bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiplex TaqMan assays for a 7-gene prognostic immune response score to differentiate risk among women with ER-negative breast cancer.
Authors: Sninsky John J. , Christopherson Cindy , Lagier Robert , Chang Monica , Kwok Shirley , Tandon Vickram , Moore Dan H. , Waldman Frederic , Degnim Amy C. , Ingle James N. , Yau Christina , Benz Christopher , Gillett Cheryl , Tutt Andrew , Wang Alice M. , Esserman Laura
Published: March 2020

10586

Background: Teschendorff et al. (Breast Cancer Res 2008) reported a 7-gene, immune response-enriched gene expression classifier using microarrays that was prognostic in women with ER-negative breast cancer. To facilitate further evaluation of the prognostic value of a classifier in archival fixed tumor tissue, we developed two multiplex TaqMan assays to quantify the expression levels of these genes, then trained and validated a 7-gene immune response score (IRS). Methods: RNA was extracted from FFPE sections of 185 ER-negative breast cancer patient samples from Mayo Clinic (n=81), Guy’s Hospital (n=50) and California Pacific Medical Center (CPMC) (n=27). Patients (N+ and N-) did not receive adjuvant therapy and were followed for a minimum of 5 years. Amplification of i) LY9, TNFRSF17, HLA-F, and IGLC2 and ii) XCL2, SPP1, C1QA and two reference genes NUP214 and PPIG were carried out in two multiplex RT-PCR TaqMan reactions and relative expression levels were determined using the DDCT method. The training set, comprised of the Mayo Clinic samples, was used to develop an IRS by using a summation of expression levels of the 7 genes. Association of the IRS with distant metastasis was assessed using a Cox proportional hazards model. The score was subsequently tested in a validation set (Guy’s + CPMC). Results: The amplification efficiency of each gene within the multiplex reactions was comparable to singleplex reactions. Duplicate amplifications showed excellent assay reproducibility and sensitivity (R2=0.98). The hazard ratio for a single standard deviation decrease in the IRS was 1.45 (95% CI 0.99-2.12, p=0.056) in the training set and 2.18 (1.32-3.61, p=0.002) in the validation set. ROC curves of continuous IRS to predict distant metastasis within 5 years had AUC of 0.74, 95% CI = 0.60-0.88. Conclusions: Robust multiplex TaqMan assays for FFPE tissue extracted RNA were developed for a 7-gene IRS. Increases in risk are associated with decreases in the IRS. Immune related gene expression clearly plays an important role in the spectrum of risk of ER-negative tumors. Additional signatures are in development that further support this conclusion.
Prevalence of TP53 p.R337H mutation in children with cancer from a public hospital in southern Brazil.
Authors: Giacomazzi Juliana , Rossi Cristina , Selistre Simone Geiger , Alemar Barbara , Roth Daniela , Brunetto Algemir Lunardi , Netto Cristina , Goldim Jose Roberto , Hainaut Pierre , Camey Suzi Alves , Ashton-Prolla Patricia
Published: March 2020

10593

Background: Childhood cancers are a common feature in Li-Fraumeni/Li Fraumeni-Like Syndromes (LFS/LFL), associated with the inheritance of a germline TP53 mutation. Recently, a specific germline mutation in exon 10 of the TP53 gene, p.R337H, has been reported at a high prevalence in Southeastern Brazil. Initial studies on this mutation claimed that the main, if not exclusive, cancer risk in carriers is childhood adrenocortical carcinoma (ADR). However, others recent reports identified p.R377H carriers among LFL families and among a larger spectrum of tumors, such as choroid plexus carcinoma (CPC) and osteosarcoma. The aim of this study was to assess the frequency of the p.R337H mutation in children diagnosed with tumors of the LFS/LFL spectrum: ADR, sarcoma, central nervous system tumors, leukemia, germline cell tumors and Wilm’s tumor) at the Children’s Cancer Institute of Rio Grande do Sul (Brazil) between 1998 and 2011. Methods: Family history (FH) was recorded in pedigrees, and DNA was extracted from peripheral blood and FFPE samples by standard methods. Screening for the p.R337H mutation was performed by allelic discrimination (TaqMan assay) and by TP53 exon 10 sequencing. Results: Analysis of 295 children diagnosed with tumors of the LFS/LFL spectrum identified the p.R337H mutation in 9/11 (81,8%) children with ADR (including a homozygous p.R337H individual) and in 2/2 (100%) children with CPC. All individuals had loss of heterozygosity in the tumor and in all cases the mutant allele occurred on the same founder haplotype. One hundred fourth-six (49,5%) patients had a cancer FH in first or second degree relatives, 47 (16,0%) had a FH of breast cancer and 49 (16,6%) had FH of LFL consistent with Chompret and/or Birch criteria. Conclusions: These results confirm the strong association of p.R337H with ADR and CPC. A FH consistent with LFL syndrome is present in a high proportion of children diagnosed with tumors of the LFS/LFL spectrum in Southern Brazil. Financial support: FIPE-HCPA, CAPES, FAPERGS and Glaxo Smith Kline.
Prognostic value of “angiogenic” risk score in early-stage NSCLC.
Authors: Sanmartin Elena , Jantus-Lewintre Eloisa , Sirera Rafael , Sanchez Jose Javier , Usó Marta , Gallach Sandra , Blasco Ana , Hernando Cristina , Martinez Nieves , Figueroa Santiago , Rolfo Christian Diego , Guijarro Ricardo , Martorell Miguel , Camps Carlos
Published: March 2020

