bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevalence of BRCA1 mutations in triple negative breast cancer (BC)
Authors: Kandel M. J. , Stadler Z. , Masciari S. , Collins L. , Schnitt S. , Harris L. , Miron A. , Richardson A. , Garber J. E. 
Published: March 2020

508 Background: 90% of BCs in women with germline BRCA1 mutations are ER, PR and HER2 negative (so-called “Triple Negatives”), and 80–90% of triple negative BCs are “basal-like” by DNA microarray and IHC analysis. Prevalence of germline BRCA1 mutations among women with triple negative BC may therefore, be elevated, and underestimated by available calculation models, which do not take tumor features into account. Methods: We randomly identified 200 women from the Dana-Farber/Harvard Cancer Center SPORE annotated specimen bank with histologically confirmed primary invasive, ER, PR and HER2 negative BC. Myriad prevalence tables for BRCA1 were used to estimate the probability that each subject carried a BRCA1 mutation according to age at BC diagnosis, family and personal history of breast and/or ovarian cancer, and Ashkenazi Jewish ancestry. Full sequencing analysis for BRCA1 germline mutations is in progress. Results: The median age at diagnosis of triple negative BC was 49 years (range 26–79). The majority of tumors were high grade (89%) ductal (95%) carcinomas; median tumor size was 2 cm, 50% had positive nodes. 3 patients had a personal history of ovarian cancer and 13 reported Ashkenazi Jewish ancestry. 44% had at least one first or second degree relative with BC; 12% had at least one relative with ovarian cancer. The estimated probability of detecting a BRCA1 mutation according to the Myriad tables ranged from 0.019 to 0.386 (median 0.039): the total expected number of BRCA1 mutations was 11. In a subgroup of 23 patients (12%), who had undergone clinical testing, 2.7 BRCA1 and 1.4 BRCA2 mutations were expected according to the Myriad tables. However, 9 deleterious BRCA1 mutations (39.1%) were found; 2 patients had a BRCA2 mutation (8.7%). Conclusions: The relative excess of BRCA1 mutations in a small group of patients with triple negative BC suggests that established risk factors alone may underestimate the prevalence of BRCA1 mutations among women with this BC subtype. We anticipate that complete BRCA1 analysis of our entire group will more definitively estimate the prevalence BRCA1 mutations among women with triple negative BC. No significant financial relationships to disclose.
TOP2A aberrations as predictive and prognostic marker in high-risk breast cancer patients. A randomized DBCG Trial (DBCG89D)
Authors: Knoop A. , Knudsen H. , Balslev E. , Rasmussen B. B. , Overgaard J. , During M. , Nielsen K. V. , Jørgensen J. T. , Mouridsen H. , Ejlertsen B. 
Published: March 2020

532 Background: The primary objective of the study was to evaluate TOP2A as predictive marker for adjuvant treatment with epirubicin in high-risk breast cancer patients. As a secondary objective the prognostic characteristics of TOP2A gene aberrations was investigated. The data presented on the predictive properties is a follow-up to the data previously published (Knoop et al, J Clin Oncol 2005; 23: 7483–90). Methods: 962 pre- and postmenopausal high-risk Danish patients were enrolled in the DBCG89D protocol. The patients were randomly allocated to either 9 × CMF (cyclophosphamide, methotrexate, 5-flurouracil) (n=495) or 9 × CEF (cyclophosphamide, epirubicin, 5-flurouracil) (n=467) every 3 weeks. Tumor-tissue was available from 806 patients (84%). The tumors were analyzed for TOP2A copy number changes with the TOP2A FISH pharmDx Kit (Dako, Glostrup). Recurrence-free survival (RFS) was used as primary end-point. Univariate and multivariate statistics were used to assess the predictive and prognostic properties of the TOP2A gene aberrations. Results: The TOP2A test was successful in 96% of the patients. Ninety-two (12.0%) patients were found to have TOP2A amplified tumors, and 86 (11.1%) to have TOP2A deleted tumors. For the primary study endpoint (RFS) a significant predictive value of TOP2A gene amplifications was found (HR=0.39; CI: 0.22–0.70; p=0.0017). A similar trend was seen with respect to TOP2A deletions (HR=0.61; CI: 0.35–1.07; p=0.082). TOP2A gene aberrations were significantly associated with several established prognostic factors and had independent prognostic value, associated with a significant worse prognosis both for RFS (p=0.036) and overall survival (p=0.012). Conclusions: The DBCG89D study has shown that TOP2A amplifications are associated with a favorable outcome of adjuvant treatment with epirubicin in primary breast cancer. Further, TOP2A aberrations demonstrated an independent prognostic value. [Table: see text]
DNA-repair gene (DRG) single nucleotide polymorphisms (SNPs) influence on response and survival in stage IV SCCHN patients treated with CDDP-based therapy
Authors: Quintela-Fandino M. , Hitt R. , Medina P. P. , Gamarra S. , Amador M. , Manso L. , Cortes Funes H. , Sanchez-Cespedes M. 
