bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationship of tumor and stromal autophagy and endocrine responsiveness in breast cancer tissues.
Authors: Ueno Takayuki , Masuda Norikazu , Saji Shigehira , Kuroi Katsumasa , Sato Nobuaki , Takei Hiroyuki , Yamamoto Yutaka , Ohno Shinji , Yamashita Hiroko , Hisamatsu Kazufumi , Aogi Kenjiro , Iwata Hiroji , Sasano Hironobu , Toi Masakazu
Published: March 2020

571

Background: Neoadjuvant endocrine therapy has been employed to improve surgical outcomes for endocrine responsive breast cancers in post-menopausal women. Endocrine responsiveness is estimated by the expression levels of hormone receptors although heterogeneity in the response is well recognized. To improve the clinical outcome, it is critical to understand how cancer tissues react to the endocrine treatment. Methods: Pre-treatment biopsy samples and post-treatment surgical samples were obtained from 116 patients enrolled onto the multicenter prospective study of neoadjuvant exemestane therapy, JFMC34-0601. Fifty-four paired samples were available for the study. Estrogen receptor, progesterone receptor, HER2, Ki-67 by immunohistochemistry and pathological response were centrally evaluated. Apoptosis was assessed by TUNEL (Roche Diagnostics, Mannheim) and M30 (Roche Diagnostics, Mannheim). Autophagy was assessed by anti-beclin 1 (Novus Biologicals, CO) and anti-LC3 (MBL, Nagoya). Clinical response was assessed based on the RECIST criteria. The Wilcoxon rank-sum test and chi-square test were used for the statistical analysis. Results: The expression of autophagy markers, beclin and LC3, in cancer cells showed significant increases by exemestane (beclin p=0.016; LC3 p=0.0004) whereas TUNEL did not show any change and M30 expression decreased (p=0.01). The increase of beclin expression was associated with the clinical response: responders showed an increase (p=0.039) while non-responders did not. Importantly, the treatment increased autophagy markers not only in cancer cells but in stromal cells (beclin p<0.0001; LC3 p=0.024) while it did not change TUNEL in stromal cells. Patients with stromal beclin-positive showed poor clinical response (3/12) and poor pathological response (0/12) while those with stromal beclin-negative showed good clinical response (26/39) and good pathological response (16/38) (clinical response p=0.011; pathological response p=0.0064). Conclusions: This study suggested that exemestane induced autophagy in both cancer and stromal cells. In addition, stromal autophagy correlated with clinical and pathological response to the endocrine treatment.
Low HER2-expression to predict impaired activity of endocrine therapy in patients with estrogen-receptor (ER) positive metastatic breast cancer (MBC).
Authors: Sparber Cornelia , Berghoff Anna Sophie , Rudas Margaretha , Dubsky Peter Christian , DeVries Catharina , Minichsdorfer Christoph , Sattlberger Claudia , Mader Robert M , Bago-Horvath Zsuzsanna , Fitzal Florian , Gnant Michael , Rottenfusser Andrea , Zielinski Christoph , Preusser Matthias , Steger Guenther G. , Bartsch Rupert
Published: March 2020

573

Background: ER cross-activation by growth-factor signalling causes resistance to endocrine therapy (ET) in patients (pts) with Her2-positive MBC. Moreover, low levels of Her2-expression (Her2 1+; Her2 2+ without gene amplification), may result in reduced efficacy of ET in early breast cancer pts. In a recently published study, these tumours had a less favourable outcome as compared to tumours with a Her2-score of 0. Here, we investigated if low levels of Her2-expression could predict for shorter progression-free survival (PFS) in MBC pts on ET. Methods: PFS on first-line ET was chosen as primary endpoint and estimated with the Kaplan-Meier method. To test for differences between PFS curves, the log-rank test was used. Association of the following variables with PFS was investigated: low Her2-expression, grading, level of ER-expression, progesterone-receptor status, Ki67 (cut-off ≤20%), prior adjuvant ET, and presence of visceral metastases. For an estimated superiority of 40% in terms of PFS in favour of the Her2-negative group, a sample of 130 pts in two groups was needed in order to rule out the null-hypothesis with a 80% power and a two-sided α of 0.025. Results: A total number of 320 ER-positive MBC pts were identified from a breast cancer database; 170 pts were available for this analysis. Median PFS on first-line ET was 11 months (m) (8.56-13.44), corresponding numbers for second-line were 6 m (4.65-7.36), and third-line 4 m (1.52-6.48), respectively; median OS from diagnosis of MBC was 58 m (48.15-67.86). None of the variables investigated were significantly associated with first-line PFS. Second-line PFS, however, was significantly shorter in pts with grade 3 tumours and prior adjuvant ET; a trend towards shorter PFS was observed in high proliferating tumours. Conclusions: In this chart review, low levels of Her2 expression did not predict for shorter PFS in pts receiving ET; PFS in different treatment lines was well in line with data from clinical trials. High tumour grading and prior adjuvant ET were associated with accelerated onset of resistance, rendering those patients candidates for early combination of ET with targeted treatment approaches.
Involvement of microRNA in the regulation of progesterone receptor in breast cancer.
Authors: Shai Ayelet , Gilam Avital , Steiner Mariana , Shomron Noam
Published: March 2020