10594

Background: Angiogenesis is a key mechanism in tumor growth and dissemination mainly regulated by VEGF family members. We analyze the expression of 11 angiogenic genes in a cohort of resectable NSCLC patients and correlate them with clinico-pathological variables and prognosis. Methods: RNA was obtained from tumor and normal lung specimens from 175 NSCLC patients. RT-PCR was performed to assess the expression of HIF1-A, PIGF, VEGFA, VEGFB, VEGFC, VEGFD, VEGFR1, VEGFR2, VEGFR3, NRP1 and NRP2. Relative expression was normalized by an endogenous gene (GUS) using the Pfaffl formulae. Differences were considered statistically significant at p<0.05. Results: We found that tumor samples had a significant higher expression of PIGF and lower expression of VEGFD, VEGFR2, and VEGFR3 compared with normal tissue (2.76X, 0.035X, 0.417X and 0.426X, respectively). The group of patients with higher expression levels of VEGFA or PlGF had a significantly reduced TTP (p=0.024 and p=0.027, respectively) and OS (p=0.055 and p=0.048, respectively) whereas those patients with values of VEGFB or VEGFD below the median had reduced TTP (p=0.020 and p=0.135, respectively) and OS (p=0.003 and p=0.089, respectively). The multivariate Cox regression analysis revealed that VEGFA, VEGFB and PlGF were independent prognostic markers for TTP and OS and based on these results we generated an “angiogenic” risk score model. TTP and OS were significantly different among the low, medium and high risk score patients (Table). Conclusions: VEGF family members are master control genes of the angiogenic process and have a crucial role in the prognostic of the disease. We found differences in the expression of four genes between tumor and normal lung samples. An “angiogenic” risk score (based on the expression of PlGF, VEGF-A and VEGF-B) significantly predicts OS and TTP in our cohort of early-stage NSCLC patients. Validation in an independent cohort is needed. Supported by grants PS09-01149 and RD06/0020/1024 from ISCIII. [Table: see text]
The efficacy of targeted next-generation sequencing for detection of clinically actionable mutations in cancer.
Authors: Wen Yu-Ye , Fang Erica , Li Yanchun , Carmack Condie Edwin , Li Marilyn M.
Published: March 2020

10598

Background: The emergence of next-generation sequencing (NGS) technologies has significantly accelerated the identification of cancer-causing mutations and the development of personalized cancer care. However, the clinical application of these technologies to detect cancer gene mutations has been extremely limited due to the long turn around time, the high cost, and large amount of input DNA required by existing NGS-based tests. Methods: We have assessed the performance of a novel NGS technology that merges multiplex PCR with ion semiconductor sequencing (AmpliSeq, Life Technologies, Inc.) in our clinical diagnostic laboratory. The test interrogates 739 common mutations in 46 cancer genes including many clinically actionable mutations concurrently. First, we studied 12 tumor samples including 4 archived FFPE, 4 blood/bone marrow, and 4 cell line samples with known mutations to evaluate the sensitivity and specificity of the test. We then studied 34 de-identified, archived FFPE tumor samples of unknown genotype to further evaluate the efficacy of the test. Results: We successfully identified all known mutations previously detected by Pyposequencing or Sanger sequencing technologies. Multiple serial dilution studies showed that the test could detect mutations at frequencies as low as 5% with 99% confidence. For the samples of unknown genotype, we detected 23 COSMIC mutations in 16 samples including HRAS, BRAF, MET, TP53 mutations in lung cancer, KRAS, PIK3CA, TP53, APC, BRAF, ERBB2 mutations in colon cancer, TP53 and KRAS mutations in breast cancer, and KIT and PDGFRA mutations in GIST. Analysis of the variant call data showed that a minimum of 100X coverage is required in order to detect mutations at 10% frequency or above; a minimum 300K final library reads are necessary in order to minimize/eliminate amplicon dropout. Conclusions: The targeted NGS test can effectively detect cancer gene mutation with input DNA as low as a few nanograms, turn around time can be as short as two days, and can significantly lower cost compared to traditional Sanger sequencing. Our experience demonstrates that this technology holds great potential for clinical use, including diagnostic and therapeutic applications.
Evaluation of the clinical utility of kallikrein-related peptidase 6 gene (KLK6) downregulation in breast cancer.
Authors: Michaelidou Kleita , Tzovaras Alexandros , Tsoukalas Nikolaos , Mavridis Konstantinos , Tsoukalas Grecory , Tsapralis Nikos , Stamatopoulou Sofia , Zylis Dimosthenis , Misitzis Ioannis , Ardavanis Alexandros , Scorilas Andreas
Published: March 2020

10606

Background: Breast cancer (BC), the most common malignancy among the female population, remains a crucial public health problem. The identification and exploitation of novel molecular biomarkers can contribute in the multidimensional approach which is required for optimal management of BC patients. The abnormal expression of several KLK members has been documented for breast cancer. Interestingly, many of these genes are found to be potential prognostic markers for this malignancy. KLK6 expression is positively associated with tumor progression in various human malignancies; however in breast cancer, it can restrain tumor progression. We therefore sought to investigate the possible clinical value of KLK6 as a breast cancer biomarker. Methods: Total RNA was isolated from 107 breast tumors and their matched normal compartments. After testing the quality of the extracted RNA, cDNA was prepared by reverse transcription. Quantitative Real-time PCR was performed, for KLK6 mRNA quantification, using the SYBR Green chemistry. Relative quantification analysis was made using the comparative Ct (2-ΔΔCT) method. HPRT1 was used as an endogenous control gene and BT-474 breast cancer cell line served as a calibrator. Results: KLK6 mRNA levels were significantly downregulated in the cancerous breast tissue specimens compared to their normal counterparts (p<0.001). Additionally, a negative association was observed between KLK6 expression status and tumor stage, given the fact that 54.2% of less advanced breast tumors (TNM stage≤ T2a) were KLK6-positive compared to the 34.6% of more advanced-stage tumors (TNM >T2a) (p=0.034). Moreover, a statistically significant negative correlation was documented between KLK6 mRNA levels and estrogen (p<0.001) and progesterone receptor (p=0.003) statuses. Conclusions: The downregulation of KLK6 in cancerous compared to normal sections of breast tissue samples reflects the reported tumor suppressor properties of KLK6 gene in breast malignancies. Furthermore, the negative association of KLK6 mRNA expression with tumor stage, ER and PR statuses reveals the putative role of KLK6 as a promising prognostic breast cancer biomarker.
Cytokeratin 19 fragment (CYFRA21-1) to predict the efficacy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in non-small cell lung cancer (NSCLC) harboring EGFR mutation.
Authors: Tanaka Kosuke , Hata Akito , Kaji Reiko , Fujita Shiro , Takeshita Jumpei , Matsumoto Takeshi , Monden Kazuya , Nagata Kazuma , Otsuka Kyoko , Nanjo Shigeki , Tachikawa Ryo , Otsuka Kojiro , Hayashi Michio , Tomii Keisuke , Katakami Nobuyuki
Published: March 2020