Published: March 2020

5505 Background: CDDP kills tumor cells by DNA cross-linking. SNPS at DRG may influence the ability of patients to respond to CDDP. We studied the role of the SNPs XPD-Asp312Asn, XPD-Lys751Gln, ERCC1-C8092A and XRCC1-Arg399Gln to influence the response to CDDP-based therapy and to predict survival in SCCHN patients Methods: SNPs were genotyped in DNA from peripheral lymphocytes using PCR-restriction fragment length polymorphism in 103 stage IV (0% M1) SCCHN patients followed prospectively. Treatment schedules were concurrent CDDP/RT (n = 28), CDDP + fluoropyrimidine (FP)→ CDDP/RT (33) or CDDP + FP + taxane→CDDP/RT (42). Endpoints: to assess the impact of the SNPs in OS (Kaplan Meier and Cox’s model) and in response to chemotherapy (multivariate multinomial regression). The covariables gender, age, treatment type, number of polymorphic (poly.) variants (0–8), smoking and alcohol consumption and amount (mg) of CDDP were included in the multivariate analysis Results: Median age 60 yrs (39–94); 97 (94%) male. After 78 months of follow-up, 24% had died, 22% had relapsed and 51% were free of disease. The allele frequencies for the homozygous common allele, heterozygous and homozygous poly. variant were: ERCC1: 53, 40 and 7%; XPD312: 50, 42 and 8%; XPD751: 35, 57 and 8%; XRCC1: 35, 51 and 13%. Overall, 9%, 16%, 22%, 20%, 24%, 6%, 1% and 1% of the patients harbored 0, 1, 2, 3, 4, 5, 6 and 7 poly. variants simultaneously. Table shows OS according to genotype. Patients with only common alleles had a median OS of 5.1 months (4.3–6.0) vs not reached for patients with ≥1 variant (p = 0.0000)(mean 6.2 (4–8.4) vs 61.3 (53–59.8). Each variant allele decreases the probability of dying 2.1 fold (p = 0.0000) on the Cox’s analysis (7 variants = 175 fold protection) and increases 2.94 fold (multinom. reg.)the probability of achieving a CR vs PD (p = 0.041) Conclusions: In our series the poly. variants at DRG are the strongest prognosis factors and accurately predict clinical response among SCCHN patients. [Table: see text] No significant financial relationships to disclose.
Re-irradiation combined with chemotherapy after salvage surgery in head and neck carcinoma: A randomized trial from the GETTEC and GORTEC groups
Authors: Janot F. , De Raucourt D. , Castaing M. , Bardet E. , Dolivet G. , Bensadoun R. , Hamoir M. , Marandas P. , Mamelle G. , Bourhis J. 