578

Background: The progesterone receptor (PgR) is a prognostic factor in ER positive breast cancers treated by adjuvant hormonal treatment. While PgR protein is usually assessed by immunohistochemistry (IHC), RT-PCR measurement of mRNA levels is provided by Oncotype Dx and other tests. Between 20-40% of tumors are discrepant in IHC and RT-PCR PgR expression, reflecting either technical problems or biological mechanisms. MicroRNAs regulate gene expression either at the mRNA or the protein translation level. Our hypothesis is that the latter potentially explains discrepancies between IHC and RT-PCR results. Methods: ER positive tumors were divided to three groups by PgR expression according to IHC and RT-PCR: (i) positive by IHC; (ii) negative by IHC and high mRNA levels by RT-PCR; (iii) negative by IHC and low mRNA levels by RT-PCR. RNA was extracted from tumors and adjacent normal tissue and the expression of PgR and microRNAs was assessed by RT-PCR. In addition, microRNAs were transfected into MCF-7 cells. The levels of PgR mRNA and protein were analyzed. Results: The PgR gene contains potential conserved binding sites for MicroRNAs 23a, 181a, 135a and 26b. Of these, miR- 23a and miR-181a showed inverse expression relative to the PgR expression in normal and tumor tissue, as expected. MicroRNA levels were determined in tumors of all three groups. The highest expression of microRNAs 23a, 181a and 26b was seen in IHC negative tumors with low levels of mRNA. Intermediate expression was seen in IHC negative tumors with high mRNA levels, and the lowest expression was detected in IHC positive tumors. Preliminary results suggest that over expression of microRNAs 23a, 181a and 26b in MCF7 cells decreased PgR levels. Conclusions: Our results suggest that microRNAs 23a , 181a and 26b regulate the level of the progesterone receptor in breast cancer and that tumors with relatively high mRNA levels may be deficient in PgR protein due to downregulation by microRNAs. [Table: see text]
Cardiac safety and efficacy of concomitant liposomal doxorubicin, docetaxel, and trastuzumab as neoadjuvant therapy in HER2-overexpressing breast cancer: A retrospective analysis.
Authors: Brunner Christine , Jaeger Thomas , Suppan Christoph , Mueller-Holzner Elisabeth , Jasarevic Zerina , Balic Marija , Goebel Georg , Marth Christian , Stoeger Herbert , Samonigg Hellmut , Hubalek Michael , Lang Alois
Published: March 2020

583

Background: Concurrent therapy of trastuzumab, anthracycline and taxane for the neoadjuvant treatment of breast cancer (BC) results in an improved rate of pathological complete response (pCR). However, there is considerable concern about the cardiac safety of this combination. The use of liposomal doxorubicin might be a valuable alternative with lower cardiotoxicity. We report cardiac safety and pCR-rate of a single arm, retrospective, multicenter analysis of neoadjuvant treatment for BC with liposomal doxorubicin, trastuzumab, and docetaxel. Methods: In this study 84 women with BC and HER2 overexpression were investigated in 3 oncological departments in Austria. All patients were treated with liposomal doxorubicin (50 - 60 mg/m²), docetaxel (75 mg/m²) and concurrent with trastuzumab for 6 cycles as neoadjuvant therapy. All patients were free of cardiovascular disease and had a left ventricular ejection fraction (LVEF) of ≥ 55%. Cardiac function was by LVEF and was examined at regular intervals(cycles 0-3, cycle 6, FU). Clinical response was evaluated by diagnostic breast imaging after cycles 3 and 6. All patients underwent surgery after neoadjuvant chemotherapy. The absence of any residual invasive cancer in the breast and axilla was defined as pathological complete response (pCR). Median follow up was 2.4 years. Results: Median age of the patients was 50 years. After 6 cycles of treatment the pCR rate was 46%. In this cohort a negative estrogen-and/or progesteron receptor was predictive for pCR (p<0.001). No patient progressed during treatment. None of the patients suffered symptomatic heart failure. Only one patient (1.6%) with asymptomatic LVEF of 45% was observed during follow-up. Conclusions: In this multicenter analysis we observed a considerably high rate of pCR in HER2-positive BC treated with liposomal doxorubicin, docetaxel and trastuzumab. The addition of liposomal doxorubicin instead of conventional doxorubicin or epirubicin entails a very favorable cardiotoxicity profile. This regimen is a safe treatment option in patients with HER-2 positive breast cancer.
Clinical and pathologic correlation of the activated form of the estrogen receptor (ER) in breast cancer (BC).
Authors: Bonneterre Jacques , Gilles Erard M. , Zukiwski Alexander A. , Bosq Jacques , Valent Alexander , Hutt Emilie , Fuqua Suzanne A.W.
Published: March 2020

592

Background: About 50% of ER positive (ERpos) BC are resistant to hormone treatment. In absence of ligand, ERs are evenly distributed in nuclei in normal tissue. Upon ligand binding, ERs dimerizes and form a discrete focal subnuclear distribution pattern (FDP), which are associated with transcriptional activation of ER. This ER FDP is observed in BC. We hypothesized that in BC that the presence/absence of ER in the FDP could predict antiestrogen activity. This study describes an immunohistochemistry (IHC) method, by which a biomarker could be developed to investigate this hypothesis. Methods: 303 archived BC biopsies were obtained along with clinical and pathology data. Biopsies were analyzed for standard HES, ER, progesterone receptor (PR) and Ki67. PR positivity was determined with distinct antibodies to the A and B isoforms. The A-ER and D-ER nuclear patterns were analyzed at x1000 magnification. Results: Mean age; 58 (17 -89). Histology: ductal 85% lobular 13%, other 2%; 84% ERpos and 84% either PRApos or PRBpos, 7% ERpos and 7% PRApos or PRBpos only. All but 3 ERpos cases had received AntiEs; Adj. chemotherapy 51%, Stage: I 51%, II 43%, III 6 %. Grade: I 24%, II 51%, III 25%. Median follow up 31 months (mo). Local or distant progression (PD) was 19%. ER status was D-ER in 78% and A-ER in 22% of the biopsies and PD was associated with the D-ER pattern (p = 0.06), e.g. the hypothetically non-functional pattern D-ER was associated with a higher rate of PD (4 vs 35). With DFS defined as time to PD or death (5 year cut off), ERpos was better that ERneg (HR= 0.38, p = 0.016). For ERpos BC, A-ER was numerically better than D-ER (HR =0.3, p=0.24 two-sided). In univariate analyses, A-ER pattern was associated with higher grade (p=0.035), anisonucleosis (p=0.06), mitotic index (p=0.02), and Ki67 (=0.08). No association was found between ER pattern and age, stage or HER2 status. Conclusions: This study supports the hypothesis that AntiEs are mainly active in BC with A-ER pattern, which is targetable by AntiEs. A larger number of events are needed to reach significance in time-dependent analyses and confirmatory studies are warranted.
Independent characterization by duel staining of progesterone receptor (PR) and estrogen receptor (ER) in breast cancer (BC).
Authors: Zukiwski Alexander A. , Caillaud Jean-Michel , Bosq Jacques , Fuqua Suzanne A. W. , Lange Carol A. , O'Shaughnessy Joyce , Gilles Erard M. , Bonneterre Jacques
Published: March 2020

