bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I, dose escalation trial to assess the safety and biological activity of recombinant human interleukin-18 (SB-485232) in combination with pegylated liposomal doxorubicin in platinum-resistant recurrent ovarian cancer.
Authors: Simpkins Fiona , Flores Aurea M. , Chu Christina , Lucci Joseph A. , Berek Jonathan S. , Coukos George , Bauman John W. , Murray Sharon Cornell , Struemper Herbert , Germaschewski Fiona , Jonak Zdenka , Gardner Olivia S. , Toso John F
Published: March 2020

5065

Background: SB-485232, a recombinant human form of interleukin-18 (IL-18), is being studied as a novel cytokine for tumor immunotherapy. IL-18 has been shown to increase the anti-tumor activity of doxorubicin in other cancer mouse models. Methods: This multi-center study enrolled 16 patients (pts), and evaluated four cycles (28 days each) of standard pegylated liposomal doxorubicin (PLD) (40 mg/m2 day 1) in combination with increasing doses of IL-18 (1, 3, 10, 30, and 100 mg/kg) on days 2 and 9 of each cycle with a 1 yr follow-up to further evaluate safety and efficacy. Results: Of the 16 pts, 10 (63%) completed study treatment and 6 (37%) did not because of disease progression (5 pts) and PLD hypersensitivity (1 pt). Thirteen (82%) were platinum resistant/refractory having received a median of > 3 prior lines of therapy. SB-485232 up to 100 mg/kg in combination with PLD had an acceptable safety profile. All 16 pts experienced at least 1 AE including chills (81%), nausea (75%), anemia (63%), fatigue (56%), hyperglycemia, and pyrexia (50% each). Eight of 16 pts had Grade 3 AEs including anemia (19%), and 6% each for abdominal pain, asthenia, dehydration, PLD hypersensitivity, edema, fatigue, hyperglycemia, hyperkalemia, jaundice, pain, nausea, vomiting, and pyelonephritis. There were no grade 4/5 AEs. Four subjects experienced 10 non-fatal SAEs with 3 related to study drug: anemia, PLD hypersensitivity, and cytokine release syndrome. Maximal SB-485232 biological activity, assessed by peripheral blood NK and T cell markers, was observed at 10mg/kg-100mg/kg. This drug combination resulted in a 6% partial response rate (RR) and a 38% stable disease rate using RECIST 1.0. Median (95% CI) time of progression-free survival (PFS) was 4.50 (3.52,--) months. Conclusions: The SB-485232/PLD combination was tolerable with minimal toxicity. These preliminary efficacy data are comparable to the historical RR and PFS observed with PLD monotherapy in platinum-resistant ovarian cancer. However, given the small sample size, this combination warrants further investigation.
Secondary surgery with intraoperative chemohyperthermia in recurrent ovarian adenocarcinoma.
Authors: Bereder Jean Marc , Desantis Mariangella , Benizri Emmanuel , Abakar-mahamat Abakar , Bernard jean-Louis , Rahili Amine , Mounier Nicolas , Benchimol Daniel
Published: March 2020

5075

Background: Optimal treatment of peritoneal recurrences in ovarian cancer is debating with second line chemotherapies. We proposed association of secondary surgery with heated intraperitoneal per operative chemotherapy (HIPEC). The aim of study is to determine prognostic factors in a single center cohort. Methods: Retrospective study of consecutive 169 patients with peritoneal recurrence from ovarian cancer were performed to evaluate HIPEC and to identify prognostic factors. Peritoneal Cancer Index (PCI) assess tumor load and completeness cytoreductive score (CCS) were used to give quality of resection CCS0 (no visible tumor), CCS1 (persistent diffuse lesions < 2.5mm), CCS2 (2.5mm <CC2< 25mm) and over CCS3 status. HIPEC is performed with platinum based regimen. Endpoint was survival. Cox's regression model was used for multivariate survival analysis and extending Cox model for modelling survival data. Results: We have operated on 197 procedures (HIPEC) in 169 patients from 2000 to 2011. Mean age was 58 years old range [28-75]. Median PCI was 10. After completion of resection, allocation of CCS was CCS0=120, CCS1=70, CCS2 & CCS3 =7. Procedure related mortality was 1% and morbidity 21%, mean length of hospital stay was 17 days range [7-51]. 3 and 5 years overall survival were respectively 64.7% and 37.4 %. Median survival was 47.6 months and the median disease free survival was 20 months. PCI >10 (even if complete resection performed) and CCS2&3 were worse prognostic factors (HR respectively = 2.64 IC 95% [1.29-5.36] and = 3.31 IC 95 % [1.55-7.08]). Modelling of these factors, is very strong to predict risk of death over the 2 first years after HIPEC. Conclusions: The chemo-hyperthermia is a standardized and reproducible feasible method. Less extensive disease and the quality of cytoreduction remain an independent factor of better outcome. To date HIPEC allows to reach the longest median time survival in peritoneal recurrent ovarian cancer. Modelling survival data is useful to know the risk of dying.
A phase I/IB dose-escalation study of BEZ235 in combination with trastuzumab in patients with PI3-kinase or PTEN altered HER2+ metastatic breast cancer.
Authors: Krop Ian E. , Saura Cristina , Rodon Ahnert Jordi , Becerra Carlos , Britten Carolyn D. , Isakoff Steven J. , Demanse David , Hackl Wolfgang , Quadt Cornelia , Silva Antonio P. , Burris Howard A. , Abu-Khalaf Maysa M. , Baselga José
Published: March 2020