Published: March 2020

5508 Background: Full dose re-irradiation combined with chemotherapy has been shown to be feasible after salvage surgery with an “acceptable” toxicity (Cancer 2001; 91:2071–6). We performed a prospective, multicentric, randomized study to assess its carcinologic value. Methods: Between 1999 and 2005, 130 head and neck cancer patients were treated with salvage surgery and then randomly assigned either to full dose re-irradiation combined with chemotherapy (arm A) or absence of post-operative treatment (arm B). Patients eligibility criteria were: recurrence or second primary in a previously irradiated area to at least 45 Gy, absence of distant metastasis, salvage surgery with macroscopic complete resection; possibility of starting adjuvant treatment within 6 weeks after salvage surgery. Patients in arm A received 60 Gy in 12 weeks combined with concomitant 5FU, Hydroxyurea, as previously described (Ann Oncol 1996;7:913–8). Cox model was adjusted with stratification factors: tumor site, center, type of event (recurrence vs second primary). Results: 65 patients were randomized in each arm, including 71% of local and/or regional relapse and 29% of second primary. There was no imbalance in the distribution of age, sex, tumor site, T and N re-staging, and histological gravity signs (N+ with ECE and/or positive margin). The most important acute toxicity related to re-irradiation and chemotherapy was mucositis with ≥ grade 3 in 29% of patients. A moderate and acceptable increase in ≥ grade 3 RTOG late toxicity was observed in arm A (trismus, mucosa, fibrosis). Progression-free survival was significantly improved in Arm A with a hazard ratio of 1.6 (CI 95%, 1.1–2.4, p = 0.01), but overall survival was not statistically different. Conclusions: This is the first randomized trial to evaluate the effect of full dose re-irradiation combined with chemotherapy after salvage surgery. The results showed that re-irradiation and chemotherapy were able to significantly improve progression-free survival, with no significant impact on survival and acceptable toxicity. Supported by ARC. No significant financial relationships to disclose.
A phase II trial of ZD6474 in patients with hereditary metastatic medullary thyroid cancer
Authors: Wells S. , You Y. N. , Lakhani V. , Hou J. , Langmuir P. , Headley D. , Skinner M. , Morse M. , Burch W. , Schlumberger M. 
Published: March 2020

5533 Background: Medullary thyroid carcinoma (MTC) is the most common cause of death in patients with hereditary syndromes caused by specific mutations in the RET protooncogene. RET activation is the oncogenic event, which results in intrinsic RET receptor tyrosine kinase activity, but other pathways, such as VEGFR- and EGFR-dependent signaling, also participate in tumor growth and development. ZD6474 is a once-daily oral agent that selectively targets RET, VEGFR and EGFR tyrosine kinases. The clinical activity of ZD6474 was evaluated in patients with hereditary MTC. Methods: In this open-label Phase II study, patients with unresectable, measurable, locally advanced or metastatic hereditary MTC and a RET germline mutation received once-daily oral doses of ZD6474 300 mg. The primary objective was to assess the objective tumor response (RECIST). Secondary objectives included assessments of biochemical response (determined by changes in plasma levels of calcitonin [CTN]) and safety/tolerability of ZD6474. An exploratory objective was to measure plasma levels of carcinoembryonic antigen (CEA). Results: As of 30 November 2005, 16 patients (6 male/10 female; median age 50 years, range 22–77) had entered the study and received initial treatment with ZD6474 300mg. The median duration of treatment was 136 days (range 16–353). Fifteen patients were evaluable for tumor response, CTN, and CEA. Objective tumor assessments have demonstrated partial responses in 3 patients (n = 2 confirmed; n = 1 unconfirmed), stable disease in 10 patients (n = 8, ≥8 and <24 weeks; n = 2, ≥24 weeks) and progressive disease in 2 patients. A >50% decrease from baseline in plasma CTN levels has been maintained for at least 4 weeks in 12/15 patients; a decrease in plasma CEA levels of the same magnitude and duration has been observed in 6/15 patients. Common adverse events (AEs) were diarrhea (n = 12) and nausea, rash and fatigue (each n = 11). CTC grade 3 AEs attributable to ZD6474 were QTc interval prolongation (n = 3), and diarrhea, skin rash and hypertension (each n = 2). Conclusions: ZD6474 shows promising evidence of clinical activity in patients with hereditary MTC. These are preliminary data and patients are still being recruited to this ongoing study. [Table: see text]
Significant clinical and biologic activity of RAF/VEGF-R kinase inhibitor BAY 43–9006 in patients with metastatic papillary thyroid carcinoma (PTC): Updated results of a phase II study
Authors: Kloos R. , Ringel M. , Knopp M. , Heverhagen J. , Rittenberry J. , Weldy L. , Arbogast D. , Collamore M. , King M. , Young D. , Shah M. 
