bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation between changes in 2- or 3-year disease-free survival (DFS) and 5-year overall survival (OS) in adjuvant breast cancer trials from 1966–2006
Authors: Ng R. C. , Pond G. R. , Tang P. A. , MacIntosh P. W. , Siu L. L. , Chen E. X. 
Published: March 2020

581 Background: Although disease-free survival (DFS) is accepted as a valid endpoint in adjuvant breast cancer trials, improvement in 2- or 3-year DFS has never been formally established as an adequate surrogate for 5- or 10-year overall survival (OS). We set out to establish if changes in 2- or 3-year DFS can be used to accurately predict changes in 5- or 10-year OS. Method: We conducted a systematic Medline search for phase III randomized adjuvant breast cancer trials published between 1966–2006 with >100 patients per arm with data for 2- and 3-year DFS as well as 5- or 10-year OS. Only trials of systemic therapies (e.g. chemotherapy, hormonal therapy) were included. We excluded studies investigating the effects of surgery, radiotherapy and neoadjuvant treatment. A univariate regression model weighted by trial sample size was constructed to determine if changes in 2-year DFS between treatment arms within trials were predictive of changes in 5- year OS. Computations of the correlation coefficient, proportion of variation, predicted estimates and 95% prediction interval were undertaken. Results: 126 studies containing 149 treatment arms met the inclusion criteria. Median sample size per trial was 533 and median follow up time was 81 months. Only 26 trials provided 10-year OS data thus association with 10-year OS was not attempted. Results were similar between analyses using either 2- or 3-year DFS, hence only 2-year DFS statistics are reported. 2-year DFS was a significant predictor of 5-year OS regardless of what other covariates were included (p<0.001). For every 1% increase in difference between treatment arms in 2-year DFS, the estimated difference in 5-year OS increased by 0.52%. The proportion of variation explained (R2) ranged from 0.38 to 0.49, with a wide prediction interval. Indeed, if a future trial accrued 1,000 patients and the 2-year DFS in the experimental arm was better than the control by 10%, the 95% prediction interval would still range from -0.2% to 11%. Conclusion: There is a statistically significant correlation, of moderate strength, between changes in 2-year DFS between treatment arms and changes in 5-year OS but the wide prediction intervals mean that the correlation is not strong enough to be used as a surrogate. No significant financial relationships to disclose.
Expression profiles can predict specific responses of capecitabine/docetaxel (C/D) based primary systemic therapy in breast cancer (BC) patients receiving neoadjuvant therapy
Authors: Perou C. , Moisa C. , Gulick S. , Tripathy D. 
Published: March 2020

587 Background: The identification of efficacious neoadjuvant chemotherapy for BC is critical, especially if regimens with good activity and fewer side effects can be identified. Methods: This open-label, multicenter study of C 825 mg/m2 twice daily d1–14 plus D 75 mg/m2 every 21d for 4 cycles for HER2-neu negative (HER2-) patients (pts), and combined with trastuzumab (T) 4 mg/kg loading dose then 2 mg/kg qw for HER2-neu positive (HER2+) pts as preoperative therapy for newly diagnosed BC T2 N1 and T3 N1 (stages II and III), has enrolled 112 pts. The study aims to determine the activity of C+D±T as primary systemic neoadjuvant therapy for operable BC and to identify potential biomarkers of response. The primary endpoint is pathological complete response, with secondary endpoints including clinical response rates after 2 and 4 cycles. Ninety-nine HER2- and 38 HER2+ pts will be recruited and evaluated for gene expression patterns, p53 mutation status, and circulating tumor cells. Results: The interim analysis for the first 30 HER2- pts shows an overall clinical response rate of 83.3% (tumor size reduction 55.5%), and 84.5% for 13 HER2+ pts (tumor size reduction 61.8%). Characteristics of 38 HER2- pts: mean age 51.9y; white 73.7%, African American (AA) 10.5%; premenopausal 36.8%, post 60.5%; ductal 86.8%, lobular 7.9%; ER+ 63.2%, ER- 36.8%. For 16 HER2+ pts: mean age 56y; white 75.0%, AA 12.5%; premenopausal 25.0%, post 75.0%; ductal 93.8%, lobular 6.3%; ER+ 43.8%, ER- 56.3%. The gene expression data (n=50) identifies tumors of all “intrinsic subtypes” and shows a potentially statistically significant association between pathological and clinical response and the HER2+/ER- subtype. Conclusions: Four cycles of C+D+T is active for HER2+ and HER 2- pts prior to surgery. Confirmation of these early results will likely require the entire study sample set. Genomic analyses continue to be conducted on pretherapy tissue samples. [Table: see text]
Dose-dense nab-paclitaxel (nanoparticle albumin-bound paclitaxel) in adjuvant chemotherapy for breast cancer: A feasibility study
Authors: Burstein H. J. , Mayer E. L. , Peppercorn J. , Parker L. M. , Hannagan K. , Moy B. , Younger J. , Schapira L. , Wulf G. , Gelman R. , Winer E. P. 
Published: March 2020

