bluuebunny/crossref_metadata_2025 huggingface dataset:
Neoadjuvant chemotherapy followed by chemoradiation in selected locally advanced squamous cervical cancer.
Authors: Cueva Juan Fernando , Martinez Lago Nieves , Vieito Maria , Gonzalez Patino Ezequiel , Curiel Garcia Maria Teresa , salvador Garrido Nuria , Palacios Ozores Patricia , Candamio Sonia , López López Rafael
Published: March 2020

5603

Background: Although there has not been a direct comparison between neoadjuvant chemotherapy followed by chemoradiation with chemoradiation alone, neoadjuvant chemotherapy is active in squamous cervical cancer. Methods: In this one arm phase II trial we accrued 25 patients from 2007 to 2012 diagnosed with squamous cervical cancer deemed poor candidates to initial chemoradiation (decided by a multidisciplinary committee). Patients had > 18 years of age, PS 0-1, adequate organ function an gave informed consent. They received neoadjuvant paclitaxel and cisplatin (80 and 33 mg/m2 respectively) on days 1,7, 15 of every 28 for two cycles and then external radiation in 1.8 Gy/ fraction with concurrent weekly cisplatin 40 mg/m2followed by brachytherapy in 5-6 applications. Dose intensity and toxicity was accrued, and both after neoadjuvant and chemoradiation patients were evaluated by RECIST 1.1 criteria for response with CT scan and pelvic MNR. Results: Baseline characteristics of the patients are listed in Table. 24 patients were evaluable for efficacy and safety. Response rate after neoadjuvant chemotherapy was 84 % (complete and partial responses in 24 and 60% of patients, respectively), without progression disease. Response rate after radiochemotherapy was 93 % (complete and partial responses in 52 and 41% of patients, respectively). After a mean of 29 months of follow up, 11 patients (45%) thus far have developed recurrent disease. Median progression-free survival and overall survival were 33 (23- 42) and 34+ m (29 – not reached). Treatment was well tolerated, without toxicities grade 3-4. Conclusions: Our weekly cisplatin-paclitaxel neoadjuvant regimen has been feasible and very effective in terms of dose delivery, tolerance and radiological responses without compromising definitive treatment with chemoradiation. If this approach is superior than the standard chemoradiation alone in this population should be explored in a randomized trial. [Table: see text]
Longitudinal quality of life (QOL) and sexual functioning in women undergoing pelvic exenteration for gynecologic malignancies.
Authors: Soliman Pamela T. , Sun Charlotte C. , Westin Shannon Neville , Ramondetta Lois M. , Bodurka Diane C. , Bradford Andrea
Published: March 2020

5608

Background: Pelvic exenteration (PE) is en bloc resection of the pelvic organs including bladder, vagina, and rectum to treat central recurrence of a gynecologic malignancy. While this procedure has high morbidity, it is the only option for cure in some patients. The goal of this study was to assess QOL and sexual functioning in women who underwent PE with vaginal and/or bladder reconstruction. Methods: All patients were enrolled prior to PE. Surveys included the SF-12 (functional status), BIS (body image), SAQ (sexual functioning), SWD (satisfaction with decision), CES-D (depression), Stoma QOL, and DUFSS completed preoperatively (preop) and post-operatively at 4-6 wks, 6 mo, 1 yr, and 2 yrs. Descriptive statistics, chi-square, Mann-Whitney, and Kruskal Wallis tests were used to evaluate the data. Results: Between 2008 and 2012, 39 women participated. Median age was 56.7 yrs. Mean physical functional status scores (SF-12) declined through 6 mo postop, with improvements at 1 and 2 yrs (p=.002) but did not reach preop levels. SF-12 mental functioning scores declined immediately postop but returned to baseline by 6 mo. BIS was significantly worse at 1ys (p=0.02) and 2 yrs (p=0.025). Mean depression (CES-D) scores decrease but remained above the clinical cutoff of 17 at 6 mo. Poor sexual function was noted preop and did not improve. High scores for social support (DUFSS) remained constant. Stoma QOL improved in the first 2 yrs but not significantly. Pts reported high satisfaction with the decision to undergo PE, which did not change over time. Conclusions: While a majority of women remained satisfied with their decision to undergo PE, the procedure was associated with depression, worsening physical functioning and poor body image despite stable social support. Interventions are currently under development to improve QOL in this patient population. [Table: see text]
Competing risks of death in NCIC CTG MA.27 adjuvant exemestane versus anastrozole.
Authors: Chapman Judy-Anne W. , Shepherd Lois E. , Ingle James N. , Muss Hyman Bernard , Pritchard Kathleen I. , Gelmon Karen A. , Whelan Timothy Joseph , Elliott Catherine , Goss Paul E.
Published: March 2020