10610

Background: EGFR mutation is independently associated with a favorable response in NSCLC patients receiving EGFR-TKIs, regardless of gender or smoking history. However, recent reports have indicated that squamous cell carcinoma patients harboring EGFR mutations show a worse response to EGFR-TKIs than adenocarcinoma patients. We hypothesized that serum CYFRA21-1 is a predictive marker in EGFR mutated patients treated with EGFR-TKIs. Methods: We retrospectively screened 160 NSCLC patients harboring EGFR mutations (exon 19 deletions, L858R in exon 21, or other minor mutations) who received either gefitinib or erlotinib between 1992 and 2011. Patients were screened for histology, sex, age, smoking status, efficacy of EGFR-TKI and tumor markers (CEA/CYFRA21-1) at initial diagnosis. Results: Out of 160 eligible patients treated with EGFR-TKIs, 77 patients with high CYFRA21-1 level (>2 ng/ml) showed statistically shorter progression-free survival (PFS) than 83 patients with normal CYFRA21-1 level (median PFS 7.5 vs 14.0 months, p=0.006). No significant difference in PFS was observed between high CEA group (>5 ng/ml) and normal CEA group (median PFS 8.6 vs 11.2 months, p=0.2423). Multivariate analysis revealed that high CYFRA21-1 level is independently associated with PFS (HR 1.35; p=0.002) as well as squamous cell carcinoma (HR 1.40; p=0.020) and performance status 2-4 (HR 2.63; p=0.003). No statistically significant difference in overall survival (OS) was observed between high CYFRA21-1 group and normal group (median OS 24.8 vs 39.1 months, p=0.104). Conclusions: High CYFRA level patients have significantly shorter PFS, which may indicate that this subgroup has a larger squamous component and thus less response to EGFR-TKIs. Serum CYFRA21-1 level is a predictive marker of EGFR-TKIs efficacy and EGFR mutated patients can be divided into two subgroups according to CYFRA21-1 level at initial diagnosis.
Evaluation of EZH2 SNPs in cholangiocarcinoma patients.
Authors: Paolicchi Elisa , Pacetti Paola , Giovannetti Elisa , Mambrini Andrea , Orlandi Massimo , Crea Francesco , Tartarini Roberta , Vasile Enrico , Danesi Romano , Peters Godefridus J , Cantore Maurizio
Published: March 2020

10611

Background: Cholangiocarcinoma (CCA) is an aggressive tumor arising from biliary tract epithelium.CCA is the second most common primary hepatic malignancy, with a progressive increasing incidence in western countries. Polycomb group protein Enhancer of Zeste homolog 2 (EZH2) is overexpressed in several human carcinomas, including CCA, where EZH2 overexpression is associated with tumor progression. The aim of this study is to evaluate the correlation between candidate EZH2 Single Nucleotide Polymorphisms (SNPs) with clinical outcome in CCA patients. Methods: Genomic DNA was extracted from blood samples of 75 patients [44 male and 31 female, with average age of 62.3 (range, 26-80 years)] affected by hystologically confirmed advanced CCA, treated with the epirubicin-cisplatin-xeloda (ECX) regimen. We performed an in silico characterization to select EZH2 SNPs (rs2302427 C/G, rs6464926 C/T, rs17171119 T/G and rs887569 C/T) from 26 EZH2 SNPs described previously. Genotyping was performed through Taqman PCR. Prognostic value of selected EZH2 SNPs was assesses by correlation with time to progression (TTP) and overall survival (OS). OS and TTP curves were obtained through Kaplan-Meier method, and comparison with survival distribution was evaluated with logrank test. Results: Through specific software (PROMO 3.0, MicroSNiper and Gene Card) we performed an in silico analysis based on functional characterization criteria (transcription factor binding-TFB, miRNA binding and missense mutations). We selected 4 EZH2 SNP alleles showing specific relevance in CCA because of their differential TFB affinity (PPARα/RXRα, E2F-1, Pax-5 and p53). The rs887569 C/T SNP was significantly associated with clinical outcome. The TT genotype predicted a significantly longer OS in CCA patients (TT vs CT-CC p=0.026). Moreover, the TT genotype showed a trend-like association with reduced risk of death (HR=0.59, 95%CI=0.33-1.05, p=0.075), at multivariate analysis. Conclusions: These results suggest the role of rs887569 EZH2 SNP as a possible predictive marker of OS in advanced CCA patients treated with ECX regimen, and offer a potential new tool for treatment optimization.
Effect of everolimus on angiogenic biomarkers in patients with tuberous sclerosis complex (TSC): Results from EXIST-1 and EXIST-2.
Authors: Franz David Neal , Kingswood Christopher , Jozwiak Sergiusz , Budde Klemens , Belousova Elena , Sparagana Steven , Zonnenberg B. A. , Frost Michael , Shah Gaurav D. , Lebrec Jeremie , Ford James , Kalfoglou Creton , Chen David , Bissler John
Published: March 2020

