bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic factors and treatment-related outcomes in patients with uterine serous cancer (USC).
Authors: deLeon Maria , Lu Lingeng , Hui Pei , Santin Alessandro , Rutherford Thomas J. , Arin-Silasi Dan , Azodi Masoud , Ratner Elena , Schwartz Peter E.
Published: March 2020

5099

Background: USC an uncommon (10%) but aggressive form of uterine cancer, causes 50% of uterine cancer deaths. The purpose of this study is to report a large single-institution experience with USC investigating the effects of clinicopathological parameters and treatment on overall (OS) and disease-free survival (DFS). Methods: Records from our institution were reviewed from 1987-2009. All 334 USC patients (pts) identified were surgically staged. Postoperative treatments used were: (1) observation (OBS, n=33); (2) platinum-based chemotherapy (PCH, n=78); (3) whole pelvis radiation therapy (WPRT, n=16); (4) PCH and vaginal apex brachytherapy (PCHR, n=165); (5) vaginal apex brachytherapy (VAB, n=35). The cancer stages were 121 pts IA (36.2%), 36 IB (10.8%), 27 II (8.1%), 39 IIIA (11.7%), 2 IIIB (0.6%), 32 IIIC1 (9.6%), 9 IIIC2 (2.7%), 28 IVA (8.4%) and 40 IVB (12%). Results: The 5-year OS for stage IA/IB, II, IIIA/IIIB, IIIC1/IIIC2, IVA/IVB were 82%, 70%, 64%, 36%, and 9%, respectively. The 5-year DFS for stage IA/IB, II, IIIA/IIIB, IIIC1/IIIC2, IVA/IVB were 82%, 68%, 56%, 24%, 6%, respectively. Advanced stage was associated with significantly shorter OS and DFS (p <0.01). The 5-year OS for stage IA/IB disease was 94% for pts who received PCHR, 90% for OBS, 75% for PCH, 65% for VAB and 0% for WPRT. The 5-year DFS for PCHR, OBS, PCH, VAB and WPRT for Stage IA/IB were 89%, 82%, 86%, 72% and 0% respectively. For stage II-IVB pts, the 5-year OS was 51% for PCHR, 0% for OBS, 23% for PCH and 20% for WPRT. The 5-year DFS for stage II-IVB with PCHR, OBS, PCH and WPRT were 42%, 0%, 17% and 13% respectively. Older age pts had worse survival, (p<0.01). Race and BMI did not impact survival. Incomplete surgical debulking (p<0.01), depth of myometrial invasion >50% (p<0.01) and lymph node metastasis (p<0.01) were all associated with worse prognosis. Conclusions: PCHR overall exhibited better OS and DFS regardless of disease stage. Age, incomplete surgical debulking, depth of myometrial invasion and lymph node involvement were independent prognostic factors in USC patients in this study.
SU2C phase Ib study of pan-PI3K inhibitor BKM120 with letrozole in ER+/HER2- metastatic breast cancer (MBC).
Authors: Mayer Ingrid A. , Abramson Vandana Gupta , Balko Justin M. , Isakoff Steven J. , Kuba Maria Gabriela , Sanders Melinda , Forero-Torres Andres , Yap Jeffrey T. , Van Den Abbeele Annick D. , Li Yisheng , Arteaga Carlos L. , Winer Eric P. ,   Stand Up to Cancer - PI3K in Women's Cancers
Published: March 2020

510

Background: Mutations in PIK3CA, the gene encoding the p110a subunit of PI3K, have been associated with antiestrogen resistance in ER+ BC. In general, antiestrogen-resistant cancers retain ER and responsiveness to estradiol. This suggests that treatment of ER+/PI3K mutant BC should include PI3K inhibitors plus antiestrogens. Methods: We conducted a phase Ib trial of letrozole (2.5 mg/d) with the pan-PI3K inhibitor BKM120 in post-menopausal patients (pts) with ER+/HER2 MBC. BKM120 (100 mg/d) was given continuously (Arm A) or intermittently (5 on/2 off days; Arm B). Upon toxicity, BKM120 was reduced to 80 and 60 mg/d. Treatment continued until unacceptable toxicity or disease progression. Disease was assessed every 2 months. FDG-PET was done at baseline and at 2 weeks in all pts in Arm A. Results: Fifty-one pts were accrued; 49 had progressed on an AI previously. Median age was 56 years (range 34-77); 95% had bone and 70% visceral metastases. Toxicities and outcomes are summarized in the table. The only DLT* in Arm A and B were transaminitis and depression, respectively; both at 100 mg. Over 50% of Arm A pts had >25% reduction in their peak SUV at the 2-week FDG-PET. Pts who did not exhibit a metabolic response by FDG-PET progressed rapidly on therapy. Three pts in Arm A had a PI3K mutation; one of them has had stable disease on treatment for >12 months. Conclusions: The combination of letrozole/ BKM120 is safe in pts with AI-refractory ER+/HER2 MBC. Arm B is ongoing and will be updated at the meeting. All tumor biopsies will be analyzed for PI3K pathway alterations. FDG-PET at 2 weeks appears to be a useful pharmacodynamic biomarker of PI3K pathway inhibition in most patients. Its value in predicting treatment response remains to be determined. [Table: see text] [Table: see text]
Phase II trial of topotecan, cisplatin, and bevacizumab for recurrent or persistent cervical cancer.
Authors: Zighelboim Israel , Wright Jason D. , Gao Feng , Case Ashley Stephens , Massad L. Stewart , Mutch David Gardner , Powell Matthew A. , Thaker Premal H. , Eisenhauer Eric Lawernce , Cohn David E. , Valea Fidel A. , Secord Angeles Alvarez , Lippmann Lynne T. , Rader Janet Sue
Published: March 2020

