bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic profiling of a clinically annotated cohort of locoregionally advanced head and neck cancers (HNC) treated with definitive chemoradiotherapy.
Authors: Seiwert Tanguy Y. , Keck Michaela K. , Zuo Zhixiang , Khattri Arun , Brown Christopher , Stricker Thomas , Rieke Damian , Lingen Mark W. , Cohen Ezra E. W. , White Kevin P. , Vokes Everett E.
Published: March 2020

5517

Background: Recent advances in genomic technology and sequencing have allowed the near comprehensive characterization of genetic abnormalities in HNC, but their correlation with clinical outcome remains to be determined. We analysed a clinically annotated cohort of locoregionally advanced HNC for copy number changes and mutations and correlated with outcome in an exploratory fashion. Methods: 120 head and neck cancers (frozen tissue) and matching normal tissues/blood from patients with locoregionally advanced HNC treated with definitive chemoradiation +/- induction at the University of Chicago were obtained from our tissue bank. DNA, RNA, protein were extracted. Barcoded, multiplexed sequencing libraries for 500 head and neck cancer associated genes (Agilent capture) were built and sequenced on Illumina HiSeq next generation sequencers. 150 commonly copy number altered and HNC relevant genes were analysed for copy number alterations (CNA) using the Nanostring nCounter platform. Respective genetic aberrations in curated pathways were allocated to tumor subgroups. Exploratory analysis correlated data with induction response and progression free survival. Confirmatory HPV testing was performed using an E6, nested, multiplex PCR. Results: ≥80% of targeted sequences were successfully captured and sequenced. Commonly mutated genes included: TP53, CDKN2A, PIK3CA, NOTCH1. Of note PIK3CA mutations were enriched in HPV(+) tumors. Commonly copy number altered genes included amplifications of VEGF1, CCND1, MYC, EGFR, MDM4, CTTN, as well as PIK3CA, and deletions of CDKN2A, SUCLG2, FHIT, TGFBR2, PTPRD, IKBKG, TRAF6, and RASSF1. CCND1, and MYC were commonly co-amplified and correlated with poor progression free survival, representing a distinct HNC phenotype. Analysis for additional genes and influence on induction response will be presented. Conclusions: Targeted, medium throughput genomic profiling is feasible, and provides the majority of HNC specific genetic aberrations at a comparably low cost. Impact on outcome (CCND1/MYC amplification) and potential treatment targets (PIK3CA mutations in HPV(+) tumors) were identified.
Lenvatinib treatment of advanced RAI-refractory differentiated thyroid cancer (DTC): Cytokine and angiogenic factor (CAF) profiling in combination with tumor genetic analysis to identify markers associated with response.
Authors: Ball Douglas Wilmot , Sherman Steven I. , Jarzab Barbara , Cabanillas Maria E. , Martins Renato , Shah Manisha H. , Bodenner Donald , Newbold Kate , Licitra Lisa F. , Topliss Duncan , Allison Roger , Kadowaki Tadashi , Funahashi Yasuhiro , Matijevic Mark , Sachdev Pallavi , O'Brien James P. , Schlumberger Martin
Published: March 2020

5518

Background: Lenvatinib is an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFRβ. In a phase II study of lenvatinib, 58 patients (pts) with DTC were enrolled and a response rate of 50% was observed (Sherman, ASCO 2011). Methods: Pts received lenvatinib at a starting dose of 24 mg oral once daily in 28-day cycles. Serum was collected at baseline (BL), on day 8 and on day 36 and concentrations of 47 CAFs were measured using multiplex bead arrays and enzyme-linked immunosorbent assay (ELISA). 33 genes (443 mutations) were examined in archival tumor tissues (n=25). Association of baseline CAF, changes in CAF levels upon treatment and gene mutation status with treatment outcomes was investigated. Results: Combination of low baseline VEGF and ANG-2 (p=0.02 and HR=0.386) correlated with longer PFS. Both baseline and changes in CAF levels demonstrated an association with gene mutation status. High baseline levels of VEGF were observed in pts with wild type RAS and BRAF (p=0.035) whereas high baseline sTIE-2 levels associated with RAS mutation (p=0.023). Supporting pre-clinical mouse xenograft tumor model developed using ANG2-overexpressing human thyroid cancer cell line FTC-286 demonstrated reduced sensitivity to lenvatinib treatment. Increased levels of IL-10 and FGF-2 8-day post-treatment (8d post-tx) significantly associated with RAS (N- or K-) and BRAF mutation. Combination of gene mutation status with baseline CAF levels provided better prediction of longer PFS compared to gene mutation alone. Hierarchical clustering modeling using changes in CAF levels 8d post-tx with tumor shrinkage identified a set of CAFs that could predict two categories of lenvatinib response: longer PFS and greater tumor shrinkage or longer PFS in the absence of significant tumor shrinkage. Conclusions: CAF profiling identified potential predictive biomarkers of lenvatinib treatment outcomes in DTC. Combination of RAS and BRAF mutation with baseline VEGF and ANG-2 or treatment-associated changes in FGF-2 and IL-10 level correlated with lenvatinib treatment response.
New DNA methylation markers associated with oral cancer (OC) development (dvlpt).
Authors: Saintigny Pierre , Lang Wenhua , Jelinek Jaroslav , Pickering Curtis R. , Feng Lei , Frederick Mitchell J. , Zhang Li , Ren Henning , Lee J. Jack , Kim Edward S. , Fan You Hong , El-Naggar Adel K. , Hong Waun Ki , Myers Jeffrey , Papadimitrakopoulou Vassiliki , Issa Jean-Pierre , Lippman Scott Michael , Mao Li
Published: March 2020