10619

Background: The efficacy and safety of everolimus, an oral mTOR inhibitor, was assessed in two randomized, double-blind, placebo-controlled, phase 3 trials: EXIST-1 (NCT00789828) and EXIST-2 (NCT00790400). EXIST-1 examined everolimus for the treatment of subependymal giant cell astrocytoma (SEGA) associated with TSC and EXIST-2 for the treatment of renal angiomyolipoma (AML) associated with either TSC or sporadic lymphangioleiomyomatosis. In each instance, everolimus was superior to placebo for the primary endpoints, SEGA and renal AML response rates. Inhibitors of mTOR have antiangiogenic effects on tumor growth in vitro and in vivo. Methods: Patients were randomized to receive everolimus (n=78) starting at 4.5 mg/m2/day (target trough, 5-15 ng/mL) or placebo (n=39) in EXIST-1 and 10 mg/day everolimus (n=79) or placebo (n=39) in EXIST-2. Plasma samples were taken at baseline and pre-dosing on day 1 of weeks 4, 12, 24, 36, and 48 of treatment. Angiogenic markers of interest were vascular endothelial growth factor (VEGF)-A and -D, placental growth factor (PlGF), soluble VEGF receptor-1 (sVEGFR1), soluble VEGF receptor 2 (sVEGFR2), c-Kit, and collagen type IV. Results: Compared with placebo, a sustained ~30% and ~60% increase in VEGF-A was observed in the everolimus arm of EXIST-1 and EXIST-2, respectively. A concomitant decrease in collagen type IV (~25% EXIST-1; ~45% EXIST-2) and sVEGFR2 (~25% both trials) was also observed in the everolimus arm. A sustained decrease (~60%) in VEGF-D was observed in the everolimus arm of EXIST-2, but not EXIST-1. In both studies, no change was observed in PlGF, sVEGFR1, or c-Kit plasma concentrations in the everolimus arm or any biomarkers evaluated in the placebo arm. Baseline sVEGFR2 and VEGF-D were ~40% and ~4-fold higher, respectively, while VEGF-A was ~50% lower in EXIST-2 compared with EXIST-1. A similar baseline plasma concentration for the other biomarkers was noted in both studies. Conclusions: Patients presenting with SEGA or renal AML associated with TSC had a reduction in plasma concentrations of sVEGFR2, collagen type IV, and VEGF-D (AML only) and an increase in VEGF-A. Everolimus may have antiangiogenic properties in TSC patients.
Cost-effectiveness analysis using a Markov model assessing the addition of bevacizumab to paclitaxel in HER2-negative metastatic breast cancer patients.
Authors: Refaat Tamer , Choi Mehee , Gaber Germaine , Small William , Kiel Krystyna D.
Published: March 2020

1069

Background: Metastatic breast cancer (MBC) remains an incurable disease despite advances in treatment modalities. In 2008, Eastern Cooperative Oncology Group 2100 trial (E2100) results led to FDA approval for bevacizumab with paclitaxel in the initial treatment of HER2-negative MBC. The addition of bevacizumab to paclitaxel led to a gain of around 2.5 months of progression-free survival (PFS), no significant benefit on overall survival (OS), and increased toxicity. In November 2011, the FDA officially revoked approval of bevacizumab for HER2-negative MBC. However, both the European Medicines Agency (EMEA) and NCCN still endorse bevacizumab for this indication. One of the greatest challenges facing healthcare worldwide is reconciling incremental clinical benefits with exponentially rising costs. This study aimed to assess the cost-effectiveness of bevacizumab with paclitaxel for HER2-negative MBC. Methods: A Markov decision tree using Data 3.5 (TreeAge Software, Inc.) was created to do decision and cost-effectiveness analyses of using bevacizumab in combination with paclitaxel versus paclitaxel alone as first-line chemotherapy in HER2-negative MBC using efficacy and toxicity data from the E2100 study. Costs were obtained from the Center for Medicare Services Drug Payment Table and Physician Fee Schedule. The model was designed from the patient and payer perspectives and sensitivity analyses were run. Results: The marginal cost between paclitaxel alone versus bevacizumab and paclitaxel was 86K with a marginal efficacy of 0.369 quality-adjusted life-years and marginal cost effectiveness of 232,720.72 USD. The expected outcome value was 1.86 for bevacizumab and paclitaxel and 1.67 for paclitaxel alone. However, the combination was not cost effective and only a marginal survival advantage that was not significant was observed. Conclusions: This study demonstrates that, despite a significant PFS advantage, the addition of bevacizumab to paclitaxel is not cost-effective for patients with HER2-negative MBC. Such data could be informative to policymakers who consider the health economics and incremental cost-effectiveness of medical therapies.
Phase I trial of ixabepilone and vorinostat in metastatic breast cancer.
Authors: Luu Thehang H. , Blanchard Suzette , Beumer Jan Hendrik , Anyang Bean N. , Somlo George , Mortimer Joanne E. , Hurria Arti , Yang Lixin , Yen Yun
Published: March 2020