508

Background: Alterations in the PI3K/AKT/mTOR pathway have been implicated in resistance to trastuzumab (T) in HER2+ breast cancer. BEZ235, a potent oral dual PI3K/mTORC1/2 inhibitor, has demonstrated growth inhibition and apoptosis in HER2+ breast cancer models, including those harboring PI3K pathway alterations, and with T resistance. In a Phase I study, BEZ235 was well tolerated as a single agent in pts with advanced solid tumors. The aim of this study was to determine the MTD of BEZ235 in combination with T in pts with T-resistant HER2+ metastatic breast cancer (mBC) with alterations of the PI3K pathway. Methods: Pts with T-resistant HER2+ mBC (i.e. disease progression during adjuvant therapy or metastatic disease on therapy with T) received oral BEZ235 daily, with weekly T (2 mg/kg). Pts were eligible for enrollment if a tumor sample was demonstrated to contain a molecular alteration of PIK3CA and/or PTEN. Dose escalation was guided by a Bayesian logistic regression model with overdose control. Results: As of 23 Sep 2011, 15 of the 19 enrolled pts were evaluable for dose escalation analysis. BEZ235 was evaluated at 3 dose levels: (1) 400 mg/day (3 pts); (2) 600 mg/day (6 pts); (3) 800 mg/day (10 pts), administered either in capsule form (400 mg) or in sachet form (600 mg and 800 mg). The MTD of BEZ235 in combination with T was estimated to be 600 mg/day. Observed DLTs were G3 nausea at 600 mg/day (1 pt), and G3 nausea, G3 fatigue and G3 skin rash (1 pt each) at 800 mg/day. The most frequent G3/4 adverse events (CTCAE v3.0) suspected to be related to study treatment were diarrhea (4 pts) and nausea (2 pts). No deaths related to study treatment occurred. 1 pt with lung and brain metastases had a partial response. 4 pts had disease stabilization for ≥4 cycles (16 weeks), including 1 pt with liver metastases, in whom BEZ235/T treatment resulted in disease stabilization for more than 21 cycles (84 weeks). Conclusions: BEZ235in combination with T demonstrated an acceptable safety profile in pts with HER2+ mBC and PI3K pathway alterations. Following the Bayesian model recommendation, the MTD for BEZ235 in combination with T was estimated to be 600 mg/day. The safety expansion arm is ongoing at the MTD.
How is the current clinical management of endometrial cancer worldwide? An international survey by the North-Eastern German Society of Gynaecological Oncology (NOGGO).
Authors: Kraetschell Robert W. , Fotopoulou Christina , Dowdy Sean Christopher , Fujiwara Keiichi , Yaegashi Nobuo , Lorusso Domenica , Casado Antonio , Mahner Sven , Herzog Thomas J. , Vergote Ignace B. , Miller David Scott , Marth Christian , Battista Marco Johannes , Lichtenegger Werner , Sehouli Jalid ,   North-Eastern German Society of Gynaecological Oncology
Published: March 2020

5087

Background: Indication, technique and extent of lymph-node-dissection (LND) in endometrial cancer (EC) remains controversial and is strongly debated in cancer community. We conducted a national- and at a second step an international-survey evaluating the current status-quo of the surgical and medical management of EC. Methods: A validated 15-item-questionnaire regarding surgical and adjuvant procedures of EC was sent to all major gynaecological cancer societies and study groups worldwide. The questionnaire could also be answered online. Results: In a phase-I-national trial, the questionnaire was validated on basis of 316 German institutions. On the phase-II-international survey a total of 302 questionnaires were answered from 24 countries, mainly from Japan (38.7%), Spain (8.3%), Austria (7%), United-Kingdom (6.3%), Italy (6%), USA (4.3%) and Canada (4%). The vast majority of the participating clinics were academic (62.8%), while 75.2% of them belonged to gynaecology. Only 0.7% of the clinics internationally reported never performing LND in EC. 62.3% of the clinics perform both a pelvic and paraaortic lymph node dissection. 59.1% of the participants performed a systematic lymph node dissection with the intention of both adequate staging and for therapeutic value. 15.05% of the clinics perform LND up to the common-iliac-arteries, 9.03% up to the inferior-mesenteric-artery and 70.6% up to the renal-veins. The most common risk-factors to indicate LND were: high-grading (93%), non-endometrioid-histology (90.1%), lymphovascular-invasion (55.3%), blood-vessel invasion (45.4%) and tumor-diameter >2cm (38.4%). For advanced stage III&IV disease the vast majority (60% and 80%, respectively) of the physicians indicated systemic chemotherapy alone. Conclusions: This study presents the large variety in clinical management of EC worldwide, underlining so the high need of future prospective randomised trials which will establish standard and evidence based treatment guidelines for EC- disease.
Clinicopathologic characteristics of endometrial cancer in Lynch syndrome.
Authors: Lecuru Fabrice , Bouquier Julie , le Frere-Belda marie-Aude , Bensaid Cherazade , Nos Claude , Laurent-Puig Pierre , Bats Anne-Sophie
Published: March 2020

5098

Background: Poor data exist on clinico-pathological description of endometrial cancer (EC) in Lynch syndrome (LS) compared with sporadic ones. To evaluate the clinico-pathological findings of Lynch-related EC to establish histological criteria to discriminate familial and sporadic EC and to decide the optimal management of patients. Methods: Retrospective study of prospective cohort of patients with LS in our institution from 1999 to 2011. We identified and described all cases of endometrial cancers. Management and follow-up were detailed. Results: Of a cohort of 126 patients with LS, 10 women developed endometrial carcinoma. The median age at diagnosis was 51 years (41-58). Five patients had an identified mutation (2 hMLH1, 2 hMSH2 and 1 hMSH6). In 9 cases, EC was the first Lynch-related tumor to occur. No patient developed ovarian cancer. All, except 2 patients (1 serous carcinoma and 1 clear cell carcinoma), had endometrioid adenocarcinoma (80%). Tumor grade was grade 1 in 3 patients, grade 2 in 5 and grade 3 in 2 patients. Forty per cent of patients had lymphovascular space involvement (LVSI). The FIGO stages were as follows: stage IA (n=7), stage IB (n=2) and stage IIIC (n=1). Four in ten patients had tumor located in the lower uterine segment. With a median follow-up of 14 months (range 9 – 40 months), recurrence occurred in one patient with a stage IB grade 2 endometrioid adenocarcinoma with LVSI. Conclusions: EC in LS is characterized by early age at onset, localization in lower uterine segment, and high rate of LVSI. Other data on histology and survival do not differ from sporadic cancers. These results suggest that we can consider conservative treatment in patients with good prognosis tumors. Further studies are required.
The effects of age on treatment and outcomes in women with stage IB-IIB cervical cancer.
Authors: Roque Dario R. , Cronin Beth , Robison Katina , Lopes Vrishali , Rizack Tina , Dizon Don S.
Published: March 2020