596

Background: The oncology literature indicates that ER and PR are linked and in BC the presence of PR usually indicates functional ER. BCs express both ER and PR to varying degree, but little has been published on expression of ER + PR in individual cancer cells. The goal of this study is to 1. Determine the expression ER and PR at the cellular level, 2. Determine if ER and PR are expressed in the same BC cells. If ER and PR are separate, this may indicate that antiestrogens and antiprogestins may target different cells. Methods: Archived 1° BC specimens were processed using standard IHC techniques for ER/PR testing. The procedure consisted of sequential double staining on the same microtone section, where the PR was visualized through brown staining using HRP/DAB, and the ER was visualized through red staining using AP/Permanent Red. The initial testing on 13 tumor samples utilized a duel anti-PR-A/B antibody (Ab) and an ER Ab. The next 63 tumor samples utilized; 1. anti-ER and anti-PR-A Abs, 2. anti-ER and anti-PR-B Abs. A pathologist experienced with IHC, interpreted and enumerated the cells staining positive for ER only, for PR only and cells staining positive for both ER & PR. The number of cells expected to be stained for both ER & PR by chance can be calculated as the rate of total ER by the rate of total PR and compared with the observed rate (paired rank test). ER/PR positivity is defined as ≥ 5% cells positive. Results: In the first series, 11/13 tumors were ERpos, 13/13 were PRpos, 7/13 tumors had both ER & PR expressed in 5-20% (median 5%) of the same tumor cells. In the 2nd series of 63 tumors; 1. 50/53 were ERpos, 52/53 were PRApos and 44/53 had both ER & PRA expressed in <5-20% (median 5%) of the same tumor cells, 2. 44/52 were ERpos, 52/52 were PRBpos and 42/52 tumors had both ER & PRB expressed in <5-20% (median 10%) of the same tumor cells. Areas of ER or PR only predominance were frequent. A paired rank test indicates that the observed rate (median 9%) of ER/PR duel staining is less than predicted (median 18%, p <0.000). Conclusions: ER & PR were expressed in the majority of tumors examined with a minority the tumor cells expressing both ER & PR. These data support evaluating antiprogestins as a different therapeutic target from ER.
Efficacy and safety of first-line (1L) pertuzumab (P), trastuzumab (T), and docetaxel (D) in HER2-positive MBC (CLEOPATRA) in patients previously exposed to trastuzumab.
Authors: Ciruelos Gil Eva Maria , Brufsky Adam , Im Young-Hyuck , Kim Sung-Bae , Clark Emma , Knott Adam , Ross Graham , Miles David
Published: March 2020

600

Background: CLEOPATRA is a global phase III trial of P + T + D vs placebo + T + D in HER2-positive 1L MBC. Results showed a significant improvement in PFS (Baselga NEJM 2012) and OS (Swain SABCS 2012) favoring P + T + D. CLEOPATRA started recruitment in 2008 soon after the approval of T in the adjuvant setting in 2006 and mandated a disease-free interval (DFI) of ≥12 mos from the end of adjuvant therapy to MBC diagnosis. Due to this, a low proportion of pts with prior T exposure was included. Here we present the efficacy and safety of 1L P + T + D in the subset of pts in CLEOPATRA with prior T exposure. Methods: Pts received P + T + D or placebo + T + D, had a DFI ≥12 mos, baseline left ventricular ejection fraction (LVEF) ≥50% and no LVEF decline to <50% during/after prior T therapy. Exploratory analyses of PFS and OS in pts with (neo)adjuvant therapy with or without T were conducted. Results: Of the study population, 47% had received (neo)adjuvant therapy and 11% had received (neo)adjuvant T; 82% of the prior T group came from Europe or North America. A univariate Cox regression analysis did not identify prior T therapy as a statistically significant risk factor for developing left ventricular systolic dysfunction (LVSD). However, due to the low number of LVSD events overall, this analysis has limited sensitivity. Conclusions: Data from CLEOPATRA show that pts with HER2-positive 1L MBC who have received prior T (DFI ≥12 mos) derive the same magnitude of benefit from the combination of P + T + D when compared with the whole study population or those who are T-naïve. This is in agreement with prior evidence of the activity of P + T in pts pretreated with T (Baselga JCO 2010). Efficacy and safety of P-T-based therapy is being explored in the PERUSE and PHEREXA trials, in a pt population with wider exposure to prior T and a shorter DFI, which may better represent current clinical practice. Clinical trial information: NCT00567190. [Table: see text]
E 1308: A phase II trial of induction chemotherapy (IC) followed by cetuximab with low dose versus standard dose IMRT in patients with human papilloma virus (HPV)-associated resectable squamous cell carcinoma of the oropharynx (OPSCC).
Authors: Marur Shanthi , Li Shuli , Cmelak Anthony , Gillison Maura L. , Ferris Robert L. , Bauman Julie E. , Zhao Weiqiang , Westra William H. , Chung Christine H. , Wagner Lynne I. , Trevarthen David R. , Jahagirdar Balkrishna N. , Colevas A. Dimitrios , Burtness Barbara ,   Eastern Cooperative Oncology Group
Published: March 2020