Published: March 2020

5534 Purpose: Oncogenic defects in the genes involving RAS-RAF-MAPK signaling pathway (RAS, BRAF, or RET/PTC) occur in ∼60% of PTC. VEGF also plays a critical role in thyroid cancer progression. Due to lack of effective treatment, systemic therapy for iodine-refractory PTC is desperately needed. Methods: The primary endpoint of this phase II trial was to assess the objective response rates of BAY 43–9006 in pts with metastatic PTC. Secondary endpoints included clinical response correlation with 1) serum thyroglobulin (Tg) levels; 2) functional imaging including FDG-PET, and DCE-MRI; and 3) tumor genotype and degree of signaling inhibition in tumor biopsies. Using a minimax 2-stage design, 16 or 25 chemo-naïve pts with iodine-refractory PTC were to be enrolled in Arm A (accessible tumor for biopsy). An exploratory Arm B was designed with a plan to halt accrual as soon as Arm A was fully accrued. Eligible pts for Arm B had other subtypes of thyroid cancer or prior chemo, and did not require tumor biopsies. Pts received BAY 43–9006 at the dose of 400 mg PO BID. Response was assessed every 8 wks using RECIST. Results: A total of 58 pts (Arm A = 20, Arm B = 38) were enrolled from October 2004 to August 2005. Median duration of follow-up is 36 weeks (range, 16–60). Of 56 pts assessable for toxicity, serious adverse events (AEs) included aspergillus infection (gr 5, n = 1), secondary AML (gr 5, n = 1) and diverticular rupture (gr 3, n = 1). Common Gr 3 AEs were hand-foot syndrome (n = 9) and musculoskeletal pain (n = 10). Two confirmed partial responses (PRs) and 6 minor responses (23–29% decrease in sum of the longest diameter) were observed in 16 evaluable pts on Arm A. In 10 Tg-response evaluable pts on Arm A, median decrease in Tg was 70% (range, 45–90). Significant decreases in tumor perfusion and SUVs were noted in such pts. In addition, one PR and one minor response (27% decrease in sum of longest diameter; 85% reduction in Tg) have been observed among 20 pts with PTC on Arm B. Data for functional imaging and tissue correlative studies will be presented. Conclusions: BAY 43–9006 is a well-tolerated targeted therapy that has significant clinical and biologic anti-tumor activity in pts with iodine-refractory metastatic PTC. No significant financial relationships to disclose.
Evaluation of patterns of failure and subjective salivary function in patients treated with intensity modulated radiotherapy for head and neck squamous cell carcinomas
Authors: Daly M. E. , Lieskovsky Y. , Pawlicki T. , Yau J. , Pinto H. , Kaplan M. , Koong A. , Goffinet D. R. , Xing L. , Le Q. 