5100

Background: Advanced age may affect the treatment choice and subsequent outcome in elderly patients with cervical cancer. Given the potential for cure with either surgery or chemoradiation in early stage disease, we aimed to determine whether a patient’s age influenced the treatment received and the outcome. Methods: Our retrospective cohort identified a total of 303 patients diagnosed with Stage IB1 through IIB cervical carcinoma who were treated at our institution between 2000 and 2010. The eligible patients were divided into two groups based on age at the time of diagnosis: <65 and > 65 years. Adjusted odd ratios were calculated to determine variables associated with treatment received (chemoradiation or surgery). Single and multivariate Cox proportional hazards modeling were used to estimate hazard ratios for variables associated with disease specific survival. Results: Of the patients meeting inclusion criteria, 253 were <65 years and 50 were > 65 years. The distribution of tumor histology, stage and grade was not different between the two groups. After adjusting for histology, stage and a validated comorbidity score, the odds ratio of receiving chemoradiation vs. surgery for the cohort > 65 years was 1.69 (OR 95% CI: 0.68-4.17). There was no significant difference in the type of primary treatment received between the two groups (P = 0.16). Persistent disease was seen in 46 (18%) of the younger patients and in 19 (38%) of the older patients (P = 0.02). In the elderly cohort the treatment received did not influence disease-specific or all-cause mortality. However, compared to women under 65, older women treated surgically had increased disease specific (HR 3.18, 95% CI: 0.98-10.3) and all-cause mortality (HR 6.53, 95% CI: 2.57-16.6). Conclusions: Age does not appear to be a factor influencing the treatment received by patients with Stage IB1-IIB cervical cancer. The type of treatment received does not seem to affect disease-specific mortality among older versus younger women. However, surgery was associated with a 6.5-fold increased risk of all cause mortality among older women when compared to women under 65 years.
Cervical cancer treatment for operable lesions in a low-resource contemporary setting.
Authors: Lynch Caroline Dorothy , Omenge Elkanah , Itsura Peter , Muliro Hellen , DelPriore Guiseppe , Rosen Barry , Washington Sierra , Strother Robert Matthew
Published: March 2020

5107

Background: To compare HIV+ and HIV- women with operable cervical cancer in a low resource contemporary setting. Methods: A retrospective study using well-matched controls from a Kenyan teaching and referral hospital. Results: 183 women were treated for cervical cancer between October 2007 and June 2011. The histologic subtype was squamous cell in all but one case. At presentation, 28 had operable lesions (Stage IA1–IIB1); 7 more received neoadjuvant chemotherapy prior to surgery. HIV seroprevalence was 54% (18/33) among initial operative cases and 57% among the neoadjuvant group (p=ns). Mean age was 42 (HIV+), and 43 (HIV-), (range 25-64). HIV- vs. HIV+ cervical cancer patients (mean CD4 count 373, 50%<200) were detected by visual inspection with acetic acid (VIA) (18% (2/11)vs 68% (15/22) p=.099), symptoms (27%(3/11) vs 14%(3/22) p=.43), or Pap smear (45% (5/11) vs .09% (2/22) p=.06), respectively.HIV+ patients (two Stage IB1, two Stage IB2) did not require more downstaging than HIV- patients (two stage IIB, one stage IIIA) before surgery (18% (4/22) vs 27% (3/11) p=.63). Surgical treatments were not statistically different in either group and included radical hysterectomy(25), total abdominal hysterectomy(2), cesarean hysterectomy(1), and total vaginal hysterectomy(5). Postoperative complications included fever, dehiscence, DVT, ileus, fistula, and infectious complications (chest, urinary tract, wound). One HIV- patient suffered postoperative fever, vesicovaginal fistula, and wound dehiscence (overall complications .06%).Lymph node involvement was noted in 7 HIV+ and 3 HIV- patients who underwent full staging procedures (p=.004). Conclusions: In patients with operable cervical cancer, HIV serostatus does not affect complication rate or influence need for downstaging prior to surgery compared to a well-matched control group. HIV+ patients were not more likely to receive neoadjuvant chemotherapy but were more likely to have positive lymph nodes. VIA detected the majority of cervical cancers HIV+ patients.
Preoperative geriatric assessment (GA) and surgical outcomes in older women with gynecological (gyn) cancer.
Authors: Li Daneng , Korc-Grodzicki Beatriz , Zhou Qin , Iasonos Alexia , Chi Dennis , Gardner Ginger J. , Lichtman Stuart M. , Tew William P.
Published: March 2020