1070

Background: VOR, an HDAC inhibitor, induces acetylation of tubulin, and decreases resistance by attenuating downstream activation of AKT, c-Raf and HER-2. Patients (pts) with MBC treated with VOR had a TTP of 8.5 months (range 4-14) and stable disease in 29% (Luu et al., 2008). Our preclinical data showed synergistic effect of IXA and VOR in MDA-MB-231 and MCF7. Methods: The primary aims were to: 1) define the maximum tolerated dose (MTD) based on dose limiting toxicities (DLT), and 2) describe the pharmacokinetics (PK) of 2 schedules of VOR and IXA. Secondary aims were to describe: 1) response rate (RR) and 2) clinical benefit rate (CBR). The study included: 1) pts with MBC; 2) ECOG PS 0-2; 3) adequate marrow and organ functions; 4) no prior IXA or VOR; and 5) < grade (gr) 1 neuropathy. Stable brain metastasis were allowed. Pts were randomized to schedule A: VOR (QDx14) + IXA (D2) Q21D; or B: VOR (D1-7 and 15-21) + IXA (D2, 9, 16) Q28D. A modified toxicity probability interval design (target toxicity rate= 0.2 and equivalence range +/- 0.05) (Ji et al, 2010) determined dose escalation guidelines. PK were assessed with LC-MS/MS assays. Results: Among 37 pts randomized, 36 were evaluable [median age (55 yrs); median prior chemotherapy regimens (3); ER and/or PR + (64%); HER2 + (19%)]. In cohort A, 16 pts were treated (1 inevaluable). The MTD was: VOR 300mg (QDx14) + IXA (32mg/m2 D2) Q21D (dose level 1). DLT was experienced by 27% (4/15) pts [gr 4 neutropenia, gr 3 fatigue/AST, hyponatremia and allergic reaction to IXA]. In cohort B, 21 pts were treated (dose level 1, n=15; dose level 2, n=6). The MTD was VOR 300mg QD (D1-7 and 15-21) + IXA 16mg/m2 (D2, 9, 16) Q28D (dose level 1), no DLTs were observed. Dose level 2 was closed with 50% (3/6) of pts experiencing DLTs [gr 3 neutropenia, hypertension, and hypokalemia]. Median cycles treated (cohort A: 6, cohort B: 4). Response in cohort A and B respectively was: 1 CR, 2 PR, 7 SD (RR: 20%, CBR: 67%) and 1 CR, 4 PR, 9 SD (RR: 33%, CBR: 93%). VOR and IXA PK were not influenced by the presence of the other drug, clearance values= 220 L/h and 20 L/h/m2, respectively. Conclusions: We established the MTD of VOR and IXA in pts with MBC. The combination demonstrated clinical activity in these heavily pretreated pts. Further studies are recommended.
Impact of the delivery of adjuvant anthracycline-based nontaxane chemotherapy schedules on the outcome of breast cancer patients: Results from a retrospective database analysis.
Authors: Chirivella Isabel , Bermejo Begona , Insa Amelia , Perez-Fidalgo Jose Alejandro , Magro Ana , Rosello Keranen Susana , Martin Paloma , Bosch Ana , Lluch Ana
Published: March 2020

1074

Background: A dose-response effect has previously been observed with CMF and anthracycline-based schedules. The objective of this post-hoc analysis was to give additional information on the impact of chemotherapy delivery on patients’ outcome. Methods: Selection criteria were to have early breast cancer (stage I-IIIA) from Jan 1980 to Dec 2000, to undergo surgery as primary treatment and to receive an anthracycline-based non-taxane schedule in the adjuvant setting. G-CSF support was not given to any patient. Chemotherapy delivery was assessed based on ≥ 2 vs. < 2 delayed cycles, ≥ 15 vs. <15 delayed days and < 85% vs. ≥ 85% of the relative dose intensity (RDI) given. Patients’ outcomes were assessed based on 5- and 10-year disease-free survival (DFS) and overall survival (OS) rates. Results: 793 breast cancer patients with a median age of 51 years (21-79) were analyzed of whom 27% had stage IIIA and 23% had stage I disease. As shown in the table, 5- and 10-year rates of DFS and OS significantly improved when adjuvant chemotherapy was optimally delivered. Conclusions: The dose-response effect is a key factor that should be taken into account when an anthracycline-based non-taxane chemotherapy is administered in the adjuvant setting. Delays and/or reductions of chemotherapy should be avoided in order to achieve the maximal benefit for the patient. This study was partially funded by Amgen SA. [Table: see text]
Randomized phase II study of two doses of pixantrone in patients with metastatic breast cancer (N1031, Alliance).
Authors: Sideras Kostandinos , Moreno-Aspitia Alvaro , Tenglin Richard Charles , Liu Heshan , Lingle Wilma L. , Reinholz Monica Madden , Halling Kevin C , Chen Beiyun , Gross Gerald G. , Mowat Rex Bradford , Dakhil Shaker R. , Perez Edith A.
Published: March 2020

1083

Background: Pixantrone (Pix) is a novel aza-anthracenedione with structural similarities to mitoxantrone and promising activity against non-Hodgkin’s lymphoma. Due to the lack of iron binding it is theorized to exhibit less cardiotoxicity than the anthracyclines. Methods: N1031 is a phase II RCT of 2 schedules of Pix, in pts with MBC. Group A pts received 180mg/m2 IV q3 wks, and group B pts 85mg/m2 IV on days 1, 8, 15 q4 wks. Eligibility included prior exposure to anthracyclines and/or taxanes, and 1 to 3 regiments in the metastatic setting (minimum of 2 if no prior adjuvant therapy given). Due to lack of long term cardiac safety data no more than 12 cycles were allowed. Frequent cardiac imaging was performed per protocol. Primary endpoint was RR and secondary endpoints included PFS, OS, safety, and QOL. Planned sample size was 25 pts per group. Results: In total 46 pts were evaluable (23 per group), mean age 55.5 yrs (range 38-79), 37% PS 0, 52% PS 1, and 11% PS 2. 80% of pts had prior exposure to doxorubicin, 72% had prior (neo)-adjuvant therapy, 76% were ER+ and 57% received prior HT. Number of prior metastatic regiments was: 1 (28%), 2 (61%) and 3 (11%). Most common adverse events (%) of any grade were: alopecia (74), anemia (74), fatigue (85), nausea (67), ANC decrease (87), and skin disorder (41). Grade 3-4 adverse events (%) at least possibly attributed to Pix and occurring in at least 2 pts were: ANC decrease (57), fatigue (9), increased AST (4%). One pt from each group (4%) had a grade 3 decrease in EF. There were no major differences between the two groups except for more oral mucositis in group A (35% vs 4%). Median number of cycles was 3 in group A (range 1-12) and 2 in group B (range 1-8). There was only 1 confirmed tumor response per group (4%,95% CI: 0.1-22%) prompting early termination of the trial. The median PFS was 2.7 mo (95% CI: 1.8-3.8), and the median OS was 8.9 mo (95% CI: 7.5-N/A). Conclusions: Pixantrone has insufficient activity in patients with MBC exposed to prior anthracyclines and/or taxanes. Adverse events were similar to prior experience with Pix. There were no major differences between the 2 schedules of administration. There was no significant cardiac toxicity seen in this trial. Correlative studies are underway.
Methallotionein expression and outcome in patients with metastatic breast cancer (MBC).
Authors: Rios-Perez Jorge Arturo , Abedin Sameem , Rosenzweig Margaret Quinn , Jung Su Yon , Bhargava Rohit , Brufsky Adam
Published: March 2020