5524

Background: We have reported that DNA methyltransferase-3B (DNMT3B) gene expression is a strong predictor of OC dvlpt. Using high-throughput DNA methylation profiles of oral preneoplastic lesions (OPL), we identified 86 candidate genes that were hypermethylated in patients (pts) developing OC and suggested that a CpG island methylation phenotype may occur early during OC dvlpt. Our aim was to validate some of the candidate genes and to study the value of LINE1 repetitive element methylation, a surrogate of global DNA methylation, as biomarkers of risk to develop OC. Methods: Validation cohort included 40 pts with a median follow-up of 4.2 years, including 14 pts who developed OC. None of them were used in the discovery phase. Frozen OPL were collected prospectively and subject to DNA extraction. We performed a quantitative analysis of the degree of methylation of LINE1, and AGTR1, FOXI2, PENK, and HOXA9 promoters CpG sites using pyrosequencing. Results: The degree of methylation of AGTR1 (Mann-Whitney P<0.0001), FOXI2 (P=0.0002), PENK (P<0.0001), but not HOXA9 (P=0.0714) was significantly higher in pts who developed OC. On the contrary, LINE1 methylation was significantly lower in pts who developed OC (P<0.0001). The median percent of methylation was used to dichotomize the pts into high versus low methylation levels. Oral cancer-free survival (OCFS) was significantly worse in pts with high levels of AGTR1 (Log-rank P=0.0229), FOXI2 (P=0.0170), and PENK (P=0.0142) promoter methylation. No significant difference was found with HOXA9. A Methylation Index (MI) was developed by averaging the percent of methylation of AGTR1, FOXI2, and PENK promoters; pts with a high MI had a worse OCFS (P=0.0031). On the other hand, pts with low levels of LINE1 methylation had a significantly worse OCFS (P=0.0118). Finally, in 26 pts, a positive correlation was observed between DNMT3B gene expression levels and the MI (rho=0.65, P=0.0003); surprisingly, there was a negative correlation with LINE1 methylation (rho=-0.74, P<0.0001). Conclusions: AGTR1, FOXI2 and PENK promoter methylation may be associated with increased OC risk in pts with OPL and correlate with DNMT3B expression. Global DNA hypomethylation is an early event in OC dvlpt.
Effects of low-level laser therapy in the prevention and treatment of concurrent chemoradiotherapy induced oral mucositis: A triple-blind randomized controlled trial.
Authors: Saxena P.U. Prakash , Fernandes Donald Jerald , Gautam Ajay , Maiya Arun , Sharan Krishna
Published: March 2020

5526

Background: Oral mucositis (OM) is the most cumbersome acute side effect of concurrent chemoradiotherapy (CCRT) for head and neck cancer (HNC). OM associated pain affects oral function also may lead to CCRT break. Several modalities have been tried to prevent and treat this complication but none has been proved successful till date. We used prophylactic Low Level Laser Therapy (LLLT) for the prevention and treatment of CCRT induced OM. Methods: In this triple blind study, 221 HNC patients scheduled to undergo CCRT were randomized into laser (n=111) and placebo (n=110) group. Laser group received LLLT (Helium Neon laser, λ=632.8nm, P=24m, W=3.0J/cm2) while placebo received sham treatment daily prior to radiation for 45days. Oral Mucositis (OM) (RTOG/EORTC Scale), oral pain (Visual Analog Scale - VAS), dysphagia (Functional Impairment Scale - FIS), weight loss, duration of analgesic use were assessed. Data was analyzed using frequencies and percentage, generalized estimating equations (GEE) and Odds ratio. Results: There was significant reduction in incidence of severe OM (F=16.64, degree of freedom df=8,876, p<0.0001) and its associated pain (F=25.06, df=8,876, p<0.0001) and dysphagia (F=20.17, df=8,876, p<0.0001) and loss of weight (F=87.56, df=8,876, p<0.0001) when compared between the Laser and placebo group. The duration of step III analgesia required was also significantly lower (p<0.001) in laser (3.2 ±1.4days) than placebo (6.7 ±2.6days) group. Conclusions: LLLT was able to decrease the incidence of CCRT induced severe OM its associated pain, dysphagia, weight loss and the duration of analgesic use. [Table: see text]
A phase II trial of cetuximab in high-risk premalignant lesions of the upper aerodigestive tract.
Authors: Califano Joseph A , Ferris Robert L. , Epstein Joel Brian , Gillespie Marion Boyd , Feldman Lawrence Eric , Gibson Michael K. , Pytynia Kristen B. , Khan Zubair
Published: March 2020

5528

Background: High risk head and neck premalignancy includes patients with prior HNSCC and loss of heterozygosity (LOH). These patients demonstrate 30-60% rates of progression to malignancy despite conventional surgical excision. We performed a phase II trial using short term therapy with cetuximab, a humanized monoclonal antibody directed against EGFR, in the treatment of high risk premalignant lesions of the UADT. Methods: Inclusion criteria required; 1) presence of 3p, 9p21, or 17p LOH, and/or 2) surgically unresectable high grade premalignant lesions, and/or 3) high grade premalignancy after curative therapy for HNSCC. Patients received cetuximab 400 mg/m2 on week one followed by 250 mg/m2 on week 2-8 or observation, with the option for crossover to cetuximab for patients originally randomized to the observation arm. Histologic grade (1=benign, 2=mild dysplasia, 3=moderate dysplasia, 4=severe dysplasia/carcinoma in situ, 5=invasive cancer) and change in grade of dysplasia was evaluated. Results: 19 patients were enrolled. Two patients discontinued therapy due to toxicity. We noted a decrease in grade of dysplasia in the cetuximab treated group (-1.0) vs. the observation group (-0.2), (Wilcoxon test p value = 0.18). In the observation group, 0/5 patients (0%) underwent complete resolution of dysplasia; while 4/12 (33.3%) treated patients had no remaining dysplasia after therapy (p = 0.26), three of these patients had complete resolution of dysplastic changes after cetuximab therapy alone. Of these three patients, two have had no recurrence of leukoplakia or dysplasia at 1.5 and 2 years. One patient treated with oral cavity dysplasia has had no recurrence of dysplasia or lesions within the oral cavity, but developed a hypopharyngeal cancer at 1.5 years after trial completion. Of 5 patients randomized to observation, three underwent crossover to cetuximab therapy, and two of these three patients had complete resolution of dysplasia. Conclusions: EGFR blockade with cetuximab alone can result in significant, durable, and complete clinical and histological resolution of moderate to severe dysplasia in at least a subset of high risk patients.
Chemotherapy-induced amenorrhea in premenopausal breast cancer patients treated with adjuvant anthracycline and taxane based chemotherapy within the SUCCESS study.
Authors: Neugebauer Julia Katharina , Rack Brigitte Kathrin , Kupka Markus , Dinkel Carina , Jaeger Bernadette Anna Sophia , Ortmann Uta , Schneeweiss Andreas , Schrader Iris , Tesch Hans , Rezai Mahdi , Soeling Ulrike , Noeding Stefanie , Zabel Frauke , Sommer Harald Leo , Friese Klaus , Beckmann Matthias W. , Janni Wolfgang
Published: March 2020