5101

Background: The prognosis associated with recurrent or persistent cervical cancer is exceedingly poor. GOG-179 demonstrated a survival benefit with the combination of cisplatin and topotecan compared to single-agent cisplatin, with the former showing median PFS of 4.6 months, median OS of 9.4 months, and a 27% objective response rate. The role of angiogenesis in cervical carcinogenesis and progression has been well documented. We evaluated the activity and safety of the combination of topotecan, cisplatin and bevacizumab in patients with incurable carcinoma of the cervix. Methods: Patients with histologically proven measurable recurrent or persistent cervical carcinoma not amenable to curative intent treatment were eligible. No prior chemotherapy for recurrence was allowed. Cisplatin 50 mg/m2 day 1, topotecan 0.75 mg/m2 days 1, 2 and 3 and bevacizumab 15 mg/kg day 1 were prescribed in a 21-day cycle. Cytokine support was allowed at physician discretion. The primary endpoint was 6-month PFS. Additionally, objective clinical response and toxicity were evaluated. Accrual goal (N=27) was based on a 50% improvement goal in 6-month PFS in relation to GOG-179 (40% to 60%), with a one-sided 0.10 significance and 80% power. Results: 27 eligible patients received a median of 3 treatment cycles (range, 1-19). All patients received radiotherapy as part of their first line treatment. Median follow-up was 8.5 months (1.2-32.9). The 6-month PFS was 59% (95%CI: 38.0-74.7). Among 26 RECIST-evaluable patients, objective response rates were (%; 95%CI): 1 CR (4%; 1-19.6), 7 PR (27%; 11.6-47.8), 11 SD (42%; 23.4-63.1) and 7 PD (27%; 11.6-47.8). Median OS was 9.8 months (95%CI: 7.7-20.6) and median PFS was 7.1 months (95%CI: 2.0-12.1). Grade 3-4 hematologic toxicity occurred in 96% of patients (thrombocytopenia 93% leukopenia 70%, anemia 70%, neutropenia 59%). Other grade 3-4 toxicities were also common (metabolic 48%, pain 37%, genitourinary 30%, constitutional 22% and gastrointestinal 19%). Conclusions: The addition of bevacizumab totopotecan and cisplatin results in a highly active but toxic regimen. Future efforts should focus on identification of predictive biomarkers and treatment modifications to minimize toxicity.
ADXS11-001 immunotherapy targeting HPV-E7: Preliminary survival data from a phase II study in Indian women with recurrent/refractory cervical cancer.
Authors: Basu Partha , Petit Robert G. ,   Gynecologic Oncology Group
Published: March 2020

5106

Background: ADXS11-001 immunotherapy is a live attenuated Listeria monocytogenes (Lm) bioengineered to secrete a HPV-16-E7 fusion protein targeting HPV transformed cells. The Lm vector serves as its own adjuvant and infects APC where it naturally cross presents, stimulating both MHC class 1 and 2 pathways resulting in specific T-cell immunity to tumors. Here we describe the preliminary survival data associated with ADXS11-001 administration in Lm-LLO-E7-015, a randomized phase II study being conducted in India in 110 patients with recurrent/refractory cervical cancer who have been treated previously with chemotherapy, radiotherapy or both. Methods: Patients are randomized to either 3 doses of ADXS11-001 at 1 x 109 CFU or 4 doses of ADXS11-001 at 1 x 109 CFU with cisplatin chemotherapy. Naprosyn and oral promethazine are given as premedications and a course of ampicillin is given 72h after infusion thereby clearing any residual vector. Patients receive CT scans at baseline and Days 84, 184, 273, 365 and 545. The primary endpoint is 12 month survival. Results: As of January 26, 2012, 88 patients have received 200 doses of ADXS11-001; with the percentage of patients alive at 6 months at 62% (34/55); at 9 months at 41% (15/37) and at 12 months at 40% (6/15). Tumor responses have been observed in both treatment arms with 3 complete responses (elimination of tumor burden) and 4 partial responses (≥30% reduction in tumor burden) by RECIST. One serious (Gr3) adverse event and 77 mild-moderate (Gr 1-2) adverse events possibly related to study treatment have been reported in 35% (31/88) of patients. The non-serious adverse events consisted predominately of transient, non-cumulative flu-like symptoms associated with infusion that responded to symptomatic treatment, or resolved on their own within hours of treatment. Conclusions: This immunotherapy can be safely administered to patients with advanced cancer alone and in combination with chemotherapy. ADXS11-001 is well tolerated and presents a predictable and manageable safety profile. Early signs of clinical benefit merit further investigation. Updated findings will be presented at the meeting.
Results from a phase Ib study of trastuzumab emtansine (T-DM1), paclitaxel (T), and pertuzumab (P) in patients with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab.
Authors: Modi Shanu , Elias Anthony D. , LoRusso Patricia , Samant Meghna , Guardino Ellie , Althaus Betsy , Krop Ian E.
Published: March 2020

528

Background: The antibody–drug conjugate T-DM1 has shown single-agent activity in phase II studies in patients (pts) with HER2–positive MBC. Preclinical data suggest synergy for T-DM1 combined with taxanes and with P. Methods: TDM4652g is a phase Ib, open-label, dose-escalation study evaluating the safety and tolerability of T-DM1 (qw and q3w) + T (qw) ± P (q3w) in pts with HER2-positive MBC previously treated with trastuzumab. A 3+3 dose-escalation scheme is used for T-DM1 + T to determine the maximum tolerated dose (MTD); P is added at this MTD. Initial restrictive dose-limiting toxicity (DLT) criteria were modified to establish a more clinically relevant MTD. Results: We report interim results with T-DM1 (qw and q3w) + T (+ P) using modified DLT criteria. 24 pts have been enrolled in these cohorts; median age was 53 yrs (range, 23–69)*; median number of prior systemic therapies in MBC was 7 (range, 2–15)*. See table below. Conclusions: Data support combining T-DM1 + T ± P at the MTD for future clinical trials. The MTD for weekly T-DM1 + T is 2.4 mg/kg + 80 mg/m2 qw; MTD for weekly T-DM1 + T + P is 2.4 mg/kg + 80 mg/m2 qw + 840 mg LD, 420 mg q3w. Updated results will be presented, including the MTD for T-DM1 q3w + T qw ± P q3w, outcomes from pts with prolonged follow-up, and duration of response from an extension trial. [Table: see text]
A phase I trial of the IGF-1R antibody IMC-A12 in combination with temsirolimus in patients with metastatic breast cancer.
Authors: Fleming Gini F. , Suman VeraJean , Goetz Matthew P. , Haluska Paul , Moynihan Timothy Jerome , Nanda Rita , Olopade Olufunmilayo I. , Pluard Timothy J. , Erlichman Charles , Chen Helen X. , Guo Zhanfang , Ellis Matthew James , Ma Cynthia X.
Published: March 2020