5108

Background: GA can predict surgical outcomes in older patients (pts); however, pre-surgical evaluation for older pts with gyn malignancies has not been well-described. This study will determine the association between GA variables with post-operative morbidity and mortality. Methods: Women 75yrs or older who had geriatric evaluation before any gyn surgery at Memorial Sloan Kettering Cancer Center (MSKCC) between 1/2010-6/2011 were identified. Pre-operative GA included: Mini-Cog Test (cognition), fall history, medication list, nutritional status (weight loss >10lbs, albumin), functional status (activities of daily living (ADL), instrumental I-ADL), and Charlson comorbidity index. Outcomes included: delirium, length of hospital stay (LOS), 30-day surgical adverse events (AE, grade 1-5, via prospective-MSKCC surgical database), 30-day hospital readmission and 6-month mortality. Utilizing bivariate analyses, associations between GA measures and post-operative outcomes were evaluated. Results: 72 pts (median age 79yrs, range 75-92) with gyn cancer (54% uterine, 36% ovarian/peritoneal/tubal, 10% cervical/vaginal/vulvar) had gyn surgery. 34 pts (47%) had stage III/IV disease. 21pts (30%) had secondary cancer history. Pt’s baseline GA measures: ADL-dependent (13%), IADL-dependent (19%), weight loss (18%), fall history (18%), mini cog score (median 4, range 0-5), Charlson score (median 2, range 0-9). 24pts (33%) had surgical AE; no significant association with age or GA. Median LOS was 2 days (range 0-20); 11pts (15%) required 30-day readmission. Delirium (p=0.01), nutrition (weight loss p=0.04, albumin p=0.04), anemia (p=0.003) and high comorbidity index (p=0.013) were associated with longer LOS. Six-month mortality was 8%; older age (p=0.02), poor functional status (lower ADL and IADL, p<0.001 and p=0.007), number of medications (p=0.05) and poor cognition (p<0.001) were associated with shorter survival. Conclusions: Surgical morbidity is common in older pts. Although AE’s were not associated with GA variables, GA can detect high-risk features for longer LOS and shorter survival. Further prospective studies with pre-operative GA and interventions are warranted.
Impact of body mass index (BMI) on the efficacy of zoledronic acid in premenopausal patients with hormone receptor positive breast cancer: An analysis of the ABCSG-12 trial.
Authors: Pfeiler Georg , Konigsberg Robert , Fesl Christian , Mlineritsch Brigitte , Stoger Herbert , Singer Christian F. , Poestlberger Sabine , Steger Guenther G. , Seifert Michael , Dubsky Peter Christian , Jakesz Raimund , Samonigg Hellmut , Bjelic-Radisic Vesna , Greil Richard , Marth Christian , Gnant Michael
Published: March 2020

514

Background: Zoledronic acid (ZOL) improves disease outcome in premenopausal patients with breast cancer (BC), especially in those with low estrogen environment. Obesity is associated with increased estrogen serum levels, which might influence the efficacy of ZOL. We investigated the impact of BMI on the efficacy of ZOL in premenopausal patients with BC. Methods: ABCSG-12 examined the efficacy of ovarian suppression using goserelin (3.6 mg q28d SC) in combination with anastrozole (ANA) or tamoxifen (TAM) ± ZOL 4 mg IV q6mo) in premenopausal women with endocrine-responsive BC. BMI was calculated using the prospectively collected data on patients’ height and weight at study entry. BMI definitions of the WHO were used: normal 18.5-24.9 kg/m2, overweight: BMI 25-29.9 kg/m2, obese BMI ≥ 30 kg/m2). Disease-free survival (DFS) and overall survival (OS) were calculated by Kaplan-Meier method and results were compared by using the log-rank test and Cox proportional hazard modeling. Results: Two thirds of the patients were normal weight (1,111) and one third was overweight (391) or obese (182). Normal weight patients treated with ZOL experienced the same benefit as overweight/obese patients treated with ZOL compared to patients without ZOL regarding disease free survival (HR 0.75, 95%CI 0.53 1.05 p = 0.09 and HR 0.71, 95%CI 0.46 1.1, p=0.12, respectively) as well as overall survival (HR 0.67, 95% CI 0.37 1.22, p=0.19 and HR 0.64, 95%CI 0.32 1.28, p=0.19, respectively). No difference regarding DFS and OS could be detected between normal weight and overweight/ obese patients treated with ZOL (HR 1.05, 95%CI 0.69 1.59, p=0.83 and HR 1.27, 95%CI 0.62 2.61, p= 0.51). Comparing normal weight patients with ZOL to obese patients with ZOL, again no difference could be observed. Conclusions: The significant outcome benefit of adjuvant zoledronic acid in ABCSG-12 can be demonstrated both in normal weight and overweight/obese premenopausal patients with early breast cancer, indicating that the bone marrow microenvironment changing impact of adjuvant bisphopshonate treatment does not correlate with patients’ BMI.
Mammostrat as an immunohistochemical multigene assay for prediction of early relapse risk in the TEAM pathology study.
Authors: Bartlett John M. S. , Bloom Kenneth J. , Robson Tammy , Lawton Thomas J. , Van De Velde Cornelis J. H. , Ross Douglas T. , Seitz Robert S. , Beck Rodney A. , Hasenburg Annette , Kieback Dirk Guenter , Putter Hein , Markopoulos Christos , Dirix Luc Yves , Seynaeve Caroline M. , Rea Daniel
Published: March 2020