6005

Background: HPV is associated with 60-80% of OPSCC. E2399 results showed IC followed by (f/b) paclitaxel (P)/3D RT (70Gy) improved 2-yr progression-free (PFS) for HPV+ compared to HPV- OPSCC. We studied a regimen with 20% radiation dose reduction to 54Gy in HPV + OPSCC patients (pts) with a clinical complete response (CCR) to IC. Methods: Stage III/IVA,B resectable HPV+ OPSCC were included. Eligible pts received IC q3 week x 3 with P 90mg/m2 days (D) 1,8, 15, cisplatin (CDDP) 75mg/m2 D1, and cetuximab (C) 400 mg/m2 D1, cycle 1 f/b C 250 mg/m2 weekly. Primary tumor and involved nodal response to IC were determined independently. Pts recieved IMRT 54Gy/27 fxs with weekly C for CCR vs. 69.3Gy/33 fxs with weekly C if <CCR. Primary endpoint was 2-year PFS; secondary endpoints were toxicity, OS, response rate, QOL and correlative biomarkers. Results: From March 2010 to Oct 2011, 90 pts were enrolled (80 analyzable). Median age was 57 years, 95% men, 93% Caucasian, 91% PS 0, 46% never smokers, 84% not current smokers. Nodal stage: 39%-N2B, 29%-N2C, T stage: 23%-T1, 50%-T2, 16%-T3, 10%-T4. 96% received all 3 cycles of IC. Grade 3/4 toxicities included: rash (25%), neutropenia (11%). During CRT: oral mucositis (31%), dysphagia (17%), radiation dermatitis (8%). Response: Biopsy at primary site post- baseline measurements rendered 7/80 pts unevaluable (UE), 6/7 had investigator-reported CCR to IC. The centrally reviewed and investigator reported primary site CCR rate to IC was 63.8% ( 95% CI: 52.2%, 74.2%) and 71.3% (95% CI: 60.0%, 80.8%), respectively. Radiation: 73.8% (59/80 pts) received low dose IMRT/C to primary [54Gy (56), 52Gy (1), 40Gy (2)]. Best overall clinical response was 86% (CR +PR+SD) with 14% UE. Rate of post-treatment neck dissection in low dose vs other RT gp is 13.4% vs 22.2% ( p value of 0.46), respectively. Median follow up is 11.8 months. Conclusions: Overall, IC with P, CDDP and C f/b low dose RT with C was well tolerated, with all pts responding and very low grade 3/4 toxicities. Data on PFS are premature. A 2 year PFS of 85% or better will be considered worthy of further study. Clinical trial information: NCT01084083.
Leptomeningeal disease and breast cancer: Relationship of outcome and subtype.
Authors: Abouharb Sausan , Ensor Joe , Loghin Monica Elena , Katz Ruth , Gonzalez-Angulo Ana M. , Esteva Francisco J. , Moulder Stacy L. , Valero Vicente , Hortobagyi Gabriel N. , Melhem-Bertrandt Amal
Published: March 2020

601

Background: Breast cancer (BC) is one of the most common tumors to involve the leptomeninges. Outcome of leptomeningeal disease (LMD) across BC subtypes is not well documented. We aimed to characterize clinical features and outcomes of LMD based on BC subtypes. Methods: We retrospectively reviewed medical records of patients diagnosed with LMD from BC (1997 to 2012). All patients had BC. Cases of LMD were based on the presence of neoplastic cells on cerebrospinal fluid examination and/or evidence of LMD by imaging studies. Survival was estimated by the Kaplan-Meier method and significant differences in survival were determined by Cox proportional hazards or log-rank tests. Results: 232 patients were included, 189 of them had available tumor subtype classified as: hormone receptor positive (HR+) BC N=67 (35.5%), human epidermal growth factor receptor 2 positive (HER2+) N=55 (29%), and 67 (35.5%) triple-negative BC (TNBC). Median age at diagnosis of LMD was 49.7 years. (Range 24-89). Median overall survival (OS) from LMD diagnosis across all subtypes was 3.1 months (95% CI, 2.5 to 3.7). Median OS correlated with BC subtype: 3.7 months (95% CI: 2.4, 6.0) in HR+, 4.0 months (95% CI: 2.6, 6.9) in HER2+, and 2.2 months (95% CI: 1.5, 3.0) in TNBC, (p=0.0002). There was an 11.4% chance a patient diagnosed with LMD would survive 1 year and the chance of surviving at least 3 years was 1.3%. When age was used as a continuous variable, older age was associated with worse outcome (p<0.0001). Patients with HER2+ BC and LMD were more likely to have received systemic therapy (ST) (70%), compared to HR+ (41%) and TNBC (41%) (p=0.002). 38% of patients with HER2+ BC received HER2 directed therapy. There was no difference in the use of intrathecal therapy (IT) (52%) across subtypes (p=0.3). Use of IT therapy (p<0.0001) and ST (p<0.0001) were both associated with improved age-adjusted OS. After adjusting for age, ST, there was no difference in OS between patients with HR+ and HER2+ BC (p =0.14), but a significant difference remained between TNBC and HER2+ BC (p < 0.0001). Conclusions: LMD carries a dismal prognosis. Our data shows that OS correlates with tumor subtype. Patients with TNBC had a significantly shorter OS compared to patients with HER2+ BC. New treatment strategies are needed.
Prognostication of survival from nasopharyngeal carcinoma by reduction of plasma Epstein-Barr viral DNA load at midpoint of radiotherapy course: A new paradigm of prognostication.
Authors: Chan Anthony T. C. , Chan Allen K.C. , Ma Brigette , Hui Edwin Pun , Mo Frankie , Chow Katherine , Leung Linda , Chu Ka Wah , Zee Benny C.Y. , Lo Dennis YM , Leung Sing Fai
Published: March 2020