554

Background: Chemotherapy induced amenorrhea (CIA) is often used as a surrogate marker for cytotoxic gonadal damage. The aim of this analysis was to identify predicitve factors for CIA in premenopausal breast cancer patients treated with adjuvant chemotherapy. Methods: The German multicenter, phase III SUCCESS trial compared 3 cycles of FEC q3w followed by 3x docetaxel q3w vs. FEC followed by Doc+gemcitabine as adjuvant treatment in patients with node positive or high risk node negative primary breast cancer. Premenopausal patients with hormone receptor positive tumors underwent endocrine treatment with tamoxifen (Tam) for 5 years. Additional goserelin (GnRH) for 2 years was given in the following cases: Age <40 years at study entry, premenopausal hormone status or regular menses within 6 months after chemotherapy. We retrospectively investigated CIA rates of 1.189 initially premenopausal patients during disease-free follow-up. Results: Median age at diagnosis was 44 years (range 21-50). The median follow up time was 44 months (range 1-62). 791 patients (66.5%) received endocrine treatment. Tam intake was reported in 370 patients, GnRH in 29 patients, Tam+GnRH in 392 patients. In 963 patients (81.0%) CIA occurred for ≥3 months after chemotherapy. In 22.7% of initially amenorrheic patients CIA was temporary. 192 patients (16.2%) had continuous menstrual bleeding. In multivariate analysis the risk of CIA was significantly higher in older patients, increasing by factor 1.32 per life year (p<0.0001). Tam intake was also associated with increased CIA rates (p=0.0032). Patients with combined Tam+GnRH were more likely to resume menses compared to patients without endocrine therapy (p=0.0056). Factors like the cytotoxic regimen, tumor stage, grading, the patient`s BMI or the use of GnRH analogues as ovarian protectants during chemotherapy did not correlate with CIA rates. Conclusions: Age was the strongest predictor for CIA. Tam administered alone increased CIA rates. Opposite effects were observed for patients who received Tam+GnRH. The addition of gemcitabine to sequential anthracyline-taxane based chemotherapy did not influence CIA.
Feasibility and short-term efficacy of four facio-cervical fields’ conformal radiotherapy for nasopharyngeal carcinoma.
Authors: Zheng Wang fang , Zhenfu Fu
Published: March 2020

5568

Background: Conventional bilateral facio-cervical fields increased the local control and overall rates for nasopharyngeal carcinoma, and generated severe late complications, while intensity-modulated radiation therapy (IMRT) may take up a lot of labor power and material resources.This study was to explore feasibility and short-term efficacy of four facio-cervical fields’ conformal radiotherapy (4F-CRT) for nasopharyngeal carcinoma. Methods: Between November 2007 and June 2009, 101 patients with histology-proven nonmetastatic NPC were rolled into this study and received 4F-CRT. 90 of all patients received four cycles chemotherapy. Results: The treatment was completed for all patients within 7 weeks. The complete response (CR) rate was 95.0% (96/101) and the partial response (PR) rate 5.0% (5/101). Overall response was 100% for nasopharyngeal lesions. The CR rate was 90.0% (91/101) and the PR rate 7.0% (7/101) in lymph node lesions. One year local control, regional control, overall survival (OS) rate, metastasis-free survival (MFS) and disease-free survival (DFS) rate are 100%, 100%, 100%, 97%, 97%, respectively. The major toxicities observed were grades 1-2 leukocytopenia. Conclusions: 4F-CRT can generate desirable dose distribution of tumor volume for nasopharyngeal carcinoma. The short-term efficacy of 4F-CRT is satisfactory and its acute toxicities are tolerable.
Effects of vandetanib on body composition in patients with advanced medullary thyroid carcinomas: Results from a placebo-controlled study.
Authors: Massicotte Marie-Helene , Borget Isabelle , Leboulleux Sophie , Baudin Eric , Baracos Vickie E. , Mansouriah Merad , Schlumberger Martin , Antoun Sami
Published: March 2020