594 Background: We sought to evaluate the feasibility of substituting nab-paclitaxel (ABI-007) for paclitaxel as part of “dose-dense” adjuvant sequential doxorubicin / cyclophosphamide (AC) followed by taxane chemotherapy. Patients and Methods: Eligible patients had stage I-III breast cancer receiving adjuvant/neoadjuvant chemotherapy, ANC > 1500, and LVEF > 50%. Patients received AC (60 mg/m2 and 600 mg/m2) every 2 weeks × 4 cycles with G-CSF support, followed by nab- paclitaxel 260 mg/m2 every 2 weeks × 4 cycles. The endpoint was incidence of treatment delay during nab-paclitaxel therapy. Results: 66 women (median age 48 years) were enrolled. Among the first 11 given nab-paclitaxel without G-CSF support, one developed febrile neutropenia, and 4 had nab-paclitaxel treatment delays related to neutropenia (ANC < 1,000). The protocol was amended to require G-CSF support (filgrastim or pegfilgrastim) during nab-paclitaxel. Among the next 55 patients, 3 had febrile neutropenia, none during nab- paclitaxel. In cycles 6–8, nab-paclitaxel was delayed only 6 times (1 neutropenia, 3 hepatic toxicity, 2 patient scheduling); 96% of these cycles were delivered on time. By comparison, 82% of such cycles were delivered on time in a prior institutional study using paclitaxel. In the full cohort, 8 patients had nab-paclitaxel dose reduction, 4 for neuropathy, while other neuropathy was moderate (grade 2, n = 6; grade 3, n=1; grade 4, n=0). Conclusions: Administration of nab-paclitaxel every 2 weeks is feasible but requires G-CSF support. Data comparing nab-paclitaxel dose-delivery, toxicities and quality of life to paclitaxel as seen in prior studies will be presented. No significant financial relationships to disclose.
Functional (PET/CT) compared to conventional (mammography [M], sonography [US], MRI) imaging: Defining novel assessment modalities for inflammatory breast cancer (IBC)
Authors: Yang W. T. , Le-Petross H. T. , Gonzalez-Angulo A. , Macapinlac H. , Macapinlac H. , Dawood S. , Resetkova E. , Hortobagyi G. N. , Cristofanilli M. 
Published: March 2020

600 Background: IBC is an aggressive frequently lethal form of breast cancer that is defined by sudden onset breast erythema often without an associated clinical or radiological breast mass. Tissue diagnosis remains problematic due to inability to define an area for biopsy. The aim of this study was to compare conventional [M, US, MRI] vs. functional imaging [PET/CT] in detecting a primary breast parenchymal lesion (BPL) at initial presentation of IBC. Methods: Patients (pts) with a new clinical diagnosis of IBC evaluated at the M. D. Anderson Cancer Center between January 2003 to December 2006 who had M, US, MRI, or PET/CT were included in this study. The visibility of a BPL and skin abnormality on each imaging modality was compared. Regional (axillary, supraclavicular, internal mammary) nodal disease confirmed by pathology was assessed at US and PET/CT. The presence of metastatic disease at diagnosis with PET/CT was documented. Results: Sixty-seven pts met eligibility criteria. Median age was 51 years, (range, 25 to 78). Of these, 61 (91%) had M, 62 (93%) had US, 21 (31%) had MRI, and 13 (19%) had PET/CT. By M, no BPL (mass or calcifications) was observed in 16% (10/61), skin-only abnormality (SOA) in 14% (9/61), and a BPL in 84% (51/61). By US, no BPL (mass or architectural distortion) and SOA were noted in 6% (4/62), and a PBL in 94% (58/62). By MRI, 21/21 (100%) showed malignant enhancing BPL and skin thickening. By PET/CT, 100% (13/13) showed hypermetabolic BPL and skin thickening. Pathologically confirmed regional nodal disease was diagnosed in 96% (59/62) by US and in 69% (9/13) by PET/CT. Distant metastases in the bone and lung were diagnosed in 15% (2/13) by PET/CT, one of which was visible on bone scan. Conclusions: MRI and PET/CT showed a primary BPL in all cases of IBC while conventional imaging (M and US) failed to reveal a BPL amenable to biopsy in up to 16%. US can diagnose regional nodal disease to facilitate loco-regional therapeutic planning. PET/CT provides additional information on distant metastasis and should be considered in the initial staging of IBC. No significant financial relationships to disclose.
Incidence trends for human papillomavirus-related (HPV-R) and unrelated (HPV-U) head and neck squamous cell carcinomas (HNSCC) in the United States (US)
Authors: Chaturvedi A. , Engels E. , Anderson W. , Gillison M. 
Published: March 2020