6015

Background: To test the hypothesis that prognostication of treatment outcome is feasible by biomarker response at mid-course of chemoradiotherapy (CRT)/ radiotherapy (RT), with respect to the plasma load of Epstein-Barr viral (EBV) DNA in nasopharyngeal carcinoma (NPC). Methods: 107 patients with stage IIB-IV NPC were prospectively studied. Plasma EBV DNA load was measured by quantitative PCR before therapy (pre-DNA), at completion of 4 weeks of CRT/RT (mid-DNA), and within 3 months of completion of therapy (post-DNA). The endpoints are post-DNA load, a recognized surrogate of survival, and clinical outcome. Results: 93% of patients had detectable EBV DNA before therapy (median load = 972 copies/ml). EBV DNA became undetectable in 55 (51%) patients at the end of week 4 of therapy. Detectable mid-DNA was associated with worse clinical outcome (median follow-up time, 6.2 years), for distant failure (HR 12.02, 95% CI 2.78-51.93; P<0.0001), progression-free survival (HR 4.05, 95% CI 1.89-8.67, P<0.0001), and overall survival (HR 3.29, 95% CI 1.37-7.90, P=0.0077). About three-quarters of all failures were associated with detectable mid-DNA, whereas about one-third of all failures were associated with detectable post-DNA. Patients with detectable mid-DNA which disappeared after RT continued to sustain a less favourable prognosis than those with undetectable mid-DNA. Stratification by tumor stage (II, III, IV) has no significant prognostic effect. Conclusions: Unfavorable EBV DNA response at mid-course of radiotherapy/chemoradiotherapy is an adverse prognosticator for treatment outcome, is linked to majority of all failures, and discriminates outcome better than tumor stage. The data could provide a basis for trial design that addresses alteration of therapy intensity during the latter phase of chemoradiotherapy, and adjuvant therapy.
Assessment of early tumor response to induction chemotherapy (IC) in locally advanced squamous-cell carcinoma of head and neck (LASCCHN) with 18FDG PET-CT: A prospective trial.
Authors: Nicolau Ulisses Ribaldo , Lima Eduardo Nobrega Pereira , Alves Marclesson S. , Oliveira Thiago Bueno , Jesus Victor Hugo Fonseca , Paiva Tadeu Ferreira , Cezana Loureno , Silva Virgilio Sousa , Pinto Paula Nicole , Porto Gislaine Machado , Pellizzon Antonio Cassio Assis , Carvalho Genival Barbosa , Kowalski Luiz Paulo
Published: March 2020

6017

Background: Response to IC with triplet regimens adding taxanes to cisplatin and 5-fluorouracil (TPF), followed by chemoradiotherapy (CRT) for LASCCHN, is usually evaluated after 2 cycles of IC, based on bidimensional WHO or modified WHO criteria. Concerns regarding toxicity profile of TPF suggest a potential benefit of an early response evaluation approach that could select patients who would be spared from a toxic regimen and promptly started on an alternative treatment. The aim of this study is to assess the ability of evaluating early response after the first IC cycle based on a 40% decrease in standard-uptake value (SUV) measured by 18 FDG PET-CT on the 14th day. Methods: Patients with LASCCHN who underwent IC with TPF were prospectively evaluated. Staging procedure included locoregional and chest imaging, endoscopic examination and FDG PET-CT. At day 14 of first cycle, a second FDG PET-CT was performed and treating physicians were blinded for these findings. All cases were conducted according to the usual post-cycle 2 WHO or modified WHO criteria evaluation. Written informed consent was obtained from all recruited patients. Results: Between February 2010 and October 2012, 40 stage III/IV LASCCHN patients (34 oropharyngeal, 3 hypopharyngeal and 3 laryngeal) were recruited. With a median follow up of 11.4 months the actuarial 2 years overall (OS) and disease free survival (DFS) of all patients were 81.4% and 69.2%, respectively. Responders (any decrease of SUV) at day 14 PET CT had a better OS (90 vs. 27% - p<0,001) and DFS (76 vs. 0% - p<0,001) as compared to non-responders. Decrease of at least 40% in the SUV of primary tumor predicted a better DFS (100 vs. 51% - p=0,007). Conclusions: These results suggest a potential role of early response evaluation with 18 FDG PET-CT in patients with LASCCHN undergoing IC. A SUV decrease of at least 40% predicts better DFS. An increase in the SUV predicts a poor prognosis.
Positron emission tomography and stage migration for head and neck cancer.
Authors: VanderWalde Noam Avraham , Salloum Ramzi George , Liu Tsai-Ling , Hornbrook Mark Christopher , O'Keeffe-Rosetti Maureen Cecelia , Ritzwoller Debra Pearson , Fishman Paul Arthur , Lafata Jennifer Elston , Khandani Amir H , Chera Bhishamjit S.
Published: March 2020

6018

Background: Positron emission tomography (PET) is often used for the staging of head and neck cancer (HNC). The purpose of this study is to explore the association between the increased utilization of PET and stage/survival in the managed care environment. Methods: Adult patients diagnosed with HNC (n=958) between 2000-2008, at 4 integrated health systems (Group Health Cooperative, Seattle; Health Alliance Plan/Henry Ford Health System, Detroit; Kaiser Permanente Colorado and Northwest, Portland) were identified via tumor registries linked to claims data. We compared AJCC stage distribution, patient/treatment characteristics, and survival between pre-PET era (2000-2004) vs. PET era (2005-2008), and those with PET vs. those without, during the PET era. AJCC stage was grouped into stage I/II (localized), stage III/IVa/IVb (locally advanced), and stage IVc (metastatic). Ordered logistic regression estimated the effects of PET utilization on upstaging. Kaplan-Meier estimates described overall survival (OS) differences between PET users and nonusers in the PET era. Cox proportional hazards regression evaluated the effect of PET use on survival. Results: There was a non-significant increase in stage III/IVa/IVb (40% to 44%) with a decrease in stage I/II (58% to 52%) between pre-PET era and PET era (p=0.11). During the PET era, patients with PET were more likely stage III/IVa/IVb and less likely stage I/II compared to patients without PET (III/IVa/IVb: 62% vs. 29%, I/II: 35% vs. 68%). On multivariate analysis those who were staged with PET were twice as likely to have locally advanced disease (OR 2.091; p=0.006). There was no difference in stage IVc. Patients with PET scans were more likely to receive chemotherapy with radiation and less likely to receive no treatment. 3-year actuarial OS for patients (all stages) with and without PET was 81% vs. 77% (p=0.261). 3-year actuarial OS for patients staged III/IVa/IVb with and without PET was 58% vs. 41% (p= 0.001). Conclusions: HNC patients were more likely to be upstaged with the use of PET. There was an improvement in survival in stage III/IVa/IVb patients, but no difference in survival across all stages. This likely reflects selection bias and stage migration rather than improved outcomes among individual patients.
A phase II study of dasatanib (BMS 354825) in recurrent or metastatic ckit-expressing adenoid cystic (ACC) and non-ACC malignant salivary glands tumors (MSGT).
Authors: Wong Stuart J. , Cohen Ezra E.W. , Karrison Theodore , Hayes David N. , Kies Merrill S. , Cullen Kevin J. , Tanvetyanon Tawee , Argiris Athanassios , Takebe Naoko , Lim Dean , Saba Nabil F. , Worden Francis P. , Gilbert Jill , Lenz Heinz-Josef , Razak Albiruni R.A. , Roberts John D. , Vokes Everett E.
Published: March 2020