534

Background: mTOR plays a critical role in promoting tumor cell growth. In preclinical studies, the anti-tumor activity of mTOR inhibitors is attenuated by feedback up-regulation of AKT mediated by IGF-1R. We designed a phase I trial to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT) and pharmacodynamic effects of the IGF-1R antibody IMC-A12 in combination with temsirolimus (tem) in patients (pts) with metastatic breast cancer (MBC) where mTOR is frequently activated. Methods: A 3+3 phase I design was chosen. Tem and IMC-A12 were administered IV days (d) 1, 8, 15, and 22 of a 4-week cycle in pts with MBC refractory to standard therapies. Tumor response was evaluated by RECIST. Adverse events (AE) were reported using CTC v3.0. Serum IGF 1 and C-peptide levels on d2 (24h post infusion) and d8 prior to drug infusion were compared to baseline (BL) using paired t-test. Results: Of 26 pts enrolled, 4 did not complete cycle 1 due to progression (3) or co-morbid condition (1). MTD was determined from remaining 22 pts aged 34-72 (median 48) years with ECOG PS 0 (55%) or 1 (45%). 86% had ER+ cancer. Median number of regimens for MBC was 4. Two DLTs at the starting DL (DL 1) necessitated dose de-escalation of tem to 20mg (DL-1), then to 15 mg (DL-2) which was tolerable (Table). Subsequent dose escalation of IMC-A12 led to DLTs in 0 of 6 in DL-2A and 2 of 3 pts in DL-2B. The MTD was defined as DL-2A. Other AEs included gr 1/2 fatigue, neutropenia, anemia, and hyperglycemia. No CR or PR, but 4 SD lasting ≥ 4 months were observed. At DL-2, -2A and -2B, serum IGF 1 levels were significantly elevated on d2 (p <0.002) and d8 compared to BL (p <0.001), but C-peptide levels were not found to differ from BL. Conclusions: The MTD for the combination of IMC-A12 and tem in pts with MBC is lower than that observed for single agents alone. A phase II study is ongoing in MBC. The study is supported in part by ASCO CDA, Komen Craft to CXM, N01-CM62205 and N01-CM-2011-00071. [Table: see text]
A meta-analysis of receptor status discordance between primary breast cancer and metastases.
Authors: Aurilio Gaetano , Disalvatore Davide , Bagnardi Vincenzo , Munzone Elisabetta , Adamoli Laura , Curigliano Giuseppe , Pruneri Giancarlo , Sciandivasci Angela , De Vita Fernando , Goldhirsch Aron , Nole Franco
Published: March 2020

546

Background: There is an increasing awareness that biology of breast cancer may evolve over time. The discordance in estrogen (ER), progesterone (PgR) and HER2 receptor status between primary breast cancer and metastases is being intensively investigated and a large amount of data has been produced. However, results from different studies seem to be conflicting and heterogeneous. To highlight this issue, a meta-analysis of published data was performed. Methods: A literature search was performed with Medline. All studies published from 1983 to 2011 comparing changes inER, PgR and/or HER2 status in patients with matched breast primary and recurrent tumors were included. We used random-effects models to estimate pooled discordance proportions. Results: We selected 42 articles, mostly reporting retrospective studies. Twenty-eight, 20 and 27 articles were focused on ER, PgR and HER2 changes, respectively. A total of 2806 tumors were evaluated for ER discordance, 1809 for PgR discordance and 2801 for HER2 discordance. The heterogeneity between study-specific discordance proportions was high (I2 >75%, p<0.0001) for ER, PgR and HER2. Pooled discordance proportions were 20% (95% CI: 16-25%) for ER, 33% (95% CI: 28-38%) for PgR and 9% (95% CI: 6-12%) for HER2. Pooled proportions of tumors shifting from positive to negative and from negative to positive were 24% and 12% for ER (p=0.0115), respectively. The same figures were 44% and 15% for PgR (p<0.0001), and 14% and 6% for HER2 (p=0.04). Conclusions: To our knowledge, this is the first meta-analysis addressing this topic. The findings strengthen the concept that changes in receptor expression may occur during the natural history of breast cancer and therefore clinical implications with possible impact on treatment choice cannot be excluded. However, the high heterogeneity observed in our analysis may explain the disagreement among oncologists on performing a reassessment of the biological features. In our opinion, only high-powered prospective and randomized trials could clarify the controversies in this field.
CYP2D6 genotype and adverse effects as indicators of plasma endoxifen in breast cancer patients taking tamoxifen.
Authors: Balakrishnar Bavanthi , Menzies Alexander M. , Ali Sayed Sahanawaz , Yeap Shang Heng , Gao Bo , Liddle Chris , Coulter Sally , Provan Pamela , Gebski Val , Hui Rina , Kefford Richard , Wilcken Nicholas , Balleine Rosemary L , Gurney Howard
Published: March 2020