564

Background: Our group previously examined if baseline patient/tumor characteristics, or prior treatment affected cause of death in MA.17, a placebo controlled extended adjuvant trial of the aromatase inhibitor (AI) letrozole. We now examine factor effects on all cause mortality in MA.27. Methods: MA.27 was an adjuvant phase III superiority trial of 5 yrs of exemestane vs anastrozole, in ER+ postmenopausal breast cancer accrued between 2003 and 2008; event free survival was similar. We examined by intention-to-treat, the multivariate time-to-breast cancer-specific (BrCa), cardiovascular (Cardio), and other causes (OT) of death with log-normal survival analysis adjusted by treatment and stratification factors (lymph node status, adjuvant chemotherapy, celecoxib, aspirin, and trastuzumab). We tested whether factors were associated with 1) all cause mortality, and if so, 2) cause-specific mortality. We also fit step-wise forward cause-specific adjusted models. Results: 7,576 women (median age 64.1 years; 5417 (71.5%) <70 yrs and 2159 (28.5%) >70 yrs) were enrolled and followed for a median of 4.1 yrs. The 432 deaths comprised: 187 (43.3%) BrCa, 66 (15.3%) Cardiovascular, and 179 (41.4%) OT MA.27 therapy was not associated with mortality (p=0.84). Five baseline factors were differentially associated with cause of death. Older age was associated with greater BrCa (p=0.03), Cardio (p<0.001), and OT (p<0.001) mortality. Pre-existing cardiovascular history led to worse Cardio mortality (p<0.001). Worse ECOG performance status led to worse OT death (p<0.001). T1 tumors were associated with less BrCa mortality (p<0.001). PgR+ tumors were also associated with less BrCa mortality (p<0.001). There were fewer BrCa deaths with Node –ve disease (p<0.001), ER+ tumors (p=0.001) and without adjuvant chemotherapy (p=0.005); there was worse Cardio mortality (p=0.01) with receipt of trastuzumab; worse OT (p=0.03) for non-whites, and without adjuvant radiotherapy (p=0.003). Conclusions: 56.7% of deaths in MA.27 patients were non-breast cancer related. We showed baseline patient and tumor characteristics, and prior treatment differentially affected cause of death. Clinical trial information: NCT00066573.
Characteristics and clinical outcome of T1 breast cancer: A national multicenter retrospective cohort study.
Authors: Gonçalves Anthony , Classe Jean-Marc , Garbay Jean-Remy , Giard Sylvia , Helene Charytansky , Cohen Monique , Belichard Monique , Faure Christelle , Uzan Serge , Hudry Delphine , Azuar Pierre , Villet Richard , Gimbergues Pierre , Tunon de Lara Christine , Esterni Benjamin , Houvenaeghel Gilles
Published: March 2020

566

Background: T1N0M0 breast cancer (BC) are generally considered as carrying good prognosis and cancer-specific survival rates after 5 to 10 years are as high as 90 or 95% in many studies. However, they constitute a heterogeneous group and many studies identified biologically-defined at-risk patients within T1 BC. The objectives of our study were to describe the main characteristics of T1a, b, and c (11-15mm) BC and to identify prognostic factors for survival. Methods: We retrospectively collected the medical files of all patients diagnosed with BC who underwent sentinel lymph node biopsy (SLNB) between January 1999 and December 2008 in 13 French sites and examined overall survival (OS) and Relapse-free survival (RFS) in T1a, T1b and T1c 11-15 mm. Results: Among 8,100 women operated, 5,423 had T1 tumors (708 T1a, 2,208 T1b and 2,508 T1c 11-15mm). T1a differed significantly from T1b tumors with respect to several parameters : younger age, more frequent negative hormonal status and positive HER2 status, less frequent lymphovascular invasion (LVI), exhibiting a mix of favorable and poor prognosis factors. After a median follow-up of 60.5 months, OS rate was 97.6% (95CI: 97.1-98) at 60 months, 95.4%(94.5-96.4) at 84 months and 90.7% (85.2-96.4) at 120 months. No significant difference was observed between T1a, T1b and T1c tumors (p=0.335). RFS rates were 94% (95CI: 93.8-95.2), 92.1% [91.1-93.2] and 83.8% (77.6-90.5) at 60, 84 and 120 months respectively. RFS was significantly higher in T1b tumors (95.9%, 95CI: 95-96.9) as compared to T1a (93.2%, 91-95.4) or T1c tumors (93.8%, 92.8-94.9), p=0.0099. In multivariate analysis, SBR tumor grade, hormone therapy and LVI were independent prognostic factors for RFS, while hormone therapy and SBR grade were independently associated with OS. Conclusions: Relatively poor outcome of patients with T1a tumors might be explained by a high frequency of risk factors in this subgroup (frequent negative hormone receptors and HER2 overexpression) and by a less frequent administration of adjuvant systemic therapy (endocrine treatment and chemotherapy). Tumor size might not be the main determinant of prognosis in T1 breast cancer.
Aromatase inhibitor pain syndromes: Classification and determination of specific risk factors—A prospective multicenter cohort study.
Authors: Cottu Paul H. , Laroche Francoise , Pierga Jean-Yves , Coste J , Medkour T , Lotz Jean-Pierre , Beerblock Karine , Tournigand Christophe , Chauvenet Laure , Decleves Xavier , Boussahira D , Batteux F , Borderie F , Perrot Serge
Published: March 2020

569

Background: Pain is frequent during Aromatase Inhibitors (AIs) treatment for breast cancer and several pain syndromes have been reported but not precisely defined. We developed a prospective multicentre study aiming at classifying AIs-related pain syndromes, comparing their impact on daily life, and identifying their specific determinants for a more targeted prevention approach. Methods: A one-year multicenter cohort prospective study, with 5 pre-scheduled visits, was carried out in early stage breast cancer women, free of pain, starting an AI treatment, recruited from 4 oncology centres. At baseline, clinical data (demography and psychosocial, cancer characteristics and treatments, pain, sleep, rheumatologic examination, cancer-related quality of life), biological data (sex hormones, vitamin D, bone biomarkers, oxidative stress, immunological and inflammatory markers), and genetic polymorphism for pain mechanisms (opioid and serotonin pathways) were recorded. Results: A cohort of 135 women was evaluated. Among them, 77 (57%) developed a pain syndrome along the study period, leading to AIs discontinuation in 12 cases. Five main different types of pain syndromes were identified: joint pain, in 48 women overall over the follow-up (36%), diffuse pain, in 30 women (22%), tendinitis, in 29 women (22%), and neuropathic pain, in 12 women (9%) and mixed types, which were frequent and often transient. Analyses demonstrated that risk factors for developing pain syndromes were baseline anxiety and impaired quality of life, while cancer features, genetic background, inflammation, immunological and sex hormone levels were not involved. Conclusions: In pain-free women with breast cancer starting an AI, risks for developing pain during the first year of treatment are slightly greater than 50%. We identified 5 main pain syndromes, joint and widespread pain being the most frequent. In all instances, initial psychological dimensions (personality, impaired quality of life and anxiety) are identified as major risk factors for pain development.
Randomized phase II placebo-controlled trial of fulvestrant plus vandetanib in postmenopausal women with bone only or bone predominant, hormone receptor-positive metastatic breast cancer (MBC): OCOG Zamboney study—NCT00811369.
Authors: Clemons Mark J. , Cochrane Brandy , Califaretti Nadia , Chia Stephen K. L. , Dent Rebecca Alexandra , Song Xinni , Robidoux Andre , Pond Gregory Russell , Parpia Sameer , Pritchard Kathleen I. , Levine Mark Norman
Published: March 2020

