bluuebunny/crossref_metadata_2025 huggingface dataset:
Multimodal therapy in patients with node-positive (stage IIIC) uterine papillary serous carcinoma: A National Cancer Database study.
Authors: Lin Jeff Feng-Hsu , Sukumvanich Paniti , Parada Keila , Krivak Thomas C. , Beriwal Sushil , Kelley Joseph L. , Olawaiye Alexander
Published: March 2020

5585

Background: Uterine papillary serous carcinoma (UPSC) is an aggressive endometrial cancer that carries a 30-40% risk of nodal metastasis. Adjuvant systemic chemotherapy has become standard of care in advanced UPSC, but the role of additional adjuvant radiotherapy is unclear. This study aims to evaluate survival outcomes of multimodal therapy through the use of the National Cancer Data Base (NCDB). Methods: All patients diagnosed with surgically-staged FIGO stage IIIC uterine papillary serous carcinoma were identified in the NCDB from 1/1998 through 12/2010. Patients were divided into those who received chemotherapy only (CT) and both chemotherapy and radiation therapy (CT+RT). Overall survival was estimated using the Kaplan-Meier method. Univariate comparison by log rank test and multivariable analysis by Cox regression modeling were performed to identify and control for prognostic factors. Results: A total of 13,356 cases of uterine cancer were identified, of which 794 were UPSC. Of these patients, 387 underwent lymphadenectomy (median 14 nodes removed) with 75 patients (median age 65) found to have stage IIIC disease. Median follow up is 20.4 (range: 0-114) months. There were no significant differences were found between the RT and CT+RT group with regards to patient demographic, medical comorbidity, treatment facility or disease characteristics. The median overall survival was 23.2 (95% CI 14.5-31.9) and 40.3 (95% CI 31.5-49.1) months, (p<0.05) for the CT and CT+RT groups, respectively. Multivariate analysis controlling for age, race, income, Charlson-Deyo comorbidity index, treatment facility type, year of diagnosis, number of lymph nodes removed, number of positive lymph nodes and tumor size found radiotherapy independently predicted improved survival [HRdeath0.024 (95% CI 0.001-0.668)]. Conclusions: Patients with stage IIIC UPSC benefit from adjuvant radiotherapy in addition to adjuvant chemotherapy.
Long-term survival in advanced-stage uterine papillary serous carcinoma.
Authors: Holman Laura L. , Iglesias David A. , Soliman Pamela T. , Pal Navdeep , Klopp Ann , Broaddus Russell , Ayeni Tina , Fleming Nicole Dierschke , Munsell Mark F. , Lu Karen H. , Westin Shannon Neville
Published: March 2020

5596

Background: Advanced-stage (III/IV) uterine papillary serous carcinoma (UPSC) has a median overall survival (OS) of ~ 3 yrs. The study objective was to determine factors associated with long-term survival in advanced stage UPSC. Methods: We performed a retrospective review of pts diagnosed with stage III or IV UPSC between 1993 and 2012. Summary statistics were used to describe demographic and clinical characteristics. OS was estimated with the Kaplan-Meier estimator. Fisher’s exact test and the Wilcoxon rank sum test were used to compare pts surviving >3 yrs with those surviving <1 yr. Results: With a median follow-up of 2.2 years (range 0.06-13.2), 262 pts with advanced stage UPSC were identified. The probability of surviving >3 yrs was 0.462, >4 yrs was 0.310, and >5 yrs was 0.228. Thirty-six (14%) pts survived >3 yrs and 37 (14%) survived <1 yr. There was no difference in median age of pts surviving >3 yrs compared to pts surviving <1 yr (60 vs 66, p=0.21). There was also no difference between groups in demographics or medical history. There were several significant differences in pathologic and treatment variables between groups (Table). Conclusions: Though rare, long-term survival in advanced stage UPSC is associated with mixed histology, combination treatment including chemotherapy, and complete response to primary therapy. Further study of the molecular basis for these differences has the potential to improve survival for all pts with this disease. [Table: see text]
Adjuvant radiation therapy in node-positive vulvar cancer.
Authors: Xanthopoulos Eric , Grover Surbhi , Corradetti Michael Nino , Mangaali Margaret , Heskel Marina , Lin Lilie
Published: March 2020

5609

Background: Adjuvant radiation (RT) has been demonstrated to improve overall survival (OS) in vulvar cancer patients with 2+ positive lymph nodes, but its role in patients with one positive lymph node is uncertain. We report on the largest and longest study of survival in patients with and without radiation following surgery in patients with vulvar cancer. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified node-positive women with squamous cell carcinoma of the vulva treated with and without external beam radiation following surgery. The Kaplan-Meier approach, log-rank tests and Cox modeling assessed OS. Results: All results are listed as women without vs with adjuvant radiation. From 1988 – 2008, 420 patients received surgery alone vs 753 women who received adjuvant radiation. Patient characteristics were well balanced across cohorts, including tumors ≤ or > than 2 cm (p = 0.31), grade (p = 0.41), marital status (p = 0.20), provider type (p = 0.49), and AJCC stage (p = 0.35). Both groups also had similar incidence of biopsy of any kind (p = 0.40), lymph node dissection (p = 0.77), median number of nodes excised (p = 0.12), and type of surgery (p = 0.49). Median age (75 vs 70 y, p <0.01) and race (94% vs 89% white, p = 0.01) were adjusted using Cox regression. Median survivor follow-up was 45 m (range 0 - 236 m). Adjuvant radiation was associated with survival across all node-positive patients (22 vs 29 m, p <0.01), as well as in the subset of women with just one positive lymph node (37 vs 70 m, p <0.01) or 2+ positive lymph nodes (14 vs 18 m, p <0.01). On multivariable Cox regression, adjuvant radiation (95% CI 0.85 - 0.96), diameter (CI 1.28 - 2.01), marital status (CI 0.65 - 0.93), the number of positive nodes (CI 1.06 - 1.11), and the ratio of positive-to-excised nodes (CI 1.61 - 2.98) were all associated with survival (p <0.01 for each). Conclusions: The largest cohort study of node-positive squamous cell carcinoma of the vulva suggests adjuvant radiation is associated with OS.Studies have reported that adjuvant radiation may provide a survival benefit in women with 2+ positive lymph nodes. Our findings suggest patients with one positive lymph node also may benefit from adjuvant radiation.
Phase II trial evaluating the use of 21-gene recurrence score (RS) to select preoperative therapy in hormone receptor (HR)-positive breast cancer.
Authors: Zelnak Amelia Bruce , Murali Sujatha , Styblo Toncred Marya , Carlson Grant Walter , Gabram Sheryl G. A. , Rizzo Monica , Torres Mylin Ann , Newell Mary , Liu Yuan , O'Regan Ruth
Published: March 2020

