (+ 0.12 ± 0.07). This difference is not correlated to sex (p = 0.7062) and smoking status (p = 0.8044). As regards spirometry, no significant difference on FEV 1% and DLC/VA appears between arms at 12 months: median FEV 1% values 3.7 ± 1.0 for B versus 2.9 ± 1.0 for P (p = 0.6221); median DLC/VA increase of 0.3 ± 1.9 (B) versus decrease of -3.8 ± 1.6 (P) (p = 0.4191). Conclusions: A significant effect of B on ultrasensitive-CRP and pulmonary function has not been shown. CRP results may indicate the lack of systemic absorption of B. Emphysema appears slightly worse in the B arm, particularly in FS; this is worth further investigation.

No significant financial relationships to disclose.
Efficacy of capecitabine in secondary prevention of skin cancer in solid organ-transplanted recipients (OTR)
Authors: Jirakulaporn T. , Mathew J. , Lindgren B. R. , Dudek A. Z.
Published: August 2020

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Background: Skin cancers are the most common malignancies in OTR. Topical 5% 5-FU has been used to successfully treat squamous cell carcinoma (SCC) in situ and actinic keratosis (AK). Capecitabine, an orally-administered prodrug of 5-FU, in combination with interferon was shown to be effective in the treatment of advanced SCC of the skin. This study was to determine the efficacy of low-dose capecitabine in secondary prevention of the skin cancers in OTR. Methods: OTR who developed recurrent skin cancers, SCC, and/or basal cell carcinoma (BCC), were given low-dose capecitabine 1g/m2 divided in two daily doses, day 1–14 of 21-day treatment cycle. Skin surveillances were performed by dermatologists every 1 to 3 months. Cumulative incidence rates of SCC, BCC, and AK before and after treatment were scored and statistically compared for each patient with a non-parametric Wilcoxon signed-rank test. Age and number of transplants were assessed with the Spearman non-parametric correlation analysis for their impact on the outcome. Results: 14 patients (12 males and 2 females) were enrolled with median age of 55 (range 40–73). 11 patients received kidney, two lung and one liver, one heart and one pancreas transplant. Two patients received double organ transplants. Mean incidence rates of SCC, BCC, and AK before treatment were 0.45, 0.05, and 4.99 lesions per month, respectively. Mean incidence rates of SCC, BCC, and AK after treatment were 0.22, 0.04, and 2.80 lesions per month, respectively. The differences in incidence rates of SCC, BCC, and AK before and after treatment were 0.24, 0.02, and 2.08 lesions per month with p value of 0.048, 0.844, and 0.151, respectively. Age and the number of transplants were not significantly related to the change in incidence rates for all skin lesion types. Six of the total of 14 patients experienced grade 3/4 toxicities, including mucositis (2), hand-foot syndrome (3), fatigue (2), nausea (1), diarrhea (2), hyperuricemia (1), and anemia (1), and all six needed capecitabine dose reduction or stopping therapy. Conclusions: Oral capecitabine significantly decreases the incidence rates of recurrent SCC in OTR and has manageable toxicity.

No significant financial relationships to disclose.
Chemoprevention with enzastaurin: First-year results
Authors: Gray J. E. , Altiok S. , Alexandrow M. , Walsh F. , Tockman M. , Bepler G.
Published: August 2020

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Background: Chemoprevention is crucial for reducing lung cancer mortality. The implementation and conduct of such trials is complex. We evaluated accrual in an ongoing trial. Methods: We are conducting a study evaluating if enzastaurin, a protein kinase C beta inhibitor, decreases the Ki-67 labeling index in bronchial epithelium after 6 months of therapy compared to placebo. Eligibility includes age 45 or younger, smoking 30 or fewer packs per year, quit for less than one 1 year, and bronchial meta/dysplasia. Results: Two-thousand eight hundred and nine potential subjects were selected from our database. Between December 2007 and November 2009, 1,242 were invited to participate by an introductory letter and at least 3 attempted telephone contacts. Phone contact was established with 621 (50%) subjects. 245 (39%) declined, 238 (38%) were ineligible, and 138 (22%) were interested in trial participation. At the first face-to-face visit, 57 out of 138 (38%) were eligible, 71 (51%) had not quit smoking for less than 1 year, one (1%) was ineligible for other reasons, and nine (7%) visits are pending. All 57 eligible subjects had an induced sputum exam: 36 had atypia, 19 were normal, and two were inadequate. Bronchoscopies with white light and laser-induced fluorescence and three or fewer biopsies have been done on 22 subjects (4 pending, 4 withdrew, 6 ineligible for bronch). Three had normal histology at all sites, 16 had metaplasia, and two had dysplasia in at least one site (84% abnormal bronchial histology rate, 1 pending). No occult cancers were identified. Conclusions: Of 1,242 preselected potential participants, 11% presented for a first face-to-face visit, 4.6% were eligible after a sputum exam, and 2.4% were fully eligible for randomization. Thus, to reach the accrual goal of 186 patients, we estimate that we will need to contact 7,700 subjects. During our 12-month period, we accessed 1,242 patients with 2.0 FTE for study coordinators (not including the pathologist, bronchoscopist, and laboratory personnel). Our expectation had been to accomplish accrual over a period of 42 months from a pool of 2,809 existing putative patients. Unless our eligibility rate of 2.4% increases, further sources of patients must be identified to accomplish our accrual goal.