574

Background: Biomarkers of bone turnover, including urine N-telopeptide (uNTx) and serum C-telopeptide (sCTx) reflect tumor-related bone breakdown and have been used as surrogate measures of response to therapy in trials. Vascular endothelial growth factor (VEGF) levels correlate with extent of bone metastases (BM). We assessed whether vandetanib, an inhibitor of VEGF, epidermal growth factor receptor and RET signalling, improved uNTx response when added to fulvestrant (F) in patients with BM. Methods: Postmenopausal patients with bone only, or bone predominant, hormone receptor positive MBC were randomised to F (500mg IM day 1, 14, 28, then monthly) with either vandetanib (100mg PO OD) (FV) or placebo (FP) until progression. The primary objective was uNTx response (>30% reduction from baseline). uNTx was collected at baseline, weekly to wk 4, at wk 12 and then every 12 wks. Secondary objectives included PFS, OS, RECIST response, pain and toxicity. Results: 61 patients were allocated to FV and 68 to FP. Median age was 59. 18% had received 1 prior chemotherapy regime and 73% prior endocrine therapy for MBC. uNTx response (n=124 pts) was 64% for FV vs. 52% for FP (p=0.20). No difference was detected between groups for median PFS; 6 months for FV vs. 4.8 months for FP, HR=0.93 (95% CI: 0.64 to 1.36). 16 patients died in FV arm vs. 21 in the FP arm, HR=0.71 (95% CI: 0.37 to 1.36). For those patients with measurable disease, clinical benefit rates were 41% and 43%, respectively, p=1.00. Serious adverse events were similar, 3.3% for FV vs. 5.9% for FP. Elevated baseline uNTx (>65 nM BCE/mmol Cr) was prognostic for PFS, HR=1.62 (95% CI: 1.08 to 2.43 and for mortality, HR= 2.4 (95% CI: 1.2 to 4.6). In an exploratory analysis uNTx was predictive of responsiveness to FV for PFS, HR=0.60 when uNTx >65 vs. HR=1.37 when uNTx <65, P = 0.025 for interaction. Conclusions: The addition of vandetanib to F did not improve biomarker response, PFS or OS compared to F alone in patients with bone predominant disease. Exploratory analyses confirmed that baseline bone turnover markers are prognostic for PFS and OS. Clinical trial information: NCT00811369.
Evaluation of the prognostic significance of RACGAP1, Ki67, and TOP2A mRNA expression in high-risk early breast cancer.
Authors: Pliarchopoulou Kyriaki , Gogas Helen , Papadimitriou Christos A. , Wirtz Ralph M , Kouvatseas George , Timotheadou Eleni , Stavridi Flora , Christodoulou Christos , Koutras Angelos , Pisanidis Nikolaos , Pentheroudakis George E. , Bafaloukos Dimitris , Samantas Epaminontas , Kalogeras Konstantine T. , Dimopoulos Meletios A. , Pectasides Dimitrios G. , Fountzilas George
Published: March 2020

582

Background: Proliferation is a major process in carcinogenesis. RACGAP1 is a protein involved in cell growth regulation and metastasis, Ki67 is a known proliferation marker and TOP2A has a key role in DNA replication and remodeling. The aim of the present study was to explore the prognostic significance of a signature of proliferation markers, such as RACGAP1, Ki67 and TOP2A on disease-free survival (DFS) and overall survival (OS) in high-risk early breast cancer patients. Methods: A total of 1681high-risk breast cancer patients, enrolled in two consecutive phase III trials, were treated with anthracycline-based adjuvant chemotherapy. Formalin-fixed paraffin-embedded tumor tissue samples from 963 of these patients were extracted using a standardized fully automated isolation method for total RNA based on silica-coated magnetic beads, followed by multiplex RT-qPCR for assessing RACGAP1, Ki67 and TOP2A mRNA expression. CALM2 was included in the same reaction, as a reference gene. Results: After a median follow-up of 107 months, 289 patients (30.0%) demonstrated disease progression and 261 (27.1%) patients died. Univariate analysis revealed that poor OS was associated with high RACGAP1 mRNA expression (p=0.0185, log-rank), high Ki67 (p=0.0219), as well as high TOP2A (p=0.0019) mRNA expression, while in multivariate analysis only TOP2A retained significance (Wald’s p=0.008). In an effort to improve prognostic significance, combinations of the expression of two or all three genes were tested, with low mRNA expression of the three genes being associated with improved DFS (HR=0.74, CI=0.56-0.98, p=0.035) and OS (HR=0.60, CI=0.42-0.85, p=0.004). However, in multivariate analysis, none of the combinations retained prognostic significance, except the combination of high RACGAP1 and TOP2A mRNA expression, which was found to be associated with decreased DFS (HR=1.26, CI=0.96-1.63, p=0.092) and OS (HR=1.49, CI=1.10-2.03, p=0.009). Conclusions: High RACGAP1 and TOP2A mRNA expression was found, in multivariate analysis, to be of adverse prognostic significance in high-risk early breast cancer patients treated with anthracycline-containing adjuvant chemotherapy.
A study on the prevalence of HER2 genetic heterogeneity and its impact on breast cancer survival.
Authors: Ho Jingshan , Chan Daniel Boon Yeow , Lee Soo-Chin , Koay Evelyn S. C.
Published: March 2020