550

Background: Tamoxifen is a prodrug. Its principal active metabolite endoxifen is a product of cytochrome P450 2D6 (CYP2D6) metabolism. The CYP2D6 gene is highly polymorphic with a number of relatively common reduced function alleles. The aim of this study was to determine whether plasma endoxifen levels were reflected by CYP2D6 genotype or adverse effects in individuals taking tamoxifen. Methods: Plasma endoxifen was measured by High Performance Liquid Chromatography / Mass Spectroscopy in 90 breast cancer patients taking 20mg tamoxifen per day. Ten CYP2D6 single nucleotide polymorphisms were assessed to designate four putative CYP2D6 functional categories: ultra-rapid (UM), extensive (EM), intermediate (IM) and poor (PM) metabolizers. CYP2D6 inhibitor use and adverse effects were documented. The study was part of an ongoing Australian trial of tamoxifen dose escalation. Results: There was marked variation in plasma endoxifen levels across the cohort (mean 27.6 nM, SD 14.3). Endoxifen levels were significantly associated with metabolizer categories (p<0.001, r= -0.44), but were not distinctive between categories. For example, in the EM category (n=46) endoxifen levels ranged from 3.8-72.2 nM (mean 32.6 nM) with levels in the lowest quartile (3.8-19.7 nM) substantially overlapping the PM category (n=11); 6.1-24.7 nM. Consistent with an impact of non-CYP2D6 genotype related factors on endoxifen levels, endoxifen was significantly lower in 18 patients taking CYP2D6 inhibitor medications (p=0.005). There was no association between endoxifen levels and vasomotor symptoms or other adverse effects of tamoxifen. Conclusions: Endoxifen levels were highly variable in patients taking standard dose tamoxifen, and not predicted by CYP2D6 genotype or adverse effects. Therapeutic monitoring of endoxifen levels may be a useful approach to assess tamoxifen activity.
A molecular diagnostic panel for thyroid cancer disease management.
Authors: Cheng Shih-Min , Qu Kevin , Abdool Adam , Sferruzza Anthony , Waldman Frederic , Reitz Richard E
Published: March 2020

5510

Background: In 2009, the American Thyroid Association revised its guidelines for patients with thyroid nodules and differentiated thyroid cancers, recommending BRAF, RAS, RET/PTC, and PAX8-PPARγ molecular testing in patients with indeterminate fine-needle aspirate (FNA) cytology. Alterations in any of these markers in thyroid nodules are strongly associated with malignancy. We studied the prevalence of these alterations in thyroid FNA specimens in order to establish a strategy to improve disease management. Methods: DNA and RNA were extracted from thyroid FNA specimens (N=149) and tested for BRAF mutations using allele-specific PCR (V600E and K601E); for RAS (H-, K-, N-) mutations using pyrosequencing (codons 12, 13, and 61); and for RET/PTC1 and RET/PTC3 rearrangements and PAX8-PPARγ translocations using RT-PCR. Results: Overall, 90 (60.4%) of the specimens had alterations in ≥1 of the 4 molecular markers (Table). BRAF V600E mutations (54.4%) were the most prevalent mutations in papillary thyroid cancer (PTC); no K601E mutations were found. RAS mutations were found in PTC, follicular adenoma (FA), and follicular thyroid cancer (FTC) specimens; half of these mutations involved N-RAS Q61. RET/PTC rearrangements were detected in 3.5% of PTC specimens and were evenly distributed between the 2 major subtypes, RET/PTC1 and RET/PTC3. PAX8/PPARγ translocations were detected in 18.8% of FTC but not in FA, probably due to small sample size. Out of 7 indeterminate thyroid nodules, 2 had BRAF mutations and 2 had RAS mutations. The presence of the 4 markers was generally mutually exclusive; only 1 PTC specimen had concurrent RAS and RET/PTC1 alterations. Conclusions: The prevalence of BRAF, RAS, RET/PTC, and PAX8/PPARγ alterations in thyroid cancer specimens highlights the potential for targeted therapeutic strategies. The mutually exclusive pattern of alterations also suggests a hierarchical screening strategy for samples with limited availability. [Table: see text]
Cetuximab/radiotherapy (CET+RT) versus concomitant chemoradiotherapy (cCHT+RT) with or without induction docetaxel/cisplatin/5-fluorouracil (TPF) in locally advanced head and neck squamous cell carcinoma (LASCCHN): Preliminary results on toxicity of a randomized, 2x2 factorial, phase II-III study (NCT01086826).
Authors: Ghi Maria Grazia , Paccagnella Adriano , Ferrari Daris , Foa Paolo , Nole Franco , Morelli Franco , Azzarello Giuseppe , D'Ambrosio Consuelo , Casanova Claudia , Guaraldi Monica , Mantovani Giovanni , Rossetto Ciro , Bonetti Andrea , Siena Salvatore , Crino Lucio , Buffoli Alberto , Koussis Haralabos , Pieri Gabriella , Gava Alessandro , Floriani Irene ,   for the GSTTC Italian Study Group
Published: March 2020

5513

Background: The standard treatment options for LASCCHN are cCHT+RT or CET+RT. Strategies to improve the efficacy with the integration of induction chemotherapy are being investigated. Primary endpoints of this study were to compare: 1) the overall survival (OS) of induction vs. no induction arms; 2) the Grade(G)3-4 in-field toxicity of cCHT+RT vs. CET+RT. Methods: Patients (pts) with unresectable LASCCHN, stage III-IV, ECOG PS 0–1 were randomized to a 2x2 factorial design: Arm A1: cCHT+RT (2 cycles of ciplatin/5fluorouracil); Arm A2: CET+RTX; Arm B1: 3 cycles of TPF followed by the same cCHT+RT; Arm B2: 3 cycles of TPF followed by CET+RT. A total of 204 deaths over 420 pts ( including the 101 randomized in the phase II part of the study comparing cCHT+RT with or w/o induction TPF) were required to detect a HR of death of 0.675 (A1+A2 vs. B1+B2; 2-sided a=0.05; b=0.20) and a 10% difference in G3-4 in-field mucosal toxicity (A1+B1 vs. A2+B2). Results: By February 2012, 387 pts over 413 pts were evaluable for toxicity. 82% of pts were male; median age was 60y; PS: 0=77.8% and 1=22.2%. Disease stage was III (31%) or IV (69%). Sites of disease were oral cavity (21.7%), oropharynx (54.8%), hypopharynx (23.5%). At a median follow-up of 21 months, 126 deaths occurred. Data on G3-4 in-field toxicity (primary endpoint) and compliance to cCHT+RT vs CET+RT are shown in the table. Conclusions: No advantage for CET+RT over cCHT+RT was observed regarding G3-4 in-field toxicities and feasibility. Pts are still being followed-up to assess OS. [Table: see text]
Prospective comparison of recurrence score and independent central pathology assessment of prognostic tools in early breast cancer (BC): Focus on HER2, ER, PR, Ki-67 results from the phase III WSG-Plan B trial.
Authors: Gluz Oleg , Kreipe Hans Heinrich , Christgen Matthias , Degenhardt Tom , Kates Ronald E. , Liedtke Cornelia , Shak Steven , Clemens Michael R. , Salem Marwa , Markmann Susanne , Liedtke Bernd , Aktas Bahriye , Henschen Stephan , Pollmanns Anke , Krabisch Petra , Uleer Christoph , Augustin Doris , Thomssen Christoph , Nitz Ulrike , Harbeck Nadia ,   West German Study Group
Published: March 2020