562

Background: Hormone receptor (HR)- positive breast cancer patients (pts) typically have lower pathological responses to pre-operative chemotherapy than HR-negative breast cancers. Objective: We evaluated the pathologic and radiologic response rates to pre-operative endocrine therapy or chemotherapy, as directed by RS, in pts with HR-positive resectable breast cancers. Methods: Pts with HR-positive breast cancers had RS performed on the initial diagnostic biopsy. Pts were treated pre-operatively as follows based on RS: ≤10, exemestane +/- goserelin for 6 to 12 months (ET); 11 to 25 randomized to ET or docetaxel-cyclophosphamide (TC) for 6 cycles (CT); ≥ 26, CT. Results: From 4/2009 to 12/2012, 66 pts signed consent for RS testing and 46 are evaluable for efficacy analysis. Median age is 57 (40 to 78); one-third of pts are African-American; 41% have clinically node positive disease. RS ranged from 2 to 57. 28 pts received CT: Pathologic complete response (PCR) rate was 10% and 60% of cancers were down-staged based on initial T-stage. Radiologic response is available for 20 pts: complete radiologic response (CRR) 15%, partial RR (PRR) 40%, progressive disease (PD) 5%. In 11 pts with RS 11 to 25: PCR 0%, down-staged 45%, up-staged 18%, radiologic responses: CRR 17%, PRR 50%, PD 17%. In 17 pts with RS ≥ 26: PCR 18%, down-staged 71%, up-staged 0%, radiologic responses: CRR 14%, PRR 36%, PD 0%. 18 pts received ET for between 6 to 22 months, 5 remain on study and have not had surgery: PCR 0%; down-staged 38%; up-staged 15%; radiologic responses: CRR 13%, PRR 40%, PD 0%. There was no correlation between RS and efficacy of ET. To date, 3 pts have relapsed, all of whom received CT. Conclusions: This is the first prospective use of the 21-gene RS to select pre-operative therapy for pts with HR-positive breast cancer. Pre-operative CT results in tumor down-staging in the majority of cancers with RS ≥ 11, though it appears to be more effective with RS ≥ 26. ET was moderately effective in down-staging cancers with RS ≤ 25. Updated results will be presented. Clinical trial information: NCT00941330, NCT00832338.
Effect of nanosomal docetaxel lipid suspension (NDLS) on response rate compared to docetaxel: A randomized phase II study in patients with locally advanced or metastatic breast cancer.
Authors: Ahmad Ateeq , Sheikh Saifuddin , Taran Rakesh , Srivastav Shanti P , Prasad Krishna , Rajappa Senthill J , Kumar Vijay , M Gopichand , Paithankar Mahesh , Sharma Manish , Rane R. C. , Ahmad Imran
Published: March 2020

577

Background: Docetaxel formulated inpolysorbate 80 and ethanol (Docetaxel) is among the most active agents in the treatment of breast cancer. The primary rationale for developing nanosomal docetaxel lipid suspension (NDLS) is to improve the drug’s safety profile by eliminating polysorbate 80 and ethanol from docetaxel formulation. Previously, we conducted a clinical study comparing pharmacokinetic parameters of NDLS and docetaxel at 75 mg/m2. The log transformed NDLS/docetaxel ratio for Cmax and AUC0-t was 149.3% and 119.3% respectively. The higher systemic availability of NDLS prompted us to conduct current efficacy study. Methods: 72 locally advanced or metastatic breast cancer patients were enrolled into the study after failure of prior chemotherapy. The mean age for the enrolled patients was 47 years and the racial make-up of the study was 100% Asian. Patients were administered NDLS or docetaxel at 75 mg/m2 as per randomization schedule, by IV infusion for one hour in each cycle of 21 days. Each patient received maximum of 6 cycles of NDLS or docetaxel. No premedication was given to the patients in NDLS treatment group. Results: Safety - The total number of post-dose AEs observed in the study was 510. The breakdown by treatment groups is as follows: AEs were reported in 91.30% and 93.88% patients who received the docetaxel and NDLS respectively. There were 34 SAEs in the study, out of which 04 SAEs resulted in death of the patients (3 in docetaxel and 1 in NDLS). Efficacy - The results showed that 4.2% patients had complete response (CR) in NDLS treatment group while there was no CR in docetaxel treatment group. Further, 31.3% partial response rate (PR) was observed in NDLS treatment group and 26.3% in docetaxel treatment group. Overall response (CR+PR) rate was 35.4% in NDLS treatment group and 26.3% in docetaxel treatment group. Stable disease (SD) was observed in 45.8% patients in NDLS group and 63.2% patients in docetaxel group. Conclusions: Overall, the NDLS was well tolerated in the multiple doses of 75 mg/m2 and found to increase response rate compared to docetaxel in breast cancer patients. Clinical trial information: CTRI/2010/091/000610.
Collaboration of AR and ERα in conferring resistance to an aromatase inhibitor.
Authors: Rechoum Yassine , Iacopetta Domenico , Barone Ines , Rovito Daniela , Ando' Sebastiano , Weigel Nancy , Fuqua Suzanne A. W.
Published: March 2020