586

Background: HER2 heterogeneity (GH) has been described in breast cancer that has conventionally been labeled as HER2 negative (FISH score <2.2). We aimed to ascertain the prevalence of GH in HER2 negative breast cancers and to investigate for any impact on survival. Methods: We reviewed HER2 FISH (Vysis) data for 158 primary breast cancer specimens from 2006-2010 which were 0 – 2+ on immunohistochemistry. HER2:CEP17 ratios were calculated for each of the 60 cells scored and cases were classified as HER2 GH according to the ASCO/CAP guidelines (GH = 5-50% tumor cells with a ratio >2.2). Results: 67% (106/158), 7% (11/158) and 26% (41/158) were HER2 negative, equivocal (FISH ratio 1.8-2.2) and positive respectively. GH was found in 43% and 100% of Her2 negative and HER2 equivocal patients respectively. Of the 117 cases (with FISH score <2.2), HER 2 GH was associated with higher histologic grade (grade 3: 81.8%, 52.3% and 33.3% in HER2 equivocal, negative with GH and negative without GH (p = 0.007). There were no significant associations with ER status or the presence of lymphovascular invasion. The mean overall survival was 63 months (95% CI 43-87), 118 months (95% CI 96-141) and 148 months (95% CI 148-168) for HER 2 equivocal, negative with GH and negative without GH patients respectively (p=0.017). In a subset analysis of HER2 negative (with FISH score <2.2), non metastatic patients, with at least a 4 year follow up period (n=63), mean overall survival was 79 months (95% CI 60-98), 119 months (95% CI 96-143) and 159 months (95% CI 139-180) for HER2 equivocal, negative with GH and negative without GH patients (p=0.034). GH remained a significant factor in the multivariate analysis irrespective of grade, stage and ER status (p=0.046). Conclusions: HER2 GH occurs in 100% of HER2 equivocal and 43% of HER2 negative breast cancers and is associated with higher histologic grade and poorer overall survival, irrespective of grade, stage or hormonal status.
Breast cancer screening: Biology of tumors detected by analog and digital mammography.
Authors: Drukker Caroline , Schmidt Marjanka , Rutgers Emiel J. , Cardoso Fatima , Kerlikowske Karla , Esserman Laura , Slaets Leen , Bogaerts Jan , van 't Veer Laura J.
Published: March 2020

587

Background: Population-based screening might be associated with a higher likelihood of a (ultra)low risk tumor assessed by the 70-gene signature (MammaPrint) (ultralow defined as indexscore >0.6, no distant metastasis observed at 5 years in the original 78 patients). The aim of this study is to determine the proportion of biologically (ultra)low risk tumors among the screen-detected tumors and to evaluate the impact of the analog versus digital screening technique. Methods: All Dutch breast cancer patients enrolled in the MINDACT trial (EORTC-10041), who were invited for the Dutch screening program (biennial, age 50-75), were included (n=1409). The proportions of 70-gene signature high, low and ultralow risk were calculated for patients with screen-detected (n=775), interval (n=390), and symptomatic, non-screening (n=244) carcinomas, taking into account analog vs. digital technology. Co-variants such as age, tumor size, grade, histological type, ER, HER2 and nodal status were included in the analyses. Results: Among the screen-detected tumors, 31.5% had a high risk, 31.2% a low risk and 37.3% an ultralow risk 70-gene signature result, compared to 47.4%, 28.5% and 24.1% among the interval carcinomas, respectively (p=0.001). Among the screen-detected carcinomas, 40.6% were detected using analog (n=315) and 59.4% using digital mammography (n=459). When using digital imaging a shift was seen among the screen-detected tumors in the proportions of high risk tumors from 27% to 35% and ultralow risk from 42% to 34%, low risk proportions remained the same (31%)(p=0.011). No such difference was seen for other tumor characteristics. Conclusions: Screen-detection was found to be associated with a higher likelihood of a biologically low risk tumor. The transition from analog to digital mammography resulted in a smaller proportion of ultralow risk and a larger proportion of high risk tumors among the screen-detected carcinomas.
Identification of the activated form of the progesterone receptor (PR) in breast cancer (BC).
Authors: Bosq Jacques , Caillaud Jean-Michel , Lange Carol A. , Fuqua Suzanne A. W. , O'Shaughnessy Joyce , Gilles Erard M. , Zukiwski Alexander A. , Bonneterre Jacques
Published: March 2020

593

Background: Upon ligand binding, PRs dimerize and form a discrete focal subnuclear distribution pattern (FDP), which are associated with transcriptional activation of PR (APR). FDP and are observed in BC independently of menopausal status. The feasibility of using an IHC technique to characterize the PR functional status has previously been reported in BC and presence/absence of APR is hypothesized to predict anti-progestin activity. This study describes an immunohistochemistry (IHC) method, by which a biomarker could be developed to investigate this hypothesis. Methods: 303 paraffin embedded/formalin fixed archival BC samples were processed with PR-A or PR- B isotype specific antibodies. Nuclear morphology was analyzed with standard microscopy at x1000, interpretation of the IHC slides was done by an experienced pathologist. Standard PR, estrogen receptor (ER), and Ki67 testing were done. Tumor grading/stage was obtained from the patients’ records. Results: Histology was ductal 85%, lobular 13%, other 2%. Consistent with prior research observations, tumors had two PR nuclear morphologies: 1. Diffuse pattern (D) where the PR was distributed evenly in a fine granular pattern or, 2. Aggregate pattern (A) where the PR is distributed in discrete clumps or aggregates. This defined 3 tumor phenotypes: A cells only (A), D cells only (D), and a heterogenous mix of A+D cells (AD). The APRpos group is defined as the A and A+ D phenotypes. Tumors were PR positive in 76% for PRA and 80% for PRB. Tumors were APRpos for PRA in 23% and independent of PR intensity score, ER, Ki67, and HER2, but associated with higher PR % positivity and higher tumor grade. Tumors were APRpos for PRB in 22% and associated with lower PR intensity and higher tumor grade, independent of ERpos %, PRpos %, Ki67 and HER2. Conclusions: PR positive BC tumors can be grouped in two categories based on PR nuclear morphology: 1. a group with diffuse and homogenous nuclear staining, 2. a group with heterogeneous area of cells having a nuclear pattern consistent with a functional or activated PR (APR). The described IHC technique to identify APR has the potential to be developed as companion diagnostic as a potential predictor of anti-progestin efficacy in patients with BC.
Prediction of early and late distant recurrence in early-stage breast cancer with Breast Cancer Index.
Authors: Zhang Yi , Schnabel Catherine A. , Schroeder Brock , Jerevall Piiha-Lotta , Jankowitz Rachel Catherine , Stal Olle , Brufsky Adam , Sgroi Dennis , Erlander Mark G.
Published: March 2020