516

Background: Some postmenopausal patients with hormone sensitive early breast cancer remain at high risk of relapse despite endocrine therapy, and might benefit additionally from adjuvant chemotherapy. The challenge is to prospectively identify such patients. The Mammostrat test uses five immunohistochemical markers to stratify patients regarding recurrence risk, and may inform treatment decisions. We tested the efficacy of this panel in the TEAM trial. Methods: Pathology blocks from 4598 TEAM patients were collected and TMAs constructed. The cohort was 47% node positive and 36% were also treated with adjuvant chemotherapy. Triplicate 0.6mm2 TMA cores were stained and positivity for p53, HTF9C, CEACAM5, NDRG1, SLC7A5 assessed. Cases were assigned a Mammostrat risk score, and distant relapse free (DRFS) and disease free survival (DFS) analysed. Results: In multivariate regression analyses, corrected for conventional clinicopathological markers, Mammostrat provided significant additional information on DRFS after endocrine therapy in ER positive node negative patients (N=1226) not receiving chemotherapy (p=0.004). Further analyses in all patients not exposed to chemotherapy, irrespective of nodal status (N=2559) and in the entire cohort (N=3837) showed Mammostrat scores provide additional information on DRFS in these groups (p=0.001 and p<0.0001 respectively; multivariate analyses). No differences were seen between the two endocrine treatment regimens. Conclusions: The Mammostrat score predicts DRFS for both exemestane and tamoxifen-exemestane treated patients irrespective of nodal status and chemotherapy. The ability of this test to provide additional outcome data following treatment provides further evidence for its’ utility in risk stratification of ER positive postmenopausal breast cancer patients.
Validation of IHC4 algorithms for prediction of risk of recurrence in early breast cancer using both conventional and quantitative IHC approaches.
Authors: Christiansen Jason , Bartlett John M. S. , Gustavson Mark , Rimm David , Robson Tammy , Van De Velde Cornelis J. H. , Hasenburg Annette , Kieback Dirk Guenter , Putter Hein , Markopoulos Christos , Dirix Luc Yves , Seynaeve Caroline M. , Rea Daniel
Published: March 2020

517

Background: Hormone receptors, HER2 and Ki67 are residual risk markers in early breast cancer. Combining these markers into a unified algorithm (IHC4) provides information on residual recurrence risk of patients treated with hormone therapies. This study aimed to independently investigate the validity of the IHC4 algorithm for residual risk prediction using both conventional (DAB)-IHC and quantitative immunofluorescence (QIF-AQUA). Methods: The TEAM pathology study recruited >4500 samples from patients treated in the TEAM trial. TMAs were stained for ER, PgR, HER2 and Ki67 using QIF-AQUA technology or DAB-based immunohistochemistry (DAB-IHC). Central HER2 FISH was performed. Quantitative image analysis was used to generate expression scores that were normalized to produce “IHC4 algorithm” as well as novel algorithm scores.  Algorithm scores were compared with disease recurrence in univariate and multivariate Cox Proportional Hazards models. Results: Both DAB-IHC and QIF-AQUA IHC4 continuous models were significant (P<0.0001) for prediction of disease recurrence with a continuous Hazard Ratio (HR) of 1.011 (1.010 – 1.013) for QIF-AQUA IHC4 versus 1.008 (1.007 – 1.010) for the DAB-IHC IHC4 model using the published IHC4 algorithm (Cuzick et al 2011).  Binning continuous model scores (4 bins) by Kaplan-Meier survival analysis was used to graphically illustrate these effects.  De novo models for both DAB-IHC and QIF-AQUA were also significantly (P<0.0001) predictive of residual risk in early breast cancer. Additionally, all 4 models were independent predictors of recurrence (P<0.0001) with other recognized clinical prognostic factors in multivariate analysis.  Although results from DAB and QIF-AQUA were modestly correlated, the QIF-AQUA model showed enhanced prediction of recurrence in both Cox Proportional Hazards Modeling and C-index calculations. Conclusions: Either conventional DAB or QIF-AQUA methods of IHC provided evidence supporting the clinical utility of IHC4 algorithms in the context of the TEAM study.  With careful standardization, either of these IHC4 assays should be considered for prediction of residual risk in early breast cancer.
Aspirin use and mortality in women with stage I-III breast cancer: A population-based study.
Authors: Barron Thomas Ian , Sharp Linda , Bennett Kathleen , Visvanathan Kala
Published: March 2020

521

Background: Recent observational studies have associated aspirin (ASP) use with large reductions in breast cancer (BC) mortality. However, these studies have provided limited information on dose or duration of ASP use, key issues relevant to translation of the results into clinical practice. Methods: Linked National Cancer Registry Ireland and prescription refill data (General Medical Services Ireland, GMS) were used to identify women aged 50-80 with incident stage I-III BC (2001-2006). ASP use was defined as high or low by the median number of ASP days’ supply (85 days) in the 90 days pre-diagnosis. Full capture of ASP use is expected as the GMS provides all medications, including ASP, without charge. Hazard ratios (HR) with 95% confidence intervals (CI) for ASP use and (i) all-cause and (ii) BC-specific mortality were estimated using Cox proportional hazards models adjusted for age, stage, grade, ER, PR, HER-2 status, comorbidity and other drug exposures. Analyses were stratified by tumor stage and nodal status. Results: 2714 women with stage I-III BC were identified (median follow-up = 3.3 years), of whom 642 (23.7%) used ASP in the 90 days pre diagnosis. High and low ASP exposure groups were strongly predictive of post-diagnosis ASP exposure levels (High: mean post diagnosis exposure duration – 83% of follow-up; dose – 75mg/day in 91% of women. Low: mean post-diagnosis exposure duration – 58% of follow-up; dose – 75mg/day in 80% of women). Women with any ASP use had a non-significant reduction in all-cause (HR 0.85 95%CI 0.68, 1.06) and BC-specific (HR 0.86 95%CI 0.65, 1.15) mortality, compared to ASP unexposed women. However, in the dose response analysis high ASP exposure was associated with a significant reduction in all-cause (HR 0.70 95% CI 0.51, 0.95) and BC-specific (HR 0.63 95% CI 0.42, 0.96) mortality. No reduction was observed for low ASP exposure. The benefits of ASP exposure were greater in early stage, node negative disease. Conclusions: Only high ASP exposure was associated with a significant reduction in all cause and BC-specific mortality. These findings may explain inconsistent results from previous studies. Our findings can inform future clinical trials.
Bisphosphonates in the adjuvant setting of breast cancer therapy: Effect on survival—A systematic review and meta-analysis.
Authors: Vidal Liath , Ben-Aharon Irit , Rizel Shulamith , Yerushalmi Rinat , Sulkes Aaron , Stemmer Salomon M.
Published: March 2020