579

Background: We have previously shown a role for AR overexpression in tamoxifen resistance in ERα-positive MCF-7 breast cancer cells; here we hypothesized that AR overexpression might similarly be involved in resistance to the aromatase inhibitor anastrazole (Anas). Methods: MCF-7 cells were transfected to express the aromatase gene (MCF-7 Arom), or the aromatase and AR (MCF-7 AR Arom cells). Western blot analysis was used to evaluate protein levels, MTT and soft agar assays to evaluate proliferation, luciferase reporter assays to evaluate transcriptional activities and confocal microscopy was used for localization. Results: Anas inhibited androstendione (AD)-stimulated growth in MCF-7 Arom cells but not in MCF-7 AR Arom cells. Similarly, Anas did not inhibit ERα transcriptional activity in MCF-7 AR Arom cells. Enhanced activation of pIGF-1R, pIRS-1, pAKT, and pMAPK were also observed in AR Arom cells, suggesting constitutive activation of nongenomic signaling in these cells. Consistent with activation of these potential treatment “escape” mechanisms, inhibitors of AKT and IGF-1R restored sensitivity to Anas. Sensitivity to Anas was also restored using the AR antagonist MDV3100, however use of Abiraterone acetate as a single agent most effectively blocked proliferation of AR-overexpressing cells. These results suggest that both AR and ERα must be blocked to restore sensitivity to hormonal therapies in AR overexpressing ERα-positive breast cancers. Unexpectedly, AR contributed to ERα transcriptional activity in MCF-7 AR Arom cells, as shown by inhibition with the AR antagonist bicalutamide. AR and ERα co-localized both in the cytoplasm and in the nucleus of AD+Anas-treated cells, suggesting potential activation of both non-genomic and nuclear-mediated effects when AR is overexpressed in ERα-positive cells. We confirmed these findings in breast cancer cells with acquired resistance to tamoxifen. Conclusions: These results show the necessity to block both AR and ER in patients whose tumors express elevated levels of AR. In addition, inhibitors to the AKT/IGF-1R signaling pathways or direct inhibition of androgen/estrogen synthesis provide alternative approaches to restore hormone sensitivity in resistant breast tumors.
Association of the canonical NF-κB pathway with clinical outcome measures in ER-negative breast cancer.
Authors: Doughty Julie C , Bennett Lindsay , Mallon Elizabeth A , Horgan Paul G. , Edwards Joanne
Published: March 2020

588

Background: Although breast cancer morality rates have fallen, resistance to treatment remains a major problem. The NF-κB pathway regulates transcription of a wide range of genes involved in inflammation, proliferation and apoptosis and are hypothesized to play a role in tumor progression. Methods: Immunohistochemistry was employed to assess expression of members of the NF-κB pathway in a cohort of 544 breast cancer specimens with full clinical follow-up. Antibodies for the p65 subunit, phosphorylated p65 at the serine 536 residue (p-p65 S536), nuclear localization signal of p65 (p65 NLS), IKKα and IKKb had specificity confirmed by both a single band of appropriate size on a western blot and appropriate expression patterns in cell pellets treated with TNFα. Results: When the full cohort was considered patients with tumors that expressed high levels of cytoplasmic IKKα had significantly shorter disease free survival compared to those with low expression (P=0.015). Increased expression of nuclear p-p65 S536 was also associated with shorter disease free survival (P=0.005). By western blot analysis we observed that expression levels of p-p65 S536 were higher in MD-MBA-231 cells which are ER negative compared to MCF-7 cells that are ER positive, suggesting that NF-κB may have a prominent role in ER negative disease. However when the cohort was subdivided, by ER status the association observed for IKKα expression and shorter disease free survival was attenuated in ER positive tumors (p=0.008). In addition this attenuation with the ER positive cohort was also observed for nuclear p-p65 S536 (P=0.002). Other members of the pathway investigated (p65, p65 NLS and IKKb) were not associated with disease free survival. Conclusions: These results suggest that in the clinical setting the NF-kB canonical pathway is associated with poor prognosis in ER positive tumors and not with ER negative tumors as the cell line work would suggest. These results require validation in an independent cohort, but highlight the need to consider subtypes of breast cancer as individual diseases with increasingly different therapeutic targets.
Differential impacts of Oncotype DX and Mammostrat prognostic indices upon the management of ER+ N0 breast cancer.
Authors: Schneider Jeffrey Gary , Ogden Lorna , Farhadfar Nosha , Turi George , Khalil Danny
Published: March 2020

599

Background: Oncotype DX (Genomic Health, Redwood City CA) and Mammostrat (Clarient, Aliso Viejo CA) are two distinct prognostic measures currently marketed to facilitate adjuvant chemotherapy decision making for ER+ breast cancer patients and their physicians. Both assays define three prognostic strata—favorable, intermediate, and unfavorable. Both assays were also validated in the same retrospective cohorts, but there is significant discordance between these assays, suggesting that assay selection may affect clinical decisions. Methods: We have previously reported that Oncotype DX significantly reduces adjuvant chemotherapy use in 89 consecutive ER+, N0 patients for whom this assay was ordered at our institution. Mammostrat assays were performed on 46 of these cases for which tumor blocks were available. Decision analysis was applied to determine changes in management that would have been most likely if Mammostrat had been substituted for Oncotype DX. Results: Oncotype DX and Mammostrat were concordant for prognostic strata in just 11 (24%) cases. Oncotype DX predicted a more favorable prognosis than Mammostrat in 27 (59%) cases, while Mammostrat predicted a more favorable prognosis in the remaining 8 (17%) cases. As shown in the Table, Oncotype DX reduced chemotherapy utilization whereas Mammostrat would have increased it. Conclusions: Despite being validated in identical patient cohorts, Oncotype DX and Mammostrat are frequently discordant and may often affect adjuvant treatment decisions in opposite directions. [Table: see text]
Adjuvant chemotherapy with S-1 after curative treatment in patients with head and neck cancer (ACTS-HNC).
Authors: Taguchi Takahide , Kubota Akira , Yoshino Kunitoshi , Tomita Kichinobu , Kohno Naoyuki , Kawabata Kazuyoshi , Fukushima Masaori , Tsukahara Kiyoaki , Takemura Hideki , Hasegawa Yasuhisa , Terada Tomonori , Nagahara Kunihiko , Nakatani Hiroaki , Higaki Yuichiro , Iwae Shigemichi , Beppu Takeshi , Hanamure Yutaka , Teramukai Satoshi , Fujii Masato ,   ACTS-HNC Study Group
Published: March 2020