552

Background: Use of multi-gene real-time PCR (RT-PCR) based assays e.g. Recurrence Score (RS) and single markers (grade, uPA/PAI-1, ER/PR, HER2, KI-67) is currently controversially discussed in early BC. Here, we present the final WSG-planB trial correlation analysis of risk assessment tools and first prospective comparison of independent central pathology IHC/FISH assessment and RT-PCR for single markers. Methods: Plan B trial (n=2,448 randomized for 6xTC vs. 4xEC-4xDOC in locally HER2- BC). RS has been used as selection criterion for cht omission in HR+ BC (if RS<11 in pN0 or pN1). uPA/PAI-1 was optionally obtained. Grade, ER/PR, HER2 (IHC/FISH), Ki-67 were evaluated by the independent trial pathologist in all tumors. Results: From 04/09 to 11/11, 3196 patients have been recruited and 2448 randomized. RS distribution in 2551 HR+ tumors: 0-11 (18%), 12-25 (60%), >25 (22%). In 354 pN0-1 patients, cht was omitted based on low risk RS (88% compliance). Central grade for n=3038 and IHC/FISH results are currently available in n=1476. Moderately significant correlations were only found between RS and both central grade (rs=0.313; p<0.001) as well as Ki-67 (rs=0.374; p<0.001) and a weak one for uPA/PAI-1, particularly due to poor correlations within the RS group <26. In 1476 locally HER2- cases, n=9 were found as 3+ and/or FISH+ by central analysis. In 6 HR+/HER2+ cases, RS revealed 2 positive, 2 equivocal and 2 negative results. In 7 cases positive for HER2 by RT-PCR central pathology revealed 4 negative results. 24 locally HR+ cases are assessed as HR- in central pathology (2%). Among these, 6 were ER positive by RT-PCR. Final correlation analyses will be presented at the meeting. Conclusions: These first prospective data demonstrate that high-risk status according to RS is predictive of high risk by other factors, but the converse is not true. Regarding controversial HER2 and HR status by RT-PCR and IHC/FISH, we found few cases with false-negative or positive RT-PCR results in HER2- BC by local pathology. However, these discrepancies could potentially have a substantial impact on clinical patient management.
Differences in biomarker expression in HNSCC according to p53 status.
Authors: Feldman-Moreno Rebecca Anne , Kemkes Ariane C. , Xiu Joanne , Blevins Richard , Esmay Paula , Battaglia Leslie , Radebach Katrina , Rose Inga , Johnston Curtis , Gatalica Zoran
Published: March 2020

5523

Background: Patients with p53 wildtype head and neck squamous cell carcinoma (HNSCC) tend to be HPV-positive, which associates with better prognosis. The purpose of this study was to explore biomarker expression profiles for insight into molecular differences in HNSCC patients based on p53 status. Methods: TP53 gene sequencing using the AmpliChip p53 microarray (Roche Molecular Systems, Inc.) was attempted on 61 HNSCC patients previously tested with Caris Target Now tumor profiling service. DNA was extracted from a FFPE sample, amplified and processed on the AmpliChip p53 microarray to detect single base pair substitution and deletion mutations in exons 2 - 11 and their flanking splice sites in the TP53 gene (GenBank X54156). EGFR FISH , HER2 IHC and 22 other predictive biomarkers, e.g. TS, TOPO2A, MGMT, etc., were assayed and retrospectively analyzed. All tests were performed in a CLIA-certified lab and interpreted by board-certified pathologists or cytogeneticists. Statistical analysis was performed using SPSS (PASW statistics17) for parametric and non-parametric tests of independence. Results: 52 cases provided sufficient quality DNA for p53 analysis and results revealed a mutation rate of 25% in HNSCC patients. Interestingly, only EGFR FISH and HER2 IHC (p=.002 and p=.004, respectively) were differentially expressed in wildtype vs. mutated p53. Matched-pair analysis in the p53 mutated subgroup (n=13) showed no significant trend regarding EGFR status (p=.763) but a slight trend towards HER-2 negativity (p=.020). In the p53 wildtype subgroup (n=39), a strong association with EGFR FISH non-amplification (n=28, 71.8%, p<.001) as well as HER-2 negativity (n=38, 97.4%, p<.001) was shown. Conclusions: To our knowledge, this is the first analysis of differential biomarker expression profiles in HNSCC based on p53 status. We hypothesize that the absence of EGFR amplification in the p53 wildtype cancers may be a contributing factor to the improved prognosis observed in HPV-positive HNSCC. Additionally, the strong association between p53 wildtype HNSCC patients and EGFR non-amplification suggests EGFR-targeted therapies like cetuximab would likely fail in p53 wildtype patients.
Influence of extracapsular extension on lymph node staging for patients with squamous cell carcinoma of the head and neck.
Authors: Baumgart Megan Ann , Acevedo-Gadea Carlos Rodrigo , Wang Zuoheng , Buta Eugenia , Davies Marianne , Deshpande Hari Anant , Decker Roy H. , Sasaki Clarence , Judson Benjamin , Herbst Roy S. , Morgensztern Daniel
Published: March 2020