5569

Background: Muscle (MT) and adipose tissue (AT) share common intra cellular pathways with tumor, thus it is not surprising to observe metabolic consequences with targeted therapies. The aim of the study was to assess the effects of vandetanib, a tyrosine kinase inhibitor (TKI) which demonstrated efficacy for the treatment of advanced medullary thyroid carcinoma (MTC), on MT and AT. Methods: 33 patients (25 men and 8 women, mean age of 54 years) with metastatic MTC received vandetanib 300 mg/d (n=23) or placebo (n=10) in the setting of the ZETA study. Cross-sectional areas (cm2) of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and MT were assessed by computed tomography imaging at 3rd lumbar vertebra and were indexed for height (cm2/m2). Comparisons between treatment and placebo were made at 3 months, and long-term evolution was evaluated over 12 months. Results: At 3 months, compared to baseline, patients treated with vandetanib gained 1.5 kg, 1.3 cm2/m2 of MT, 5.1 cm2/m2 of VAT and 4.5 cm2/m2 of SAT. In contrast, patients under placebo lost 1.5 kg (p=0.02), 1.0 cm2/m2 of MT (p=0.009), 5.5 cm2/m2 of SAT (p=0.004) and gained significantly less VAT (0.6 cm2/m2) (p=0.02). At 12 months, compared to baseline, patients treated with vandetanib gained 2 kg (NS), lost 0.3 cm2/m2 MT (NS), gained 3.4 cm2/m2 of VAT (NS) and 8.7 cm2/m2 of SAT (95% CI, 1.1 to 16.2). A significant decrease of calcitonin (defined as ≤50% compared to baseline) was associated with higher weight (p=0.01), VAT (p=0.01), and total adipose tissue (p=0.02). Conclusions: Beyond its proved efficacy in MTC treatment, and despite common intracellular pathways, vandetanib is the only studied TKI to preserve MT and to restore AT. Further research is needed to explore whether the relationship between changes of VAT and vandetanib treatment results from a direct metabolic action of vandetanib or is a consequence of biochemical tumor control.
Correlation of microbiomic profiles with disease status and MDR1 methylation in head and neck squamous cell carcinoma (HNSCC).
Authors: Funchain Pauline , Bebek Gurkan , Bennett Kristi L , Burkey Brian , Eng Charis
Published: March 2020

5573

Background: Recent studies of the aerodigestive tract have uncovered the functional importance of the microbiome, the total collection of microorganisms that reside within the human host. Furthermore, specific bacterial species have been shown to be etiologic agents or show potential as a screening biomarker in cancers including gastric, colon and pancreas. Here, we hypothesize that specific microbial populations may contribute to HNSCC pathogenesis via epigenetic modifications in inflammatory- and HNSCC-associated genes. Methods: Matched tumor and adjacent normal fresh frozen tissue specimens were collected from 55 prospectively enrolled HNSCC patients. Microbiomic profiles were obtained using Sanger sequencing of 16S rDNA PCR products. Methylation status of four genes previously linked to HNSCC or inflammation (MDR1, IL8, RARB, TGFBR2) was assessed in 49 samples by combined bisulfite restriction analysis and by Illumina HumanMethylation27 chip. Principle component analysis and multivariate analysis of covariance (MANCOVA) were used to identify bacterial subpopulations significantly associated with HNSCC and relevant clinical variables. Results: In this cohort, median age is 62, male:female ratio is 3:2, 16% are HPV+. Specific bacterial subpopulations associate with HNSCC over normal tissue and correlate with larger tumor size and higher nodal stage (p<0.05). Furthermore, microbial populations can separate tumors by tobacco (p<0.005) but not alcohol (p>0.7) status. Bacterial profiles are independent of HPV status. MDR1 promoter methylation is seen in tumor samples but not in normal oral mucosa (22/49 vs 0/49), and associates with specific microbiomic subpopulations in the order Enterobacteriales and phylum Tenericutes (p<0.001). Additionally, MDR1 methylation correlates with regional nodal metastases. Conclusions: Specific bacterial subpopulations differ between normal and tumor tissue and show association to specific clinicopathologic features, suggesting a role for microbial profiling in HNSCC as a novel area of investigation for diagnosis, prognostication, and therapeutic targeting.
Identification of head and neck cancers (SCCHN) that may respond to dual inhibition of EGFR and HER3 signaling.
Authors: Shames David S. , Stern Howard , Walter Kim , Jiang Brittany , Fu Ling , Do An , Raja Rajiv , Wilson Tim , Settleman Jeff , Sliwkowski Mark X. , Pirzkall Andrea , Amler Lukas C.
Published: March 2020

5575

Background: Oncogenic signaling through the epidermal growth factor receptor family is one of the most frequent alterations found in human epithelial cancers. These receptor tyrosine kinases mediate their effects via high-level co-expression and homo- and heterodimerization events that drive tumor growth, metastasis, and survival. Extensive preclinical studies suggested that some cell lines depend on oncogenic autocrine signaling through HER3 (Wilson et al.). This phenotype was particularly prominent in cell lines derived from SCCHN and was strongly correlated with high HRG expression. Interestingly, two patients with SCCHN tumors that expressed high levels of HRG in our phase Ia trial (abstract #95245) of MEHD7954A, a dual-action human IgG1 antibody that blocks ligand binding to EGFR and HER3 (Schaefer et al.) had partial responses. To further explore the hypothesis that high-level HRG expression defines a sub-population of SCCHN that may be sensitive to agents targeting HER3, and to identify other potential target indications for the development of MEHD7954A, we evaluated the expression of HRG in large cohorts of multiple solid tumor indications. Methods: HER3 and HRG expression was analyzed by qRT-PCR in 648 formalin-fixed paraffin embedded primary tumor samples from patients with NSCLC, SCCHN, melanoma, CRC and triple-negative breast cancer. Results: SCCHN-derived tumor samples had the highest levels of HRG expression, exhibiting a bimodal distribution in SCCHN – a pattern that is clearly distinct when compared to other tumor types. These data suggest that high HRG levels and potentially HER3-dependent autocrine signaling occur more frequently in SCCHN than in other tumors. Further we investigated whether overexpression of HRG in SCCHN correlated with stage and disease outcome. Updated results from these extended studies will be presented. Conclusions: SCCHN tumors exhibit bimodal expression of HRG, suggesting that HRG expression levels may be useful in identifying a subset of patients most likely to benefit from inhibition of HER3 activity. Antitumor activity in such patients has been observed in a phase I study of MEHD7954A (abstract #95245).
Aromatase inhibitors and cardiac outcomes in women undergoing cardiac angiography after early breast cancer.
Authors: Seruga Bostjan , Zadnik Vesna , Grasic Kuhar Cvetka , Marinko Tanja , Zorman Darko , Cufer Tanja , Zakotnik Branko , Ocana Alberto , Amir Eitan
Published: March 2020