594

Background: Breast Cancer Index (BCI) is a continuous risk index based on the combination of HOXB13:IL17BR (H:I) and the Molecular Grade Index (MGI) that estimates the individual risk of recurrence in ER+, LN- breast cancer patients. In the current study, a modified BCI model was developed using untreated breast cancer patients in order to evaluate its pure prognostic value, and to better optimize BCI for both early and late risk assessment. Methods: A model was built by linearly combining H:I and MGI weighted by their corresponding Cox regression coefficients using ER+ LN- patients from the untreated arm of the prospective Stockholm trial (N=283). Validation was performed in 2 independent ER+, LN- cohorts: the TAM arm of the Stockholm trial (N=317), and a multisite cohort of TAM-treated patients (N=358). Correlation of BCI with distant metastasis was evaluated by Kaplan-Meier analysis using the log rank test, and multivariate analysis adjusting for standard prognostic factors was performed using Cox proportional hazards. Results: The BCI linear model was significantly associated with risk of cumulative (0-10y), early (<5y) and late (≥5y) distant metastasis. Based on pre-specified cutpoints, BCI classified 64% and 55% patients as low-, 21% and 22% as intermediate-, and 16% and 23% as high-risk, with 10-y rates of distant recurrence (95% CI) of 4.8% (1.7-7.8%) and 6.6% (2.9–10.0%), 11.7% (3.1–19.5%) and 23.3% (12.3-33.0%), 21.1% (18.5–32.0%) and 35.8% (24.5–45.5%), in the Stockholm TAM and multisite cohort, respectively. Conclusions: BCI demonstrated significant prognostic performance beyond clinicopathological factors to predict cumulative, early and late risk of recurrence in early stage breast cancer patients. Use of BCI at diagnosis should enable clinicians to identify patients who are at high risk of late recurrence and may benefit from an additional 5y of hormonal therapy. [Table: see text]
Effect of PK-guided tamoxifen dose escalation on endoxifen serum concentrations in CYP2D6 intermediate and poor metabolizers.
Authors: Opdam Frans , Dezentje Vincent O. , den Hartigh Jan , Guchelaar Henk-jan , Hessing Trees , van der Straaten Tahar , Vree Robert , Batman Erdogan , Maartense Eduard , Smorenburg Carolien H. , Zeillemaker Anneke , Brakenhoff J. A. C. , Los Maartje , Kuijer Philomeen , Putter Hein , Dieudonné Anne-Sophie , Neven Patrick , Van De Velde Cornelis J. H. , Nortier J. W. R. , Gelderblom Hans
Published: March 2020

595

Background: Breast cancer patients with absent or reduced CYP2D6 activity may benefit less from tamoxifen treatment because of impaired biotransformation to the active metabolite endoxifen. We investigated whether a temporary one-step dose escalation of tamoxifen in CYP2D6 poor (PM) and intermediate metabolizers (IM) could increase endoxifen serum concentration to a similar level observed in CYP2D6 extensive metabolizers (EM) without increasing toxicity. Methods: From a prospective study population of early breast cancer patients using tamoxifen, 12 CYP2D6 poor and 12 intermediate metabolizers were selected and included in a one-step tamoxifen dose escalation study during two months. The escalation dose (120 mg maximum) was calculated by multiplying the individual’s endoxifen level divided by the median endoxifen concentration (33.7 nM) observed in CYP2D6 extensive metabolizers by 20 mg. Toxicity was assessed and all patients returned to the standard dose of 20 mg after two months. Results: Tamoxifen dose escalation in CYP2D6 poor and intermediate metabolizers significantly increased endoxifen concentrations (PMs: from 8.0 nM to 27.3 nM, p<0.001; IMs: from 17.8 nM to 30.3 nM, p=0.002) without increasing side effects. In intermediate but not in poor metabolizers dose escalation increased endoxifen to levels comparable with those observed in extensive metabolizers using tamoxifen 20 mg once daily (33.7 nM). Conclusions: CYP2D6 genotype and endoxifen guided tamoxifen dose escalation increased endoxifen concentrations without increasing short term side effects. Whether such tamoxifen dose escalation is effective and safe in view of long term toxic effects is uncertain and needs to be explored. Clinical trial information: NTR1509.
A comparative analysis of distant recurrence risk assessments by Oncotype DX recurrence score alone and integrated with clinicopathologic factors in early-stage breast cancer.
Authors: Kelly Ciara Marie , Beamish Rose , McCaffrey John , SMITH Martina , Crown John , O'Connor Miriam , McGee Sharon F. , O'Reilly Seamus , Moylan Eugene J. , Gonzalez-Angulo Ana M. , Litton Jennifer Keating , Pusztai Lajos , Kelly Catherine Margaret
Published: March 2020