5532

Background: Although extracapsular extension (ECE) is a known poor prognostic factor in head and neck squamous cell carcinoma (HNSCC) and recommended to be collected by the current AJCC manual, it currently does not influence the final stage. We evaluated the prognostic impact of ECE in 4 primary sites. Methods: The Surveillance Epidemiology and End Results (SEER) was queried for patients with squamous cell cancers of the oral cavity (OC), oropharynx (OP), hypopharynx (H) and larynx (L), known ECE status, M0, and diagnosed between 2004 and 2007. Survival curves were estimated by the Kaplan-Meier and compared by Cox proportional hazards models. Results: There were 23,384 patients meeting eligibility criteria, including 14,664 (62.7%) N0, 6483 (27.7%) N+ without ECE (NECE), and 2237 (9.6%) with ECE. ECE was associated with decreased 3-year overall survival (OS), compared to NECE, for all lymph node stages including N1 (52% vs 61%, HR 1.32, p = 0.001), N2a (60% vs 76%, HR 1.82, p<0.001), N2b (44% vs 62%, HR 1.62, p<0.001), N2c (34% vs 47%, HR 1.43, p<0.001), N3 (31% vs 44%, HR 1.38, p=0.012). ECE was also an independent poor prognostic factor for cancer in the OC (HR 1.43, p < 0.001), OP (HR 1.44, p < 0.001), H (HR 1.58, p = 0.01), and L (HR 1.28, p = 0.01). The comparison between ECE and NECE with one additional N degree showed no significant OS difference, except OP N1 and H N2a ECE, where survival was inferior to OP N2a and H N2b NECE respectively (Table). Conclusions: ECE is a significant predictor for poor outcomes in HNSCC, with survival equivalent to one additional degree of N involvement. [Table: see text]
Longitudinal Oncology Registry of Head and Neck Carcinoma (LORHAN): Analysis of African American patients.
Authors: Hayes David N. , Peng Guangbin , Pennella Eduardo , Cuyun Carter Gebra , Muehlenbein Catherine E. , Covello Kelly L. , Corral Mitra , Obasaju Coleman
Published: March 2020

5533

Background: Previous retrospective analyses show poor outcomes for African American (AA) patients with head and neck carcinoma (HNC). Such racial disparities are not well understood, but patient (pt) demographics, comorbidities, tumor site, and human papillomavirus (HPV) status are suggested to play a role. Methods: The LORHAN registry was used to identify pts ≥18 yrs of age with de novo, non-metastatic HNC, and a record of survival time. This study evaluated pt and treatment characteristics by race, and conducted adjusted Cox regression analyses of overall survival (OS) and progression-free survival (PFS) to identify prognostic factors and interactions, and estimate hazard ratios (HRs) of AA vs. non-Hispanic white (NHW). Results: Baseline pt characteristics (see table below). The median OS/3-yr rate was 41.7 mo/51% in AA vs. 52.9 mo/70% in NHW, (age-adjusted HR: 1.73 [95% CI: 1.45, 2.08]). The median PFS/3-yr rate was 29.6 mo/43% in AA and 49.9 mo/62% in NHW, (age-adjusted HR: 1.64 [95%CI: 1.40, 1.93]). Multivariate analysis of OS and PFS showed that AA race, stage III and IV, PS 2, and smoking were significantly associated with a worse HR, while OP demonstrated a favorable HR over other sites. Significant interaction tests led to subgroup analyses for OS showing an elevated risk in AA with OP (HR: 2.62 [95%CI: 1.95, 3.52]) and similar risk elevations in male AA as well as in AA with PS 0-1 when compared to NHW in the corresponding subgroups. Conclusions: Controlling for other factors like PS and smoking, a worse prognosis was seen in AA males with OP localized SCCHN. Further investigation to improve the outcomes in this population is warranted. [Table: see text]
An open-labeled, multicentric clinical study of cetuximab combined with intensity-modulated radiotherapy (IMRT) plus concurrent chemotherapy in locoregionally advanced (LA) nasopharyngeal carcinoma (NPC): A 2-year follow-up report.
Authors: Chen Chun-yan , Zhao Chong , Gao Li , Lang Jin-yi , Pan Jian-ji , Hu Chao-su , Jin Feng , Wang Ren-sheng , Xie Conghua , Lin Tongyu , Lu Tai-xiang
Published: March 2020

5535

Background: To evaluate the safety and efficacy outcomes of concurrent cetuximab plus IMRT and cisplatin in Chinese patients with LA NPC. Methods: Patients with primary stage III-IVb (UICC/AJCC 2002 staging system) and non-keratinizing NPC were enrolled in this prospective, multicentric, phase II study. Cisplatin (80mg/m2,q3week) and cetuximab (400mg/m2 one w before radiation, and then 250mg/m2/w) were given concurrently. The prescription dose of IMRT to GTVnx (primary tumor in nasopharynx) was 66 Gy - 75.9 Gy, GTVnd (positive cervical lymph nodes) was 60 Gy - 70Gy, The response rate was evaluated according to RECIST 1.0 criteria, and adverse events (AEs) were graded according to NCI CTCAE V3.0 criteria. Results: From July 2008 to April 2009, 100 patients were enrolled (74 male), with median age of 43 years. The proportion of stage III, IVa and IVb patients were 71%, 22% and 7% respectively. 99% of enrolled patients completed the planned treatment. AEs were within the expected range and manageable. No toxic death occurred during the treatment. Acneiform skin eruptions, mucositis, in-field dermatitis, xerostomia and neucopenia were the most common seen AEs, with 64% grade 2/3 acneiform eruptions, 26% grade 2/3 in-field dermatitis, 90% ≥ grade 2 mucositis (2 cases of grade 4 mucositis with spontaneous bleeding), 40% ≥ grade 2 xerostomia and 8% grade 2/3 neucopenia. With a median follow-up time of 23.5 months, the 2 year overall survival (OS), disease-free survival (DFS), local recurrence-free survival, regional (cervical lymph node) recurrence free survival and distant metastasis-free survival rates for the ITT population were 91%, 89%, 90%, 90% and 89%, respectively Multivariate analysis showed that N stage was the only prognostic factor for OS (p=0.0392, HR=2.946) and DFS (p=0.0062, HR=4.246) in these patients. Conclusions: Cetuximab combined with IMRT plus concurrent cisplatin in patients with LA NPC shows satisfactory 2-year locoregional control rate and 2-year overall survival. The combination seems to be well tolerated with a manageable side-effect profile.
A phase II study of sorafenib in combination with cisplatin and 5-fluorouracil in the treatment of recurrent or metastatic nasopharyngeal carcinoma.
Authors: Xue Cong , Yu Qitao , Pan Jian-ji , Sun Yuanlu , Zhang Li
Published: March 2020