558

Background: Data show that in post-menopausal women with early breast cancer, longer use of aromatase inhibitor (AI) is associated with increased odds of ischemic heart disease. Here we explore the association between adjuvant AI use and cardiac disease in women undergoing cardiac angiography after a diagnosis of early breast cancer. Methods: We linked a database of 7,681 women who underwent cardiac angiography at the University Clinical Center of Ljubljana between December 2004 and November 2010 with the Cancer Registry for Slovenia. Women with early breast cancer that subsequently underwent cardiac angiography were identified. Information on cardiovascular risk factors was retrieved from the patients’ charts and from discharge letters after cardiac angiography. The endpoint of interest was a diagnosis of ischemic heart disease or left ventricular dysfunction (IHD-LVD) without evidence of valvular heart disease at the time of angiography. Conditional, logistic regression was used to test for associations between variables. Results: Among 117 eligible women 75% (n=88) were postmenopausal and 62% (n=73) had hormonal receptor positive (HR+) disease. Of these 42% (n=31) were treated with AI. Overall, 48% (n=56) of women were found to have IHD-LVD. In patients with HR+ breast cancer, use of AIs was significantly associated with IHD-LVD as compared to tamoxifen alone (HR 2.50, 95% CI 1.01-6.29, p=0.046). For each year of AI therapy, there was a trend for higher odds of IHD-LVD (OR: 1.25, 95% CI 0.95-1.67, p=0.116). This effect appeared independent of age, body mass index, baseline hypertension, hypercholesterolemia, diabetes and heart disease or prior anthracyclines exposure. Among all patients, use of anthracyclines and left-sided irradiation was associated with non-significant increases in IHD-LVD (HR 2.37, 95% CI 0.89-6.09, p=0.45 and HR 1.28, 95% CI 0.69-2.40, p=0.44 respectively). Conclusions: Compared to tamoxifen, AIs are associated with a time dependent increase in IHD-LVD. This risk appears independent of other risk factors for heart disease. Anthracycline exposure and left breast or chest wall radiation showed non-significant associations with IHD-LVD in this small cohort.
Neoadjuvant chemotherapy followed by definitive local treatment in locally advanced carcinoma maxillary sinus.
Authors: Patil Vijay , Prabhash Kumar , Noronha Vanita , Joshi Amit , Muddu Vamshi , Chauhan Bharat , Juvekar S , Chaukar D. , Chaturvedi Pankaj , Pai P. S. , Dcruz A. K.
Published: March 2020

5585

Background: Locally advanced carcinoma of maxillary sinus has been historically reported to have poor prognosis. We evaluated the role of neoadjuvant chemotherapy in improving the outcome in these patients. Methods: 41 patients with locally advanced borderline resectable (stage IVa) or unresectable maxillary carcinoma (stage IVb) were treated with induction chemotherapy between 2008 and 2011. The protocol included 2 cycles of chemotherapy, response assessment and multidisciplinary clinic review for definitive local treatment. The demographic profile, response to induction therapy, toxicity of chemotherapy, definitive treatment received, time to treatment failure (TTF) and overall survival (OS) were analysed. Univariate and multivariate analysis was performed to determine factors associated with response, TTF and OS. Results: The cohort of 41 patients had a median age of 48 years (22-71) with male preponderance (80.5%). The chemotherapy included two drugs (platinum and taxane) in 34 patients (82.9%) and three drugs (platinum, taxane and 5 FU) in 7(17.1%) The taxane utilized was docetaxel in 22 patients (53.7%) and paclitaxel in 19 patients (46.3%). There was no complete response, stable disease in 18 (43.9%), partial response in 16 (39%), and progression in 7 (17.1%) patients. All patients competed two cycles of chemotherapy, adequate dose intensity was maintained in 33 patients (78%) and there were no deaths. Post-induction, the treatment planned included surgery in 12 (29.3%), CT-RT in 24 (58.5%), radical RT in 1 (2.4%), palliative RT in 1 (2.4%) and palliative chemotherapy in 3 ( 7.3%) patients. Overall, the median TTF was 10.2 months. With 16 deaths, the median OS was not reached. Only response post-induction was significantly associated with better TTF (p=0.02). Grade 3 tumor (p=0.04) and baseline serum albumin more than 4 mg/dl (p=0.02) were associated with better OS. Grade 3-4 neutropenia, febrile neutropenia and loose motions were seen in 21.1%, 23.8% and 15.8% respectively. Conclusions: In unresectable maxillary carcinoma, induction chemotherapy has clinically significant benefit with acceptable toxicity. Response to induction was the only significant factor for improved TTF.
Pattern of symptoms in head and neck cancer (HNC) survivors treated with radiation therapy (RT): Association with systemic therapy.
Authors: Rosenthal David Ira , Gunn Gary Brandon , Garden Adam S. , Lu Charles , Mendoza Tito R. , Morrison William H. , Frank Steven J. , Beadle Beth Michelle , Phan Jack , Fuller Clifton David , Hanna Ehab Y. , Ang K. Kian , Cleeland Charles S.
Published: March 2020