548

Background: The role of bisphosphonates (BP) in the adjuvant setting in breast cancer has been evaluated in several studies, yielding inconsistent evidence. We performed a systematic review and meta-analysis of all randomized controlled trials (RCTs) that evaluate the effects of BP treatment on survival in patients with early breast cancer in the adjuvant setting. Methods: RCTs that compared BP therapy in addition to the standard adjuvant therapy (cytotoxic or hormonal) with standard adjuvant therapy only were identified by searching the Cochrane Library, LILACS, MEDLINE databases and conference proceedings (12.2011). Hazard ratios (HRs) of overall survival (OS), disease-free survival (DFS) and relative risks of adverse events were estimated and pooled. All statistical tests were two-sided. Results: Thirteen trials met the inclusion criteria., among which are the two recently published abstracts of large scale RCTs (NSABP-B34, GAIN) evaluating a total of 15,762 patients. Ten trials reported the OS outcome. Meta-analysis revealed no statistically significant benefit for BP (HR 0.89, 95% CI = 0.79 to 1.01). Nine trials reported the DFS outcome. Meta-analysis revealed no statistically significant better DFS for the intervention (HR 0.95 (0.80-1.11)). Six trials reported DFS stratified upon menopausal status. Postmenopausal patients who were treated with BP therapy had statistically significant better DFS than the control group (HR 0.81(0.69-0.95)). In meta-regression, chemotherapy was negatively associated with HR of OS (coefficient, -0.23; standard error, 0.144). BP therapy resulted in less fractures in the intervention arm, but higher incidence of osteonecrosis of the jaw and pyrexia. Conclusions: Our meta-analysis indicates a positive effect for adjuvant BP on survival outcomes only in postmenopausal patients with breast cancer. Meta-regression appraised the effect of confounders such as chemotherapy, showed a negative association between chemotherapy use and the effect of bisphosphonates on survival. Further large scale RCTs are warranted to unravel the specific subgroups and adjuvant treatments that would benefit from the addition of BP in the adjuvant setting.
DeCIDE: A phase III randomized trial of docetaxel (D), cisplatin (P), 5-fluorouracil (F) (TPF) induction chemotherapy (IC) in patients with N2/N3 locally advanced squamous cell carcinoma of the head and neck (SCCHN).
Authors: Cohen Ezra E. W. , Karrison Theodore , Kocherginsky Masha , Huang Chao H , Agulnik Mark , Mittal Bharat Bhushan , Yunus Furhan , Samant Sandeep , Brockstein Bruce , Raez Luis E. , Mehra Ranee , Kumar Priya , Ondrey Frank G. , Seiwert Tanguy Y. , Villaflor Victoria Meucci , Haraf Daniel J. , Vokes Everett E.
Published: March 2020

5500

Background: IC is associated with lower distant failure (DF) rates in SCCHN but an improvement in overall survival (OS) has not been validated. The goal of this trial was to determine whether IC prior to chemoradiotherapy (CRT) improves survival compared to CRT alone. Methods: In this phase 3, open-label trial, subjects with pathologically confirmed SCCHN; N2/N3 disease without metastases; no prior therapy; KPS ³ 70%; and intact organ function were randomized to CRT alone (CRT arm) [5 days of D (25 mg/m2), F (600 mg/m2), hydroxyurea (500 mg BID), and RT (150 cGy BID) followed by a 9 day break] or to 2 cycles of IC [D (75 mg/m2), P (75 mg/m2), F (750 mg/m2 day 1-5)] followed by the same CRT (IC arm). Primary endpoint was OS. Secondary endpoints included DF free survival, failure pattern, and recurrence-free survival (RFS). 280 subjects provided 80% power to detect a hazard ratio HR=0.5 for OS (a=0.05). Results: 280 subjects were accrued from 2004-09 with minimum follow-up 24 months. Of 142 patients randomized to IC, 91% received 2 cycles and 87% continued to CRT. Treatment adherence during CRT was high for docetaxel and hydroxyurea, but fewer than 75% of the patients received target dose of 5FU in both arms. RT was delivered without major deviations in 94% and 95% of patients on IC and CRT arms, respectively. The most common grade 3-4 toxicities during IC were febrile neutropenia (9%) and mucositis (8%), and during CRT (both arms combined) they were mucositis (45%), dermatitis (19%), and leukopenia (17%). Only grade 3-4 leukopenia and neutropenia rates were significantly higher in IC (p=0.002 and p=0.02, respectively). Table shows efficacy. Conclusions: High survival rates were observed in both arms. Further analysis and follow-up may provide insight into why the significant decrease in DF did not translate into improved OS. [Table: see text]
PD-1:PD-L1(B7-H1) pathway in adaptive resistance: A novel mechanism for tumor immune escape in human papillomavirus-related head and neck cancers.
Authors: Lyford-Pike Sofia , Peng Shiwen , Taube Janis M. , Westra William H. , Akpeng Belinda , Wang Hao , Drake Charles G. , Chen Lieping , Topalian Suzanne Louise , Pardoll Drew M. , Pai Sara I
Published: March 2020