5538

Background: Nasopharyngeal carcinoma (NPC) is a disease with distinctive epidemiology and clinical behavior compared with Head and neck cancer (HNC) and more common in South-East Asia. Sorafenib monotherapy has been shown modest anticancer activity in HNC and NPC (C Elser et al; JCO 2007). This study was to evaluate the efficacy and tolerability of sorafenib combined with cisplatin and 5-fluorouracil (5-FU) for patients with recurrent or metastatic NPC. Methods: A phase II, single arm clinical trial was conducted in three centers in China. Chemotherapy-naive histologically confirmed NPC patients with recurrent or metastatic disease were enrolled. Patients received oral sorafenib 400mg bid continuously until disease progression or unacceptable toxicity, cisplatin 80mg/m2 intravenously (iv) on day 1-5, and 5-FU 400mg/m2 iv infusion for 96 hours on day 1. Treatment was repeated every 21 days for a maximum of 6 cycles. Results: 54 patients were enrolled. Most patients were with bone metastases (70.0%), followed by liver (56%) and lung metastases (56%). The median chemotherapy administrated was 4.0 cycles (range, 2 - 6 cycles). The disease control rate (DCR) reached 90.7%, including one complete response (CR), 41 partial responses (PR) and 7 stable diseases (SD). Median PFS was 7.2 months (95% CI 6.8-8.4 months) and median OS was 11.8 months (95% CI 10.6-18.7 months). Tumor cavitation after treatment was observed in 32.1% of patients with lung metastases. Decreased percentage of contrast update in responder patients (PR and CR) with liver metastases was also observed by Contrast-Enhanced Doppler ultrasound. The major toxicities include hand foot syndrome (HFS), myelo-suppression and gastrointestinal reaction.Dose reduction of sorafenib was required in 22 patients (40.7%) and dose interruption in 14 patients (25.9%) because of toxicity. Conclusions: Sorafenib combined with cisplatin and 5-FU has an encouraging efficacy profile with tolerable toxicity. Further randomized studies are needed to confirm the clinical benefit of sorafenib combined with chemotherapy in recurrent or metastatic NPC.
Patterns of care in elderly patients with squamous cell carcinoma of the head and neck: A SEER-Medicare analysis.
Authors: VanderWalde Noam Avraham , Meyer Anne-Marie , Tyree Seth D , Zullig Leah L. , Carpenter William Ruffin , Weissler Mark C , Shores Carol G. , Hayes David N. , Chera Bhishamjit S.
Published: March 2020

5539

Background: Head and neck squamous cell carcinoma (HNSCC) is predominantly a disease of the elderly, however age and co-morbidity may affect therapy decisions. The purpose of this study was to assess the patterns of care of elderly HNSCC patients and identify factors associated with non-receipt of surgery and chemoradiation (CRT). Methods: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database (1992-2007) we identified a retrospective cohort of non-metastatic HNSCC patients and categorized them into treatment cohorts. Comparisons were made between surgery vs. non-surgery, and CRT vs. non-CRT cohorts. Multivariate logistic regression models examined factors associated with non-receipt of treatment. Variables included tumor location, stage, year of diagnosis, age, gender, marital status, race, comorbidity, race-comorbidity interaction, SEER region, socioeconomic variables, and hospital affiliations. Results: The final cohort of 11,336 were 63% male and 83% white. 52% had no co-morbidities, 44% had oral cavity HNSCC, 52% were diagnosed between 2002 and 2007, 58% had surgery, and 21% received CRT. For the CRT vs. non-CRT model, increasing age (OR = 0.93; 95% CI 0.92 -0.94) and non-whites with co-morbidity (OR = 0.71; 95% CI 0.55 – 0.92) were associated with decreased likelihood of receiving CRT. More advanced staged disease, oropharyngeal tumor location, and diagnosis after 2002 were associated with increased likelihood of receiving CRT. For the surgery versus non-surgery model, age was not associated with receipt of surgery (OR 0.99; 95% CI 0.99-1.00), nor was existence of comorbidity in white patients (OR 0.97; 95% CI 0.88-1.05). However, recent year of diagnosis, non-oral cavity tumor location, and advanced stage were all associated with reduced likelihood of receiving surgery. During the 15 year surveillance period, patients were less likely to receive surgery, and CRT was used more often. Conclusions: Age may influence the non-receipt of CRT in this elderly cohort but does not appear to be significantly associated with the non-receipt of surgery. There has been an increasing trend in the receipt of CRT with a decrease in surgery over the past 15 years.
A multi-institutional phase II trial of pazopanib monotherapy in advanced anaplastic thyroid cancer.
Authors: Bible Keith Christopher , Suman VeraJean , Menefee Michael E. , Smallridge Robert C. , Molina Julian R. , Maples William James , Karlin Nina J. , Traynor Anne M. , Kumar Priya , Goh Boon C. , Lim Wan-Teck , Bossou Ayoko R , Isham Crescent R , Webster Kevin P. , Kukla Andrea K. , Bieber Carolyn , Burton Jill K. , Harris Pamela Jo , Erlichman Charles
Published: March 2020