6022

Background: ACC is a rare disease, accounting for 1/3rd of MSGT, in which 90% of cases express the protein product of the ckit proto-oncogene. Dasatinib is a potent and selective inhibitor of five oncogenic PTKs/kinase families including ckit. We conducted a phase II study to determine the antitumor activity of dasatinib in ACC and non-ACC MSGT. Methods: In a two-stage design, adult patients (pts) with recent radiographic progressive, recurrent or metastatic ACC, + cKIT, were treated with dasatinib 70 mg PO BID. Pts with non-ACC MSGT of other histologic types, were treated as a separate cohort. Response was assessed every 8 wks by imaging using RECIST criteria. The study design stipulated enrollment of n=40 ACC patients (20 in stage I and 20 in stage II) and 25 non-ACC patients (14 in stage I and 11 in stage II). Results: Fifty-four pts were enrolled, 40 ACC and 14 non-ACC. One additional pt was a screen failure. Baseline data on 54 pts are: M:F = 28:26, median age 56.6 yrs (range 20-82), PS 0:1:2 = 24:28:2, prior radiation:chemotherapy = 44:21. The most frequent adverse events experienced (as % of pts, worst grade 2 or higher and at least possibly related to study drug) were: fatigue (28%), nausea (19%), headache (15%), lymphopenia (11%), dyspnea (11%), alanine aminotransferase increased (7%), anorexia (7%), vomiting (7%), alkaline phosphatase increased (6%), diarrhea (6%), and non-cardiac chest pain (6%). No grade 4 adverse events occurred and only 15 pts experienced a grade 3 adverse event (at least possibly attributed to study drug), primarily dyspnea (4 patients) and fatigue (3 patients). Significant cardiac toxicity was observed in one pt (grade 3 prolonged QT corrected interval). Among ACC pts, best response to dasatinib: 0 pts (0%) had PR, 21 pts (52%) had SD (range 2.8-13.8 months), 12 pts (30%) had PD, and 2 died prior to cycle 2. Median PFS was 4.8 mos. For 14 evaluable non-ACC pts, none had an objective response, triggering early stopping. 7 had SD (range 1.4-6.6 months), and 4 PD. Conclusions: Although there were no objective responses, dasatinib is well tolerated, with tumor stabilization achieved by 52% of ACC pts. Dasatinib demonstrated no activity in non-ACC MSGT. Clinical trial information: NCT00859937.
PARTNER: A randomized phase II study of docetaxel/cisplatin (doc/cis) chemotherapy with or without panitumumab (pmab) as first-line treatment (tx) for recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).
Authors: Wirth Lori J. , Dakhil Shaker R. , Kornek Gabriela , Axelrod Rita , Adkins Douglas , Pant Shubham , O'Brien Paul E. , Debruyne Philip R. , Oliner Kelly S. , Dong Jun , Bach Bruce A.
Published: March 2020

6029

Background: PARTNER was a multicenter, randomized phase II estimation study evaluating 1stEline tx of R/M SCCHN with doc/cis ± pmab. Methods: Patients (pts) were randomized 1:1 to doc/cis with pmab (Arm 1) or doc/cis alone (Arm 2). Arm 1 received 9 mg/kg pmab on day 1 of each 21-day cycle, and all pts received 1stEline doc/cis both at 75 mg/m2 on day 1 for up to 6 cycles. In Arm 1, pts could receive pmab monotherapy upon completion of 6 cycles of doc/cis until disease progression (PD). In Arm 2, pts could receive pmab as 2ndEline monotherapy upon PD. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. HPV status was determined using p16 INK IHC. No formal hypothesis was tested. Results: Baseline characteristics were balanced between arms. Of 103 pts, HPV status was evaluable in 66 (64%); 29% were HPV positive. Efficacy results are shown (Table). Worst grade 3/4 adverse events (AEs) were 73% in Arm 1 vs 56% in Arm 2. Conclusions: Median PFS was increased in both arms over historical doublet cytotoxic chemotherapy. PFS and ORR were higher in the pmab arm in the overall population, in the HPV positive (n=19) group, and in the HPV negative (n=47) group. There was an increase in grade 3/4 AEs with this regimen. The crossover design, with 57% of Arm 2 pts receiving pmab as 2ndEline monotherapy, confounds interpretation of OS. Clinical trial information: NCT00454779. [Table: see text]
Trastuzumab-based adjuvant chemotherapy for breast cancer: Early myocardial dysfunction detected by “speckle tracking” echocardiography (STE).
Authors: Mantovani Giovanni , Dessi Mariele , Orgiano Laura , Piras Alessandra , Cadeddu Christian , Deidda Martino , Ghiani Massimo , Antoni Giorgia , Serpe Roberto , Mercuro Giuseppe
Published: March 2020