1085

Background: Platinum-based agents are important components of therapy of metastatic breast cancer (MBC) and triple negative breast cancer. Their use can be limited by development of resistance. Metallothioneins (MT) are low molecular weight proteins believed to bind bivalent metal ions such as platinum and zinc. MT expression has been associated with decreased survival in breast cancer patients. A proposed mechanism confers resistance to platinum-based agents by their inactivation or limitation of their activity by MT binding. Methods: MT expression in 99 women with MBC (selected at random from our database of 800 women with MBC) was determined from primary breast cancer tissue (n=80) or metastatic tissue n=19). MT expression was determined by immunohistochemistry, and graded as negative, weak, moderate or strong. Clinical data was obtained through our database and supplemented by chart review. Overall survival from breast cancer diagnosis (OS), progression free survival for first metastastic regimen (PFS), and time from first metastasis to death or last update (metastatic survival, MS), were calculated through December 2011 using the log rank test. Results: Consistent with prior studies, moderate to strong MT expression was associated with decreased 5-year OS (p=.03). There was no correlation between MT expression and PFS or MS in this cohort. Surprisingly, MT expression at any degree was strongly associated with better MS in patients with MBC that received carboplatin-based regimens in the first line (n=25, p=.0005) or at any line (n=41, p=.0437). Conclusions: Consistent with prior studies, MT expression was associated with decreased survival in patients with MBC. Surprisingly, MT expression was associated with longer MS in patients with MBC that received carboplatin. These findings are inconsistent with the hypothesis that MT expression causes chemoresistance to platinum based agents in patients with metastatic breast cancer. Further studies are needed to elucidate the mechanisms behind these findings.
Amrubicin as second- or third-line treatment for patients with HER2-negative metastatic breast cancer (MBC): A phase II trial of the Sarah Cannon Research Institute (SCRI).
Authors: Barton John H. , Raefsky Eric , Harwin William N. , Inclan Alejandro A. , Miletello Gerald , Hainsworth John D. , Burris Howard A. , Yardley Denise Aysel
Published: March 2020

1086

Background: Anthracyclines demonstrate significant activity in breast cancer, but the potential for cardiotoxicity is dose-limiting. Amrubicin is a novel anthracycline with broad-spectrum preclinical activity and low potential for cardiotoxicity. We present phase II results from a phase I/II trial of amrubicin as second/third- line therapy for HER2- negative MBC. Methods: Women with measurable HER2-negative MBC with 1 or 2 prior chemotherapy regimens for metastatic disease and normal LVEF were eligible. Prior anthracycline- containing adjuvant therapy was allowed. Amrubicin 110 mg/ m2 IV every 3 weeks was administered until disease progression or intolerable toxicity. Tumor assessments were performed every 6 weeks and LVEF assessments every 12 weeks. The primary endpoint was progression free survival (PFS); a median PFS ≥ 4.5 months was considered a study result meriting further development of amrubicin. Results: 48 evaluable patients (pts) were treated from 1/2010 to 9/2011. Baseline characteristics included median age 57; 23% were triple-negative; 33% had 2 prior chemotherapy regimens for MBC; 38% had anthracycline- containing adjuvant therapy. Median treatment duration was 6 weeks (2 cycles), range 1- 12+ cycles. 8 pts (17%) had objective RECIST responses (1 CR, 7 PR); 5 of the 8 responders had received anthracycline-containing adjuvant therapy. 24 additional pts (50%) had stable disease at first reevaluation. The median PFS for all patients was 2.8 months (95% CI 1.6- 4.0 months); median PFS was similar for pts with 1 vs 2 previous regimens for MBC (95% CI 2.5 vs 4.0 months). 24% of pts were progression-free at 6 months. Neutropenia was the most common grade 3/4 toxicity (63%; 6% febrile neutropenia). No grade 3/4 non- hematologic toxicity occurred in > 5% pts. No cardiotoxicity occurred. Only 1 pt discontinued amrubicin due to toxicity (grade 2 fatigue). Conclusions: Amrubicin had good tolerability, no cardiotoxicity and was active as a second/third-line treatment for HER2- negative MBC, including pts previously treated with adjuvant anthracyclines. The median PFS was comparable to other standard single agents in the MBC setting.
Quantitative measures of FDG PET after neoadjuvant chemotherapy to predict breast cancer patient survival.
Authors: Currin Erin-Siobhain Ross , Dunnwald Lisa K , Doot Robert K , Schubert Erin K , Kurland Brenda F , Mankoff David A. , Specht Jennifer M.
Published: March 2020

1088

Background: In patients with locally advanced breast cancer (LABC), qualitative FDG positivity following neo-adjuvant chemotherapy (NC) has been shown to be inversely associated with survival (Emmering, Annals Oncol, 2008). We investigated quantitative measures of post-therapy FDG uptake, namely standardized uptake value (SUV) and glycolytic flux (Ki), as predictors of breast cancer survival. Methods: Forty-seven patients with LABC underwent dynamic FDG PET scans close to or at the end of NC and prior to surgical resection. Post-therapy FDG uptake at the primary tumor site was measured by mean SUV from 45-60 minutes after FDG injection, maximum SUV (SUVmax) from 50-55 minutes, and FDG glycolytic flux (Ki). Pathologic response (PR) was assessed for at the time of surgical resection. Cox proportional hazards models were used to estimate associations between log-transformed measures of post-therapy FDG uptake, PR and outcome. Results: Median SUVmax was 1.9 (0.9 – 9.2) and median Ki was 2.2 (0.02 – 47.7) mL/min/g. Median follow-up for relapse was 5.7 years with 11 events and 6.3 years for survival with 10 deaths. PR was not significant for DFS (p = .39) or OS (p= .48). Post-therapy FDG uptake measures showed a statistically significant ability to predict survival. SUVmax predicted DFS (p=0.02) and OS (p=0.01). Ki was associated with DFS (p <0.01) and OS (p <0.01). PET measured hazard ratios were not attenuated in multivariate analysis controlling for known prognostic markers such as primary tumor PR and nodal status. However, multivariate survival models appeared highly influenced by one patient with the shortest survival time (1.3 years) and highest SUVmax and Ki. Without this patient, Ki remained a borderline independent predictor of DFS (p= .08) and OS (p= .07), but SUVmax was no longer significant for DFS (p= .32) or OS (p=0.26). Conclusions: Our analysis suggests that quantitative measures of post-therapy FDG PET provide information beyond PR for predicting which LABC patients are at highest risk for relapse and death. This information may be useful in directing post-surgery treatment. Supported by NIH grants CA42045, CA138293, and CA148131.
Is there a need for sentinel lymph node biopsy in microinvasive breast cancer?
Authors: Kapoor Nimmi S. , Shamonki Jamie , Yoon Jeong Lim , Chung Cathie T. , Giuliano Armando E.
Published: March 2020