Published: March 2020

5536 Background: Conventional RT (CRT) for head and neck squamous cell carcinoma (HNSCC) is associated with severe late side effects which can worsen quality of life of surviving patients. Intensity-modulated radiotherapy (IMRT) allows the delivery of tumoricidal doses to the target volume while maintaining tolerable doses to critical organs. Several previous studies have demonstrated promising results for tumor control and disease free survival for HNSCC treated with IMRT. In this study, we correlated patterns of failure with target volume delineations in HNSCC treated with IMRT at our instittuion and evaluated subjective xerostomia outcomes after IMRT as compared to CRT. Material and Methods: Between 1/00 and 4/05, 69 patients with newly diagnosed non-metastatic HNSCC underwent curative parotid sparing IMRT at Stanford University. Sites included were oropharynx (39), oral cavity (8), larynx (8), hypopharynx (8) and unknown primary (6). Forty-six patients received definitive IMRT (66 Gy, 2.2 Gy/fraction), and 23 patients received post-operative IMRT (60.2 Gy, 2.15 Gy/fraction). Fifty-one patients also received concomitant chemotherapy. Post-treatment salivary gland function was evaluated by a validated xerostomia questionnaire (XQ) in 29 IMRT and 75 matched non-IMRT patients > 6 months after completing RT. Results: At a median follow-up of 17 months for living patients (range 6.5–60), 7 locoregional failures were observed, 5 in the gross target volume (GTV), 1 in the clinical target volume (CTV), and 1 at the junction of the IMRT and supraclavicular fields. The 2-year Kaplan Meier estimates of locoregional control and overall survival were 92% and 80% for definitive IMRT and 85% and 85% for post-op IMRT patients, respectively. The mean total XQ score was significantly better for IMRT than for non-IMRT patients (p = 0.006). Conclusions: The predominant pattern of failure in IMRT treated patients is in the GTV. Parotid sparing with IMRT resulted in decreased subjective xerostomia and may improve quality of life in irradiated HNSCC patients. No significant financial relationships to disclose.
Prognostic value of VEGFC, HER2 and HER3 gene expression in recurrent squamous cell head and neck tumors
Authors: Fountzilas G. , Angouridakis N. , Wirtz R. M. , Claas S. , Nikolaou A. , Kalogeras K. T. 
Published: March 2020

5538 Background: The main prognostic variables of head and neck squamous cell carcinoma (HNSCC) are the location and size of the tumor and the presence of cervical lymph node metastases. Differential gene expression of members of the HER and VEGF families is a common feature in HNSCC. To elucidate the prognostic value and the interrelation of these factors we performed a detailed gene expression analysis within HNSCC tissue samples Methods: We analyzed fresh frozen tissue from 48 recurrent HNSCC tumors stored at -80oC. RNA was isolated with the RNeasy kit (Qiagen, Inc.), followed by kinetic one-step RT-PCR for the expression of 8 candidate genes (EGFR, HER2, HER3, HER4, VEGFA, VEGFB, VEGFC and VEGFD). Raw data (Ct values) were normalized to RPL37A expression (housekeeper gene) and candidate gene expression between patient groups with differential clinical outcomes was analyzed by using Genedata Expressionist and GraphPad Prism 4 software packages. Median patient follow-up from initial diagnosis was 27 months. Results: Overexpression of VEGFA and EGFR was prominent in most tumors, but did not appear to have any prognostic value. However, VEGFC expression was significantly higher (p = 0.0002) in the tumors of patients with poor overall survival (< 27 months). Interestingly, these tumors were further characterized by significantly lower expression levels of HER2 and HER3. Median survival of patients with tumor VEGFC expression levels of >600 was calculated to be 42 months from initial diagnosis (Kaplan-Meier Survival Analysis), compared to 182 months in the rest of the patients. Conclusions: We have found that elevated VEGFC expression and low expression of HER2 and HER3 correlate with poor outcome in recurrent HNSCC patients. VEGFC preferably binds to the VEGFR3, which is predominantly expressed on lymphatic vessels. Overexpression of VEGFC may therefore result in the establishment of intratumoral lymphatic vessels, which have been shown to facilitate the dissemination of tumor cells into lymph nodes and the formation of distant metastases. We conclude that the determination of VEGFC, HER2 and HER3 expression may be of high prognostic value in HNSCC patients and that it may serve in the early identification of aggressive HNSCC subtypes. No significant financial relationships to disclose.
Concurrent chemotherapy practice patterns for head and neck cancer: What is standard of care?
Authors: Wong S. J. , Agha Z. , Milligan S. 