5589

Background: We sought, in a large, long-term follow-up cohort, to determine benchmark cross-sectional analysis of HNC patient (pt) symptom profiles as a function of chemotherapy (CT)/RT strategy. Methods: Pts treated with RT with or without CT in remission > 18 mos. were surveyed with the MD Anderson Symptom Inventory–Head and Neck Module (MDASI-HN). Clinical data were extracted. Data were tabulated, and group comparison performed using non-parametric analyses. Results: 250 pts participated; 81% were male. Median age at RT was 54 years. 87% had oropharynx HNC. Most were T1/X (41%), 37% T2 and, 22% T3/4. For N-category, most were N2 (55%), <5% N3, and 40% NX-1. 18% had induction CT, 26% concurrent, 5% both, and 50% had none. At a median follow-up time of 5.9 years (range 2-15), 11% of pts were entirely symptom free, 31% reported ≤mild symptom severity, 20% ≤moderate, and 38% reported ≥1 symptom as severe. 16% of pts receiving RT alone and 11% sequential CT followed by RT were symptom free, vs. 1% of those receiving concurrent CT (chi-square p<0.01), and the symptom distribution profile was distinct (p<0.03). The proportion of pts who received concurrent CT reporting any severe symptom item was 44%, vs. 36% of those not receiving concurrent CT (p=n.s.). No difference was seen in the moderate to severe (M/S) symptom report by treatment group. For all MDASI-HN items, most pts rated “0” or “not present”, except dry mouth and difficulty swallowing items, where mild symptoms were most likely (36% and 33%). The most common symptoms rated M/S were dry mouth, swallowing, choking, fatigue, and mouth and throat mucus reported by 42%, 23%, 18%, 16%, and 16%. MVA demonstrated T-stage and primary site, but not CT cohort correlated with M/S symptom report. Conclusions: Cumulatively, most pts had no more that mild symptom severity, but a substantial group of pts experience M/S levels. The symptom severity profile was highest with concurrent CT, though this effect appears mediated by disease specific factors. The addition of sequential CT to RT did not to appear to alter M/S symptom report substantially; however, concurrent pts were almost never symptom free, in contrast to induction and no CT cohorts.
The impact of the Oncotype Dx breast cancer assay in clinical practice: Systematic review and meta-analysis.
Authors: Carlson Josh John , Roth Joshua A.
Published: March 2020

560

Background: Many studies have evaluated the Oncotype Dx Breast Cancer Assay (ODX) and its impact on adjuvant chemotherapy (ACT) treatment decisions. However, it can be difficult for clinicians and other stakeholders to interpret the collective findings of these studies, as they were conducted in diverse settings and have limited sample sizes. To address this issue, we conducted a systematic review and meta-analysis to synthesize ODX results and provide insights about the utility of ODX in actual clinical practice. Methods: We performed a systematic review of ODX studies using PubMed, Embase, ASCO, and SABCS. Studies were included if patients had ER +, node -, early stage breast cancer, reported use of ODX to inform actual ACT decisions, and reported outcomes of interest, including: 1) distribution of ODX recurrence scores (RS); 2) impact of ODX on ACT recommendations; 3) impact of ODX on ACT use; and 4) proportion of patients following the treatment suggested by the ODX RS. Results: A total of 28 studies met inclusion criteria. The distribution of RS categories was 48.8% low, 39.0% intermediate, and 12.2% high (21 studies, 4,156 patients). ODX changed the clinical-pathological ACT recommendation in 33.4% of patients (8 studies, 1,437 patients). In patients receiving ODX, receipt of ACT was: 28.2% overall, 5.8% low, 37.4% intermediate, and 83.4% high. High RS patients were significantly more likely to follow the treatment suggested by ODX vs. low RS patients RR: 1.07 (1.01–1.14). Conclusions: The pooled results for the impact of ODX on ACT recommendations are consistent with most individual studies to date. However, the proportion of intermediate RS results is nearly 2-fold higher than reported in the ODX development studies by Paik et al., which may have implications for the clinical utility and cost impacts of testing. Also, high RS vs. low RS patients were more likely to follow the ODX results, suggesting a tendency toward aggressive treatment despite a low ODX RS. Finally, there was a lack of studies on the impact of ODX on ACT use vs. standard approaches, suggesting additional studies are warranted. [Table: see text]
Evaluation of variables that may impact chemotherapy (CT) administration after determination of Oncotype DX (ODX) recurrence score (RS).
Authors: Bowen Kristina E. , Gilmore James W. , Szabo Stephen , Haislip Sally , Hassell Robert , Cooper Joseph , Richardson Steve , Fitzgerald Meghan , Feinberg Bruce A.
Published: March 2020

571

Background: Cardinal Health Specialty Solutions (CHSS) partners with payers to manage clinical care pathways in oncology and rheumatology. Observations from one such pathway with CareFirst BlueCross Blue Shield revealed lower than expected use of CT in patients (pts) with estrogen receptor-positive early-stage breast cancer (ESBC) at high-risk for recurrence by ODX RS. To better understand physician behavior, CHSS examined patterns of care in a large private practice oncology group with a robust EMR, Georgia Cancer Specialists (GCS). Pt characteristics and physician-prescribing patterns were analyzed to determine variables that most impacted the physician’s decision to treat high-risk pts with CT. Methods: Using the GCS EMR from 2009 to 2011, we retrospectively identified pts with ESBC (stage I-II, node-negative, estrogen receptor-positive, HER2-negative) who underwent ODX testing. We determined the number of pts with a RS value in the low- (RS <18), intermediate- (RS 18-30), and high-risk (RS ≥31) groups along with the number of pts who subsequently received CT in each category. The use of CT in high-risk pts was analyzed by pt age, tumor size, tumor grade, and physician prescribing patterns. Results: Of the 1908 pts identified with ESBC, 788 were eligible for ODX testing and 288 (37%) underwent testing. Fifty percent of pts were in the low-, 34% in intermediate-, and 16% in the high-risk groups. Six percent of low-, 41% of intermediate-, and 83% of high-risk pts received CT. In high-risk pts analyzed by age, CT was used in 100% of pts ≤ 45 years (y), 86% in pts 46-55 y, 86% in pts 56-65 y, and 25% in pts >66 y. CT use in high-risk pts was 82% and 86% in pts with tumor sizes <2 cm and 2-5 cm, respectively; and, 100%, 60%, and 91% in pts with grade 1, 2, or 3 tumors, respectively. Of the 41 physicians who were evaluated, 10 (24%) used ODX <15% of the time, 13 (32%) used ODX 15-40%, 10 used (24%) used ODX 41-60%, and 8 (20%) used ODX > 60% of the time. There were no significant differences in patterns of CT use. Conclusions: The less than expected use of CT in high-risk patients appears to be related to physician preference and pt age. Tumor size and grade did not appear to influence choice of therapy.
Complementary role of Ki67 index and 70-gene signature (MammaPrint) high-risk patients in the St Gallen risk group with uncertain chemotherapy suggestion.
Authors: Pronzato Paolo , Mustacchi Giorgio , Generali Daniele Giulio , Bottini Alberto
Published: March 2020