5506

Background: Human papillomavirus-associated head and neck squamous cell carcinomas (HPV-HNSCC) are associated with a strong host immune response. Despite ample tumor infiltrating lymphocytes (TILs), the cancer is able to persist and grow. Here, we provide evidence for an adaptive immune resistance mechanism mediated through the PD-1:PD-L1 pathway. Methods: We evaluated the peripheral blood and tumor infiltrating lymphocytes for PD-1 expression using flow cytometry in HPV-HNSCC patients. We evaluted PD-L1 expression within the tumors using immunohistochemistry. We performed functional assays evaluating IFN-gamma secretion of PD-1+ and PD-1(-) CD8+ T cells isolated from the tumor microenvironment of PD-L1+ and PD-L1(-) HPV-related head and neck cancers. Results: We found the majority of CD8+ TILs in HPV-HNSCC express the PD-1 co-inhibitory receptor. We report a striking association between expression of its ligand PD-L1 on tumor cells and tumor associated macrophages, and the presence of TILs. Interestingly, membranous PD-L1 staining on tumor cells and CD68+ antigen presenting cells was geographically localized to the periphery of tumor nests and juxtaposed to fronts of infiltrating T cells. Functional assays demonstrated that PD-1-dependent T cell inhibition required expression of PD-L1 in the tumor microenvironment. Finally, we report localized expression of PD-L1 in the deep crypts of normal tonsils, the site of HPV infection and origin of HPV-HNSCC. Conclusions: Our findings support the role of the PD-1:PD-L1 interaction in creating an immune-privileged site for initial viral infection and subsequently adaptive immune resistance once tumors are established and suggest a rationale for therapeutic blockade of this pathway in patients with HPV-HNSCC.
Safety of everolimus for women over 65 years of age with advanced breast cancer (BC): 12.5-mo follow-up of BOLERO-2.
Authors: Pritchard Kathleen I. , Burris Howard A. , Rugo Hope S. , Gnant Michael , Baselga José , Piccart-Gebhart Martine J. , Noguchi Shinzaburo , Dakhil Shaker R. , Srimuninnimit Vichien , Puttawibul Puttisak , Osborne Karen , Mukhopadhyay Pabak , Taran Tanya , Sahmoud Tarek , Campone Mario , Hortobagyi Gabriel N.
Published: March 2020

551

Background: Postmenopausal women with estrogen-receptor–positive (ER+) BC who relapse/progress on a nonsteroidal aromatase inhibitor (NSAI) are usually treated with the steroidal AI exemestane (EXE); but there is no currently approved treatment for this indication. The BOLERO-2 trial showed that adding everolimus (EVE), an oral inhibitor of mammalian target of rapamycin (mTOR), to EXE significantly improved clinical benefit beyond that of EXE alone (Hortobagyi et al, SABCS 2011, Abstract S3-7). As many women with advanced BC are elderly, the tolerability profile of EVE + EXE in this population is of interest. Methods: BOLERO-2 is a phase III, randomized, trial comparing EVE (10 mg once daily) vs placebo (PBO), both plus EXE (25 mg once daily) in postmenopausal women with advanced ER+ BC progressing or recurring after NSAIs. Safety data with a focus on elderly patients are reported at 12.5 mo median follow-up. Results: Baseline disease characteristics, age, and prior cancer therapy were well balanced between treatment arms (N = 724). At 12.5 months’ median follow-up, the addition of EVE to EXE significantly improved progression-free survival in patients <65 (HR = 0.37; P < .05) or ≥65 years of age (HR = 0.56; P < .05). Adverse events (AEs) of special interest (all grades) occurring more frequently with EVE vs PBO (overall study population) included stomatitis (66.6% vs 11.3%), infections (50.4% vs 25.2%), rash (44.0% vs 8.4%), pneumonitis (18.7% vs 0.4%), and hyperglycemia (15.4% vs 2.5%). Elderly EVE-treated patients (≥65 years) had similar or marginally lower incidence of stomatitis (52.1%), rash (32.3%), pneumonitis (14.6%), and hyperglycemia (12.5%) compared with the overall population. Grade 3/4 AEs in patients ≥70 years of age (n = 161) reported only among patients receiving EVE (n = 118) included fatigue (10.2%), anemia (10.2%), hyperglycemia (8.5%), stomatitis (7.6%), dyspnea (6.8%), pneumonitis (5.1%), neutropenia (3.4%), and hypertension (3.4%). Conclusions: Adding EVE to EXE was well tolerated in the overall population and in elderly patients with advanced BC; grade 3/4 AEs were uncommon and manageable. Overall, AEs were consistent with the known safety profile of EVE.
Role of c-MET pathway in the outcome prediction of cetuximab-based therapy in patients with recurrent or metastatic squamous cell carcinoma of the head and neck.
Authors: Casado Victoria , Arranz Juan Luis , Zazo Sandra , Martin Valades Jose Ignacio , Madoz Juan , Domine Manuel , Perez-Gonzalez Nuria , Lobo Francisco , Rincon Raul , Rubio Gustavo , Canadas Carmen , Leon Ana , Izarzugaza Yann , Campos Angel , Serrano Gloria , Carames Cristina , Rojo Federico , Garcia-Foncillas Jesus
Published: March 2020