No significant financial relationships to disclose.
Low bone density in premenopausal women at high risk for breast cancer
Authors: O'Dea A. P. , Thirunavu M. , Nydegger J. , Klemp J. R. , Kimler B. F. , Fabian C. J.
Published: August 2020

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Background: Tamoxifen when used in the high estrogen milieu of premenopausal women may reduce bone density. However, the proportion of premenopausal women at increased risk for breast cancer who have low bone density and are likely to take tamoxifen is unknown. Methods: Premenopausal women attending a high-risk clinic were invited to take part in an ongoing prospective study assessing bone mineral density (BMD) loss. Women on bisphosphonates or those previously treated with selective estrogen receptor modulators were excluded. BMD was measured by DEXA, serum 25-hydroxyvitamin D (25OHD) by chemiluminescence, and information on risk factors for osteoporosis and breast cancer was obtained by questionnaire. Results: 106 premenopausal women were entered between April and October 2008. Median age was 42 (range 23–57), median body mass index (BMI) was 25 kg/m2 (range 15–44). All but two were Caucasian. 13% had a prior biopsy with atypical hyperplasia (AH) or in situ carcinoma, 36% had a family history of osteoporosis, 56% took calcium supplements, and 47% took vitamin D supplements. Median sun exposure was 480 minutes per month, the majority with sunscreen. Median serum 25OHD was 34 ng/ml. Five had deficiency (< 20 ng/mL), and 45 women deficiency or insufficiency (< 32 ng/mL). Seven subjects ages 31 to 48 had evidence of low BMD (T-score of less than -1.0 in the spine or hip.) One woman with low BMD by DEXA had a 25OHD level < 32 ng/ml. Women with low BMD had lower BMIs (median of 22 vs. 25 kg/m2, p = 0.020) than women with normal bone density. There was no difference in history of vitamin D and calcium supplement use, and low 25OHD levels did not explain the low T-scores. Information on vitamin D receptor polymorphisms associated with BMD loss is pending. Importantly, 21% of women with a prior biopsy demonstrating AH or in situ carcinoma had evidence of bone density loss compared to 4% of women without such a biopsy (p = 0.048). Conclusions: Premenopausal women with a history of AH or in situ carcinoma are most likely to take tamoxifen for primary prevention and in our ongoing study have a high enough incidence of low bone density to make baseline assessment by DEXA a consideration, particularly for those with predisposing factors such as low BMI and lack of sun exposure.

No significant financial relationships to disclose.
Knowledge and beliefs about breast cancer in rural women and indigenous population of southern Mexico
Authors: Saldana-Tellez M. , Marcial-Toledo S. , Terrazas-Espitia S. , Vazquez-Luna J. , Guzman-Patraca C. , Venegas- Hernandez L. , Perez-Romero J. , Gutierrez-Delgado F.
Published: August 2020

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Background: Rural and indigenous women are generally considered to be at lower risk of breast cancer than women living in urban environments. However, a rising breast cancer incidence rates among those women has been reported. Moreover, up to 90% of those women are diagnosed as having advanced disease. With the aim to improve preventive programs in that population, this study evaluated socio-demographic factors associated with breast cancer early detection and women's knowledge about this malignancy. Methods: Between March 2008 and November 2008, women attending cancer screening programs in our clinic were asked to answer a questionnaire focusing on socio-demographic issues, breast cancer risk factors, breast self examination (BSE), mammography, and perception of breast cancer risk. Results: 838 consecutive women (median age 40 years, range: 15–85) were evaluated. 443 (53%) of them were 40 years and older. The highest education level was 9 years in 408 (49%), 72 (9%) were illiterates and 721 (86%) have no medical insurance. 104 (12%) women practice BSE. The main source of breast cancer awareness was physicians and media in 270 (32%) and 214 (26%) women, respectively. 285 (34%) women knew about breast cancer risk factors, 255 (30%) identified symptoms and signs, and 460 (55)% of them identified lump as the most common sign. 441 (53%) women recognized mammography as the best diagnostic tool in detecting breast cancer, but only 79 (18%) out of 443 women 40 years and older, reported having had a mammogram. Mammograms were not done in 364 (82%) women because of financial issues and difficulty in accessing facilities that perform mammography. 311 (37%) women thought that they were at higher risk of developing breast cancer. Conclusions: Rural and indigenous women have a poor knowledge about breast cancer. Low level education, lack of medical insurance, financial issues, insufficient mammography facilities, and low perception of breast cancer risk are the most important barriers to increase women´s participation in early breast cancer detection. These factors should be considered to improve preventive breast cancer programs.

No significant financial relationships to disclose.