6004

Background: To establish the efficacy of adjuvant chemotherapy with S-1 (tegafur gimeracil oteracil potassium) after curative treatment in patients with advanced squamous cell carcinoma of the head and neck (SCCHN), we conducted a randomized phase III study to investigate whether S-1 is superior to UFT (uracil/tegafur). Methods: Patients with SCCHN who had received curative treatment and were confirmed to be tumor-free were randomly assigned to receive UFT (300 or 400 mg/day for 1 year) or S-1 (80, 100, or 120 mg/day for 1 year). The primary end point was disease-free survival (DFS). Secondary end points were overall survival (OS), relapse-free survival (RFS), and safety. We estimated that 500 patients were needed to establish the primary end point. Results: From April 2006 through November 2008, a total of 526 patients (262 assigned to UFT; 264 assigned to S-1) were enrolled. The 3-year DFS rate was 66.0% in the UFT group and 64.1% in the S-1 group (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.66 to 1.16; [log-rank], P = .34). The 3-year OS rate was 75% in the UFT group and 82.9% in the S-1 group (HR, 0.64; 95% CI, 0.44 to 0.94; [log-rank], P = .022). The 3-year RFS rate was 63.6% in the UFT group and 68.2% in the S-1 group (HR, 0.81; 95% CI, 0.60 to 1.09; [log-rank], P = .16). There were no significant differences in 3-year DFS or RFS; however, the 3-year OS was significantly better in the S-1 group. The incidence of the following grade 3 or 4 events was significantly higher in the S-1 group: oral mucositis/stomatitis (2.4%), leukopenia (5.2%), neutropenia (3.6%), and thrombocytopenia (5.0%). Conclusions: S-1 was not demonstrated to be superior to UFT in terms of 3-year DFS; however, 3-year OS was significantly better with S-1 than with UFT. Clinical trial information: NCT00336947.
Effect of PDL-1 expression on prognosis in head and neck squamous cell carcinoma.
Authors: Vasilakopoulou Maria , Velcheti Vamsidhar , Rampias Theodoros , Sasaki Clarence , Rimm David , Fountzilas George , Psyrri Amanda
Published: March 2020

6012

Background: The recent demonstration that immunotherapeutic approaches may be clinically effective for cancer patients has renewed the interest for this therapeutic strategy. Engagement of programmed death-1 receptor (PD-1), expressed on activated T-cells, by its ligands, results in a negative regulatory effect, with inhibition of downstream cellular signaling events. Our aim was to investigate the expression and prognostic significance of immunoresistance molecule PDL-1 (the negative regulator programmed death-1-ligand 1) on an annotated HNSCC tissue microarray. Methods: A tissue array composed of 400 larynx cancers treated with surgery followed by radiotherapy was constructed. PDL-1 protein expression levels were assessed using automated quantitative protein analysis (AQUA). The objectives of this analysis were to determine the association of PDL-1 with efficacy outcomes ( overall survival (OS), progression-free survival (PFS), and event-free survival (EFS) ). The univariate and multivariate Cox proportional hazards models were used to evaluate the relationship between PDL-1 and event-time distributions. Event-time distributions were estimated by the Kaplan-Meier method and compared by the log-rank test. Results: Mean follow-up time for the entire cohort was 39.34 months. Two-hundred thirty eight of 400 cases had sufficient tissue for AQUA analysis. High tumor PDL-1 expression was associated with favorable outcome for OS (P=0.029) and trended towards improved DFS (P=0.06) at 5 years. In multivariable analysis, adjusting for well-characterized prognostic variables, PDL-1 expression status retained its prognostic significance for OS and there was again a trend for PFS (p=0.05). Conclusions: This paradoxical result is in accordance with reported studies in HPV-associated HNSCC where PD-1(+) T cells were associated with favorable clinical outcome. It is possible that PDL-1 detection may reflect a previous immune response against tumors. Further work will determine whether PD-1/PD-L1 blockade induces tumor regression in HNSCC.
Differences in sexual practices and their role in gender, age, and racial disparities in HPV-positive HNSCC.
Authors: Fakhry Carole , Cullen Kevin J. , Bowie Janice , Thorpe Roland , D'Souza Gypsyamber
Published: March 2020