1105

Background: There is limited data on the long-term outcome of patients with microinvasive breast cancer. Moreover, predictors of lymph node involvement and the impact of multifocal microinvasion are not well understood. We examined the occurrence of nodal metastasis and the significance of multifocality on disease recurrence. Methods: Patients with T1mic breast cancer, defined as tumors ≤1mm, surgically managed at our institute between 1995-2010 were identified. Specimen slides were independently reviewed. Multivariable analysis (MVA) was used to predict lymph node involvement and disease recurrence. Results: Fifty-two patients with T1mic breast cancers were identified. Median patient age was 53 (range 30-92), median size of in-situ disease was 3cm (range 0.1-12cm). Ten patients (19.2%) had multiple foci of microinvasion (range 2-7). The majority of tumors were high-grade (76.9%). When the invasive tumor component was evaluated, 31 of 41 (73.8%) were ER positive, 40.5% were HER2+(15/37), and only one was ER-/PR-/HER2-. Twenty-nine patients (55.8%) had breast conserving surgery and 23 had mastectomies. Lymph nodes were assessed in 48 patients; there was 1 macrometastasis (2.1%), 4 micrometastases (8.3%) and 4 (8.3%) with isolated tumor cells. Seven of 9 patients with lymph node involvement underwent adjuvant chemotherapy. Univariable analysis showed that ER(-) invasive disease and high-grade DCIS tumors were more likely to have involved lymph nodes. On MVA, only negative ER status was a significant predictor of lymph node metastasis (p<0.02). At median follow-up of 83 months (range 6-172 months), 3 patients (6.3%) had disease recurrence (1 local, 1 distant, 1 local and distant) at 8, 17, and 130 months from presentation. All patients with recurrence had negative lymph nodes and only one focus of microinvasion. No factors predicted disease recurrence. Conclusions: Microinvasive breast cancer clearly has the ability to metastasize and recur, but in this series only 2% of patients presented with nodal macrometastasis. The evaluation of lymph nodes in T1mic cancer is unnecessary in the majority of patients. In our cohort, neither lymph node status nor multifocal microinvasion predicts recurrence.
Post-neoadjuvant chemotherapy sentinel node biopsy and axillary sampling for node negative (N0) axilla.
Authors: Parmar Vani , Nair Nita S. , Hawaldar Rohini W , Vanmali Vaibhav , Prabhu Aruna Laxman , Kaushik Rucha Vishal , Shet Tanuja , Desai Sangeeta , Badwe Rajendra A.
Published: March 2020

1108

Background: Post neoadjuvant chemotherapy (NACT) sentinel node biopsy (SNB) is not a standard of care due to the wide variability in false negative rate (FNR), varying from 5.7% to 33%. In operable breast cancer (OBC), FNR of less than 10% is acceptable. We attempted to find out the reliability of low axillary sampling(LAS), with dissection limited below the first intercostobrachial nerve, to correctly identify the node negative axilla in the post NACT clinically node negative (N0) patients. Methods: Women with large operable (LOBC) and locally advanced breast cancer (LABC), post-NACT clinically N0, underwent concomitant blue dye-colloid guided SNB and LAS. The identification rate, FNR, and negative predictive value (NPV) of both procedures were compared. Results: Post-NACT 209 eligible women underwent combined LAS and SNB procedure. At presentation, the tumors were large (median 5.0 cm) with 70% clinically palpable nodes. All patients received 4 cycles of neo-adjuvant anthracycline-based chemotherapy and were clinically node negative after chemotherapy. SNB was defined as blue and/or hot node plus palpable node(s). A blue or hot node (median 2 nodes) was identified in 93.8%, and median of 5 sentinel nodes were removed. The false negative rate of SNB was 15.3% (95% CI 8.7%-25.3%). The LAS technique comparatively had nodal yield in 98.5% with median 8 nodes removed; and FNR 8.5% (95% CI, 4.2%-16.6%, p=0.19). Comparative NPV for LAS and SNB were 94.6% and 91.8% respectively. Conclusions: Axillary sampling results for FNR and NPV are similar if not superior to SNB and could be a reliable method of axillary nodal evaluation in advanced breast cancers following neo-adjuvant chemotherapy.
Magnetic resonance imaging (MRI) evaluation of pathologic complete response (pCR) in different breast cancer subtypes after neoadjuvant chemotherapy (NAC).
Authors: Gonzalez-Cortijo Lucia , Hornedo Javier , Sainz de la Cuesta Ricardo , Hernandez-Cortes Gines , Perez-Carrion Ramon , Gonzalez Federico , Acevedo Agustin , del Cerro Elia , Linares Susana , Maldonado Antonio , Cabrera Antonio , Counago Felipe , Diaz-Gavela Ana , Rodriguez-Marquez Cristina , Henriquez Alexandra , Murillo Raquel , Martin del Yerro Jose Luis , Sanz Ignacio , Recio Manuel , Martinez de Vega Vicente
Published: March 2020