598

Background: Treatment planning for patients with node negative, ER-positive, HER-2 negative breast cancer often incorporates the use of prognostic and predictive tools like Oncotype DX. Prior to the availabilty of Oncotype DX, clinicopathologic factors such as age, nodal status, tumour size and grade were used to determine risk of recurrence (ROR). RSPC represents a validated formal integration of oncotype DX recurrence score (RS) and clinicopathologic factors that further refines prognostic accuracy. RSPC does not improve the prediction of likelihood of chemotherapy benefit. The objective of this study was to compare distant recurrence risk assessment by RS and RSPC. Methods: We included patients with node negative, ER-positive, HER2-negative breast cancer who had Oncotype DX testing routinely or on clinical trial. We retrospectively reviewed patient charts and extracted clinicopathological and RS data. We calculated the RSPC using the RSPC educational tool. A comparative analysis was performed looking at the statification of patients into low (LR), intermediate (IR) and high (HR) ROR groups by RS and RSPC. The cut offs for low, intermediate and high risk by the RSPC were set to less than 12%, 12-20% and more than 20% risk of distant recurrence at 10yrs, corresponding to the risks of recurrence associated with the RS categories. Results: We identified 658 patients from 5 academic hospitals in Ireland and the US. Oncotype DX RS classified the following proportions of patients into three risk groups for distant recurrence: LR, n=334 (50.5%), IR, n=259 (39.4%), HR, n=67 (10.1%). RSPC classified the following proportion of patients into the three risk groups for recurrence: LR, n= 455 (69.1%), IR, n=110 (16.7%), HR, n=93 (14.1%). RSPC reclassified 72.6% (n=188) of the IR group (59.1% (n=153) from IR to LR and 13.5% (n=35) from IR to HR). RPSC reclassified 10.5% (n=35) of the LR group (8.1% (n=27) from LR to IR, and 2.4% (n=8) from LR to HR). RSPC reclassified 25.3% (n=17) of the HR group (17.9% (n=12) from HR to IR, and 7.4% (n=5) from HR to LR). Conclusions: RSPC reclassified 240 patients (36.5%) and was most helpful reassigning the IR group.
Genomic profiling of kinase genes in head and neck squamous cell carcinomas to identify potentially targetable genetic aberrations in FGFR1/2, DDR2, EPHA2, and PIK3CA.
Authors: Keck Michaela K. , Zuo Zhixiang , Khattri Arun , Brown Christopher D. , Stricker Thomas , Weichselbaum Ralph R. , Lingen Mark W. , Cohen Ezra E.W. , White Kevin P. , Vokes Everett E. , Hammerman Peter S. , Seiwert Tanguy Y.
Published: March 2020

6010

Background: Development of targeted therapies in head and neck squamous cell carcinoma (HNSCC) has been limited due to the lack of validated, oncogenic genetic aberrations. We determined mutations and copy number (CN) events in kinases in a 120 patient cohort in order to identify new potential treatment targets. Methods: Fresh frozen tumor (≥70%) and matched normal tissue from 120 patients with treatment-naïve, locoregionally advanced HNSCC were evaluated using targeted, massively parallel sequencing (Illumina HiSeq) for 60 cancer-relevant, targetable kinases (as well as PI3K related tumor suppressors). CN analysis was performed on the NanoString nCounter for 40 cancer relevant kinases. Mutations were modeled bioinformatically using the CHASM oncogenic driver prediction algorithm and reviewed for prior occurrence in COSMIC. Results: We identified somatic mutations in three potentially targetable receptor tyrosine kinases: 7 (5.8%) mutations were identified in DDR2, 3 (2.5%) mutations in FGFR2, and 4 (3.3%) mutations in EPHA2. Furthermore we identified multiple mutations in several PI3K family members including PIK3CA (N=22 (18,3%)) as well as PI3K related tumor suppressors (PTEN N=3 (2.5%)), INPP4B N=7 (5.8%)). Several mutations showed low CHASM scores consistent with oncogenic driver characteristics. We identified recurrent copy number aberrations in two kinases – FGFR1 (N=15 (13%), median CN:3.27 (3.03-15.662)), and EGFR (N=13 (11%), median CN: 3.73 (2.93-17.75)). Interestingly similar mutations/copy number events have been described in other cancer types including endometrial, and lung squamous cell carcinomas. Conclusions: We identified multiple novel mutations and copy number events in 45% of tumors: genetic aberration in FGFR1, FGFR2, DDR2, EPHA2, and the PI3K pathway are candidate oncogenic drivers that are potentially targetable. Results are corroborated by similar aberrations in other cancer types e.g. lung squamous cell carcinomas that are already being explored as therapeutic targets. Further validation and initiation of focused clinical trials in mutation pre-selected patients is indicated.
Association of the 3'-untranslated region KRAS-variant with cisplatin resistance in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.
Authors: Weidhaas Joanne B. , Lee Ju-Whei , Slebos Robbert , Howard Jason , Perez Jimena , Gilbert Jill , Nallur Sunitha , Paranjape Trupti , Garcia Joaquin J. , Burtness Barbara , Forastiere Arlene A. , Chung Christine H.
Published: March 2020

6016

Background: A germline mutation in let-7 complementary site 6 (LCS6) within the KRAS 3'-untranslated region (rs61764370, the KRAS-variant: TG/GG) is known to associate with poor outcome and drug resistance in various cancers compared to the wild type allele (TT). We examine the prognostic significance of the KRAS-variant in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Methods: The KRAS-variant was determined in 116 tumor DNA samples from HNSCC patients enrolled in 3 clinical trials and a tissue collection study using a previously validated PCR-based assay. Results: KRAS-variant status could be determined in 108/116 (93%) samples and an allele frequency of TG/GG was 28.7%. These results were correlated with patient demographics, p16/human papillomavirus (HPV) status and clinical outcome. There was no association between p16/HPV status and the KRAS-variant status (Fisher’s exact test, p=1.0). The KRAS-variant was associated with poor progression-free survival in patients treated with cisplatin+/-cetuximab (log-rank p=0.002) but this association was not observed in docetaxel/bortezomib treated patients (log-rank p=0.89). Conclusions: KRAS-variant is a potentially promising biomarker of poor prognosis and a predictive biomarker of cisplatin resistance in R/M HNSCC. Prospective validation is warranted. Clinical trial information: NCT00003809.
Radiographic extracapsular extension (ECE) and treatment outcomes in locally advanced oropharyngeal carcinoma (OPC).
Authors: Kann Benjamin H. , Buckstein Michael , Carpenter Todd J. , Golchin Ava , Bakst Richard Lorne , Misiukiewicz Krzysztof , Genden Eric Michael , Posner Marshall R. , Kostakoglu Lale , Som Peter M. , Gupta Vishal
Published: March 2020