6032

Background: Human papillomavirus associated head and neck cancers (HPV-HNC) have been steadily rising in the U.S., while HPV-unassociated HNCs have declined due to reductions in tobacco use. The trend of increasing HPV-HNC has been attributed to the sexual revolution, but not well explored. Individuals with HPV-HNC tend to be younger, white, and male and HPV-HNC is strongly associated with sexual behaviors. Methods: This analysis included 2270 men and 2261 womenfrom the 2009-10 National Health and Nutrition Examination Survey (NHANES) who answered a survey on demographic and behavioral risk factors. Participants also provided an oral rinse and gargle sample for HPV DNA analysis. Prevalence of sexual behaviors and oral HPV infection were calculated by gender, age cohort (18-29, 30-44, 45-59, 60-69), and race using NHANES samples weights to provide unbiasedestimates for the US population. Results: Men (85%) and women (83%) were similarly likely to have ever performed oral sex, but men had more lifetime oral and vaginal sexual partners and higher oral HPV16 prevalence (each p<0.001).Ever having performed oral sex was less common among 60-69 than 30-44 year old men (74% vs. 92%, p<0.001) and women (71% vs. 91%, p<0.001). Older individuals also had less lifetime sexual partners, but marginally higher oral HPV16 prevalence. Whites were more likely than blacks (90%vs69%, p<0.001) to have ever performed oral sex, to have more lifetime oral sex partners and higheroral HPV16 prevalence(each p<0.001). Prevalence ratios of ever performing oral sex for men vs. women (PR=1.03), 45-59 vs 60-69 year olds(PR=1.25), and whites compared to blacks (PR=1.32) were modest relative to more striking prevalence ratios for oral HPV infection andHPV-HNC(each PR>1.5). Conclusions: There are significant gender, age-cohort, and racial differences in oral sexual practices in a representative sample of the U.S population. Although men, younger age-cohorts, and whites have higher exposures to sexual behaviors of interest, the magnitude of these behavioral differences does not appear large enough to explain the observed disparities in oral HPV infection and HPV-HNC.
CAPRA: Safety, efficacy, and translational biomarkers of weekly everolimus, carboplatin, and paclitaxel as induction therapy for locally advanced head and neck squamous cell carcinoma (HNSCC).
Authors: Raymond Eric , Le Tourneau Christophe , Gatineau Michel , Delord Jean-Pierre , Fayette Jérôme , Dreyer Chantal , Tijeras-Raballand Annemilai , Albert Sebastien , Granier Muriel , Chibaudel Benoist , Hadengue Alexandra , Aissat Nasredine , Slimane Khemaies , Faivre Sandrine J.
Published: March 2020

6036

Background: ThePI3K/mTOR pathway is activated in >50% of HNSCC with preclinical synergism between everolimus and carboplatin/paclitaxel. Methods: Patients (pts) with untreated locally advanced HNSCC with ECOG PS<2 received 9 consecutive weekly (w) cycles (cy) of CAPRA combining everolimus (30 mg/w at dose-level 1 then 50 mg/w at dose-level 2) with carboplatin (AUC2) and paclitaxel (60 mg/m2) followed by chemoradiotherapy. Endpoints were safety (CTCv3.0), antitumor activity (RECIST1.1), pharmacodynamic biomarkers on tumor biopsy. Results: A total of 50 pts with stage IV HNSCC (41 males, 9 females, median age 61) were enrolled. Among 7 patients included in the phase I, no dose-limiting toxicity was reported and the recommended dose (RD) of everolimus was 50 mg/w. Safety evaluation in 46 pts treated at RD for 325 cy and a mean number cy/pt of 7.1 (95%CI: 6.3-7.8) showed grade (Gr) 1-2 adverse events consisting of asthenia (50%), nausea/vomiting (28%), alopecia (26%), mucositis (24%), and constipation (20%). Hematological toxicities (Gr1-2/3-4) were neutropenia (35%/39%), anemia (61%/17%), and thrombocytopenia (54%/13%). Everolimus-related Gr3 toxicities were rashes (1pt), pruritus (1pt), dyspnea (1pt), hyperglycemia (2pts), and Gr1-2 hypercholesterolemia (23pts). There was no toxic death. Among 38 pts evaluable for antitumor activity, one pt experienced a complete response (2.6%), 29 pts a partial response (76.3%), and 8 pts a stable disease (21%) for an overall response rate of 79% (no progression reported). Interestingly, 20 major responses (>50% reduction tumor volume) were observed in large necrotic primary tumors/N3 involvement. Efficacy was not correlated to KRAS/BRAF/PI3KCA/EGFR mutations. Significant decreases of Ki67/p-S6K activities were observed in post CAPRA biopsies compared to baseline. Conclusions: Weekly everolimus with carboplatin/paclitaxel as induction regimen was well tolerated with 11% grade 3 and no grade 4/5 toxicity. Translational data showed direct effects of everolimus in tumors. CAPRA yields high rate of objective responses in patients with locally advanced HNSCC. Clinical trial information: NCT01333085.
Quantitative measurements of p95HER2 (p95) protein expression in tumors from patients with metastatic breast cancer (MBC) treated with trastuzumab: Independent confirmation of the p95 clinical cutoff.
Authors: Duchnowska Renata , Sperinde Jeff , Haddad Mojgan , Chenna Ahmed , Paquet Agnes , Lie Yolanda , Weidler Jodi , Huang Weidong , Winslow John William , Jankowski Tomasz , Czartoryska-Arlukowicz Bogumila , Wysocki Piotr Jan , Foszczynska-Kloda Malgorzata , Radecka Barbara , Litwiniuk Maria Malgorzata , Zok Jolanta , Wisniewski Michal , Zuziak Dorota , Biernat Wojciech , Jassem Jacek
Published: March 2020