1111

Background: MRI is being used to address treatment response to NAC in breast cancer patients. However, its ability to predict pCR in histologically different tumors remains unclear. We tried to investigate the usefulness of MRI in evaluation of pCR in different breast cancer subtypes after treatment with NAC. Methods: Serial MRI studies were acquired before, during and after NAC in 75 evaluable patients. MRI interpretation included lesion size, morphology and dynamic enhanced evaluation imaging with initial and late enhancement. On the basis of the final MRI, response was determined to be a clinically complete response (CCR) when no residual tumor and no late enhancement were found. By using inmunohistochemistry and fluorescence in situ hybridization (FISH) for human epidermal growth factor receptor 2 (HER2/neu) amplification, tumors were divided into three subtypes: triple negative, HER2 positive, and estrogen receptor (ER) positive/HER2 negative. Every patient received chemotherapy with taxanes and anthracyclines and HER2 positive tumors were treated with trastuzumab. All patients received surgery. pCR was defined as no residual invasive tumor in the surgical specimen. Ductal carcinoma in situ residual disease was considered pCR. Results: 22 of 75 patients (29%) achieved a CCR on the final MRI. Of 22 patients with CCR all 22 (100%) were confirmed pathologically. 19 were pathologic complete responses and 3 showed in situ microscopic residual disease. 12 (55%) were HER2 positive tumors, 4 (18%) were triple negative tumors and 6 (27%) were ER positive/HER2 negative tumors. The negative predictive value of MRI for predicting pCR after NAC was 100%. Conclusions: Absence of both residual tumor and late enhancement in MRI predict pCR with high accuracy in triple negative, HER2 positive and ER positive/HER2 negative breast cancer after NAC.
Comparison of long-term results of endoscopic video-assisted breast surgery (VABS) between transaxillary retromammary approach (TARM) and periareolar approach.
Authors: Yamashita Koji , Haga Shunsuke , Shimizu Kazuo
Published: March 2020

1112

Background: The breast conserving surgery (BCS) and the sentinel node (SN) biopsy became to be recognized as the standard treatment for early breast cancers. We have reported about cosmetic effectiveness and lower infestation of the video-assisted breast surgery (VABS) for the breast diseases. We devised the trans-axillary retro-mammary (TRAM) approach of VABS. It needs only one skin incision in the axilla and can treat any tumor of the breast without making any injuries on the breast skin. We evaluated the aesthetic results and the curability of this surgical method. Methods: We have performed VABS on 300 patients since December, 2001. The newly devised TARM was performed on 120 patients of early breast cancer, stage I and II. After endoscopic SN biopsy, we elongated the axillary skin incision to 2.5 cm. We dissected major pectoral muscle fascia to detach retromammary tissue behind the tumor. We cut the mammary gland with clear surgical margin, and removed it through the axillary port. The breast reconstruction was made by filling absorbable oxydized cellulose. The postoperative aesthetic results were evaluated by ABNSW. Results: BCS was performed on 286 patients (26 after preoperative chemotherapy) and skin-sparing mastectomy on 14. There was no serious complication after surgery. Surgical margin was minimally positive in 2. The original shapes of the breast were preserved well. The follow-up is 126 months at maximum and 74 months on average. There is 3 locoregional recurrences and 14 distant metastases. 5-year survival rate is 97.3%. With regard to TARM, The skin incision only in the axilla made better looks and shapes of the breast. It could be applied for tumors in any area of the breast without tumor nipple extension. The reconstruction with oxidized cellulose needs no excessive detachment of the skin beyond the surgical margin. The postoperative esthetic results were excellent and better. The sensory disturbance was minimal. All patients expressed great satisfaction. Conclusions: VABS can be considered as a good surgical procedure concerning locoregional control and esthetics. TARM is better on the patients without tumor nipple extension.
Predictors of recurrence in postmastectomy patients with one to three positive lymph nodes.
Authors: Moo Tracy-Ann , McMillan Robert , Lee Michele , Stempel Michelle , Patil Sujata , Ho Alice Y. , El-Tamer Mahmoud
Published: March 2020

1118

Background: Although the role of post mastectomy radiation therapy (PMRT) is well established in women with ≥ 4 positive axillary lymph nodes (ALN), its indications in patients with 1-3 positive ALN is controversial. A recent large meta-analysis suggested a survival benefit in patients with 1-3 positive ALN who received PMRT. However, because recurrence rates in this group are low, identifying a subgroup of patients at higher risk for locoregional recurrence (LRR) could aid decision-making about PMRT. Methods: From an institutional database, 1,333 breast cancer patients who underwent mastectomy between 1996 and 2006 and had 1-3 positive ALN were identified. Among these, T3/T4 tumors and those who received PMRT were excluded. 926 patients were analyzed. The Kaplan-Meier method and Cox regression was used to explore clinicopathologic features that predicted LRR, distant metastases (DM), and recurrence-free survival (RFR). Results: Median follow-up was 7yrs. LRR occurred in 49 patients and DM in 126 patients. LRR and/or DM occurred in 146. On univariate analysis, factors significantly affecting LRR recurrence were increasing tumor size (p=0.04), age <50 (p=0.003), histologic grade (p=0.03), nuclear grade (p=0.008), lymphovascular invasion (LVI) (p<0.0001), and macroscopic ALN metastases (p=0.02). On multivariate analysis, age <50 (p=0.0012) and the presence of LVI (p<0.0001) predicted a higher LRR; increasing tumor size (p=0.0005), age <50 (p=0.04), higher histologic grade (p=0.01), number of positive ALN (p=0.04), LVI (p=0.02), macroscopic ALN metastases (p=0.02), and no chemotherapy (p=0.02) predicted a significantly lower RFR. Conclusions: Pts with T1-2 tumors and 1-3 positive ALN are at low risk of isolated LRR; however, patients <50 and with LVI may have additional risk that warrants consideration of PMRT.