6001 Background: HNSCC are etiologically heterogeneous, with one subset primarily attributable to HPV and another to tobacco and alcohol. Methods: Data from SEER9 program registries were used to investigate the potential influence of HPV on incidence and survival of HNSCC in the US from 1973–2003. HNSCCs (N=58,158) were classified by anatomic site as potentially HPV-R (base of tongue; tonsil; oropharynx; N=16,712) or HPV-U (lip; tongue; gum; floor of mouth; palate; other mouth; hypopharynx; ill-defined sites of lip, oral cavity, and pharynx; N=41,446). Joinpoint regression was used to assess incidence trends and life-table methods were used to compare survival for HPV-R and HPV-U HNSCCs. Results: For HPV-R HNSCCs, age-adjusted incidence increased significantly from 1973–2003 (annual percent change [APC] = 0.65), particularly among males (APC=1.02), whites (APC=0.89), and younger ages (APCs for 30–39 = 1.46; 40- 49=1.92; 50–59=0.61, and =60= -0.66). By contrast, HPV-U HNSCC incidence was stable from 1973–1983 and then decreased significantly from 1983–2003 (APC= -2.42). Mean age at diagnosis was younger for HPV-R HNSCC than HPV-U (61.1 vs. 64.5 years; p<0.001), and from 1973- 2003, decreased significantly for HPV-R, but increased for HPV-U. Improvements in overall survival (OS) were observed for HPV-R (all stages) and HPV-U (regional and distant) HNSCC treated by radiotherapy (RT) from 1973–2003, but were more marked for HPV-R HNSCC, e.g. absolute increase in two-year OS for regional disease of 24.4% (vs. 5.8% for HPV-U). OS for HPV-R (local and regional) was significantly better than HPV-U HNSCC if treated by RT, but worse if not so treated. Conclusions: The proportion of HNSCC that is potentially HPV- R increased in the US from 1973–2003, particularly among recent birth cohorts, perhaps due to changing sexual and smoking behaviors. Recent improvements in locoregional control with RT-based therapy may be due in part to a gradual shift in the etiology of the underlying disease. No significant financial relationships to disclose.
Potential advantage of studying preoperative sentinel node mapping with three-dimensional images by a hybrid single photon emission CT (SPECT)/CT system for breast cancer
Authors: Ibusuki M. , Yamamoto Y. , Kawasoe T. , Kai K. , Shiraishi S. , Tomiguchi S. , Iwase H. 
Published: March 2020

601 Background: Lymph node status is one of the key factors in determining the stage, appropriate therapy and outcome in patients with breast cancer. Accurate identification of sentinel nodes (SNs) has clinical importance for each patients before surgery. The purpose of this study was to assess the role of Single-photon emission computed tomography (SPECT)/CT lymphoscintigraphy in SN identification for patients with breast cancer, and to analyze the impact of such information on estimating metastases to SNs. Methods: Two hundred and twenty-three clinically node-negative patients were underwent SN biopsy between July 2002 and November 2006. CT and SPECT images were obtained after injection of subcutaneal 1mCi (99m)Tc-nanocolloid, allowing identification of SN. Target and non-target structures, including lymph nodes identified by SPECT, were drawn by SPECT/CT combined system, which was comprised of a two-detector SPECT system and a multiple-detector CT at the same platform. We compared the anatomical location of SNs demonstrated on the 3D SPECT/CT images and correlation to SN positivity. Results: SPECT/CT uptake was detected in 221 cases (99.1%). 3D SPECT/CT images visualized accurate localization of SNs in each cases. Total number of biopsied SNs were 315 , and the most frequent locations of SN were trapezoid area in the upper side of axilla. We defined this area as ‘Pectoral area (PA)’. In SN negative (SN-) patients, 228 (98.3%) SNs were found in PA, and 4 (1.7%) SNs were out of this area such as parasternal area. In SN positive (SN+) patients, 65(78.3%) SNs were in the PA, and 18(21.7%)SNs were out of PA ,respectively. Significant differences (p<0.01 ,chi-square test) were found in SNs distribution whether in or out of PA between SN+ and SN- patients. Conclusions: SN biopsy navigated by 3D-SPECT/CT can clarify the preoperative anatomical localization of SNs in patients with breast cancer. Atypical distribution of SNs out of PA may suggest SN positivity as a reflection of the failure of lymphatic drainage systems. No significant financial relationships to disclose.
Phase II study of combination cetuximab and weekly paclitaxel in patients with metastatic/recurrent squamous cell carcinoma of head and neck (SCCHN): Spanish Head and Neck Cancer Group (TTCC)
Authors: Hitt R. , Irigoyen A. , Nuñez J. , Grau J. , Garcia Saenz J. , Pastor M. , Jara C. , Garcia Giron C. , Hidalgo M. , Cruz Hernandez J. 
Published: March 2020