604

Background: Expression of p95 in HER2-positive breast cancer is potentially a major determinant of trastuzumab resistance because p95 lacks the trastuzumab binding site while retaining kinase activity. Previously, an optimal clinical cutoff for a continuous measurement of p95 expression was defined in a training set of trastuzumab-treated MBC patients (Clin Cancer Res, 16:4226, 2010). Methods: Quantitative H2T (HERmark HER2-total) and p95 assays (VeraTag, Monogram Biosciences) were retrospectively performed on formalin-fixed, paraffin-embedded tumors from an independent series of 240 trastuzumab-treated MBC patients. The pre-specified cutoff for p95 was tested to determine whether p95 above the cutoff in the HER2-positive subset correlated with worse progression-free survival (PFS) and overall survival (OS), as was observed in the training set. P95 expression was also assessed by immunohistochemistry (IHC) using the same antibody as the p95 VeraTag assay. Results: In the subset of tumors assessed as H2T-positive (N=190), p95 VeraTag values above the pre-defined cutoff correlated with shorter PFS (HR=1.41; p=0.043) and shorter OS (HR=1.72; p=0.021) where both outcomes were stratified by hormone receptor status and tumor grade. The hormone receptor positive patients (N=78) primarily drove the shorter PFS (HR=2.08, p=0.0026) and OS (HR=2.28, p=0.0099) observed in the p95-high subset. In contrast to the quantitative p95 VeraTag measurements, p95 IHC was not significantly correlated with outcomes. Conclusions: A clinical p95 cutoff (VeraTag assay) predictive of clinical outcomes derived from a previous training dataset was confirmed in a second independent clinical series. In contrast, p95 IHC did not correlate with outcomes. The observed consistency in the p95 VeraTag cutoff across different cohorts of MBC patients treated with trastuzumab justifies additional studies employing blinded analyses in larger series of patients. Clinical relevance of p95 protein expression remains to be established in a controlled clinical trial.
Role of adjuvant radiation in patients with squamous cell carcinomas of the oral cavity.
Authors: Maron Steven Brad , Gould Rothberg Bonnie , Otremba Michael , Judson Benjamin , Morgensztern Daniel
Published: March 2020

6042

Background: Although surgery is the initial treatment of choice for patients with stage III squamous cell carcinoma (SCC) of the oral cavity (OC), the role of adjuvant radiotherapy (RT) remains undefined. We evaluated the differences in outcome according to stage subsets and use of adjuvant RT. Methods: The Surveillance Epidemiology and End Results (SEER) database was queried for patients with SCCOC, treated with surgery (S), RT, or both (SRT); older than 21 years; and diagnosed between 2004 and 2009. Patients with extracapsular lymph node extension or multiple primary cancers were excluded. Overall Survival (OS) rates were estimated by the Kaplan-Meier method and compared using log-rank testing as well as Cox proportional hazards. Results: Among the 1,051 patients meeting eligibility criteria, the most common treatment was SRT (49.1%), followed by S alone (28.9%), and RT alone (22.0%). The 5-year OS ranged from 33.3% in T3N1 to 52.8% in T1N1. Compared to S alone, the addition of RT improved 5-year OS in the entire cohort from 39.5% to 51.1% (HR 0.69, 95% CI 0.54-0.87, p = 0.002). This benefit, however, was significant only for stage T3N0 with a trend towards improvement in the T3N1 group. No significant benefit was observed in T1N1 or T2N1 disease (Table). Conclusions: Stage III SCC of the oral cavity is a heterogeneous disease with significant differences in survival according to its subsets. Adjuvant RT was associated with improved survival for patients with stage T3N0 disease but not T1N1 or T2N1. The benefit of RT in T3N1 cases did not reach statistical significance likely due to the small number of patients. If confirmed in prospective studies, further subdivision of stage III SCC of OC may be necessary, and the indication for RT may be restricted to patients with T3 disease. [Table: see text]
Phase (Ph) I/II study of investigational Aurora A kinase (AAK) inhibitor MLN8237 (alisertib): Updated ph II results in patients (pts) with small cell lung cancer (SCLC), non-SCLC (NSCLC), breast cancer (BrC), head and neck squamous cell carcinoma (HNSCC), and gastroesophageal cancer (GE).
Authors: Melichar Bohuslav , Adenis Antoine , Havel Libor , Lockhart Albert C. , Bennouna Jaafar , Schusterbauer Claudia , Dansky Ullmann Claudio , Zhang Bin , Benaim Ely , Dees Elizabeth Claire
Published: March 2020

605

Background: MLN8237 is an investigational oral AAK inhibitor being evaluated in pts with hematologic (Ph III) and non-hematologic malignancies. We report here Ph II results from a, 5-arm study of single agent MLN8237 in pts with advanced, predominantly refractory, solid tumors (NCT01045421; closed for enrolment). Methods: Pts ≥18 years with relapsed/refractory disease measurable by RECIST, ECOG PS 0–1, and ≤2 prior (≤4 for BrC pts) cytotoxic chemotherapy regimens were enrolled. Pts with stable brain metastases were eligible. Pts were treated at the recommended Ph II dose; 50 mg BID for 7 d in 21-d cycles. For each cohort, a Simon’s 2-stage design was employed for Ph II, with ≥2 responses required in the first 20 response-evaluable pts to proceed to stage 2. The primary endpoint was overall response rate (ORR) by RECIST v1.1; safety and progression-free survival (PFS) were key secondary endpoints. Results: As of Dec 2012, 47 SCLC, 23 NSCLC, 49 BrC, 45 HNSCC and 47 GE pts in Ph II were response-evaluable (median age, 61 yrs [range 30–88]). NSCLC did not proceed to stage 2. ORR was 9%, 6%, and 4% in HNSCC, GE, and NSCLC pts, respectively; median PFS was 2.7, 1.5 and 3.1 months. BrC and SCLC data are shown in the Table. 92% of pts had a drug-related adverse event (DRAE). 57% of pts had Gr ≥3 DRAEs; including neutropenia (38%), anemia (10%), stomatitis (8%), and thrombocytopenia (6%). 22 pts died during the study; none were study-drug related. Conclusions: Single-agent activity of MLN8237 was evaluated across a range of solid tumors with a manageable toxicity profile. Encouraging Ph2 data in BrC and SCLC pts suggest that MLN8237 warrants further evaluation in these tumor types. Clinical trial information: NCT01045421. [Table: see text]
Squamous cell carcinoma of the oral cavity (SCCOC) in young patients: The Dana Farber Cancer Institute experience.
Authors: Hanna Glenn J. , Haddad Robert I. , Barletta Justine A. , Posner Marshall R. , Lorch Jochen H.
Published: March 2020