579

Background: St Gallen (SG) Consensus Panel on adjuvant treatment recommends the use of proliferation markers and multigene assays when choosing the appropriate treatment in addition to traditional parameters. Ki67 predictive/prognostic value is widely accepted; we tested its role in increasing the accuracy of risk prediction among Mammaprint (MP) /High(HR) or /Low Risk (LR) breast cancer patients with a SG risk uncertain for chemotherapy selection. Methods: MP was determined (courtesy of Agendia, Amsterdam) in 3 Italian Hospitals on 305 consecutive samples of breast cancer patients. We focused on SG “Intermediate Risk” Group (HER2 neg, no VI and: ER>10<50%, or G2 or Ki67 >15<30% or N1a or T>2<5cm), where the indication for adjuvant CHT still remains uncertain. In MP/HR cases, a “low” Ki67 value (<15%) was used to eliminate CHT suggestion and viceversa an “intermediate” Ki67 value (>15<30%) in MP/LR cases. Results: Overall, 72/305 pts (26.6%) were in SG intermediate risk group with a median age of 64 years (26-98). Ki67 was non available in 4.1% of cases, MP rejected in 16.6%, HR was detected in 39 (54.2%), whereas LR in 21 (29.2%). Ki67 resulted low in 23 MP/HR cases (59%), intermediate in 6 MP/LR cases (28.5%) and in 3 out 12 MP/Rejected cases (25%). The overall concordance between MP and Ki67 was 28/57 (49.1%), MP rejected excluded. Overall MP suggested 39/60 CHT (65%), Ki67 29/69 (42%). Conclusions: The risk of relapse is a continous variable and MP evaluates it in a dichotomy (low vs high) wich could decrease the accuracy of the test. In the selected SG Group, the average risk of 5 yr relapse is around 20% (EBCTCG, Lancet 2011) and MP HR cases in our experience account for 55%. A low Ki67 value could help avoid more than 20% of cytotoxic treatments suggested by MP. In the same way, according to an ER value <50% (2 cases), an intermediate Ki67 value could suggest a more aggressive treatment in a further 13% of cases MP LR (6/21) or Rejected (3/12). MP probably overestimates the risk in 20% of cases and underestimates it in further 20%. Ki67 could be usefull for a more personalized treatment in patients where the indication for adjuvant chemotherapy added to endocrine treatment is uncertain.
Immunocytochemistry staining for ER and PR in circulating tumor cells as compared to primary tumor or metastatic biopsy.
Authors: Bischoff Farideh Z. , Pircher Tony J , Pham Tam , Wong Karina , Villarin Eligie , Kalinsky Kevin , Mayer Julie Ann
Published: March 2020

584

Background: Hormone receptor (estrogen receptor [ER] and progesterone receptor [PR]) status in all breast cancer patients is recommended for selection of treatment options. However, the analytical sensitivity of immunohistochemistry (IHC) in detecting low levels of ER/PR is often poor and is likely due to methodological variation. Because biopsy is not often feasible in all patients with recurrent and/or metastatic breast disease, circulating tumor cells (CTCs) offer an attractive alternative source of tumor tissue for determining ER/PR status and can be monitored more readily to enable a more effective course of treatment. Methods: Twenty mL of peripheral blood was collected prospectively from 15 patients diagnosed with late stage metastatic/recurrent breast cancer. CTCs were isolated using the microfluidic OncoCEE platform. A cocktail of antibodies was utilized for CTC capture and detection with an expanded anti-cytokeratin (CK) cocktail mixture and anti-CD45. ER/PR protein expression was assessed by immunocytochemistry (ICC) on the cells captured within the microchannels and compared to IHC performed on the primary tumor or metastatic biopsy. Results: CK+/CD45-/DAPI+ cells were located and assessed for ER/PR ICC. Among the 15 cases, a high concordance (13/15; 87%) in ER/PR status between IHC and ICC results was observed. Two cases were found to be discordant where one was positive by IHC and negative on the CTCs, and the other was negative by IHC and positive on the CTCs. However, both cases that were discordant had low numbers of detected CTCs. Conclusions: There is significant heterogeneity between ER/PR protein expression in CTCs and primary tumor/metastatic biopsy, and this status may change over time due to therapy. ER/PR ICC on CTCs from peripheral blood using the OncoCEE platform is shown to be feasible with high concordance (87%) in ER/PR status between primary tumor/metastatic biopsy (by IHC) and CTCs (by ICC). The significance of heterogeneity at the ER/PR protein level in CTCs ascertaining to the prognosis and predictive response to anti-estrogen therapy needs further evaluation in larger prospective clinical trials.
Multiple chemotherapy (CT) lines in metastatic breast cancer (MBC): Which survival benefit for women with hormone receptor (HR)-positive disease?
Authors: Palumbo Raffaella , Bernardo Antonio , Riccardi Alberto , Sottotetti Federico , Teragni Cristina , Bernardo Giovanni
Published: March 2020