5520

Background: Activation of the c-MET oncogene promotes tumor growth, invasion and metastasis in several tumor types. In addition, c-MET has been reported in consort with EGFR and/or be activated as a compensatory pathway in the presence of EGFR blockade resulting a mechanism of acquired resistance to EGFR inhibitors in lung and colorectal carcinoma. We investigated the impact on cetuximab sensitivity of HGF, c-MET, c-MET activation and c-MET gene status in recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC) patients. Methods: A single-institution retrospective analysis including 50 HNSCC patients was carried out. For each case, formalin-fixed tumor specimens were assayed for HGF, total and phosphorylated Y1234/35 c-MET (p-c-MET) by immunohistochemistry and c-MET gene by FISH. Overexpression criteria were defined by ROC curves for each protein and amplification was defined by >2 copies in at least two of the three studied tumor areas. Results were analyzed for association with clinico-pathological features and survival outcomes for cetuximab-treated patients (median follow-up 75 months). Results: c-MET overexpression was detected in 26 (52%) of patients, c-MET amplification in 15 (30%) and p-c-MET in 12 (24%). Amplification was associated with c-MET overexpression (p=0.004). HGF overexpression was observed in 8 (12%) associated with c-MET phosphorylation (p=0.001), suggesting a paracrine activation of receptor. No significant association with clinico-pathological parameters was detected. Log-rank test showed significantly worse outcome in c-MET overexpressing patients for progression-free (PFS) (p=0.002) and overall survival (OS) (p=0.045); p-c-MET was correlated with worse PFS (p=0.014) and OS (p<0.001). In multivariate logistic regression analysis, p-c-MET was an independent prognostic factor for PFS (HR 6.5; 95% CI 1.5-8.9). Conclusions: HGF/c-MET pathway correlated with worse outcome in cetuximab-based regimen treated HNSCC patients, acting as a resistance mechanism for EGFR inhibitors and supporting a dual blocking HGF/c-MET and EGFR pathways for treatment of these patients.
Outcomes of HIV patients treated with chemoradiotherapy (CRT) for squamous cell carcinoma of the head and neck (SCCHN).
Authors: Mourad Waleed Fouad , Hu Kenneth , Shourbaji Rania Ayman , Li Zujun , Culliney Bruce , Harrison Louis Benjamin
Published: March 2020

5531

Background: SCCHN with HIV is a challenging clinical situation in the medical arena due to limited data. We report our outcomes and the impact of chemotherapy (CT) and HPV on this patient (pt) population Methods: This is a single institution retrospective study of 71 HIV pts with SCCHN treated from 1998-2011. The median age at RT and HIV diagnosis was 51 (32-72) and 34 (25-50) respectively. HIV duration was 11 yrs (6-20). Stage I-II, III and IV were 22, 27 and 51% respectively. Pts treated with RT alone were 37% and CRT 63% {CDDP 91%}. Fifty pts were on HAART during treatment and 50% of pts with SCC of the oropharynx were HPV+. Median dose of 70, 63 and 54 Gy were delivered at 1.8-2 Gy/fraction to gross disease, high and low risk neck respectively. Twelve pts (17%) underwent neck dissection for N3 Results: With a median follow up of 50 months (12-140) the median weight loss was 20 lbs (6-40). Acute skin desquamation and mucositis grades ≤ 2 and 3 were 76 and 24% respectively. Treatment breaks ≥ 10 and 5 days were 7 and 21% respectively. One pt died from induction CT, 1 was hospitalized for grade 4 mucositis and 1 developed osteoradionecrosis during CRT. Late dysphagia grades ≤ 2, 3 and 4 were 74, 15 and 11%. Late xerostomia grades ≤ 2 and 3 were 77 and 23% respectively. The median CD4 count and viral load before, during and after treatment were 370, 135, 100 and 0, 160, 260 respectively. Seven pts (10%) developed second primary malignancy. The 4 yr locoregional control (LRC) and overall survival (OS) were 69% and 55% respectively. Chi-square test shows significant relationship between LRC and RT duration, as well as between CT and lower CD4 counts and higher viral load (P=0.001). Positive trends were observed between (weight loss ≤10% and LRC) and (absence of second malignancy and OS) (P=0.271). There was no significant relationship between HPV +ve or CT on either LRC or OS. Conclusions: The addition of CT to RT yielded higher morbidity and mortality without clear benefit on LRC or OS. HIV per se seems to have a -ve impact on HPV +ve pts outcomes. Comparing observed rates of LRC and OS, our data show that RT±CT administered for HIV +ve pts with SCCHN appears to be less effective than HIV-ve pts. Larger size studies are warranted to optimize the management of this growing patient population.
Gingival cancer: 11 year follow-up at Karolinska University Hospital (2000-2010).
Authors: Simonoska Rusana
Published: March 2020

5536

Background: In Sweden, approximately 500-600 cases of oral cancer are diagnosed every year. These include cancer of the gingiva, retromolar trigonum, bucca, hard palate, tongue and floor of the mouth. Each year, around 15 cases of gingival cancer (GC) are diagnosed in the Stockholm region. The goal of this study was to study the onset of symptoms, treatment, prognosis, and sequelae of GC in order to optimize the treatment. Methods: The study consists of a retrospective review of medical records of all diagnosed cases of GC in Stockholm region between 2000-2010, identified through the ENT-clinic Karolinska Hospital patient database. Results: Our retrospective study comprised 156 patients diagnosed with GC. The average age was 72 years sharing equally between the sexes, 50% were smokers. 98% had a squamous cell carcinoma (scc). Presenting symptoms were often lump or ulceration in the gums, pain, bleeding or discomfort/misfit of dentures. Around 30% had premalignant lessons in the oral cavity before diagnosis. 3/4-th of all GC was localized in the lower jaw. 66% of the GC-patients presented as aT4 cancer. At presentation, 26% had a regional metastasis and of those 90% had their primary tumor in the lower jaw. Six cases had bilateral neck disease. 81% of the patients with regional metastasis had low to medium grade of scc differentiation of the primary tumor. 84% of all patients with regional metastasis had a T4 primary tumor. Neck dissection was performed in 38% (n=59). Of these 35 cases where staging neck, i.e. N0 at presentation and in 7 cases (20%) a positive neck disease was found. The risk for second primary was 15%. The overall 5-year survival was 24%. Conclusions: Advanced age and high number of T4 cancer at diagnosis partly explains the poor survival statistics. Almost 30% of the patients in our material have had premalignant lessons in the oral cavity before the cancer diagnosis and are at high risk for new tumors (second primary); therefore patients with GC should be followed up for at least 5 years, possibly longer in the presence of premalignant lessons. GC of the lower jaw is more likely to metastasize than GC of the upper jaw. Due to 20% occult metastasis occurrence in the staging neck cases, we recommend staging neck dissection for patients with GC.