6054

Background: Young patients (≤ age 45) with SCCOC and limited tobacco and alcohol exposure represent a distinct clinical entity with a poor prognosis. These patients are poorly characterized. We report our institution’s experience treating these patients over the past decade. Methods: Patients ≤ 45 years with SCCOC treated between 2001 and 2012 were identified retrospectively. Patient characteristics and treatment were recorded. Results: A total of 99 patients were identified (34 F and 65 M). Median age at diagnosis was 34 and 38 years, respectively (range 14 to 45 years). Thirty one (91.2%) women were never or former smokers with fewer than 10 pack-years, as compared with 50 (76.9%) men (p = 0.07). In women, 33 (97.1%) reported minimal to no alcohol use, compared with 52 (80%) men (p = 0.02). Oral tongue was the primary site in the majority of patients (30 F, 58 M). Surgical resection was the primary treatment modality (30, 88.2% F vs. 44, 68% M). Post-op radiation or chemoradiation was applied depending on stage and pathological findings. Stage: 53/99 (53.5%) presented with stage I or II disease and 46/99 (46.5%) had stage III or IV disease. Males on average had more advanced stage disease at presentation (33/65, 50.8%). Four of 7 women and 4 out of 18 men tested positive for human papilloma virus (HPV). Seven women (20.6%) and 13 (20%) men demonstrated evidence of local or locoregional recurrence with a median time to recurrence of 5 years and 0.67 years (range 1-10 and 0.08-11), respectively. Second primaries were rare (2, 5.88% F vs. 0, 0% M). Two women (5.9%) and 9 men (13.9%) died from recurrent disease. Overall, 4 (30.8%) women with stage III, IV disease demonstrated recurrence vs. 6 (18.2%) men (p = 0.35). Conclusions: In our experience, young patients with SCCOC have high cure rates that do not appear to be inferior to other sites in the head and neck area. Men and women are equally affected. Further clinical and genomic characterization for this group of patients is warranted.
A randomized, multicenter, open phase II study of cetuximab with docetaxel, cisplatin as induction chemotherapy in unresectable, locally advanced head and neck squamous cell carcinoma (LA-HNSCC).
Authors: Koh Youngil , Lee Keun-Wook , Kim Sung-Bae , Park Kyong Hwa , Shin Sang Won , Kang Jin Hyoung , Keam Bhumsuk , Lee Se-Hoon , Heo Dae Seog
Published: March 2020

6069

Background: In this randomized phase II trial, we investigated the efficacy and safety of cetuximab in induction chemotherapy and followed by concurrent chemoradiotherapy (CCRT) in LA-HNSCC. Methods: Patients were randomized to receive 3 cycles of docetaxel (75 mg/m2) and cisplatin (75 mg/mg2) every 3 weeks with or without cetuximab (CDP vs. DP). CCRT was given as a definitive treatment. Patients in CDP arm received CCRT with weekly cetuximab (250 mg/m2) and cisplatin (30 mg/m2), while patients in DP arm received CCRT with weekly cisplatin. Primary endpoint was objective response rate (ORR) after induction chemotherapy. Results: 92 patients were randomized to receive either CDP (48) or DP (44). The median age was 59 years (range 29 – 73 years). The location of primary disease included oropharynx (41), hypopharynx (24), larynx (13) and oral cavity (14). 40 of the 48 patients in CDP arm and 40 of the 44 patients in DP arm completed 3 cycles of chemotherapy. Reason for incompletion in CDP arm included hypersensitivity (1), septic shock (1), skin rash (1), seizure (1), arterial thrombosis (1), unexplained death (1), unsatisfactory response (1), and withdrawal of informed consent (1). ORR to chemotherapy in CDP arm and DP arm was 81% (4 CR and 35 PR) and 82% (4 CR and 32 PR), respectively. 3 patients were not evaluable for response in CDP arm due to unexplained early death (1), septic shock (1), and hypersensitivity reaction after the first dose of cetuximab (1). CCRT completion rate after the completion of CDP and DP was 80% and 85%, respectively. Median PFS and OS were not reached in either arm, with a median follow-up time of 33 months. CDP arm showed 70% and 88% of PFS and OS rate, while DP arm showed 56% and 74% of PFS and OS at 3 years, when intend-to-treat analysis was performed. If we limited to the patients who received 3 cycles of CDP or DP, we saw 78% and 59% of 3-year PFS rate, respectively and 94% and 73% of 3-year OS rate, respectively. Conclusions: Addition of cetuximab during induction and CCRT phase may compromise completion rate of 3 cycles of induction chemotherapy but does not compromise completion of CCRT and shows promising survival data. Clinical trial information: NCT00623558.
Phase I/II trial of crolibulin and cisplatin in solid tumors with a focus on anaplastic thyroid cancer: Phase I results.
Authors: Gramza Ann Wild , Balasubramaniam Sanjeeve , Fojo Antonio Tito , Ward Jean , Wells Samuel A.
Published: March 2020