6019

Background: Pathologic ECE (pECE) of tumor through lymph node (LN) is a poor prognosticator for OPC and typically diagnosed upon surgical LN removal. At our institution, experienced radiologists routinely identify ECE on pretreatment CT. The prognostic value of radiographic ECE (rECE) is less clear and may prove clinically useful. In this study, we evaluate rECE as an independent prognosticator in OPC. Methods: Retrospective review of 185 patients with locally advanced OPC treated in our department from 2006-2012. 109 patients had accessible pretreatment CT reports clearly stating the presence or absence of rECE. Patients were treated with definitive concurrent chemoradiation therapy (CCRT) (30%), induction chemo then CCRT (47%), or surgery with adjuvant CCRT (14%) or RT (9%). Kaplan-Meier survival analysis compared these cohorts for locoregional control (LRC), distant control (DC), and progression-free (PFS) and overall survival (OS); log-rank tests were performed for significance. Multivariate analysis was conducted via cox-regression. Results: Median follow-up of the 109 patients was 31 months (range: 1-80 months). 61 patients had rECE(+) and 48 had rECE(-) scans. There was no significant difference between the cohorts in terms of median age, stage, treatment type, smoking history, or tumor HPV status. There was a difference in nodal stage with 83% of rECE(+) patients having N2-3 disease versus 67% of rECE(-) patients (p=0.02). On univariate analysis, there were differences between the rECE(-) versus rECE(+) cohorts in OS (4yr: 92% vs 72%, p=0.01), PFS (4yr: 92% vs 62%, p=0.002), and DC (4yr: 98% vs 76%, p=0.006), with no difference in LRC (4yr: 95% vs 91%, p=0.35). On multivariate analysis factoring in age, smoking history, stage, and treatment type, rECE presence was a negative predictor of OS (hazard ratio, 0.26; 95% CI, 0.07 to 0.95) and PFS (hazard ratio, 0.23; 95% CI, 0.06 to 0.81), with DC approaching significance (hazard ratio, 0.13; 95% CI, 0.02 to 1.05). Conclusions: While pECE is an established risk factor for locally advanced OPC, this study suggests that rECE may be an independent poor prognosticator of PFS, OS and DC with potential importance in guiding clinical management.
Phase II study of everolimus and sorafenib for the treatment of metastatic thyroid cancer.
Authors: Sherman Eric Jeffrey , Ho Alan Loh , Fury Matthew G. , Baxi Shrujal S. , Haque Sofia , Lipson Brynna Lane , Kurz Sarah , Fagin James A. , Pfister David G.
Published: March 2020

6024

Background: Everolimus is an oral inhibitor of the mammalian target of rapamycin (mTOR). Unpublished work from the Fagin lab shows that mTORC1 is also required for the growth promoting effects of the oncoproteins RET/PTC, RAS and BRAF in rat thyroid PCCL3 cells. Further work shows synergy of mTORC inhibitors with RET kinase inhibitors in medullary thyroid cancer cell lines. Sorafenib is an oral kinase inhibitor with in vitro activity against multiple targets, including RAF, RET, VEGFR1, and VEGFR2 that is compendium approved for the treatment of radioactive iodine-refractory (RAIR) and medullary (MTC) thyroid cancer. Methods: The study was a single institution, two-stage phase II design. Primary objective was response rate initiated on 9/21/2010. Eligible patients (pts) had progressive, RAIR/fluorodeoxyglucose (18-F)-avid, recurrent/metastatic, non-anaplastic, thyroid cancer; RECIST measurable disease; and adequate organ/marrow function. Sorafenib was given at 400 mg orally twice a day and Everolimus at 5 mg orally once daily. 41 patients were enrolled; 36 were eligible for the primary endpoint of response and 3 were evaluable for toxicity only at the data cutoff date of 1/10/13. Seventeen patients are still actively on study. Mutational analyses of tissue is ongoing. Results: Of the 41 eligible pts, demographics: female- 44% (18); median age-61 years (35-79). Grade 4-5 adverse events at least possibly related to drug: grade 4- Alanine Aminotransferase Increase (1 pt): grade 4- Hyperglycemia (1 pt): grade 4-Pancreatitis (1 pt). Histology and response data by partial response, confirmed and unconfirmed, (PR), stable disease (SD) and progression of disease (POD) are in the table below. The median time on treatment is 167 days (range 1 to 797 days) at the cutoff date of 1/10/2013. Conclusions: The combination of sorafenib and everolimus shows promising results, especially in the Hurthle cell and medullary subgroups where data from studies at Ohio State have suggested very poor response to sorafenib alone. Clinical trial information: NCT01141309. [Table: see text]
A phase II, multicenter, open-label, single-arm trial of famitinib in patients with advanced recurrent and/or metastatic nasopharyngeal carcinoma (NPC) after two previous treatment regimens.
Authors: Huang Yan , Zhang Li , Pan Jian-ji , Hu Guoqing , Gang Wu , Xiong Jian ping , Hu Chaosu , Lin Lizhu , Yu Hao , Jiang Haoyuan
Published: March 2020