6012 Background: Cetuximab and paclitaxel have shown to be active in SCCHN pts and preclinical data has demonstrated a possible synergy for the combination. In a variety of tumor types, weekly paclitaxel has demonstrated an improved safety profile and activity as compared to every 3 weeks paclitaxel, providing the rationale to study the combination of cetuximab and weekly paclitaxel in metastatic/recurrent SCCHN. Methods: Pts were required to have a y performance status (KPS) = 70%, measurable disease using RECIST criteria, and may have received one regimen of induction and/or concomitant chemotherapy, but not within the recurrent/metastatic setting. Treatment included weekly paclitaxel 80 mg/m2 and cetuximab (initial dose of 400 mg/m2, followed by a weekly infusion of 250 mg/m2). Biopsies of tumors and samples of blood are being analyzed for correlative markers including EGFR gene copy number -FISH-, polymorphisms of intron 1 of the EGFR, and downstream EGFR pathway markers and mutations. Results: 46 planned pts were enrolled from Ap-2006 to Sep-2006. Median age is 60 years (range 42–78). Median KPS is 80% (range 70–100%). 35 pts are evaluable for response. Complete responses have been observed in 7 pts, partial responses in 18 pts, and stable disease in 6 pts for an overall response rate of 71% and disease control rate of 88%. 44 pts are evaluable for safety. Main grade 3/4 toxicities(NCI): 8 pts had acne- like rash; 7 neutropenia but only 1 febrile neutropenia; 6 asthenia; 3 mucositis; 2 infusion related reactions to paclitaxel and 1 to cetuximab; 2 peripheral neuropathies; 1 diarrhea; 1 vomiting; and 1 conjunctivitis. Conclusions: This trial shows that the combination of cetuximab and weekly paclitaxel is well tolerated and provides very encouraging activity in advanced/recurrent SCCHN. The full data, including biomarker results, will be presented at the annual meeting. No significant financial relationships to disclose.
Prognostic factors for clinical benefit after epidermal growth factor receptor (EGFR) directed therapy in squamous cell carcinomas of the head and neck (SCCHN)
Authors: Halpern A. B. , Kasza K. , Kocherginsky M. , Clark G. , Vokes E. E. , Williams R. , Cohen E. E. 
Published: March 2020

6025 Background: Single agent EGFR tyrosine kinase inhibitors (TKI) have demonstrated reproducible response rates of 5–15% in treatment of SCCHN. The subset of patients that benefits most from these agents remains unknown. We undertook a review of data from 5 clinical trials administering EGFR TKI in order to determine if there are clinical characteristics that are associated with response or benefit. Methods: We reviewed individual patient data from 5 clinical trials of erlotinib, lapatinib, or gefitinib. The primary endpoint was association of clinical variables with clinical benefit, defined as response (CR or PR) and stable disease (SD) >4 months. Secondary correlative endpoints included progression-free survival (PFS) and overall survival (OS). Logistic regression and Cox proportional hazard models were used to conduct univariate and multivariate analysis. Results: 319 subjects were included in the analysis with a median age of 59 years, 79% male. Disease status at start of therapy was local only in 43%, metastatic only in 29%, and both in 27%. Performance status (PS) was 0 in 25%, 1 in 62%, and 2 in 13%. Observed responses were: 1% CR, 6% PR, 24% SD >4 mo, 18 % SD3 in 6%) and diarrhea (grade 1 in 30%, grade 2 in 10%, grade 3 in 5%). Lower PS (p=0.06, OR (0/2)=3.1), age 70+ (p=0.02, OR= 2.1), and development of rash (p<0.01, OR=3.6), and diarrhea (p=0.03, OR=1.8) were associated with higher response rates. These variables were also associated with longer OS and PFS. Conclusions: Clinical parameters that appear to predict response to EGFR TKI include PS and age. EGFR mechanistic toxicities that develop during therapy are highly associated with benefit and suggest a relationship between drug exposure and outcome. No significant financial relationships to disclose.
Correlation of Src activation with epithelial-mesenchymal transformation and aggressive features of head and neck squamous carcinoma
Authors: El-Naggar A. K. , Lippman S. M. , Johnson F. M. , Mandal M. , Myers J. N. , Williams M. D. , Rosenthal D. I. , Weber R. S. , Gallick G. 
Published: March 2020