6074

Background: Anaplastic thyroid cancer (ATC) is one of the most aggressive of all solid tumors, with a median survival of 3-5 months. Chemotherapy has not impacted local control or survival. Crolibulin (CRO) is a microtubule destabilizing agent that disrupts vascular endothelial cells, and in turn, blood flow to the tumor. Preclinical studies showed synergism with cisplatin (CIS). The phase I portion of this phase I/II study, designed to assess the safety and tolerance of CRO and CIS in patients with solid tumors, has completed accrual. Methods: Patients with advanced solid tumors, ECOG ≤ 1, and adequate organ function were treated on a dose escalation schema with CIS (75-100 mg/m2) IV day 1 and CRO (13-20 mg/m2) IV days 1, 2, 3 (21-day cycles). CIS and CRO were continued until unacceptable toxicity or progressive disease (PD), with an option to continue CRO alone if toxicity was CIS-related. Results: Between Jan 2011 and Jan 2013, 21 patients were enrolled and assigned CIS/CRO (mg/m2) at 75/13 (6), 75/20 (3), and 100/20 (12). Diagnoses were as follows: ATC (16), urothelial carcinoma (2), prostate carcinoma (2) and mesothelioma (1). Patients received a median of 2 cycles of CIS/CRO (range: 1-6). Presently, four remain on CIS/CRO and one on CRO alone. The most common grade (G) 3 toxicities were: lymphopenia (33%), hyponatremia (29%), anemia (19%), hypertension during infusion (14%), and hypophosphatemia (9%). There were two G4 toxicities: elevated lipase and thrombocytopenia; and one G5 toxicity of laryngeal hemorrhage related to tumor erosion. There were two dose-limiting toxicities: G3 pancreatitis at dose level (DL) 1 and laryngeal hemorrhage at DL3. Eight ATC patients were treated at DL3. Of these, one (13%) had RECIST 1.1 complete response (CR) and one (13%) had stable disease (SD). Three (38%) had PD, and three are not yet evaluable. The CR has been on study for > 12 months and remains on CRO alone. Conclusions: CIS plus CRO deserves further evaluation as a regimen for ATC. The MTD of CIS/CRO is 100 mg/m2 IV day 1 and 20mg/m2 IV days 1, 2, 3 every 21 days. This combination is well tolerated, with toxicity primarily related to CIS. The phase II portion of this trial will compare CIS/CRO versus CIS in ATC patients. Clinical trial information: NCT01240590.
Relationship between level of lymph node metastasis (LNM) and survival in head and neck squamous cell carcinoma (HNSCC).
Authors: Xing Yan , Zhang Jianjun , Lin Heather , Sturgis Erich M. , Garden Adam S. , Gold Kathryn A. , Lee J. Jack , William William Nassib
Published: March 2020

6087

Background: Evidence from small cohorts suggests that level of LNM predicts survival in patients with HNSCC. This study sought to investigate the prognostic value of level of LNM in a large populational database and contrast it with the current AJCC classification of lymph node involvement. Methods: SEER registry was queried for patients with stage I-IVB HNSCC of oral cavity (OC), oropharynx (OP), larynx (LAR) and hypopharynx (HP) diagnosed from 2004 to 2009 (N=39,699, median follow-up 2.3 years). Each anatomic group was divided into 3 subgroups based on level of LNM (no LNM, LNM to levels 1-3, 4 or 5), and 4 subgroups based on AJCC classification (N0, N1, N2, N3). Overall survival (OS) in each subgroup was computed (Kaplan-Meier method) and compared (log-rank test). Concordance statistics (C-index) were used to assess the accuracy of LNM classification by level vs AJCC in predicting OS. Results: Both AJCC and level of LNM-based classifications predicted OS in patients with OC, LAR, and HP cancers. For OP, neither AJCC nor level of LNM-based classification predicted OS as expected (lower OS for N0 vs N1/2 or levels 1-3/4) (Table). The performance of level of LNM-based classification was comparable to AJCC N staging for OC, LAR and HP. Conclusions: Level of LNM is a prognostic factor for OC, LAR and HP HNSCC. Classification by level of LNM reached similar accuracy as AJCC N staging in predicting OS for OC, LAR and HP. Neither classification is satisfactory for OP, illustrating the need to refine the staging system in this subgroup. [Table: see text]
Phosphorylated ribosomal S6 (p-S6) as an indicator of HER2 signaling targeted drug resistance.
Authors: YangKolodji Gloria Wangrong , Mehta Arjun , Gray Mike J , Tripathy Debu
Published: March 2020

609

Background: Thetargeting of HER2/neu oncoprotein with trastuzumab (Herceptin) has altered the natural history of HER2+ breast cancer, however, its clinical benefit is limited by de novo and/or acquired resistance which almost always develops in the advanced setting. While several mechanisms of resistance have been postulated, none are validated for clinical use to best select patients for treatment. Our study aims were to identify predictive biomarkers based on reproducible differences in HER2 initiated signaling pathway observed in trastuzumab-resistant, HER2-overexpressing human breast cell line models. Methods: Exposing HER2+ breast cancer cells BT474 and SKBR3 to 200 µg/ml of trastuzumab for 12 months, we established two trastuzumab-resistant, HER2 overexpressing breast cancer models BtRT and SkRT. MTT assay was used to characterize drug sensitivities of the cells. Immunocytochemistry and immunoblotting were used to assess the expression levels of HER2 signaling pathway proteins. The impact of trastuzumab on cell cycle process was analyzed by FACS. EdU incorporation was adapted to measure cell proliferation. Results: Trastuzumab-resistant cells had a higher proliferation rate and altered expression levels of HER2 signaling pathway proteins such as p-mTOR, p-S6k1, p-Akt, p-S6, and p-4EBP1, in comparison with parental cell lines. A downstream effector of HER2/Akt/mTOR pathway, phosphorylated ribosomal protein S6 (p-S6), was highly expressed and could not be suppressed by trastuzumab in the resistant cells. When the resistant cells were treated with selected HER2/Akt/mTOR pathway targeted drugs including lapatinib, erlotinib, linsitinib, AZD2014, MK-2206, everolimus and BEZ235, the level of p-S6 in these cells was found to be inversely correlated to the drug induced growth inhibition of these cells. Conclusions: p-S6 is a feasible and easy to measure molecular readout of HER2-targeted therapy resistance. This marker is a good candidate for further clinical validation to predict or efficiently measure a patient’s response to HER2/Akt/mTOR targeted drugs and to test novel agents that would reverse resistance and improve the outcome of trastuzumab refractory, HER2 overexpressing breast cancer.