6026

Background: Famitinib is an oral, small molecular multiple tyrosine-kinase inhibitor (TKI), targeting stem cell growth factor receptor (c-Kit), platelet derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR). So far, few target therapies show acceptable efficiency in advanced recurrent and/or metastatic nasopharyngeal carcinoma (RM-NPC) patients. The primary object of this study is to determine the safety and efficacy of famitinib in patients with RM-NPC. Methods: This study recruited histologically diagnosed RM-NPC patients who failed more than two lines of systemic chemotherapy. Other eligible criteria included ECOG PS≤2, adequate organ function and no prior exposure to other c-Kit, PDGFR or VEGFR TKIs. The patients received famitinib orally at a dose of 25 mg once daily until the disease progression or intolerable toxicity. Results: From May 2011 to Sep 2012, 58 patients (Simon’s two-stage design, 28+30) were recruited at 8 sites in China. The clinical benefit rate (partial response or stable disease maintained≥12 weeks, tumor response was evaluated every 4 weeks) is 32.8%, including 5 PR and 16 SD patients. Median PFS was 3.2 months. The most frequently observed hematologic toxicities included thrombocytopenia, leucopenia and neutropenia; non-hematologic AEs were hypertension, proteinuria, and hand-foot syndrome. All adverse events were generally mild-to-moderate (grade 1/2) and manageable with supportive treatment; grade 3/4 incidence was relatively low. Conclusions: This phase II study shows that famitinib demonstrates substantial clinical benefits in patients with advanced RM-NPC and the drug-related adverse reactions were most predictable and tolerable, no special toxicity was reported. Biomarker analysis for responder and non-responder is still ongoing and will be present at the meeting. Clinical trial information: NCT01392235.
Identification of a gene expression profile associated with progression-free survival (PFS) in relapsed or metastatic (RM) head and neck squamous cell cancer (HNSCC) patients (pts) treated with first-line cetuximab and platinum therapy.
Authors: Bossi Paolo , De Cecco Loris , Perrone Federica , Cortelazzi Barbara , Cossu Rocca Maria , Marco Siano , Sponghini Andrea , Bergamini Cristiana , Locati Laura D. , Mirabile Aurora , Granata Roberta , Resteghini Carlo , Pilotti Silvana , Canevari Silvana , Licitra Lisa F.
Published: March 2020

6027

Background: First-line chemotherapy with platinum and cetuximab is usually offered to RM-HNSCC pts. In the Extreme trial a median PFS time of 5.6 months was reported. However, a small fraction of pts achieves a prolonged PFS (> than 12 months). Until now, no recognized predictive biological factor has been identified. Methods: A group of 14 pts treated with a first-line platinum and cetuximab with a PFS exceeding 12 months (long PFS) and a group of 26 pts with a PFS less than 5.6 months (short PFS) were selected. Tumor specimens of the recurrence (25 cases) or, if not available, of the primary tumor were collected. In order to identify molecular profiles deregulated between the 2 groups, a gene expression microarray analysis was performed using the Whole-Genome DASL assay and HumanHT-12_v4 BeadArray chips (lllumina). Results: The 2 groups were well balanced in regard to recognized prognostic factors (performance status, weight loss, prior radiotherapy, tumor grade, site of primary tumor, residual disease at primary tumor site). Mean PFS was 21 months in long (range 13-36) and 4 months in short PFS group (range 1-5). By class comparison analysis between the 2 groups, the expression pattern of 136 genes was found differentially expressed (FDR<0.05). In long PFS group, EGFR and genes associated to EGFR pathway including CDCP1 and EPGN were up regulated, as well as its ligand (EREG). Several members of the Kallikrein serine proteases gene family are present among the most upregulated genes in long PFS group, suggesting the involvement of extracellular-matrix remodelling. In addition to cellular morphology, pathways analysis showed an enriched modulation of genes belonging to cell-to-cell signalling, DNA replication/DNA repair and lipid metabolism. Conclusions: Our analysis suggests that a specific molecular signature may be associated with long and short PFS after platinum/cetuximab first line chemotherapy in RM-HNSCC pts. To our knowledge, it is the first study attempting to generate hypotheses in this field and further validation is required.
The results of first-line chemotherapy in 108 patients affected by recurrent or metastatic salivary gland malignacies (RMSGM).
Authors: Airoldi Mario , Garzaro Massimiliano , Raimondo Luca , Pedani Fulvia , Bellini Elisa , Ostellino Oliviero , Riva Giuseppe , Pecorari Giancarlo
Published: March 2020

6038

Background: Recurrent/metastatic salivary gland malignancies (RMSGM) are not manageable by means of surgery and/or radiotherapy; chemotherapy (CT) represents a palliative strategy without any curative purposes. In this abstract we report the results of CT in 108 cases of RMSGM. Methods: We enrolled 108 patients with radiologically documented progression of RMSGM. Five pts received cisplatin (DDP) 100 mg/sm d 1, q 3wks; 8 pts doxorubicin (DOX) 75 mg/sm d1, q 3wks; 30 pts vinorelbine (VNB) 30 mg/sm d. 1 and 8, q 3 wks; 9 pts DDP 60 mg/ sm + epirubicin (EPI) 60 mg/sm + 5-FU 600 mg/sm d.1, q 3 wks; 42 pts DDP 80 mg/sm d.1 + VNB 25 mg/sm d. 1,8 , q 3 wks, and 14 pts carboplatin (CBDCA) AUC 5.5 + paclitaxel (Taxol; TAX) 175 mg/sm d.1, q 3 wks. The maximum number of CT cycles was 6. Results: Patients characteristics were as follows: 65 males (60%) and 43 females (40%); median age: 57 yrs (range 20-74); 42 pts (39%) had ECOG PS=0 and 66 pts(61%) PS 1-2 (0-2); histological evaluation was as follow: adenocarcinoma 28 pts (26%), adenoid cystic carcinoma 63pts (58%), undifferentiated carcinoma 12 pts (11%) and malignant mixed tumors 5 pts (5%); the disease was local in 40 pts (37%), local + distant metastases in 30 pts (28%) and only metastatic in 38 pts (35%). Conclusions: DDP is the probably the most effective single drug scheme; our data suggest that VNB has superimposeable results with a better gastroenteric and renal toxicity profile. Single drug CT seems less effective than multi drug CT with DDP-based schemes. DDP+EPI+5-FU is as effective as DDP+VNB; CBDCA+TAX seems to have worse clinical outcomes than DDP combinations. The impact of CT on symptoms is quite good while on survival needs further investigations, moreover our data confirm the need of new biological target agents to improve clinical outcomes in RMSGM. [Table: see text]