589

Background: Although the development of modern systemic therapies has clearly improved outcome of patients with MBC, the true impact of further CT on overall survival (OS) and QoL of these women is still debated. The aim of this study was to determine which benefit could be brought by successive CT lines in patients with HR-positive disease, aiming to identify factors affecting outcome and survival. Methods: This retrospective analysis included 980 women treated with CT for MBC at our Institution over a eight year period (July 2000-July 2008). With OS data updated in March 2010, the median follow-up was 146 months (range 48-198), OS and time to treatment failure (TTF) were calculated according to the Kaplan-Meyer method for each CT line. Cox proportional hazards model was used to identify factors that could influence TTF and OS. Results: Median OS evaluated from day 1 of each CT line decreased with the line number from 34.8 months for first line to 8.2 months for 7 or more lines). Median TTF ranged from 9.2 months to 7.8 and 6.4 months for the first, second and third line, respectively, with no significant decrease observed beyond the third line (median 5.2 months, range 4.8-6.2). No statistically significant difference was found between HR-positive and HR-negative patients in terms of OS and TTF by each CT line. In univariate analysis factors positively linked to a longer duration of TTF for each CT line were positive hormonal receptor status, more than 3 hormonotherapy lines, absence of liver metastasis, adjuvant CT exposure, response to CT for the metastatic disease; in the multivariate analysis the duration of TTF for each CT line was the only one factor with significant impact on survival benefit for subsequent treatments, in both HR-positive and negative populations (p<0.001). Conclusions: Our results support the benefit of multiple lines of CT in a significant subset of women treated for MBC, since each CT line may contribute to a longer OS. Of interest, such a benefit was also observed for patients with HR-positive disease, although the number of hormonotherpy lines received did not significantly influence the outcome.
ESR1 gene amplification and protein expression in 946 patients with resected breast cancer: A Hellenic Cooperative Oncology Group (HeCOG) translational research study.
Authors: Pentheroudakis George E. , Batistatou Anna , Dafni Urania , Bobos Mattheos , Tsolaki Eleftheria , Kotoula Vassiliki , Kampletsas Eleftherios , Lazaridis George , Papadimitriou Christos A. , Gogas Helen , Kalogeras Konstantine T. , Pavlidis Nicholas , Fountzilas George
Published: March 2020

592

Background: Discrepant data have been reported on the incidence of ESR1 gene amplification in breast cancer, its correlation to clinicopathologic characteristics and its impact on prognosis. Methods: Formalin-fixed paraffin-embedded (FFPE) tumor tissue samples from 946 patients participating in two adjuvant chemotherapy phase III trials (HE10/97 and HE10/00) were centrally assessed in tissue microarrays by immunohistochemistry (IHC) for estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2). FISH was also performed for HER2, TOP2A and ESR1 using commercially available dual (for ESR1) and triple (for HER2 and TOP2A) hybridization probes. Results: The majority of patients had >T2 (69%), node-positive, ER-positive (>1% stained cells, 73%) tumors managed with resection, chemotherapy and hormonotherapy (76%). Only 38 tumors (4.0%) had ESR1 gene amplification (ESR1/CEN6 ratio >2) and 514 (54.3%) ESR1 gene gain (1<ratio<2). The number of ESR1 gene copies was 3-4 in 251 (26.5%) and 5-10 in 42 (4.4%) of cases. HER2 and TOP2A gene amplification was seen in 234 (25.3%) and 101 (10.9%) of tumors, respectively. We studied the immunohistochemical expression of ER protein by evaluating the percentage of stained cells, the Allred score (0-2, 26.8%; 3-6, 62.5%; 7-8, 10.7% of tumors) and the semiquantitative H-Score (50-100, 13.8%; 101-200, 36.8%; 201-300, 15% of tumors). ESR1 gene amplification was significantly associated with taxane therapy, age >50, postmenopausal status, grade III-IV, absence of HER2 amplification and ER protein expression (p<0.05). At a median follow-up of 92 months, univariate Cox regression analysis showed that ER protein expression, but not ESR1 gene status, was a predictor of favorable outcome. In multivariate analysis, tumor size >5 cm, >4 involved nodes and negative/low ER protein expression by Allred score were independent adverse prognostic factors. Conclusions: Our data showed a rather low incidence of ESR1 gene amplification and failed to confirm its prognostic/predictive utility. ESR1 mRNA expression data will be presented at the meeting.
Quality of life assessment in CLEOPATRA, a phase III study combining pertuzumab with trastuzumab and docetaxel in metastatic breast cancer.
Authors: Cortes Javier , Baselga José , Im Young-Hyuck , Ross Graham , Clark Emma , Knott Adam , Swain Sandra M.
Published: March 2020

598^

Background: CLEOPATRA compared the efficacy and safety of the HER2 dimerization inhibitor pertuzumab (P) plus trastuzumab (T) and docetaxel (D) with placebo (Pla)+T+D in HER2-positive 1st-line MBC. Pts in both arms received a median of 8 cycles of D; Pla/P+T was continued until progressive disease (PD). The safety profile in both arms was similar with a substantial decrease in adverse events (AEs) once chemotherapy finished. The independently assessed progression-free survival was significantly improved with P+T+D compared with Pla+T+D; objective response and duration of response were also improved with P+T+D (Baselga NEJM 2012). Here we report health-related quality of life (HRQoL) data from CLEOPATRA. Methods: Time to deterioration of HRQoL was evaluated using the FACT-B questionnaire and defined as decrease from baseline (BL) of ≥5 points in the TOI-PFB subscale score. Female pts completed questionnaires every 3rd cycle of therapy within 3 days before each tumor assessment until independently determined PD. An exploratory analysis investigated time to deterioration in breast cancer symptoms and functions. Results: 56.7% (Pla+T+D) and 59.5% (P+T+D) of pts experienced deterioration of HRQoL during the study based on TOI-PFB. The median time to deterioration was 18.3 vs 18.4 wks (~6 cycles) (HR 0.97; P = .7161). At Cycle 6, the mean reduction in TOI-PFB score from BL was –3.5 (Pla+T+D) vs –3.0 (P+T+D). At subsequent cycles, when most pts had discontinued D, mean reductions were smaller, suggesting that after an early decline patients’ scores improved slightly. Overall, mean changes were small in both arms. Compliance with completion of the FACT-B questionnaire was ≥75% beyond the 1st year in both arms. An exploratory analysis suggested that time to deterioration in BCS score, which measures symptoms and issues relevant in breast cancer, was delayed with P+T+D (18.3 vs 26.7 wks; HR 0.77; P = .0061). Conclusions: Combining P with T+D appears to have no detrimental effect on HRQoL. Results suggest that P+T+D is associated with a substantial delay in the time to deterioration in BCS score as would be expected given the improved efficacy and the low incidence of AEs once D is discontinued.