6026 Background: The role of the epithelial-mesenchymal transition (EMT) is crucial to invasive and progression of several epithelial malignancies. The role of this process in head and neck squamous cell carcinoma (HNSCC) remains poorly defined. Methods: Eleven head and neck squamous cancer cell lines and 50 primary tumor specimens formed the materials for this study. We used Western blotting, immunohistochemistry, RT-PCR cell motility assay to determine the expression and the functional implications of several cell adhesions and singling molecular associated with EMT in these tumors. Results: Our results showed Src and E-Cadherin to be paradoxically overexpressed in the majority of cell lines and in primary tumor tissues relative to normal squamous mucosa. In both cell lines and tumor tissues elevation of activated Src was accompanied by down-regulation of E-Cadherin and vimentin detection. In-vitro inhibition of Src led to the increased E-Cadherin of expression and cell proliferation in squamous carcinoma cell lines. Immunophenotypic analysis of the protein products of these genes in primary tumor tissues demonstrated a spectrum of changes that correlated significantly with the differentiation, invasive patterns, sarcomatoid transformation and lymph node status. Our results show that high activated Src and low E-Cadherin expression were correlated with finger-like invasive pattern, poor differentiation, sarcomatoid transformation and lymph node metastasis in HNSC. Conclusions: Our study indicates that Src and E-Cadherin play a major role in EMT invasion and progression of head and neck squamous carcinoma. These proteins may be targeted in the therapeutic intervention of patients with HNSCC. No significant financial relationships to disclose.
Phase I dose escalation study of fractionated stereotactic radiosurgery (fSRS) for recurrent squamous cell carcinoma of the head and neck (SCCHN)
Authors: Heron D. E. , Ferris R. L. , Burton S. , Lai S. , Karamouzis M. V. , Gooding W. , Johnson J. , Smith R. P. , Argiris A. , Grandis J. 
Published: March 2020

6029 Background: Limited-field re-irradiation has been used as salvage and palliative therapy in recurrent previously irradiated SCCHN. Its primary limitation is the dose to critical structures, such as the spinal cord. With its greater degree of conformality, accuracy and limited number of fractions (fx), extracranial fSRS has become an attractive alternative. Prior reports have used 25 Gy in 5 fx in recurrent SCCHN. This phase I trial assessed the safety of fSRS and established a starting dose for a planned phase II trial with concurrent cetuximab. Methods: Eligibe patients (pts) had pathologically-confirmed SCCHN that recurred post standard therapies, ECOG performance status 0–2, and measurable disease. All pts were staged and planned with PET-CT and were treated with the CyberKnife Frameless Radiosurgery System (Accuray, Sunnyvale, CA). Prior therapies included: radiation therapy (all pts, dose range: 50.4–88 Gy), surgery (n=22), chemotherapy (n=14). fSRS was delivered in 5 fx, every other day in 2 weeks, and dose escalated in successive cohort of 4 pts at 5 dose levels: I: 5 Gy/fx (25 Gy), II: 6.4 Gy/fx (32 Gy), III: 7.2Gy/fx (36 Gy), IV: 8 Gy/fx (40 Gy), and V: 8.8 Gy/fx (44 Gy). Dose limiting toxicities (DLT) was assessed up to 4-week period post fSRS. Dose tiers 4 and 5 were expanded to include more patients when no DLT were observed in the earlier cohorts. Results: 25 pts were enrolled and 19 were evaluable for response (tier I:4, II:4 III:3 IV:7 V:7). Median age 62 years (range 35–86), Male/Female: 24/1, 7 ECOG Performance status 0 (n=7), PS 1 (n=11), PS 2 (n=7). There were no DLTs observed to date. Toxicities included: grade 2 dysphagia (n=1) and grade 1 mucositis (n=2). Best responses: CR=1, PR=5, SD=9, PD=4 with an overall response rate of 31% (95% CI 13%-56%). Additionally, in this cohort with inoperable recurrent SCCHN 15/19 pts (79%) had stable or responding disease at last follow-up. The median survival was 24 weeks. Conclusions: Re-irradiation with fSRS is feasible and well tolerated up to a total dose of 44 Gy (8.8 Gy/fx). A phase II trial incorporating concomitant cetuximab is currently approved. No significant financial relationships to disclose.