603

Background: While anthracycline-induced type 1 cardiotoxicity is well established, type 2 trastuzumab (TZM)-induced cardiotoxicity, although less relevant and reversible, is nonetheless significant in combination with other drugs, such as taxanes (TAX). A paradigmatic clinical example of this regimen is the adjuvant setting of breast cancer patients overexpressing HER-2. In the present study we chose STE with longitudinal and circumferential Strain (S) and Strain Rate (SR), as a very sensitive tool to timely identifying left ventricular dysfunction. The biological markers of chronic inflammation/oxidative stress were also studied. Methods: A phase IV prospective non-randomized study was carried out to assess cardio-toxicity induced by the combination of epirubicin (EPI) + TAX followed by TZM administered with the conventional schedule in adjuvant setting of breast cancer patients (pts) overexpressing HER-2. Inclusion criteria: 18–70 y, histologically confirmed HER-2+ve breast cancer candidates for TZM-based 3 weekly regimen; LVEF ≥55%; ECOG PS score 0-1, no history of cardiac disease. STE parameters (longitudinal and circumferential S and SR) and chronic inflammation (IL-6 and TNF-a)/oxidative stress (reactive oxygen species) markers were assessed at baseline before TZM and after each of the subsequent 18 TZM administrations. Results: Forty pts (mean±SD age 53±10 y) were assessed up to the 8th TZM administration. A progressive reduction of longitudinal SR was observed, becoming significant from the 4th TZM dose (0.65±0.18 s-1 vs 0.81±0.16 s-1, p<0.005); a significant reduction of circumferential SR (0.60±0.15 s-1 vs 0.51 ±0.14 s-1, p< 0.01) and rotation index was also observed from the 2ndTZM dose. These changes are all indicative of myocardial systolic dysfunction. No changes of biological parameters were observed. Conclusions: The sequential administration of TZM after EPI/TAX induced an early left ventricular dysfunction detected by STE which persisted at least up to the 8th TZM administration. This study is in progress with close monitoring of pts and its ultimate goal is to select pts candidates for an effective cardio protective treatment.
Phase I study of weekly albumin-bound paclitaxel (ab-P) plus weekly cetuximab (Cet) plus intensity-modulated radiation therapy (IMRT) in patients with stage III/IVb head and neck squamous cell carcinoma (HNSCC).
Authors: Fury Matthew G. , Sherman Eric Jeffrey , Rao Shyam S. , Wolden Suzanne L. , Smith-Marrone Stephanie , Ng Kenneth K. , Mueller Boris , Gelblum Daphna Y. , Dutta Pinaki R. , Lee James , Shen Ronglai , Kurz Sarah , Katabi Nora , Haque Sofia , Lee Nancy Y. , Pfister David G.
Published: March 2020

6034

Background: There is a clinical need to improve the efficacy of standard Cet + concurrent RT for pts with stage III/IVB HNSCC. Taxanes have potent activity against HNSCC, and ab-P may offer therapeutic advantages in comparison with other drugs of this class. Methods: This was a single institution phase I study with a modified 3 + 3 design. 4 dose levels (DLs) of weekly ab-P were explored (30, 45, 60, and 80 mg/m2) during IMRT. Standard Cet (450 mg/m2 loading dose followed by 250 mg/m2 weekly) concurrent with IMRT (total dose, 70 Gy) was prescribed for all pts. The maximum-tolerated dose (MTD) would be exceeded if >2/6 pts experienced DLTs at a given dose level. NCI CTCAE v.3 was used, and DLT monitoring extended until 2 wks after IMRT. Results: 25 eligible pts (20M, 5F) enrolled, with median age 58 years (range, 46-84) and median KPS 90 (range 80-100). Primary tumor sites were oropharynx, 20 (10 HPV pos, 5 HPV neg, 5 not done); neck node with unknown primary, 2; and larynx, oral cavity, and maxillary sinus, 1 each. Two pts never received ab-P and were deemed inevaluable. At DL 1 (ab-P, 30 mg/m2), there was one DLT (g.4 pneumonia) among 6 pts. At DL2 (ab-P, 45 mg/m2), there were 2 DLTs (g.4 cerebrovascular accident; g.3 decrease in L. ventricle ejection fraction/CHF exacerbation) among 6 pts. At DL3 (ab-P, 60 mg/m2), there was 1 DLT (g.3 supraventricular tachycardia) among 6 pts. MTD was exceeded at DL4 (ab-P, 80 mg/m2) with 3 DLTS (g.3 neuropathy, g.3 dehydration, g.3 anemia) among 5 evaluable pts. For the entire study population, most common ≥ g3 AEs were: lymphopenia 100%, functional mucositis, 56%, and pain in throat/oral cavity, 52%. There were no treatment-related deaths. Among 23 evaluable pts at a median follow up of 29 months, 2y PFS rate is 64% (95% CI: 41-80%) and 2y OS rate is 90% (95% CI: 66-97). Conclusions: The recommended phase II dose is ab-P 60 mg/m2 weekly when given concurrently with IMRT and standard weekly Cet. This regimen merits further study as an alternative to IMRT + Cet alone for pts who require a non-platinum regimen. This study was approved and funded by the NCCN from general research support provided by Celgene, Inc. Clinical trial information: NCT00736619.
A phase II study of suberoylanilide hydroxamic acid (SAHA) in subjects with locally advanced, recurrent, or metastatic adenoid cystic carcinoma (ACC).
Authors: Goncalves Priscila Hermont , Kummar Shivaani , Siu Lillian L. , Hansen Aaron Richard , Savvides Panayiotis , Sukari Ammar , Chao Joseph , Heilbrun Lance K. , Pilat Mary Jo , Smith Daryn W. , Casetta Lindsay , Boerner Scott Anthony , LoRusso Patricia
Published: March 2020