Published: March 2020

5542 Background: The superiority of concurrent high dose cisplatin and radiation (RT) compared to RT alone for pts with locally advanced squamous cell cancer of the head and neck (SCCHN) has been demonstrated in large prospective phase III clinical trials. However, little is known regarding general prescribing patterns for chemotherapy (CT) utilization in combined modality treatment (CMT) for SCCHN. We conducted the present study to gain insight as to whether results from pivotal phase III trials affect utilization of concurrent CT in academic and community centers. Methods: We analyzed individual data from 326 SCCHN pts treated with concurrent CT and RT between 03/2003 and 12/2004 from 53 centers (43 community-based, 7 academic, and 3 VA or military) using electronically captured data from IntelliDose, a chemotherapy order software program. Results: Of 326 total pts, 123 pts (38%) received single agent cisplatin. From this group, 71 (58%) received low dose cisplatin (<74 mg/m2, mean initial dose 67 mg), while 52 patients (42%) received high dose cisplatin (≥ 74 mg/m2, mean initial dose 189 mg). 72 pts (22%) received carboplatin/paclitaxel, 60 pts (18%) received cisplatin /5FU, 18 pts (5.5%) received single agent carboplatin, while 6 pts (1.8%) received cetuximab either alone or in combination with cisplatin. Other infrequently used regimens (each < 5%) cumulatively accounted for 14% of pts treated. Comparison of chemotherapy utilization between academic and community-based practice centers showed no statistical difference with respect to use of high dose cisplatin versus low dose cisplatin, or single agent cisplatin versus non-cisplatin regimens. Conclusions: Despite evidence from phase III studies that concurrent high dose cisplatin is the standard of care for CMT of locally advanced SCCHN, utilization of other regimens, such as weekly low dose cisplatin, are commonly utilized. [Table: see text]
Preliminary results of concurrent chemotherapy with intensity-modulated radiation therapy (IMRT) for advanced cancer of the larynx/hypopharynx
Authors: Lee N. , Chan K. , Zhung J. , Wolden S. , Su Y. B. , Kraus D. , Singh B. , Shaha A. , Shah J. , Pfister D. G. 
Published: March 2020

5544 Purpose: Retrospective review of an institution’s IMRT experience in treating advanced laryngeal/hypopharyngeal carcinoma with concurrent chemotherapy. Methods: Between 1/02–6/05, 31 patients with advanced laryngeal/hypopharyngeal carcinoma (74% T3/T4 disease;71% stage IV) underwent combined modality treatment. There were 20 laryngeal and 11 hypopharyngeal carcinomas. All patients received definitive IMRT with a median RT dose of 70 Gy. Concurrent chemotherapy was also given to all patients [cis-platinum (100mg/m2/cycle) or carboplatin/5-fluorouracil (J Clin Oncol 2004;22:69) every 3 weeks for 2–3 planned cycles; 3 patients received a weekly paclitaxel/carboplatin program]. Prophylactic feeding tubes (PEG) were placed in all patients. Acute toxicity and late xerostomia were scored using the RTOG radiation morbidity scale. The 2-year estimates for local progression-free rate (LPF), regional progression-free rate (RPF), distant metastases-free rate (DMF), and overall survival (OS) were calculated using the Kaplan-Meier method. Results: With a median follow-up of 17 months (range: 7–48), 2-year estimates of LPF, RPF, DMF, and OS rates were 76%, 94%, 96%, 87%, respectively. All patients with local failure of laryngeal carcinoma had persistent disease at the end of treatment. Grade ≥2 mucositis was experienced by 68% of the patients during treatment. Xerostomia continued to decrease over time from the end of RT and only 4 still complained of Grade 2 xerostomia. A greater proportion of patients with hypopharynx than larynx cancer were still PEG-dependent (55% versus 25%) after combined modality treatment at the time of this analysis. One patient developed laryngeal necrosis. Conclusions: These preliminary results show that IMRT, in combination with chemotherapy, achieved encouraging local control rates in patients with advanced laryngeal/hypopharyngeal carcinoma. Xerostomia improved over time. Pharyngoesophageal stricture with PEG dependency remains a problem especially in patients with hypopharyngeal carcinoma. Strategies using the ability of IMRT to limit the dose delivered to the esophagus and inferior constrictor musculature may be useful to further minimize this late complication. No significant financial relationships to disclose.