5544

Background: Pazopanib, an orally bioavailable multitargeted inhibitor of kinases including VEGF-R, demonstrated impressive activity in metastatic differentiated thyroid cancer (49% durable RECIST PRs) and promising preclinical activity in anaplastic thyroid cancer (ATC) models, prompting its evaluation also as a candidate therapeutic in advanced ATC. Methods: A multicenter single arm phase II trial of 800 mg pazopanib daily was undertaken with the primary endpoint of RECIST response rate. The trial was designed such that there would be a 90% chance of detecting a response rate of >20% at the 0.10 significance level when the true tumor response rate is >5%. A pre-specified stopping rule designated that enrollment would cease unless 1 or more RECIST PRs+CRs were observed in the first 14 of 33 potential patients. Eligibility required informed consent, >18 years of age, performance status ECOG 0-2, systolic blood pressure (BP) <140 mm Hg and diastolic BP <90 mm Hg at entry, QTc interval <480 msecs, and measurable disease by RECIST criteria. Anatomical imaging and toxicity evaluations were required every 4 weeks. Results: Sixteen patients were enrolled. One patient withdrew prior to therapy, leaving 15 evaluable patients – 33.3% were male, with a median age of 66 years (range 45-77); 11 of 15 patients had progressed through prior systemic therapy. Four patients required 1-2 dose reductions, with the most common severe toxicities (CTC-AE version 3.0 grades 3-5) hypertension (13%) and pharyngolaryngeal pain (13%). Reasons for treatment discontinuation included: disease progression (12 pts), death on study due to a vascular event possibly related to treatment (1 pt.), and intolerability (radiation recall tracheitis – 1 pt, and uncontrolled hypertension – 1 pt). Although transient disease regression was observed in several patients, there were no confirmed RECIST tumor responses, triggering study closure at time of interim analysis. Two patients are alive with disease 9.9 months and 2.9 years post-registration; the remaining 13 died of disease. The median time to progression was 62 days and the median survival time was 111 days. Conclusions: Pazopanib has poor single agent activity in advanced anaplastic thyroid cancer.
Antitumor activity of cabozantinib (XL184) in a cohort of patients (pts) with differentiated thyroid cancer (DTC).
Authors: Cabanillas Maria E. , Brose Marcia S. , Ramies David A. , Lee Yihua , Miles Dale , Sherman Steven I.
Published: March 2020

5547

Background: Cabozantinib (cabo) is an oral, potent inhibitor of MET, VEGFR2, and RET that is currently undergoing evaluation in several oncology indications. Differentiated thyroid cancer (DTC) pts were included in this study based on involvement of the MET, VEGFR, and RET signaling pathways in this disease. The primary objective of this study is to determine the effect of cabo on single dose PK of the CYP2C8 substrate rosiglitazone (rosi). Anti-tumor activity and safety were also evaluated. Methods: Metastatic DTC pts who were enrolled to this study were required to be RAI-refractory, have progressed on standard therapies and have measurable disease. Cabo was given daily at a dose of 140 mg free base (equivalent to 175mg salt form) starting at Day 2. Rosi (4mg) was given Day 1 and Day 22 to complete PK assessment for drug-drug interaction (DDI). Cabo was continued until PD. On Day 57 and every 8 weeks thereafter subjects underwent tumor assessments by mRECIST. Results: 15 DTC pts were enrolled. Median number of prior regimens was 2 (11/15 pts had at least 1 prior VEGFR inhibitor). 8/15 pts (53%) had confirmed PRs including 1 pt with marked improvement of a bone infiltrating lesion; 6 (40%) had best response of SD; all 14 pts with ≥1 post-baseline scan experienced tumor regression (range: -9 to -55%). Disease control rate (PR + SD): 80% at 16 weeks; 10/15 (67%) remain on cabo with a median follow-up of 7.3 months. Median PFS and OS have not been reached. Most common Gr 3/4 AEs were: diarrhea (20%), lipase increased (20%), hypertension (13%) and palmar-plantar erythrodyesthesia (13%); one related Gr 5 event reported: hemoptysis due to aorto-trachael fistula in a pt with history of prior mediastinal XRT and extensive neck surgeries. PK data suggest that clinically relevant doses of cabo do not alter the Cmax or AUC0-24h of rosi, consistent with no inhibition of CYP2C8. Conclusions: In pts with DTC, cabo treatment resulted in substantial anti-tumor activity. The safety profile of cabo was comparable to that seen with other VEGFR TKIs. PK data suggest no DDI between cabo and rosi (CYP2C8 substrate).
Response of chemoradiation therapy after induction chemotherapy failure in locally advanced head and neck squamous cell carcinoma (LA-HNSCC).
Authors: Lim Yoojoo , Keam Bhumsuk , Koh Youngil , Lee Kyung-Hun , Kim Tae Min , Lee Se-Hoon , Hah Jeong-Hun , Kwon Tack-Kyun , Kim Dong-Wan , Wu Hong-Gyun , Sung Myung-Whun , Heo Dae Seog , Kim Kwang Hyun
Published: March 2020

5552

Background: Although induction chemotherapy (IC) for LA-HNSCC has shown high response rates, some patients do not respond to IC. Surgery has been the usual choice for the non-responding patients, but practically, not all of these patients are eligible for operation. The purpose of this study was to evaluate the efficacy of definitive radiation therapy (RT) for the HNSCC patients who failed IC. Methods: We have retrospectively analyzed the outcome of patients with LA-HNSCC who were initially treated with IC at Seoul National University Hospital between Jan. 2006 and Dec. 2010. Chemotherapeutic regimens used were 5-FU/cisplatin, docetaxel/5-FU/cisplatin, and docetaxel/cisplatin with or without cetuximab. After IC, patients were treated with RT, concurrent chemoradiation (CCRT), or surgery, either alone or with postoperative RT. Treatment modality was chosen on multi-disciplinary basis of our institution. Response was evaluated using RECIST criteria. Results: A total of 225 LA-HNSCC patients treated with IC were analyzed. Median age was 54 (range 24-77). Primary tumor locations were oral cavity (39.5%), nasal cavity/paranasal sinus (13.1%), oropharynx (13.1%), nasopharynx (13.1%), larynx (7.9%) and hypopharynx (13.1%). Among the 225 patients, 38 (16.9%) patients did not respond to IC [stable diseases (SD) = 23 (10.2%), progressive disease (PD) = 15 (6.7%)], and their median overall survival was 14.5 months. Among the 38 non-responders, 14 (36.8%) patients were undertaken surgery and 22 (57.8%) unresectable or inoperable patients were treated with either definitive RT or CCRT. Responses to subsequent definitive RT or CCRT for 20 evaluable patients were as follows: complete response = 6 (30.0%), partial response = 7 (35.0%), SD = 3 (15.0%), PD = 4 (20.0%) Overall response rate to definitive RT or CCRT in non-responder to IC was 65.0% (95%CI: 44.1%- 85.9%). Nine out of 15 patients who showed PD to IC received definitive RT or CCRT and interestingly, 3 (33.3%) patients responded to definitive RT or CCRT. Conclusions: A significant portion of HNSCC patients who failed to IC can benefit from subsequent definitive RT or CCRT. Further prospective study is warranted.