6045

Background: SAHA is a small molecule inhibitor of histone deacetylases (HDAC). Based on confirmed responses noted in 2 ACC patients treated with SAHA at our institution; we initiated this phase II trial. Methods: Patients with LA, recurrent or metastatic ACC and adequate organ function were eligible. Any prior number of chemotherapy regimens was allowed. Tumor tissue and blood were collected for correlative studies. SAHA was administered orally 400 mg daily for 28 days. The primary objective was to evaluate response rate (RR). Secondary endpoints included: time to tumor response (TTR); response duration (RD); progression-free survival (PFS); overall survival (OS); and adverse events (AE). 29 evaluable patients were needed in a Simon 2-stage optimal design to distinguish RR of at most 5% vs. at least 20%, with alpha = 0.15 and power = 0.90. Results: 30 evaluable patients (overenrolled by 1) were accrued from at 5 different centers between August 2010 and June 2012. Median follow up among the censored patients is 3.8 months for PFS, and 7.2 months for OS. 19 patients were female, 24 were Caucasian, median age was 53 years (range 21-73); 21 patients had a performance status of 1; 20 patients were chemo-naïve. The median number of cycles completed was 5 (range 1-27+). Lymphopenia (n=5), hypertension (n=3), oral pain (n=2), thromboembolic events (n=2) and fatigue (n=2) were the only grade 3 AEs that occurred in more than 1 patient. 5 patients were dose reduced due to AEs. At the time of data cut-off, 9/30/2012, 1 patient with lung metastasis had a PR, with RD of 11.2+ months. TTR was 7.7 months. SD was the best response in 25 patients. Median PFS is 12.7 months (90% confidence interval lower limit: 3.7 months). Median OS has not been reached. There were 6 patients with PFS > 1 year. The correlative studies results will be presented. Conclusions: SAHA shows promise in the treatment of ACC. We are awaiting genomic analysis of the tumors to study the basis of clinical benefit (PR and SD) of SAHA in ACC. Future drug combination studies in ACC are being considered focusing on the epigenetic mechanism of SAHA. Supported by 5U01CA062487/19. Clinical trial information: NCT01175980.
Recombinant adenoviral human p53 gene combined radio- and chemotherapy after a tumorectomy in treatment of laryngeal carcinoma in advanced stage.
Authors: Chen Fei , Wang Feng
Published: March 2020

6050

Background: To investigate the benefits of post-surgery using recombinant adenoviral human p53 gene (rAd-p53) combined with radio- and chemo-therapy in treatment of laryngeal carcinoma in advanced stage. Methods: A total of 61 patients with a stage III or IV laryngeal cancer, 51 males and 10 females with an average age of 63.2, were randomly divided into three groups: G1, G2 and G3. The 18 G1 patients received no treatment after surgery. The patients in G2 (21 patients) and G3 (22 patients) received rAd-p53 followed by radio-and chemo-therapy, and only radio- and chemo-therapy, respectively. The rAd-p53 was injected into the surgery wound bed at a dose of 2 x 1012 viral particles (VP) once per 3 days for 5 times. Radiotherapy was given at a total dose of 63-67 Gy in 7 weeks. The chemo-regimen included 5- Fu 500 mg/ m2 from day 1 to day 5 and DDP 30 mg / m2 from day 1 to day 3 in a treatment course of 21days for two courses. Results: All the study patients were followed up for at least 3 years. One patient in G2 lost to follow up. The local control rates (no recurrence) at 3 years were 38.9% (7/18), 75.0% (15/20), and 54.5% (12/22) for G1, G2, and G3, respectively. The 3-years progress free survivals (PSF) were 38.9%, 50.0%, and 45.0% for G1, G2, and G3, respectively. The 3-years overall survivals (OS) were 38.9%, 65.0%, and 45.0% for G1, G2, and G3, respectively. The three efficacy endpoints of G2 were significantly better than both G1 and G3. These efficacy measures of G3 were significantly higher than G1. Conclusions: Post-surgery chemo- and radiotherapy is necessary to increase the local control rate, prolong both PRF and OS. The rAd-p53 gene therapy can farther increase the efficacy measures.
Neoadjuvant erlotinib, erlotinib-sulindac, or placebo: A randomized, double-blind biomarker modulation study in operable head and neck squamous cell carcinoma (HNSCC).
Authors: Bauman Julie E. , Gross Neil D. , Gooding William E. , Denq William , Thomas Sufi M. , Wang Lin , Chiosea Simion I. , Hood Brian L , Flint Melanie S , Sun Mai , Conrads Thomas P. , Ferris Robert L. , Johnson Jonas Talmadge , Kim Seungwon , Argiris Athanassios , Wirth Lori J. , Siegfried Jill , Grandis Jennifer R.
Published: March 2020

6051

Background: The epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) pathways are upregulated in HNSCC. Crosstalk potentiates growth, proliferation and invasion. Preclinical models show synergistic anti-tumor effects from dual blockade. We evaluated biomarker modulation in paired tumor specimens from a 3-arm phase 0 trial of erlotinib, a small molecule EGFR inhibitor; erlotinib + sulindac, a non-selective COX inhibitor; vs. placebo. Methods: Patients (pts) with untreated stage II-IVb HNSCC were randomized 5:5:3 to neoadjuvant erlotinib 150 mg daily (Arm 1, n = 19), erlotinib + sulindac 150 mg twice daily (Arm 2, n = 16), or placebo (n = 12). Pts were treated for 7-14 days. Tumor specimens were collected pre- and post-treatment. The primary endpoint was change in Ki-67 proliferative index. We hypothesized an ordering in Ki-67 down-modulation, with Arm 2 > Arm 1 > placebo. A Jonckheere-Terpstra test evaluated trend; a Wilcoxon test was applied to pairwise contrasts. We prepared tissue microarrays for IHC, to explore pharmacodynamic modulation of 21 EGFR and COX-2 pathway constituents including EGFR, Src, STAT3, Akt, EP2 and EP4. Results: From Dec 2005 – Dec 2008, 48 pts enrolled; 28 tumor pairs were evaluable for biomarker modulation. Class toxicities of EGFR inhibition, including acneiform rash and diarrhea, were observed on Arms 1 and 2. Compared to placebo, Ki-67 was reduced by erlotinib (p = 0.0005) or by erlotinib-sulindac (p = 0.0001). There was a trend in ordering of Ki-67 down-modulation, with greater effect from the addition of sulindac (exact Jonckeheere-Terpstra, Arm 1 vs. 2, p = 0.003). Among 21 protein candidates tested for association with Ki-67, only low baseline p-Src correlated with greater Ki-67 reduction in both erlotinib groups (R2 = 0.312, p = 0.024). Conclusions: Relative to placebo, brief neoadjuvant treatment with erlotinib or erlotinib-sulindac significantly decreased the proliferative index in operable HNSCC. Sulindac enhanced Ki-67 down-modulation. Efficacy studies of dual EGFR-COX inhibition are justified. Baseline p-Src warrants further study as a resistance biomarker for anti-EGFR therapy. Clinical trial information: NCT01515137.